WO2017161136A1 - Acid salts for vaginal drug delivery - Google Patents

Abstract

The disclosure provides a composition comprising a drug that is the salt of one or more basic nitrogen atoms targeted for vaginal delivery and one or more acidic excipients. The disclosure further provides a method comprising administering the composition to the vagina of a subject, and a kit comprising a container comprising the composition and instructions for the use thereof.

Description

ACID SALTS FOR VAGINAL DRUG DELIVERY

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S.

Provisional Patent Application No. 62/310,586, filed March 18, 2016, which is incorporated herein by reference.

FIELD OF INVENTION

[0002] This invention relates to drug delivery devices and therapeutic treatment using the devices.

BACKGROUND

[0003] All publications listed or referenced herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0004] Intravaginal rings (IVRs), sub-dermal implants, rapidly dissolving tablets and inserts, and pessaries/suppositories are routinely used for the delivery of drugs both topically and systemically to vaginal or rectal tissue. Typically, some of these devices are made from a polymer matrix such as silicone, and the drug is dispersed throughout the matrix. Release of the drug occurs by diffusion of the drug molecules through the polymer matrix and partitioning into the fluid in the area of the body where the device is placed (e.g. , in the vaginal fluid for an IVR). Two examples of matrix release devices are the IVR products Nuvaring, for the delivery of contraceptive hormones, and Estring, for the delivery of estradiol for hormone replacement therapy in menopausal women. Semisolid compositions (ointments, hydrogels), douches, tablets, inserts, and films also are options for intravaginal delivery. Delivery of drugs (i.e. , small molecule therapeutics) to the vagina is complicated, however, by vaginal biology (e.g. , anatomy, microflora, components of vaginal fluids, immunity, menstruation, and the like). There exists a need in the art for a drug delivery system that provides increased control over the intravaginal release of drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Exemplary embodiments are illustrated in the referenced figures. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than restrictive.

[0006] Figure 1A-1B depict, in accordance with an embodiment of the invention, (A) a combination pod-IVR with tenofovir disoproxil fumarate (TDF), maraviroc (MVC), and emtricitabine (FTC) pods. MVC pods have three delivery channels per pod and TDF and FTC have one delivery channel per pod. (B) Cross-sectional view of a pod-IVR sectioned through a pod with three delivery channels. The compressed drug core (1) is coated with a release polymer (2). Delivery channels (3) of diameter d in the impermeable silicone ring material (4) expose the pod to the vaginal fluids. The pod is sealed in a pre-formed cavity in the blank ring using a backfill of silicone (5).

[0007] Figure 2 depicts, in accordance with an embodiment of the invention, daily in vitro TDF release rates from pod-IVRs using deionized water (100 mL) at 25°C and 60 RPM shaking. Circles, TDF formulation 053-13002, (TDF, 64.5%; Avicel PH-101 (microcrystalline cellulose), 32.0%; Compritol (glyceryl dibehenate), 3.0%; magnesium sterarate, 0.5%), 4 pods per IVR; triangles, TDF formulation 053-13019 (TDF, 69.3%; MCC (Ceolus KG-1000), 23.7%; HPMC (Methocel E5 Prem LV), 3.0%; sodium steryl fumarate (Pruv), 4.0%), 4 pods per IVR;

diamonds, OCIS Std (TDF, 99.5%; magnesium stearate, 0.5%), 1x1.5 mm, 6 pods per IVR; 2x1.5 mm, 4 pods per IVR.

[0008] Figure 3 depicts, in accordance with an embodiment of the invention, daily in vivo TDF release rates from pod-IVRs in sheep shown as individual values and means (horizontal lines). Circles, TDF formulation 053-13002, (TDF, 64.5%; Avicel PH-101 (microcrystalline cellulose), 32.0%; Compritol (glyceryl dibehenate), 3.0%; magnesium sterarate, 0.5%), 4 pods per IVR; triangles, TDF formulation 053-13019 (TDF, 69.3%; MCC (Ceolus KG-1000), 23.7%; HPMC (Methocel E5 Prem LV), 3.0%; sodium steryl fumarate (Pruv), 4.0%), 4 pods per IVR; diamonds, OCIS Std (TDF, 99.5%; magnesium stearate, 0.5%), 1x1.5 mm, 6 pods per IVR; 2x1.5 mm, 4 pods per IVR.

