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WO2011014850A2 - Formulations à usage topique à base d'un eutectique - Google Patents

Formulations à usage topique à base d'un eutectique Download PDF

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Publication number
WO2011014850A2
WO2011014850A2 PCT/US2010/044036 US2010044036W WO2011014850A2 WO 2011014850 A2 WO2011014850 A2 WO 2011014850A2 US 2010044036 W US2010044036 W US 2010044036W WO 2011014850 A2 WO2011014850 A2 WO 2011014850A2
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Prior art keywords
agent
pharmaceutical composition
eutectic
fungal
pharmaceutically acceptable
Prior art date
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PCT/US2010/044036
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WO2011014850A3 (fr
Inventor
Servet Buyuktimkin
Nadir Buyuktimkin
Jagat Singh
John M. Newsam
Dominic King-Smith
Edward Kisak
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Nuvo Research Inc
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Nuvo Research Inc
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Publication of WO2011014850A3 publication Critical patent/WO2011014850A3/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • a eutectic temperature is a temperature at which a mixture of two or more substances can exist in equilibrium with the same proportional composition in both liquid and solid phases.
  • Figure 1 illustrates the behavior of a two-component system containing substances A and B that form a eutectic mixture.
  • a eutectic point is a point on the phase diagram describing a composition and temperature at which all of the mixture's components will melt or (assuming no supercooling or hysteresis) crystallize simultaneously from the molten state, hi Figure 1, the eutectic point describes a composition containing 50% B, but it can occur at another percentage depending on the compounds involved.
  • a eutectic mixture is often undesired, but it can be a useful property of drug combinations or formulations.
  • formulations comprising eutectic mixtures have been viewed as unstable, the melting point depression of a eutectic mixture can be accompanied by an increase in the mixture's dermal solubility and transdermal permeation, which can increase a drug's bioavailability. See, e.g., Barry, B. W. Eur. J.
  • EMLA eutectic mixture of the local anesthetics lidocaine and prilocaine
  • an object of this invention is to improve the transungual delivery of a drug, particularly an anti-fungal agent, and to increase its retention in the nail, which is frequently suggested to be correlated with drug
  • Onychomycosis is a fungal infection that affects the toenails (-80% of cases) and the fingernails (-20% of cases).
  • the most common causative pathogens of onychomycosis are Trichophyton rubrum and Trichophyton interdigitale (also known as Trichophyton mentagrophytes). These pathogens represent the cause of roughly 70% and 20% of onychomycosis cases, respectively.
  • causative agents include Epidermophyton floccosum, Trichophyton violaceum, Microsporum gypseum, Trichophyton tonsurans, Trichophyton soudanense, Trichophyton verrucosum, Candida and Neoscytalidium (also known as Scytalidium), Scopulariopsis, and Aspergillus.
  • the infection may involve any component of the nail unit, including the nail matrix, the nail bed or the nail plate. See Blumberg, M. "Onychomycosis," http://www.emedicine.com/derm/topic300.htm, accessed July 7, 2008.
  • Distal lateral subungual onychomycosis is the most common form of infection, hi this variant, the infection begins around the edges of the nail and can cause inflammation in these areas while concurrently spreading to the underside of the nail. The result is
  • Onychomycosis is a very difficult condition to cure.
  • Today it is commonly treated with an antifungal medication that is delivered to the systemic circulation, in spite of the fact that the onychomycosis infection is localized to the nail structure. This can result in serious and unwanted side effects, including gastrointestinal symptoms, liver abnormalities, rashes, taste disturbances, hypertension, and drug-drug interactions with a wide range of other medications.
  • Topical drugs for the treatment of onychomycosis are available. However, they are not very effective in the treatment of the disease.
  • Penlac ® (ciclopirox 8% solution) is a topical treatment which has been approved in the United States for the treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to Trichophyton rubrum.
  • the drug is not very effective in the treatment of onychomycosis, providing complete cure (defined as clear nail and negative mycology) in less than 10% of the intent-to-treat population in the Phase III studies used to obtain approval in the United States. Further, relapse appears to be a significant issue with this drug. See Casciano J. et al. Manag. Care 2003, 12(3), 47-54;
  • Terbinafine has also been approved by the US Food and Drug
  • terbinafine hydrochloride cream 1% (tradename Lamisil ® ) is available as an over-the-counter product, and the label specifically notes that the product should not be used on nails. (For package information, see
  • the present invention provides topical compositions, methods for preparation, and methods of treatment involving the incorporation of a eutectic melt into a formulation.
  • the formulations enhance permeability and bioavailability, and they are useful in ungual or dermal applications.
  • the present invention provides an anti-fungal
  • the pharmaceutical composition for topical application.
  • the pharmaceutical composition comprises, consists essentially of, or consists of an anti-fungal agent, a eutectic agent, and an optional pharmaceutically acceptable low-boiling solvent.
  • the anti-fungal agent and the eutectic agent form a eutectic melt, which enhances the delivery of the anti-fungal agent or permits higher concentrations of the anti-fungal agent to be incorporated into the
  • composition is substantially anhydrous.
  • the present invention provides an alternative anti-fungal pharmaceutical composition for topical application.
  • the pharmaceutical composition comprises, consists essentially of, or consists of an anti-fungal agent, a eutectic agent, a second eutectic agent, and a pharmaceutically acceptable low-boiling solvent.
  • the eutectic agent and the second eutectic agent form a eutectic melt, which enhances the delivery of the anti-fungal agent or permits higher concentrations of the anti-fungal agent to be incorporated into the pharmaceutical composition.
  • the composition is substantially anhydrous.
  • the present invention provides a method for preparing a pharmaceutical composition for topical use, the method comprising, consisting essentially of, or consisting of the steps of 1) adding an anti-fungal agent to a eutectic agent to form an admixture and 2) heating the admixture until it is substantially homogeneous. When mixed and heated, the anti-fungal agent and the eutectic agent form a eutectic melt.
  • the present invention provides an alternative method for preparing a pharmaceutical composition for topical use, the method comprising, consisting essentially of, or consisting of the steps of 1) forming a eutectic melt by admixing two or more eutectic agents and heating the admixture until it is substantially homogeneous; 2) adding an anti-fungal agent to the eutectic melt to form a further admixture and 3) heating the further admixture until it is substantially homogeneous.
  • the present invention provides a method for treating a fungal infection in a subject, the method comprising, consisting essentially of, or consisting of the step of applying a topical anti-fungal composition to a subject to treat the fungal infection.
  • the topical anti-fungal composition comprises an anti-fungal agent, a eutectic agent, and an optional pharmaceutically acceptable low-boiling solvent.
  • the anti-fungal agent and the eutectic agent form a eutectic melt, which enhances the permeability of the anti-fungal agent.
  • the present invention provides an alternative method for treating a fungal infection in a subject, the method comprising, consisting essentially of, or consisting of the step of applying a topical anti-fungal composition to a subject to treat the fungal infection.
  • the topical anti-fungal composition comprises an anti-fungal agent, a eutectic agent, a second eutectic agent, and a pharmaceutically acceptable low-boiling solvent.
  • the eutectic agent and the second eutectic agent form a eutectic melt, which enhances the permeability of the anti-fungal agent.
  • an anti-fungal agent and a eutectic agent form a eutectic melt, and as a whole, the pharmaceutical composition that comprises them is substantially a eutectic melt, hi an alternative and preferred aspect, although the anti-fungal agent and the eutectic agent form a eutectic melt, as a whole, the pharmaceutical composition that comprises them is not a eutectic melt.
