HK1193574A - Conjugate-based antifungal and antibacterial prodrugs - Google Patents

Description

Conjugate-based antifungal and antibacterial prodrugs

RELATED APPLICATIONS

This application claims the benefit of indian patent application No. IN1770/DEL/201, filed on day 22/6/2011 under one or more of U.S. code 35, items 119(a) -119(d), and U.S. provisional application No. 61/514,305, filed on day 2/8/2011 under U.S. code 35, item 119(e), the contents of both applications being incorporated herein by reference IN their entirety.

Technical Field

The present invention relates to the field of personal care products. More particularly, the present invention relates to conjugate-based antifungal and antibacterial prodrugs formed by coupling antifungal or antibacterial agents with linkers or carriers, and nanoparticles comprising the conjugate-based prodrugs. The invention also relates to conjugated prodrugs in the form of nanoparticles. The invention also relates to unconjugated antifungal and antibacterial agents in nanoparticle form together with one or more lipids.

Background

Dandruff is a chronic scalp disorder that causes peeling and flaking of the skin. The cause of dandruff is not fully understood. Currently, fungi of the genus Malassezia (Malassezia) are considered to be possible pathogenic bacteria (Dawson, Thomas l., j.investig.dermotol.symp.proc. (2007),12: 1519). These fungi are highly dependent on external lipids for in vitro growth (Chen TA, Hill PV2005, Vet Dermatol16: 4). The lipid dependence of Malassezia can be explained by the apparent deletion of the fatty acid synthase gene (Jun Xu, et al PNAS,2007,104: 18730). Furthermore, the inability to synthesize fatty acids can be complemented by the presence of various secreted lipases to assist in the harvesting of host lipids. As a result, these fungi metabolize the triglycerides present in the sebum by these lipases, thereby producing lipid by-products. Penetration of some of these lipid by-products into the top layer of the epidermis (i.e., the stratum corneum) can elicit an inflammatory response in the susceptible, which can disrupt homeostasis, resulting in unstable lysis of stratum corneum cells. The primary treatment for dandruff is topical application of antifungal agents, which reduces the level of malassezia on the scalp. Typically, the antifungal agent is applied to the scalp as a component of a shampoo or other hair care composition. However, the anti-dandruff agent is in contact with the scalp for a short period of time, thereby requiring the hair care composition to be repeatedly used for a long period of time. A durable, durable treatment for dandruff would represent an advance in the art.

In view of the above, there is a need for such anti-dandruff agents: which provides increased durability for long lasting effects and is easy and inexpensive to manufacture.

Disclosure of Invention

Described herein are novel conjugate-based antifungal or antibacterial prodrugs formed by coupling at least one antifungal or antibacterial agent with at least one linker and/or carrier. In certain embodiments, the conjugate-based prodrug has the general structure:

(AFA)_m-X-(L)_nwherein:

AFA is an antifungal or antibacterial agent;

l is a carrier;

x is a linker;

m ranges from 2 to 10; and is

n ranges from 2 to 10.

Typically, m is 2, 3, 4 or 5. And n is 2, 3, 4 or 5.

In certain embodiments, the conjugate-based prodrug has the general formula:

[(AFA)_m’-X]_p-L, wherein:

AFA is an antifungal or antibacterial agent;

l is a carrier;

x is a linker;

m' is 1 to 10; and is

p is 1 to 10.

Typically, m is 1, 2, 3, 4 or 5. And p is 1, 2, 3, 4 or 5. In certain embodiments, m' and p are both 1.

In certain embodiments, the conjugate-based prodrug has the general formula:

AFA-[X-(L)_n’]_qwherein:

AFA is an antifungal or antibacterial agent;

l is a carrier;

x is a linker;

n' is 1 to 10; and is

q is 1 to 10, with the proviso that q' and n are not both 1.

Typically, n' is 1, 2, 3, 4 or 5. Typically, q is 1, 2, 3, 4 or 5. In certain embodiments, q is 1 and n' is 2.

In certain embodiments, the conjugate-based antifungal prodrug has the general formula:

(AFA)_m”-X, wherein:

AFA is an antifungal or antibacterial agent;

x is a linker; and is

m' is 1 to 10.

Typically, m "is 1, 2, 3, 4 or 5. In certain embodiments, m "is 2.

When the conjugate comprises 2 or more antifungal and/or antibacterial agents, such agents may be the same or different. Similarly, when the conjugate comprises 2 or more carriers, such agents may be the same or different.

Also described herein are personal care compositions comprising an effective amount of the conjugate-based antifungal or antibacterial prodrugs described herein.

In another aspect, the present invention provides a method for treating or preventing dandruff, the method comprising: the personal care compositions described herein are applied to the scalp of a subject in need thereof.

In another aspect, the present invention provides a method for treating or preventing acne, the method comprising: the personal care compositions described herein are applied to the skin of a subject in need thereof.

Drawings

Figures 1A-21 show exemplary conjugated prodrugs, carriers, and linkers. In FIGS. 13 and 14, RC₂OH may be selected from, but is not limited to: carboxylic acid selected from the group consisting of C₈To C₂₆Saturated or unsaturated fatty acids of the carbon chain; having a terminal-CO₂Polymers of H functional groups (e.g. PLGA, PLA, HO)₂C-PEG-CO₂H, etc.); having a-CO₂Antibacterial agents of H functional group, alpha-hydroxy acids; a beta-hydroxy acid; azelaic acid; adapalene; glycolic acid or its formulaDerivatives wherein R' may be of the formula-CO₂Antibacterial agents of H functional groups or carboxylic acids that can be used to modulate the 'hydrophilic lipophilic balance' of the conjugate (e.g., PLGA); salicylic acid or a compound of formulaDerivatives wherein R' may be of the formula-CO₂Antibacterial agents of H functional groups or carboxylic acids that can be used to modulate the 'hydrophilic lipophilic balance' of the conjugate (e.g., PLGA); amino acids or peptides, 10-Undecylenic acid, succinic acid or formula thereofWherein R "is an antibacterial agent with-OH functionality or an alcohol that can be used to modulate the 'hydrophilic-lipophilic balance' of the conjugate (e.g., HO-PEG-OH). In FIGS. 17 and 20, R (CO)₂H)₂May be any dicarboxylic acid, for example, R (CO)₂H)₂Can be selected from azelaic acid, formula (II)Wherein n is 1 to 500, an oxygen-containing dibasic acid (oxadiacid) of the formula PEG-disuccinate of (wherein n is 1 to 500); formula (II)Wherein m is 1 to 28; aspartic acid, glutamic acid, having-CO at both ends₂Polymers of H functional groups (e.g. HO)₂C-PEG-CO₂H) (ii) a Or having-CO at both ends₂A natural or synthetic linker of H functionality.

Figure 22 is a schematic of a conjugated prodrug of the invention.

Figures 23 and 24 show the size distribution of nanoparticles comprising clindamycin undecane (figure 23) and clindamycin laurate (figure 24) described herein.

Figures 25-27 are photographs of MIC agar plate assays of TEG-based conjugates (figure 25), methylene and ethylene-based conjugates (figure 26), KMP and KAH conjugates (figure 27). The concentrations of drug used were 0.0625 μ g/ml to 16 μ g/ml (FIG. 25), 0.0625 μ g/ml to 8 μ g/ml as well as growth control, physiological saline and 1% DMSO (FIG. 26), and 0.125 μ g/ml and 4 μ g/ml (FIG. 27).

Fig. 28 is a photograph of representative inhibition zones measured by the agar well diffusion method.

Fig. 29 is a line graph showing a comparison of biological potency between the control ketoconazole, Ketoconazole Methylene Palmitate (KMP) and the negative control keton-hexadecylacetamide (KAH) by inhibition zone. The prodrug conjugate contains an ester linkage, while the negative control KAH contains an amide linkage.

Fig. 30 is a line graph showing Time kill assay for malassezia furfur (m.furfur) with ketoconazole and ketoconazole-methylene-caprylate (KMC) at a concentration of 0.25 μ g/ml.

Figure 31A is a line graph showing Time kill assays for malassezia furfur with different concentrations of the prodrug KMC. The concentration of the prodrug KMC ranges from 0.125. mu.g/ml to 1.0. mu.g/ml.

Fig. 31B is a line graph showing the Time kill assay for malassezia furfur with different concentrations of unconjugated ketoconazole. The concentration of ketoconazole ranges from 0.125. mu.g/ml to 1.0. mu.g/ml.

Figures 32A-32C are schematic illustrations of the retention within the follicles and enhanced uptake of drugs by fungi or bacteria of Nanoparticles (NPs). Fig. 32A is a schematic of a cross-section of a hair follicle showing the presence of microorganisms on the stratum corneum. It also shows the epidermis-facing nanoparticles retained in the vacuolar space, which extravasate slowly and continuously with sweat and sebum. Fig. 32B is a schematic showing the interaction of intact nanoparticles, released drug and released lipid moieties with microorganisms. The presence of the lipid moiety, which is a food product for lipophilic microorganisms, enhances the uptake of intact nanoparticles and/or released drugs, ultimately leading to cell death. Fig. 32C is a schematic illustration of an embodiment of a nanoparticle described herein.

Detailed Description

Described herein are novel conjugate-based antifungal and/or antibacterial prodrugs formed by coupling at least one antifungal agent or antibacterial agent to at least one carrier, either directly or via a linker. Also described herein are nanoparticles comprising an unconjugated antifungal or antibacterial agent and a lipid.

The compositions described herein (e.g., conjugate-based antifungal or antibacterial compositions, nanoparticles comprising them, and nanoparticles comprising an unconjugated antifungal or antibacterial agent and a lipid) can be used to treat fungal or bacterial infections. The compositions described herein can be administered locally (e.g., topically) or systemically.

The compositions described herein may be used in personal care compositions, such as hair care compositions and skin care compositions. These personal care compositions can be used to treat or prevent dandruff. The compositions described herein may also be used in skin care compositions for the treatment or prevention of acne. In certain embodiments, the compositions described herein may be used to treat fungal or bacterial infections. For example, the compositions described herein may be used to treat oral/vaginal candidiasis, intestinal roundworm (ring worm), (tinea infections of the body, scalp, beard, eczema marginalis, and tinea pedis), nail infections, ear infections, and the like.

In certain embodiments, the conjugate-based prodrug has the general structure:

AFA-X-L, wherein:

AFA is an antifungal or antibacterial agent;

l is a carrier; and is

X is a linker.

In certain embodiments, the conjugate-based antifungal or antibacterial prodrug has the general formula:

AFA-X-AFA, wherein:

AFA is an antifungal or antibacterial agent; and is

X is a linker.

Without wishing to be bound by theory, the conjugated prodrugs of the present invention provide a number of advantages over unconjugated antifungal and/or antibacterial agents. For example, formulating conjugated prodrugs into nanoparticles would allow for better capture in the microcracks of the skin or scalp. This in turn may allow for increased retention time on the skin and/or scalp; thereby allowing for lower amounts of active agent and improving bioavailability. The linker and/or the vector may provide a synergistic effect. Additionally, the linker and/or the carrier may provide penetration enhancement. The conjugated prodrugs may also provide sustained release of the antifungal or antibacterial agent, thereby providing better pharmacokinetics.

Nanoparticles

The conjugate-based prodrug and the unconjugated antifungal or antibacterial agent can be formulated into particles, such as nanoparticles or microparticles. It may be advantageous to formulate conjugate-based prodrugs or unconjugated drugs into particles. For example, the particles may be better trapped in the microcracks of the skin or scalp, providing a durable, long lasting effect. Therefore, it is possible to use a lower concentration of the antifungal agent or antibacterial agent than conventional antifungal agents and antibacterial agents.

The term "nanoparticle" as used herein denotes a particle: the size is 10 m^-9Or 10 parts per billion and less than 1 meter^-6Or on the order of parts per million. The term "nanoparticle" includes nanospheres; a nanorod; a nanoshell; and a nanoprism; and these nanoparticles may be part of a nano-network. The term "nanoparticle" also includes liposomes and lipid particles having a nanoparticle size. The particles may be, for example, monodispersed or polydispersed, and the diameter of the particles of a given dispersion may vary, for example, between about 0.1-100nm in diameter.

Without limitation, at least 7 types of nanoparticles can be formulated: (1) nanoparticles formed from a polymer or other material on which the conjugate-based prodrug is absorbed/adsorbed or forms a coating on the nanoparticle core; (2) nanoparticles formed from a core formed from a conjugate-based prodrug, the core coated with a polymer or other material; (3) nanoparticles formed from a polymer or other material to which a conjugate-based prodrug is covalently attached; (4) nanoparticles formed from conjugate-based prodrugs and other molecules; (5) nanoparticles formed so as to comprise a generally homogeneous mixture of the conjugate-based prodrug and the components of the nanoparticles or other non-pharmaceutical substance; (6) a pure drug or a mixture of drugs with nanoparticles coated on top of a core of a conjugate-based prodrug; and (7) nanoparticles consisting entirely of the conjugate-based prodrug. Although discussed above with reference to conjugated prodrugs, similar types of nanoparticles with unconjugated antibacterial or antifungal agents can also be prepared.

In certain embodiments, the nanoparticle is from about 1nm to about 1000nm, from about 50nm to about 500nm, from about 100nm to about 250nm, or from about 200nm to about 350nm in size. In one embodiment, the nanoparticles are from about 100nm to about 1000 nm. In another embodiment, the nanoparticles are from about 80nm to about 200nm in size. In one embodiment, the nanoparticles are from about 50nm to about 500nm in size. In certain embodiments, the size of the nanoparticle is about 158nm, about 218nm, or about 305 nm. In certain embodiments, the nanoparticle has a size of about 337nm, about 526nm, about 569nm, about 362nm, about 476nm, about 480nm, about 676nm, about 445nm, about 434nm, about 462nm, about 492nm, about 788nm, about 463nm, or about 65 nm.

The nanoparticles described herein generally have a narrow size distribution as measured by the polydispersity index (PdI). The term "polydispersity index" as used herein is a measure of the width of the distribution of a sample and is generally defined as the relative variation of the associated decay rate distribution, as known to those skilled in the art. For a discussion of semi-invariant diameters and polydispersity, see B J.Fisken, "visualizing the method of cumulants for the analysis of dynamic light-scattering data," Applied Optics,40(24), 4087-. Typically, the polydispersity of the nanoparticles described herein is less than about 0.8. In certain embodiments, the polydispersity of the nanoparticle is less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.25, less than about 0.2, less than about 0.15, less than about 0.1, or less than about 0.05. In certain embodiments, the polydispersity of the nanoparticle is about 0.072, about 0.1, about 0.149, or about 0.236, about 0.165, about 0.221, about 0.177, about 0.213, about 0.264, about 0.241, about 0.251, about 0.273, about 0.211, about 0.181, about 0.249, about 0.298, about 0.348, or about 0.282.

Without limitation, the nanoparticles may comprise other components in addition to the prodrug conjugates or unconjugated drugs described herein. For example, the nanoparticles may comprise one or more of the following: polymers, anionic polymers, cationic polymers, amphiphilic polymers, surfactants, lipids, phospholipids, cationic lipids, amphiphilic lipids, excipients, and the like. If present in the nanoparticles, each additional component may be present in an amount within the following range: about 0.01% to about 90%, for example, about 0.01% to about 80%, about 0.01% to about 70%, about 0.01% to about 60%, about 0.01% to about 50%, about 0.01% to about 40%, about 0.01% to about 30%, about 0.01% to about 25% of the total weight of the nanoparticle. It will be appreciated that the amount of one component is independent of the amount of the second component in the liposome or emulsion.

In certain embodiments, the additional component is stearic acid-PEG-stearic acid or lecithin.

The surfactant that may be added to the nanoparticles may be any one of anionic, cationic, amphoteric, and nonionic surfactants. Examples of anionic surfactants include: fatty acid esters such as sodium stearate, potassium oleate, and sodium tallowate which can be semi-cured; alkyl sulfates such as sodium lauryl sulfate, ammonium tris (2-hydroxyethyl) lauryl sulfate and sodium stearyl sulfate; benzene sulfonates such as sodium nonylbenzene sulfonate, sodium dodecylbenzene sulfonate, sodium octadecylbenzene sulfonate and sodium dodecyldiphenyl ether disulfonate; naphthalene sulfonates such as sodium dodecylnaphthalene sulfonate and naphthalene sulfonic acid formalin condensates; sulfosuccinates such as bis Sodium lauryl sulfosuccinate and sodium dioctadecyl sulfosuccinate; polyoxyethylene sulfates such as sodium polyoxyethylene lauryl ether sulfate, sodium tris (2-hydroxyethyl) aminopolyoxyethylene lauryl ether sulfate, sodium polyoxyethylene stearyl ether sulfate and sodium polyoxyethylene lauryl phenyl ether sulfate; and phosphates such as potassium dodecyl phosphate and sodium octadecyl phosphate. Examples of the cationic surfactant include: alkylamine salts such as octadecylammonium acetate and cocoamine acetate; and quaternary ammonium salts such as dodecyltrimethylammonium chloride, octadecyltrimethylammonium chloride, dioctadecyldimethylammonium chloride and dodecylbenzyldimethylammonium chloride. Examples of amphoteric surfactants include: alkyl betaines such as dodecyl betaine and octadecyl betaine; and amine oxides such as dodecyl dimethyl amine oxide. Examples of the nonionic surfactant include: polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether and polyoxyethylene (9-octadecenyl) ether; polyoxyethylene phenyl ethers such as polyoxyethylene octyl phenyl ether and polyoxyethylene nonyl phenyl ether; ethylene oxide polymers such as polyethylene oxide and copolymers of ethylene oxide and propylene oxide; sorbitan fatty acid esters such as sorbitan laurate, sorbitan palmitate, sorbitan stearate, sorbitan (9-octadecenoic acid) ester, sorbitan (9-octadecenoic acid) triester, polyoxyethylene sorbitan laurate, polyoxyethylene sorbitan palmitate, polyoxyethylene sorbitan stearate, polyoxyethylene sorbitan octanoate triester, polyoxyethylene sorbitan (9-octadecenoic acid) ester, and polyoxyethylene sorbitan (9-octadecenoic acid) triester; sorbitol fatty acid esters such as polyoxyethylene sorbitol (9-octadecenoic acid) tetraester; glycerin fatty acid esters such as glyceryl octadecanoate and glyceryl (9-octadecenoic acid) ester; polyalkylene oxide block copolymers such as poloxamers (available under the trade mark) (BASF) commercially availableTo).

Suitable commercially available amphoteric surfactants include, but are not limited to: obtainable from Rhodia Novecare (Cranbury, N.J.)HMA sodium lauroamphoacetate (38% solids) andULTRA L32 sodium lauroamphoacetate. Suitable commercially available linear alcohol ethoxylates include, but are not limited to: straight chain primary 10-12 carbon number alcohols available from Huntsman performance products (The Woodlands, Tex.)L12-6 six moles ethoxylate. Suitable commercially available alkyl sulfates include, but are not limited to: available from Stepan Company (Northfield,111.)B-29 sodium octyl sulfate. Suitable commercially available nonionic surfactants include, but are not limited to: oxo-alcohol polyglycol ethers such as are available from Clariant Corporation (Cranbury, N.J.)UD 070 CI 1-oxo-ol polyglycol ether (7 EO). Suitable commercially available linear alkyl benzene sulfonic acids and their salts include, but are not limited to: available from Nease corporation (Cincinnati, Ohio)98S dodecylbenzenesulfonic acid and40S sodium dodecylbenzene sulfonate.

In certain embodiments, the surfactant is PEG-35 hydrogenated castor oil, poloxamer 188 or sodium laureth sulfate.

Some examples of materials that can serve as excipients include: (1) sugars such as mannitol, lactose, maltose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and derivatives thereof, such as sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) lubricants such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol (PEG); (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline water; (18) ringer's solution; (19) ethanol; (20) a pH buffer solution; (21) polyesters, polycarbonates and/or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids; (23) serum components such as serum albumin, HDL, and LDL; (22) c ₂-C₁₂Alcohols, such as ethanol; and (23) other non-toxic compatible materials employed in pharmaceutical formulations.

In certain embodiments, the excipient is mannitol.

Without limitation, the conjugates can be formulated into any type of nanoparticle including, but not limited to, liposomes, emulsions, microemulsions, nanoemulsions, self-microemulsifying drug delivery systems (SMEDDS), polymeric nanoparticles, solid-lipid nanoparticles, nanostructured liquid crystals, and the like.

In certain embodiments, the conjugated prodrug or unconjugated drug may be formulated into a liposome. The term "liposome" as used herein includes any compartment encapsulated by a lipid layer (which may be a monolayer or bilayer). Liposomes can be characterized by membrane type and by size. Liposomes are also known in the art as lipid vesicles. To form liposomes, lipid molecules comprise an elongated non-polar (hydrophobic) portion and a polar (hydrophilic) portion. The hydrophobic and hydrophilic portions of the molecule are preferably located at both ends of the elongated molecular structure. When such lipids are dispersed in water, they spontaneously form a bilayer membrane, which is referred to as a lamella or self-lining vesicle. The thin layer consists of 2 mono-lamellar sheets of lipid molecules, their non-polar (hydrophobic) surfaces facing each other and their polar (hydrophilic) surfaces facing the aqueous medium. The membrane formed by the lipid encapsulates a portion of the aqueous phase in a manner similar to the cell membrane that encapsulates the cell contents. Thus, the bilayer of the liposome has similarities to a cell membrane without the protein component in the cell membrane.

The liposomes used in the present invention are preferably formed from lipids such as: the lipids, when combined, form relatively stable vesicles. A variety of lipids useful for preparing such liposomes are known in the art. Preferred lipids include, but are not limited to: neutral and negatively charged phospholipids or sphingolipids and sterols, such as cholesterol. Lipid selection is generally guided by considerations such as liposome size and stability in personal care compositions.

Liposomes comprise unilamellar vesicles composed of a single lipid layer and typically having a diameter of 20-100 nanometers; large Unilamellar Vesicles (LUVS), typically larger than 100nm, can also be produced by sonication of multilamellar liposomes. In certain embodiments, the liposomes have a diameter in the range of 20nm to 400 nm.

The liposomes may further comprise one or more additional lipids and/or other components such as sterols, e.g., cholesterol. Additional lipids can be included in the liposome composition for a variety of purposes, such as preventing lipid oxidation, stabilizing the bilayer, reducing aggregation during formation, or attaching a carrier to the liposome surface. Any of a number of additional lipids and/or other components may be present, including amphiphilic, neutral, cationic, anionic lipids, and programmable fusogenic lipids. Such lipids and/or components may be used alone or in combination.

The liposome composition can be prepared by a variety of methods known in the art. See, for example, U.S. Pat. nos. 4,235,871, 4,737,323, 4,897,355, and 5,171,678; published International applications WO1996/14057 and WO1996/37194, Felgner, P.L. et al, Proc. Natl.Acad.Sci., USA (1987)8:7413-7417, Bangham, et al, M.mol.biol. (1965)23:238, Olson, et al, Biochim.Biophys.acta (1979)557:9, Szoka, et al, Proc. Natl.Acad.Sci. (1978)75:4194, Mayhew, et al, Biochim.Biophys.acta (1984)775:169, Kim, et al, Biochim.Biophys.acta (1983)728:339, and Fukunaga, et al, Endocrinol. (1984)115:757, the contents of which are incorporated herein by reference in their entirety.

In certain embodiments, the conjugated prodrug or unconjugated drug may be formulated as an emulsion. As used herein, an "emulsion" is a heterogeneous system in which one liquid is dispersed in another liquid in the form of droplets. Emulsions are often biphasic systems consisting of 2 immiscible liquid phases that are intimately mixed and dispersed with each other. Either phase of the emulsion may be semi-solid or solid, as may be the case with emulsion-type ointment bases and creams. The conjugate may be present as a solution in an aqueous phase, an oil phase, or as a separate phase itself.

In certain embodiments, the composition is formulated as a nanoemulsion. The term "nanoemulsion" refers to emulsions that: wherein the particles have a size on the nanometer scale. The nanoemulsion also comprises a thermodynamically stable isotropic clear dispersion of 2 immiscible liquids, stabilized by an interfacial film of surface active molecules. Emulsion formulations administered via dermatological, oral and parenteral routes and methods for their preparation have been reviewed in the literature, see, for example, Idson, Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (eds.), 1988, Marcel Dekker, inc., New York, n.y., volume 1, page 199; rosoff, Pharmaceutical desk age Forms, Lieberman, Rieger and Bank (eds.), 1988, Marcel Dekker, Inc., New York, N.Y., Vol.1, p.245; and Block, Pharmaceutical desk oven, Lieberman, Rieger and Banker (eds.), 1988, Marcel Dekker, inc., New York, n.y., volume 1, page 335, the entire contents of which are incorporated herein by reference in their entirety.

In certain embodiments, conjugated prodrugs or unconjugated drugs may be formulated into polymeric nanoparticles. The term "polymeric nanoparticle" as used herein refers to a carrier system in which the prodrug conjugate is retained, encapsulated or adsorbed. The term polymeric nanoparticles may be used to denote nanospheres and nanocapsules. Nanospheres are composed of a polymer matrix in which the prodrug conjugate is retained, encapsulated or adsorbed. The nanocapsules are composed of a polymeric container that encapsulates a core, wherein the prodrug conjugate can be dissolved, retained or dispersed in the core and/or adsorbed in a polymeric wall.

Generally, the production method of polymer nanoparticles may be classified as an in-situ polymerization method or a method using a preformed polymer. Polymers which are customarily used in the preparation of nanoparticles are, for example, poly (lactide), poly (lactide-glycolide), poly (caprolactone), poly (amide), poly (anhydride), poly (amino acid), poly (ester), poly (cyanoacrylate), poly (phosphazene), poly (phosphate ester), poly (ester amide), poly (dioxanone), poly (acetal), poly (acetals), poly (carbonates), poly (orthocarbonates), degradable poly (urethanes), chitin, chitosan, poly (hydroxybutyrate), poly (hydroxyvalerate), poly (maleic acid), poly (alkylene oxalate), poly (alkylene succinate), poly (hydroxybutyrate-co-hydroxyvalerate) and copolymers, terpolymers, oxidized cellulose or combinations or mixtures of these materials. Some polymers that have proven to be of particular interest are poly (E-caprolactone) (PCL; e.g., poly (E-caprolactone) 65 Kd-Sigma Aldrich); methacrylic acid copolymers and methacrylates or acrylates (e.g. of) (ii) a Poly (alkyl methacrylates); poly (methyl methacrylate) (e.g., PMM).

The polymeric nanoparticles can be produced, for example, by the following method: (i) in situ polymerization of monomers (latex) or dispersions (pseudolatex or artificial latex) of preformed polymers is described in De JaeghereF et al, Nanoparticles. in: Mathiewitz E, eds. The Encyclopedia of Controlled drug delivery.New York, N.Y.: Wiley and Sons Inc;1999:641 and Courre P, et al, Controlled drug delivery with nanoparticles: Eur J Pharm Biopharm.1995;41: 2-13; (ii) emulsion-evaporation methods for pharmaceutical use are first proposed by Gurny R, Peppas N a, Harrington D, Banker G s. development of biological and injectable substrates for controlled release of potential drugs. drug Dev. Ind pharm.1981;7:1-25 (based on U.S. Pat. No. 4,177,177), wherein the polymer is dissolved in a volatile organic solvent immiscible with water, the organic solution is dispersed in an aqueous phase containing an emulsifier and an oil/water emulsion formation enhancer; and (iii) interfacial deposition methods of preformed polymers (nanoprecipitation) described by fesi et al in patent U.S. patent No. 5,049,322. The contents of all references cited in this paragraph are incorporated herein by reference.

Organic solvents that can be used to prepare the nanoparticles are: small chain alcohols (methanol, ethanol, isopropanol, etc.), small chain ketones (acetone, methyl-ethyl-ketone, etc.), light hydrocarbons or mixtures of light hydrocarbons (hexane, petroleum ether, etc.), lightly chloridized hydrocarbons (chloroform, methylene hydrochloride, trihydrochloride ethylene, etc.), or other common light solvents such as acetonitrile (acetonitryl), dioxane, etc. Acetone is a particularly interesting solvent.

Surfactants are often used to avoid aggregation of the particles upon storage. Examples of surfactants that can be used are: lecithin, synthetic, anionic (e.g., sodium lauryl sulfate), cationic (e.g., quaternary ammonium), or nonionic (e.g., sorbitan monoesters with or without polyoxyethylene residues, ethers formed from fatty alcohols and polyethylene glycols, polyoxyethylene-polypropylene glycols, etc.). Particularly interesting combinations include: lipophilic surfactants with low hydrophilic-lipophilic (EHL) balance values (e.g. sorbitan esters-Span 20 or Span60), and hydrophilic surfactants with high EHL values (ethoxylated sorbitan esters-tween 80), or indeed only a single nonionic surfactant with high EHL (such as tween 80).

In certain embodiments, the prodrug conjugate may be formulated as a self-microemulsifying drug delivery system (SMEDDS). Self-microemulsifying drug delivery systems can be described as optically isotropic systems of oil, surfactant and drug which form oil-in-water microemulsions upon gentle stirring in the presence of water. Pharmaceutical SMEDDS can thus be viewed as concentrates that disperse rapidly to form oil-in-water microemulsions when introduced into the body.

In certain embodiments, the prodrug conjugate may be formulated as a solid lipid nanoparticle. Solid Lipid nanoparticles may be prepared in any conventional manner in the art, for example, as described in Stuchlik, M. and Zak, S. (Lipid-Based Vehicle for Oral Delivery, biomed. papers145(2):17-26, (2001)). Solid lipid nanoparticles can be prepared in a thermal homogenization process by homogenizing molten lipid at high temperature. In this method, the solid lipid is melted and the prodrug conjugate is dissolved in the melted lipid. The preheated dispersion medium is then mixed with the conjugate-laden lipid melt and the combination is mixed with a homogenizer to form a crude pre-emulsion. High pressure homogenization is then performed at a temperature above the melting point of the lipid to produce an oil/water-nanoemulsion. The nanoemulsion was cooled to room temperature to form solid lipid nanoparticles.

Alternatively, the solid lipid nanoparticles may be prepared in a cold homogenization process. In this process, the lipid is melted and the prodrug conjugate is dissolved in the melted lipid. The prodrug-loaded lipid is then solidified in liquid nitrogen or dry ice. The solid prodrug-lipid is milled in a powder mill to form 50-100 μm particles. The lipid particles are then dispersed in a cold aqueous dispersion medium and homogenized at room temperature or below to form solid lipid nanoparticles.

Antifungal agent

The term "antifungal agent" as used herein is intended to mean a substance capable of inhibiting or preventing the growth, viability and/or reproduction of fungal cells. Preferred antifungal agents are those capable of preventing or treating fungal infections of animals or plants. One preferred antifungal agent is a broad spectrum antifungal agent. However, the antifungal agent may also be specific for one or more particular fungal species.

Examples of antifungal agents include, but are not limited to: azoles (e.g., fluconazole, isaconazole, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole, ravuconazole, etc.), polyenes (e.g., natamycin, rusomycin, nystatin, amphotericin B, etc.), echinocandins (e.g., colcisas (cantidas)), pradimicin (e.g., benamicin, wakamycin, coprocin, allylamine, etc.), triclosan, piroctone, fenpropimorph, terbinafine, and derivatives and analogs thereof. Other antifungal agents include those described in, for example, the following documents: international patent publication Nos. WO2001/066551, WO2002/090354, WO2000/043390, WO2010/032652, WO2003/008391, WO2004/018485, WO2005/006860, WO2003/086271, WO 2002/067880; U.S. patent application publication nos. 2008/0194661, 2008/0287440, 2005/0130940, 2010/0063285, 2008/0032994, 2006/0047135, 2008/0182885; and U.S. patent nos. 6,812,238, 4,588,525, 6,235,728, 6,265,584, 4,942,162, and 6,362,172, all of which are incorporated herein by reference.

In certain embodiments, the antifungal agent is an azole-based antifungal agent. An azole-based antifungal agent refers to an antifungal agent comprising at least one azole in its structure. Preferred azoles include imidazoles and triazoles. Exemplary azole-based antifungal agents include, but are not limited to: fluconazole, isaconazole, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole and ravuconazole. In certain embodiments, the azole-based antifungal agent is attached to the linker or carrier through the ring-nitrogen of the azole moiety.

In certain embodiments, the antifungal agent comprises at least one free hydroxyl group. Exemplary antifungal agents containing a free hydroxyl group include, but are not limited to: ciclopirox, fluconazole, voriconazole, piroctone, triclosan, raviconazole and isaconazole. In certain embodiments, the antifungal agent comprising a free hydroxyl group is attached to the linker or carrier through the free hydroxyl group.

In certain embodiments, the antifungal agent is an antifungal peptide. Antifungal peptides are well known in the art (see, e.g., De Lucca et al, Rev. Iberoam. Micol.17:116-120 (2000)). The antifungal peptide may be a naturally occurring peptide or an analog thereof, or it may be a synthetic peptide. The term "analog" as used herein means a naturally occurring antifungal peptide that has been chemically modified to increase its effectiveness and/or reduce its toxic/side effects. Exemplary antifungal peptides may include, but are not limited to: syringomycins, syringostatin, syringotoxin, syringomycins, echinocandins, pneumocandins, alcularhizins, muellendomycin, cecropin, alpha-defensins, beta-defensins, novispirins and combinations thereof. Other antifungal peptides include those described in, for example, U.S. Pat. No. 6,255,279 and U.S. patent application publication nos. 2005/0239709, 2005/0187151, 2005/0282755 and 2005/0245452, which are incorporated herein by reference in their entirety.

The term "fungus" as used herein includes a variety of nucleated, spore-bearing organisms, which are devoid of chlorophyll. Examples include yeast, moulds (mildecs), moulds (molds), rust and mushrooms. Examples of fungi include, but are not limited to: aspergillus fumigatus (Aspergillus fumigatus), Aspergillus flavus (Aspergillus flavus), Aspergillus nidulans (Aspergillus nidulans), Candida albicans (Candida albicans), Candida glabrata (Candida glabrata), Candida guilliermondii (Candida guilliermondii), Candida krusei (Candida krusei), Candida vitis (Candida lucitae), Candida parapsilosis (Candida parapsilosis), Candida tropicalis (Candida tropicalis), Cryptococcus neoformans (Cryptococcus eodormans), Saccharomyces orientalis (Issatchenkia orientalis), Coccidioides (Coccidioides), Paracocci (Paracoccidides), Histoplasma (Histoplasma), Blastomyces (Blastomyces) and Neurospora crassa (Neurospora).

In certain embodiments, the fungus belongs to the malassezia genus (e.g., malassezia furfur, malassezia pachydermata (m.pachydermatis), malassezia globosa (m.globosa), malassezia restriction (m.resticta), malassezia spongiosa (m.sloffiae), malassezia symptomatica (m.sympodialis), malassezia microarea (m.nana), malassezia macrocarpa (m.yamatoensis), malassezia dermatitis (m.dermatis), and malassezia blumea obtusa (m.obtusise).

Without wishing to be bound by theory, the malassezia species responsible for most skin diseases in humans (the most common cause including dandruff and seborrheic dermatitis) is malassezia globosa (although limited malassezia and malassezia furfur are also involved). The rash of tinea versicolor (pityriasis versicolor) is also due to infection by the fungus. Since the fungus requires fat for growth, it is most commonly found in areas with many sebaceous glands: the scalp, face and upper part of the body. When the fungus grows too fast, the natural renewal of the cells is disturbed and dandruff appears together with itching (similar processes may also occur with other fungi or bacteria).

Thus, in certain embodiments, the antifungal agent is an antifungal agent effective against a fungus of the genus malassezia. In some other embodiments of this aspect, the antifungal agent is an antifungal agent effective against malassezia globosa fungi.

In certain embodiments, the antifungal agent is itraconazole or ketoconazole.

Antibacterial agents

The term "antibacterial agent" as used herein is defined as a compound that: the compounds have a bactericidal or bacteriostatic effect after contact with bacteria. The term "bactericidal" as used herein is defined to mean having a destructive killing effect on bacteria. The term "bacteriostatic" as used herein is defined to mean having an inhibitory effect on the growth of bacteria.

Examples of antibacterial agents include, but are not limited to: macrolides or ketolides such as erythromycin, azithromycin, clarithromycin, and telithromycin; beta-lactams including penicillins, cephalosporins, and carbapenems such as carbapenems, imipenem, and meropenem; monobactams such as penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin, cephalothin, cefapirin, cephradine, ceftazidime, ceftizoxime, cefamandole, cefuroxime, cephalexin, cephacrylene, cefaclor, chloroceph, cefoxitin, cefmetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, cefepime and aztreonam; quinolones such as nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin, gatifloxacin (ganefloxacin), gemifloxacin and pazufloxacin; antibacterial sulfonamides and antibacterial sulfanilamides including p-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole and phthalylsulfathiazole; aminoglycosides such as streptomycin, neomycin, kanamycin, paromomycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekacin, and isepamicin; tetracyclines such as tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline; rifamycins such as rifamycin (rifampicin), also known as rifampin (rifampin), rifapentine, rifabutin, benzoxazinorifamycin, and rifaximin; lincosamines such as lincomycin and clindamycin; glycopeptides such as vancomycin and teicoplanin; streptogramines such as quinupristin and dalfopristin; oxazolidinones such as linezolid; polymyxins, colistins and colistins; trimethoprim, bacitracin, and fosfomycin.

In certain embodiments, the antibacterial agent is effective against propionibacterium acnes (p.acnes).

In certain embodiments, the antibacterial agent is an anti-acne agent. The term "anti-acne agent" as used herein means any chemical agent that is effective in treating acne and/or the symptoms associated therewith. Anti-acne agents are well known in the art, such as U.S. patent application publication No. 2006/0008538 and U.S. patent No. 5,607,980, the contents of both of which are incorporated herein by reference. Examples of useful anti-acne agents include, but are not limited to: keratolytic agents such as salicylic acid, salicylic acid derivatives, and resorcinol; tretinoin acids such as retinoic acid, tretinoin, adapalene, tazarotene; sulfur-containing D-and L-amino acids and their derivatives and salts; lipoic acid; antibiotics and antimicrobials such as benzoyl peroxide, triclosan, chlorhexidine gluconate, octopirox, tetracycline, 2,4,4' -trichloro-2 ' -hydroxydiphenyl ether, 3,4,4' -trichlorobanilide, niacinamide, tea tree oil, rofecoxib, azelaic acid and its derivatives, phenoxyethanol, phenoxypropanol, phenoxyethanol, ethyl acetate, clindamycin, erythromycin and meclocycline; sebostats, such as flavonoids; and bile salts such as scymnol sulfate and its derivatives, deoxycholate, and cholate; and combinations thereof. These agents are well known and commonly used in the personal care field.

