WO2022076804A1 - Multifunctional contraceptive gel compositions and related methods of use - Google Patents

Abstract

The present disclosure provides compositions and methods related to contraceptives and contraceptive formulations. In particular, the present disclosure provides novel compositions and methods related to contraceptive gels having higher contraceptive success rates than currently available products and methods. The present disclosure also provides contraceptive gels formulated to prevent sexually-transmitted diseases and to improve male erectile function.

Description

MULTIFUNCTIONAL CONTRACEPTIVE GEL COMPOSITIONS

AND RELATED METHODS OF USE

CROSS REFERENCE TO RELATED APPLICATIONS

|0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63/089,298 filed October 8, 2020, which is incorporated herein by reference in its entirety for all purposes.

FIELD

[0002] The present disclosure provides compositions and methods related to contraceptives and contraceptive formulations. In particular, the present disclosure provides novel compositions and methods related to contraceptive gels having higher contraceptive success rates than currently available products and methods. The present disclosure also provides contraceptive gels formulated to prevent sexually-transmitted diseases and to improve male erectile function.

BACKGROUND

[0003] The population explosion has become recognized as a major worldwide problem. Globally, more than 200 million pregnancies occur each year, and 50% of them are unintended. Therefore, the research and development of contraceptives has received much attention in the past decades. Currently, condoms are the most commonly used method of contraception, yet most people agree that using condoms reduces the quality of sexual intercourse. Spermicides are a group of contraceptive drugs that can be applied in the vagina before intercourse to avoid pregnancy. They have the potential to be combined with other carriers and to become stable on the genitals, achieving contraception, and at the same time, improving the sexual experience when compared to condoms. As a consequence, the improvement of spermicidal drug formulations in contraceptive gels, in terms of both efficiency and efficacy, has become the focus of research.

[0004] One of the most common spermicidal agents is nonoxynol-9 (N-9), but recently published research shows that a nonoxynol-9-containing marketed formulation was only 67% effective at killing sperm in vivo. Also, the long-term use of N-9 can destroy the normal vaginal flora, causing vaginal irritation, hyperemia, edema, or even cervical epithelial damage. Damage to endometrial epithelial cells may increase the likelihood of STD transmission, including AIDS. Thus, the use of alternative spermicidal agents in contraceptive gels, along with other additives that improved user experience while lowering the risks associated with N-9, would contribute to safer, more enjoyable intercourse.

SUMMARY

[0005] Embodiments of the present disclosure include a contraceptive gel composition. In accordance with these embodiments, the composition includes an effective amount of gossypol or a pharmaceutically acceptable salt thereof, an effective amount of an anti-viral compound, and a gel-forming polymer.

[0006] In some embodiments, the gossypol or pharmaceutically acceptable salt thereof is gossypol acetate. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 100 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 5 mg/ml to about 15 mg/ml.

|0007] In some embodiments, the anti-viral compound is a nucleotide analogue reverse transcriptase inhibitor (NRTI). In some embodiments, the anti-viral compound is selected from the group consisting of abacavir, didanosine, emtricitabine, bictegravir, lamivudine, stavudine, tenofovir, zalcitabine, aciclovir and zidovudine. In some embodiments, the anti-viral compound is tenofovir or a derivative thereof. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 20 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.5 mg/ml to about 4.0 mg/ml.

|0008] In some embodiments, the gel-forming polymer is responsive to changes in pH. In some embodiments, the gel-forming polymer is derived from acrylic acid. In some embodiments, the gel-forming polymer is carbomer or a derivative thereof. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.1% to about 5.0%. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.5% to about 2.0%. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 4.0 to about 5.0.

[0009] In some embodiments, the composition further comprises an erectile enhancement agent. In some embodiments, the erectile enhancement agent is selected from the group consisting of Sildenafil (VIAGRA), vardenafil (LEVITRA, STAXYN), tadalafil (CIALIS) and avanafil (STENDRA), and nitroglycerin. In some embodiments, the erectile enhancement agent is nitroglycerin. In some embodiments, the nitroglycerin is present in the composition at a concentration ranging from about 0.1% to about 5.0%. In some embodiments, the erectile enhancement agent is nitroglycerin, and the nitroglycerin is present in the composition at a concentration ranging from about 0.5% to about 2.0%.

[0010] Embodiments of the present disclosure also include a kit comprising any of the compositions described herein, and at least one container. In some embodiments, the kit further includes instructions for administering the composition to a human.

[0011] Embodiments of the present disclosure also include a method of preventing pregnancy using any of the compositions described herein. In accordance with these embodiments, the method includes topically administering a pharmaceutically effective amount of the composition to a surface of a female subject’s vagina and/or to a surface of a male subject’s penis.