  • the eutectic agent and at least one other eutectic agent in the formulation form a eutectic melt, and as a whole, the
  • compositions that comprises them is also substantially a eutectic melt, hi an alternative and preferred aspect, although the eutectic agent and the second eutectic agent form a eutectic melt, as a whole, the pharmaceutical composition is not a eutectic melt.
  • the pharmaceutical composition is substantially or essentially anhydrous.
  • the pharmaceutical composition comprises less than 5% water (e.g., 4%, 3%, 2%, 1%, or less than 1% water).
  • FIG. 1 illustrates the behavior of a two-component system containing substances A and B that form a eutectic mixture.
  • the liquidus line separates the completely molten (liquidus) phase from the melt+crystal phase.
  • the solidus line separates the melt+crystal phase from the all-crystal (solidus) phase.
  • FIG. 2A describes the terbinafine penetration profiles through shed snake skin from the first series of specific eutectic formulations (Table 2) at 4, 20, and 24 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard error of the mean.
  • FIG. 2B describes the terbinafine retention in shed snake skin from the first series of specific eutectic formulations (Table 2) at 24 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard deviation of the mean.
  • FIG. 3A describes the terbinafine penetration profiles through shed snake skin from the second series of specific eutectic formulations (Table 3) at 4, 20, and 24 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard error of the mean.
  • FIG. 3B describes the terbinafine retention in shed snake skin from the second series of specific eutectic formulations (Table 3) at 24 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard deviation of the mean.
  • FIG. 4A describes the terbinafine penetration profiles through shed snake skin from the third series of specific eutectic formulations (Table 4) at 4, 20, and 24 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard error of the mean.
  • FIG. 4B describes the terbinafine retention in shed snake skin from the third series of specific eutectic formulations (Table 4) at 24 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard deviation of the mean.
  • FIG. 5A describes the terbinafine penetration profiles through shed snake skin from the fourth series of specific eutectic formulations (Table 6) at 4, 20, and 24 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard error of the mean.
  • FIG. 5B describes the terbinafine retention in shed snake skin from the fourth series of specific eutectic formulations (Table 6) at 24 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard deviation of the mean.
  • FIG. 6A describes the terbinafine penetration profiles through shed snake skin from the fifth series of specific eutectic formulations (Table 7) at 4, 20, and 24 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard error of the mean.
  • FIG. 6B describes the terbinafine retention in shed snake skin from the fifth series of specific eutectic formulations (Table 7) at 24 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard deviation of the mean.
  • FIG. 7 describes the terbinafine penetration profiles through shed snake skin from the sixth, lacquer-type series of specific eutectic formulations (Table 8) at 4 and 20 hours after application. Lamisil ® was used as the control. Each set of error bars represents the standard error of the mean.
  • FIG. 8 A describes a comparison of the terbinafine retention in bovine hoof after 306 hr of a control (Lamisil®) and two specific eutectic formulations (Table 9). Each set of error bars represents the standard deviation of the mean.
  • FIG. 8B describes a comparison of the terbinafine permeation profiles through bovine hoof of a control (Lamisil ® ) and two specific eutectic formulations (Table 9) at 66, 114, 162, 210, 258, and 306 hours after application. Each set of error bars represents the standard error of the mean.
  • FIG. 9A illustrates the terbinafine permeation from exemplary terbinafine
  • NRI-1002-03 (identified in the figure legend as NRI-1002-03-030310) through human cadaver nail, compared to a control (Lamisil ® ).
  • Each set of error bars represents the standard error of the mean.
  • FIG. 9B illustrates the terbinafine permeation from exemplary terbinafine formulation NRI-1002-04 (identified in the figure legend as NRI-1002-04-0302.0) through human cadaver nail, compared to a control (Lamisil ® ). Each pair of error bars represents the standard error of the mean.
  • FIG. 9C illustrates the terbinafine permeation from exemplary terbinafine formulations NRI-1002-04vl and NRI-1002-04 v2 through human cadaver nail, compared to a control (Lamisil ® ). Each pair of error bars represents the standard error of the mean
  • FIG. 9D illustrates the terbinafine permeation from exemplary terbinafine formulation NRI-1002-04v3 (identified in the figure legend as NRI-04-60710-v3) through human cadaver nail, compared to a control (Lamisil ® ). Each pair of error bars represents the standard error of the mean [0041]
  • FIG. 10 illustrates the relative terbinafine permeation through human cadaver nail of exemplary terbinafine formulations NRI-1002-04vl, NRI-1002-04v2, and NRI-1002-04v3, expressed as enhancement in accumulated terbinafine flux relative to Lamisil ® .
  • compositions consisting of, consisting essentially of, or comprising a "first" and a “second” component the second component as used herein is chemically different from the first component (e.g., a composition comprising terbinafine hydrochloride and lidocaine).
  • Anti-fungal agent includes a compound that has the ability to kill, to stop the growth, or to slow the growth of a fungus in vitro or in vivo as well as a compound that can prevent or alleviate a fungal infection in vitro or in vivo.
  • Representative anti-fungal agents include allylamine anti-fungal agents such as terbinafine, amorolf ⁇ ne, naftifine, butenafine, and pharmaceutically acceptable salts thereof.
  • Eutectic agent includes a compound that, in combination with at least a second eutectic agent, forms a eutectic melt.
  • Representative eutectic agents include menthol, phenol, 2-amino-2-methylpropanol, choline chloride, urea, panthenol, niacinamide, citric acid, betaine, arginine, resorcinol, butylated hydroxytoluene, 4-chloroxylenol, camphor, glycerin monolaurate, lauryl alcohol, certain pharmaceutical agents (e.g., allylamine antifungal agents such as terbinafine and butenafine; local anesthetics such as lidocaine and prilocaine), and the like.
  • allylamine antifungal agents such as terbinafine and butenafine
  • local anesthetics such as lidocaine and prilocaine
  • compounds A, B, and C can each be a eutectic agent as defined herein even if compounds A and C cannot be combined with each other to form a eutectic melt.
  • a compound is a eutectic agent in a specific embodiment of a composition, it is able to form a eutectic melt with at least a second compound contained in that embodiment of the composition.
  • Eutectic melt includes a combination of two or more eutectic agents that form a substantially homogeneous mixture of liquids that is stable at one or more temperatures between about 10 °C and about 50 °C (e.g., between about 10 0 C, 15 °C, 20 0 C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 0 C, and the temperatures in between).
  • the eutectic melt is further characterized in that the melting point of the eutectic melt is lower than the melting point of at least one of the two or more eutectic agents that comprise the mixture, hi another embodiment, the melting point of the eutectic melt is lower than the melting points of two or more eutectic agents that comprise the mixture. In a further embodiment, the melting point of the eutectic melt is lower than the melting point of all of the eutectic agents that comprise the mixture.
  • both the solid and liquid phases have about the same proportional composition of eutectic agents.
  • the melting point of a eutectic melt is lower than the melting point of other mixtures containing the same components, but with different proportions of the same eutectic agents.
  • At least one of the liquid components of the eutectic melt is a solid when in purified or non-mixed form at the same temperature, and the component's change from solid to liquid state is caused by its melting point depression upon mixing with the other component or components.
  • the melting point of at least one, more than one, or all of the eutectic agents is greater than 24 °C, 30 0 C, 36 0 C, 40 °C, or 50 0 C.
  • the melting point of all of the eutectic agent components of the eutectic melt is greater than 10 0 C.
  • the melting point of the eutectic melt is lower than 24 °C, and the melting point of at least one, more than one, or all of the eutectic agent components of the eutectic melt is greater than 24 °C, 30 °C, 36 °C, 40 0 C, or 50 0 C.