In addition, the anti-acne agent may be an antimicrobial peptide having activity against propionibacterium acnes. Antimicrobial peptides are ubiquitous in Nature and play an important role in the innate immune system of many species (Zasloff, Nature415:389- & 395(2002) and Epand et al, Biochim Biophys Acta1462:11-28 (1999)). The antimicrobial peptide may be a naturally occurring peptide or an analog thereof, or it may be a synthetic peptide. As used herein, "analog" means a naturally occurring antimicrobial peptide that has been chemically modified to increase its effectiveness and/or reduce its toxic side effects. The antimicrobial peptide may be a peptide known to be effective against gram-positive bacteria. Non-limiting examples include: antibiotics such as nisin, subtilin, epidermin and gallidermin; a defensin; cecropin, such as drosophila toxin; cecropins such as cecropin a, bacteriocin and lepidopterans (lepidopteran); xenopus laevis antibacterial peptides; melittin peptides; histatin-like proteins; brevinins; and combinations thereof. In addition, antimicrobial peptides having activity against propionibacterium acnes have been reported, for example, in U.S. patent application publication nos. 2005/0282755, 2005/02455452, and 2005/0209157 and U.S. patent No. 6,255,279, which are incorporated herein by reference in their entirety. Suitable examples of antimicrobial peptides having reported activity against propionibacterium acnes include, but are not limited to: novispirins (Hogenhaug, supra), and those described in U.S. patent application publication No. 2007/0265431 (the contents of which are incorporated herein by reference).

In certain embodiments, the antibacterial agent is clindamycin.

Carrier

Various entities (e.g., carriers) can be coupled to the antifungal or antibacterial agent. Vectors may include naturally occurring molecules, or recombinant or synthetic molecules. Vectors may include, but are not limited to: a polymer; carboxylated polymers, hydroxylated polymers, polyethylene glycol (PEG); mono-or di-carboxylated PEG; comprises C₆-C₂₆An alkyl fatty acid, which may be optionally substituted and/or interspersed with heteroatoms, aryl, heteroaryl, cyclyl, or heterocyclyl; comprises C₆-C₂₆Alcohols of alkyl radicals, which may optionally be interrupted by hetero atoms, aryl radicals, heteroaryl radicals, cyclic radicals or hetero atomsCyclic group substitution and/or interspersion; glycerol; derivatives of glycerol, amino acids; a nucleic acid; an antibacterial agent; an antifungal agent; an alpha-hydroxy acid; a beta-hydroxy acid; a dibasic acid; an oxygen-containing dibasic acid; a peptide; a peptidomimetic; polylysine, a cationic group; spermine; spermidine; a polyamine; a thyrotropin; a melanocyte stimulating factor; a lectin; a glycoprotein; a surfactant protein a; mucin; a glycosylated polyamino acid; transferrin, aptamer; immunoglobulins (e.g., antibodies); insulin, transferrin; albumin; a sugar; lipophilic molecules (e.g., steroids, bile acids, cholesterol, cholic acids, and fatty acids); a vitamin A; a vitamin E; vitamin K; a vitamin B; folic acid; b12; riboflavin; biotin; pyridoxal; a vitamin cofactor; a lipopolysaccharide; hormones and hormone receptors; a lectin; a carbohydrate; a multivalent carbohydrate; a radiolabeled marker; a fluorescent dye; and any combination thereof. The carrier may be substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) substituents. The carrier may be a therapeutic agent.

In certain embodiments, the carrier comprises a free carboxyl group or a free hydroxyl group. The carboxyl or hydroxyl group may be the point of attachment of the linker.

In certain embodiments, the carrier is a fatty acid comprising 6-25 carbons. In certain embodiments, the carrier is a fatty acid selected from the group consisting of: octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid, pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, myristoleic acid, palmitoleic acid, hexadecene-6-acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, elaidic acid (Linoelaidic acid), alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, cis-11-octadecenoic acid, cis-11-eicosenoic acid, undecylenic acid, cis-13-docosenoic acid, neoheptanoic acid, neononanoic acid, neodecanoic acid, isostearic acid, 10-undecenoic acid, and adapalene.

In certain embodiments, the carrier is an alkanol, e.g., C ₆-C₂₅An alkanol. In certain embodiments, the carrier is an alkanol selected from the group consisting of: undecanol, lauryl alcohol, myristyl alcohol, cetyl alcohol, oleyl alcohol.

In certain embodiments, the carrier is polyethylene glycol (PEG) or an analog or derivative thereof. The PEG carrier may have the general formula-O-CH₂CH₂[OCH₂CH₂]_aR, wherein a is 1-500, and R may be H, OH, O-alkyl (e.g., O-CH)₃) Amino, alkylated amino, protected amino. Suitable PEGs include, but are not limited to, PEGs having an average molecular weight in the range of about 200 g/mole to about 30,000 g/mole.

In certain embodiments, the carrier is a biocompatible polymer. The term "biocompatible" as used herein means that it exhibits substantially no cytotoxicity or immunogenicity when in contact with body fluids or tissues. The term "polymer" as used herein means oligomers, co-oligomers, polymers and copolymers, for example, random block copolymers, segmented copolymers, star copolymers, graft copolymers, gradient copolymers, and combinations thereof.

The term "biocompatible polymer" denotes a polymer that: when used inside a subject, it is non-toxic, chemically inert and substantially non-immunogenic, and it is substantially insoluble in blood. The biocompatible polymer may be non-biodegradable or preferably biodegradable. Preferably, the biocompatible polymer is also non-inflammatory when used in situ.

Biodegradable polymers are disclosed in the art. Examples of suitable biodegradable polymers include, but are not limited to, linear polymers such as polylactide, polyglycolide, polycaprolactone, copolymers of polylactic and polyglycolic acids, polyanhydrides, polyepsilon caprolactone, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polydihydropyrans, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly (malic acid), poly (amino acids), polyvinylpyrrolidone, polyethylene glycols, polyhydroxycellulose, polymethylmethacrylate, chitin, chitosan, copolymers of polylactic and polyglycolic acid, poly (glycerol sebacate) (PGS) and copolymers, terpolymers, and copolymers comprising one or more of the foregoing. Other biodegradable polymers include, for example, gelatin, collagen, silk, chitosan, alginate, cellulose, polynucleic acids, and the like.

Suitable non-biodegradable, biocompatible polymers include, by way of example, cellulose acetate (including cellulose diacetate), polyethylene, polypropylene, polybutylene, polyethylene terephthalate (PET), polyvinyl chloride, polystyrene, polyamides, nylons, polycarbonates, polysulfides, polysulfones, hydrogels (e.g., acrylic acid), polyacrylonitrile, polyvinyl acetate, cellulose acetate butyrate, cellulose nitrate, copolymers of urethane/carbonate, copolymers of styrene/maleic acid, poly (ethyleneimine), Pluronic (poloxamers 407, 188), hyaluronidase (Hyaluron), heparin, agarose, pullulan, and copolymers comprising one or more of the foregoing, such as ethylene/vinyl alcohol copolymer (EVOH).

In certain embodiments, the biocompatible polymer is a copolymer of polylactic acid and polyglycolic acid, poly (glycerol sebacate) (PGS), poly (ethyleneimine), Pluronic (poloxamer 407, 188), hyaluronidase, heparin, agarose, or pullulan.

In certain embodiments, the carrier is an amino acid or a peptide. The term "peptide" as used herein denotes 2 or more amino acids linked to each other by amide bonds or modified peptide bonds. The peptide carrier may be through its N-terminal amino group, C-terminal carboxyl group, or a functional group at a side chain of an amino acid of the peptide (e.g., amino group, hydroxyl group, thiol group)Carboxyl) linkage. In certain embodiments, the peptide carrier is linked through its C-terminal carboxyl group. In certain embodiments, the peptide comprises 2-20 amino acids. In one embodiment, the peptide comprises 2-10 amino acids. The peptide may comprise an amino acid selected from the group consisting of: alanine; arginine; asparagine; aspartic acid; (ii) cysteine; glutamic acid; (ii) glutamine; glycine; (ii) histidine; isoleucine; leucine; lysine; methionine; phenylalanine; (ii) proline; serine; threonine; tryptophan; tyrosine; valine; homocysteine; phosphoserine; threonine phosphate; phosphotyrosine; a hydroxyproline; gamma-carboxyglutamic acid; hippuric acid; octahydroindole-2-carboxylic acid; 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid; penicillamine (3-mercapto-D-valine); ornithine (Orn); citrulline; alpha-methyl-alanine; p-benzoylphenylalanine; p-aminophenylalanine; p-fluorophenylalanine; phenylglycine; propargylglycine, N-methylglycine (sarcosine, Sar); and tert-butylglycine; diaminobutyric acid, 7-hydroxy-tetrahydroisoquinoline carboxylic acid; naphthylalanine; biphenylalanine; cyclohexylalanine; amino-isobutyric acid (Aib); norvaline; norleucine (Nle); a tertiary leucine; tetrahydroisoquinoline carboxylic acid, 2-piperidinecarboxylic acid; phenylglycine; homophenylalanine; cyclohexylglycine; dehydroleucine, 2-diethylglycine, 1-amino-l-cyclopentanecarboxylic acid, 1-amino-l-cyclohexanecarboxylic acid; amino-benzoic acid; amino-naphthoic acid; gamma-aminobutyric acid; difluorophenylalanine, 3-piperidinecarboxylic acid, N-alpha-imidazoleacetic acid (IMA); thienyl-alanine; tert-butyl glycine; deaminated-Tyr; aminopentanoic acid (Ava); pyroglutamic acid (b) <Glu); α -aminoisobutyric acid (α Aib); gamma-aminobutyric acid (gamma Abu); α -aminobutyric acid (α Abu); α γ -aminobutyric acid (α γ Abu); 3-pyridylalanine (Pal); isopropyl-alpha-N^εLysine (ILys); naphthylalanine (Nal); alpha-naphthylalanine (alpha-Nal); beta-naphthylalanine (A)Nal); acetyl-Naphthylalanine (Ac-Naphthylalanine); a is generated by the first and second light sources,naphthylalanine, N^ε-picolioyl-lysine (PicLys); 4-halo-phenyl, 4-pyrolidinyl alanine; hexahydroisonicotinic acid (inip); a beta-amino acid; their isomers, analogs and derivatives; and any combination thereof. Those skilled in the art will recognize that this definition includes D-and L-amino acids, alpha-and beta-amino acids, chemically modified amino acids, naturally occurring amino acids that are incapable of producing a protein, unusual amino acids, and chemically synthesized compounds having the characteristic properties of amino acids known in the art.

Furthermore, the term "amino acid" as used herein includes such compounds: which deviate from the structure of naturally occurring amino acids, but which essentially have the structure of amino acids such that they can be substituted within peptides which retain their activity, e.g., biological activity. Thus, for example, in certain embodiments, amino acids may also include amino acids having side chain modifications or substitutions, and also include related organic acids, amides, and the like. Without limitation, the amino acid may be one that is capable of producing a protein or one that is not capable of producing a protein. The term "protein-producing" as used herein indicates that the amino acid can be incorporated into a protein in a cell via well-known metabolic pathways.

In certain embodiments, the peptide vector comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) D amino acid. The D amino acid may be present at any position in the peptide. When more than one D amino acid is present, they may or may not be positioned adjacent to each other. When 3 or more D amino acids are present, some of the D amino acids may be present next to another D amino acid while some of the D amino acids are not present next to another D amino acid.

In certain embodiments, the peptide carrier comprises at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) modified amide bond to link 2 amino acids of the peptide together. The modified peptide bond may be present at any position in the peptide. When present beyond a peptide substitution linkage, they may be positioned immediately adjacent to each other (e.g., on both sides of a given amino acid) or not (e.g., only one side of a given amino acid is linked to the next amino acid via a peptide substitution linkage). Exemplary modified amide linkages include, but are not limited to: reduced psi peptide bonds, ureas, thioureas, carbamates, sulfonylureas, trifluoroethylamines, o- (aminoalkyl) -phenylacetic acids, p- (aminoalkyl) -phenylacetic acids, m- (aminoalkyl) -phenylacetic acids, thioamides, tetrazoles, boronic esters, and olefinic groups.

In certain embodiments, the peptide vector comprises at least one (e.g., 1, 2, 3,4, 5, 6, 7, 8, 9, 10, or more) β -amino acid. The beta-amino acid may be present at any position in the peptide. When more than one β -amino acid is present, they may or may not be located immediately adjacent to each other, and they may or may not be located immediately adjacent to each other. When 3 or more beta-amino acids are present, some of the beta-amino acids may be present next to another beta-amino acid while some of the beta-amino acids are not present next to another beta-amino acid. Exemplary β -amino acids include, but are not limited to: l- β -homoproline hydrochloride; (±) -3- (Boc-amino) -4- (4-biphenyl) butyric acid; (±) -3- (Fmoc-amino) -2-phenylpropionic acid; (1S,3R) - (+) -3- (Boc-amino) cyclopentanecarboxylic acid; (2R,3R) -3- (Boc-amino) -2-hydroxy-4-phenylbutyric acid; (2S,3R) -3- (Boc-amino) -2-hydroxy-4-phenylbutyric acid; (R) -2- [ (Boc-amino) methyl group]-3-phenylpropionic acid; (R) -3- (Boc-amino) -2-methylpropionic acid; (R) -3- (Boc-amino) -2-phenylpropionic acid; (R) -3- (Boc-amino) -4- (2-naphthyl) butanoic acid; (R) -3- (Boc-amino) -5-phenylpentanoic acid; (R) -3- (Fmoc-amino) -4- (2-naphthyl) butyric acid; (R) - (-) -pyrrolidine-3-carboxylic acid; (R) -Boc-3, 4-dimethoxy- β -Phe-OH; (R) -Boc-3- (3-pyridyl) - β -Ala-OH; (R) -Boc-3- (trifluoromethyl) - β -Phe-OH; (R) -Boc-3-cyano- β -Phe-OH; (R) - Boc-3-methoxy- β -Phe-OH; (R) -Boc-3-methyl- β -Phe-OH; (R) -Boc-4- (4-pyridyl) - β 0-homoalanine-OH; (R) -Boc-4- (trifluoromethyl) - β 1-homophenylalanine-OH; (R) -Boc-4- (trifluoromethyl) - β 2-Phe-OH; (R) -Boc-4-bromo- β 3-Phe-OH; (R) -Boc-4-chloro- β 4-homophenylalanine-OH; (R) -Boc-4-chloro- β 5-Phe-OH; (R) -Boc-4-cyano- β 6-homophenylalanine-OH; (R) -Boc-4-cyano- β 7-Phe-OH; (R) -Boc-4-fluoro- β 8-Phe-OH; (R) -Boc-4-methoxy- β 9-Phe-OH; (R) -Boc-4-methyl- β -Phe-OH; (R) -Boc- β 0-Tyr-OH; (R) -Fmoc-4- (3-pyridyl) - β 1-homoalanine-OH; (R) -Fmoc-4-fluoro- β 2-homophenylalanine-OH; (S) - (+) -pyrrolidine-3-carboxylic acid; (S) -3- (Boc-amino) -2-methylpropionic acid; (S) -3- (Boc-amino) -4- (2-naphthyl) butanoic acid; (S) -3- (Boc-amino) -5-phenylpentanoic acid; (S) -3- (Fmoc-amino) -2-methylpropionic acid; (S) -3- (Fmoc-amino) -4- (2-naphthyl) butanoic acid; (S) -3- (Fmoc-amino) -5-hexenoic acid; (S) -3- (Fmoc-amino) -5-phenyl-pentanoic acid; (S) -3- (Fmoc-amino) -6-phenyl-5-hexenoic acid; (S) -Boc-2- (trifluoromethyl) - β 3-homophenylalanine-OH; (S) -Boc-2- (trifluoromethyl) - β 4-homophenylalanine-OH; (S) -Boc-2- (trifluoromethyl) - β 5-Phe-OH; (S) -Boc-2-cyano- β 6-homophenylalanine-OH; (S) -Boc-2-methyl- β 7-Phe-OH; (S) -Boc-3, 4-dimethoxy- β 8-Phe-OH; (S) -Boc-3- (trifluoromethyl) - β 9-homophenylalanine-OH; (S) -Boc-3- (trifluoromethyl) - β -Phe-OH; (S) -Boc-3-methoxy- β 0-Phe-OH; (S) -Boc-3-methyl- β 1-Phe-OH; (S) -Boc-4- (4-pyridyl) - β 2-homoalanine-OH; (S) -Boc-4- (trifluoromethyl) - β 3-Phe-OH; (S) -Boc-4-bromo- β 4-Phe-OH; (S) -Boc-4-chloro- β 5-homophenylalanine-OH; (S) -Boc-4-chloro- β 6-Phe-OH; (S) -Boc-4-cyano- β 7-homophenylalanine-OH; (S) -Boc-4-cyano- β 8-Phe-OH; (S) -Boc-4-fluoro- β 9-Phe-OH; (S) -Boc-4-iodo- β -homophenylalanine-OH; (S) -Boc-4-methyl- β 0-homophenylalanine-OH; (S) -Boc-4-methyl- β 1-Phe-OH; (S) -Boc- β 2-Tyr-OH; (S) -Boc- γ, γ -diphenyl- β 3-homoalanine-OH; (S) -Fmoc-2-methyl- β 4-homophenylalanine-OH; (S) -Fmoc-3, 4-difluoro- β -homophenylalanine-OH; (S) -Fmoc-3- (trifluoromethyl) - β -homophenylalanine-OH; (S) -Fmoc-3-cyano- β -homophenylalanine-OH; (S) -Fmoc-3-methyl- β -homophenylalanine-OH; (S) -Fmoc-gamma, gamma-diphenyl-beta-homoalanine-OH, 2- (Boc-aminomethyl) phenylacetic acid, 3-amino-3- (3-bromophenyl) propionic acid, 3-amino-4, 4, 4-trifluoro-alanine-OH Butyric acid, 3-aminobutyric acid, DL-3-aminoisobutyric acid, ultrapure DL-beta-aminoisobutyric acid, DL-beta-homoleucine, DL-beta 0-homomethionine, DL-beta 1-homophenylalanine, DL-beta 2-leucine, DL-beta 3-phenylalanine, L-beta 4-homoalanine hydrochloride, L-beta 5-homoglutamic acid hydrochloride, L-beta 6-homoglutamyl amine hydrochloride, L-beta 7-homohydroxyproline hydrochloride, L-beta 8-homoisoleucine hydrochloride, L-beta 9-homoleucine hydrochloride, L-beta-homolysine dihydrochloride, L-beta 0-homomethionine hydrochloride, L-beta 1-homophenylalanine allyl ester hydrochloride, L-beta 2-homophenylalanine hydrochloride Hydrochloride, L-beta 3-homoserine, L-beta-homothreonine, L-beta-homotryptophan hydrochloride, L-beta-homotyrosine hydrochloride, L-beta-leucine hydrochloride, Boc-D-beta-Leu-OH, Boc-D-beta-Phe-OH, Boc-beta-³-homoproline-OH, Boc- β -Glu (OBzl) -OH, Boc- β -homoarginine (Tos) -OH, Boc- β 0-homoglutamic acid (OBzl) -OH, Boc- β 1-homoproline (Bzl) -OH (dicyclohexylammonium) salt technical grade; boc-beta 2-homolysine (Z) -OH, Boc-beta 3-homoserine (Bzl) -OH, Boc-beta 4-homothreonine (Bzl) -OH, Boc-beta 5-homotyrosine (Bzl) -OH, Boc-beta 6-Ala-OH, Boc-beta 7-Gln-OH, Boc-beta 8-homoalanine-OAll, Boc-beta 9-homoalanine-OH, Boc-beta-homoglutamylamine-OH, Boc-beta 0-homoisoleucine-OH, Boc-beta 1-homoleucine-OH, Boc-beta 2-homomethionine-OH, Boc-beta 3-homophenylalanine-OH, Boc-beta-homotryptophan-OMe, Boc-beta-Leu- OH, Boc-beta-Lys (Z) -OH (dicyclohexylammonium) salt, Boc-beta-Phe-OH; ethyl 3- (benzylamino) propionate, Fmoc-D-beta-homophenylalanine-OH, Fmoc-L-beta ³-homoproline, Fmoc-beta-D-Phe-OH, Fmoc-beta-Gln (Trt) -OH, Fmoc-beta 0-Glu (OtBu) -OH, Fmoc-beta 1-homoarginine (Pmc) -OH, Fmoc-beta 2-homoglutamine (Trt) -OH, Fmoc-beta 3-homoglutamic acid (OtBu) -OH, Fmoc-beta 4-homohydroxyproline (tBu) -OH, Fmoc-beta 5-homolysine (Boc) -OH, Fmoc-beta 6-homoserine (tBu) -OH, Fmoc-beta 7-homothreonine (tBu) -OH, Fmoc-beta 8-homotyrosine (tBu) -OH, Fmoc-beta 9-Ala-OH, Fmoc-beta-Gln-OH, Fmoc-beta 0-homoalanine-OH, Fmoc-beta 1-homoglutamic acid aminoamide-OH, Fmoc-beta 2-homoisoleucine-OH, Fmoc-beta 3-homoleucine-OH, Fmoc-beta 4-homomethionine-OH, Fmoc-beta 5-homophenylalanine-OH, Fmoc-beta 6-homotryptophan-OH, Fmoc-beta 7-Leu-OH, Fmoc-beta 8-Phe-OH, N-acetyl-DL-beta 9-phenylalanine, Z-D-beta-dab (Boc) -OH, Z-D-beta-dab (Fmoc) -OH pure; Z-DL-beta-homoalanine, Z-beta-D-homoalanine-OH, Z-beta-Glu (OtBu) -OH industrial grade; z-beta-homotryptophan (Boc) -OH, Z-beta-Ala-OH; z-beta-Ala-ONp pure; z-beta-dab (Boc) -OH, Z-beta-dab (Fmoc) -OH, Z-beta-homoalanine-OH; beta-alanine; beta-alanine BioXtra; beta-alanine ethyl ester hydrochloride; beta-alanine methyl ester hydrochloride; beta-glutamic acid hydrochloride; cis-2-amino-3-cyclopentene-1-carboxylic acid hydrochloride; cis-3- (Boc-amino) cyclohexanecarboxylic acid; and cis-3- (Fmoc-amino) cyclohexanecarboxylic acid.

In certain embodiments, the peptide comprises an amino acid selected from the group consisting of: lys, Arg, His, and any combination thereof. In certain embodiments, the amino acid attached to the linker is selected from Tyr, Ser, and Thr. Thus, the peptide may comprise Tyr, Ser or Thr at the N-or C-terminus for attachment to other moieties of the conjugate. In one embodiment, the peptide carrier is a Lys-His-Lys-His-Lys-His hexapeptide.

In certain embodiments, the vector is selected from the group consisting of: undecylenic acid; palmitic acid; oleic acid, linoleic acid, lauric acid, Lys-His-Lys-His-Lys-His hexapeptide; l-or D-tyrosine; l-or D-serine; l-or D-threonine; a peptide of 2-10 amino acids; chitosan; pullulan; and any combination thereof. In certain embodiments, the carrier is a 2-10 amino acid peptide, wherein the N-terminal or C-terminal amino acid is L-or D-tyrosine, L-or D-serine, or L-or D-threonine; chitosan; pullulan; and any combination thereof.

The carrier may be used to formulate the conjugated prodrug into nanoparticles. For example, the carrier may be a part that self-assembles to form a particle. The carrier may be a molecule, such as a polymer that may be formulated into a gel, e.g., a hydrogel or an organogel. The term "hydrogel" refers to a crosslinked, water-insoluble, aqueous material. Hydrogels have many desirable properties for biomedical applications. For example, they can be made non-toxic and tissue compatible, and they are often highly permeable to water, ions and small molecules.

Gels generally comprise a solid crosslinked polymer network capable of forming a stable system in equilibrium with an interpenetrating swelling agent. A plurality of formsPolymers of gels are known in the art. Suitable gels include polymers, copolymers and block polymers based on monomers containing ionizable groups or polymerizable double bonds. Exemplary monomers include, but are not limited to: acrylic acid, methyl methacrylate, methacrylic acid, ethyl acrylate, vinylsulfonic acid, styrene, styrenesulfonic acid (e.g., p-styrenesulfonic acid), maleic acid, crotonic acid, vinyl phosphate, vinyl phosphonate, ethylene, propylene, styrene, vinyl methyl ether, vinyl acetate, vinyl alcohol, acrylonitrile, acrylamide, N- (C)₁-C₆Alkyl) acrylamides (such as N-isopropylacrylamide, N-t-butylacrylamide), and the like. The gel is prepared by homopolymerizing or copolymerizing any of the foregoing monomers. Other suitable gel materials may include alginate, chitosan, collagen, gelatin, hyaluronate, fibrin, agarose, and derivatives thereof. The gel may be a copolymer as described above, in which a conjugated prodrug has been incorporated as a comonomer component.

The gel may be crosslinked so that it assumes a physically stable form when hydrated or dehydrated. Suitable crosslinking may be provided by incorporating from about 0.5% to about 1.5% by weight of a crosslinking agent into the gel. Crosslinking may also be provided by incorporating from about 0.01mol% to about 15mol% of a crosslinking agent into the gel.

Suitable cross-linking agents include compounds that: the molecule of which has a plurality of reactive groups. Such molecular crosslinking agents may be N, N' -methylene-bisacrylamide or Divinylbenzene (DVB), ethylene glycol dimethacrylate, divinyl ketone, vinyl methacrylate, and divinyl oxalate. Ionic crosslinking using ions such as metal ions may also be employed. Crosslinking using electromagnetic waves (such as gamma rays) is also possible. The crosslinking may also be based on electrostatic interactions, hydrogen bonding, hydrophobic interactions or (micro) crystallization.

The ionically crosslinkable polymers may be anionic or cationic in nature and include, but are not limited to: carboxy, sulphate, hydroxy and amine functionalisationA polymer. The crosslinking ion used to crosslink the polymer may be anionic or cationic, depending on whether the polymer is anionically or cationically crosslinkable. Suitable crosslinking ions include, but are not limited to, cations selected from the group consisting of: calcium, magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper, cobalt, lead, and silver ions. The anion may be selected from, but is not limited to: phosphate, citrate, borate, succinate, maleate, adipate and oxalate ions. More broadly, the anion is derived from a polybasic organic or inorganic acid. Preferred crosslinking cations are calcium, iron and barium ions. The most preferred crosslinking cations are calcium and barium ions. The most preferred crosslinking anion is phosphate. Crosslinking may be performed by contacting the polymer with atomized droplets containing dissolved ions. For example, in the presence of ionic crosslinkers or divalent cations (such as Ca) ²⁺、Ba²⁺And Sr²⁺) In the presence of collagen or alginate gelling occurs.

Joint

The term "linker" as used herein denotes an organic moiety linking 2 moieties of a compound. The joint generally comprises: a direct bond or atom such as oxygen or sulfur, a unit such as NR¹、C(O)、C(O)NH、SO、SO₂、SO₂NH or a chain of atoms, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkynyl, substituted or unsubstituted alkynyl, Alkyl heterocyclic alkene A group, alkylheterocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylheteroaryl, wherein one or more methylene groups may be replaced with O, S, S (O), SO, or a combination thereof₂、N(R¹)₂C (o), a cleavable linker, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycle interrupted or terminated therewith; wherein R is¹Is hydrogen, acyl, aliphatic group or substituted aliphatic group.

The linker may be attached to the ring nitrogen of the azole moiety of the antifungal or antibacterial agent. Alternatively, the linker may be attached to the hydroxyl or carboxyl group of the antifungal or antibacterial agent. The linker may also be attached to a heteroatom of an antifungal or antibacterial agent, for example, O, S or N.

In certain embodiments, the linker comprises at least one cleavable linking group, i.e., the linker is a cleavable linker. Without wishing to be bound by theory, the use of a cleavable linker may provide for the sustained release of the antifungal or antibacterial agent from the conjugate. This may provide better pharmacokinetics. For example, using a lipase cleavable linker, no or slight cleavage occurs in the absence of fungi. Thus, no or slight amounts of drug are released, thereby reducing any toxicity of the drug.

The cleavable linking group is such that: it is sufficiently stable, but it is cleaved under specific conditions or with specific enzymes. In a preferred embodiment, the cleavable linker is at least 10-fold or more, preferably at least 100-fold faster in rate of cleavage under the particular conditions or under the first reference conditions (which may be selected, for example, to mimic or represent intracellular conditions) as compared to the reference conditions.

The linker may comprise a cleavable linking group that is cleavable by a particular enzyme. The type of cleavable linking group incorporated into the linker may depend on the intended use. For example, malassezia globosa uses 8 different types of lipases as well as 3 phospholipases to break down the oil on the scalp. Thus, a linker comprising an ester bond in the presence of malassezia globosa is cleaved more efficiently than in the absence of malassezia globosa.

The cleavable linker may be sensitive to a cleaving agent (e.g., pH, redox potential, or presence of a degrading molecule). Typically, the lytic agent is present or found at a higher level or activity within the cell than in serum or blood. Examples of such degradation agents include: redox agents, which are selected for specific substrates, or which are not substrate specific, including, for example, oxidases or reductases or reducing agents such as thiols present in the cell that can degrade redox cleavable linking groups by reduction; an esterase; an amidase; endosomes or agents that can create an acidic environment, e.g., those that create a pH of 5 or less; enzymes, peptidases (which may be substrate specific) and proteases, and phosphatases that can hydrolyze or degrade acid-cleavable linkers by acting as generalized acids.

In certain embodiments, a cleavable linker in the presence of a malassezia species cleaves at least 1.25, 1.5, 1.75, 2, 3, 4, 5, 10, 25, 50, or 100 times faster than in the absence of a malassezia species. In certain embodiments, a cleavable linking group is cleaved by less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, or 1% in the absence of a malassezia species as compared to the presence of a malassezia species.

In certain embodiments, the linker is a Generally Recognized As Safe (GRAS) excipient.

In certain embodiments, the linker is-CH (R)¹) -, wherein R¹Is H or C₁-C₆Alkyl, the latter optionally substituted by one or more of hetero atoms, aryl, heteroaryl, cyclyl and heterocyclylMultiple substitutions and/or interspersions. In one embodiment of the linker, R¹Is H or methyl, i.e. the linker is-CH₂-or-CH (CH)₃) -. As shown in figure 1, when this linker is used to link an azole-based antifungal or antibacterial agent to a carboxylated carrier, the conjugate may undergo spontaneous cleavage after the linkage is cleaved by esterase to release the azole-based agent and formaldehyde or acetaldehyde. Similar spontaneous cleavage can also occur when linkers are used to attach at the noncyclic nitrogen atom of an antifungal or antibacterial agent. Some exemplary conjugates comprising such linkers are shown in figure 1. Conjugates comprising the linker can be synthesized using aldehydes, such as formaldehyde, acetaldehyde, paraformaldehyde, and paraformaldehyde. Although FIG. 1 shows the linker as being attached at a ring nitrogen of the azole moiety of the agent, the linker may also be used to attach at an acyclic nitrogen of the agent. The second moiety attached through the linker may comprise a carboxyl group or a hydroxyl group. Thus, any moiety comprising a free carboxyl group or a free hydroxyl group may be conjugated to the agent. Thus, the linker may be used to attach a second linker (e.g., a linker comprising a free carboxyl group and/or a free hydroxyl group) to the agent, as shown in fig. 5-7.

The linker may be pyridoxine (vitamin B)₆) Or an analogue or derivative thereof. Thus, in certain embodiments, the linker isOrOrWherein R is^2aIs a hydroxy protecting group; r^2bIs C₁-C₆Alkyl, which may be optionally substituted or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl groups; and R is^NIs absent, H, C₁-C₆Alkyl or acyl, each of which may be optionally substitutedAnd (4) generation. In certain embodiments of the linker, R^2aIs acyl, i.e. C (O) R^2cWherein R is^2cIs C₁-C₆An alkyl group. In one embodiment, R^2aIs C (O) CH₃. Preferably, R^2bIs methyl or ethyl. When R is^NWhen so, the linker comprises a counter anion. The counter anion may be Cl^-、Br^-、I^-Or a pharmaceutically acceptable anion. Some exemplary conjugates comprising such linkers are shown in figure 2. Conjugates comprising the linker may be synthesized with pyridoxine.

In certain embodiments, the linker is polyethylene glycol (PEG) or an analog or derivative thereof. The PEG linker may have the general formula-CH₂CH₂[OCH₂CH₂]_aOHC₂CH₂-, where a is 1 to 500. Suitable PEGs include, but are not limited to, PEGs having an average molecular weight in the range of about 200 g/mole to about 30,000 g/mole. Using HOCH ₂CH₂[OCH₂CH₂]_aOHC₂CH₂Dihydroxy PEG to OH, conjugates comprising PEG linkers can be synthesized, where a is 1-500.

In certain embodiments, the linker is-CH₂C(R^3aR^3b)CH(OR^3c)C(O)N(R^3d)-(CH₂)_b-, wherein R^3aAnd R^3bIndependently is H or C₁-C₆Alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl groups; r^3cIs H or a carrier; r^3dIs H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted; and b is 1 to 10. R^3aAnd R^3bMay be the same or different. In one example, R^3aAnd R^3bAre both methyl groups. In certain embodiments of the linker, b is 2 or 3. The linker may be used to link 2 antifungal or antibacterial agents together. When used to link 2 antifungal agents or antibacterial agentsWhen taken together, the carrier may be attached at the hydroxyl group. Conjugates comprising the linker can be synthesized using an aldehyde (e.g., paraformaldehyde or a dialdehyde) and panthenol or dihydroxy PEG. Such linkers can undergo water-mediated cleavage.

In certain embodiments, the linker isWherein R is⁴Is halo, CN, CF3, alkyl, alkenyl, cyclyl, heterocyclyl, aryl, heteroaryl, NO ₂、OR⁶、OC(O)R^4a、OC(O)OR^4a、N(R^4a)₂、NHC(O)R^4a、NHC(O)OR^4a、C(O)R^4a、C(O)OR^4a、SR^4aOr SO₂R^4aEach of which may be optionally substituted; r^4aIndependently at each occurrence is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted; and c is 0 to 4. In one embodiment, c is 0. Conjugates comprising the linker can be synthesized using p-hydroxybenzyl alcohol. Some exemplary conjugates comprising such linkers are shown in figures 3 and 4. As shown in FIGS. 3 and 4, cleavage of the linker results in the formation of p-hydroxybenzyl alcohol or an analog or derivative thereof.

In certain embodiments, the linker is based on a diol, e.g., -CH₂CH(R⁶) -, where R is H or C₁-C₆Alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl groups. In one embodiment of the linker, R⁶Is methyl. When this linker is used to link an azole-based antifungal or antibacterial agent and a carboxylated carrier, the conjugate undergoes spontaneous cleavage after esterase cleavage of the linkage to release the diol. Using HOCH₂CH(R⁶) Diols in the form of OH, conjugates comprising the linker can be synthesized.

The linker may be based on alpha-hydroxy acids or the like An analog or derivative. Thus, in certain embodiments, the linker is-CH (R)⁷) C (O) -, wherein R⁷Is H, C₁-C₆Alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl. In one embodiment, R⁷Is methyl. Typically, the linker is used to attach the support at the hydroxyl group of the support. When this linker is used to link an azole-based antifungal or antibacterial agent and a hydroxyl-containing carrier, the conjugate undergoes spontaneous cleavage after esterase cleavage of the linkage to release an alpha-hydroxy acid (e.g., lactic acid or an analog or derivative thereof). Conjugates comprising the linker can be synthesized using alpha-hydroxy acids such as glycolic, lactic and mandelic acids.

In certain embodiments, the linker is-CH (R)⁸) OC (O) -L' -C (O) O-, wherein R⁸Is H or C₁-C₆An alkyl group; and L' is an alkyl group, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl groups, heteroaryl groups, cyclic groups, or heterocyclic groups, each of which may be optionally substituted. In one embodiment of the linker, L' is- (CH) ₂OCH₂)_d-, where d is 1 to 500. In one embodiment of the linker, L' is- (CH)₂)_e-, where e is 1 to 28. In one embodiment of the linker, L' is-CH (N (R)^N)₂)-(CH(R^8a)_f-, wherein R^8aIs H or C₁-C₆An alkyl group; r^NIndependently at each occurrence is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted; and f is 1 to 10. Preferably f is 1, 2 or 3. Preferably R^8aIs H or methyl. In one embodiment, R^NIs methyl. In another embodiment, L' is-O-CH (R)^8b) -, wherein R^8bIs H or C₁-C₆An alkyl group. In one embodiment, R^8bIs methyl. In one embodiment, L' is-CH₂CH₂C(O)O-[CH₂CH₂O]_f’C(O)CH₂CH₂-, where f' is 1 to 500. The linker may be used to attach a support comprising a hydroxyl group. Using aldehydes (e.g., paraformaldehyde or a dialdehyde) and dicarboxylic acids (such as those shown in fig. 5 and those described herein), conjugates comprising the linker can be synthesized. Some exemplary conjugates comprising such linkers are shown in fig. 5. In one embodiment, the linker is azelaic acid.

In certain embodiments, the linker is-CH (R)⁹) OC (O) -or-CH (R)⁹) OC (O) -L' -or-CH (R) ⁹) OC (O) -L' -Y-C (O) -, wherein R⁹Is H or C₁-C₆An alkyl group; y is O, S or NH; and L' is an alkyl group, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl groups, heteroaryl groups, cyclic groups, or heterocyclic groups, each of which may be optionally substituted. In one embodiment of the linker, L' is- (CH)₂OCH₂)_gCH₂-, where g is 1 to 500. In one embodiment of the linker, L' is- (CH)₂CH₂O)_gCH₂CH₂-, where g is 1 to 500. In one embodiment of the linker, L' is- (CH)₂)_hCH₂-, where h is 1 to 28. In one embodiment of the linker, L' is-CH (N (R)^N)₂(CH(R^9a)_iWherein R is^9aIs H or optionally substituted C₁-C₆An alkyl group; r^NIndependently at each occurrence is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted; and i is 1 to 10. Preferably i is 1, 2 or 3. In one embodiment, R^NIs methyl. In one embodiment, R^9aIs H or methyl. In another embodiment, L' is-O-CH (R)^8b) -, wherein R^9bIs H or C₁-C₆An alkyl group. In one embodiment, R^9bIs methyl. In one embodiment, L' is-CH₂CH₂C(O)O-[CH₂CH₂O]_i’C(O)CH₂CH₂-, where i' is 1 to 500. In certain embodiments of the linker, i' is. In one embodiment of the linker, the linker is-CH (CH) ₃)-OC(O)O-[CH₂CH₂O]_i’CH₂CH₂-, where i' is 1 to 500. In one embodiment of the linker, the linker is-CH (CH)₃)-OC(O)O-[CH₂CH₂O]_i’CH₂CH₂-, where i' is 1 to 500. In one embodiment of the linker, the linker is-CH (CH)₃)-OC(O)O-[CH₂CH₂O]_i’CH₂CH₂-, where i' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In another embodiment of the linker, the linker is-CH (CH)₃)-OC(O)O-[CH₂CH₂O]_i’CH₂CH₂-OC(O)-CH(CH₃) -, where i' is 1 to 500. In one embodiment of the linker, the linker is-CH (CH)₃)-OC(O)O-[CH₂CH₂O]_i’CH₂CH₂-OC(O)-CH(CH₃) -, where i' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In another embodiment of the linker, the linker is-CH₂-OC(O)O-(CH₂)_h’-c (o) -, wherein h' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. Conjugates comprising the linker can be synthesized using an aldehyde (e.g., paraformaldehyde or a dialdehyde) and a carboxylic acid (such as those shown in fig. 6), or using a 1-haloalkyl ester (e.g., a compound). In certain embodiments, the 1-haloalkyl ester can be a 1-chloroethyl ester. Some exemplary linker-containing conjugates described in this paragraph are shown in fig. 6.