[0009] Figure 4 depicts, in accordance with an embodiment of the invention, daily in vivo TDF release rates from pod-IVRs (4 pods per IVR; manufactured with lxl mm center delivery channel, 2 x 1.5 mm holes punched for inner and outer delivery channels) in sheep shown as individual values and means (horizontal lines). The formulations are defined in Table 1.

[0010] Figure 5 depicts, in accordance with an embodiment of the invention, solubility of TDF as a function of medium pH. VFS, vaginal fluid simulant (i).

DETAILED DESCRIPTION OF THE INVENTION

[0011] All references cited herein are incorporated by reference in their entirety as though fully set forth. Unless defined otherwise, 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. Allen et al., Remington: The Science and Practice of Pharmacy 22^nd ed.,

Pharmaceutical Press (September 15, 2012); Hornyak et al., Introduction to Nanoscience and Nanotechnology, CRC Press (2008); Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology 3^rd ed., revised ed., J. Wiley & Sons (New York, NY 2006); Smith, March 's Advanced Organic Chemistry Reactions, Mechanisms and Structure 7^th ed., J. Wiley & Sons (New York, NY 2013); and Singleton, Dictionary ofDNA and Genome Technology 3^rd ed., Wiley-Blackwell (November 28, 2012), provide one skilled in the art with a general guide to many of the terms used in the present application.

[0012] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Indeed, the present invention is in no way limited to the methods and materials described. For purposes of the present invention, certain terms are defined below.

[0013] "Conditions" and "disease conditions," include, but are not limited to, conditions that can be treated or prevented through the use of one or more agents administered via the vagina. Examples of conditions treated or prevented in the context of the invention include microbial infection, such as HIV infection.

[0014] As used herein, the term "HIV" includes HIV- 1 and HIV-2.

[0015] As used herein, the term "agent" includes any substance capable of treating a disease or condition described or referenced herein.

[0016] As used herein, the term "API" means active pharmaceutical ingredient, which includes agents described herein. [0017] The terms "drug delivery system" and "implant" are used interchangeably herein, unless otherwise indicated.

[0018] "Mammal," as used herein, refers to any member of the class Mammalia, including, without limitation, humans and nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domesticated mammals, such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs, and the like. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be included within the scope of this term.

[0019] An IVR platform, termed the "pod-IVR", is described in detail in the literature (1-2). In the pod-IVR, a drug substance is formulated into a pod: a compressed core of the drug that is coated with one or more polymer membranes to modulate the release rate of the agent from the IVR. Each pod is accessed by one or more delivery channels in the impermeable IVR structure that expose part of the pod's polymer membrane surface to the outside of the ring, enabling independent and precise control of the delivery rate of the agent. Figure 1 shows a combination IVR formulated with the antiretroviral (ARV) drugs tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and maraviroc (MVC).

[0020] The pod-IVR can contain from one to ten drug pods in any combination (i.e. , up to ten pods of a single drug, or any combination of up to ten total pods of multiple drugs). The delivery rate of each agent is determined by the additive effect of the solubility of the drug substance and by three independently variable parameters: the composition and thickness of the pod's polymer membrane coating, the size and number of delivery channels through the ring exposing each individual pod to the vaginal fluid, and the number of pods of each agent in the ring. By tailoring these three pod-IVR parameters to a particular drug substance, the delivery rate may be precisely controlled over as many as three orders of magnitude. Successful in vitro and in vivo delivery at pharmacologically relevant rates from pod-IVR devices has been achieved for APIs spanning a broad range of physicochemical characteristics (3) from lipophilic hormones to hydrophilic drugs, and even proteins (4) and bacteria (5). A five-drug pod-IVR was previously developed as a proof-of-concept, advanced multipurpose prevention technology (MPT), combining three ARV drugs from different mechanistic classes with estradiol and etonogestrel as contraceptives for prevention of HIV infection and unintended pregnancy (3d). In certain cases, one or more of the APIs in the IVR formulation is/are an acid salt, such as TDF (3e).