  • a mixture is heated until the components are liquid or substantially liquid to form a eutectic melt
  • a mixture is heated to a temperature above 50 °C to form a eutectic melt (e.g., 60 °C, 65 °C, 70 °C, 70 0 C, 80 °C, 85 0 C, 90 °C, 95 °C, or l00 °C).
  • "Finite dosing" as used herein generally includes an application of a limited reservoir of an active agent. The reservoir of the active agent is depleted with time, leading to a tapering off of the active absorption rate after a maximum absorption rate is reached.
  • Infinite dosing as used herein generally includes an application of a large reservoir of an active agent.
  • the reservoir of the active agent is not significantly depleted with time, thereby providing a long-term, continuous steady-state of active absorption.
  • Low-boiling solvent indicates a pharmaceutically acceptable solvent or mixture of solvents with a boiling point of less than 100 °C at standard temperature and pressure.
  • Representative low-boiling solvents include acetone, ethyl acetate, ethanol, and the like.
  • “Lower alkanol” as used herein includes straight- or branched-chain alkyl alcohols of 1 to about 6 carbon atoms. Representative lower alkanols include methanol, ethanol, n- propanol, isopropanol, n-butanol, t-butanol, n-pentanol, 3-pentanol, and the like.
  • “Melt composition” as used herein includes a mixture of at least two liquids.
  • the "melting point” as used herein is the temperature at which a solid changes from solid to liquid phase under standard pressure (i.e., 1 atm or 101.325 kPa). If a solid melts over a temperature range, the melting point is the temperature at which the liquid phase first appears under standard pressure.
  • the term "or” as used herein should in general be construed non-exclusively. For example, an embodiment of "a composition comprising A or B" would typically present an aspect with a composition comprising both A and B. "Or” should, however, be construed to exclude those aspects presented that cannot be combined without contradiction (e.g., a formulation pH that is between 9 and 10 or between 7 and 8).
  • Penetration enhancer includes an agent or a combination of agents that improves the transport of molecules such as a pharmaceutically or cosmetically active agent into or through a natural membrane such as skin or nail.
  • a pharmaceutically or cosmetically active agent into or through a natural membrane such as skin or nail.
  • Various conditions may occur at different sites in the body, either in the skin or below the skin, creating a need to target delivery of compounds. For example, in a treatment for onychomycosis, delivery of the active agent to the tissue underlying the nail may be necessary to achieve therapeutic benefit.
  • a “penetration enhancer” may be used to assist in the delivery of an active agent i) directly to the skin, nail, or underlying tissue; or ii) indirectly via systemic distribution to the site of the disease.
  • a penetration enhancer may be a pure substance or may comprise, consist essentially of, or consist of a mixture of different chemical entities.
  • a percentage range when a percentage range is taught, it incorporates all full or partial percentages in between (i.e., within the bounds of the range). For example, a percentage range of 15 to 25% would also teach the specific values of 17.36% and 21%. A percentage range of about 13% to 17% would also teach the specific values of 12.97%, 16%, and 14.1%.
  • substantially anhydrous as used herein includes compositions without deliberately added water.
  • a substantially anhydrous composition can contain up to 5% w/w water, which may be adventitiously incorporated from impurities in the starting materials, side products from reactions or manufacturing processes, or air absorption.
  • substantially homogeneous designates a composition that includes at least 90%, 95%, or 99% by weight of a single phase, although it may include small amounts of a different phase (e.g., a liquid phase containing a small amount of immiscible liquid or a solid).
  • substantially liquid designates a composition that includes at least 90%, 95%, or 99% by weight of a liquid phase, although it may include small amounts of at least one solid phase.
  • Substituted phenol as used herein includes hydroxybenzenes and
  • dihydroxybenzenes with from 1 to 3 additional substituents independently selected from the group of acyl, alkyl, alkenyl, alkoxy, amido, amino, aryl, carboxy, and halo substituents.
  • Topical application includes the administration of a composition, (e.g., a formulation containing a pharmaceutically or cosmetically active agent) to the skin, nail, mucosa, or other localized region of the body. Topical application may result in the delivery of an active agent to the skin, the nail plate, the nail bed, a localized region of the body, a localized volume of the body, or the systemic circulation.
  • a composition e.g., a formulation containing a pharmaceutically or cosmetically active agent
  • Topical application may result in the delivery of an active agent to the skin, the nail plate, the nail bed, a localized region of the body, a localized volume of the body, or the systemic circulation.
  • Topical formulation as used herein includes a formulation that is suitable for topical application to the skin, a nail, or a mucosa.
  • a topical formulation may, for example, be used to confer a therapeutic or cosmetic benefit to its user.
  • Topical formulations can be used for local, regional, transdermal, or transungual application of substances.
  • Transdermal as used herein includes a process that occurs through the skin.
  • the terms “transdermal,” “percutaneous,” and “transcutaneous” can be used interchangeably.
  • “transdermal” may also include epicutaneous.
  • Transdermal application as used herein includes administration through the skin. Transdermal application can be used for systemic delivery of an active agent; however, it is also useful for delivery of an active agent to tissues underlying the skin with minimal systemic absorption. In certain embodiments, “transdermal application” may also include epicutaneous application.
  • Transungual as used herein includes a process that occurs through the nail.
  • Transungual application includes administration to or through a nail.
  • Transungual application can be used for systemic delivery of an active agent. However, it is preferably used for delivery of an active agent to the nail or to tissues underlying or surrounding the nail with minimal systemic absorption.
  • the pharmaceutical compositions of the instant invention incorporate an anti-fungal agent.
  • the anti-fungal agent is a member of the classes of azoles (including imidazoles and triazoles) such as miconazole, ketoconazole, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, itraconazole, fluconazole, voriconzole, terconazole, isavuconazole, ravuconazole, and posaconazole; polyenes such as natamycin, rimocidin, filipin, nystatin, candicidin, nystatin, candicidin, and amphoteracin B; thiazoles such as abafungin; echinocandins; allyl
  • pyridones such as ciclopirox olamine
  • miscellaneous antifungal agents such as undecylenic acid. See Brunton, L. L. et al. The Goodman and Gilman 's Manual of
  • the antifungal agent is an allylamine anti-fungal agent
  • the allylamine anti-fungal agent is selected from the group consisting of amorolfine, butenafine, naftifine, terbinafine, and a pharmaceutically acceptable salt thereof.
  • the allylamine anti-fungal agent is terbinafine or a pharmaceutically acceptable salt thereof.
  • the anti-fungal agent's mechanism of action is inhibition of the ergosterol synthesis pathway in a fungus.
  • the anti-fungal agent's mechanism of action is inhibition of the enzyme squalene epoxidase.
  • the anti-fungal agent is useful in the treatment of a mammal, including a human and a domestic or farm animal, such as a dog, horse, cat, sheep, pig, or cow. Non-limiting preferred mammals are humans.
  • the formulation comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 25, 30, 31 or 35% of the anti-fungal agent by weight.
  • the formulation comprises at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 25, 30, 31 or 35% of the anti-fungal agent by weight.
  • the formulation comprises about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25% of the anti-fungal agent by weight as well as all partial percentages in between.
  • the formulation comprises from about 5 to 25% of the anti-fungal agent by weight. Still more preferably, the formulation comprises from about 8 to about 22%. Yet still more preferably, the formulation comprises from about 8 to about 15, about 10 to about 15, about 10 to about 20, about 13 to about 22, about 13 to about 20, or about 15 to about 20% by weight. Still more preferably, the formulation is about 10% by weight. Alternatively, the formulation is about 15% by weight. Alternatively, the formulation is about 20% by weight.
  • compositions described as specific embodiments herein include anti- fungal agents
  • inventive eutectic melts and formulations should not be construed as being limited to anti-fungal agents.