In certain embodiments, the linker is-CH (R)^10a)OC(O)-L’-C(O)OCH(R^10b) -, wherein R ^10aAnd R^10bIndependently is H or C₁-C₆Alkyl, which may be optionally substituted; and L' is alkyl, which may be optionalSubstituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl or heterocyclyl groups, each of which may be optionally substituted. R^10aAnd R^10bMay be the same or different. In one embodiment, R^10aAnd R^10bAre both methyl groups. In one embodiment, R^10aAnd R^10bAre all H. In one embodiment of the linker, L' is- (CH)₂OCH₂)_j-, where j is 1 to 500. In one embodiment of the linker, L' is- (CH)₂)_k-, where k is 1 to 28. In one embodiment of the linker, L' is-CH (N (R)^N)₂(CH(R^10c)_tWherein R is^10cIs H or optionally substituted C₁-C₆An alkyl group; r^NIndependently at each occurrence is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted; and t is 1 to 10. Preferably t is 1, 2 or 3. In one embodiment, R^NIs methyl. In one embodiment, R^10cIs H or methyl. In another embodiment, L' is-O-CH (R)^10d) -, wherein R^10dIs H or C₁-C₆An alkyl group. In one embodiment, R^10dIs methyl. In one embodiment, L' is-CH ₂CH₂C(O)O-[CH₂CH₂O]_t’C(O)CH₂CH₂-, where t' is 1 to 500; -CH₂-OC(O)-(CH₂)_k’-C(O)O-CH₂-, wherein k' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In one embodiment of the linker, the linker is a conjugate comprising the linker that can be synthesized using an aldehyde (e.g., paraformaldehyde or a dialdehyde) and a dicarboxylic acid (such as those shown in fig. 7 and those described herein). Some exemplary conjugates comprising such linkers are shown in fig. 7.

In certain embodiments, the linker is-c (o) -L ' -c (o) -, -c (o) -L ' -Y-, or-c (o) -L ' -Y-c (o) -, wherein Y is O, S or NH; and isL' is an alkyl group, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl groups, heteroaryl groups, cyclic groups, or heterocyclic groups, each of which may be optionally substituted. In one embodiment of the linker, L' is- (CH)₂OCH₂)_a’-, where a' is 1 to 500. In one embodiment of the linker, L' is- (CH)₂)_b’-, where b' is 1 to 28. In certain embodiments, L' is C₁-C₆Alkyl groups, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl or ethylene. In one embodiment of the linker, L' is-CH (N (R)^N)₂(CH(R^11c)_c’Wherein R is ^11cIs H or optionally substituted C₁-C₆An alkyl group; r^NIndependently at each occurrence is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted; and c' is 1 to 10. Preferably c' is 1, 2 or 3. In one embodiment, R^NIs methyl. In one embodiment, R^11cIs H or methyl. In another embodiment, L' is-O-CH (R)^11d) -, wherein R^11dIs H or C₁-C₆An alkyl group. In one embodiment, R^11dIs methyl. In one embodiment, L' is-CH₂CH₂C(O)O-[CH₂CH₂O]_d’C(O)CH₂CH₂-, where d' is 1 to 500. Conjugates comprising the linker can be synthesized using dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, undecanedioic acid, and dodecanedioic acid. In addition, using the dibasic acids shown in fig. 11 and 12, conjugates comprising the linkers can be synthesized. Some exemplary conjugates comprising such linkers are shown in fig. 11, 12, and 17-21. Such linkers can be used to conjugate 2 antifungal and/or antibacterial agents together, as shown in fig. 17-21. The 2 antifungal agents and/or antibacterial agents linked together may be the same or different.

In some embodimentsIn one embodiment, the linker is-C (O) -L' -C (O) O- [ CH ]₂CH₂O]_v’-, where v 'is 1 to 500 and L' is C₁-C₂₀An alkyl group, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl groups, heteroaryl groups, cyclic groups, or heterocyclic groups, each of which may be optionally substituted. In one embodiment of the linker, L' is- (CH)₂OCH₂)_e’-, where e' is 1 to 500. In one embodiment of the linker, L' is- (CH)₂)_f’-, where f' is 1 to 28. In certain embodiments, L' is C₁-C₆Alkyl groups, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl or ethylene. In one embodiment of the linker, L' is-CH (N (R)^N)₂(CH(R^12c)_g’Wherein R is^12cIs H or optionally substituted C₁-C₆An alkyl group; r^NIndependently at each occurrence is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted; and g' is 1 to 10. Preferably g' is 1, 2 or 3. In one embodiment, R^NIs methyl. In one embodiment, R^12cIs H or methyl. In another embodiment, L' is-O-CH (R)^13d) -, wherein R^13dIs H or C₁-C₆An alkyl group. In one embodiment, R ^13dIs methyl. In one embodiment, L' is-CH₂CH₂C(O)O-[CH₂CH₂O]_h’C(O)CH₂CH₂-, where h' is 1 to 500. Conjugates comprising the linker can be synthesized using dicarboxylic acids and PEG. Some exemplary conjugates comprising such linkers are shown in fig. 16.

The linker may be a dicarboxylic acid. Exemplary dicarboxylic acids include, but are not limited to: acetone dicarboxylic acid; acetylene dicarboxylic acid; n-acetyl glutamic acid; ACPD; adipic acid; aldaric acids; 2-amino-3-carboxymuconic acid semialdehyde; alpha-aminoadipic acid; 2-aminocyclopconic acid; aspartic acid; azelaic acid; 4,4' -azobis (4-cyanovaleric acid); (ii) Bacillus, hi ol; bicinchoninic acid; camphoric acid; carbamoylaspartic acid; carbocisteine; chicoric acid; cilastatin; clinofibrate; diaminopimelic acid; glyoxylic acid; a dihydroxymalonic acid; a dimer acid; dimercaptosuccinic acid; dipicolinic acid; behenic acid; dodecanedioic acid; folic acid; fumaric acid; fumarylacetoacetate salts; 2, 5-furandicarboxylic acid; glutaconic acid; glutamic acid; 4- (γ -glutamylamino) butyric acid; glutaric acid; 3-hydroxyaspartic acid; alpha-hydroxyglutaric acid; hypoglycemic amino acid B; iminodiacetic acid; opuntin of Opuntia ficus-indica; isophthalic acid; itaconic acid; alpha-ketoadipic acid; alpha-ketoglutaric acid; lepidolide; maleic acid; maleylacetic acid; malic acid; malonic acid; pyromellitic acid; meglutong; methyl fumaric acid; pyruvic diacid; N-methyl-D-aspartic acid; 3-methylpentenedioic acid; methyl malonic acid; muconic acid; nedocromil; oxalic acid; oxaloacetic acid; oxalyl diaminopropionic acid; oxalyl glycine; pamoic acid; PCCG-4; phthalic acid; pimelic acid; pre-benzoic acid; quinolinic acid; sebacic acid; gamma-mucic acid; (ii) a suberic acid; succinic acid; tartaric acid; tartronic acid; terephthalic acid; thiomalic acid; thiadizoic acid; and a wound healing acid. In addition, polymers containing 2 or more carboxyl groups may also be used as linkers such as dicarboxylic acids. Some exemplary conjugates comprising dicarboxylic acids as linkers are shown in fig. 17-21.

In certain embodiments, the linker is a β -hydroxy acid. Examples of beta hydroxy acids that can be used as linkers include, but are not limited to: a 3-hydroxy 1-alkanoic acid wherein said alkane is selected from the group consisting of alkanes having from about 3 to about 25 carbon atoms. Some beta-hydroxy acids are 3-hydroxybutyric acid, 3-hydroxyvaleric acid, 3-hydroxyhexanoic acid, tropicamic acid and troxacarboxylic acid. Other suitable beta-hydroxy acids are described in U.S. Pat. No. 5,665,776. One preferred beta-hydroxy acid for use as a linker is salicylic acid.

Beta Hydroxy Acids (BHA) are oil soluble. Thus, BHA works very effectively to clean white and black heads by penetrating into pores that are clogged by the accumulation of sebum and dead cells. BHA is a powerful exfoliant that breaks down the skin plug in the well and is able to reach deeper into infected wells than alpha hydroxy acid. BHA has a lower risk of skin irritation due to its anti-inflammatory effect. BHA can reduce the appearance of blotches on sun damaged skin. Potential side effects of BHA include itching, pain, burning and redness. The risk of scar formation is higher in dark people.

An exemplary BHA is salicylic acid. Salicylic acid is effective in reducing and eliminating induration, eczema, psoriasis, warts and dandruff. Salicylic acid acts by promoting the shedding of damaged skin cells and the growth of new skin cells. It keeps the skin pores clean, thus minimizing clogging, and actively breaks down all forms of acne. Salicylic acid relaxes dry and damaged skin plaques by softening the epidermal protein-keratin. It remains on the skin surface long enough to adequately treat the pores. Salicylic acid is safe for sensitive skin; minor side effects include dryness, a shiny feel, redness and skinning.

In certain embodiments, the linker is a polyhydroxy acid, which is typically an organic carboxylic acid compound having at least 2 hydroxyl groups in the molecule and having a preferred molecular weight of about 100 to about 300. The polycarboxylic acids can be divided into aldonic acids (aldonic acids), aldaric acids and uronic acids (aldonic acids). These include gluconic acid, ribonic acid, galactonic acid, glucoheptonic acid, glucuronic acid, galacturonic acid, glucaric acid, galactaric acid, lactobionic acid, and the like.

Alpha Hydroxy Acids (AHAs) act by preventing cells on the skin surface from attaching to each other. AHA can cause the top layer of skin to peel and slough off, revealing underlying new and smoother skin. It is effective in removing skin problems such as eczema, psoriasis, acne and age spots; and help stimulate collagen growth in the cells. One major side effect of AHA is the increase in sun sensitivity of the area to which it is applied. AHA can cause irritation, redness, itching, or burning of the skin, and can sometimes lead to scarring of darker skin tones.

An exemplary AHA is glycolic acid. Glycolic acid has an excellent ability to penetrate the skin. Glycolic acid reduces wrinkles, scarring and hyperpigmentation and many other skin conditions, such as actinic keratosis, hyperkeratosis, seborrheic keratosis, and can be used to improve the appearance and texture of skin. Glycolic acid reacts with the upper layers of the epidermis, weakening the binding properties of lipids that hold dead skin cells together. This allows the stratum corneum to exfoliate, exposing living skin cells. It may be a skin irritant.

Another AHA is mandelic acid. Mandelic acid has antibacterial properties and is used as a substitute for glycolic acid in skin care.

Although AHA is a single chain molecule that allows rapid penetration through the skin; polyhydroxy acids (PHAs) are multi-chain molecules (and larger size) that make it penetrate the skin more slowly. PHA is absorbed at a slower rate, which can reduce side effects such as stinging or irritation. PHAs are considered the next generation of AHAs because they can be natural and non-toxic. PHA can regulate keratinization, cell development in the top layer of the skin, and normalize stratum corneum exfoliation and thickness. Mild surface penetration reduces sensitivity and discomfort. Exemplary PHAs include, but are not limited to: lactobionic acid, galactose and gluconic acid.

Lactobionic acid is PHA (gluconolactone + galactose) derived from lactose in cow's milk. Due to its 8 hydroxyl groups which bind more water, its performance outperforms other humectants such as glycerol, sorbitol and glycolic acid. Lactobionic acid has antioxidant properties that block oxygen radical induced tissue damage. It forms a gel film that binds to the skin to provide smoothing and healing benefits, and increases hydration and swelling. It has anti-aging benefits, especially against sensitive skin.

Galactose is a chemically neutral PHA. Galactose helps wound healing and protein synthesis. Galactose is used in collagen synthesis and cell migration that can enhance wound healing.

Gluconic acid is a PHA known to provide beneficial effects to skin.

When a carbohydrate (also called aldose) is oxidized from an aldehyde to a carboxyl group at the carbon 1 position, the product is called an aldonic acid. For example, when glucose is oxidized at the carbon 1 position, the product is gluconic acid. Aldonic acids typically have multiple hydroxyl groups. Aldonic acids may exist as stereoisomers such as D, L and DL, or R, S and RS. Many aldonic acids form intramolecular lactones, glucuronolactone, by removing 1 mole of water between the carboxyl and 1 hydroxyl group. The following are representative aldonic acids: 2, 3-dihydroxypropionic acid (glyceric acid); 2,3, 4-trihydroxybutyric acid (stereoisomers; erythro-and erythro-keto-acid lactones, threonic acid and threonic acid lactone); 2,3,4, 5-tetrahydroxypentanoic acid (stereoisomers; ribo-and ribonolactones, arabino-and arabinonolactones, xylo-and xylonolactones, lyxonic acid and lyxonolactone); 2,3,4,5, 6-pentahydroxyhexanoic acid (stereoisomers; arabinonic and allosteric lactones, altronic and altronic, gluconic and gluconolactone, mannonic and mannonolactone, gulonic and gulonolactone, idonic and idonolactone, galactonic and galactonic lactones, talonic and talonolactone); 2,3,4,5,6, 7-hexahydroxy heptanoic acid (stereoisomers; alloheptonic and alloheptonolactone, glucoheptonic and glucoheptonolactone, mannoheptonic and mannoheptonolactone, guloheptolactone, idoheptonolactone, galactoheptonolactone, taloheptolactone and taloheptolactone).

Aldaric acids typically have multiple hydroxyl groups attached to a carbon chain surrounded by 2 carboxyl groups. Many aldaric acids form intramolecular lactones, i.e., aldonolactones, by removing 1 mole of water between one of the 2 carboxyl groups and 1 hydroxyl group, such as the formation of glucaric acid lactone from glucaric acid. Aldaric acids may exist as stereoisomers such as D, L and DL, or R, S and RS. Exemplary aldaric acids include, but are not limited to: 2, 3-dihydroxybutane-1, 4-dioic acid (stereoisomers; erythrodioic acid and threonic acid); 2,3, 4-Trihydroxypentane-1, 5-dioic acid (stereoisomers; ribaric and ribarolactone, arabinosyland arabinosyllactone, xylaric and xylaric lactone, lyxolitic and lyxolitic lactone); 2,3,4, 5-tetrahydroxyhexane-1, 6-dioic acid (stereoisomers; allose and allose lactone, altrose and altrose lactone, glucaric acid and glucarate lactone, manno and manno lactone, gulonic and gulonic lactone, iditic and idite lactone, galactaric and galactaric lactone, talonic and talose lactone); 2,3,4,5, 6-pentahydroxyheptane-1, 7-dioic acid (stereoisomers; alloheptedioic acid and alloheptedioic acid lactone, altepinedioic acid and altepinedioic acid lactone, glucoheptedioic acid and glucoheptedioic acid lactone, mannoheptedioic acid and mannoheptedioic acid lactone, gulepinedioic acid and gulepinedioic acid lactone, idoheptedioic acid and idoheptedioic acid lactone, galactoheptedioic acid and galactoheptedioic acid lactone, taloheptenedioic acid and taloheptenedioic acid lactone).

Uronic acids are typically obtained from carbohydrates (aldoses) by oxidation of the terminal carbon to a carboxyl group, and the carbon 1 position remains as an aldehyde group, such as glucuronic acid from glucose. Like aldonic and aldaric acids, uronic acids also have multiple hydroxyl groups attached to the carbon chain between 2 functional groups (in this case, one aldehyde group and one carboxyl group). Many uronic acids exist as intramolecular lactones (glucuronolactones, such as glucuronolactones from glucuronic acid). Uronic acids can exist as stereoisomers such as D, L and DL, or R, S and RS. Exemplary uronic acids include, but are not limited to: erythrouronic and threonic acids, ribouronic and ribouronic acids lactone, arabinouronic and arabinouronic acid lactone, xylouronic and xylouronic acid lactone, lyuronic and lyxouronic acid lactone, allosuronic and allosuronic acid lactone, altronic and altronic acid lactone, glucuronic and glucuronic acid lactone, mannuronic and mannuronic acid lactone, guluronic and guluronic acid lactone, iduronic and iduronic acid lactone, galacturonic and galacturonic acid lactone, taluronic acid and taluronic acid lactone, allohepturonic and allohepturonic acid lactone, altretaronic and altretaronic acid lactone, glucohepturonic and glucohepturonic acid lactone, mannuronic and mannohepturonic acid lactone, gulohepteuronic and gulhepturonic acid lactone, idohepturonic acid and idohepturonic acid lactone, gulohepteuronic acid and gulohepteuronic acid lactone, idohepturonic acid and idohepturonic acid lactone, glucohepturonic acid and glucohepturonic acid lactone, glucohepturonic and glucohepturonic acid lactone, and, Galactohepturonic acids and galactohepturonolactones, talohepturonic acids and talohepturonolactones.

In certain embodiments, the linker is a direct bond. Exemplary conjugates having a bond as a linker include clindamycin lauric acid conjugates, clindamycin adapalene conjugates, and erythromycin-lauric acid conjugates shown in fig. 16 and 17.

In certain embodiments, the linker is PLGA, PLA. An exemplary conjugate comprising PLGA as the linker is shown in fig. 17.

In certain embodiments, the linker is a branched linker. The branching point of the branched linker may be at least trivalent, but may be a tetravalent, pentavalent, or hexavalent atom, or a group exhibiting such multiple valencies. In certain embodiments, the branch point is-N, -N (Q) -C, -O-C, -S-C, -SS-C, -C (O) N (Q) -C, -OC (O) N (Q) -C, -N (Q) C (O) -C, or-N (Q) C (O) O-C; wherein Q in each occurrence is independently H or optionally substituted alkyl. In certain embodiments, the branch point is glycerol or a derivative thereof.

The linkers described herein may be used together to form a longer linker comprising 2 or more linkers described herein. For example, -CH (R) may be substituted¹) The-type linker is linked to a linker based on a carboxylic acid molecule. One such exemplary extended linker is-CH (R) as described above ⁹) OC (O) -or-CH (R)⁹) OC (O) -L' -or-CH (R)⁹)OC(O)-L’-Y-C(O)-。

In certain embodiments, conjugate-based prodrugs of the invention may comprise 2 or more carrier molecules. When 2 or more carriers are present in a conjugated prodrug, the carriers can be the same, all different, or a combination of the same and different. Without limitation, each vector may be attached by similar linkers or by different types of linkers.

Personal care compositions

The conjugate-based prodrugs of the present invention may be used in personal care compositions, such as hair care compositions and skin care compositions. The personal care compositions of the present invention comprise an effective amount of at least one conjugate-based prodrug in a range from about 0.001 wt% to about 10 wt%, preferably from about 0.1 wt% to about 5 wt%, and more preferably from about 0.5 wt% to about 3 wt% of the total weight of the composition. The term "effective amount" as used herein is the amount of conjugate-based prodrug in the personal care composition necessary to achieve the desired improvement.

In addition to conjugate-based prodrugs, the personal care compositions of the present invention may also include other drugs or surface agents to achieve synergistic or synergistic effects. Drugs and other surface agents that may be incorporated into the composition include: those that ameliorate or eradicate age spots, keratoses, and wrinkles; local analgesics and anesthetics; an anti-acne agent; an antibacterial agent; an anti-yeast agent; an antifungal agent; an antiviral agent; anti-dandruff agents; an anti-dermatitis agent; an antihistamine; an antipruritic agent; an antiemetic agent; anti-motion sickness agents; an anti-inflammatory agent; an anti-excessive keratolytic agent; an antiperspirant; anti-psoriasis agents; anti-seborrhea agents; hair conditioners and hair treatment agents; anti-aging and anti-wrinkle agents; sunscreens and sunblocks; a skin lightening agent; a decolorizing agent; a vitamin; a corticosteroid; a tanning agent; a humectant; a hormone; retinoic acid compounds; gum disease or oral care agents; a topical cardiovascular agent; particulate, induration and wart removal agents; and a depilatory agent.

Examples of such agents include, but are not limited to: azelaic acid, triclosan, alpha-hydroxy acids, glycolic acid, mandelic acid, beta-hydroxy acids, salicylic acid, polyhydroxy acids, lactobionic acid, galactose, gluconic acid, adapalene, abacavir, acebutolol, acetaminophen, acetaminosalol, acetazolamide, acetohydroxamic acid, acetylsalicylic acid, abamectin, alclomethasone, acrivastine, fentanyl (actiq), acyclovir, adapalene, adefovir dipivoxil, adenosine, albuterol, alfuzosin, allopurinol, xanthine, almotriptan, alprazan, alprenolol, aluminum acetate, aluminum chloride, aluminum chlorohydrate, aluminum hydroxide, amantadine, amiloride, amsacrine, aminobenzoic acid (PABA), aminocaproic acid, aminosalicylic acid, amiodarone, amitriptyline, amlodipine, amoxapine, amorolfine, amoxapine, salpindol, amoxapine, Amphetamine, ampicillin, anagrelide, anastrozole, dithranol, apomorphine, aprepitant, arbutin, aripiprazole, ascorbic acid, ascorbyl palmitate, atazanavir, atenolol, atoxetine, atropine, azathioprine, azelaic acid, azelastine, azithromycin, bacitracin, beclomethasone dipropionate, bemeting, benazepril, benflumethiazide, benzocaine, benzonatate, benzophenone, benzalkonium, bepril, betamethasone dipropionate, betamethasone valerate, brimonidine, brompheniramine, bupivacaine, buprenorphine, bupropion, brimonidine, butenafine, butoconazole, cabergoline, caffeic acid, caffeine, calcipotriene, camphor, candesartan cilexetil, capsaicin, cefditoren pivoxil, cefpodoxime, levofloxacin, and celecoxib, Cetirizine, sevimerine, chitosan, chlordiazepoxide, chlorhexidine, chloroquine, chlorothiazide, chloroxylenol, chlorpheniramine, chlorpromazine, chlorpropamide, ciclopirox, cilostazol, cimetidine, cinacalcet, ciprofloxacin, citalopram, citric acid, cladribine, clarithromycin, clemastine, clindamycin, clioquinol, clobetasol propionate, clomiphene, clonidine, clopidogrel, clotrimazole, clozapine, cocaine, codeine, cromolyn, crotamiton, cyclizine, cyclobenzaprine, cycloserine, cytarabine, dacarbazine, dalfopristin, dapsone, daptomycin, daunorubicin, deferoxamine, dehydroepiandrosterone, delavirdine, desipramine, desloratadine, desoximetasone, dexmedetomidine, dexmedroxypamide, dexmedroxypromine, dexmedroxypamide, dexmedroxil, imipramine, ciprofloxacin, chlorpheniramine, chlorp, Diazepam, bicyclovirine, didanosine, dihydrocodeine, dihydromorphine, diltiazem, 6, 8-dimercaptooctanoic acid (dihydrolipoic acid), diphenhydramine, diphenoxylate, dipyridamole, propipirtine, dobutamine, dofetilide, dolasetron, donepezil, dopa-esters, dopamine, dorzolamide, doxepin, doxorubicin, doxycycline, doxylamine, doxycycline, doxylamine, duloxetine, dyclonine, econazole, eflornithine (eflorthine), eletriptan, emtricitabine, enalapril, ephedrine, epinephrine, ephedrine, epirubicin, eptidine, erythromycin, escitalopram, esmolol, esomeprazole, estazolam, estradiol, etanide, ethisterone, etidocaine, etomidine, famidipine, dihydromorphine, 6, 8-dimercaptone (dihydrolipoic acid), diphenoxylate, doxylamine, dofetamine, doxylamine, dobutamine, doxylamine, do, Fentanyl, ferulic acid, fexofenadine, flecainide, fluconazole, flucytosine, fluocinonide, 5-fluorouracil, fluoxetine, fluphenazine, flurazepam, fluvoxamine, formoterol, furosemide, galactarolide, galactonic acid, galactonolactone, galantamine, gatifloxacin, gefitinib, gemcitabine, gemifloxacin, glycolic acid, griseofulvin, guaifenesin, guanethidine, histamine N-amidinate, haloperidol, haloprogin, hexylresorcinol, homatropine, vesudoxine, hydralazine, hydrochlorothiazide, hydrocortisone 21-acetate, hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydromorphone, hydroquinone monoether, hydroxyzine, hyoscyamine, hypoxanthine, ibuprofen, ichthammol, idarubicin, imatinib, imipramine, imiquimod, indinavir, indomethacin, irbesartan, irinotecan, isotatalin, isoproterenol, itraconazole, kanamycin, ketamine, ketanserin, ketoconazole, ketoprofen, ketotifen, kojic acid, labetalol, lactic acid, lactobionic acid, lamivudine, lamotrigine, lansoprazole, letrozole, leuprolide, levalbuterol, levofloxacin, lidocaine, linezolid, lobelin, loperamide, losartan, loxapine, ergotamine, sulfamylon, malic acid, maltobionic acid, mandelic acid, maprotiline, mebendazole, mecamylamine, meclizine, meclocycline, memantin, menthol, pethidine, mepivacaine, mercaptopurine, mescalin, methofurazoline, oxacillin, metaproterenol, metazanine, metformin, methadone, medroxide, medroxypurine, Methamphetamine, methotrexate, methoxamine, methyldopate, methyldopamide, 3, 4-methylenedioxymethamphetamine, methyl lactic acid, methyl nicotinate, methylphenidate, methyl salicylate, methimide, metolazone, metoprolol, metronidazole, mexiletine, miconazole, midazolam, midodrine, meglumine, minocycline, minoxidil, mirtazapine, mitoxantrone, moexiprilat, molindone, moxabenzone, morphine, moxifloxacin, moxonidine, mupirocin, nadolol, naftifine, nalbuphine, nalmefene, naloxone, naproxen, nefazodone, nelfinavir, neomycin, nevirapine, nicardipine, nicotine, nifedipine, nimodipine, nizine, noradrenaline, nystatin, oxcarbazepine, octreotide, methoxyoctreotide, octyl cinnamate, octocryl, Octyl salicylate, ofloxacin, olanzapine, olmesartan medoxomil, olopatadine, omeprazole, ondansetron, oxiconazole, oxotremorine, oxybenzone, oxybutynin, oxycodone, oxymetazoline, padetamol O, palonosetron, pantothenic acid, panthenol, paroxetine, pimoline, penciclovir, penicillamine, penicillin, pentazocine, pentobarbital, pentostatin, pentoxifylline, pergolide, perindopril, pameprine, phencyclidine, phenelzine, pheniramine, phenmetrazine, phenobarbital, phenol, phenoxybenzamine, phentolamine, phenylephrine, phenylpropanolamine, phenytoin, physostigmine, pilocarpine, pimozide, pimozolol, pindolol, glipidone, pimazine, piperonyl butoxide, podophyllotoxin, podophyllin, prixol (paxopepti) and pramipexole O Pramoxine, prazosin, prednisone, praterol, prilocaine, procainamide, procaine, procarbazine, promazine, promethazine, propafenone, dexpropoxyphene, propranolol, prothiocypyrimidine, protiline, pseudoephedrine, pyrethrin, mepyramine, pyrimethamine, quetiapine, quinapril, quinethazone, quinidine, quinupristin, rabeprazole, reserpine, resorcinol, retinal, 13-cis-retinoic acid, retinol, retinyl acetate, retinyl palmitate, ribavirin, ribonic acid, ribonolactone, rifampin, rifapentine, rifaximin, riluzole, rimantadine, risedronate, risperidone, ritodrine, rivastigmine (rivasfigmine), rizatriptan, ropinirole, pimecron, salicylamide, salicylic acid, prilocalne, procaine, procarbazine, pyrilamine, pyrimethamine, quetiapine, ritin, ritonazine, and other compounds, Scopolamine, selegiline, selenium disulfide, 5-hydroxytryptamine, sertindole, sertraline, sibutramine, sildenafil, sotalol, streptomycin, strychnine, sulconazole, sulfanilazole, sulfanilamide, sulfadimidine, sulfachlorpyridazine, sulfaxetine, sulfadiazine, sulfadimethoxine, sulfadoxine, sulfaguananol, sulfalene, sulfamethizole, sulfamethoxazole, sulfapyrazine, sulfapyridine, sulfasalazine, sulfaisothiazole, sulfathiazole, sulfisoxazole, tadalafil, tamsulosin, tartaric acid, tazarotene, tegaserod, telithromycin, telmisartan, temozolomide, tenofovir disoproxil, terazozine, terbinafine, terbutaline, terfenadine, tetracaine, tetracycline, tetrahydrozoline, theobromine, thiabendazole, thiozolirtine, thiozolirtisone, Tioltipraz, thymol, tiagabine, timolol, tinidazole, tioconazole, tirofiban, tizanidine, tobramycin, tocainide, tolazoline, tolbutamide, tolnaftate, tolterodine, tramadol, tranylcypromine, trazodone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone acetonide, triamterene, triazolam, triclosan, trifluoroperazine, trimethoprim, trimipramine, tripelennamine, triprolidine, tromethamine, tropic acid, tyramine, undecylenic acid, urea, urocanic acid, ursodeoxycholic acid, vardenafil, venlafaxine, verapamil, vitamin E acetate, voriconazole, warfarin, xanthine, zafirlukast, zaleplon, zinc pyrithione, zolmitriptan and zolpidem.

Azelaic acid is a naturally occurring dicarboxylic acid. Azelaic acid can inhibit DNA synthesis by keratinocytes and is comedolyitc. Azelaic acid has a dose-dependent antimicrobial effect against staphylococcus epidermidis and propionibacterium acnes. At higher concentrations, azelaic acid can produce a burning sensation.

Triclosan is an antibacterial agent found in many household products such as first aid creams, mouth rinses, deodorants, toothpaste, hand soap and facial cleansers (Clearsil). Triclosan will remove the accumulation of bacteria below the surface of the skin. The primary benefit of triclosan is its ability to remain on the skin for extended periods of time. Triclosan is not very water soluble and has a slow degradation time, which allows it to remain on the skin after washing and continue to destroy bacteria. Overuse can lead to the development of new bacterial strains with antibiotic resistance and can cause environmental hazards. Triclosan is most successful when combined with products containing benzoyl peroxide or salicylic acid. Triclosan can act as a protectant that increases the persistence and effectiveness of other treatments for acne.

Alpha Hydroxy Acids (AHAs) act by preventing cells on the skin surface from attaching to each other. AHA can cause the top layer of skin to peel and slough off, revealing underlying new and smoother skin. It is effective in removing skin problems such as eczema, psoriasis, acne and age spots; and help stimulate collagen growth in the cells. One major side effect of AHA is the increase in sun sensitivity of the area to which it is applied. AHA can cause irritation, redness, itching, or burning of the skin, and can sometimes lead to scarring of darker skin tones.

An exemplary AHA is glycolic acid. Glycolic acid has an excellent ability to penetrate the skin. Glycolic acid reduces wrinkles, scarring and hyperpigmentation and many other skin conditions, such as actinic keratosis, hyperkeratosis, seborrheic keratosis, and can be used to improve the appearance and texture of skin. Glycolic acid reacts with the upper layers of the epidermis, weakening the binding properties of lipids that hold dead skin cells together. This allows the stratum corneum to exfoliate, exposing living skin cells. It may be a skin irritant.

Another AHA is mandelic acid. Mandelic acid has antibacterial properties and is used as a substitute for glycolic acid in skin care.

Beta Hydroxy Acids (BHA) are oil soluble. Thus, BHA works very effectively to clean white and black heads by penetrating into pores that are clogged by the accumulation of sebum and dead cells. BHA is a powerful exfoliant that breaks down the skin plug in the well and is able to reach deeper into infected wells than alpha hydroxy acid. BHA has a lower risk of skin irritation due to its anti-inflammatory effect. BHA can reduce the appearance of blotches on sun damaged skin. Potential side effects of BHA include itching, pain, burning and redness. The risk of scar formation is higher in dark people.

An exemplary BHA is salicylic acid. Salicylic acid is effective in reducing and eliminating induration, eczema, psoriasis, warts and dandruff. Salicylic acid acts by promoting the shedding of damaged skin cells and the growth of new skin cells. It keeps the skin pores clean, thus minimizing clogging, and actively breaks down all forms of acne. Salicylic acid relaxes dry and damaged skin plaques by softening the epidermal protein-keratin. It remains on the skin surface long enough to adequately treat the pores. Salicylic acid is safe for sensitive skin; minor side effects include dryness, a shiny feel, redness and skinning.

Although AHA is a single chain molecule that allows rapid penetration through the skin; polyhydroxy acids (PHAs) are multi-chain molecules (and larger size) that make it penetrate the skin more slowly. PHA is absorbed at a slower rate, which can reduce side effects such as stinging or irritation. PHAs are considered the next generation of AHAs because they can be natural and non-toxic. PHA can regulate keratinization, cell development in the top layer of the skin, and normalize stratum corneum exfoliation and thickness. Mild surface penetration reduces sensitivity and discomfort. Exemplary PHAs include, but are not limited to: lactobionic acid, galactose and gluconic acid.

Lactobionic acid is PHA (gluconolactone + galactose) derived from lactose in cow's milk. Due to its 8 hydroxyl groups which bind more water, its performance outperforms other humectants such as glycerol, sorbitol and glycolic acid. Lactobionic acid has antioxidant properties that block oxygen radical induced tissue damage. It forms a gel film that binds to the skin to provide smoothing and healing benefits, and increases hydration and swelling. It has anti-aging benefits, especially against sensitive skin.

Galactose is a chemically neutral PHA. Galactose helps wound healing and protein synthesis. Galactose is used in collagen synthesis and cell migration that can enhance wound healing.

Gluconic acid is a PHA known to provide beneficial effects to skin.

Adapalene has been shown to enhance the efficacy of surface clindamycin. The application of adapalene gel to the skin 3-5 minutes prior to the application of clindamycin enhances the penetration of clindamycin into the skin. It has exfoliative and anti-inflammatory effects. It may be more effective than tretinoin 0.025% gel in the treatment of acne.

The personal care compositions of the present invention may further comprise one or more optional components known for use in hair care or personal care products, provided that the optional components are physically and chemically compatible with the essential components described herein, or do not otherwise unduly impair product stability, aesthetics or performance. Individual concentrations of such optional components may range from about 0.001% to about 10% by weight of the composition.

Non-limiting examples of optional components for use in the composition include deposition aids, cationic polymers, nonionic polymers, dispersed particles, conditioning agents (silicones and organic conditioning oils), moisturizers, suspending agents, other anti-dandruff actives, viscosity modifiers, dyes, non-volatile solvents or diluents (water soluble and insoluble), pearlescent aids, foam boosters, other surfactants or non-ionic co-surfactants, pediculicides, pH regulators, perfumes, preservatives, chelating agents, proteins, skin actives, sunscreens, uv absorbers, vitamins, antioxidants, preservatives, fillers, surfactants, UVA and/or UVB sunscreens, perfumes, thickeners, wetting agents, anionic polymers, nonionic polymers, amphoteric polymers, viscosity/foam stabilizers, opacifiers/pearlescers, sunscreen agents, Masking agents, stabilizers, hair conditioners, humectants, antistatic agents, anti-freeze agents, buffers, dyes and pigments. These adjuvants are well known in the cosmetic art and are described in numerous publications, see for example Harry's Book of cosmetics, 8 th edition, Martin Rieger, eds, Chemical Publishing, New York (2000).

The personal care compositions of the present invention may include a deposition aid. Deposition aids are included to effectively enhance deposition of the components of the personal care composition. The deposition aid may comprise any material that enhances the deposition of components of the personal care composition on the hair, scalp or skin. Preferably, the deposition aid is a cationic polymer. The concentration of the deposition aid in the personal care composition should be sufficient to effectively enhance deposition of the components and generally ranges from about 0.05% to about 5%, preferably from about 0.075% to about 2.5%, more preferably from about 0.1% to about 1.0% by weight of the personal care composition.

The compositions of the present invention may contain a cationic polymer. The concentration of the cationic polymer in the composition typically ranges from about 0.05% to about 3%, preferably from about 0.075% to about 2.0%, more preferably from about 0.1% to about 1.0%, by weight of the composition. Preferred cationic polymers have a cationic charge density of at least about 0.9meq/gm, preferably at least about 1.2meq/gm, more preferably at least about 1.5meq/gm, but also preferably less than about 7meq/gm, more preferably less than about 5 meq/gin. The pH of the intended application of the composition is generally in the range of from about pH3 to about pH9, preferably from about pH4 to about pH 8. Such suitable cationic polymers typically have an average molecular weight of from about 10,000 to 1000 ten thousand, preferably from about 50,000 to about 500 ten thousand, more preferably from about 100,000 to about 300 ten thousand.

Suitable cationic polymers for use in the compositions of the present invention contain cationic nitrogen-containing moieties such as quaternary ammonium or cationic protonated amino moieties. The cationic protonated amines can be primary, secondary or tertiary amines (preferably secondary or tertiary), depending on the particular material and the selected pH of the composition. Any anionic counterions can be used in conjunction with the cationic polymers so long as the polymers remain soluble in water, in the composition, or in the coacervate phase of the composition, and so long as the counterions are physically and chemically compatible with the essential components of the composition or do not otherwise unduly impair product performance, stability, or aesthetics. Non-limiting examples of such counterions include halides (e.g., chloride, fluoride, bromide, iodide), sulfate, and methylsulfate.

Non-limiting examples of cationic polymers are described in CTFA Cosmetic ingredient dictionary, 3 rd edition, Estrin, Crosley, and Haynes, (The Cosmetic, Toiletry, and Fragrance Association, Inc., Washington, D.C. (1982)).