[0021] Following preliminary studies in sheep (6) and pig-tailed macaques (3e), there was continued development of a pod-IVR delivering TDF in combination with other APIs. The next phase of preclinical development involved a TDF dose-ranging study in sheep designed to identify a lead formulation for subsequent evaluation in women.

[0022] Surprisingly, the formulations evaluated in sheep afforded unexpected in vivo release rates based on in vitro dissolution studies and rVR configuration.

[0023] Unexpectedly, TDF formulation 053-13002 led to similar in vivo release rates irrespective of the diameter and number of delivery channels (Fig. 3, circles). Changing the TDF formulation increased the overall daily in vivo release rate, but again, led to similar rates irrespective of IVR configuration (Fig. 3, triangles and diamonds). The effects were not observed in the many animal and clinical studies carried out previously with the pod-IVR platform where in vitro and in vivo release rates of drugs other than TDF were correlated.

[0024] These unexpected results led to the hypothesis that physiological factors such as vaginal fluid volume and/or pH were driving TDF release from the IVRs. This hypothesis was tested by formulating TDF admixed with a variety of excipients in the drug core, as shown in Table 1.

Table 1. Novel TDF formulations to increase in vivo release rates.

Formulation Excipient(s) Concentration (%, w/w)

TDF-Ctrl magnesium stearate⁸ ( 5

TDF-Cit citric acid monohydrate 20

magnesium stearate 0.5

TDF-Glu/Gly glycogen 5

£⁾-glucose monohydrate 10

magnesium stearate 0.5

TDF-Cit/Glu/Gly citric acid monohydrate 20

glycogen 5

£⁾-glucose monohydrate 10 magnesium stearate 0.5

TDF-FTC FTC 30

magnesium stearate 0.5

'Remainder TDF; §Control

[0025] The citric acid was designed to maintain a low pH in the drug core, the

glucose/glycogen mixture was thought to act as an osmotic agent to bring vaginal fluids into the drug core, and the FTC was designed to act as a solubilizer for the TDF. In vivo release rates for these formulations obtained from a crossover sheep study are shown in Figure 4.

[0026] The data in Figure 4 clearly demonstrate that, unexpectedly and non-obvious to one expert in the art, vaginal pH is the primary physiological factor driving release of a drug that is the salt of one or more basic nitrogen atoms {e.g., TDF) from the IVR. The in vitro solubility of TDF as a function of buffer pH and the results are shown in Figure 5.

[0027] The solubility of TDF was very dependent on medium pH, with a mid-point in the sigmoidal fit (Fig. 5, dotted line) of pH 5.41. The vaginal pH of healthy women {i.e.,

lactobacillus-dominated vaginal microbiota) is between 2.8-4.2, while dysbiotic vaginal microbiomes lead to vaginal fluid pH values between 4.5 and 6.5, even as high as 8 in some cases (7). Based on our unexpected results, this wide vaginal pH range will require an acidic excipient to be admixed with a drug that is the salt of one or more basic nitrogen atoms {e.g., TDF) to provide controlled, predictable drug release.

[0028] The disclosure provides a composition for intravaginal delivery {i.e., an intravaginal composition or formulation) comprising a drug that is a salt of one or more basic nitrogen atoms and one or more acidic excipients. Examples of drug that is a salt of one or more basic nitrogen atoms include, but are not limited to, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide hemifumarate (TAF2), abacavir sulfate, atazanavir sulfate, darunavir hydrochloride, delavirdine mesylate, etravirine hydrobromide, indinavir sulfate, maraviroc phosphate, nelfinavir mesylate, rilpivirine hydrochloride, and saquinavir mesylate. In various aspects, the drug is TDF or TAF2. Optionally, TDF or TAF2 comprises 60%-99.5% w/w of the composition {e.g., 64.5%-99.5%, such as 64.5%, 69.5%, 79.5%, 84.5%, or 99.5% w/w of the composition).