  • Other classes of drugs that are potentially useful in topical, transdermal, or transungual drug delivery can also benefit from the permeation enhancement afforded by use of eutectic melts and the solutions prepared from them (e.g., local anesthetics, analgesics, steroidal or non-steroidal anti-inflammatory drugs, hormones, nicotine or nicotine analogs, and the like).
  • eutectic agents are used in the present invention.
  • the compounds can be classified as phenol and certain substituted phenols, certain terpenes that are solid at room temperature, urea, choline chloride-type zwitterionic materials (e.g., deep eutectic solvents), and combinations thereof.
  • the instant invention is intended to embrace all pharmaceutically acceptable eutectic agents and is not restricted to these classes.
  • Table 1 provides a list of exemplary eutectic agents useful in some specific embodiments of the instant invention.
  • Table 1 Exemplary Eutectic Agents and Their Melting Points
  • eutectic melts useful for the instant invention are the following:
  • the eutectic agent is selected from the group of phenol, a pharmaceutically acceptable substituted phenol, a quaternary aminoalkanol, a quaternary amino acid salt, a terpene, and urea.
  • the eutectic agent is selected from the group of phenol, resorcinol, thymol, choline chloride, camphor, menthol, and urea.
  • the eutectic melt is a permeation enhancer.
  • the eutectic melt provides a rate of permeation at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-fold that of a comparative formulation without the eutectic melt.
  • An exemplary procedure for identifying the rate of permeation is, e.g., a Franz cell procedure such as the one described in Example 26.
  • the formulation comprises about 0.1% to 25% (w/w) urea. In more preferred aspects, the formulation comprises about 5% to 15% (w/w) urea. Still more preferably, the formulation comprises about 5% to 10%, about 7% to 10%, about 7% to 13%, about 10% to 13% (w/w), about 10% to 15%, or about 12% to 15% (w/w) urea. Alternatively, the formulation comprises about 7, 8, 9, 10, 11, 12, or 13% (w/w) urea; more preferably, about 10% (w/w) urea.
  • At least one of the eutectic agents is a pharmaceutically active agent (e.g., an anti-fungal agent as described above or a local anesthetic).
  • the pharmaceutically active agent is selected from the group of benzocaine, chloroprocaine, cyclomethycaine, larocaine, propoxycaine, procaine, proparacaine, tetracaine, articaine, bupivacaine, carticaine, cinchocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecaine, and a pharmaceutically acceptable salt thereof (i. e. , a pharmaceutically acceptable salt of any compound in the group). More preferably, the pharmaceutically active agent is lidocaine or a pharmaceutically acceptable salt thereof.
  • the eutectic agent is an aromatic or heteroaromatic ester (ArCOOR) with an alkyl substituent on the aromatic or heteroaromatic ring (Ar) and an alkylamino or dialkylamino substituent on the ester alcohol (i.e., R Ar-COO-R-NR R ).
  • the eutectic agent is an aromatic or heteroaromatic amide (ArCON(R')R) with an alkyl substituent on the aromatic or heteroaromatic ring and an alkylamino or
  • the amide or ester eutectic agent is also a pharmaceutically active agent.
  • the formulation comprises at least about 5, 10, 14, 15, 20, 25, 30, 35, 40, 50, 53, 55, 60, 70, 75, 80, 90, or 100% of the eutectic melt by weight. In other aspects, the formulation comprises at most about 5, 10, 14, 15, 20, 25, 30, 35, 40, 50, 53, 55, or 60% of the eutectic melt by weight.
  • the formulation consists or consists essentially of the eutectic melt and an optional low-boiling solvent.
  • the formulation comprises a eutectic melt.
  • the formulation comprising the eutectic melt is not itself a eutectic melt.
  • the eutectic melt forms a stable, substantially
  • the eutectic melt forms a stable, substantially homogeneous mixture of liquids at one or more temperatures between 10 °C and 15 °C, between 15 °C and 20 °C, between 20 °C and 25 °C, between 25 °C and 30 °C, between 30 0 C and 35 °C, between 35 °C and 40 °C, between 40 °C and 45°C, or between 45 0 C and 50 0 C.
  • the low-boiling solvent is a lower alkanol. More preferably, the low-boiling solvent is ethanol.
  • the formulation comprises about 5 to 60% as well as all full or partial percentages in between. In certain other aspects, the formulation comprises at least about 5, 10, 14, 15, 20, 25, 30, 35, 40, 50, 53, 55, or 60% of the low-boiling solvent by weight, hi still other aspects, the formulation comprises at most about 5, 10, 14, 15, 20, 25, 30, 35, 40, 50, 53, 55, 60, 70, 75, 80, 90, or 100% of the low- boiling solvent by weight.
  • the formulation comprises about 20 to about 50% ethanol as well as all full or partial percentages in between (e.g., 44% or 43.68% ethanol). More preferably, the formulation comprises about 25 to about 45% ethanol. Still more preferably, the formulation comprises about 30 to about 45, about 30 to about 41, about 35 to about 45, about 40 to about 45, about 25 to about 40, about 25 to about 36, about 30 to about 36, or about 25 to about 31% ethanol.
  • a low-boiling solvent has a boiling point of less than 90 0 C at standard temperature and pressure. More preferably, the low-boiling solvent has a boiling point of less than 80 °C at standard temperature and pressure.
  • the pharmaceutical composition is a homogeneous mixture.
  • the pharmaceutical composition is a solution or a liquid and is substantially free of precipitates at about 37 0 C. More preferably, the pharmaceutical composition is a solution or a liquid and is substantially free of precipitates at about 25 °C.
  • the composition additionally comprises at least one pharmaceutically acceptable surfactant, emulsifier, thickener, or lacquer-forming agent. In a preferred aspect, the composition additionally comprises at least one surfactant, emulsifier, thickener, or lacquer-forming agent.
  • the thickener is selected from the group consisting of a cellulose polymer, a carbomer, a polyvinyl pyrrolidone, a polyvinyl alcohol, a poloxamer, a xanthan gum, a locust bean gum, a guar gum and mixtures thereof.
  • the formulation includes a cellulosic thickener.
  • Suitable cellulosic thickeners include, but are not limited to, hydroxypropyl cellulose (HPC) of various grades, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, dextran, guar gum, pectin, starch, cellulose, and the like. More preferably, the cellulosic thickener is HPC.
  • the formulation comprises about 0.5% to about 5% (w/w) of the thickener, such as about 0.5, about 0.6, about 0.7, about 0.8, 0.9, 1, 1.5, 1.8, 1.9, 2, 2.1, 2.2, 2.5, 3, 4, or 5% as well as all full or partial percentages in between. More preferably, the formulation comprises from about 0.5% to 1% or about 0.5 to 2% of a thickener. Still more preferably, the formulation comprises about 2% of a thickener.
  • the formulation comprises about 1% of a thickener.
  • the formulation comprises isopropyl myristate (IPM).
  • IPM isopropyl myristate
  • the isopropyl myristate is present from about 2.5% to 15% (w/w), such as about 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, or 15%.
  • the isopropyl myristate is present from about 2.5% to 10%, about 2.5% to 7.5%, about 2.5% to 10%, about 5% to 15%, or about 10% to 15% (w/w) isopropyl myristate.
  • the formulation includes about 2.5, 5, 7.5, or 10% (w/w) isopropyl myristate.
  • the formulation is a composition selected from the group consisting of a cream, an emulsion, a lotion, an organogel, an ointment, and a transdermal patch.
  • the composition additionally comprises an anti-oxidant.