Non-limiting examples of suitable cationic polymers include copolymers of vinyl monomers having cationic protonated amine or quaternary ammonium functionalities with water soluble barrier monomers such as acrylamide, methacrylamide, alkyl and dialkyl acrylamides, alkyl and dialkyl methacrylamides, alkyl acrylates, alkyl methacrylates, vinyl caprolactone or vinyl pyrrolidone.

Suitable cationic protonated amino and quaternary ammonium monomers for the cationic polymers included in the compositions herein include: vinyl compounds substituted with dialkylaminoalkyl acrylate, dialkylaminoalkyl methacrylate, monoalkylaminoalkyl acrylate, monoalkylaminoalkyl methacrylate, trialkyl methacryloxyalkyl ammonium salt, trialkyl acryloxyalkyl ammonium salt, diallyl quaternary ammonium salts, and vinyl quaternary ammonium monomers having a nitrogen-containing ring of a cyclic cation, such as pyridinium, imidazolium, and quaternized pyrrolidones, e.g., alkyl vinyl imidazolium, alkyl vinyl pyridinium, alkyl vinyl pyrrolidone salts.

Other suitable cationic polymers for use in the composition include: copolymers of 1-vinyl-2-pyrrolidone and 1-vinyl-3-methylimidazolium salts (e.g., hydrochloride salt) (referred to in the industry by Cosmetic, toiletty, and Fragrance Association ("CTFA") as polyquaternium-16); copolymers of 1-vinyl-2-pyrrolidone and dimethylaminoethyl methacrylate (referred to in the industry by CTFA as polyquaternium-11); cationic diallyl quaternary ammonium-containing polymers including, for example, dimethyldiallylammonium chloride homopolymer, copolymers of acrylamide and dimethyldiallylammonium chloride (referred to in the industry by CTFA as polyquaternium 6 and polyquaternium 7, respectively); amphoteric copolymers of acrylic acid, including copolymers of acrylic acid and dimethyldiallylammonium chloride (referred to in the industry by CTFA as polyquaternium 22), terpolymers of acrylic acid with dimethyldiallylammonium chloride and acrylamide (referred to in the industry by CTFA as polyquaternium 39), and terpolymers of acrylic acid with methacrylamidopropyltrimethylammonium chloride and methyl acrylate (referred to in the industry by CTFA as polyquaternium 47).

Other suitable cationic polymers for use in the composition include polysaccharide polymers, such as cationic cellulose derivatives and cationic starch derivatives. Preferred cationic cellulose polymers are salts of hydroxyethyl cellulose reacted with trimethylammonium substituted epoxide, known in the industry (CTFA) as polyquaternium 10 and available from Amerchol Corp. (Edison, n.j., USA) as their Polymer LR, JR and KG series of polymers. Other suitable types of cationic cellulose include the polymeric quaternary ammonium salts of hydroxyethyl cellulose reacted with lauryl dimethyl ammonium-substituted epoxide, which is known in the industry (CTFA) as polyquaternium 24. These materials are available from Amerchol Corp under the commercial name Polymer LM-200.

Other suitable cationic polymers include cationic guar gum derivatives such as guar hydroxypropyltrimonium chloride, specific examples of which include: the Jaguar series commercially available from Rhone-Poulenc Incorporated, and the N-Hance series commercially available from Aqualon Division of Hercules, Inc. Other suitable cationic polymers include quaternary nitrogen-containing cellulose ethers, some examples of which are described in U.S. Pat. No. 3,962,418. Other suitable cationic polymers include copolymers of etherified cellulose, guar and starch, some examples of which are described in U.S. Pat. No. 3,958,581. When used, the cationic polymers herein may be soluble in the composition or may be soluble in complex coacervates in the composition formed by the cationic polymer and anionic, amphoteric and/or zwitterionic detersive surfactant component described hereinbefore. Complex coacervates of cationic polymers can also be formed with other charged species in the composition.

Polyalkylene glycols having a molecular weight of greater than about 1000 are useful herein. A polyethylene glycol polymer useful herein is PEG-2M (also referred to asN-10, available from Union Carbide and as PEG-2,000); PEG-5M (also known as Polyox)N-35 and PolyoxN-80, available from Union Carbide and as PEG-5,000 and polyethylene glycol 300,000); PEG-7M (also known as Polyox)N-750 available from Union Carbide); PEG-9M (also known as Polyox)N-3333, available from Union Carbide); and PEG-14M (also known as Polyox)N-3000, available from Union Carbide).

The compositions of the present invention may comprise dispersed particles. The composition of the invention may comprise at least 0.025 wt% of dispersed particles, more preferably at least 0.05 wt%, more preferably at least 0.1 wt%, even more preferably at least 0.25 wt% and more preferably at least 0.5 wt% of dispersed particles. In the compositions of the present invention, it is preferred to incorporate no more than about 20% by weight of the dispersed particles, more preferably no more than about 10%, more preferably no more than 5%, even more preferably no more than 3% and more preferably no more than 2% by weight of the dispersed particles.

Conditioning agents include any material used to provide a particular conditioning benefit to the hair and/or skin. Conditioning agents useful in the compositions of the present invention typically comprise a water-insoluble, water-dispersible, non-volatile liquid which forms emulsified liquid particles or is solubilized by surfactant micelles, dissolved in the anionic detersive surfactant component (described above). Suitable conditioning agents for use in the compositions are those typically characterized as silicones (e.g., silicone oils, cationic silicones, silicone gums, high refractive silicones, and silicone resins), organic conditioning oils (e.g., hydrocarbon oils, polyolefins, and fatty acid esters), or combinations thereof, or those conditioning agents that would otherwise form liquid dispersed particles in the aqueous surfactant matrix herein.

The conditioning agent of the composition of the present invention may be an insoluble silicone conditioning agent. The silicone conditioning agent particles may comprise volatile silicones, non-volatile silicones, or combinations thereof. Non-volatile silicone conditioning agents are preferred. If volatile silicones are present, they are generally not essential to their use as solvents or carriers for commercially available forms of non-volatile silicone material ingredients (such as silicone gums and resins). The silicone conditioner particles may comprise a silicone fluid conditioner and may also comprise other ingredients, such as a silicone resin, to improve silicone fluid deposition efficiency or enhance the gloss of the hair.

The concentration of silicone conditioning agent is generally in the range of from about 0.01% to about 10%, preferably from about 0.1% to about 8%, more preferably from about 0.1% to about 5%, more preferably from about 0.2% to about 3% by weight of the composition. Non-limiting examples of suitable silicone conditioning agents and optional suspending agents for silicones are described in U.S. re-assigned patent No. 34,584, U.S. patent No. 5,104,646, and U.S. patent No. 5,106,609. The silicone conditioning agent used in the composition of the present invention preferably has the following viscosity measured at 25 ℃: from about 20 to about 2,000,000 centistokes ("csk"), more preferably from about 1,000 to about 1,800,000csk, even more preferably from about 50,000 to about 1,500,000csk, more preferably from about 100,000 to about 1,500,000 csk.

The dispersed silicone conditioning agent particles typically have a volume average particle diameter in the range of from about 0.01m to about 50 μm. For small particles to be applied to the hair, the volume average particle diameter typically ranges from about 0.01 μm to about 41 μm, preferably from about 0.01 μm to about 2 μm, more preferably from about 0.01 μm to about 0.51 μm. For larger particles to be applied to the hair, the volume average particle diameter typically ranges from about 5 μm to about 125 μm, preferably from about 10 μm to about 90 μm, more preferably from about 15 μm to about 70 μm, more preferably from about 20 μm to about 50 μm.

For background material on silicones, including the section discussing silicone fluids, gums and resins, and silicone preparation, see: encyclopedia of Polymer Science and Engineering, Vol.15, 2 nd edition, p.204-308, John Wiley & Sons, Inc. (1989).

The silicone fluid comprises a silicone oil, which is a flowable silicone material having a viscosity measured at 25 ℃ of: less than 1,000,000csk, preferably from about 5csk to about 1,000,000csk, more preferably from about 100csk to about 600,000 csk. Suitable silicone oils for use in the compositions of the present invention include polyalkylsiloxanes, polyarylsiloxanes, polyalkylarylsiloxanes, polyether siloxane copolymers, and mixtures thereof. Other insoluble, non-volatile silicone fluids having hair conditioning properties can also be used.

Other silicone fluids suitable for use in the compositions of the present invention are insoluble silicone gums. These gums are polyorganosiloxane materials having a viscosity greater than or equal to 1,000,000csk measured at 25 ℃. Silicone gums are described in: U.S. Pat. No. 4,152,416, Noll and Walter, Chemistry and Technology of Silicones, New York, Academic Press (1968); and General Electric silicon Rubber Product Data Sheets SE30, SE33, SE54 and SE 76. Specific non-limiting examples of silicone gums for use in the compositions of the present invention include: polydimethylsiloxane, (polydimethylsiloxane) (methylvinylsiloxane) copolymer, polydimethylsiloxane) (diphenylsiloxane) (methylvinylsiloxane) copolymer, and mixtures thereof.

Other non-volatile, insoluble silicone fluid conditioning agents suitable for use in the compositions of the present invention are those known as "high refractive index silicones" which have a refractive index of at least about 1.46, preferably at least about 1.48, more preferably at least about 1.52, more preferably at least about 1.55. The refractive index of the polysiloxane fluid is typically less than about 1.70, typically less than about 1.60. In this context, polysiloxane "fluids" include oils as well as gums.

Silicone fluids suitable for use in the compositions of the present invention are disclosed in U.S. patent No. 2,826,551, U.S. patent No. 3,964,500, U.S. patent No. 4,364,837, british patent No. 849,433, and Silicon Compounds, petrich Systems, Inc (1984).

Silicone resins may be included in the silicone conditioning agents of the compositions of the present invention. These resins are highly crosslinked polymeric siloxane systems. The crosslinking is introduced by incorporating trifunctional silanes and tetrafunctional silanes with monofunctional silanes or difunctional silanes or both during the preparation of the silicone resin.

Specifically, the silicone material and silicone resin can be readily identified according to a shorthand nomenclature system known to those of ordinary skill in the art as the "MDTQ" nomenclature. Under this system, silicones are described in terms of the presence of different siloxane monomer units that make up the silicone. In short, the symbol M denotes a single functional unit (CH3)3SiO 05; d represents the bifunctional element (CH3)2 SiO; t represents the trifunctional unit (CH3) Si 015; and Q represents the tetra (quadra) -or tetra (tetra) -functional unit SiO 2. The initials of the unit symbols (e.g., M ', D ', T, and Q ') represent substituents other than methyl, and must be well-defined for each occurrence.

Preferred silicone resins for use in the compositions of the present invention include, but are not limited to: MQ, MT, MTQ, MDT and MDTQ resins. Methyl is a preferred organosilicon substituent. Particularly preferred silicone resins are MQ resins, wherein the ratio of M to Q is from about 0.5:1.0 to about 1.5:1.0, and the average molecular weight of the silicone resin is from about 1000 to about 10,000.

The conditioning component of the compositions of the present invention may also comprise from about 0.05% to about 3%, preferably from about 0.08% to about 1.5%, more preferably from about 0.1% to about 1%, by weight of the composition, of at least one organic conditioning oil as a conditioning agent, either alone or in combination with other conditioning agents such as silicones (described above).

Suitable organic conditioning oils for use as conditioning agents in the compositions of the present invention include, but are not limited to: hydrocarbon oils having at least about 10 carbon atoms such as cyclic hydrocarbons, straight chain aliphatic hydrocarbons (saturated or unsaturated), and branched chain aliphatic hydrocarbons (saturated or unsaturated), including polymers and mixtures thereof. The linear hydrocarbon oil is preferably from about C to about C19. Branched hydrocarbon oils (including hydrocarbon polymers) typically contain more than 19 carbon atoms.

Specific non-limiting examples of these hydrocarbon oils include: paraffin oil, mineral oil, saturated and unsaturated dodecane, saturated and unsaturated tridecane, saturated and unsaturated tetradecane, saturated and unsaturated pentadecane, saturated and unsaturated hexadecane, polybutene, polydecene, and mixtures thereof. Branched isomers of these compounds, as well as higher chain length hydrocarbons, may also be used, examples of which include highly branched, saturated or unsaturated alkanes such as the all-methyl substituted isomers of hexadecane and eicosane, for example, the all-methyl substituted isomers of hexadecane and eicosane, such as 2,2,4,4,6,6,8, 8-dimethyl-10-methylundecane and 2,2,4,4,6, 6-dimethyl-8-methylnonane available from Permethyl corporation. Hydrocarbon polymers such as polybutene and polydecene are preferred. One preferred hydrocarbon polymer is polybutene, such as a copolymer of isobutylene and butene. Such a commercially available material is L-14 polybutene available from Amoco Chemical Corporation.

The organic conditioning oils used in the compositions of the present invention may also include liquid polyolefins, more preferably liquid poly-a-olefins, more preferably hydrogenated liquid poly-a-olefins. The polyolefins used herein are prepared by polymerization of C4 to about C14 olefin monomers (preferably about C6 to about C12).

Non-limiting examples of olefin monomers useful in preparing the polyolefin liquids herein include: ethylene, propylene, 1-butene, 1-pentene, 1-hexene, 1-octene, 1-decene, 1-dodecene, 1-tetradecene, branched isomers such as 4-methyl-l-pentene, and mixtures thereof. Refinery feedstocks or effluents containing olefins are also suitable for use in the production of polyolefin liquids. Preferred hydrogenated a-olefin monomers include, but are not limited to: 1-hexene to 1-hexadecene, 1-octene to 1-tetradecene, and mixtures thereof.

Other suitable organic conditioning oils for use as conditioning agents in the compositions of the present invention include, but are not limited to, fatty acid esters having at least 10 carbon atoms. These fatty acid esters include esters having hydrocarbyl chains derived from fatty acids or alcohols (e.g., mono-esters, polyol esters, and di-and tri-formates). The hydrocarbyl residue of the fatty acid ester thereof may include or have covalently bonded thereto other compatible functional groups such as amide and alkoxy moieties (e.g., ethoxy or ether linkages, etc.).

Specific examples of preferred fatty acid esters include, but are not limited to: isopropyl isostearate, hexyl laurate, hexyl isolaurate, isohexyl palmitate, isopropyl palmitate, decyl oleate, decyl isooleate, hexadecyl stearate, decyl stearate, dihexyldecyl adipate, lauryl lactate, myristyl lactate, cetyl lactate, oleyl stearate, oleyl oleate, oleyl myristate, lauryl acetate, cetyl propionate, and oleyl adipate.

Other fatty acid esters suitable for use in the composition of the invention are mono-formates of the general formula R ' COOR, wherein R ' and R are alkyl or alkenyl residues and the sum of the carbon atoms in R ' and R is at least 10, preferably at least 22.

Other fatty acid esters suitable for use in the compositions of the present invention are di-and tri-alkyl and alkenyl esters of carboxylic acids, such as esters of C4 to C8 dicarboxylic acids (e.g., C1 to C22 esters of succinic, glutaric and adipic acids, preferably C1 to C6). Specific non-limiting examples of di-and tri-alkyl and alkenyl esters of carboxylic acids include isocetyl stearyl stearate, diisopropyl adipate, and tristearyl alcohol citrate.

Other fatty acid esters suitable for use in the compositions of the present invention are those known as polyol esters. Such polyol esters include alkylene glycol esters such as ethylene glycol mono-and di-fatty acid esters, diethylene glycol mono-and di-fatty acid esters, polyethylene glycol mono-and di-fatty acid esters, propylene glycol mono-and di-fatty acid esters, polypropylene glycol monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, mono-and di-fatty acid glycerides, polyglycerol poly-fatty esters, ethoxylated glycerol monostearate, 1, 3-butylene glycol distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

Other fatty acid esters suitable for use in the compositions of the present invention are glycerides, including, but not limited to, mono-, di-, and triglycerides, preferably di-and triglycerides, more preferably triglycerides. For use in the compositions described herein, the glycerides are preferably mono-, di-, and tri-esters of glycerol and long chain carboxylic acids (such as C10 to C22 carboxylic acids). Many of these types of materials can be derived from vegetable and animal fats and oils, such as castor oil, safflower oil, cottonseed oil, corn oil, olive oil, cod liver oil, almond oil, avocado oil, palm oil, sesame oil, lanolin, and soybean oil. Synthetic oils include, but are not limited to: triolein and tristearin dilaurin glyceride.

Other fatty acid esters suitable for use in the compositions of the present invention are water-insoluble synthetic fatty acid esters.

Specific non-limiting examples of suitable synthetic fatty acid esters for use in the compositions of the present invention include: p-43 (C8-C10 triester of trimethylolpropane), MCP-684 (tetraester of 3,3 diethanol-1, 5 pentanediol), MCP121 (C8-C10 diester of adipic acid), all available from Mobil chemical Company.

Conditioners described in U.S. patent nos. 5,674,478, and 5,750,122 by the Procter & Gamble Company are also suitable for use in the compositions herein. Those conditioning agents described in U.S. Pat. No. 4,529,586(Clairol), U.S. Pat. No. 4,507,280(Clairol), U.S. Pat. No. 4,663,158(Clairol), U.S. Pat. No. 4,197,865(L 'Oreal), U.S. Pat. No. 4,217,914(L' Oreal), U.S. Pat. No. 4,381,919(L 'Oreal), and U.S. Pat. No. 4,422,853(L' Oreal) are also suitable for use herein.

The compositions of the present invention may contain a humectant. The moisturizer herein is selected from: polyols, water-soluble alkoxylated nonionic polymers, and mixtures thereof. As used herein, humectants are preferably used at the following levels: from about 0.1% to about 20%, more preferably from about 0.5% to about 5%, by weight of the composition.

Polyols useful herein include: glycerol, sorbitol, propylene glycol, butylene glycol, hexylene glycol, ethoxylated glucose, 1, 2-hexanediol, hexanetriol, dipropylene glycol, erythritol, trehalose, diglycerin, xylitol, maltitol, maltose, glucose, fructose, sodium chondroitin sulfate, sodium hyaluronate, sodium adenosine phosphate, sodium lactate, pyrrolidone carbonate, glucosamine, cyclodextrin, and mixtures thereof.

Water-soluble alkoxylated nonionic polymers useful herein include polyethylene glycols and polypropylene glycols having a molecular weight of up to about 1000, such as those having the CTFA designation PEG-200, PEG-400, PEG-600, PEG-1000, and mixtures thereof.

The composition of the present invention may further comprise a suspending agent at a concentration effective to suspend the water-insoluble in dispersed form in the composition or to adjust the viscosity of the composition. Such concentrations range from about 0.1% to about 10%, preferably from about 0.3% to about 5.0%, by weight of the composition.

Suitable suspending agents include crystalline suspending agents that can be classified as acyl derivatives, long chain amine oxides, or combinations thereof. Such suspending agents are described in U.S. Pat. No. 4,741,855.

The compositions of the invention may also contain vitamins and amino acids such as: water-soluble vitamins such as vitamin B1, B2, B6, B12, C, pantothenic acid, panthenyl ethyl ether, panthenol, biotin, and their derivatives, water-soluble amino acids such as asparagine, alanine, indole, glutamic acid, and their salts, water-insoluble vitamins such as vitamin A, D, E and their derivatives, and water-insoluble amino acids such as tyrosine, tryptamine, and their salts.

The compositions of the present invention may also contain pigment materials such as nitroso, monoazo, bisazo, carotenoids, triphenylmethane, triarylmethane, xanthene, quinoline, oxazine, azine, anthraquinone, indigo, thioindigoid, quinacridone, phthalocyanine, vegetable and natural dyes, including water soluble dye components. The compositions of the present invention may also contain a chelating agent.

Personal care compositions are well known in the art. See, for example, US patent nos. 6,274,150, 6,599,513, 6,0969,169, 4,735,742, 6,451,300, 4,942,161, 5,456,851, 5,854,246, 6,099,870, 7,094,422, 7,732,450, 6,663,875, 6,812,238, 7,732,450, 5,654,293, 6,099,870, 6,375,939, 6,451,300, 6,649,155, 6,451,300, 6,419,913, 6,451,300 and 6,451,300, US patent application publication nos. US 2010/6,451,300, US 2009/6,451,300, US 2006/6,451,300, US 2003/6,451,300, US 2008/6,451,300, US 2010/6,451,300, US 2009/6,451,300, US 2007/6,451,300 and US20080152611, and WO2001051014, WO 2001061060351, WO 20030006032002003000620020020020030006679, WO 2002012002012002012003002003000383200336780, WO 2002002002002002003000371200300200337780, WO 2002002002002002002003000371200337780, WO 2002002002002002002002002003000392337780, WO 200200200200200200200200200200200200300037146, WO 20020020020020020020020020020030020030020030020030020030020030020030020030020030020030020030046, WO 200200200200200200200200200200200200200200200200200200200200200200200200200200200200200200200200200200200300200200300200300200200200200200200200200200200200200200200200200200200200200200200200200200300200200200200200200300200200200200200300. The above compositions may be formulated with the conjugated prodrugs of the invention. For example, the active ingredients of the above compositions may be replaced with conjugated prodrugs of the invention.

In certain embodiments, the personal care composition is a hair care composition. The hair care composition can be used for preventing dandruff. Hair care compositions are defined herein as compositions that can be used to treat hair, including, but not limited to, shampoos, conditioners, rinses, lotions, aerosols, gels, mousses, and tints. The hair care compositions of the present invention comprise an effective amount of at least one conjugate-based prodrug (e.g., conjugate-based antifungal prodrug) in the range of from about 0.001% to about 10%, preferably from about 0.1% to about 5%, and more preferably from about 0.5% to about 3% by weight of the total weight of the composition. The term "effective amount" as used herein is the amount of conjugate-based antifungal prodrug in the hair care composition required to achieve the desired improvement.

In addition to the conjugate-based prodrugs, the hair care compositions may comprise a cosmetically acceptable medium for the hair care compositions, examples of which are described, for example, in U.S. patent nos. 6,280,747, 6,139,851, and 6,013,250, which are all incorporated herein by reference. For example, these hair care compositions may be aqueous, alcoholic or hydro-alcoholic solutions, the alcohol preferably being ethanol or isopropanol, in proportions of from about 1 to about 75% by weight of the total weight of the hydro-alcoholic solution. Additionally, the hair care composition may contain one or more conventional cosmetic or dermatological additives or adjuvants, including, but not limited to, antioxidants, preservatives, fillers, surfactants, UVA and/or UVB sunscreens, fragrances, thickeners, moisturizers, anionic polymers, nonionic polymers, amphoteric polymers, viscosity/foam stabilizers, opacifiers/pearlescers, masking agents, stabilizers, hair conditioners, moisturizers, antistatic agents, anti-freeze agents, buffering agents, dyes, and pigments. These adjuvants are well known in the cosmetic art and are described in numerous publications, see for example Harry's Book of cosmetics, 8 th edition, Martin Rieger, eds, Chemical Publishing, New York (2000).

The conjugate-based antifungal prodrugs can be used in shampoos. Suitable shampoo compositions are well known in the art. For example, Wells et al in U.S. Pat. No. 6,930,078, Patel et al in U.S. Pat. No. 5,747,436, and niemieic et al in U.S. Pat. No. 6,908,889 describe the components of shampoo compositions. The shampoo composition may be an aqueous, hydro-alcoholic or oil-in-water (O/W) or water-in-oil-in-water (W/O/W) emulsion. The shampoo compositions of the present invention contain an effective amount of the conjugate-based antifungal prodrug in an amount of from about 0.001% to about 10%, preferably from about 0.1% to about 5%, and more preferably from about 0.5% to about 3% by weight of the total weight of the composition. The balance of the shampoo composition is made up of the fluid vehicle, surfactant, and other additives. Typically, the fluid vehicle comprises water and other solvents, which may include, but are not limited to, mineral oil and fatty alcohols.

Surfactants are the major components of shampoo compositions. The amount of primary surfactant is generally in the range of between about 10% and 20%, more typically from about 8 to about 18%, based on the weight of the final composition. A second surfactant may also be present, typically in the range of about 0 to about 6%. The surfactant of the shampoo compositions according to the present invention may comprise one or more of anionic, nonionic, amphoteric or cationic surfactants or combinations thereof. Examples of anionic surfactants include, but are not limited to: soap, alkyl and alkyl ether sulfates and alpha-olefin sulfonates. Preferred anionic surfactants are lauryl (ammonium, sodium, triethanolamine and diethanolamine and laureth (sodium and ammonium)) sulfate. The second anionic surfactant includes, but is not limited to: sulfosuccinates, linear alkylbenzenesulfonates, N-acylmethyltaurates, N-acylsarcosinates, acylisothionates, N-acyl polypeptide condensates, polyalkoxylated ether glycolates, monoglyceride sulfates, fatty glyceryl ether sulfonates. Examples of nonionic surfactants include, but are not limited to: fatty alkanolamides, amine oxides, polymeric ethers, polysorbate 20, PEG-80 sorbitan and nonoxynol. Examples of amphoteric surfactants include, but are not limited to: betaine, alkyl-substituted amino acids (sodium lauraminopropionate and sodium lauriminopropionate).

Shampoo compositions according to the invention may also contain viscosity and foam stabilizing agents, typically in amounts ranging from about 1.5 to about 5% by weight of the final composition. Specific examples of viscosity/foam stabilizers include, but are not limited to: alkanolamides (such as cocamide MEA).

In addition, the shampoo compositions may contain minor proportions of one or more conventional cosmetic or dermatological additives or adjuvants, provided that they do not interfere with the desired mildness, performance or aesthetic characteristics of the final product. The total concentration of added ingredients is often less than 5%, preferably less than 3%, by weight of the total composition. Such minor components include, but are not limited to: opacifiers/pearlescers such as stearic acid derivatives (e.g., ethylene glycol monostearate or ethylene glycol distearate); a solvent; masking agents such as disodium Ethylenediaminetetraacetate (EDTA) and its salts, citric acid or polyphosphates; a stabilizer; thickeners such as salts of anionic agents (e.g., sodium chloride or ammonium chloride); PEG-120 methyl glucose dioleate and PEG-150 pentaerythritol tetrastearate for anionic/nonionic formulations; hair conditioners such as cationic polymer polyquaternium 10(Ucarepolymers), cationic guar (Jacquar C-261N), polyquaternium-7 (Merquatpolysiloxanes), and silicones such as polydimethylsiloxanes and aminopolydimethylsiloxanes; a humectant; an antistatic agent; antifreeze, buffer; antioxidants such as BHT, BHA and tocopherol; ultraviolet absorbers such as benzophenone; preservatives, such as parabens; a fragrance; and dyes or pigments. These adjuvants are well known in the cosmetic arts and are described in numerous publications, see, for example, Harry's Book of cosmetics, supra.

The final essential component in the shampoo composition is water, which will provide the balance of the aqueous medium that makes up the shampoo composition. Typically, the proportion of water ranges from about 53% to about 95%, preferably from 68% to about 92%, most preferably from about 80% to about 87%, by weight of the resulting shampoo composition.

Shampoo compositions of the invention may be prepared using conventional formulation and mixing techniques. Where it is desired to melt or dissolve the solid surfactant or wax component, these may be added to a premix or some portion of the surfactant and heated to melt the solid component, for example, from about 50 ℃ to about 95 ℃. The mixture may then optionally be processed through a high shear mill and cooled before mixing into the remaining components. The composition typically has a final viscosity of about 2,000 to about 20,000cps (centipoise). The viscosity of the composition can be adjusted by conventional techniques, including the addition of sodium chloride or ammonium xylene sulfonate as needed.

The hair care composition may further comprise one or more anti-dandruff agents. The term "anti-dandruff agent" as used herein means any chemical agent that is effective in treating dandruff and/or the symptoms associated therewith. Anti-dandruff agents are well known in the art. See, e.g., U.S. patent application publication Nos. 2004/0202636 and 2003/0003070, and U.S. patent No. 6,284 234, the entire contents of which are incorporated herein by reference. Generally, antidandruff agents are effective antifungal agents against the fungus malassezia spp. Suitable anti-dandruff agents include, but are not limited to: pyrithione salts such as calcium, magnesium, barium, strontium, zinc, and zirconium pyrithione salts; azoles such as climbazole, ketoconazole and itraconazole, piroctone olamine salt (octopirox); undecylenic acid, undecylenamidopropyl betaine (AMPHORAM)) Coal tar (NeutrogenaT/gel, CAS No. 8030-31-7; salicylic acid (Ionil T); selenium disulfide (Selsun Blue) and tea tree, and mixtures thereof. One pyrithione salt is the zinc salt of 1-hydroxy-2-pyrithione (also known as zinc pyrithione). These antifungal agents are generally available from commercial sources. For example, zinc pyrithione is available from Olin Corporation (Norwalk, Conn.); octopirone is available from Hoechst AG (Frankfurt, Germany); AMPHORAMAvailable from CECA Arkema Group (France); and ketoconazole are available from Alfa Chem (Kings Point, n.y.).

In certain embodiments, the personal care composition is a skin care composition. The skin care composition can be used for preventing acne. Skin care compositions are defined herein as compositions for treating skin, including, but not limited to, skin conditioners, moisturizers, vanishing creams, anti-wrinkle products, skin cleansers, and body washes. The skin care compositions of the present invention include any composition that can be topically applied to the skin, including, but not limited to, lotions, creams, gels, sticks, sprays, ointments, cleansing liquid lotions, cleansing solid strips, pastes, foams, powders, shaving creams, and swabs.

The skin care compositions of the present invention may comprise several types of cosmetically acceptable surface carriers including, but not limited to, solutions, colloidal suspensions, dispersions, emulsions (microemulsions, nanoemulsions, multiple emulsions, and non-aqueous emulsions), hydrogels, and vesicles (liposomes, multilamellar vesicles (novosomes)). Suitable cosmetically acceptable surface carrier components and methods of formulation are well known in the art and are described, for example, in U.S. patent No. 6,797,697 and U.S. patent application publication nos. 2005/0142094 and 2005/0008604, international patent application publication nos. 2006/029818 and 2000/062743, the entire contents of which are incorporated herein by reference. Those skilled in the art will appreciate different methods for producing these different product forms.

The skin care compositions of the present invention comprise an effective amount of at least one conjugate-based prodrug (e.g., conjugate-based antibacterial prodrug) in the range of from about 0.001% to about 10%, preferably from about 0.1% to about 5%, and more preferably from about 0.5% to about 3% by weight of the total weight of the composition. The term "effective amount" as used herein is the amount of conjugate-based prodrug in the skin care composition necessary to achieve the desired improvement.

Typically, the cosmetically acceptable medium for skin care compositions comprises water and other solvents including, but not limited to, mineral oils and fatty alcohols. The cosmetically acceptable medium is from about 10% to about 99.99% by weight of the composition, preferably from about 50% to about 99% by weight of the composition, and may form the balance of the composition in the absence of other additives.

The term "cosmetically acceptable medium" as used herein means a formulation that: which is used for treating skin, hair and/or nails and contains one or more ingredients used by those skilled in the art to formulate a product for treating skin, hair and/or nails. The cosmetically acceptable medium may be in any suitable form, i.e., a liquid, cream, emulsion, gel, thickened lotion or powder, and typically contains water, and may contain a cosmetically acceptable solvent and/or one or more surfactants.

The skin care composition may further comprise basic cosmetic raw materials including, but not limited to, hydrocarbons, esters, fatty alcohols, fatty acids, emulsifiers, moisturizers, viscosity modifiers, and silicone-based materials. The compositions of the present invention may contain a plurality of these base components. The total concentration of added ingredients is typically less than 50%, preferably less than 20%, most preferably less than 10% by weight of the total composition. Those skilled in the art will appreciate the different concentrations and combinations of these base components to achieve the desired product form.

Suitable hydrocarbons that may be used in the compositions of the present invention include, but are not limited to: mineral oil, isohexadecane, squalane, hydrogenated polyisobutene, petrolatum, paraffin wax, microcrystalline wax and polyethylene.

Suitable esters that may be used in the compositions of the present invention include, but are not limited to: isopropyl palmitate, octyl stearate, caprylic/capric triglyceride, vegetable waxes (Canelilla, Caranauba), vegetable oils (natural glycerides) and vegetable oils (jojoba).

Suitable fatty alcohols that may be used in the compositions of the present invention include, but are not limited to: myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol and behenyl alcohol.

Suitable emulsifiers that may be used in the compositions of the present invention include, but are not limited to: anionic (TEA/K stearate (triethanolamine/potassium stearate), sodium lauryl stearate, sodium cetostearyl sulfate and beeswax/borax), nonionic (glyceryl di-stearate, PEG (polyethylene glycol) -100 stearate, polysorbate 20, steareth 2 and steareth 20), and cationic (distearyldimethylammonium chloride, behenylbenzyldimethylammonium chloride and cetylpyridinium chloride), polymeric (acrylates/C10-30 alkyl acrylate crosspolymers, polyacrylamides, polyquaternium-37, propylene glycol, dicaprylate/dicaprate and PPG-1 trideceth-6) and silicone-based materials (alkyl modified dimethicone copolyols) and polyglyceryl esters and ethoxylated di-fatty acid esters.

Exemplary humectants for use in the compositions of the invention include, but are not limited to: propylene glycol, sorbitol, butylene glycol, hexylene glycol, acetamide MEA (acetylethanolamine), honey, and sodium PCA (sodium 2-pyrrolidone carboxylate).

Viscosity modifiers that may be used in the compositions of the present invention include, but are not limited to: xanthan gum, magnesium aluminum silicate, sodium carboxymethylcellulose and hydrogenated castor oil.

In addition, the skin care composition may contain one or more conventional functional cosmetic or dermatological additives or adjuvants, so long as they do not interfere with the desired mildness, performance or aesthetic characteristics of the final product. CTFA (The Cosmetic, Toiletry, and fragrance Association; now known as Personal Care Products Council) International Cosmetic Ingredient Dictionary and Handbook, eleventh edition (2006), and McCutcheon's Functional Materials, North America and International edition, MC Publishing Co. (2007) describe a variety of Cosmetic and pharmaceutical ingredients commonly used in skin Care compositions, which are suitable for use in The compositions of The present invention. The compositions of the present invention may contain a variety of such additional optional components. The total concentration of the added ingredients is generally less than about 20%, preferably less than about 5% and most preferably less than about 3% by weight of the total composition. Such components include, but are not limited to: surfactants, emollients, humectants, stabilizers, film forming materials, fragrances, colorants, chelating agents, preservatives, antioxidants, pH modifiers, antimicrobials, water repellents, dry feel modifiers, vitamins, plant extracts, hydroxy acids (such as alpha-hydroxy acids and beta-hydroxy acids), and shadow tanning agents. Examples of common raw materials and suitable adjuvants for acne treatment compositions are described in: beumer et al, supra and Robinson et al, supra.

Method of treatment

The invention also provides a method for treating or preventing a fungal or bacterial infection in a subject. The method comprises the following steps: administering to a subject in need thereof a composition described herein. Without limitation, a fungal or bacterial infection may be selected from: oral/vaginal candidiasis, intestinal endless worms (tinea infections of the body, scalp, beard, eczema marginalis, and tinea pedis), nail infections, ear infections, and the like. Furthermore, the subject may be a human or non-human animal (e.g. for veterinary applications), i.e.

The term "administering" as used herein means placing a composition described herein into a subject by a method or route that results in the composition being at least partially localized at a desired site. The compositions described herein may be administered by any suitable route that results in effective treatment of the subject, i.e., administration results in delivery to the desired location in the subject where at least a portion of the composition is delivered. Exemplary modes of administration include, but are not limited to: injection, infusion, instillation, or ingestion. "injection" includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracerobrospinal and intrasternal injection and infusion. Without limitation, administration may be local or systemic.

In certain embodiments, the application is topical, e.g., the composition is applied topically to the desired site.

The present invention also provides a method for treating or preventing dandruff comprising: applying to the scalp of a subject a hair care composition comprising at least one conjugate-based antifungal prodrug as described herein. The hair care composition may be rinsed off the scalp or left on the scalp depending on the type of composition used. The compositions described herein may be applied to the scalp by a variety of means including, but not limited to, spraying, brushing, and hand painting.

In another aspect, there is provided a method for treating or preventing acne, the method comprising: applying the skin care composition described herein to the skin of a subject in need thereof. After application, the skin care composition may be rinsed off the skin or left on the skin, depending on the type of composition used. The skin care composition may be applied to the scalp by a variety of means including, but not limited to, spraying, brushing, and hand painting.

As used herein, "subject" refers to a human or an animal. Typically, the animal is a vertebrate such as a primate, rodent, domestic animal or hunting animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., rhesus monkeys. Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalos, feline species, e.g., domestic cats, canine species, e.g., dogs, foxes, wolves, avian species, e.g., chickens, emus, ostriches, and fish, e.g., trout, catfish, and salmon. Patients or subjects include any subset of the foregoing, e.g., all of the foregoing, but do not include one or more populations or species such as humans, primates, or rodents. In certain embodiments of aspects described herein, the subject is a mammal, e.g., a primate, e.g., a human. The terms "patient" and "subject" are used interchangeably herein. The terms "patient" and "subject" are used interchangeably herein. The subject may be male or female.

Preferably, the subject is a mammal. The mammal may be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans may be advantageously used as the subject, which represents an animal model of a disorder associated with autoimmune disease or inflammation. In addition, the methods and compositions described herein can be used to treat domesticated animals and/or pets.

In certain embodiments, the subject is a human.

In some other embodiments, the subject is a non-human animal.

The subject may be a subject: which has been previously diagnosed as having, or identified as suffering from, or having a disorder characterized by a fungal or bacterial infection.

In certain embodiments, the subject is in need of treatment for dandruff and/or acne.

In certain embodiments, the subject is in need of treatment for oral or vaginal candidiasis, helminthoid (tinea infections of the body, scalp, beard, eczema marginalis, and tinea pedis), nail infections, or ear infections.

The subject may be a subject: it is currently treating dandruff, acne, oral or vaginal candidiasis, intestinal roundworm (tinea infections of the body, scalp, beard, eczema marginalis, and tinea pedis), nail infections or ear infections.

In certain embodiments of aspects described herein, the method further comprises: prior to initiation of treatment using the methods described herein, a fungal infection in a subject is diagnosed.

In certain embodiments of aspects described herein, the method further comprises: prior to initiation of treatment using the methods described herein, the subject is diagnosed for dandruff, acne, oral or vaginal candidiasis, helminth (tinea infections of the body, scalp, beard, eczema marginalis, and tinea pedis), nail infections, or ear infections.

In certain embodiments, the subject is an animal, i.e., the compositions and methods described herein for veterinary applications.