[0029] In various embodiments, the disclosure concerns the addition of one or more acidic excipients to one or more APIs (drugs) in salt form delivered vaginally. The following non- exclusive list of acids form pharmaceutically acceptable salts: hydrochloric, sulfuric, phosphoric acid, acetic, ethanesulfonic, 1,2-ethanedisulfonic, methanesulfonic, ethanesulfonic, 1,2- ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-chlorobenzenesulfonic, 2- naphthalenesulfonic, p-toluenesulfonic, and camphorsulfonic acid. Useful acidic excipients preferably form acceptable tablets when compacted with the API (e.g. , if delivered from pod- IVRs). Optionally, one or more of the acidic excipients comprises an organic acid. Examples of acceptable acidic excipients suitable for use in the context of the disclosure include, but are not limited to: citric acid, DL- lactic acid, L-lactic acid, £⁾-lactic acid, other organic acids widely found in nature such as fumaric acid, maleic acid, succinic acid, tartaric acid, malonic acid, sorbic acid, etc. In various aspects, the acidic excipient is citric acid monohydrate (e.g. , about 0.5-80%, about 1-50%, about 5-40%, about 10-30%, about 15-25%, or about 20% w/w).

[0030] In some aspects, the acidic excipient added to the API salt is the same as the acid used to create the API salt in the first place. For example, TDF is a fumarate salt and the excipient used to formulate the TDF core could be fumaric acid. Preferably, the acidic excipient included in the composition provides adequate tablet quality obtained upon compaction. In the case of TDF, for instance, addition of citric acid monohydrate (20% w/w) resulted in good quality tablets upon compaction. A second consideration in the choice of acidic excipient is the impact it will have on the vaginal mucosa and the vaginal microbiome. For example, the use of lactic acid as an acidic excipient is expected to have a beneficial impact in this regard, although lactic acid is not the only acidic excipient having this beneficial effect.

[0031] Other suitable excipients for use in the context of the disclosure include, but are not limited to, absorbent cotton, acacia, adipic acid, adonitol sugar, agarose, alcohol, alkyl fumarate, allantoin, alum, aluminium magnesium, aluminium sulfate, arabitol, ascorbic acid, barium sulfate, bentonite, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzoic acid, benzyl alcohol, beta cyclodextrin, butylated hydroxyanisole, butylated