  • Preferred anti-oxidants for use in the present invention include butylated hydroxytoluene, butylated hydroxyanisole, ascorbyl linoleate, ascorbyl dipalmitate, ascorbyl tocopherol maleate, calcium ascorbate, ascorbic acid, carotenoids, kojic acid and its pharmaceutically acceptable salts, thioglycolic acid and its pharmaceutically acceptable salts (e.g., ammonium), tocopherol, alpha tocopherol, tocopherol acetate, tocophereth-5, tocophereth-12, tocophereth- 18, or tocophereth-80.
  • the anti-oxidant may also be a eutectic agent.
  • the composition comprises about 0.01% to 5.0% of antioxidant as well as all fractions or percentages in between.
  • the composition comprises up to about 5% anti-oxidant.
  • the composition comprises about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.10% of the anti-oxidant.
  • the composition comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0% of the antioxidant.
  • the composition comprises 0.5, 1,0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0% antioxidant.
  • the formulation is more viscous than water at standard temperature and pressure (STP).
  • the formulation has a kinematic viscosity of more than about 1 centistokes (cSt) or a dynamic viscosity of more than about 1 centipoise (cP).
  • the dynamic viscosity of the formulation is at least about 2, 3, 4, 5, 7, 10, 12, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100, 150, 200, 250, 500, 1000, 2000, 3000, 5000, 10,000 cP at STP.
  • the dynamic viscosity of the formulation is at least about 10 4 , 5 x 10 4 , 10 5 , 5 x 10 5 , 10 6 , 5 x 10 6 , 10 7 or 10 8 cP at STP.
  • the formulation is thixotropic (i.e., it decreases in viscosity upon being stirred or shaken).
  • the formulation is acidic, hi certain aspects, the formulation has a pH of below 7.5, of below 6.5, of below 5.5, of below 4.5, of below 3.5, or of below 2.5. hi certain other aspects, the pH of the formulation may range from about 1.5 to about 7, about 2 to about 7, about 3 to about 7, about 4 to about 7, or about 5 to about 7. hi still other aspects, the pH of the formulation may range from about 1.5 to about 5.5, about 2.5 to about 5.5, about 3.5 to about 5.5, or about 4.5 to about 5.5. [0105] hi yet another aspect, the formulation is basic, hi certain aspects, the formulation has a pH of above 7, of above 8, of above 9, of above 10, of above 11, or of above 12.
  • the pH of the formulation may range from about 7 to about 12.5, about 7 to about 11.5, about 7 to about 10.5, about 7 to about 9.5, or about 7 to about 8.5.
  • the pH of the formulation may range from about 9 to about 12.5, about 9 to about 11.5, about 9 to about 10.5, or about 8.5 to about 10.
  • the formulation is neutral.
  • the formulation has a pH of about 7.
  • the formulation has a pH from about 6 to about 8.5, from about 5.5 to about 8, about 6 to about 8, about 6.5 to about 8.5, or from about 6.5 to about 7.5.
  • the topical formulations of the present invention comprise a pH-adjusting agent
  • the pH-adjusting agent is a base.
  • Suitable pH- adjusting bases include amines (e.g., diethanolamine or triethanolamine), bicarbonates, carbonates, and hydroxides such as alkali or alkaline earth metal hydroxides as well as transition metal hydroxides.
  • the pH-adjusting agent is preferably sodium hydroxide and is present in an amount sufficient to adjust the pH of the composition to between about pH 4.0 to about 8.5; more preferably, to between about pH 5.5 to about 7.0, such as 6.0 or 6.5.
  • the pH-adjusting agent can also be an acid, an acid salt, or mixtures thereof, hi a preferred embodiment, the pH-adjusting agent is an acid.
  • the pH-adjusting agent can also be a buffer.
  • Suitable buffers include citrate/citric acid buffers, acetate/acetic acid buffers, phosphate/phosphoric acid buffers, formate/formic acid buffers, propionate/propionic acid buffers, lactate/lactic acid buffers, carbonate/carbonic acid buffers, ammonium/ammonia buffers, and the like, hi certain embodiments, the buffer is an acidic buffer system (e.g., benzocaine).
  • the formulations of the current invention have the advantage of containing high concentrations of low-solubility or hard-to-formulate drugs such as terbinafine or butenafine.
  • Such concentrated formulations may be of particular benefit in treatment of chronic diseases of the nail or other difficult-to-treat areas of the body (e.g., onychomycosis) because the high concentrations can 1) increase the effective concentration of drug in the affected area or 2) improve retention of the drug at or near the affected area.
  • the solubility of terbinafine in various aqueous and organic solvents was investigated (Example 29). The findings indicated that terbinafine shows high solubility in organic solvents, lower solubility in non-polar solvents and moderate solubility in aqueous solvents with a pH of 4 and 6.
  • the pharmaceutical composition has a terbinafine solubility ranging from about 10% to about 30% (w/v).
  • the pharmaceutical composition has a terbinafine solubility of at least 10% (w/v), at least 15% (w/v), at least 20% (w/v), at least 25% (w/v), or at least 30% (w/v).
  • the pharmaceutical composition has a terbinafine solubility of at least 21% (w/v), at least 22% (w/v), at least 23% (w/v), or at least 24% (w/v).
  • the formation of eutectic mixtures is often undesirable.
  • formulations comprising eutectic mixtures have typically been viewed as unstable.
  • the topical formulations have the advantage of maintaining chemical and/or physical stability over time, even where the concentration of the active has been increased.
  • Tables 15 to 24 for instance, the chemical and physical attributes of preferred topical formulations were monitored over the course of a one- or three-month period.
  • the pharmaceutical composition is substantially stable with respect to its chemical and/or physical attributes over a predetermined period of time.
  • the measurable attributes may include, but are not limited to, percentage of active, percentage of impurities, or visual attributes such as colour and the presence of particulates.
  • the pharmaceutical composition is substantially stable following storage for about 4, 8 or 12 weeks at 25°C. In still other aspects of the invention, the pharmaceutical composition is substantially stable following storage for about 4, 8 or 12 weeks at 40°C.
  • the eutectic melt formulations of the current invention can function as penetration enhancers because of their decreased melting points. See Dhamecha, D. L. et al. Intl. J. ofPharm. and Pharmaceut. ScL 2009, 1(1), 24-46.
  • a eutectic melt formulation can display superior penetration ability in comparison to a non-eutectic melt formulation with a similar concentration of active ingredient.
  • a formulation is designed for high penetration, for high retention in the skin or nail, or for both high penetration and high retention of the anti-fungal agent.
  • the optimal formulation will have a balance between penetration and retention, enabling an effective amount of the active ingredient to pass through the skin or nail, but also enabling it to stay in the target area for a sufficient duration to achieve its intended effect upon the fungus.
  • topical formulations of the present invention provide nail retention of the anti-fungal agent which exceeds that provided by oral therapy.
  • the anti-fungal agent which exceeds that provided by oral therapy.
  • the concentration of terbinafme in test nails treated with the inventive formulations can reach at least 3.1+ mcg/mg, which is more than three orders of magnitude higher than that observed in the patients receiving oral therapy.
  • the permeation rate of the anti- fungal agent will be sufficient to provide concentrations of the agent in the nail that exceed those attained when the anti-fungal agent is administered orally, hi more preferred aspects of the invention, concentrations of the anti-fungal agent achieved in the nail are at least 2-, 10-, 100-, 1000- or 10,000-fold greater than the level achieved by oral therapy to achieve effective treatment of onychomycosis, hi even more preferred aspects of the invention, concentrations of the anti-fungal agent achieved in the nail are at least 1-, 2-, 3-, A-, 5-, 10-, 50-, 100-, 500-, 1000-, 2000-, 4000-, 5000-, or 10,000-fold greater than the level achieved by oral therapy to achieve effective treatment of onychomycosis.