Prodrugs

Without wishing to be bound by theory, the conjugate-based prodrugs described herein are antifungal or antibacterial prodrugs. As used herein, "prodrug" refers to a compound that: it can be converted into the active compound via some chemical or physiological process (e.g., enzymatic process and metabolic hydrolysis). Thus, the term "prodrug" also denotes a precursor of a pharmaceutically acceptable biologically active compound. Prodrugs may be inactive, i.e., esters, when administered to a subject, but convert in vivo to the active compound, e.g., by hydrolysis to a free carboxylic acid or free hydroxyl group. Prodrug compounds often offer the advantage of solubility, histocompatibility, or delayed release in an organism. The term "prodrug" is also intended to include any covalently bonded carriers that release the active compound in vivo when such prodrug is administered to a subject. Prodrugs of active compounds can be prepared by modifying functional groups present in the active compound in the following manner:

The modification is cleaved to the parent active compound in routine procedures or in vivo. Prodrugs include compounds that: wherein a hydroxyl group, an amino group or a mercapto group is bonded to any of such groups: when a prodrug of the active compound is administered to a subject, the group cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to: acetate, formate and benzoate derivatives of alcohols, or acetamide, formamide and benzamide derivatives of amine functionality in the active compounds, and the like. See Harper, "Drug tension", Jucker, eds., "Progress in Drug research4:221-294(1962)," Morozwinch et al, "Application of pharmaceutical organic primers and adhesives, APHA acid phase.Sci.40 (1977)," biological Carrier Drug in Drug research Denn, thermal and Application, E.B. Roche, R.Roche, AP HA acid phase.Sci.40 (1977), "biological Carrier Drug in Drug research in Drug discovery, thermal and Application, E.B. Roche, R.P. Drug research 1997, (1987)," H.P.G. diffusion, section viewer (1985), "Progress in Drug discovery, J.E.P.J.J.1985.," Progress in Drug discovery, 1997, J.7., "Progress of Drug discovery, 1987"; Progress in Drug discovery, J.7., "Progress in Drug discovery, 1985.," Progress, J.7., "Progress in Drug discovery, No. 345. Release, No. 35.," Progress, No. 345. 1987., "Progress in Drug discovery, No. 7.," Progress, No. 7, Drug discovery, No. 7, Drug discovery, release, No. 7, Drug discovery, No. 7, Drug discovery, No. 7, Drug discovery No. 7, Drug discovery No. 7, Drug discovery No. 7, transport Processes in Pharmaceutical Systems, G.L.Amidon, P.I.Lee and E.M.Topp, eds., Marcell Dekker, pp.185-218 (2000); Balant et al, "precursors for the improvement of Drug administration", Eur.J.drug metals, Pharmaceutical compositions, 15(2):143-53(1990); Baliamane and Sinko, "introduction of multiple Delivery Systems, Drug Delivery Systems, injection Delivery Systems, Im39 (1-3)' 209(1999); Brownoil," chemical Delivery Systems, plug application, reaction of Drug Delivery Systems, "write Delivery Systems, 7" ("1-3)" 3 "(1999), chemical Delivery Systems, 7" ("1-3)" 3 ", write Systems, 7. 1997) 1-7," 10. 7, "Delivery Systems, 7" (1-7) and 1-3 "(7. application, published) 3. application, 3. D.7. application, published application the use of precursors, Arfv. Drug Delivery Rev.19(2): 115. about.130 (1996); Fleisher et al, "Design of precursors for improved Targeting by intracellular Targeting", Methods Enzymat.112 (Drug Enzyme Targeting, Pt.A):360-81, (1985); Farqhar D, et al, "biological recoverable Phosphate-Protective Groups", Pharms. Sci.72 (324. about.325. about.3., "biological Protective Group of proteins, III. about.7. about.9. about.J.," biological Delivery of proteins, III. about.7. about.about.7. about.7. about.9. about.7. about., "peptides: a current review of the clinical and therapeutic applications", Drugs45(6):866-94(1993), "Sinhababu and Thaker," Drugs of anti-cancer agents ", Adv. Drug Delivery Rev.19(2):241 273(1996)," Stella et al, "Drugs. Do. the human infection in clinical practice", Drugs29(5):455-73(1985); Tan et al, "Development and optimization of anti-HIV nuclear Drug Delivery and Drugs, Drugs of Drug Delivery, A review of the viral cell therapy, tissue-therapy and therapy, 1997, 23. 5.," therapy-therapy of anti-HIV Drug Delivery, 2. the "therapy of infection-HIV Drug Delivery", Drug Delivery, drug Delivery Rev.39 (l-3):63-80(1999); Waller et al, "Prodrugs", Br.J. Clin.Pharmac.28:497-507(1989), the entire contents of which are incorporated herein by reference in their entirety.

Nanoparticles comprising an active agent and a lipid

One of the major limitations of available topical antifungal and antibacterial formulations is the very short residence time of the drug on the application surface. For example, in the case of anti-dandruff shampoos applied to the scalp and hair, the active drug is washed off the scalp immediately after the hair is washed. Thus, the drug does not have sufficient time to elicit its response as an antifungal effect. Therefore, there is an unmet need to design a formulation that can allow the drug to stay on the scalp for a longer time so that it can exhibit its effect on fungi. To serve this purpose, provided herein are nanoparticulated systems in a suitable size range that will enhance the retention of the nanoparticles on the application area. In the case of dandruff, the nature of the nanoparticles allows for controlled release of the drug, although it is expected that the nanoparticles will be trapped in the microcracks of the scalp and the intracapsular spaces of the hair follicles and remain for a longer period of time. Furthermore, the lipid dependence of lipophilic fungi and bacteria can be exploited to develop nanoparticulated systems comprising a suitable lipid source (e.g., fatty acids; tri-, di-, or mono-glycerides; or other lipids) that serve as food for the microorganism. Thus, nanoparticulated systems will utilize the 'trojan horse strategy' to enhance the uptake of intact nanoparticles or released drugs.

Thus, in another aspect, provided herein is a nanoparticle comprising: (i) a first component selected from an antifungal agent, an antibacterial agent, or a combination thereof; and (ii) a second component selected from a lipid, a polymer, or a combination thereof. It should be understood that the discussion and embodiments of the nanoparticles discussed above also apply to this aspect.

The first and second components may be present in the nanoparticles in any amount. For example, the first and second components may be independently present in an amount of about 0.01 wt% to about 99 wt%, based on the total weight of the nanoparticle. In certain embodiments, the first or second component is present in an amount of about 0.01 wt% to about 99 wt%, about 0.01 wt% to about 90 wt%, about 0.01 wt% to about 80 wt%, about 0.01 wt% to about 70 wt%, about 0.01 wt% to about 60 wt%, about 0.01 wt% to about 50 wt%, about 0.01 wt% to about 40 wt%, about 0.01 wt% to about 30 wt%, about 0.01 wt% to about 25 wt%, about 0.1 wt% to about 80 wt%, about 0.1 wt% to about 70 wt%, about 0.1 wt% to about 60 wt%, about 0.1 wt% to about 50 wt%, about 0.1 wt% to about 40 wt%, about 0.1 wt% to about 30 wt%, about 0.0 wt% to about 25 wt%, based on the total weight of the nanoparticle.

In certain embodiments, the first or second component is present in a particular amount having a lower limit of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 50, 60, 70, 80, or 85 weight percent and an upper limit of about 22, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 50, 60, 70, 80, 85, or 90 weight percent, based on the total weight of the nanoparticle.

In certain embodiments, the first and second components may be covalently linked to each other. When the first and second components are covalently linked to each other, they may be in the form of conjugated prodrugs as discussed above. Alternatively, the first component and the second component are not covalently linked to each other.

The nanoparticles comprising the first and second components may be selected from: liposomes, polymeric nanoparticles, nanoemulsions, self-microemulsifying drug delivery systems (SMEDDS), solid-lipid nanoparticles (SLN), nanostructured liquid crystals, albumin-based nanoparticles, dendrimers, carbon nanotubes, Nanostructured Lipid Carriers (NLCs), polymersomes, nanocrystals, nanoemulsions, and the like.

In certain embodiments, the nanoparticles comprising the first and second components may further comprise a surfactant. Exemplary surfactants are described above.

In certain embodiments, the nanoparticles comprising the first and second components may further comprise an excipient. Exemplary molecules that can be used as excipients are also described above.

In certain embodiments, the second component is a lipid. The lipid may be selected from: fatty acids, fatty alcohols, glycerolipids (e.g., monoglycerides, diglycerides, and triglycerides), phospholipids, glycerophospholipids, sphingolipids, sterol lipids, prenyl lipids (prenol lipids), glycolipids, polyketides, and any combination thereof.

In certain embodiments, the lipid may be selected from: tripalmitin (Tripalm), ceteth-10, egg lecithin, soya lecithin, glyceryl monocaprylate (Capmul MCM C8EP), Capmul MCM C10, glyceryl tricaprylateCapric acid glyceride (355EP/NF), glyceryl distearate (type I) EP (Precirol ATO5), lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid, pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, nonacosanoic acid, melissic acid, hentriacontanoic acid, lacceric acid, tricosanoic acid, germanic acid, triacontanoic acid, α -linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, γ -linolenic acid, dihomo- γ -gamma-linolenic acid, arachidonic acid, oleic acid, elaidic acid, eicosenoic acid, erucic acid, nervonic acid, Mead, myristoleic acid, palmitoleic acid, myristoleic acid, melissic, Hexadecene-6-acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, elaidic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid, pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, myristoleic acid, palmitoleic acid, hexadecene-6-acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, elaidic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, cis-11-octadecenoic acid, cis-11-eicosenoic acid, alpha-linolenic acid, eicosanoic acid, Undecylenic acid, cis-13-docosenoic acid, neoheptanoic acid, neononanoic acid, neodecanoic acid, isostearic acid, 10-undecylenic acid, phosphatidic acid (phosphatidate, PA), phosphatidylethanolamine (cephalin, PE), phosphatidylcholine (lecithin, PC), Phosphatidylserine (PS), Phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), phosphatidylinositol diphosphate (PIP2), phosphatidylinositol triphosphate (PIP3), ceramide phosphorylcholine (sphingomyelin, SPH), ceramide phosphoryl Monoethanolamine (sphingomyelin, Cer-PE), ceramide phosphoryl glycerol, cholestane, cholane, pregnane, androstane, estrane, cholesterol, octanol, 2-ethylhexanol, nonanol, decanol, undecanol, lauryl alcohol, tridecanol, myristyl alcohol, pentadecanol, cetyl alcohol, palmitoyl alcohol, heptadecanol, stearyl alcohol, isostearyl alcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol, linolenyl alcohol, linoleyl alcohol, ricinoleyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, ceryl alcohol, 1-heptacosyl alcohol, montanyl alcohol, octacosyl alcohol, 1-nonacosyl alcohol, melissyl alcohol, 1-triacontanol, tetratriacontyl alcohol, cetostearyl alcohol, propylene glycol dicaprate, 1, 3-propylene glycol dicaprylate, caprylic acid/capric acid ester of saturated C12-18 fatty alcohol, Propylene glycol dicaprate, 1, 3-propylene glycol dicaprylate/dicaprate, glyceryl tricaprylate/tricaprate, caprylic/capric triglyceride, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/tricaprate, caprylic/capric triglyceride, glyceryl tricaprylate/caprate, glyceryl triacetate, glyceryl tricaprylate, triolein, and any combination thereof.

The nanoparticulated system described herein provides a novel mechanism for enhancing the uptake of intact nanoparticles and/or released drugs by lipophilic fungi and lipophilic bacteria. These nanoparticle systems are useful for treating fungal and bacterial infections in humans and other mammals. The present invention provides nanoparticles represented by a general graphical representation (fig. 32).

The nanoparticulated systems disclosed herein may be formulated as polymeric nanoparticles, liposomes, albumin-based nanoparticles, dendrimers, carbon nanotubes, Solid Lipid Nanoparticles (SLNs), Nanostructured Lipid Carriers (NLCs), self-microemulsifying drug delivery systems (SMEDDS), polymersomes, nanocrystals, nanoemulsions, and the like. These nanoparticles can be prepared using methods commonly used by those skilled in the art for preparing different types of nanoparticles.

After production, the nanoparticle dispersion can be centrifuged at high speed to pellet the nanoparticles or concentrated using a centrifugal filtration device, dialysis membrane, tangential (cross) flow filtration system. The concentrated dispersion can be lyophilized using a cryoprotectant to obtain free-flowing nanoparticles. Nanoparticle dispersions or lyophilized powders can be characterized using Scanning Electron Microscopy (SEM) and/or Transmission Electron Microscopy (TEM) and/or Atomic Force Microscopy (AFM) imaging and other means. Furthermore, the nanoparticles can be formulated into any dosage form depending ultimately on the medical application for the particular clinical indication.

One or more of the following numbered paragraphs may further describe the invention.

1. A conjugate-based antifungal or antibacterial prodrug of the formula:

(i)(AFA)_m-X-(L)_nwherein: AFA is an antifungal or antibacterial agent; l is a carrier; x is a linker; m ranges from 1 to 10; and n ranges from 2 to 10;

(ii)[(AFA)_m’-X]_p-L, wherein: AFA is an antifungal or antibacterial agent; l is a carrier; x is a linker; m' is 1 to 10; and p is 1 to 10;

(iii)AFA-[X-(L)_n’]_qwherein: AFA is an antifungal or antibacterial agent; l is a carrier; x is a linker; n' is 1 to 10; and q is 1 to 10, with the proviso that q' and n are not both 1; or

(iv)(AFA)_m”-X, wherein: AFA is an antifungal or antibacterial agent; x is a linker; and m' is 1 to 10.

2. The conjugate-based prodrug of paragraph 1, wherein m' and p are 1.

3. The conjugate-based prodrug of paragraph 1, wherein q is 1 and n' is 2.

4. The conjugate-based prodrug of paragraph 1, wherein m "is 2.

5. The conjugate-based prodrug of paragraph 1, wherein the conjugate-based prodrug is a nanoparticle.

6. The conjugate-based prodrug of paragraph 5, wherein the nanoparticle is 1nm to 1000nm in size.

7. The conjugate-based prodrug of any of paragraphs 1-6, wherein the prodrug is formulated into a nanoparticle selected from the group consisting of: liposomes, polymeric nanoparticles, nanoemulsions, self-microemulsifying drug delivery systems (SMEDDS), solid-lipid nanoparticles, nanostructured liquid crystals, and any combination thereof.

8. The conjugate-based prodrug of paragraph 7, wherein the nanoparticle is 20nm to 500nm in size.

9. The conjugate-based prodrug of any of paragraphs 1-8, wherein the linker is attached to the ring-nitrogen of the azole moiety of the antifungal agent or the antibacterial agent, or the linker is attached to the hydroxyl group of the antifungal agent or the antibacterial agent.

10. The conjugate-based prodrug of any of paragraphs 1-9, wherein the linker is a cleavable linker.

11. The conjugate-based prodrug of any of paragraphs 1-10, wherein the linker is cleaved by an esterase.

12. The conjugate-based prodrug of paragraph 11, wherein the esterase is a lipase.

13. The conjugate-based prodrug of any of paragraphs 1-12, wherein the linker is cleaved by a lipase from the fungus malassezia.

14. The conjugate-based prodrug of paragraph 13, wherein the fungus belongs to the genus malassezia.

15. The conjugate-based prodrug of any of paragraphs 1-14, wherein the linker is selected from the group consisting of:

(i)-CH(R¹) -, wherein R¹H or C₁-C₆An alkyl group which may be optionally substituted and/or interspersed with one or more of heteroatoms, aryl groups, heteroaryl groups, cyclic groups and heterocyclic groups;

(ii)OrWherein R is^2aIs a hydroxy protecting group; r^2bIs C₁-C₆Alkyl, which may be optionally substituted or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl groups; and R is^NIs absent, H, C₁-C₆Alkyl or acyl, each of which may be optionally substituted;

(iii) formula-CH₂CH₂[OCH₂CH₂]_aOHC₂CH₂The polyethylene glycol of (a), wherein a is 1 to 50;

(iv)-CH₂C(R^3aR^3b)CH(OR^3c)C(O)N(R^3d)-(CH₂)_b-, wherein R^3aAnd R^3bIndependently is H or C₁-C₆Alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl groups; r^3cIs H or a carrier; r^3dIs H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted; and b is 1 to 10;

(v)wherein R is⁴Is halo, CN, CF3, alkyl, alkenyl, cyclyl, heterocyclyl, aryl, heteroaryl, NO₂、OR⁶、OC(O)R^4a、OC(O)OR^4a、N(R^4a)₂、NHC(O)R^4a、NHC(O)OR^4a、C(O)R^4a、C(O)OR^4a、SR^4aOr SO₂R^4aEach of which may be optionally substituted; r^4aIndependently at each occurrence is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted; and c is 0 to 4;

(vi)-CH₂CH(R⁶) -, where R is H or C₁-C₆Alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl groups;

(vii)-CH(R⁷) C (O) -, wherein R⁷Is H, C₁-C₆Alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl;

(viii)-CH(R⁸) OC (O) -L' -C (O) O-, wherein R⁸Is H or C₁-C₆An alkyl group; and L' is alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, or heterocyclyl groups, each of which may also be optionally substituted;

(ix)-CH(R⁹)OC(O)-、-CH(R⁹)OC(O)-L’-、-CH(R⁹) OC (O) -L' -Y-or-CH (R)⁹) OC (O) -L' -Y-C (O) -, wherein R⁹Is H or C₁-C₆Y is O, S or NH; and L' is alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, or heterocyclyl groups, each of which may be optionally substituted;

(x)-CH(R^10a)OC(O)-L’-C(O)OCH(R^10b) -, wherein R^10aAnd R^10bIndependently is H or C₁-C₆Alkyl, which may be optionally substituted; and L' is C₁-C₂₀Alkyl, which may optionally be substituted by one or more heteroatoms, aryl, heteroaryl, cyclyl or heterocyclyl groupsSubstitution and/or dispersion, each of which may be optionally substituted;

(xi) -C (O) -L ' -C (O) -, -C (O) -L ' -Y-or-C (O) -L ' -Y-C (O) -, wherein Y is O, S or NH; and L' is alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, or heterocyclyl groups, each of which may be optionally substituted;

(xii)-C(O)-L’-C(O)O-[CH₂CH₂O]_v’-, wherein v 'is 1 to 500 and L' is alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl or heterocyclyl, each of which may be optionally substituted;

(xiii)PLGA；

(xiv) A direct bond;

(xv) A dicarboxylic acid;

(xvi) A beta-hydroxy acid;

(xvii) A polycarboxylic acid; and

(xviii) Any combination thereof.

16. The conjugate-based prodrug of any of paragraphs 1-15, wherein the antifungal agent comprises an azole moiety or a hydroxyl group.

17. The conjugate-based prodrug of any of paragraphs 1-16, wherein the antifungal agent is selected from the group consisting of: fluconazole, isaconazole, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole, ravuconazole, natamycin, rusomycin, nystatin, amphotericin B, echinocandin, colsais, pradimicin, benamicin, wakamycin, coprinus, allylamine, triclosan, piroctone, fenpropimorph, terbinafine, antifungal peptides and derivatives and analogs thereof.

18. The conjugate-based prodrug of any of paragraphs 1-17, wherein the antibacterial agent is effective against propionibacterium acnes.

19. The conjugate-based prodrug of any of paragraphs 1-15 or 18, wherein the antibacterial agent is selected from the group consisting of: macrolides or ketolides such as erythromycin, azithromycin, clarithromycin, and telithromycin; beta-lactams including penicillins, cephalosporins, and carbapenems such as carbapenems, imipenem and meropenem; monobactams such as penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin, cephalothin, cefapirin, cephradine, ceftazidime, ceftizoxime, cefamandole, cefuroxime, cephalexin, cephacrylene, cefaclor, chloroceph, cefoxitin, cefmetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, cefepime and aztreonam; quinolones such as nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin, gatifloxacin, gemifloxacin and pazufloxacin; antibacterial sulfonamides and antibacterial sulfanilamides including p-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole and phthalylsulfathiazole; aminoglycosides such as streptomycin, neomycin, kanamycin, paromomycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekacin, and isepamicin; tetracyclines such as tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline; rifamycins such as rifamycin (also known as rifampin), rifapentine, rifabutin, benzoxazinorifamycin, and rifaximin; lincosamines such as lincomycin and clindamycin; glycopeptides such as vancomycin and teicoplanin; streptogramines such as quinupristin and dalfopristin; oxazolidinones such as linezolid; polymyxins, colistins and colistins; and trimethoprim and bacitracin.

20. The conjugate-based prodrug of any of paragraphs 1-19, wherein the carrier comprises a carboxyl group or a hydroxyl group.

21. The conjugate-based prodrug of any of paragraphs 1-20, wherein the carrier is a polymer; carboxylated polymers, hydroxylated polymers, polyethylene glycols; carboxylated PEG comprising C₆-C₂₆An alkyl fatty acid, which may be optionally substituted and/or interspersed with heteroatoms, aryl, heteroaryl, cyclyl, or heterocyclyl; an amino acid; a peptide; a nucleic acid; glycerol, substituted glycerols, antibacterial agents, antifungal agents; alpha-hydroxy acids, beta-hydroxy acids, dicarboxylic acids, oxo diacids, and any combination thereof.

22. The conjugate-based prodrug of any of paragraphs 1-21, wherein the carrier is a fatty acid selected from the group consisting of: octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid, pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, myristoleic acid, palmitoleic acid, hexadecen-6-oic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, elaidic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, cis-11-octadecenoic acid, cis-11-eicosenoic acid, undecenic acid, cis-13-docosenoic acid, neoheptanoic acid, neononanoic acid, neodecanoic acid, isostearic acid, 10-undecenic acid, adapalene,

23. The conjugate-based prodrug of any of paragraphs 1-21, wherein the carrier is a polymer selected from the group consisting of: PLGA, PLA, PEG, chitosan, pullulan, polylactide, polyglycolide, polycaprolactone, copolymers of polylactic and polyglycolic acid, polyanhydrides, polyepsilon caprolactone, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polydihydropyrans, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly (malic acid), poly (amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polymethylmethacrylate, chitin, chitosan, copolymers of polylactic and polyglycolic acid, poly (glycerol sebacate) (PGS) and copolymers, terpolymers, gelatin, collagen, silk, chitosan, alginates, cellulose, polynucleic acids, cellulose acetate (including cellulose diacetate), Polyethylene, polypropylene, polybutylene, polyethylene terephthalate (PET), polyvinyl chloride, polystyrene, polyamide, nylon, polycarbonate, polysulfide, polysulfone, hydrogel (e.g., acrylic acid), polyacrylonitrile, polyvinyl acetate, cellulose acetate butyrate, cellulose nitrate, copolymers of urethane/carbonate, copolymers of styrene/maleic acid, poly (ethyleneimine), Pluronic (poloxamers 407, 188), hyaluronidase, heparin, agarose, pullulan, ethylene/vinyl alcohol copolymers (EVOH), and copolymers comprising one or more of the foregoing.

24. The conjugate-based prodrug of any of paragraphs 1-21, wherein the carrier is selected from the group consisting of: undecylenic acid; palmitic acid; oleic acid, linoleic acid, lauric acid, lys-his-lys-his-lys-his hexapeptide; l-or D-tyrosine; l-or D-serine; l-or D-threonine; a peptide of 2-10 amino acids; chitosan and pullulan.

25. The conjugate-based prodrug of any one of paragraphs 1-24, wherein the conjugate is ketoconazole methyl palmitate, ketoconazole 1-ethyl palmitate, ketoconazole methyl laurate-1-ethyl laurate, ketoconazole methyl undecylenate-1-ethyl oleate, ketoconazole methyl oleate-1-ethyl oleate, ketoconazole methyl linoleate, ketoconazole 1-ethyl linoleate, ketoconazole-methylene-PLGA, ketoconazole-pyridoxine-undecenoic acid, ketoconazole-panthenol dimer, ketoconazole-propylene glycol-hexapeptide, ketoconazole-lactic acid-chitosan, ketoconazole-methylene-oxoacid (oxaacid) -chitosan, ketoconazole-methylene-oxodiacid dimer, ketoconazole-oxodiacid dimer, Ketoconazole-methylene-glutamic acid dimer, clindamycin-lauric acid conjugate, clindamycin-glycolic acid-PLGA conjugate, clindamycin-succinic acid-PLGA conjugate, clindamycin-adapalene conjugate, erythromycin-lauric acid conjugate, erythromycin-lactic acid-lauric acid conjugate, lauric acid-PLGA-erythromycin conjugate, adapalene-triethylglycosyl-erythromycin conjugate, clindamycin dimer with azelaic acid, clindamycin dimer with carboxylated PEG, clindamycin dimer with glutamic acid, clindamycin dimer with oxydiethylacetic acid, clindamycin triclosan conjugate, clindamycin-glutamic acid-triclosan conjugate, or clindamycin-oxydiethylacetic acid-triclosan conjugate.

26. A nanoparticle, comprising: (i) a first component selected from an antifungal agent, an antibacterial agent, or a combination thereof; and (ii) a second component selected from a lipid, a polymer, or a combination thereof.

27. The nanoparticle of paragraph 26, wherein the first component is about 0.01 wt% to about 99 wt% based on the total weight of the nanoparticle.

28. The nanoparticle of paragraphs 26 or 27, wherein the lipid is about 0.01 wt% to about 99 wt% based on the total weight of the nanoparticle.

29. The conjugate of any of paragraphs 26-28, wherein the first component and the second component are not covalently linked to each other.

30. The nanoparticle of any of paragraphs 26-29, wherein the nanoparticle is selected from the group consisting of: liposomes, polymeric nanoparticles, nanoemulsions, self-microemulsifying drug delivery systems (SMEDDS), solid-lipid nanoparticles (SLN), nanostructured liquid crystals, albumin-based nanoparticles, dendrimers, carbon nanotubes, Nanostructured Lipid Carriers (NLCs), polymersomes, nanocrystals, nanoemulsions, and the like.

31. The nanoparticle of any of paragraphs 26-30, wherein the nanoparticle is from about 1nm to about 1000nm in size.

32. The nanoparticle of any of paragraphs 26-31, wherein the nanoparticle is from about 20nm to about 500nm in size.

33. The nanoparticle of any of paragraphs 26-32, wherein the nanoparticle further comprises a surfactant.

34. The method of paragraph 33, wherein the surfactant is about 0.01 wt% to about 30 wt% based on the total weight of the nanoparticle.

35. The nanoparticle of any of paragraphs 26-34, wherein the nanoparticle further comprises a carrier or excipient.

36. The nanoparticle of paragraph 35, wherein the excipient is about 0.01 wt% to about 30 wt% based on the total weight of the nanoparticle.

37. The nanoparticle of any one of paragraphs 26-36, wherein the lipid is selected from the group consisting of: fatty acids, fatty alcohols, glycerolipids (e.g., monoglycerides, diglycerides, and triglycerides), phospholipids, glycerophospholipids, sphingolipids, sterol lipids, pentadienol lipids, glycolipids, polyketides, and any combination thereof.

38. The nanoparticle of any one of paragraphs 26-37, wherein the lipid is selected from the group consisting of: tripalmitin (Tripalm), ceteth-10, egg lecithin, soya lecithin, glycerol monocaprylate (Capmul MCM C8EP), Capmul MCM C10, glycerol tricaprylate/decanoate (Tri) 355EP/NF), glyceryl distearate (type I) EP (Precirol ATO5), lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid, pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, nonacosanoic acid, melissic acid, hentriacontanoic acid, laccerotic acid, thirty-three-membered carboxylic acidAlkanoic acid, grignard acid, hexadecanoic acid, alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, oleic acid, elaidic acid, eicosenoic acid, erucic acid, nervonic acid, Mead, myristoleic acid, palmitoleic acid, hexadecen-6-oic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, elaidic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexanoic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid, pentacosanoic acid, eicosanoic acid, docosan, Cerotic acid, heptacosanoic acid, montanic acid, myristoleic acid, palmitoleic acid, hexadecen-6-oic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, elaidic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, cis-11-octadecenoic acid, cis-11-eicosenoic acid, undecylenic acid, cis-13-docosenoic acid, neoheptanoic acid, neononanoic acid, neodecanoic acid, isostearic acid, 10-undecenoic acid, phosphatidic acid (phosphatidate, PA), phosphatidylethanolamine (cephalin, PE), phosphatidylcholine (lecithin, PC), Phosphatidylserine (PS), Phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), phosphatidylinositol diphosphate (PIP2), Phosphatidylinositol triphosphate (PIP3), ceramide phosphorylcholine (sphingomyelin, SPH), ceramide phosphorylethanolamine (sphingomyelin, Cer-PE), ceramide phosphorylglycerol, cholestane, cholane, pregnane, androstane, estrane, cholesterol, octanol, 2-ethylhexanol, nonanol, decanol, undecanol, lauryl alcohol, tridecanol, myristyl alcohol, pentadecanol, cetyl alcohol, palmitoleic alcohol, heptadecanol, stearyl alcohol, isostearyl alcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol, ricinoleyl alcohol, nonadecanol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, ceryl alcohol, 1-heptacosyl alcohol, montanyl alcohol, octacosyl alcohol, 1-nonacosyl alcohol, melissyl alcohol, 1-myricyl alcohol, 1-phosphoryl alcohol -triacontanol, tetratriacontanol, cetostearyl alcohol, propylene glycol dicaprate, 1, 3-propylene glycol dicaprylate, caprylic/capric acid ester of saturated C12-C18 fatty alcohol, propylene glycol dicaprate, 1, 3-propylene glycol dicaprylate/dicaprate, glyceryl tricaprylate/tricaprate, caprylic/capric triglyceride, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/tricaprate, caprylic/capric triglyceride, glyceryl tricaprylate/caprate, glyceryl triacetate, glyceryl tricaprylate, triolein, and any combination thereof.

39. The conjugate of any one of paragraphs 26-38, wherein the antifungal agent is selected from the group consisting of: zinc pyrithione, piroctone olamine, abafungin, abaconazole, allicin, amorolfine, anidulafungin, benzoic acid keratolytic agent, butenafine, butoconazole, caspofungin, ciclopirox (ciclopirox olamine), citronella Oil, clotrimazole, coconut Oil, crystal violet, econazole, fenticonazole, fluconazole, flucytosine or 5-fluorocytosine, griseofulvin, haloprogin, iodine, isavuconazole, isoconazole, itraconazole, ketoconazole, lemon myrtle, micafungin, miconazole, naftifine, neem seed Oil, olive leaf extract, omoconazole, orange Oil, oxiconazole, palmarole Oil, patchouli, polygonum hydropiper, posaconazole, ravuconazole, selenium, sertaconazole, sulconazole, tea tree Oil-ISO 4730 ("Oil of melaleuuca, Terpinen-4-type oils (oils of melanizole, terpinen-4-ol) "), terbinafine, terconazole, tioconazole, tolnaftate, undecylenic acid, voriconazole, zinc selenium disulfide, fluconazole, isaconazole, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole, ravuconazole, natamycin, rusomycin, nystatin, amphotericin B, echinocandin, colsaise, pradimicin, benamicin, warfarin, coprocetin, allylamine, triclosan, piroctone, fenpropimorph, terbinafine, antifungal peptides and their derivatives and analogs.

40. The conjugate of any of paragraphs 26-39, wherein the antibacterial agent is selected from the group consisting of: macrolides or ketolides such as erythromycin, azithromycin, clarithromycin, and telithromycin; beta-lactams including penicillins, cephalosporins, and carbapenems such as carbapenems, imipenem, and meropenem; monobactams such as penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin, cephalothin, cefapirin, cephradine, ceftazidime, ceftizoxime, cefamandole, cefuroxime, cephalexin, cephacrylene, cefaclor, chloroceph, cefoxitin, cefmetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, cefepime and aztreonam; quinolones such as nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin, gatifloxacin, gemifloxacin and pazufloxacin; antibacterial sulfonamides and antibacterial sulfanilamides including p-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole and phthalylsulfathiazole; aminoglycosides such as streptomycin, neomycin, kanamycin, paromomycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekacin, and isepamicin; tetracyclines such as tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline; rifamycins such as rifamycin (also known as rifampin), rifapentine, rifabutin, benzoxazinorifamycin, and rifaximin; lincosamines such as lincomycin and clindamycin; glycopeptides such as vancomycin and teicoplanin; streptogramines such as quinupristin and dalfopristin; oxazolidinones such as linezolid; polymyxins, colistins and colistins; and trimethoprim and bacitracin.

41. A personal care composition comprising an effective amount of the conjugate-based prodrug of any of paragraphs 1-25 or the nanoparticle of any of paragraphs 26-40.

42. The personal care composition of paragraph 41, wherein the composition further comprises a drug or a surface agent.

43. The personal care composition of paragraph 42, wherein said drug or said surface agent is selected from the group consisting of: those that ameliorate or eradicate age spots, keratoses, and wrinkles; local analgesics and anesthetics; an anti-acne agent; an antibacterial agent; an anti-yeast agent; an antifungal agent; an antiviral agent; anti-dandruff agents; an anti-dermatitis agent; an antihistamine; an antipruritic agent; an antiemetic agent; anti-motion sickness agents; an anti-inflammatory agent; an anti-excessive keratolytic agent; an antiperspirant; anti-psoriasis agents; anti-seborrhea agents; hair conditioners and hair treatment agents; anti-aging and anti-wrinkle agents; sunscreens and sunblocks; a skin lightening agent; a decolorizing agent; a vitamin; a corticosteroid; a tanning agent; a humectant; a hormone; retinoic acid compounds; gum disease or oral care agents; a topical cardiovascular agent; particulate, induration and wart removal agents; a depilatory agent; and any combination thereof.

44. The personal care composition of paragraphs 42 or 43, wherein the drug or the surface agent is selected from the group consisting of: azelaic acid, triclosan, alpha-hydroxy acids, glycolic acid, mandelic acid, beta-hydroxy acids, salicylic acid, polyhydroxy acids, lactobionic acid, galactose, gluconic acid, adapalene, abacavir, acebutolol, acetaminophen, acetaminosalol, acetazolamide, acetohydroxamic acid, acetylsalicylic acid, Avermentane, Alvastigmine, fentanyl, acyclovir, adapalene, Adefovir Dipivoxil, adenosine, albuterol, Alfuzosin, allopurinol, allopurin, Almotriptan, alprazan, alprenol, aluminum acetate, aluminum chloride, aluminum chlorohydrate, aluminum hydroxide, amantadine, amiloride, amsacrine, aminobenzoic acid (PABA), aminocaproic acid, aminosalicylic acid, amiodarone, amitriptyline, amlodipine, Amocamazine, Amoxicoquinol, Amorphophalli, Amoxicolone, Amoxamine, Amoxicapine, Amoxamine, Amoxicodendron, Amoxicolone, Amoxicodendron, Amoxicillin, Amoxicodendron, Ampicillin, anagrelide, anastrozole, dithranol, apomorphine, aprepitant, arbutin, aripiprazole, ascorbic acid, ascorbyl palmitate, atazanavir, atenolol, atomoxetine, atropine, azathioprine, azelaic acid, azelastine, azithromycin, bacitracin, beclomethasone, benazepril, benflumethiazide, benzocaine, benzonatate, benzophenone, benztropine, bepril, betamethasone dipropionate, betamethasone valerate, brimonidine, brompheniramine, bupivacaine, buprenorphine, bupropion, brevitone, brivaracetam, butenafine, butoconazole, cabergoline, caffeic acid, caffeine, calcipotriene, camphor, candesartan cilexetine, capsaicin, cefditoren pivoxil, cefepime, celecoxib, cetirizine, and cetirizine, Sevelamer, chitosan, chlordiazepoxide, chlorhexidine, chloroquine, chlorothiazide, chloroxylenol, chlorpheniramine, chlorpromazine, chlorpropamide, ciclopirox, cilostazol, cimetidine, cinacalcet, ciprofloxacin, citalopram, citric acid, cladribine, clarithromycin, clemastine, clindamycin, clioquinol, clobetasol propionate, clomiphene, clonidine, clopidogrel, clotrimazole, clozapine, cocaine, codeine, cromoglycine, cromipron, cyclizine, cyclobenzaprine, cycloserine, cytarabine, dacarbazine, dalfopristin, dapsone, daptomycin, daunorubicin, deferoxamine, dehydroepiandrosterone, delavirdine, desipramine, desloratadine, desmopressin, dexamethasone, dextomimedine, dexamethimine, dexamphetamine, citalopram, chlorpheniramine, citrate, chlorpheniramine, chlorpyrim, clomipramine, clohydramine, clo, Bicyclic virine, didanosine, dihydrocodeine, dihydromorphine, diltiazem, 6, 8-dimercaptooctanoic acid (dihydrolipoic acid), diphenhydramine, diphenoxylate, dipyridamole, propiram, dobutamine, dofetilide, dolasetron, donepezil, dopa ester, dopamine, dorzolamide, doxylamine, doxepin, doxorubicin, doxycycline, doxylamine, doxepipine, duloxetine, dyclonine, econazole, eflornithine, eletriptan, emtricitabine, enalapril, ephedrine, epinephrine, ephedrine, epirubicin, eptidine, ergotamine, erythromycin, escitalopram, esmolol, esomeprazole, estazolam, estradiol, etaneric acid, ethinylestradiol, etilenetinine, etidocaine, etomidine, famtidine, famatidine, felodipine, fentanil, fertilde, Fexofenadine, flecainide, fluconazole, flucytosine, fluocinonide, 5-fluorouracil, fluoxetine, fluphenazine, flurazepam, fluvoxamine, formoterol, furosemide, galactarolide, galactaric acid, galactonolactone, galantamine, gatifloxacin, gefitinib, gemcitabine, gemifloxacin, glycolic acid, griseofulvin, guaifenesin, guanethidine, histamine N-amidinate, haloperidol, haloprogin, homatropine, homosalazine, hydralazine, hydrochlorothiazide, hydrocortisone 21-acetate, hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydromorphone, hydroquinone, monoether, hydroxyzine, hyoscyamine, hypoxanthine, ibuprofen, ichthammol, idarubicin, flutriafolacin, fluvone, flu, Imatinib, imipramine, imiquimod, indinavir, indomethacin, irbesartan, irinotecan, isotalin, isoproterenol, itraconazole, kanamycin, ketamine, ketanserin, ketoconazole, ketoprofen, ketotifen, kojic acid, labetalol, lactic acid, lactobionic acid, lamivudine, lamotrigine, lansoprazole, letrozole, leuprolide, levalbuterol, levofloxacin, lidocaine, linezolid, lobeline, loperamide, losartan, loxapine, ergot diethylamide, sulfamylon, malic acid, maltobionic acid, mandelic acid, maprotiline, mebendazole, mecamylamine, meclizine, meclocycline, memantin, menthol, pethidine, mepivacaine, mercaptopurine, mescalin, methofurazol, oxcinalnaline, metaproterenol, metformin, methadone, methamphetamine, ketoprofen, methotrexate, methoxamine, methyldopate, methyldopamide, 3, 4-methylenedioxymethamphetamine, methyl lactate, methyl nicotinate, methylphenidate, methyl salicylate, methylthiomidate, metolazone, metoprolol, metronidazole, mexiletine, miconazole, midazolam, midodrine, meglumine, minocycline, dil, mirtazapine, mitoxantrone, moexiprilat, molindone, momobenzone, morphine, moxifloxacin, moxonidine, mupirocin, nadolol, naftifine, nalmefene, naloxone, naproxen, nefazodone, nelfinavir, neomycin, nevirapine, nicardipine, nicotine, nifedipine, nimodipine, nisodipine, nizatidine, noradrenaline, nystatin, octopamine, octreotide, methoxycinnamate, octyl salicylate, Ofloxacin, olanzapine, olmesartan medoxomil, olopatadine, omeprazole, ondansetron, oxiconazole, oxotremorine, oxybenzone, oxybutynin, oxycodone, oxymetazoline, padetamol O, palonosetron, pantothenic acid, panthenolide, paroxetine, pimoline, penciclovir, penicillamine, penicillin, pentazocine, pentobarbital, pentostatin, pentoxifylline, pergolide, perindopril, pameprazole, phencyclidine, phenelzine, pheniramine, phenmetrazine, phenobarbital, phenol, phenoxybenzamine, phendroxyepine, phenylpropanolamine, phenytoin, physostigmine, pilocarpine, papriine, mupiroxol, pipamazine, piperonyl butoxide, piperacillin, podophyllotoxin, pramoxine, pramipexole, zolosin, zolozolol, domonazine, panthenol, penoxpocetine, penciclovir, pen, Prednisone, pravastatin, prilocaine, procainamide, procaine, procarbazine, promazine, promethazine propionate, propafenone, dextropropoxyphene, propranolol, propylthiouracil, protiline, pseudoephedrine, pyrethrin, mepyramine, pyrimethamine, quetiapine, quinapril, quinethazone, quinidine, quinupristin, rabeprazole, reserpine, resorcinol, retinal, 13-cis-retinoic acid, retinol, retinyl acetate, retinyl palmitate, ribavirin, ribonic acid, ribonolactone, rifampin, rifapentine, rifaxine, rifaximin, riluzole, rimantadine, risedronic acid, risperidone, ritodrine, rivastigmine, rizatriptan, ropinirole, salicylamide, salicylic acid, salmeterol, hyoscyamine, letine, selenium, 5-hydroxytryptamine, sertindole, sertraline, sibutramine, sildenafil, sotalol, streptomycin, strychnine, sulconazole, sulfanilamide, sulfabenzoyl, sulfabromouracil, sulfacetamide, sulfachlorpyridazine, sulfaxetine, sulfadiazine, sulfadimethoxine, sulfadoxine, sulfaguanidine, sulfalene, sulfamethizole, sulfaxazole, sulfapyrazine, sulfapyridine, sulfasalazine, sulfisothiazole, sulfathiazole, sulfisoxazole, tadalafil, tamsulosin, tartaric acid, tazarotene, tegaserod, telithromycin, telmisartan, temozolomide, tenofovir, terazosin, terbinafine, terbutaline, terconazole, terfenadine, tetracaine, tetracycline, tetrahydrozoline, alkali, theophylline, thiazoxazole, thioridazine, tebuconazole, thymol, thiohydralazine, thymol, tiagabine, theobromine, thiohydramine, thiohydralazine, thio, Timolol, tinidazole, tioconazole, tirofiban, tizanidine, tobramycin, tocainide, tolazoline, tolbutamide, tolnaftate, tolterodine, tramadol, tranylcypromine, trazodone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone acetonide, triamterene, triazolam, triclosan, trifluoroperazine, trimethoprim, trimipramine, tripelennamine, triprolidine, tromethamine, tropine, tyramine, undecylenic acid, urea, urocanic acid, ursodeoxycholic acid, valdinafine, venlafaxine, verapamil, vitamin E acetate, voriconazole, warfarin, xanthine, zafirlukast, zaleplon, zinc pyrithione, ziprasidone, zolmitriptan, zolpidem, and any combination thereof.