hydroxytoluene, calcium acetate, calcium carbonate, calcium lactate, carbomer (Carbopol), cellulose, Ceteth-20 (polyoxy-ethylene 20 cetyl ether), cetostearyl alcohol, cetyl alcohol, cetyl dimethicone copolyol, cetyl esters wax, cetyl palmitate, cetyl pyridinium chloride, chamomile tea, chitosan, cholesterol, citric acid, cocoa butter, coconut oil glycerides, collagen, colloidal silicon dioxide, copper sulfate, corn oil, cremophor, crospovidone, cystine, dextrose, diacetin, diacetyl phosphate, dibasic calcium phosphate, dichlorodifluoromethane, dichlorotetrafluoro- ethane, diethylaminoethyl stearamide, diglycol, disodium edetate, dulcitol, EDTA, egg albumin, ethyl cellulose, ethylene glycol, gelatin, glacial acetic acid, glutamic acid, glycerides of fatty acids, glycerin, glycerogelatin, glyceryl monostearate, glyceryl stearate, glycine, glycogen, guar gum, hibitane acetate, hydrochloric acid, hydrogen peroxide, hydrogenated palm oil, hydrous lanolin, hydroxyethyl cellulose, hydroxyethyl methacrylate, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl, isopropyl myristate, isopropyl palmitate, lactic acid, lactose, lanolin, laureth (polyoxyethylene lauryl ether), lecithin, light mineral oil, magnesium stearate, maltodextrin, maltose, mannitol, massa estarinum, massupol, methionine, methyl cellulose, methyl parabens, methyl stearate, mineral oil, myristic acid, nitric acid, Novata hard fats, octyl dodecanol, oxyquinoline sulfate, palm kernel oil, palm oil, panthenol, peanut oil, peglicol 5 oleate, pegoxol 7 stearate, phenylethyl alcohol, phosphoric acid, piperazine hexahydrate, poloxyethylene stearate, polyacrylamide, polycarbophil, polyethylene, polyethylene glycol, polyethylene oxide, polyglyceryl methacrylate, polyoxyethylene, polyoxypropylene, polysorbates, polyvinyl alcohol, potassium bitartarate, potassium carbonate, potassium hydroxide, potassium sorbate, povidone (polyvinyl pyrrolidone, polyvidone), pregelatinized starch, promulgen D, propyl parabens, propylene glycol, Quillaia saponins, Rayon, ricinoleic acid, Solvaderm pink perfume, silica gel, silicone polymers (polydimethylsiloxane/ dimethicone/ simethicone), sodium alginate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium carbonate, sodium carboxymethyl cellulose, sodium chloride, sodium cetearyl sulfate, sodium citrate, sodium dibasic phosphate, sodium dihydrogen citrate, sodium ethyl parabens, sodium hyaluronate, sodium hydroxide, sodium lactate, sodium lauryl sulfate, sodium monobasic phosphate, sodium propionate, sodium propyl parabens, sodium starch glycolate, sorbic acid, sorbitan esters, sorbitol, spermaceti wax, stannous chloride, starch (potato, maize), stearic acid, stearyl alcohol, sucrose, talc, tartaric acid, titanium dioxide, tragacanth, triacetin, urea, vitamins A, D, and E, water, white ceresin wax, white soft paraffin, white wax (bleached bees' wax), witepsol (Wecobee), xanthan gum, and xylitol. Excipients are further described in, e.g. , Tambwekar et al., (2001) Compendium of Pharmaceutical Excipients for Vaginal Formulations. Pharm. Tech. 25, 14-24; and Inactive Ingredient Search for Approved Drug Products. (2017) US Food and Drug Administration Center for Drug Evaluation and Research, found at

www.accessdata.fda.gov/scripts/cder/iig/index.cfm, both of which are hereby incorporated by reference in its entirety. [0032] The disclosure further provides a method for delivering a drug to a subject. The method comprises administering the composition described herein to the vagina of a subject. In various embodiments, the drug TDF or TAF2. The disclosure further provides a method for treating, preventing, or reducing the likelihood of a subject developing a condition, the method comprising administering the composition to the vagina of a subject in need thereof, thereby treating, preventing, or reducing the likelihood of the subject developing the condition. In some aspects, the condition is infection, such as a bacterial, yeast, or viral infection, and ailments that result from infection. Examples of infections include, e.g., HIV infection, hepatitis B infection, hepatitis C infection, Gonorrhea (Neisseria gonorrhoeae infection), Chlamydia (Chlamydia trachomatis infection), Syphilis (Treponema pallidum infection). Thus, the disclosure provides a method for treating or preventing viral infection in a subject in need thereof, such as a subject diagnosed with an infection or at risk of infection. It will be appreciated that "treating" does not require a 100% eradication of virus from the subject. Any decrease or maintenance in virus titer (including delay in spread of infection) constitutes a beneficial biological effect in a subject. Similarly, "preventing" does not require a complete preclusion of viral infection; any delay in manifestation of viral infection or associated symptoms is contemplated.

[0033] Optionally, the composition is provided in the form of a douche, gel or ointment, insert, tablet, or film. For example, in some aspects, the formulation is a dry formulation (e.g., a powder, freeze-dried insert, or tablet) and is not a gel. Excipients suitable for use in formulations are described further herein and include, e.g., gelatin, mannitol, aspartame, sodium methyl paraben, and sodium propyl parabens; sorbic acid; and/or poly(acrylic acid). In various embodiments, the method comprises providing a sustained release drug delivery system; and introducing the sustained release drug delivery system into the vagina of the subject. Sustained release delivery systems are merely examples of options for delivering a drug to a subject. The materials and methods described herein are not limited to, e.g., sustained release systems comprising non-biodegradeable materials (such as intravaginal rings), although the composition of the disclosure may be included in an intravaginal ring in various embodiments.