  • the pharmaceutical composition is formulated as a cream, an emulsion, a gel (e.g., a hydrogel, an organogel, or an inorganic or silica gel ), a lotion, a lacquer, an ointment, a solution (e.g., a highly viscous solution), or a transdermal patch.
  • a gel e.g., a hydrogel, an organogel, or an inorganic or silica gel
  • a lotion e.g., a hydrogel, an organogel, or an inorganic or silica gel
  • a solution e.g., a highly viscous solution
  • transdermal patch e.g., a transdermal patch.
  • the composition is a solution or a gel.
  • the composition is a lacquer or a patch.
  • Eutectic melts may also be incorporated into various types of patches (e.g., adhesive, reservoir, and the like).
  • the eutectic melt is prepared by heating above 80 °C. Alternatively, the eutectic melt is prepared by heating to about 80 °C. In another aspect, the eutectic melt is prepared by heating above 85 0 C. Alternatively, the eutectic melt is prepared by heating to about 85 0 C. hi still another aspect, the eutectic melt is prepared by heating above 90 °C. Alternatively, in a preferred embodiment, the eutectic melt is prepared by heating to about 90 0 C. hi yet still another alternative aspect, the eutectic melt is prepared by heating to a temperature between about 80 °C to about 90 °C.
  • the invention describes a method for treating a fungal infection comprising the step of applying a topical anti-fungal composition to a subject to treat the fungal infection.
  • the pharmaceutical composition is applied to a nail of the subject, hi other aspects, the pharmaceutical composition is applied to the nail and the surrounding tissue of the nail of the subject, hi another aspect, the pharmaceutical composition is applied to the skin of the subject.
  • the anti-fungal agent or other drug is delivered locally to the nail with minimal systemic absorption, hi yet another aspect, the anti-fungal agent or other drug is delivered to and through the nail with minimal systemic absorption. In a still yet another aspect, the anti-fungal agent or other drug is delivered to the tissue surrounding or under the nail with minimal systemic absorption.
  • the anti-fungal agent or other drug is delivered locally to the skin with minimal systemic absorption, hi yet another aspect, the anti-fungal agent or other drug is delivered to and through the skin with minimal systemic absorption. In a still yet another aspect, the anti- fungal agent or other drug is delivered to the tissue surrounding or under the area of skin application with minimal systemic absorption.
  • the subject is a human.
  • the subject is a non-human mammal.
  • the fungal infection is onychomycosis, hi one aspect, the fungal infection is caused by Trichophyton rubrum or Trichophyton interdigitale (also known as Trichophyton mentagrophytes).
  • the treatment is continued for at least 12 weeks. More preferably, the treatment is continued for at least six months.
  • the treatment is applied one, two, three or four times a day for 1, 2, 3, 4, 5, 6 or 7 days
  • the treatment is applied ,once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days or once every week.
  • the nail or tissue to which the treatment will be applied is cleaned and the remains of prior treatment removed prior to fresh application of the treatment.
  • compositions of the present invention may, if desired, be presented in a bottle, jar, or other container-closure system approved by the FDA or other regulatory bodies, which may contain one or more unit dosage forms containing the active ingredient.
  • the package or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of
  • Method A Preparation of Eutectic Melt with Active Agent As a Eutectic Agent: hi this method, an active agent is added to at least one eutectic agent and heated at approximately 80-90 0 C until melting to form a eutectic melt.
  • Method B Preparation of Eutectic Melt with Addition of Active Agent: In this method, a eutectic agent and at least a second eutectic agent are mixed and heated to form a eutectic melt. An active agent is added to the molten mixture and stirred with heating at approximately 80-90 0 C until the active agent is dissolved. The mixture is allowed to cool to room temperature. The observed liquid phase is either opaque or transparent without any large amount of crystals.
  • the eutectic melt produced by either method is generally very viscous and formulated by dissolving in an appropriate solvent (generally ethanol and/or ethyl acetate, in some cases with small amount of lactic acid or similar materials) to give a non-aqueous eutectic formulation. After preparation, these formulations are each applied to the nail model membrane on the top compartment of a Franz diffusion cell for membrane permeation and membrane retention studies as described below.
  • an appropriate solvent generally ethanol and/or ethyl acetate, in some cases with small amount of lactic acid or similar materials
  • a eutectic melt of choline chloride and urea was prepared by heating. Arginine base was added, and the mixture was heated to 90 0 C to form a further eutectic melt.
  • a eutectic melt of choline chloride and urea was prepared by heating. Niacinamide was added, and the mixture was heated to 90 0 C to form a eutectic melt. Terbinafine hydrochloride was added to the mixture, and after re-heating and cooling, the resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, and lactic acid was added to enhance the solution's clarity. The final formulation is a highly viscous solution.
  • a eutectic melt of choline chloride and phenol was prepared by mixing and heating at 90 0 C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol and ethyl acetate was used to dissolve the gel, producing the final formulation as a highly viscous solution.
  • Example 13 (Table 3-F25):
  • a eutectic melt of choline chloride and resorcinol was prepared by mixing and heating at 90 0 C. After addition of terbinafme hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol and ethyl acetate was used to dissolve the gel, producing the final formulation as a highly viscous solution.
  • a eutectic melt of choline chloride and BHT was prepared by mixing and heating at 90 0 C. After addition of terbinafme hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, producing the final formulation as a highly viscous solution.
  • Example 15 (Table 3-F27):
  • a eutectic melt of choline chloride and citric acid was prepared by mixing and heating at 90 0 C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, producing the final formulation as a highly viscous solution.
  • Example 16 (Table 3-F28):
  • a eutectic melt of choline chloride, urea, and betaine was prepared by mixing and heating at 90 0 C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, producing the final formulation as a highly viscous solution.
  • a eutectic melt of choline chloride, menthol, and 4-chloroxylenol was prepared by mixing and heating at 90 0 C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, producing the final formulation as a highly viscous solution.
  • Example 18 (Table 4-F31):
  • a eutectic melt of choline chloride and urea was prepared by mixing and heating at 90 0 C. After addition of terbinafme hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol was used to dissolve the gel, and lactic acid was added to enhance the solution's clarity. Hydroxypropyl cellulose (low- viscosity form, HYl 17, available from Spectrum Chemical and Laboratory Products, Gardena California) was added to obtain a gel. The final formulation is a highly viscous gel.
  • Example 20 (Table 4-F33):
  • a eutectic melt of choline chloride and urea was prepared by mixing and heating at 90 0 C. After addition of menthol and camphor, the mixture was heated at 90 0 C and mixed to obtain a eutectic melt. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol and dimethyl sulfoxide (“DMSO”) were used to dissolve the resulting gel, and hydroxypropyl cellulose (low- viscosity form, HY 117) was added to obtain the final formulation as a highly viscous gel.
  • DMSO dimethyl sulfoxide
  • a eutectic melt of menthol and camphor was prepared by mixing and heating at 90 0 C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol, ethyl acetate, and glycerin monolaurate was used to dissolve the gel, producing the final formulation as a highly viscous solution.
  • Example 22 (Table 4-F35):
  • a eutectic melt of menthol, phenol, and camphor was prepared by mixing and heating at 90 0 C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol/ethyl acetate was used to dissolve the gel, producing the final formulation as a highly viscous solution.
  • a eutectic melt of menthol, resorcinol, and camphor was prepared by mixing and heating at 90 0 C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol and ethyl acetate was used to dissolve the gel, producing the final formulation as a highly viscous solution.