[0012] In some embodiments, the method further includes simultaneously preventing viral infection in the female subject and/or the male subject. In some embodiments, the method further includes simultaneously enhancing erectile function in the male subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIGS 1A-1D: Fabrication and characterization of multifunctional contraceptive gel compositions. Schematic diagram illustrating the mixing process of drugs and gel material (FIG. 1A). Representative SEM images of multifunctional contraceptive gel compositions (scale bar: 100 pm (left panel) and 10 pm (right panel)). The image in the right panel is a magnification (lOx) of the image in the left panel (FIG. IB). Gel composition in a glass bottle that has been flipped upside down (FIG. 1C). Rheological properties of the multifunctional contraceptive gels of the present disclosure (FIG. ID).

[0014] FIGS. 2A-2E: The spermicidal and cytotoxic effects of the gel in vitro. Sperm morphology under the microscope (FIG. 2A). Spermicidal efficiency of contraceptive gels containing different concentrations of gossypol acetate (FIG. 2B). Cytotoxicity of the multifunctional conceptive gel compositions of Hela cells (FIG. 2C). CC50 of the multifunctional contraceptive gel compositions (FIG. 2D). Eive/dead staining images (FIG. 2E).

[0015] FIGS. 3A-3B: Anti-viral effects. Confocal images of viral transfection under different concentrations of tenofovir (FIG. 3A). Quantitative analysis of Tenofovir inhibiting viral transfection (FIG. 3B).

[0016] FIGS. 4A-4D: Determination of the estrus cycle and mating success. Determination of the estrus cycle in rats (FIG. 4A). Method of injecting gel into the vagina of female rats (FIG. 4B). Mating behavior in rats and the discovery of vaginal plugs (FIG. 4C). Morphology of rat sperm and rat sperm found in rat vaginal lavage fluid after mating (FIG. 4D).

[0017] FIGS. 5A-5D: The contraceptive effect of the gel. Timeline of the mating assessment (FIG. 5A). Ultrasonic examination of the uterus of rats before and after pregnancy, and images of newborn rats (FIGS. 5B-5C). Number of newborn rats in each group that underwent mating assessment (FIG. 5D).

[0018] FIGS. 6A-6D: Improvement of male erectile disfunction do to gel compositions. Differences in mating incubation period between the gel group and the control group (FIG. 6A). Differences in the number of mating events between the gel group and the control group. Mating events were monitored during the first 20 minutes after the males and females were placed in the same cage (FIG. 6B). Characteristic mating behavior of males (right rat) and females (left rat) (FIG. 6C). Non-erect (top) vs. erect (bottom) male rats (FIG. 6D).

|0019] FIGS. 7A-7C: Rat serum and complete blood count test results. Comparison of renal function indices in rat serum between the gel group and the control group (FIG. 7A). Comparison of inflammatory response indices in rat whole blood between the gel group and the control group (FIG. 7B). Comparison of liver function indices in rat serum between the gel group and the control group (FIG. 7C). ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

DETAILED DESCRIPTION

[0020] Embodiments of present disclosure provide compositions and methods related to contraceptives and contraceptive formulations. In particular, the present disclosure provides novel compositions and methods related to contraceptive gels having higher contraceptive success rates than currently available products and methods. The present disclosure also provides contraceptive gels formulated to prevent sexually-transmitted diseases and to improve male erectile function.

[0021] In accordance with these embodiments, a carbomer-based gel comprising a contraceptive component (e.g., gossypol acetate), an anti-viral component (e.g., Tenofovir), and an erectile enhancement agent (e.g., nitroglycerin) was formulated. The pH of the composition was adjusted to about 3.5-4.5 to make it compatible with the vagina. In vitro, porcine sperm was used to conduct sperm inactivation studies, and anti-viral efficiency was examined by GFP-lentiviral transfection of HeLa cells cultured on the gel. In vivo, female rats were treated with intra-vaginal administrations of the gel via syringe, and then paired with male rats to assess fertility. To test male erectile ability, male rats had the gel applied to their penises and the frequency with which they attempted to mate was observed.

[0022] As described further herein, in vitro, the gossypol component of the contraceptive gel was an effective spermicide; for example, when the concentration of gossypol acetate was about 10 mg/ml, the spermicidal ability reached 100% after 30s. Additionally, the tenofovir component in the gel significantly inhibited lentiviral transfection efficiency in cell-containing media. Overall, the contraceptive gel compositions of the present disclosure successfully prevented females from conceiving after successful mating in 6 pairs of rats. Further, increased sexual frequency was observed in male rats who had the gel applied to their penises, a behavior attributed to the nitroglycerin component of the gel. Thus, embodiments of the present disclosure include novel contraceptive gel compositions that demonstrate higher contraceptive success rates than that of contraceptive gels sold in the market, and which have the added benefit of helping to prevent sexually transmitted diseases (STD) and improving male libido during sexual intercourse.