45. The personal care composition of any of paragraphs 41-44, wherein the composition further comprises at least one cosmetic raw material or adjuvant selected from the group consisting of: antioxidants, preservatives, fillers, surfactants, UVA and/or UVB sunscreens, perfumes, thickeners, humectants, anionic polymers, nonionic polymers, amphoteric polymers, viscosity/foam stabilizers, opacifiers/pearlescers, masking agents, stabilizers, hair conditioners, humectants, antistatic agents, anti-freeze agents, buffers, dyes, pigments, hydrocarbons, esters, fatty alcohols, fatty acids, emulsifiers, viscosity modifiers, silicone-based materials, surfactants, emollients, humectants, stabilizers, film-forming materials, perfumes, colorants, chelating agents, preservatives, antioxidants, pH adjusters, water repellents, dry feel modifiers, vitamins, plant extracts, hydroxy acids, organic sunscreens, inorganic sunscreens, peptide-based inorganic sunscreens, and tanning agents.

46. The personal care composition of any of paragraphs 41-45, wherein the personal care composition is a hair care composition selected from the group consisting of: shampoos, conditioners, hair dyes, lotions, aerosols, gels, mousses and tints.

47. A method for treating or preventing dandruff comprising the steps of: administering the composition of any of paragraphs 41-46 to the scalp of a subject in need thereof.

48. The personal care composition of any of paragraphs 41-45, wherein the personal care composition is a skin care composition selected from the group consisting of: lotions, creams, gels, sticks, sprays, ointments, cleansing liquid lotions, cleansing solid bars, pastes, foams, powders, shaving creams and swabs.

49. A method for treating or preventing acne in a subject, said method comprising the steps of: administering the composition of any of paragraphs 41-46 or 48 to the skin of a subject in need thereof.

50. A method of treating or preventing a fungal or bacterial infection in a subject, the method comprising: administering the composition of any of paragraphs 1-25 or 26-40.

51. The method of paragraph 50, wherein said administering is topical or systemic.

52. The method of paragraph 50 or 51, wherein the fungal or bacterial infection is selected from the group consisting of: oral/vaginal candidiasis, intestinal endless (e.g., tinea infections of the body, scalp, beard, eczema marginalis, tinea pedis), nail infections, ear infections, and any combination thereof.

53. The method of any of paragraphs 50-52, wherein the subject is a mammal.

54. The method of any one of paragraphs 50-53, wherein the subject is a human.

55. The method of any one of paragraphs 50-53, wherein the subject is a non-human mammal.

56. The use of the composition of any of paragraphs 1-25 or 26-40 for treating or preventing a fungal or bacterial infection in a subject.

57. The use of paragraph 56, wherein the composition is applied topically or administered systemically.

58. The use of paragraphs 56 or 57 wherein the fungal or bacterial infection is selected from the group consisting of: oral/vaginal candidiasis, intestinal endless (e.g., tinea infections of the body, scalp, beard, eczema marginalis, tinea pedis), nail infections, ear infections, and any combination thereof.

59. The use of any one of paragraphs 56-58, wherein the subject is a mammal.

60. The use of any one of paragraphs 56-59, wherein the subject is a human.

61. The use of any one of paragraphs 56-59, wherein the subject is a non-human mammal.

Definition of

For convenience, several terms used herein, in the specification, examples, and appended claims are collected here. Unless otherwise indicated or implied by context, the following terms and phrases include the meanings provided below. The following terms and phrases do not exclude the meaning of such terms and phrases as they may have in the art, unless expressly stated otherwise or apparent from the context. The definitions are provided to aid in the description of particular embodiments and are not intended to limit the claimed invention, as the scope of the invention is defined only by the claims. Also, unless the context dictates otherwise, terms in the singular shall include the plural and terms in the plural shall include the singular.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any known methods, devices, and materials can be used in the practice or testing of the present invention, the methods, devices, and materials in this regard are described herein.

The term "comprising" or "including" as used herein is intended to denote the essential compositions, methods, and individual components thereof, of the present invention, and whether or not it is necessary, yet open to unspecified elements.

The term "consisting essentially of … …" as used herein means those elements required for a given embodiment. The terms allow for the presence of additional elements that do not materially affect the basic and novel or functional characteristics of the embodiments of the invention.

The term "consisting of … …" means the compositions, methods, and respective components thereof described herein, excluding any elements not listed in the description of the embodiments.

Other than in the working examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein are to be understood as being modified in all instances by the term "about". The term "about" used in connection with a percentage may mean ± 1%.

The singular terms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The term "comprising" means "including". The abbreviation "e.g" (for example) "is derived from latin exempli gratia (for example) and is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g" (for example) "is synonymous with the term" for example ".

The terms "reduce", "reduced/reduction", "reduce" or "inhibit" are used herein to generally mean reducing a statistically significant amount. However, for the avoidance of doubt, "reduced/reduction" or "reduced" or "inhibition" means a reduction by at least 10% relative to a reference level, such as at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including 100% (e.g. relative to the deficiency level of the reference sample), or any reduction between 10-100% relative to the reference level.

The terms "increased" or "enhancement" or "activation" are used herein generically to mean an increase in a statistically significant amount; for the avoidance of any doubt, the terms "increased" or "enhancement" or "activation" mean an increase of at least 10% relative to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including 100%, or any increase between 10-100% relative to a reference level; or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold or at least about 10-fold increase, or any increase between 2-fold and 10-fold or greater, relative to a reference level.

The term "statistically significant" or "significantly" means statistically significant, and typically means 2 standard deviations (2SD) below or above normal marker concentrations. The term denotes statistical evidence of the presence of a difference. It is defined as the possibility of making a decision to reject a null hypothesis when it is actually true. The decision is usually made using a p-value.

"treating," "preventing," or "ameliorating" means delaying or preventing the onset of, reversing, alleviating, ameliorating, inhibiting, slowing or stopping the progression, exacerbation or regression, progression or severity of a condition associated with such disease or disorder. In one embodiment, at least one symptom of the disease or disorder is reduced by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%.

The terms "effective" and "effectiveness" as used herein include pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the treatment to produce a desired biological effect in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects at the cellular, organ, and/or organism level (often referred to as side effects) resulting from administration of the treatment. By "less effective" is meant that the treatment results in a therapeutically significantly lower level of pharmacological effectiveness and/or a therapeutically greater level of adverse physiological effects.

For the sake of brevity, the chemical moieties defined and referenced throughout may be monovalent chemical moieties (e.g., alkyl, aryl, etc.) or multivalent moieties with appropriate structures as would be apparent to one of skill in the art. For example, an "alkyl" moiety may represent a monovalent residue (e.g., CH) ₃-CH₂-) or in other cases, the divalent linking moiety can be an "alkyl" group, in which case one of skill in the art would understand that the alkyl group is a divalent residue (e.g., -CH₂-CH₂-) which is equivalent to the term "alkylene". Similarly, where a divalent moiety is desired and described as "alkoxy," "alkylamino," "aryloxy," "alkylthio," "aryl," "heteroaryl," "heterocyclic," "alkyl," "alkenyl," "alkynyl," "aliphatic," or "cycloalkyl," those skilled in the art will understand that the terms "alkoxy," "alkylamino," "aryloxy," "alkylthio," "aryl," "heteroaryl," "heterocyclic," "alkyl," "alkenyl," or "cycloalkyl" are used herein to describe"," alkynyl "," aliphatic "or" cycloalkyl "denotes the corresponding divalent moiety.

The term "halogen" denotes any residue of fluorine, chlorine, bromine or iodine.

The term "acyl" denotes an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl or heteroarylcarbonyl substituent, any of which may be further substituted by a substituent. Exemplary acyl groups include, but are not limited to: (C)₁-C₆) Alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, t-butylacetyl, etc.), (C) ₃-C₆) Cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolidin-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofurylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl (e.g., thienyl-2-carbonyl, thienyl-3-carbonyl, furyl-2-carbonyl, furyl-3-carbonyl, 1H-pyrroloformyl-2-carbonyl, 1H-pyrroloformyl-3-carbonyl, benzo [ b]Thienyl-2-carbonyl, and the like). In addition, the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portions of the acyl groups may be any of the groups described in the respective definitions.

The term "alkyl" denotes a saturated or unsaturated nonaromatic hydrocarbon chain which may be straight or branched and which contains the indicated number of carbon atoms (these include, but are not limited to, propyl, allyl or propargyl) which may optionally be interrupted by N, O or S. E.g. C₁-C₆As indicated, the group may have 1 to 6 (inclusive) carbon atoms therein.

The term "alkenyl" denotes an alkyl group comprising at least one double bond. Exemplary alkenyl groups include, but are not limited to: for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.

The term "alkynyl" denotes an alkyl group comprising at least one triple bond.

The term "alkoxy" denotes an-O-alkyl residue.

The term "aminoalkyl" denotes an alkyl group substituted with an amino group.

The term "sulfhydryl" denotes a-SH residue.

The term "thioalkoxy" denotes a-S-alkyl residue.

The term "aryl" denotes a monocyclic, bicyclic or tricyclic aromatic ring system, wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted by a substituent. Exemplary aryl groups include, but are not limited to: phenyl, naphthyl, anthracenyl, cyclopentcycloheptapentaenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.

The term "arylalkyl" denotes an alkyl group substituted with an aryl group.

The term "cyclyl" or "cycloalkyl" denotes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, e.g., 3 to 8 carbons, and, e.g., 3 to 6 carbons, wherein the cycloalkyl group may additionally be optionally substituted. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and the like.

The term "heteroaryl" denotes an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic) selected from O, N or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O or S (if monocyclic, bicyclic, or tricyclic, respectively)), wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Exemplary heteroaryl groups include, but are not limited to: pyridyl, furyl or furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl or thienyl, pyridazinyl, pyrazinyl, quinolinyl, indolyl, thiazolyl, naphthyridinyl, and the like.

The term "heteroarylalkyl" denotes an alkyl group substituted with a heteroaryl group.

The term "heterocyclyl" denotes a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic) selected from O, N or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O or S (if monocyclic, bicyclic, or tricyclic, respectively)), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Exemplary heterocyclic groups include, but are not limited to: piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

The term "haloalkyl" denotes an alkyl group having 1, 2, 3 or more halogen atoms attached thereto. Exemplary haloalkyl groups include, but are not limited to: chloromethyl, bromoethyl, trifluoromethyl, and the like.

The term "optionally substituted" means that the specified group or moiety (such as alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, etc.) is unsubstituted or substituted with 1 or more (typically 1 to 4) substituents independently selected from the substituents listed below in the definition of "substituent" or otherwise specified.

The term "substituent" means a group that is "substituted" at any atom of the group on an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl. Suitable substituents include, but are not limited to, halo, hydroxy, oxo, nitro, haloalkyl, alkyl, alkenyl, alkynyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbonyl (carbanoyl), arylcarbonylo (carbanoyl), aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonylamino, aralkylsulfonylamino, alkylcarbonyl, acyloxy, cyano, or ureido. In some cases, 2 substituents together with the carbon to which they are attached may form a ring.

In many cases, protecting groups are used during the preparation of the compounds of the present invention. The term "protected" as used herein means that the specified moiety has a protecting group appended thereto. In certain preferred embodiments of the invention, the compounds contain one or more protecting groups. A variety of protecting groups may be employed in the process of the present invention. In general, protecting groups will provide chemical functionality that is inert to the particular reaction conditions, and can be attached to and removed from such functionality in a molecule without substantially destroying other portions of the molecule.

Representative protecting groups are disclosed in: greene and Wuts, Protective Groups in organic Synthesis, Chapter 2, 2 nd edition, John Wiley & Sons, New York, 199. Examples of hydroxy protecting groups include, but are not limited to: t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2, 4-dinitrophenyl, benzyl, 2, 6-dichlorobenzyl, diphenylmethyl, p' -dinitrobenzhydryl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, benzoylformate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivaloate, benzoate, p-phenylbenzoate, 9-fluorenylmethylcarbonate, methanesulfonate, and tosylate. Exemplary amino-protecting groups include, but are not limited to: carbamate protecting groups such as 2-trimethylsilylethoxycarbonyl (Teoc), 1-methyl-1- (4-biphenyl) ethoxycarbonyl (Bpoc), tert-Butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trihaloacetyl, benzoyl and nitrophenylacetyl; sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imide protecting groups such as phthalimido and dithiasuccinyl groups.

The term "isomer" as used herein means a compound having the same molecular formula but differing in structure. The only difference is that the configuration and/or conformational isomers are referred to as "stereoisomers". The term "isomer" is also used to denote enantiomers.

The term "enantiomer" is used to describe one of a pair of molecular isomers that are mirror images of each other and do not overlap. Other terms used to designate or refer to enantiomers include "stereoisomers" (because of different arrangements or stereochemistry around the chiral center; although all enantiomers are stereoisomers, not all stereoisomers are enantiomers) or "optical isomers" (because of the optical activity of pure enantiomers, which is the ability of different pure enantiomers to rotate plane polarized light in different directions). Enantiomers generally have the same physical properties, such as melting and boiling points, and also have the same spectral properties. Enantiomers can be distinguished from each other in their interaction with plane polarized light as well as in biological activity.

The symbols "R and S" are used to indicate the absolute configuration of a molecule with respect to its chiral center. The symbols may appear as prefixes or as suffixes; they may or may not be separated from isomers by hyphens; they may or may not be hyphenated; and they may or may not be surrounded by brackets.

The symbols or prefixes "(+) and (-)" are used to designate the symbols of the compound that rotate plane polarized light, (-) means that the compound is left-handed (rotated left) and the compound that is pre-labeled (+) is right-handed (rotated right).

The terms "racemic mixture", "racemic compound" or "racemate" refer to a mixture of two enantiomers of a compound. The ideal racemic mixture is such that: wherein a 50:50 mixture of the two enantiomers of the compound is present such that the optical rotation of the (+) enantiomer cancels the optical rotation of the (-) enantiomer.

The term "resolution", when used in reference to a racemic mixture, means the separation of the racemate into its two mirror enantiomeric forms (i.e., (+) and (-); the (R) and (S) forms). The term may also denote the enantioselective conversion of one isomer of the racemate into the product.

The term "enantiomeric excess" or "ee" denotes a reaction product wherein one enantiomer is produced in excess of the other, and is defined with respect to a mixture of the (+) -and (-) -enantiomers, given as a molar or weight or volume ratio F₍₊₎And F_(-)(wherein, F₍₊₎And F_(-)The sum of (1). Enantiomeric excess is defined as F ₍₊₎-F_(-) ^*And the percentage of enantiomeric excess is 100x F₍₊₎-F_(-) ^*. The "purity" of an enantiomer is described by its ee or percent ee (% ee).

Whether expressed as "purified enantiomers" or "pure enantiomers" or "resolved enantiomers" or "enantiomeric excess compounds," these terms are intended to indicate that the amount of one enantiomer exceeds the amount of the other enantiomer. Thus, when referring to an enantiomeric preparation, the percentage of the major enantiomer (e.g., mole or weight or volume) and/or the enantiomeric excess percentage of the major enantiomer (or either) can be used together to determine whether the preparation represents a purified enantiomeric preparation.

The term "enantiomeric purity" or "enantiomeric purity" of an isomer means a qualitative or quantitative measure of the purified enantiomer; typically, such metrics are expressed based on ee or enantiomeric excess.

The terms "substantially purified enantiomer", "substantially resolved enantiomer", "substantially purified enantiomeric preparation" all mean preparations (e.g., derived from a starting material, substrate, or intermediate that is not optically active): wherein one enantiomer has been enriched over the other, and more preferably wherein the other enantiomer comprises less than 20%, more preferably less than 10%, and more preferably less than 5%, and more preferably less than 2% of the enantiomer or enantiomeric preparation.

The terms "purified enantiomer", "resolved enantiomer" and "purified enantiomeric preparation" all mean preparations (e.g., derived from a non-optically active starting material, substrate or intermediate): wherein one enantiomer (e.g., the R-enantiomer) has been enriched over the other, and more preferably wherein the other enantiomer (e.g., the S-enantiomer) comprises less than 30%, preferably less than 20%, more preferably less than 10% of the preparation (e.g., in this particular case, the R-enantiomer is substantially free of the S-enantiomer) and more preferably less than 5% and more preferably less than 2%. Purified enantiomers substantially free of other enantiomers can be synthesized, or purified enantiomers can be synthesized in a stereospecific procedure, followed by a separation step, or purified enantiomers can be derived from racemic mixtures.

The term "enantioselectivity" (also known as the enantiomeric ratio, indicated by the symbol "E") refers to the ability of an enzyme to produce one enantiomer relative to the other from a racemic substrate in a racemic mixture of products; in other words, it is a measure of the ability of the enzyme to distinguish enantiomers. A non-selective reaction has an E of 1, while a resolution with an E exceeding 20 is generally considered to be advantageous for synthesis or resolution. Enantioselectivity consists in the difference in conversion between the target enantiomers. The obtained reaction product is rich in one of enantiomers; in contrast, the residual substrate is enriched in the other enantiomer. For practical purposes, it is generally desirable to obtain a large excess of one enantiomer. This is achieved by terminating the conversion process at a certain degree of conversion.

The term "pharmaceutically acceptable salt" as used herein denotes conventional non-toxic salts or quaternary ammonium salts of compounds, e.g., derived from non-toxic organic or inorganic acids. These salts may be prepared in situ during the manufacture of the administration vehicle or dosage form, or as follows: separately reacting the purified compound in its free base or acid form with a suitable organic or inorganic acid or base and isolating the salt thus formed in a subsequent purification process. Conventional non-toxic salts include: salts derived from inorganic acids such as sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. See, e.g., Berge et al, "Pharmaceutical Salts", J.pharm.Sci.66:1-19(1977, the contents of which are incorporated herein by reference in their entirety.

In certain embodiments of aspects described herein, representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, succinate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthenate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate, and the like.

The term "analog" as used herein refers to a compound resulting from the substitution, or deletion of a different organic group or hydrogen atom from the parent compound. Thus, some monoterpenoids may be considered as analogues of monoterpenes, or in some cases, other monoterpenoids (including derivatives of monoterpenes). An analog is structurally similar to the parent compound, but may differ by even the same valency as the element it replaces and by a single element of a group of the periodic table.

The term "derivative" as used herein means a chemical moiety that is structurally related to another moiety (i.e., the "original" moiety, which may be referred to as the "parent" compound). "derivatives" may be prepared in one or more steps from structurally related parent compounds. The phrase "closely related derivatives" refers to such derivatives: the molecular weight does not differ by more than 50% from the weight of the parent compound. The general physical and chemical properties of closely related derivatives are also similar to those of the parent compound.

Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the following claims. Further, where not already indicated, those of ordinary skill in the art will appreciate that any of the various embodiments described and illustrated herein can be further modified to incorporate features shown in any of the other embodiments disclosed herein.

The following examples illustrate some embodiments and aspects of the invention. Those skilled in the relevant art will appreciate that various modifications, additions, substitutions and the like can be made without departing from the spirit or scope of the invention and that such modifications and changes are encompassed within the scope of the invention as defined in the following claims. The following examples do not limit the invention in any way.

Examples

Example 1: synthesis of ketoconazole-methylene-fatty acid ester conjugates.

As shown in scheme 1, ketoconazole-methylene-fatty acid conjugates (3a-3h) were synthesized.

Route scheme 1

Ketoconazole-methylene-palmitate conjugate (3 b):

Step-1: synthesis of chloromethyl palmitate (2 b): palmitic acid (0.3g,1.17mmol) was dissolved in 5ml Dichloromethane (DCM) and then sodium bicarbonate (0.4g,4.68mmol), 5ml water and tetrabutylammonium sulfate (0.135ml,0.117mmol) were added. The resulting solution was stirred vigorously at 0 ℃. After 10min chloromethyl chlorosulphate in DCM (0.14ml,1.4mmol) was added to the reaction mixture and the resulting solution was stirred vigorously until room temperature was reached. The organic layer was extracted with DCM, washed with brine and finally dried over sodium sulfate to give pure chloromethyl palmitate (0.3g,85% yield).

Step-2: synthesis of ketoconazole-methylene-palmitate conjugate (3 b): ketoconazole (0.26g,0.49mmol), chloromethyl palmitate (0.3g,0.98mmol), sodium iodide (0.147g,0.98mmol) were suspended in acetonitrile, and the resulting solution was refluxed for 4 hours under an argon atmosphere. The reaction mixture was filtered, concentrated, and the residue was triturated with ether to give the crude product. The crude product was purified by column chromatography on silica gel (silica) (60-120 mesh) eluting with 4-5% MeOH in DCM to give the compound as a yellow solid (0.3g, 65% yield).¹H-NMR(500MHz,CDCl₃):δ_H0.885(t,3H),1.24-1.25(bs,24H),1.668-1.73(m,2H),2.157(s,3H),2.28-2.31(t,2H),3.07-3.14(dd,4H),3.667-3.71(d,3H),3.74-3.75(d,2H),3.72(m,1H),3.81-4.11(m,2H),4.12-4.413(m,1H),4.856(s,2H),6.0-6.117(dd,2H),6.84(d, J =9Hz,2H),6.93(d, J =9Hz,2H),7.31-7.36(m,2H),7.48(s,2H),7.7-7.72(d, J =8.5, 1H), 9.7.7-7.72 (d, J =8, 9H), 1H). ESI-MS, observed in M/z 799.5(M), calculated 799.4 (M).

Similarly, other methylene fatty acid ester conjugates were also synthesized from ketoconazole using a procedure similar to that described above for 3 b. Mass spectrometry data for some of the synthesized ketoconazole-methylene-fatty acid conjugates are shown in table 1.

Table 1:

example 2: synthesis of ketoconazole-1-ethylene-fatty acid ester conjugate.

As shown in scheme 2, ketoconazole-1-ethylene-fatty acid ester conjugates (6a-6g) were synthesized.

Route map 2

Ketoconazole-1-ethylene-palmitate conjugate (6 b):

step 1: synthesis of palmitoyl chloride (4 b): to a stirred solution of palmitic acid (0.2g,0.78mmol) in 6-7ml DCM was added one drop of Dimethylformamide (DMF), followed by oxalyl chloride (0.087ml,1.014 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the resulting product (85-90% isolated yield) was used in the next step without further purification.

Step 2: synthesis of 1-chloroethyl palmitate (5 b): palmitoyl chloride (2.0ml,6.6mmol) was dissolved in a minimal amount of acetonitrile and paraformaldehyde (0.3ml,2.2mmol), zinc chloride (anhy) (0.027g,0.199mmol) was mixed withThe molecular sieves are added together to the resulting reaction mixture. The reaction mixture was heated at 60-65 ℃ for 2 hours and cooled to room temperature. The resulting mixture was diluted with dichloromethane and filtered through Celite (Celite). The filtrate was concentrated and the residue was purified by flash silica (silica) column chromatography (60-120 mesh). While eluting with 1-2% EtOAC/hexanes, the desired semi-solid white product was obtained (0.84 g, 40% yield).

And step 3: synthesis of ketoconazole-1-ethylene-palmitate conjugate (6 b): ketoconazole (0.1g,0.19mmol), 1-chloroethyl palmitate (0.121g,0.38mmol), sodium iodide (NaI,0.057g,0.38mmol) were suspended in 10ml acetonitrile and the resulting solution was refluxed for 4 hours under argon atmosphere. The reaction mixture was cooled, filtered and concentrated to give a crude residue. The residue was triturated with ether and purified by flash column chromatography on silica gel (silica) (60-120 mesh) eluting with 4-6% MeOH in DCM to give the compound as a yellow solid (0.1g,60% yield).¹H-NMR(500MHz,CDCl₃):δ_H0.894(t,3H),1.24-1.3(bs,24H),1.67(m,2H),1.89-1.92(m,3H),2.16(s,3H),2.27-2.31(m,2H),3.03-3.1(dd,4H),3.62-3.65(m,2H),3.77-3.808(m,4H),3.81-3.942(m,2H),4.3-4.45(m,1H),4.94-5.07(m,2H),6.84(d, J =9Hz,2H),6.93(d, J =9Hz,2H),7.31-7.36(m,2H),7.48(s,2H),7.7-7.72(d, J =8.5Hz,1H),9.9(s, 1H). ESI-MS, observed in M/z 813.73(M),407.3(M/2),428.18(M/2+23), calculated 813.41 (M).

Similarly, other ethylene fatty acid ester conjugates were also synthesized from ketoconazole using a procedure similar to that described above for 6 b. Mass spectrometry data for some of the synthesized ketoconazole-ethylene-fatty acid conjugates are shown in table 2.

Table 2:

example 3: synthesis of ketoconazole-N-hexadecyl-acetamide conjugate (8).

As shown in scheme 3, ketoconazole-N-hexadecyl-acetamide conjugate (8) was synthesized. It was considered a negative control compound for comparison with methylene and ethylene fatty acid ester prodrug conjugates. The biological potency of this compound 8 was compared to other prodrug ester and carbonate conjugates.

Route map 3

Step-1: synthesis of 2-chloro-N-hexadecyl-acetamide (7): to a stirred solution of hexadecylamine (0.4g,1.65mmol) in 10ml DCM was added 4-dimethylaminopyridine (DMAP,0.243g,1.98 mmol). The solution was cooled at-15 ℃ and a solution of chloroacetic anhydride (0.24g,1.98mmol) in DCM was added dropwise to the reaction mixture while maintaining the temperature at-15 ℃. After stirring for 5-6 hours, the resulting solution was allowed to reach room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, 1N HCl and finally brine. The combined organic layers were dried over sodium sulfate and evaporated to give a crude brown solid. The solid obtained was almost pure and was used in the next step without further purification.

Step-2: synthesis of ketoconazole-N-hexadecyl-acetamide conjugate (8): ketoconazole (0.15g,0.28mmol), 2-chloro-N-hexadecyl-acetamide (0.3g,0.946mmol), sodium iodide (0.142g,0.946mmol) were suspended in 10ml acetonitrile, and the resulting solution was refluxed under argon atmosphere for 4 hours. The reaction mixture was filtered, concentrated, and the residue was triturated with ether to give the crude product. The crude product was purified by silica gel (silica) column chromatography eluting with 4-6% MeOH in DCM to give the compound as a yellow solid (0.17g,65% yield). ¹H-NMR(500MHz,CDCl₃):δ_H0.87(t,3H),1.23-1.25(bs,26H),1.44-1.46(m,2H),2.16(s,3H),3.08(q,2H),3.21-3.36(m,4H),3.67-4.07(m,8H),4.39-4.43(m,1H),4.81(s,2H),5.98(s,2H),6.84(d, J =9Hz,2H),6.93(d, J =9Hz,2H),7.31-7.36(m,2H),7.48(s,2H),7.7-7.72(d, J =8.5Hz,1H),9.9(s, 1H). ESI-MS, observed in M/z 812.54(M),406.84(M/2),427.17(M/2+23), calculated 812.43 (M).

Example 4: synthesis of ketoconazole-1-ethylene-fatty acid carbonate conjugate.

As shown in scheme 4, ketoconazole-1-ethylene-fatty acid carbonate conjugates (11a-e) were synthesized.

Route map 4

Synthesis of ketoconazole-1-ethylene-fatty-ester conjugate (11 b):

step-1: synthesis of 1-chloroethyl lauryl carbonate (10 b): lauryl alcohol (1g,5.36mmol) was dissolved in 6ml DCM, and triethylamine (1.2ml,8.58mmol) was added thereto. The resulting solution was cooled at-15 ℃ and chloroethyl chloroformate (0.75ml,6.97mmol) in DCM was slowly added to the reaction mixture. The resulting solution was stirred to reach room temperature. At the end of 8 hours, the reaction mixture was diluted with DCM, washed with water and brine solution and finally dried over sodium sulfate. The crude liquid was used directly for the next quaternization with ketoconazole.

Step-2: synthesis of ketoconazole-1-ethylene-lauryl carbonate (11 b): ketoconazole (0.7g,1.32mmol), 1-chloroethyl lauryl carbonate (1.1g,3.95mmol) and sodium iodide (0.6g,3.95mmol) were suspended in 15ml acetonitrile and the resulting solution was refluxed under argon for 4 hours. The reaction mixture was filtered, concentrated, and the residue was triturated with ether to give the crude product. The crude product was purified by chromatography on a silica gel (silica) column (60-120 mesh) eluting with 4-5% MeOH in DCM to give the compound as a yellow solid (0.72g,60% yield).¹H-NMR(500MHz,CDCl₃):δ_H0.9(t,3H),1.27(bs,16H),1.61-1.63(m,2H),1.92-1.96(dd,3H),2.18(s,3H),3.17-3.23(m,4H),3.82-4.20(m,11H),4.4-4.43(m,1H),4.89-5.06(m,2H),6.84(d, J =9Hz,2H),6.93(d, J =9Hz,2H),7.31-7.36(m,2H),7.48(s,2H),7.7-7.72(d, J =8.5Hz,1H),9.9(s, 1H). ESI-MS, observed in M/z 787.58(M), calculated 787.36 (M).

Similarly, other fatty acid carbonate conjugates were also synthesized from ketoconazole using a procedure similar to that described above for 11 b. Mass spectrometry data for some of the synthesized ketoconazole-carbonate-fatty acid conjugates are shown in table 3.

Table 3:

example 5: synthesis of Ketoconazole-1-ethylene-DEG/TEG/PEG-fatty acid carbonate conjugates 18a-d, 19a-d and 20 a-d.

ketoconazole-1-ethylene-DEG/TEG/PEG-fatty acid carbonate conjugates 18a-d, 19a-d and 20a-d were synthesized as shown in scheme 5.

Route map 5

Synthesis of ketoconazole-lauryltriethylglycerol-carbonate conjugate (19 b):

step-1: synthesis of lauryl chloride (4 b): to a stirred solution of lauric acid (1g,5.0mmol) in 10ml of dichloromethane was added a drop of dimethylformamide followed by oxalyl chloride (0.556ml,6.48 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and 0.98g (85-90% yield) of the resulting product was used in the next step without further purification.

Step-2: synthesis of triethyleneglyceryl-laurate (13 b): triethylene glycol (TEG,1.65ml,12.36mmol) was dissolved in 10ml DCM, and triethylamine (0.7ml,4.94mmol) was added thereto. Lauroyl chloride (0.9g,4.12mmol) was dissolved in minimal DCM and added slowly to the reaction mixture. The resulting solution was stirred at room temperature overnight under argon atmosphere. The reaction mixture was diluted with DCM and washed successively with water (2 × 10ml), 0.5N HCl (10ml × 2) and finally dried over sodium sulphate to give the crude pure solid product (0.9g,70% yield) which was used directly in the chloroethylation reaction. ¹H-NMR(500MHz,CDCl₃):δ_H0.874(t,3H),1.25(bs,16H),1.59-1.64(m,2H),2.31-2.35(m,2H),2.96-2.98(m,1H),3.62-3.77(m,10H),4.23 and 4.31-4.32(bs, 2H). ESI-MS, observed M/z 332.5(M), calculated 332.2 (M).

Step-3 Synthesis of 1-chloroethyl-lauryltriethylglycerol-carbonate (16 b): to a stirred solution of 1-chloroethyl chloroformate (0.2ml,1.95mmol) in 6ml DCM was added dropwise a mixture of triethyleneglyceryl-laurate (0.5g,1.5mmol) and triethylamine (0.3ml,2.1mmol) in 10ml DCM maintaining the temperature at-15 ℃. The reaction was stirred until room temperature was reached. The reaction mixture was diluted with DCM, washed successively with water, 0.5N HCl, brine solution and finally dried over sodium sulfate. The crude oil-like product (0.46g,70%) was used directly for the next quaternization with ketoconazole.

Step-4: synthesis of ketoconazole-lauryltriethylglycerol-carbonate conjugate (19 b): ketoconazole (0.454g,0.85mmol), 1-chloroethyl-lauryltriethylenetriallyl-carbonate (1.12g,2.55mmol) and sodium iodide (0.39g,2.6mmol) were suspended in 15ml acetonitrile and the resulting solution was refluxed for 3-4 hours under argon atmosphere. The reaction mixture was filtered, concentrated, and the residue was triturated with ether to give the crude product. The crude product was purified by silica gel (silica) column chromatography eluting with 4-5% MeOH in DCM to give the compound as a yellow pure solid (0.5g,55% yield). ¹H-NMR(500MHz,CDCl₃):δ_H0.875(t,3H),1.25(bs,16H),1.57-1.61(m,2H),1.92-1.96(dd,3H),2.18(s,3H),2.3(t,2H),3.07-3.13(m,4H),3.63-4.04(m,12H),4.14-4.45(m,12H),4.89-5.06(m,2H),6.84(d, J =9Hz,2H),6.93(d, J =9, 2H),7.31-7.36(m,2H),7.48(s,2H),7.7-7.72(d, J =8.5Hz,1H),9.9(s, 1H). ESI-MS, observed at M/z of 933.8(M), calculated 933.42 (M).

Example 6: synthesis of bis- (ketoconazole-1-ethylene) ] -DEG/TEG/PEG-dicarbonate conjugates 23 a-c.

As shown in scheme 6, a bis- (ketoconazole-1-ethylene) ] -DEG/TEG/PEG-dicarbonate conjugate (23a-c) was synthesized.

Route map 6

[ bis- (ketoconazole-1-ethylene)]-Synthesis of triethyleneglyceryl-dicarbonate conjugate (23b) The composition is as follows:

step-1: synthesis of bis- (1-chloroethyl) -triethyleneglyceryl-dicarbonate (22b) to a stirred solution of 1-chloroethyl chloroformate (5.6ml,52mmol) in 10ml DCM, a mixture of triethylenediol (3.0g,20mmol) and triethylamine (6.9ml,50.0mmol) was added dropwise while maintaining the temperature at-15 ℃. The reaction mixture was allowed to reach room temperature and stirred for 6-8 h. After completion, the reaction mixture was diluted with DCM, washed with water, brine and finally dried over sodium sulfate. The organic layer was evaporated to give crude. The crude product (4.1 g, 65%) was used directly in the next step without further purification.

Step-2: [ bis- (ketoconazole-1-ethylene)]-synthesis of triethyleneglyceryl-dicarbonate conjugate (23 b): to bis- [ 1-chloroethyl-triethylenetetralcarbonyl carbonate](0.3g,0.94mmol) to a stirred solution in 10ml acetonitrile was added sodium iodide (0.35g,2.35mmol) and ketoconazole (1.0g,1.88 mmol). The reaction mixture was heated at 85 ℃ for 4-5 hours. The resulting solution was cooled to room temperature, filtered and concentrated to give the crude. The crude material was purified by flash silica (silica) column chromatography eluting with 5-6% MeOH/DCM to isolate 50% (0.75gm) of the compound as a yellow pure solid.¹H-NMR(500MHz,CDCl₃):δ_H1.86-1.93(t,6H),2.15(s,6H),3.09-3.27(dd,8H),3.62-3.97(m,32H),4.15-4.367(m,4H),4.86-5.0(m,4H),6.6-6.67(d,2H),6.84(d, J =9Hz,4H),6.93(d, J =9Hz,4H),7.31-7.36(m,4H),7.48(s,4H),7.7-7.72(d, J =8.5Hz,2H),9.9(s, 2H). MALDI-TOF, M/z observation 1479.4(M + iodocounterion), calculated 1352.4 (M).