  • Example 24 Table 4-F37
  • a eutectic melt of menthol, resorcinol, lauryl alcohol, and camphor was prepared by mixing and heating at 90 0 C. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. A mixture of ethanol and ethyl acetate was used to dissolve the gel, producing the final formulation as a highly viscous solution.
  • a eutectic melt of choline chloride and urea was prepared by mixing and heating at 90 0 C. After addition of menthol and lauryl alcohol, the mixture was heated at 90 0 C and mixed to obtain a eutectic melt. After addition of terbinafine hydrochloride, the mixture was heated and mixed to obtain a viscous gel. The resulting gel is stable at room temperature. Ethanol and glycerin monolaurate was used to dissolve the resulting gel, and hydroxypropyl cellulose (low- viscosity form, HY 117) was added to obtain the final formulation as a highly viscous gel.
  • Example 26 Results of Transdermal Experiments
  • Shed snake skin was used as a model membrane as it is composed of keratinaceous material similar to that of a nail. Analysis was carried out on an Agilent 1100 high performance liquid chromatography (HPLC) instrument. An isocratic elution method was used in conjunction with acetonitrile and an ion-pairing reagent in a phosphate buffer at pH 3.0 as the mobile phase on a Zorbax Reverse Phase C8 column.
  • HPLC high performance liquid chromatography
  • formulations F1-F4 are eutectic melts with lidocaine. It is evident that the addition of other eutectic agents enhance the permeation significantly.
  • F5-F8 do not contain lidocaine.
  • F5 is a gel-type eutectic formulation with choline chloride/urea/AMP and shows the best permeation behavior from the first set.
  • control and placebo do not provide any significant permeation or retention.
  • FIGS. 3 A and 3B illustrate the results of transdermal studies on eutectic melts with additional ingredients.
  • the formulations F21-F23 show the highest permeation behavior in this second set. All contain a urea/choline chloride-based eutectic melt in conjunction with other excipients.
  • F21, F22, F24 and F25 exhibit the highest retention of the above formulations.
  • the data shows that certain phenolic eutectic agents, such as phenol (F24) and resorcinol (F25), produce terbinafine fluxes lower than those from other formulations in the set, such as F21 and F22.
  • Table 4 Third Set of Eutectic Formulations
  • formulations F31-F34 contain 10% or less of the active agent, whereas formulations F35-F37 have 14.3% active and formulation F38 contains -10.9% active. It appears that at least for this set of formulations, the precise terbinafine concentration is not critical to performance.
  • F31-F33 are choline chloride/urea-based eutectic formulations and they all provide similar terbinafine permeation behavior, whereas F34 is a camphor/menthol/glycerin monolaurate-based eutectic formulation.
  • F35 has similar constituents to F34, except glycerin is replaced by phenol.
  • F36 is a resorcinol version of F35, and F37 contains additional lauryl alcohol as compared to F36.
  • F38 is a choline chloride/urea based eutectic formulation containing glycerin monolaurate, lauryl alcohol, and menthol eutectic melts.
  • formulations are especially effective.
  • formulations F31, F32 and also F36 and F37 show the highest terbinafine skin retention from among the third formulations set.
  • the marketed control affords minimal terbinafine skin retention.
  • F48 is a non- eutectic melt formulation, identical in composition to that of F41, but obtained by simple combination of the ingredients. Notably, it does not provide significant terbinafme permeation enhancement. [0183] As displayed in FIG. 5B, these composition modifications that lead to substantial changes in terbinafme permeation, have little impact on terbinafme skin retention in the shed- snake-skin model system.
  • phosphatidylcholine has some potential benefit as a terbinafme permeation enhancer (F53 and F55). However, a high lecithin concentration reduces terbinafme permeation (F51).
  • Other anionic detergents (F56-F58) tested as replacements for choline chloride do not exhibit synergistic behavior with urea like that of choline chloride.
  • FIG. 7 illustrates the results for exemplary lacquer-type formulations (Table 8). Although the lecithin-containing formulation F61 shows some terbinafme permeation enhancement, the choline chloride-containing formulation F66 exhibits the most pronounced terbinafme permeation enhancement of the set.
  • Bovine hoof was used as a model nail substrate as it is composed of keratinaceous material quite similar to human nail.
  • Franz cells with a 3-mL receptor well volume were used in conjunction with bovine hoof slices.
  • the donor well had an area of ⁇ 0.55 cm 2 .
  • Receptor wells were filled with isotonic phosphate buffered saline (PBS) with a pH of 5.5.
  • Bovine hoof slices of thickness 1 mm were cut from a bovine hoof obtained from a local
  • the slices were soaked for at least 24 hours in water and then glued to the donor and receptor cell of the Franz cell with adhesive. A pinch clamp was applied to the assembly.
  • Test formulations were applied to the hoof at a dosing level of 5 ⁇ l per dose. Formulation was applied to the hoof slice on a daily basis. Before each application, a dry Q-tip cotton swab was used mechanically to remove any residual formulation from previous applications.
  • the Franz cells were maintained at 32 °C by placement in an incubator, and the receptor wells of the Franz cells were stirred with a magnetic stir bar. Sample aliquots were drawn from the receptor wells at varying times (as shown in the figures reporting permeation data) and replaced with fresh buffer.
  • the eutectic melt formulations exhibited higher terbinafine permeation enhancement even at micro doses in comparison to the control cream (Lamisil ® ). Dosing was performed at 5 ⁇ l/day for every formulation tested, including the control.
  • the permeation enhancement ratio for formulation T09501-01 relative to control is modest at early time points, the ratio increases significantly with time.
  • the eutectic melt formulations display terbinafine bovine hoof retentions of up to ten-fold greater than that seen with Lamisil ® Cream.
  • Tables 1OA and 1OB describe several exemplary anti-fungal compositions, at differing terbinafine concentrations.
  • a eutectic melt of choline chloride and urea was generated by mixing and heating at 90 0 C.
  • terbinafine hydrochloride the mixture was heated and mixed to obtain a viscous gel.
  • the resulting gel is stable at room temperature.
  • lactic acid, Tween 20, EPM, limonene (if present) and antioxidants (if present) were added.
  • FIGS. 9A-D illustrate terbinafine permeation test results for four exemplary antifungal compositions with differing terbinafine concentrations. As demonstrated, penetration for the active compositions was much better than for the control. In the case of the experiment for which accumulated dose data are depicted in FIG.
  • Table 11 provides a comparison of the relative terbinafine permeation
  • Buffer Preparation Buffers were prepared at 50 mM concentration using ammonium acetate (pH values of 4.0 and 10.0) or ammonium phosphate (pH values of 6.0, 7.0, and 8.0).
  • Solubility Sample Preparation 100 to 800 mg of terbinafine hydrochloride was transferred to separate 4-mL vials. To each vial 2 ml of the solvent to be investigated was added. Samples were capped and then rotated for 24 hours at room temperature. The samples were then allowed to settle overnight at room temperature. Approximately 0.4 mL of the supernatant was removed and transferred to a 0.45 ⁇ m Nylon microcentrifuge filter and clarified. Samples were diluted with 50% methanol to within the calibration range. [0205] Sample Analysis: Samples were analyzed by HPLC using methodology based on Standard Test Method STM.004. The STM.004 HPLC conditions were modified to reduce the run time to about 5 minutes. Calibration standards at approximately 0.00, 0.02, 0.1, 0.25, 0.65, and 1.0 mg/mL were used to construct a calibration curve, from which sample concentrations were determined and corrected for dilution to achieve the final solubility result.
  • Terbinafine hydrochloride shows moderate solubility in aqueous solvents with pHs of 4 and 6, but it shows substantially lower solubility at pHs 7, 8, and 10.