[0034] In this regard, the disclosure further provides a sustained release drug delivery system comprising: one or more reservoirs, wherein said one or more reservoirs are formed by walls comprising a drug-impermeable material; one or more channels in fluid communication with said one or more reservoirs, wherein the walls of said one or more channels are formed by one or more drug-impermeable material; and one or more drug cores located within one or more of said one or more reservoirs and accessible by one or more of said one or more channels. The drug core comprises the composition described herein and is coated with a drug-permeable polymer membrane. In one aspect, the drug delivery system is in the form of an intravaginal ring with one or more reservoirs.

[0035] The disclosure further provides a kit comprising the composition described herein in a container and instructions for the use thereof. Optionally, the composition is provided in a sustained release drug delivery system.

[0036] The various methods and techniques described above provide a number of ways to carry out the invention. Of course, it is to be understood that not necessarily all objectives or advantages described can be achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as taught or suggested herein. A variety of alternatives are mentioned herein. It is to be understood that some preferred embodiments specifically include one, another, or several features, while others specifically exclude one, another, or several features, while still others mitigate a particular feature by inclusion of one, another, or several advantageous features.

[0037] Furthermore, the skilled artisan will recognize the applicability of various features from different embodiments. Similarly, the various elements, features and steps discussed above, as well as other known equivalents for each such element, feature or step, can be employed in various combinations by one of ordinary skill in this art to perform methods in accordance with the principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in diverse

embodiments.

[0038] Although the application has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the application extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and modifications and equivalents thereof. [0039] In some embodiments, the terms "a" and "an" and "the" and similar references used in the context of describing a particular embodiment of the application (especially in the context of certain of the following claims) can be construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (for example, "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application.

[0040] Preferred embodiments of this application are described herein, including the best mode known to the inventors for carrying out the application. Variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the application can be practiced otherwise than specifically described herein. Accordingly, many embodiments of this application include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the application unless otherwise indicated herein or otherwise clearly contradicted by context.

[0041] All patents, patent applications, publications of patent applications, and other material, such as articles, books, specifications, publications, documents, things, and/or the like, referenced herein are hereby incorporated herein by this reference in their entirety for all purposes, excepting any prosecution file history associated with same, any of same that is inconsistent with or in conflict with the present document, or any of same that may have a limiting affect as to the broadest scope of the claims now or later associated with the present document. By way of example, should there be any inconsistency or conflict between the description, definition, and/or the use of a term associated with any of the incorporated material and that associated with the present document, the description, definition, and/or the use of the term in the present document shall prevail.

[0042] In closing, it is to be understood that the embodiments of the application disclosed herein are illustrative of the principles of the embodiments of the application. Other modifications that can be employed can be within the scope of the application. Thus, by way of example, but not of limitation, alternative configurations of the embodiments of the application can be utilized in accordance with the teachings herein. Accordingly, embodiments of the present application are not limited to that precisely as shown and described.

REFERENCES

Baum, M. M.; Butkyavichene, I.; Gilman, J.; Kennedy, S.; Kopin, E.; Malone, A. M.; Nguyen, C; Smith, T. J.; Friend, D. R.; Clark, M. R.; Moss, J. A., An Intravaginal Ring for the Simultaneous Delivery of Multiple Drugs. J. Pharm. Sci. 2012, 101 (8), 2833-2843.

Moss, J. A.; Baum, M. M., Microbicide Vaginal Rings. In Drug Delivery and Development of Anti-HIV Microbicides, das Neves, J.; Sarmento, B., Eds. Pan Stanford Publishing: Singapore, 2014; pp 221-290.