Example 7: synthesis of bis- (ketoconazole-methylene-acid ester) conjugates.

As shown in scheme 7, a bis- (ketoconazole-methylene-acid ester) conjugate (26) was synthesized.

Route map 7

Step-1: synthesis of bis- (1-chloromethyl) -nonane-diester (25): azelaic acid (3.0g,15.94mmol) was dissolved in 50ml DCM followed by addition of sodium bicarbonate (10.71g,127.52mmol), 50ml water and tetrabutylammonium sulfate (3.7ml,3.19 mmol). The resulting solution was stirred vigorously at 0 ℃. After 10min chloromethyl chlorosulphate in DCM (3.9ml,38.25mmol) was added to the reaction mixture and the resulting solution was stirred vigorously to reach room temperature. The organic layer was extracted with DCM, washed with brine and finally dried over sodium sulfate to give pure bis- (1-chloromethyl) -nonane-diacid ester (3.8g,85% yield).

Step-2: [ bis- (ketoconazole-methylene)]-synthesis of nonane-diester conjugate (26): ketoconazole (7.48g,14.08mmol), bis- (1-chloromethyl) -nonane-diester (2.0g,7.04mmol), sodium iodide (2.1g,14.08mmol) were suspended in acetonitrile and the resulting solution was refluxed for 4 hours under argon atmosphere. The reaction mixture was filtered, concentrated, and the residue was triturated with ether to give the crude product. The crude product was purified by column chromatography on silica gel (silica) (60-120 mesh) eluting with 4-5% MeOH in DCM to give the compound as a yellow solid (5 g, 50% yield).¹H-NMR(500MHz,CDCl₃):δ_H1.23-1.26(m,3H),1.52-1.61(m,2H),2.16(s,3H),2.29(q,2H),3.07-3.14(dd,4H),3.667-3.71(d,3H),3.74-3.75(d,2H),3.72(m,1H),3.81-4.11(m,2H),4.12-4.413(m,1H),4.856(s,2H),6.0-6.117(dd,2H),6.84(d,J=9Hz,2H),6.93(d,J=9Hz,2H),7.31-7.36(m,2H),7.48(s,2H),7.7-7.72(d,J=8.5Hz,1H),9.9(s,1H)。

Example 8: synthesis of itraconazole-methylene-fatty acid ester conjugates.

As shown in scheme 8, itraconazole-methylene-fatty acid ester conjugates (27a-g) were synthesized.

Route map 8

Synthesis of itraconazole-methylene-caprylate conjugate (27 g):

step-1: synthesis of chloromethyl octanoate (2 g): octanoic acid (5.0g,34.7mmol) was dissolved in 40ml DCM followed by addition of sodium bicarbonate (11.66g,138.8mmol), 40ml water and tetrabutylammonium sulfate (3.7ml,3.47 mmol). The resulting solution was stirred vigorously at 0 ℃. After 10min chloromethyl chlorosulphate in DCM (4.2ml,41.6mmol) was added to the reaction mixture and the resulting solution was stirred vigorously to reach room temperature. The organic layer was extracted with DCM, washed with brine and finally dried over sodium sulfate to give pure chloromethyl octanoate (5.3g,80% yield).

Step-2: synthesis of itraconazole-methylene-caprylate conjugate (27 g): itraconazole (3.67g,5.2mmol), chloromethyl octanoate (2.0g,10.41mmol), sodium iodide (1.56g,10.41mmol) were suspended in acetonitrile, and the resulting solution was refluxed under an argon atmosphere for 4 hours. The reaction mixture was filtered, concentrated, and the residue was triturated with ether to give the crude product. The crude product was purified by column chromatography on silica gel (silica) (60-120 mesh) eluting with 4-5% MeOH in DCM to give the compound as a yellow solid (2.7 g, 60% yield). ESI-MS, observed in M/z 861.7(M), calculated 861.36 (M).

Example 9: nanoparticulate ketoconazole prodrug conjugates.

Nanoparticulate formation of some ketoconazole-fatty acid conjugates was examined by 2 different methods: nano-precipitates and nano-emulsions.

Nano-precipitation: in this method, the prodrug conjugate and a different external amphiphilic carrier (e.g., a lipid or polymer) are first dissolved in a mixture solution of tetrahydrofuran and acetone (1:3) and added dropwise to water containing a surfactant (0.1-0.25%) under vigorous stirring. The final solution was then stirred at room temperature for 18-20 hours to evaporate the organic solvent. The resulting solution was then diluted, centrifuged, and analyzed by zeta-size sorter to obtain particle size and homogeneity of the solution. Table 4 shows the composition, size and Polydispersity (PDI) of some nanoparticles prepared from ketoconazole-methylene-caprylate conjugate (KMC).

Table 4:

nanoemulsion in this method, the prodrug is dissolved in lauryl alcohol or a mixture of ethanol and captex355 (diglyceride/triglyceride of caprylic acid). The lipid-based solution is added to a specific percentage of a surfactant, such as hydrogenated PEG35 castor oil (cremophor EL). The mixture of lipid and surfactant is then titrated in water until it forms a cloudy liquid that appears to consist of a coarse emulsion. The resulting solution was analyzed by zeta-size sorter to obtain particle size and homogeneity of the solution. Table 5 shows the composition and size of some nanoemulsions prepared from ketoconazole-methylene-caprylate conjugate (KMC).

Table 5:

example 10: synthesis of antibacterial clindamycin conjugates.

As shown in scheme 9, clindamycin fatty acid conjugates 32a-f were synthesized.

Route map 9

Synthesis of clindamycin undecylenate (32a)

Step-1: synthesis of clindamycin acetonide (30): to a suspension of clindamycin hydrochloride (1g,2.167mmol) in acetone (20ml) under argon at room temperature was added an iodine tablet (0.220g,0.866 mmol). The reaction mixture was stirred at room temperature for 5-6 hours. The iodine was then quenched with saturated aqueous sodium thiosulfate and the excess acetone was evaporated using a rotary evaporator. The remaining aqueous phase was extracted with DCM (3 × 15 ml). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was passed through a silica gel (silica) column (eluent-MeOH: DCM;0.2:9.8) to give clindamycin acetonide as a white fluffy powder. R _f0.6(MeOH:DCM;1:9)

Step-2: synthesis of clindamycin acetonide undecylenate (31 a): to a stirred solution of undecylenic acid (0.238g,1.292mmol) in anhydrous DCM was added DIC dropwise at 0 ℃. The reaction mixture was stirred at room temperature for 15 min. Then, a solution of clindamycin acetonide (0.5g,1.077mmol) and DMAP (0.039g,0.323mmol) in DCM was added dropwise at 0 deg.C and stirring was continued for another 4 hours. The reaction mixture was diluted with DCM and quenched with saturated aqueous ammonium chloride and 1N HCl. The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was passed through a silica gel (silica) column (eluent-MeOH: DCM;0.1:9.9) to give clindamycin acetonide undecylenate as a viscous yellow compound. R_f0.9(MeOH:DCM;1:9)。

Step-3: synthesis of clindamycin undecylenate (32 a): to a stirred solution of clindamycin acetonide undecylenate (0.713g,1.1308mmol) in MeOH at 0 deg.C was added dropwise an aqueous solution of HBF₄(1.34ml). The reaction mixture was stirred at room temperature for 1 hour. Evaporating the methanol; NaHCO is added₃The aqueous suspension was added to the residue, which was then extracted with DCM (3 × 15 ml). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was passed through a silica gel (silica) column (eluent-MeOH: DCM;0.125:9.875) to give clindamycin undecylenate as a syrupy pale yellow compound. R _f0.7(MeOH:DCM;1:9)。δ_H(500MHz,CDCl₃)0.93(3H, t, J6.5),1.25-1.45(16H, m),1.54(3H, d, J6.5),1.66(1H, m),2.05(2H, m),2.11(2H, m),2.14(3H, s),2.41(2H, t, J7.5),2.45(3H, s),2.75(1H, d, J10.5),3.09(1H, dd, J7.0 and 3.0),3.25(1H, br s),3.67-3.69(2H, m),3.87(1H, dd, J9.5 and 10.0),4.10(1H, d, J9.5),4.20(1H, dd, J9.5 and 10.0),4.72(1H, 7.5, J5, 5H, 5.5, 5H, 5.5, 5H, 5.5, 5H, 5.5, 5H, 5.5.5, 5H, 5.5, 5H, 5H, 5.5H, 5H, 5. HRMS, m/z observed 591.2728, C₂₉H₅₂ClN₂O₆S⁺(M+H)⁺The calculated value was 591.3229.

Synthesis of clindamycin palmitate (32 b): in a similar manner as described for clindamycin undecylenate, clindamycin palmitate is synthesized from clindamycin. Delta_H(500MHz,CDCl₃)0.92(6H, m, J6.5),1.25-1.52(24H, m),1.53(3H, J6.5),1.67(2H, m),1.95(2H, m),2.11(2H, m),2.12(3H, s),2.38(2H, t, J7.5),2.42(3H, s),2.73(1H, d, J10.5),3.08(1H, dd, J10.5 and 3.5),3.23(1H, br s),3.67(1H, br s),3.85(1H, dd, J10.5 and 10.0),4.08(1H, d, J10),4.19(1H, dd, J8.5 and 10.0),4.72(1H, q, 6.5), 10.5 (1H, 5H, 5/5H, 5₃₄H₆₄ClN₂O₆S⁺(M+H)⁺The calculated value was 663.4168.

Similarly, other fatty acid conjugates were also synthesized from clindamycin using a procedure similar to that described above for 32 b. Mass spectrometry data for some synthetic clindamycin conjugate fatty acid conjugates are shown in table 6.

Table 6:

name of Compound	Molecular formula	Quality of observation	Calculated mass
				Clinomycin laurate (32c)	C30H56ClN2O6S+[M+1]+	607.2750	607.3542
Clindamycin stearate (32d)	C36H68ClN2O6S+[M+1]+	691.4557	691.4481
				Clindamycin oleate (32e)	C36H66ClN2O6S+[M+1]+	689.4393	689.4325
Linoleic acid clindamycin (32f)	C36H64ClN2O6S+[M+1]+	687.4228	687.4168

Example 11: synthesis of clindamycin salicylic acid conjugate.

As shown in scheme 10, clindamycin salicylate conjugates were synthesized.

Route map 10

Step-1: synthesis of clindamycin acetonide (30): to a suspension of clindamycin hydrochloride (1g,2.167mmol) in acetone (20ml) under argon at room temperature was added an iodine tablet (0.220g,0.866 mmol). The reaction mixture was stirred at room temperature for 5-6 hours. The iodine was then quenched with saturated aqueous sodium thiosulfate and the excess acetone was evaporated using a rotary evaporator. The remaining aqueous phase was extracted with DCM (3 × 15 ml). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was passed through a silica gel (silica) column (eluent-MeOH: DCM;0.2:9.8) to give clindamycin acetonide as a white fluffy powder. R_f0.6(MeOH:DCM;1:9)。

Step-2: synthesis of clindamycin acetonide acetylsalicylate (35): to a stirred reaction mixture containing oxalyl chloride (0.21g,1.666mmol) and DCM at 0 deg.C was added DMF (0.5ml) dropwise. After bubbling stopped, the mixture was added to a stirred reaction mixture containing acetylsalicylate (aspirin) (0.15g,0.833mmol) and DCM and stirred for 2 hours. The reaction mixture was added dropwise to a reaction mixture containing clindamycin acetonide (0.351g,0.7575mmol), TEA (0.114g,1.1363mmol) in anhydrous DCM at 0 deg.C and stirred for 3 hours. The reaction mixture was washed with 1N HCl and extracted with DCM. To be combined with The organics were dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellowish powder. R_f0.4(EtOAc:Hex;1:1)。

Step-3: synthesis of clindamycin acetylsalicylate (36): to a stirred reaction mixture containing clindamycin acetonide acetylsalicylate (0.5g,0.7972mmol) and MeOH at 0 deg.C was added dropwise an aqueous solution of HBF₄(1.5ml) and stirred for 5 hours. A few drops of concentrated HCl were added and stirred for 72 hours. Methanol was evaporated and NaHCO was added₃Aqueous suspension and extracted with DCM (3 × 15 ml). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was passed through a silica gel (silica) column (eluent-MeOH: DCM;0.15:9.85) to give a yellowish powder. R_f0.2(MeOH:DCM;0.2:9.8)。δ_H(500MHz,CDCl₃)0.93(6H, m),1.250-1.411(7H, m),1.537(3H, s),2.005(3H, s),2.353-2.459(1H, m),2.485(3H, br s),3.014-3.038(1H, m),3.117(1H, s),3.298(1H, m),4.064-4.078(1H, d, J7),4.437(1H, m),4.477(1H, m),4.553(1H, m),4.668(1H, m),4.668(1H, m),5.400-5.612(2H, m),6.886-6.917(1H, m),6.961-6.977(1H, m),7.14-7.19(1H, m),7.448-7.464(1H, m),7.859(1H, br s), HRZ/C, HRZ, and the like₂₅H₃₈ClN₂O₇S⁺(M-Ac+H)⁺The calculated value was 545.2083.

Similarly, other methylene fatty acid ester conjugates were also synthesized from ketoconazole using a procedure similar to that described above for clindamycin acetylsalicylate 36.

Example 12: synthesis of clindamycin dimer of azelaic acid.

As shown in scheme 11, clindamycin dimer of azelaic acid was synthesized (38).

Route map 11

Step (ii) of-1: synthesis of clindamycin acetonide (30): to a suspension of clindamycin hydrochloride (1g,2.167mmol) in acetone (20ml) under argon at room temperature was added an iodine tablet (0.220g,0.866 mmol). The reaction mixture was stirred at room temperature for 5-6 hours. The iodine was then quenched with saturated aqueous sodium thiosulfate and the excess acetone was evaporated using a rotary evaporator. The remaining aqueous phase was extracted with DCM (3 × 15 ml). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was passed through a silica gel (silica) column (eluent-MeOH: DCM;0.2:9.8) to give clindamycin acetonide as a white fluffy powder. R_f0.6(MeOH:DCM;1:9)

Step-2: synthesis of dimer of clindamycin acetonide and azelaic acid (37): to a stirred solution of azelaic acid (0.202g,1.077mmol) in dry DCM at 0 deg.C was added DIC (0.380g,3.015mmol) dropwise. The reaction mixture was stirred at room temperature for 15 min. Then, a solution of clindamycin acetonide (1.0g,2.154mmol) and DMAP (0.078g,0.646mmol) in DCM was added dropwise at 0 deg.C and stirring was continued for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and 1N HCl and extracted with DCM. The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was passed through a silica gel (silica) column (eluent-MeOH: DCM;0.1:9.9) to give the desired clindamycin derivative as a solid colorless compound. R _f0.8(MeOH:DCM;1:9)。

Step-3: synthesis of a dimer of clindamycin and azelaic acid (38): to a stirred reaction mixture containing the dimer of clindamycin acetonide and azelaic acid (0.690g,0.689mmol) and methanol at 0 deg.C, HBF was added dropwise₄Aqueous solution (1.16ml) and stirred for 2 hours. Evaporating the methanol; NaHCO is added₃Was added to the residue, which was then extracted with DCM (3X15 ml). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was passed through a silica gel (silica) column (eluent-MeOH: DCM;0.1:9.9) to give the desired clindamycin dimer derivative as a solid colorless compound. R_f0.6(MeOH:DCM;1:9)。δ_H(500MHz,CDCl₃)0.93(6H, t, J6.5), 1.27-1.35(8H, m), 1.44(2H, d, J11.5),1.54(6H, d, J7.0), 1.66(2H, m), 2.05(4H, m), 2.11(4H, m),2.13(6H, s), 2.41(4H, t, J7.5), 2.45(6H, br s), 2.75(2H, d, J11), 3.08(2H, dd, J10.0 and 3.0), 3.25(2H, br s), 3.69(2H, m), 3.86(2H, dd, J10.0 and 10.0), 4.10(2H, d, J9.5, 4.5, 19.5H, 5.5, 5J 5, 5H, 5.5, 5, 5.5H, 5, 5.5, 5H, 5.5, 5H, 5.5, 5, 5.5H, 5, 5.5, 5H, 5, 5.5H, 5H, 5. ESI-MS, m/z observed 501.73, C₄₅H₈₀Cl₂N₄O₁₂S₂₂ ⁺[(M+2H)/2]⁺²The calculated value was 501.23.

Example 13: and (3) synthesis of a clindamycin triclosan conjugate.

As shown in scheme 12, clindamycin triclosan conjugate (41) was synthesized.

Route map 12

Step-1: synthesis of clindamycin acetonide succinate (39): to a stirred reaction mixture containing succinic anhydride (0.214g,2.154mmol) and THF was added dropwise a solution of DMAP (N, N' -dimethylaminopyridine) (0.052g,0.4308mmol) in THF at 0 deg.C and stirred for 1 hour. To the above stirred reaction mixture was added dropwise a solution of clindamycin acetonide (0.5g,1.077mmol) and TEA in THF at 0 deg.C and stirred for 18 hours. It was then heated at 35 ℃ for 20 hours. The reaction mixture was stirred and concentrated in vacuo. The residue was washed with 1N HCl and extracted with DCM (3X15 ml). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. R_f0.4(MeOH:DCM;1:9)。

Step-2: synthesis of clindamycin acetonide succinate triclosan (40): to a solution containing clindamycin acetonide succinate (0.323g,0.5715mmol) and anhydrous DCM at 0 deg.CTo the reaction mixture was stirred, DIC (0.1g,0.8001mmol) was added dropwise and stirred for 10 min. To the stirred reaction mixture above, a solution of triclosan (0.165g,0.5715mmol) and DMAP (N, N' -dimethylaminopyridine) (0.020g,0.1714mmol) in anhydrous DCM was added dropwise at 0 deg.C and stirred for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and 1N HCl and extracted with DCM (3X15 ml). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a viscous yellow compound. R _f0.9(MeOH:DCM;1:9)。

Step-3: synthesis of clindamycin succinate triclosan (41): to a stirred reaction mixture containing clindamycin acetonide succinate triclosan (0.210g,0.2510mmol) and MeOH at 0 deg.C was added dropwise an aqueous solution of HBF₄(0.4ml) and stirred for 18 hours. Evaporating the methanol; adding NaHCO₃Aqueous suspension and extracted with DCM (3 × ml). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was passed through a silica gel (silica) column (eluent-MeOH: DCM;1:9) to give a yellowish powder. R_f0.7(MeOH:DCM;0.2:9.8)。δ_H(500MHz,CDCl₃)0.90(3H, m),1.135-1.467(7H, m),1.514(3H, s),2.160(3H, s),2.472(3H, br s),2.719-2.826(3H, m),3.039-3.077(1H, m),3.117(1H, br s),3.190-3.229(1H, d, J19.5),3.663-3.688(1H, m),3.847(1H, m),3.979-4.011(1H, m),4.058-4.076(1H, d, J9),4.152-4.169(1H, d, J8.5),4.348-4.468(2H, m),4.686(1H, br s), 367-5.149 (1H, br s),5.489(1H, m), 5.489-6.797 (1H, d, J6.798, J), 866 (1H, b.7H, m), 5.489H, 5.489-5.489 (1H, m), 5.489H, 5.489-7, 367, 36875H, 5.489(1H, m). ESI-MS, m/z observed 797.07, C₃₄H₄₃Cl₄N₂O₉S⁺(M+H)⁺The calculated value was 797.14.

Example 14: synthesis of triclosan fatty acid conjugates.

As shown in scheme 13, triclosan fatty acid conjugates (43) were synthesized.

Route map 13

Step-1: synthesis of triclosan laurate (43): to a stirred reaction mixture containing oxalyl chloride (2.534g,19.96mmol) and DCM at 0 deg.C was added DMF (0.6ml) dropwise. After bubbling stopped, the mixture was added to a stirred reaction mixture containing lauric acid (2.0g,9.98mmol) and DCM and stirred for 2 hours. The reaction mixture was added dropwise to a reaction mixture containing triclosan (2.64g,9.14mmol), TEA (2.09g,20.72mmol) and anhydrous DCM at 0 deg.C and stirred for 3 hours. The reaction mixture was washed with 1N HCl and extracted with DCM. The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was passed through a silica gel (silica) column (eluent-MeOH: DCM;0:10) to give an oily liquid. R_f0.9(MeOH:DCM;0.2:10)。δ_H(500MHz,CDCl₃)0.881(3H,t,J6.5),1.230-1.252(16H,m),1.632(2H,quin,J7,7.5),2.463(2H,t,J7.5),6.838(1H,d,J3),6.856(1H,d,J3.5),7.149-7.157(1H,m),7.186-7.191(1H,m),7.444(1H,d,J2.5)ESI-MS，C₂₄H₂₉Cl₃O₃Has an m/z observation of 501.73, C₂₄H₂₉Cl₃O₃ ⁺[(M+2H)/2]⁺²The calculated value was 501.23.

Example 16: preparation of nanoparticles of clindamycin conjugates.

Nanoparticle formation was performed on some of the clindamycin prodrug clindamycin conjugates. Nanoparticles are formed by 2 techniques: polymeric nanoparticles are formed by nanoprecipitation, and self-assembled nanoparticles are formed by a membrane hydration process.

Formation of polymeric nanoparticles by nanoprecipitation: clindamycin undecylenate (25mg) was dissolved in THF (1.0 ml). This solution was then added dropwise to a 1% aqueous PVA solution at room temperature with stirring at 1200 rpm. Stirring was continued for 24 hours to remove THF. The dispersion was then centrifuged at 1000rpm for 10min to remove any larger particles. As shown in fig. 23, the resulting dispersion had an average particle size of about 218nm with a sharp distribution (PDI = 0.149).

Self-assembled nanoparticles are formed by a membrane hydration process: egg lecithin (3mg) and clindamycin laurate (10mg) were dissolved in 4.0ml of dichloromethane. The solvent was removed under vacuum and the residue was hydrated with 1.0ml of water. The resulting mixture was rotated on a rotary evaporator at 60 ℃ for 1 hour under normal pressure to obtain crude self-assembled particles (or liposomes). The crude pellet was passed through a SephadexG-25 column to remove any free clindamycin laurate. The initial turbid fractions were collected, pooled together and finally passed through a size extruder (30X separation) fixed with a 200nm membrane. The treated liposomal suspension was characterized by a malvern zetasizer to obtain a size distribution. The resulting distribution was narrow and the average size of the liposomes was about 158nm, as shown in figure 24.

Example 17: in vitro bioefficacy studies of the synthetic antifungal conjugates.

The efficacy of the antifungal conjugates of the present invention was studied mainly by 3 methods:

(i) minimum Inhibitory Concentration (MIC) was determined by a) agar plate serial dilutions and b) liquid medium macrodilution and microdilution methods

(ii) Inhibition Zones (ZOI) were determined by a) agar well diffusion method and b) Kirby Bauer disk diffusion method

(iii) Time kill kinetics determination by the alamar blue and viable count method

Minimum Inhibitory Concentration (MIC): MIC is herein taken as the minimum inhibitory concentration that inhibits 100% of fungal growth, which is equivalent to the Minimum Fungicidal Concentration (MFC).

Culturing Malassezia furfur on agar plates prepared with Leeming Notman (LN) medium [ Journal of Clinical Microbiology (1987),25:2017-9 and references therein]. To obtain MIC by the agar dilution method, a suitable dilution of the dissolved antifungal composition is added to an autoclaved solution containing molten LN medium in graduated cylinders. The solution was vortexed and the contents poured into a separate sterile petri dish, labeled accordingly. Once the plates were solidified, an inoculum of Malassezia furfur adjusted to a specific CFU/ml was streaked on agar plates and subjected to CO₂Incubate in atmosphere for 2 days. After incubation, the plates were visually observed to observe the growth of malassezia furfur. MIC was defined as the lowest experimental dilution of antifungal active that produced no growth. The MIC values of the antifungal agents were compared to the MIC values of the control compound ketoconazole. The potency of the antifungal active agent is indicated by the corresponding MIC value.

Equipment and reagents: microorganisms: malassezia furfur (MTCC 1374); agar medium 60ml Leeming Notman medium was used for each active agent to be tested at their various concentrations; solvent: DMSO (dimethyl sulfoxide), water, other solvents suitable for the active agent; culture dish: each antifungal active agent was sterilized at a concentration of 3 dishes per test, size =15mmx100 mm.

And (3) experimental operation: liquid media and agar dilutions are routinely used in antimicrobial susceptibility testing. Therefore, to study MIC, agar plate dilution method was performed with LN medium. Each experimental protocol was performed in triplicate and performed as follows:

(i) LN medium was prepared according to the manufacturer's instructions.

(ii) The medium was autoclaved (121 ℃,15min) and cooled to 50 ℃. The antibiotics chloramphenicol (working concentration 0.25mg/ml) and cycloheximide (working concentration 0.04mg/ml) and 2% olive oil were added accordingly.

(iii) After the medium is cooled, the amount of antifungal composition and control solution needed is calculated. Stock solutions of antifungal compositions and controls at specific concentrations were prepared in DMSO. Concentration ranges were tested according to MIC of antifungal agent.

(iv) The appropriate volume (for the highest dilution) was taken from the stock solutions separately and further diluted with LN medium to reach the required range at the final volume.

(v) As an example, the first dilution was made up to 120ml and aseptically mixed into 200ml autoclaved graduated cylinders, vortexed for 20 seconds, and 20ml each poured into 3 sterile petri dishes appropriately labeled. Similarly, controls were also prepared using the above procedure. In this way, all dilutions were done and agar plates containing the antifungal composition and controls were prepared.

(vi) The plates were placed in a biosafety cabinet for curing, after which they were stacked and stored for contamination check the next day.

(vii) The next day, inoculum preparation was performed, adjusting inoculum density to 5.1 × 10³And the agar plates containing the drug were aseptically streaked.

(viii) Placing the plate on CO₂In an incubator at (30 + -2) deg.C and 5% CO₂Incubations were read after every 24 hours for 6 days.

Figure 25 shows representative photographs of MIC agar plate assays of TEG-based conjugates. Figure 26 shows representative photographs of MIC agar plate assays based on methylene and ethylene conjugates. Figure 27 shows representative photographs of MIC agar plate assays of conjugates KMP and KAH.

MIC values for some exemplary ketoconazole prodrug conjugates are summarized in table 7.

Table 7: MIC values for some exemplary ketoconazole conjugates.

Conjugates	MIC(μM)
		Ketoconazole-methylene-octanoate (KMC)	0.94-3.7
Ketoconazole-methylene-oleate (KMO)	1.88-7.5
		Ketoconazole-methylene-linoleate (KMLi)	7.5
Ketoconazole-methylene-laurate (KML)	1.88-3.7
		Ketoconazole-methylene-undecenoate (KMU)	3.7-7.5
Ketoconazole-methylene-palmitate (KMP)	1.88
		Ketoconazole-ethylene-octanoate (KEC)	1.88
Ketoconazole-1-ethylidene-oleate (KEO)	1.88-3.7
		Ketoconazole-1-ethylene-laurate (KEL)	1.88-3.7
Ketoconazole-1-ethylene-undecenoate (KEU)	1.88-7.5
		Ketoconazole-1-ethylene-palmitate (KEP)	3.7-7.5
Ketoconazole-1-ethylene-myristate (KEM)	1.88-3.7
		Ketoconazole-1-ethylene-oleyl carbonate (KCO)	1.88
Ketoconazole-triethylglycero-ketoconazole	0.94-3.7
		Ketoconazole-oleyl-triethylenetrialkyl carbonate	7.5-15

Comparative study of ketoconazole conjugates by zone of inhibition (ZOI) assay: malassezia furfur is a normal microflora of human skin that secretes extracellular lipases that act on the ester/carbonate linkages of fatty acids in their surrounding environment and provide nutrients for their survival. The negative control compound, keto-N-hexadecylacetamide (KAH), was synthesized as described in example 3. KAH served as a negative control because the linker between the fatty acid and ketoconazole was an amide bond. The lipase enzyme cannot act on the amide bond and cleave the compound back to ketoconazole. Comparative bioefficacy studies were performed with ketoconazole conjugate (KMP) and negative control (KAH) and positive control ketoconazole.

ZOI was determined by the agar well diffusion method to study complete inhibition of microbial growth.

Equipment and reagents: microorganisms: malassezia furfur (MTCC 1374); agar medium 60ml Leeming Notman medium was used for each active agent to be tested at their various concentrations; solvent: DMSO, water, other solvents suitable for the active agent; culture dish: 3 petri dishes per concentration to be tested, sterilized, size =15mmx100mm for each antifungal active agent; and a sterile pipette for perforating (6mm diameter) in agar plates.

And (3) experimental operation: the ZOI was determined by the agar well diffusion method to show inhibition of microbial growth. The experiments were performed as follows:

(i) sabaroud's Dextrose Agar (SDA) medium was prepared according to the manufacturer's instructions.

(ii) SDA medium was autoclaved (121 ℃,15min) and cooled to 50 ℃. Chloramphenicol (working concentration 0.25mg/ml), cycloheximide (working concentration 0.04mg/ml) and 2% olive oil were added accordingly.

(iii) Inoculum was prepared by a hemocytometer, adjusting inoculum density to 5.1x10³And the agar plates containing the drug were aseptically streaked.

(iv) After the medium had cooled, a 6mm wide hole was punched in the agar plate using a sterile pipette.

(v) The amounts of antifungal composition and control solution were calculated as needed. Stock solutions with specific concentrations of antifungal composition and control were prepared in DMSO.

(vi) An appropriate volume of 60 μ l was taken from the stock containing various prodrug concentrations as well as the negative control compound.

(vii) Placing the plate on CO₂In an incubator at (30 + -2) deg.C and 5% CO₂Incubations, read out every 24 hours for 6 days. ZOI was defined as the lowest drug concentration when complete inhibition of malassezia furfur was observed around the wells.

FIG. 28 shows a photograph of representative ZOIs measured by the agar well diffusion method. As the data summarized in fig. 29 indicate, the inhibition zone sizes for ketoconazole-fatty acid conjugates and ketoconazole are similar. However, the inhibition zone size of the negative control KAH was absent.

Time kill kinetics determination: experiments were performed to confirm the inhibition of microbial growth. The killing of yeast isolates by one or more antifungal agents is determined under controlled conditions, referred to as a time kill assay. The time kill kinetics result is an index measure of anti-fungal/bacterial efficacy. In general, the inhibition of fungal growth is directly proportional to the anti-fungal efficacy of the prodrug compounds tested.

Flasks containing Sabouraud's glucose broth (SDB) containing 2% olive oil were inoculated with malassezia furfur. The active prodrug compound and the control compound ketoconazole were then added to the liquid medium at the specified concentrations. Samples were removed from the flasks at predetermined time points, diluted with sterile water, and streaked onto SDA agar plates. After incubation of the plates at the specified temperature, visible growth of colonies of malassezia furfur was observed. The number of observed colonies was counted and converted to colony forming units/ml, i.e., CFU/ml SDB medium. Thus, the lower the CFU/ml value, the better the antifungal effect of the test compound.

Equipment and reagents: microorganisms: malassezia furfur (MTCC 1374); agar medium 60ml Leeming Notman medium was used for each active agent to be tested at their various concentrations; solvent: DMSO, water, other solvents suitable for the active agent; culture dish: 3 petri dishes per concentration to be tested, sterilized, size =15mmx100mm for each antifungal active agent; and a test tube: 15ml falcon sterile test tube.

And (3) experimental operation: the experiments were performed as follows:

(i) malassezia furfur was allowed to reach log phase by overnight incubation on SDA agar plates. Cell concentration was determined by a hemocytometer to obtain the initial inoculum density of the experiment. 1ml of the conditioned inoculum was added to 9ml of SDB containing 2% olive oil, the latter with cycloheximide and chloramphenicol antibiotics.

(ii) After addition of liquid medium, the inoculum density is reduced to a dilution factor of 1:10, e.g. 5x10 for the starting inoculum⁵CFU/ml, diluted to 5X10⁴CFU/ml。

(iii) 1.5ml of each liquid medium diluted inoculum was added to a 15ml falcon tube. These reaction tubes were prepared for prodrug compounds at 0.25xMIC, 0.5xMIC, 1xMIC, 2xMIC, and 4xMIC and 8xMIC concentrations, and the tubes were gently vortexed.

(iv) The predetermined point is selected accordingly. At each time interval, 100 μ Ι each was removed and vortexed for 30 seconds. The reaction tube was returned to 30 ℃ with 5% CO as quickly as possible₂The incubator of (1).

(v) From 100. mu.l of the solution, 30. mu.l each were plated on SDA agar plates. After streaking and incubation of the plates, colonies were counted manually after 48 h.

The standardized parameters for the antifungal time kill test of yeast are shown in table 8. The results of the time kill kinetics assay are shown in table 9 and fig. 30-31B. The data for the time kill curve in fig. 30 (at 4 hours, using 0.25 μ g/ml) indicate better uptake of KMC versus ketoconazole. Thus, KMC was found to act faster than ketoconazole at 0.25. mu.g/ml. This observation was valid for the concentration range of ketoconazole and KMC (0.125-1.0 μ g/ml) as demonstrated in fig. 31A and 31B.

Table 8: standardized protocol for time kill assay of antifungal agents on yeast

Table 9: data for ketoconazole, KMC and time kill kinetics assay in the absence of drug

Lipase-mediated hydrolysis of ketoconazole conjugates: in this study, lipase mediated hydrolysis of ketoconazole conjugates was studied.

Equipment and reagents: microorganisms: malassezia furfur (MTCC 1374); culture medium: 50ml SDB containing 2 different concentrations (125 and 250. mu.g/ml) of the active agent to be tested; solvent: medium, water, other solvents suitable for the active agent; and a test tube: 15ml falcon sterile test tube.

And (3) experimental operation: the experiments were performed as follows:

(i) malassezia furfur was allowed to reach log phase by overnight incubation on SDA agar plates. Cell concentration was determined by a hemocytometer to obtain the initial inoculum density of the experiment.

(ii) 1ml of the conditioned inoculum (10)⁵CFU/ml) was added to 10ml of SDB containing 2% olive oil with cycloheximide and chloramphenicol antibiotics and prodrug at a concentration of 250 μ g/ml. The final mixture was vortexed for 30 seconds.

(iii) 5ml of the above mixture was transferred to a 15ml falcon tube and 5ml of SDBO (SDB with olive oil) was added serially to prepare a prodrug concentration of 125. mu.g/ml and the resulting solution was vortexed.

(iv) Similarly, the negative control KAH was placed in SDBO medium containing the same concentration of prodrug, without inoculum. The tubes were then incubated at 32 ℃ with 5% CO₂And (4) incubation. On day 3, 1ml of the reaction mixture (including the reaction mixture containing KAH solution) was removed and extracted 3 times with ethyl acetate to quantitatively measure the remaining prodrug and converted drug under the same experimental conditions.

(v) The sample was concentrated and analyzed by HPLC.

As can be seen from the data in table 10, the ketoconazole conjugates are sensitive to fungal secreted lipases compared to the amide conjugate KAH. Determination of the percent cleavage of the prodrug to drug was analyzed by HPLC. The test organism was malassezia furfur and the test principle was performed as an evaluation of the hydrolysis rate of the prodrug.

TABLE 10 Lipase-mediated cleavage of prodrug into drug as determined by HPLC analysis.

Example 18: in vitro potency studies of synthetic antibacterial conjugates.

Staphylococcus aureus can cause skin infections, among many other types of infections. It can cause cellulitis (infection of the skin and tissue located in the immediate vicinity of the skin), boils (infection of pus-filled hair follicles), abscesses (accumulation of pus in or under the skin), carbuncles (infection larger than abscesses, usually with several openings to the skin), impetigo (skin infection with pus-filled blisters) and rashes (skin appearing as reddish or red areas). To investigate the efficacy of the synthetic conjugates of the present invention, experiments were performed to demonstrate complete inhibition of the growth of microorganisms. In this experiment, the MIC was determined by an agar plate serial dilution method to evaluate the potency of the synthesized conjugates.

Minimum Inhibitory Concentration (MIC): MIC is an indicator of the measure of anti-acne efficacy. Generally, the lower the MIC value of a composition, the higher its antibacterial efficacy because of its inherent ability to inhibit bacterial growth.

In this experiment, Staphylococcus aureus was cultured on agar plates made with Chapman medium [ American Veterimental Research (1947)8:173 ]. To determine the MIC by the agar dilution method, an appropriate dilution of the dissolved antibacterial composition was added to an autoclaved measuring cylinder containing molten Chapman's Medium (CM). The cartridge was vortexed and the contents poured into a separate sterile petri dish, labeled accordingly. After the plates were solidified, the plates were streaked with an inoculum of Staphylococcus aureus adjusted to a specific CFU/ml and incubated in an anaerobic jar for 2 days. After incubation, the plates were observed for visible staphylococcus aureus growth. MIC was defined as the lowest experimental dilution of the antibacterial active that produced no growth. The MIC values of the antibacterial active agent were compared with those of the control compound clindamycin. The potency of an antibacterial agent is indicated by the MIC value.

Equipment and reagents: microorganisms: staphylococcus aureus (MTCC 3160); agar medium: 60ml Chapman medium was used for each active agent to be tested at their various concentrations; solvent: DMSO (dimethyl sulfoxide), water, other solvents suitable for the active agent; and the concentration of each antifungal agent to be tested in triplicate sterilized dishes.

And (3) experimental operation: liquid media and agar dilutions are routinely used in antimicrobial susceptibility testing. To investigate the minimum inhibitory concentration, an agar plate dilution method was performed with Chapman medium. Each experimental protocol was performed in triplicate. The experiments were performed as follows:

(i) chapman medium was prepared according to the manufacturer's instructions.

(ii) The medium was autoclaved (121 ℃,15min), cooled to 50 ℃, and then antibiotics were added.

(iii) After the medium was cooled, the required amounts of antibacterial composition and control solution were calculated. Stock solutions of the antibacterial composition and controls at the desired concentrations were prepared in DMSO.

(iv) Appropriate volumes were removed from the stock solutions, respectively, and further diluted with Chapman medium to reach the desired range at the final volume.

(v) As an example, the first dilution was made up to 120ml and mixed under sterile conditions, vortexed for 20 seconds, and 20ml each was poured into 3 sterile petri dishes appropriately labeled. Similarly, controls were also prepared using the above procedure.