  • Terbinafine hydrochloride shows high solubility in polar organic solvents such as ethanol and DMSO, but lower solubility in non-polar solvents such as ethyl acetate and isopropyl myristate.
  • the solubility in current prototype topical formulations (NRI- 1002-03 and NRI- 1002-04) is high and ranges from 214 to 235 mg mL '1 , corresponding to 21-24% w/v.
  • Example 30 Stability Studies of Exemplary Terbinafine Formulations
  • This example describes the short-term physical and chemical stability of terbinafine formulations for a period of up to three months under long-term ⁇ i.e., 25 ⁇ 2° C, 40% ⁇ 5% relative humidity (RH)) conditions.
  • HPLC High-performance liquid chromatography
  • Table 13 sets forth the results of a three-month stability study on NR1-1002-03 at 25 °C and ambient humidity.
  • Table 14 sets forth the results of a three-month stability study on NR1-1002-03 at 40 °C and 75% relative humidity.
  • Table 15 sets forth the results of a three-month stability study on NR1-1002-04 at 25 °C and ambient humidity.
  • Table 16 Three-Month Stability Study of Terbinafine Formulation NRl-1002- 04 (40 0 C)
  • Table 16 sets forth the results of a three-month stability study on NRl - 1002-04 at 40 °C and 75% relative humidity.
  • Table 17 sets forth the results of a one-month stability study on NRI- 1002-04v 1 at 25 °C and ambient humidity.
  • Table 18 One-Month Stability Study of Terbinafme Formulation NRl -1002- 04vl (40 0 C)
  • Table 18 sets forth the results of a one-month stability study on NRI- 1002-04v 1 at 40 °C and 75% relative humidity.
  • Table 19 sets forth the results of a one-month stability study on NRI- 1002-04v2 at 25 0 C and ambient humidity.
  • Table 20 One-Month Stability Study of Terbinafme Formulation NRl-1002- 04v2 (40 0 C)
  • Table 20 sets forth the results of a one-month stability study on NRI- 1002-04v2 at 40 0 C and 75% relative humidity.
  • Table 21 sets forth the results of a one-month stability study on NRI- 1002-04- 060710- v3 at 25 0 C and ambient humidity.
  • Table 22 One-Month Stability Study of Terbinafme Formulation NRl-1002- 04v3 (40 0 C)
  • Table 22 sets forth the results of a one-month stability study on NRI- 1002-04- 060710-v3 at 40 °C and 75% relative humidity.

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Abstract

Cette invention concerne des compositions à usage topique, des procédés de préparation, et des méthodes de traitement impliquant l'incorporation d'un eutectique à l'état fondu dans une formulation. La formulation améliorée peut accroître la perméabilité et la biodisponibilité. Dans certains modes de réalisation spécifiques, cette invention concerne une composition pharmaceutique antifongique à usage topique comprenant un agent antifongique, au moins un agent eutectique, et un solvant à bas point d'ébullition pharmaceutiquement acceptable.
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WO2011079234A3 (fr) * 2009-12-23 2011-08-18 Nuvo Research Inc. Formulation de terbinafine à grande perméation
EP2664327A1 (fr) * 2012-05-14 2013-11-20 Almirall S.A. Compositions pharmaceutiques topiques comprenant du terbinafide et de l'urée
US8778365B1 (en) 2013-01-31 2014-07-15 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US9144553B2 (en) 2012-12-21 2015-09-29 Teikoku Pharma Usa, Inc. Compositions and methods for transdermal delivery of hormones and other medicinal agents
US9433680B2 (en) 2013-01-31 2016-09-06 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US9446131B2 (en) 2013-01-31 2016-09-20 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US9452173B2 (en) 2013-01-31 2016-09-27 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
WO2017062761A1 (fr) 2015-10-07 2017-04-13 Exodos Life Sciences Lp Compositions antifongiques topiques
WO2017216722A3 (fr) * 2016-06-13 2018-03-01 Vyome Biosciences Pvt. Ltd. Compositions antifongiques synergiques et leurs procédés
FR3058905A1 (fr) * 2016-11-18 2018-05-25 Universite Du Littoral Cote D'opale Procede d'epuration d'un effluent gazeux
CN109689034A (zh) * 2016-06-13 2019-04-26 维奥梅治疗有限公司 协同抗真菌组合物及其方法
WO2019214838A1 (fr) * 2018-05-09 2019-11-14 Eviderm Institute Ab Utilisation d'une composition contenant de l'alcool pour améliorer la fonction barrière de la peau
WO2020223097A1 (fr) * 2019-04-30 2020-11-05 Bayer Healthcare Llc Compositions analgésiques topiques
WO2020223093A1 (fr) * 2019-04-30 2020-11-05 Bayer Healthcare Llc Compositions de gel analgésique topique
WO2021034192A1 (fr) 2019-08-19 2021-02-25 Seranovo Holding B.V. Formulation pharmaceutique de sel eutectique
CN113024362A (zh) * 2021-03-10 2021-06-25 中国科学院上海药物研究所 一种辅酶qh与烟酰胺的共晶及其制备方法和用途
CN113382753A (zh) * 2018-10-24 2021-09-10 瑟拉诺沃有限公司 用于口服药物制剂的深共晶溶剂平台
WO2022010367A1 (fr) * 2020-07-10 2022-01-13 Aquafortus Technologies Limited Solution de séchage par solvant et processus s'y rapportant
US11241520B2 (en) * 2014-08-07 2022-02-08 Cook Medical Technologies Llc Compositions and devices incorporating water-insoluble therapeutic agents and methods of the use thereof
CN114981379A (zh) * 2019-10-08 2022-08-30 哈尔卢克斯股份有限公司 治疗甲癣的组合物和方法
CN114949324A (zh) * 2022-06-15 2022-08-30 浙江工业大学 一种生物相容性抗菌凝胶膜的制备方法
WO2023245256A1 (fr) * 2022-06-24 2023-12-28 Royal Melbourne Institute Of Technology Gels antimicrobiens
US20240091148A1 (en) * 2018-08-01 2024-03-21 Novilla Pharmaceuticals, Inc. Eutectic solvents comprising pharmaceutical agents, and methods of making and use thereof
WO2024175915A1 (fr) 2023-02-21 2024-08-29 University Of Reading Compositions pour administration topique
CN118831062A (zh) * 2024-06-21 2024-10-25 江苏知原药业股份有限公司 一种稳定性好且溶出度高的阿普米司特片及其制备方法
CN119707642A (zh) * 2025-02-28 2025-03-28 深圳杉海创新技术有限公司 一种苯乙基间苯二酚甜菜碱共晶及其制备方法和应用

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US11241520B2 (en) * 2014-08-07 2022-02-08 Cook Medical Technologies Llc Compositions and devices incorporating water-insoluble therapeutic agents and methods of the use thereof
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EP3359133A4 (fr) * 2015-10-07 2019-06-12 Exodos Life Sciences LP Compositions antifongiques topiques
WO2017216722A3 (fr) * 2016-06-13 2018-03-01 Vyome Biosciences Pvt. Ltd. Compositions antifongiques synergiques et leurs procédés
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FR3058905A1 (fr) * 2016-11-18 2018-05-25 Universite Du Littoral Cote D'opale Procede d'epuration d'un effluent gazeux
WO2019214838A1 (fr) * 2018-05-09 2019-11-14 Eviderm Institute Ab Utilisation d'une composition contenant de l'alcool pour améliorer la fonction barrière de la peau
US20240091148A1 (en) * 2018-08-01 2024-03-21 Novilla Pharmaceuticals, Inc. Eutectic solvents comprising pharmaceutical agents, and methods of making and use thereof
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