(a) Keller, M. J.; Malone, A. M.; Carpenter, C. A.; Lo, Y.; Huang, M.; Corey, L.; Willis, R.; Nguyen, C; Kennedy, S.; Gunawardana, M.; Guerrero, D.; Moss, J. A.; Baum, M. M.; Smith, T. J.; Herold, B. C, Safety and Pharmacokinetics of Acyclovir in Women Following Release From a Silicone Elastomer Vaginal Ring. . Antimicrob. Chemother. 2012, 67 (8), 2005-2012; (b) Moss, J. A.; Malone, A. M.; Smith, T. J.; Butkyavichene, I.; Cortez, C; Gilman, J.; Kennedy, S.; Kopin, E.; Nguyen, C; Sinha, P.; Hendry, R. M.; Guenthner, P.; Holder, A.; Martin, A.; McNicholl, J.; Mitchell, J.; Pau, C.-P.; Srinivasan, P.; Smith, J. M.; Baum, M. M., Safety and Pharmacokinetics of Intravaginal Rings Delivering Tenofovir in Pig-tailed Macaques. Antimicrob. Agents Chemother. 2012, 56 (11), 5952-5960; (c) Moss, J. A.; Malone, A. M.; Smith, T. J.; Kennedy, S.; Kopin, E.; Nguyen, C; Gilman, J.; Butkyavichene, I.; Vincent, K. L.; Motamedi, M.; Friend, D. R.; Clark, M. R.; Baum, M. M., Simultaneous Delivery of Tenofovir and Acyclovir via an Intravaginal Ring. Antimicrob. Agents Chemother. 2012, 56 (2), 875-882; (d) Moss, J. A.; Malone, A. M.; Smith, T. J.; Kennedy, S.; Nguyen, C; Vincent, K. L.; Motamedi, M.; Baum, M. M., Pharmacokinetics of a Multipurpose Pod-intravaginal Ring Simultaneously Delivering Five Drugs in the Ovine Model. Antimicrob. Agents Chemother. 2013, 57 (8), 3994-3997; (e) Moss, J. A.; Srinivasan, P.; Smith, T. J.; Butkyavichene, I.; Lopez, G.; Brooks, A. A.; Martin, A.; Dinh, C. T.; Smith, J. M.; Baum, M. M., Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model. Antimicrob. Agents Chemother. 2014, 58 (9), 5125-5135.

Gunawardana, M.; Baum, M. M.; Smith, T. J.; Moss, J. A., An Intravaginal Ring for the Sustained Delivery of Antibodies. J. Pharm. Sci. 2014, 103 (11), 3611-3620. Gunawardana, M.; Mullen, M.; Yoo, J.; Webster, P.; Moss, J. A.; Baum, M. M., Sustained Delivery of Commensal Bacteria from Pod-intravaginal Rings. Antimicrob. Agents Chemother. 2014, 58 (4), 2262-2267.

Moss, J. A.; Baum, M. M.; Malone, A. M.; Kennedy, S.; Kopin, E.; Nguyen, C; Gilman, J.; Butkyavichene, I.; Willis, R.; Vincent, K. L.; Motamedi, M.; Smith, T. J., Tenofovir and Tenofovir Disoproxil Pharmacokinetics from Intravaginal Rings. Aids 2012, 26 (6), 707-710. O'Hanlon, D. E.; Moench, T. R.; Cone, R. A., Vaginal pH and Microbicidal Lactic Acid when Lactobacilli Dominate the Microbiota. PLoS One 2013, 8 (11), e80074.

Claims

CLAIMS What is claimed is:

1. A composition comprising

a drug that is the salt of one or more basic nitrogen atoms targeted for vaginal delivery; and

one or more acidic excipients.

2. The composition of claim 1, wherein one or more of the acidic excipients comprise an organic acid.

3. The composition of claiml, wherein one or more of the acidic excipients are selected from the group consisting of: citric acid, Z)L-lactic acid, L-lactic acid, £⁾-lactic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, malonic acid.

4. The composition of any of claims 1-3, wherein the drug is TDF or tenofovir alafenamide hemifumarate (TAF₂).

5. A method for treating, preventing, or reducing the likelihood of a subject developing a condition, the method comprising:

introducing the composition of any one of claims 1-4 into the vagina of the subject, thereby treating, preventing, or reducing the likelihood of the subject developing the condition.

6. A kit, comprising a container comprising the composition of any one of claims 1-4, and instructions for the use thereof.

7. A method comprising administering the composition of any one of claims 1-4 to the vagina of a subject.