(vi) Placing the flat plate in a biological safety cabinet for solidification; after curing, the plates are stacked and stored.

(vii) The next day, inoculum preparation, inoculum density adjustment, and sterile streaking of drug-containing agar plates were performed.

(viii) The plates were incubated in an incubator at (36. + -.2) ℃ under anaerobic conditions, and read out after every 24 hours for 6 days. MIC was defined as the lowest drug concentration at which complete inhibition of staphylococcus aureus was observed.

MIC values for some clindamycin prodrug conjugates are shown in table 11.

Table 11: MIC values, μ g/ml concentrations, for different clindamycin conjugates.

Conjugates	MIC(μg/ml)
		Clindamycin palmitate	128
Clindamycin-laurate	128
		Clindamycin stearate	32
Clindamycin-10-undecenoate	128
		Clindamycin-succinate-triclosan	32

Example 19: nanocrystallization of antifungal and antibacterial agents

Some antifungal and antibacterial agents for surface applications are nanocrystallized. Nanoparticles were formed using 2 protocols: nanoprecipitation is performed using a single polymer and using a combination of polymers. The polymeric nanoparticle formation using nanoprecipitation and further processing of the resulting dispersion is exemplified using zinc pyrithione as an antifungal agent.

Preparation of polymeric nanoparticles of ZPTO

Several nanoparticle dispersions were prepared using zinc pyrithione in combination with different polymers and fatty acid/lipid combinations, some of which were further processed to ultimately yield a free flowing powder with stable nanoparticles and appreciable drug content.

Precipitation of ZPTO using poly (vinyl alcohol) (PVA) nanoprecipitations: a solution of zinc pyrithione, DMSO, and THF was added dropwise to a 1% aqueous PVA solution (80% hydrolysis) with stirring at about 1200 rpm. The dispersion was stirred for an additional 24 hours to remove THF, then centrifuged at 1000rpm for 10 minutes to remove larger particles (if present). The articles were then subjected to Dynamic Light Scattering (DLS) analysis [ Z ] using Malvern Zetasizer ZS90_avg:337nm,PDI:0.165]。

Nanoprecipitation of ZPTO using palmitin (tripalmitin) and PVA: a solution of zinc pyrithione, palm olein, DMSO, and THF was added dropwise to a 1% aqueous PVA solution (80% hydrolysis) with stirring at about 1200 rpm. The dispersion was stirred for an additional 24 hours to remove THF, then centrifuged at 1000rpm for 10 minutes to remove larger particles (if present). The preparation was then subjected to DLS analysis [ Z ]_avg:526nm,PDI:0.221]。

ZPTO was nano-precipitated using Capmul MCM C8EP (monocaprylate) and PVA: a solution of zinc pyrithione, capmul MCM C8EP (from Abitec), DMSO, and THF was added dropwise to a 1% aqueous PVA solution (80% hydrolysis) with stirring at about 1200 rpm. The dispersion was stirred for a further 24 hours and then centrifuged at 1000rpm for 10 minutes to remove larger particlesParticles (if present). The supernatant was concentrated by means of a centrifugal filter unit (50 kD; from Millipore). The concentrated dispersion was then subjected to DLS analysis [ Z _avg:731nm,PDI:0.349]Drug loading efficiency (90%), compared to the bioactivity of ZPTO not nanoformulated. Finally, the concentrated dispersion was lyophilized using sucrose as cryoprotectant (5%) and the drug content (7%) was also determined.

Precipitation of ZPTO with PLGA, Capmul MCM C8EP and PVA nanoparticles: a solution of zinc pyrithione, PLGA, capmul MCM C8EP (from Abitec) and DMSO was added dropwise to a 1% aqueous PVA solution (80% hydrolysis) with stirring at about 1200 rpm. The dispersion was stirred for an additional 24 hours and then centrifuged at 1000rpm for 10 minutes to remove larger particles, if any. The preparation was then subjected to DLS analysis [ Z ]_avg:330nm,PDI:0.176]。

ZPTO (sodium laureth sulfate) was precipitated using PLGA, Capmul MCM C8EP and SLES nanoparticles: a solution of zinc pyrithione, PLGA, capmul MCMC 8EP and DMSO was added dropwise to a 0.1% aqueous SLES solution with stirring at about 1200 rpm. The dispersion was stirred for another 48 hours and then centrifuged at 1000rpm for 10 minutes to remove larger particles, if any. The supernatant was concentrated by means of a centrifugal filter unit (50KD; from Millipore). The concentrated dispersion was then subjected to DLS analysis [ Z_avg:140nm,PDI:0.231]Drug loading efficiency (48%) was compared to the bioactivity of the non-nanofabricated ZPTO. The concentrated dispersion was finally lyophilized with mannitol as cryoprotectant (2-5%) and the drug content (8%) was also determined.

Table 12 summarizes data for some exemplary zinc pyrithione nano-articles.

TABLE 12 average size distribution (Z) of some Zinc pyrithione nano-articles_avg) Polydispersity index (PDI) and major composition.

Claims (61)

1. A conjugate-based antifungal or antibacterial prodrug of the formula:

(i)(AFA)_m-X-(L)_nwherein: AFA is an antifungal or antibacterial agent; l is a carrier; x is a linker; m ranges from 1 to 10; and n ranges from 2 to 10;

(ii)[(AFA)_m’-X]_p-L, wherein: AFA is an antifungal or antibacterial agent; l is a carrier; x is a linker; m' is 1 to 10; and p is 1 to 10;

(iii)AFA-[X-(L)_n’]_qwherein: AFA is an antifungal agent orAn antibacterial agent; l is a carrier; x is a linker; n' is 1 to 10; and q is 1 to 10, with the proviso that q' and n are not both 1; or

(iv)(AFA)_m”-X, wherein: AFA is an antifungal or antibacterial agent; x is a linker; and m' is 1 to 10.

2. The conjugate-based prodrug of claim 1, wherein m' and p are 1.

3. The conjugate-based prodrug of claim 1, wherein q is 1 and n' is 2.

4. The conjugate-based prodrug of claim 1, wherein m "is 2.

5. The conjugate-based prodrug of claim 1, wherein the conjugate-based prodrug is a nanoparticle.

6. The conjugate-based prodrug according to claim 5, wherein the nanoparticle is 1nm to 1000nm in size.

7. The conjugate-based prodrug of any of claims 1-6, wherein the prodrug is formulated into a nanoparticle selected from the group consisting of: liposomes, polymeric nanoparticles, nanoemulsions, self-microemulsifying drug delivery systems (SMEDDS), solid-lipid nanoparticles, nanostructured liquid crystals, and any combination thereof.

8. The conjugate-based prodrug according to claim 7, wherein the nanoparticle is 20nm-500nm in size.

9. The conjugate-based prodrug of any of claims 1-8, wherein the linker is attached to the ring-nitrogen of the azole moiety of the antifungal agent or the antibacterial agent, or the linker is attached to the hydroxyl group of the antifungal agent or the antibacterial agent.

10. The conjugate-based prodrug of any of claims 1-9, wherein the linker is a cleavable linker.

11. The conjugate-based prodrug of any of claims 1-10, wherein the linker is cleaved by an esterase.

12. The conjugate-based prodrug of claim 11, wherein the esterase is a lipase.

13. The conjugate-based prodrug of any one of claims 1-12, wherein the linker is cleaved by a lipase from the fungus malassezia spp.

14. The conjugate-based prodrug according to claim 13, wherein the fungus belongs to the genus malassezia.

15. The conjugate-based prodrug of any of claims 1-14, wherein the linker is selected from the group consisting of:

(i)-CH(R¹) -, wherein R¹H or C₁-C₆An alkyl group which may be optionally substituted and/or interspersed with one or more of heteroatoms, aryl groups, heteroaryl groups, cyclic groups and heterocyclic groups;

(ii)orWherein R is^2aIs a hydroxy protecting group; r^2bIs C₁-C₆Alkyl, which may be optionally substituted or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl groups; and R is^NIs absent, H, C₁-C₆Alkyl or acyl, each of which may be optionally substituted;

(iii) formula-CH₂CH₂[OCH₂CH₂]_aOHC₂CH₂The polyethylene glycol of (a), wherein a is 1 to 50;

(iv)-CH₂C(R^3aR^3b)CH(OR^3c)C(O)N(R^3d)-(CH₂)_b-, wherein R^3aAnd R^3bIndependently is H or C₁-C₆Alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl groups; r^3cIs H or a carrier; r^3dIs H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl or heteroaryl, each of which may be optionally substituted; and b is 1 to 10;

(v)wherein R is⁴Is halo, CN, CF3, alkyl, alkenyl, cyclyl, heterocyclyl, aryl, heteroaryl, NO₂、OR⁶、OC(O)R^4a、OC(O)OR^4a、N(R^4a)₂、NHC(O)R^4a、NHC(O)OR^4a、C(O)R^4a、C(O)OR^4a、SR^4aOr SO₂R^4aEach of which may be optionally substituted; r^4aEach occurrence is independently H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl or heteroaryl, each of whichOne may be optionally substituted; and c is 0 to 4;

(vi)-CH₂CH(R⁶) -, where R is H or C₁-C₆Alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl groups;

(vii)-CH(R⁷) C (O) -, wherein R⁷Is H, C₁-C₆Alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, and heterocyclyl;

(viii)-CH(R⁸) OC (O) -L' -C (O) O-, wherein R⁸Is H or C₁-C₆An alkyl group; and L' is alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, or heterocyclyl groups, each of which may also be optionally substituted;

(ix)-CH(R⁹)OC(O)-、-CH(R⁹)OC(O)-L’-、-CH(R⁹) OC (O) -L' -Y-or-CH (R)⁹) OC (O) -L' -Y-C (O) -, wherein R⁹Is H or C₁-C₆An alkyl group; y is O, S or NH; and L' is alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, or heterocyclyl groups, each of which may be optionally substituted;

(x)-CH(R^10a)OC(O)-L’-C(O)OCH(R^10b) -, wherein R^10aAnd R^10bIndependently is H or C₁-C₆Alkyl, which may be optionally substituted; and L' is C₁-C₂₀An alkyl group, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl groups, heteroaryl groups, cyclic groups, or heterocyclic groups, each of which may be optionally substituted;

(xi) -C (O) -L ' -C (O) -, -C (O) -L ' -Y-or-C (O) -L ' -Y-C (O) -, wherein Y is O, S or NH; and L' is alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl, or heterocyclyl groups, each of which may be optionally substituted;

(xii)-C(O)-L’-C(O)O-[CH₂CH₂O]_v’-, wherein v 'is 1 to 500 and L' is alkyl, which may be optionally substituted and/or interspersed with one or more heteroatoms, aryl, heteroaryl, cyclyl or heterocyclyl, each of which may be optionally substituted;

(xiii)PLGA；

(xiv) A direct bond;

(xv) A dicarboxylic acid;

(xvi) A beta-hydroxy acid;

(xvii) A polycarboxylic acid; and

(xviii) Any combination thereof.

16. The conjugate-based prodrug of any of claims 1-15, wherein the antifungal agent comprises an azole moiety or a hydroxyl group.

17. The conjugate-based prodrug of any of claims 1-16, wherein the antifungal agent is selected from the group consisting of: fluconazole, isaconazole, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole, ravuconazole, natamycin, rusomycin, nystatin, amphotericin B, echinocandin, colsais, pradimicin, benamicin, wakamycin, coprinus, allylamine, triclosan, piroctone, fenpropimorph, terbinafine, antifungal peptides and derivatives and analogs thereof.

18. The conjugate-based prodrug of any of claims 1-17, wherein the antibacterial agent is effective against propionibacterium acnes.

19. The conjugate-based prodrug of any one of claims 1-15 or 18, wherein the antibacterial agent is selected from the group consisting of: macrolides or ketolides such as erythromycin, azithromycin, clarithromycin, and telithromycin; beta-lactams including penicillins, cephalosporins, and carbapenems such as carbapenems, imipenem and meropenem; monobactams such as penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin, cephalothin, cefapirin, cephradine, ceftazidime, ceftizoxime, cefamandole, cefuroxime, cephalexin, cephacrylene, cefaclor, chloroceph, cefoxitin, cefmetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, cefepime and aztreonam; quinolones such as nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin, gatifloxacin, gemifloxacin and pazufloxacin; antibacterial sulfonamides and antibacterial sulfanilamides including p-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole and phthalylsulfathiazole; aminoglycosides such as streptomycin, neomycin, kanamycin, paromomycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekacin, and isepamicin; tetracyclines such as tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline; rifamycins such as rifamycin (also known as rifampin), rifapentine, rifabutin, benzoxazinorifamycin, and rifaximin; lincosamines such as lincomycin and clindamycin; glycopeptides such as vancomycin and teicoplanin; streptogramines such as quinupristin and dalfopristin; oxazolidinones such as linezolid; polymyxins, colistins and colistins; and trimethoprim and bacitracin.

20. The conjugate-based prodrug of any of claims 1-19, wherein the carrier comprises a carboxyl group or a hydroxyl group.

21. The conjugate-based prodrug of any of claims 1-20, wherein the carrier is a polymer; carboxylated polymers, hydroxylated polymers, polyethylene glycols; carboxylated PEG comprising C₆-C₂₆An alkyl fatty acid, which may be optionally substituted and/or interspersed with heteroatoms, aryl, heteroaryl, cyclyl, or heterocyclyl; an amino acid; a peptide; a nucleic acid; glycerol, substituted glycerols, antibacterial agents, antifungal agents; alpha-hydroxy acids, beta-hydroxy acids, dicarboxylic acids, oxo diacids, and any combination thereof.

22. The conjugate-based prodrug of any of claims 1-21, wherein the carrier is a fatty acid selected from the group consisting of: octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid, pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, myristoleic acid, palmitoleic acid, hexadecene-6-acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, elaidic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, cis-11-octadecenoic acid, cis-11-eicosenoic acid, undecylenic acid, cis-13-docosenoic acid, neoheptanoic acid, neononanoic acid, neodecanoic acid, isostearic acid, 10-undecenic acid, adapalene.

23. The conjugate-based prodrug of any of claims 1-21, wherein the carrier is a polymer selected from the group consisting of: PLGA, PLA, PEG, chitosan, pullulan, polylactide, polyglycolide, polycaprolactone, copolymers of polylactic and polyglycolic acid, polyanhydrides, polyepsilon caprolactone, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polydihydropyrans, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly (malic acid), poly (amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polymethylmethacrylate, chitin, chitosan, copolymers of polylactic and polyglycolic acid, poly (glycerol sebacate) (PGS) and copolymers, terpolymers, gelatin, collagen, silk, chitosan, alginates, cellulose, polynucleic acids, cellulose acetate (including cellulose diacetate), Polyethylene, polypropylene, polybutylene, polyethylene terephthalate (PET), polyvinyl chloride, polystyrene, polyamide, nylon, polycarbonate, polysulfide, polysulfone, hydrogel (e.g., acrylic acid), polyacrylonitrile, polyvinyl acetate, cellulose acetate butyrate, cellulose nitrate, copolymers of urethane/carbonate, copolymers of styrene/maleic acid, poly (ethyleneimine), Pluronic (poloxamers 407, 188), hyaluronidase, heparin, agarose, pullulan, ethylene/vinyl alcohol copolymers (EVOH), and copolymers comprising one or more of the foregoing.

24. The conjugate-based prodrug of any of claims 1-21, wherein the carrier is selected from the group consisting of: undecylenic acid; palmitic acid; oleic acid, linoleic acid, lauric acid, lys-his-lys-his-lys-his hexapeptide; l-or D-tyrosine; l-or D-serine; l-or D-threonine; a peptide of 2-10 amino acids; chitosan and pullulan.

25. The conjugate-based prodrug of any of claims 1-24, wherein the conjugate is ketoconazole methyl palmitate, ketoconazole 1-ethyl palmitate, ketoconazole methyl laurate, ketoconazole 1-ethyl laurate, ketoconazole methyl undecylate, ketoconazole 1-ethyl undecylate, ketoconazole methyl oleate, ketoconazole 1-ethyl oleate, ketoconazole methyl linoleate, ketoconazole 1-ethyl linoleate, ketoconazole-methylene-PLGA, ketoconazole-pyridoxine-undecylenic acid, ketoconazole-ubiquinol dimer, ketoconazole-propylene glycol-hexapeptide, ketoconazole-lactic acid-chitosan, ketoconazole-methylene-oxoacid-chitosan, ketoconazole-methylene-oxodiacid dimer, ketoconazole-methyl ester-carboxylic acid-ester, ketoconazole-methyl ester-oxodiacid dimer, ketoconazole-methyl ester, Ketoconazole-methylene-glutamic acid dimer, clindamycin-lauric acid conjugate, clindamycin-glycolic acid-PLGA conjugate, clindamycin-succinic acid-PLGA conjugate, clindamycin-adapalene conjugate, erythromycin-lauric acid conjugate, erythromycin-lactic acid-lauric acid conjugate, lauric acid-PLGA-erythromycin conjugate, adapalene-triethylglycosyl-erythromycin conjugate, clindamycin dimer with azelaic acid, clindamycin dimer with carboxylated PEG, clindamycin dimer with glutamic acid, clindamycin dimer with oxydiethylacetic acid, clindamycin triclosan conjugate, clindamycin-glutamic acid-triclosan conjugate, or clindamycin-oxydiethylacetic acid-triclosan conjugate.

26. A nanoparticle, comprising: (i) a first component selected from an antifungal agent, an antibacterial agent, or a combination thereof; and (ii) a second component selected from a lipid, a polymer, or a combination thereof.

27. The nanoparticle of claim 26, wherein the first component is about 0.01 wt% to about 99 wt% based on the total weight of the nanoparticle.

28. The nanoparticle of claim 26 or 27, wherein the lipid is about 0.01 wt% to about 99 wt% based on the total weight of the nanoparticle.

29. The conjugate of any one of claims 26-28, wherein the first component and the second component are not covalently linked to each other.

30. The nanoparticle of any one of claims 26-29, wherein the nanoparticle is selected from the group consisting of: liposomes, polymeric nanoparticles, nanoemulsions, self-microemulsifying drug delivery systems (SMEDDS), solid-lipid nanoparticles (SLN), nanostructured liquid crystals, albumin-based nanoparticles, dendrimers, carbon nanotubes, Nanostructured Lipid Carriers (NLCs), polymersomes, nanocrystals, nanoemulsions, and the like.

31. The nanoparticle of any one of claims 26-30, wherein the nanoparticle is from about 1nm to about 1000nm in size.

32. The nanoparticle of any one of claims 26-31, wherein the nanoparticle is from about 20nm to about 500nm in size.

33. The nanoparticle of any one of claims 26-32, wherein the nanoparticle further comprises a surfactant.

34. The method of claim 33, wherein the surfactant is about 0.01 wt% to about 30 wt% based on the total weight of the nanoparticle.

35. The nanoparticle of any one of claims 26-34, wherein the nanoparticle further comprises a carrier or excipient.

36. The nanoparticle of claim 35, wherein the excipient is about 0.01 wt% to about 30 wt% based on the total weight of the nanoparticle.

37. The nanoparticle of any one of claims 26-36, wherein the lipid is selected from the group consisting of: fatty acids, fatty alcohols, glycerolipids (e.g., monoglycerides, diglycerides, and triglycerides), phospholipids, glycerophospholipids, sphingolipids, sterol lipids, pentadienol lipids, glycolipids, polyketides, and any combination thereof.

38. The nanoparticle of any one of claims 26-37, wherein the lipid is selected from the group consisting of: tripalmitin (Tripalm), ceteth-10, egg lecithin, soya lecithin, glycerol monocaprylate (Capmul MCM C8EP), Capmul MCM C10, glycerol tricaprylate/decanoate (Tri)355EP/NF), glyceryl distearate (type I) EP (Precirol ATO5), lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid, pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, nonacosanoic acid, melissic acid, hendecanoic acid, laccerotic acid, tricosanoic acid, grignard acid, hexatriacontanoic acid (Ceroplasticid), Hexatriacontylic acid (Hexatriacontylic acid), alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, oleic acid, elaidic acid, eicosenoic acid, erucic acid, nervonic acid, Mead, myristoleic acid, palmitoleic acid, hexadecen-6-oic acid, myri, Oleic acid, elaidic acid, vaccenic acid, linoleic acid, elaidic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid, pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, myristoleic acid, palmitoleic acid, hexadecene-6-oic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, elaidic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, cis-11-octadecenoic acid, cis-11-eicosenoic acid, Undecylenic acid, cis-13-docosenoic acid, neoheptanoic acid, neononanoic acid, neodecanoic acid, isostearic acid, 10-undecylenic acid, phosphatidic acid (phosphatidate, PA), phosphatidylethanolamine (cephalin, PE), phosphatidylcholine (lecithin, PC), Phosphatidylserine (PS), Phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), phosphatidylinositol diphosphate (PIP2), phosphatidylinositol triphosphate (PIP3), ceramide phosphorylcholine (sphingomyelin, SPH), ceramide phosphorylethanolamine (sphingomyelin, Cer-PE), ceramide phosphorylglycerol, cholestane, cholane, pregnane, androstane, isodecanoic acid, isostearic acid, 10-undecenoic acid, phosphatidic acid (phosphatidate, PA), phosphatidylethanolamine (cephalin, PE), phosphatidylinositol (phosphatidylcholine, PC), Phosphatidylserine (PS), Phosphatidylinositol (PI), Estrane, cholesterol, octanol, 2-ethylhexanol, nonanol, decanol, undecanol, lauryl alcohol, tridecanol, myristyl alcohol, pentadecanol, cetyl alcohol, palmitoleic alcohol, heptadecanol, stearyl alcohol, isostearyl alcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol, linolenyl alcohol, linoleyl alcohol, ricinoleyl alcohol, nonadecanol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, ceryl alcohol, 1-heptacosyl alcohol, montanyl alcohol, octacosyl alcohol, 1-nonacosyl alcohol, melissyl alcohol, 1-triacontyl alcohol, tetratriacontyl alcohol, cetostearyl alcohol, propylene glycol dicaprate, 1, 3-propylene glycol dicaprylate, caprylic/capric acid ester of a saturated C12-C18 fatty alcohol, propylene glycol dicaprate, tridecanoyl decanoate, myristyl, 1, 3-propanediol dicaprylate/dicaprate, glyceryl tricaprylate/tricaprate, caprylic/capric triglyceride, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/tricaprate, caprylic/capric triglyceride, glyceryl tricaprylate/caprate, glyceryl triacetate, glyceryl tricaprylate, triolein, and any combination thereof.

39. The conjugate of any one of claims 26-38, wherein the antifungal agent is selected from the group consisting of: zinc pyrithione, piroctone olamine, abafungin, abaconazole, allicin, amorolfine, anidulafungin, benzoic acid keratolytic agent, butenafine, butoconazole, caspofungin, ciclopirox (ciclopirox olamine), citronella Oil, clotrimazole, coconut Oil, crystal violet, econazole, fenticonazole, fluconazole, flucytosine or 5-fluorocytosine, griseofulvin, haloprogin, iodine, isavuconazole, isoconazole, itraconazole, ketoconazole, lemon myrtle, micafungin, miconazole, naftifine, neem seed Oil, olive leaf extract, omoconazole, orange Oil, oxiconazole, palmarole Oil, patchouli, polygonum hydropiper, posaconazole, ravuconazole, selenium, sertaconazole, sulconazole, tea tree Oil-ISO 4730 ("Oil of melaleuuca, Terpinen-4-type oils (oils of melanizole, terpinen-4-ol) "), terbinafine, terconazole, tioconazole, tolnaftate, undecylenic acid, voriconazole, zinc selenium disulfide, fluconazole, isaconazole, itraconazole, ketoconazole, miconazole, clotrimazole, voriconazole, posaconazole, ravuconazole, natamycin, rusomycin, nystatin, amphotericin B, echinocandin, colsaise, pradimicin, benamicin, warfarin, coprocetin, allylamine, triclosan, piroctone, fenpropimorph, terbinafine, antifungal peptides and their derivatives and analogs.

40. The conjugate of any one of claims 26-39, wherein the antibacterial agent is selected from the group consisting of: macrolides or ketolides such as erythromycin, azithromycin, clarithromycin, and telithromycin; beta-lactams including penicillins, cephalosporins, and carbapenems such as carbapenems, imipenem, and meropenem; monobactams such as penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin, cephalothin, cefapirin, cephradine, ceftazidime, ceftizoxime, cefamandole, cefuroxime, cephalexin, cephacrylene, cefaclor, chloroceph, cefoxitin, cefmetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, cefepime and aztreonam; quinolones such as nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin, gatifloxacin, gemifloxacin and pazufloxacin; antibacterial sulfonamides and antibacterial sulfanilamides including p-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole and phthalylsulfathiazole; aminoglycosides such as streptomycin, neomycin, kanamycin, paromomycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekacin, and isepamicin; tetracyclines such as tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline; rifamycins such as rifamycin (also known as rifampin), rifapentine, rifabutin, benzoxazinorifamycin, and rifaximin; lincosamines such as lincomycin and clindamycin; glycopeptides such as vancomycin and teicoplanin; streptogramines such as quinupristin and dalfopristin; oxazolidinones such as linezolid; polymyxins, colistins and colistins; and trimethoprim and bacitracin.

41. A personal care composition comprising an effective amount of a conjugate-based prodrug of any one of claims 1-25 or a nanoparticle of any one of claims 26-40.

42. The personal care composition of claim 41, wherein the composition further comprises a drug or a surface agent.

43. The personal care composition of claim 42, wherein the drug or the surface agent is selected from the group consisting of: those that ameliorate or eradicate age spots, keratoses, and wrinkles; local analgesics and anesthetics; an anti-acne agent; an antibacterial agent; an anti-yeast agent; an antifungal agent; an antiviral agent; anti-dandruff agents; an anti-dermatitis agent; an antihistamine; an antipruritic agent; an antiemetic agent; anti-motion sickness agents; an anti-inflammatory agent; an anti-excessive keratolytic agent; an antiperspirant; anti-psoriasis agents; anti-seborrhea agents; hair conditioners and hair treatment agents; anti-aging and anti-wrinkle agents; sunscreens and sunblocks; a skin lightening agent; a decolorizing agent; a vitamin; a corticosteroid; a tanning agent; a humectant; a hormone; retinoic acid compounds; gum disease or oral care agents; a topical cardiovascular agent; particulate, induration and wart removal agents; a depilatory agent; and any combination thereof.

44. The personal care composition of claim 42 or 43, wherein the drug or the surface agent is selected from the group consisting of: azelaic acid, triclosan, alpha-hydroxy acids, glycolic acid, mandelic acid, beta-hydroxy acids, salicylic acid, polyhydroxy acids, lactobionic acid, galactose, gluconic acid, adapalene, abacavir, acebutolol, acetaminophen, acetaminosalol, acetazolamide, acetohydroxamic acid, acetylsalicylic acid, Avermentane, Alvastigmine, fentanyl, acyclovir, adapalene, Adefovir Dipivoxil, adenosine, albuterol, Alfuzosin, allopurinol, allopurin, Almotriptan, alprazan, alprenol, aluminum acetate, aluminum chloride, aluminum chlorohydrate, aluminum hydroxide, amantadine, amiloride, amsacrine, aminobenzoic acid (PABA), aminocaproic acid, aminosalicylic acid, amiodarone, amitriptyline, amlodipine, Amocamazine, Amoxicoquinol, Amorphophalli, Amoxicolone, Amoxamine, Amoxicapine, Amoxamine, Amoxicodendron, Amoxicolone, Amoxicodendron, Amoxicillin, Amoxicodendron, Ampicillin, anagrelide, anastrozole, dithranol, apomorphine, aprepitant, arbutin, aripiprazole, ascorbic acid, ascorbyl palmitate, atazanavir, atenolol, atomoxetine, atropine, azathioprine, azelaic acid, azelastine, azithromycin, bacitracin, beclomethasone, benazepril, benflumethiazide, benzocaine, benzonatate, benzophenone, benztropine, bepril, betamethasone dipropionate, betamethasone valerate, brimonidine, brompheniramine, bupivacaine, buprenorphine, bupropion, brevitone, brivaracetam, butenafine, butoconazole, cabergoline, caffeic acid, caffeine, calcipotriene, camphor, candesartan cilexetine, capsaicin, cefditoren pivoxil, cefepime, celecoxib, cetirizine, and cetirizine, Sevelamer, chitosan, chlordiazepoxide, chlorhexidine, chloroquine, chlorothiazide, chloroxylenol, chlorpheniramine, chlorpromazine, chlorpropamide, ciclopirox, cilostazol, cimetidine, cinacalcet, ciprofloxacin, citalopram, citric acid, cladribine, clarithromycin, clemastine, clindamycin, clioquinol, clobetasol propionate, clomiphene, clonidine, clopidogrel, clotrimazole, clozapine, cocaine, codeine, cromoglycine, cromipron, cyclizine, cyclobenzaprine, cycloserine, cytarabine, dacarbazine, dalfopristin, dapsone, daptomycin, daunorubicin, deferoxamine, dehydroepiandrosterone, delavirdine, desipramine, desloratadine, desmopressin, dexamethasone, dextomimedine, dexamethimine, dexamphetamine, citalopram, chlorpheniramine, citrate, chlorpheniramine, chlorpyrim, clomipramine, clohydramine, clo, Bicyclic virine, didanosine, dihydrocodeine, dihydromorphine, diltiazem, 6, 8-dimercaptooctanoic acid (dihydrolipoic acid), diphenhydramine, diphenoxylate, dipyridamole, propiram, dobutamine, dofetilide, dolasetron, donepezil, dopa ester, dopamine, dorzolamide, doxylamine, doxepin, doxorubicin, doxycycline, doxylamine, doxepipine, duloxetine, dyclonine, econazole, eflornithine, eletriptan, emtricitabine, enalapril, ephedrine, epinephrine, ephedrine, epirubicin, eptidine, ergotamine, erythromycin, escitalopram, esmolol, esomeprazole, estazolam, estradiol, etaneric acid, ethinylestradiol, etilenetinine, etidocaine, etomidine, famtidine, famatidine, felodipine, fentanil, fertilde, Fexofenadine, flecainide, fluconazole, flucytosine, fluocinonide, 5-fluorouracil, fluoxetine, fluphenazine, flurazepam, fluvoxamine, formoterol, furosemide, galactarolide, galactaric acid, galactonolactone, galantamine, gatifloxacin, gefitinib, gemcitabine, gemifloxacin, glycolic acid, griseofulvin, guaifenesin, guanethidine, histamine N-amidinate, haloperidol, haloprogin, homatropine, homosalazine, hydralazine, hydrochlorothiazide, hydrocortisone 21-acetate, hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydromorphone, hydroquinone, monoether, hydroxyzine, hyoscyamine, hypoxanthine, ibuprofen, ichthammol, idarubicin, flutriafolacin, fluvone, flu, Imatinib, imipramine, imiquimod, indinavir, indomethacin, irbesartan, irinotecan, isotalin, isoproterenol, itraconazole, kanamycin, ketamine, ketanserin, ketoconazole, ketoprofen, ketotifen, kojic acid, labetalol, lactic acid, lactobionic acid, lamivudine, lamotrigine, lansoprazole, letrozole, leuprolide, levalbuterol, levofloxacin, lidocaine, linezolid, lobeline, loperamide, losartan, loxapine, ergot diethylamide, sulfamylon, malic acid, maltobionic acid, mandelic acid, maprotiline, mebendazole, mecamylamine, meclizine, meclocycline, memantin, menthol, pethidine, mepivacaine, mercaptopurine, mescalin, methofurazol, oxcinalnaline, metaproterenol, metformin, methadone, methamphetamine, ketoprofen, methotrexate, methoxamine, methyldopate, methyldopamide, 3, 4-methylenedioxymethamphetamine, methyl lactate, methyl nicotinate, methylphenidate, methyl salicylate, methylthiomidate, metolazone, metoprolol, metronidazole, mexiletine, miconazole, midazolam, midodrine, meglumine, minocycline, dil, mirtazapine, mitoxantrone, moexiprilat, molindone, momobenzone, morphine, moxifloxacin, moxonidine, mupirocin, nadolol, naftifine, nalmefene, naloxone, naproxen, nefazodone, nelfinavir, neomycin, nevirapine, nicardipine, nicotine, nifedipine, nimodipine, nisodipine, nizatidine, noradrenaline, nystatin, octopamine, octreotide, methoxycinnamate, octyl salicylate, Ofloxacin, olanzapine, olmesartan medoxomil, olopatadine, omeprazole, ondansetron, oxiconazole, oxotremorine, oxybenzone, oxybutynin, oxycodone, oxymetazoline, padetamol O, palonosetron, pantothenic acid, panthenolide, paroxetine, pimoline, penciclovir, penicillamine, penicillin, pentazocine, pentobarbital, pentostatin, pentoxifylline, pergolide, perindopril, pameprazole, phencyclidine, phenelzine, pheniramine, phenmetrazine, phenobarbital, phenol, phenoxybenzamine, phendroxyepine, phenylpropanolamine, phenytoin, physostigmine, pilocarpine, papriine, mupiroxol, pipamazine, piperonyl butoxide, piperacillin, podophyllotoxin, pramoxine, pramipexole, zolosin, zolozolol, domonazine, panthenol, penoxpocetine, penciclovir, pen, Prednisone, pravastatin, prilocaine, procainamide, procaine, procarbazine, promazine, promethazine propionate, propafenone, dextropropoxyphene, propranolol, propylthiouracil, protiline, pseudoephedrine, pyrethrin, mepyramine, pyrimethamine, quetiapine, quinapril, quinethazone, quinidine, quinupristin, rabeprazole, reserpine, resorcinol, retinal, 13-cis-retinoic acid, retinol, retinyl acetate, retinyl palmitate, ribavirin, ribonic acid, ribonolactone, rifampin, rifapentine, rifaxine, rifaximin, riluzole, rimantadine, risedronic acid, risperidone, ritodrine, rivastigmine, rizatriptan, ropinirole, salicylamide, salicylic acid, salmeterol, hyoscyamine, letine, selenium, 5-hydroxytryptamine, sertindole, sertraline, sibutramine, sildenafil, sotalol, streptomycin, strychnine, sulconazole, sulfanilamide, sulfabenzoyl, sulfabromouracil, sulfacetamide, sulfachlorpyridazine, sulfaxetine, sulfadiazine, sulfadimethoxine, sulfadoxine, sulfaguanidine, sulfalene, sulfamethizole, sulfaxazole, sulfapyrazine, sulfapyridine, sulfasalazine, sulfisothiazole, sulfathiazole, sulfisoxazole, tadalafil, tamsulosin, tartaric acid, tazarotene, tegaserod, telithromycin, telmisartan, temozolomide, tenofovir, terazosin, terbinafine, terbutaline, terconazole, terfenadine, tetracaine, tetracycline, tetrahydrozoline, alkali, theophylline, thiazoxazole, thioridazine, tebuconazole, thymol, thiohydralazine, thymol, tiagabine, theobromine, thiohydramine, thiohydralazine, thio, Timolol, tinidazole, tioconazole, tirofiban, tizanidine, tobramycin, tocainide, tolazoline, tolbutamide, tolnaftate, tolterodine, tramadol, tranylcypromine, trazodone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone acetonide, triamterene, triazolam, triclosan, trifluoroperazine, trimethoprim, trimipramine, tripelennamine, triprolidine, tromethamine, tropine, tyramine, undecylenic acid, urea, urocanic acid, ursodeoxycholic acid, valdinafine, venlafaxine, verapamil, vitamin E acetate, voriconazole, warfarin, xanthine, zafirlukast, zaleplon, zinc pyrithione, ziprasidone, zolmitriptan, zolpidem, and any combination thereof.

45. The personal care composition of any one of claims 41-44, wherein the composition further comprises at least one cosmetic raw material or adjuvant selected from the group consisting of: antioxidants, preservatives, fillers, surfactants, UVA and/or UVB sunscreens, perfumes, thickeners, humectants, anionic polymers, nonionic polymers, amphoteric polymers, viscosity/foam stabilizers, opacifiers/pearlescers, masking agents, stabilizers, hair conditioners, humectants, antistatic agents, anti-freeze agents, buffers, dyes, pigments, hydrocarbons, esters, fatty alcohols, fatty acids, emulsifiers, viscosity modifiers, silicone-based materials, surfactants, emollients, humectants, stabilizers, film-forming materials, perfumes, colorants, chelating agents, preservatives, antioxidants, pH adjusters, water repellents, dry feel modifiers, vitamins, plant extracts, hydroxy acids, organic sunscreens, inorganic sunscreens, peptide-based inorganic sunscreens, and tanning agents.

46. The personal care composition of any one of claims 41-45, wherein the personal care composition is a hair care composition selected from the group consisting of: shampoos, conditioners, hair dyes, lotions, aerosols, gels, mousses and tints.

47. A method for treating or preventing dandruff comprising the steps of: administering to the scalp of a subject in need thereof a composition according to any one of claims 41-46.

48. The personal care composition of any one of claims 41-45, wherein the personal care composition is a skin care composition selected from the group consisting of: lotions, creams, gels, sticks, sprays, ointments, cleansing liquid lotions, cleansing solid bars, pastes, foams, powders, shaving creams and swabs.

49. A method for treating or preventing acne in a subject, said method comprising the steps of: administering the composition of any one of claims 41-46 or 48 to the skin of a subject in need thereof.

50. A method of treating or preventing a fungal or bacterial infection in a subject, the method comprising: administering a composition according to any one of claims 1-25 or 26-40.

51. The method of claim 50, wherein the administration is topical or systemic.

52. The method according to claim 50 or 51, wherein the fungal or bacterial infection is selected from the group consisting of: oral/vaginal candidiasis, intestinal endless (e.g., tinea infections of the body, scalp, beard, eczema marginalis, tinea pedis), nail infections, ear infections, and any combination thereof.

53. The method of any one of claims 50-52, wherein the subject is a mammal.

54. The method of any one of claims 50-53, wherein the subject is a human.

55. The method of any one of claims 50-53, wherein the subject is a non-human mammal.

56. Use of the composition of any one of claims 1-25 or 26-40 for treating or preventing a fungal or bacterial infection in a subject.

57. The use of claim 56, wherein the composition is applied topically or administered systemically.

58. The use according to claim 56 or 57, wherein the fungal or bacterial infection is selected from the group consisting of: oral/vaginal candidiasis, intestinal endless (e.g., tinea infections of the body, scalp, beard, eczema marginalis, tinea pedis), nail infections, ear infections, and any combination thereof.

59. The use of any one of claims 56-58, wherein the subject is a mammal.

60. The use of any one of claims 56-59, wherein the subject is a human.

61. The use of any one of claims 56-59, wherein the subject is a non-human mammal.