[0023] Section headings as used in this section and the entire disclosure herein are merely for organizational purposes and are not intended to be limiting.

1. Definitions

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0025] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “and” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. [0026] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6- 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

10027] “Correlated to” as used herein refers to compared to.

[0028] The terms “administration of’ and “administering” a composition as used herein refers to providing a composition of the present disclosure to a subject in need of treatment. The compositions of the present disclosure may be administered by topical (e.g., in contact with skin or surface of body cavity), oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by spray, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

[0029] The term “composition” as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such a term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure and a pharmaceutically acceptable carrier and/or excipient. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present disclosure is contemplated. Accordingly, the pharmaceutical compositions of the present disclosure include those that also contain one or more other active ingredients, in addition to a compound of the present disclosure. The weight ratio of the compound of the present disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Combinations of a compound of the present disclosure and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present disclosure and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

[0030] The term “pharmaceutical composition” as used herein refers to a composition that can be administered to a subject to treat or prevent a disease or pathological condition, and/or to improve/enhance one or more aspects of a subject’s physical health. The compositions can be formulated according to known methods for preparing pharmaceutically useful compositions (e.g., as a gel or hydrogel). Furthermore, as used herein, the phrase “pharmaceutically acceptable carrier” means any of the standard pharmaceutically acceptable carriers. The pharmaceutically acceptable carrier can include diluents, adjuvants, and vehicles, as well as implant carriers, and inert, non-toxic solid or liquid fillers, diluents, or encapsulating material that does not react with the active ingredients of the invention. Examples include, but are not limited to, phosphate buffered saline, physiological saline, water, and emulsions, such as oil/water emulsions. The carrier can be a solvent or dispersing medium containing, for example, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Formulations containing pharmaceutically acceptable carriers are described in a number of sources which are well known and readily available to those skilled in the art. For example, Remington's Pharmaceutical Sciences (Martin E W, Remington's Pharmaceutical Sciences, Easton Pa., Mack Publishing Company, 19.sup.th ed., 1995) describes formulations that can be used in connection with the subject invention.

[0031] The term “pharmaceutically acceptable carrier, excipient, or vehicle” as used herein refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered and which is approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. A carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbents that may be needed in order to prepare a particular composition. Examples of carriers etc. include but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The use of such media and agents for an active substance is well known in the art.

|0032] As used herein, the term “effective amount” generally means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” generally means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0033] The term “combination” and derivatives thereof, as used herein, generally means either, simultaneous administration or any manner of separate sequential administration of a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and Compound B or a pharmaceutically acceptable salt thereof, in the same composition or different compositions. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form (e.g., one compound may be administered topically and the other compound may be administered orally).

[0034] As used herein, the term “subject” and “patient” as used herein interchangeably refers to any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse, a non-human primate (e.g., a monkey, such as a cynomolgus or rhesus monkey, chimpanzee, etc.) and a human). In some embodiments, the subject may be a human or a non-human. In one embodiment, the subject is a human. The subject or patient may be undergoing various forms of treatment.

[0035] As used herein, the term “treat,” “treating” or “treatment” are each used interchangeably herein to describe reversing, alleviating, or inhibiting the progress of a disease and/or injury, or one or more symptoms of such disease, to which such term applies, and/or to improve/enhance one or more aspects of a subject’s physical health. Depending on the condition of the subject, the term also refers to preventing a disease, and includes preventing the onset of a disease, or preventing the symptoms associated with a disease (e.g., viral infection). A treatment may be either performed in an acute or chronic way. The term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. Such prevention or reduction of the severity of a disease prior to affliction refers to administration of a treatment to a subject that is not at the time of administration afflicted with the disease. “Preventing” also refers to preventing the recurrence of a disease or of one or more symptoms associated with such disease.

|0036] As used herein, the term “salts” and “pharmaceutically acceptable salts” generally refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids can include, e.g., acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, and isethionic, and the like. Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In some instances, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, isopropanol, and the like. Lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 985.

[0037] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

2. Contraceptive Compositions

[0038] Currently, marketed contraceptive gel products do not have high efficacy rates. Gossypol, extracted from cotton, has been used to make oral contraceptives for men, and gossypol derivatives, especially gossypol acetate, have been shown to effectively reduce sperm activity in vitro. However, it was shown to damage the seminiferous epithelium and possibly lead to lifelong male infertility in oral administration. This led to the hypothesis that internal medication could be converted into external medication to minimize the side effects in the development of a new type of contraceptive gel with gossypol acetate as a component. In vitro experiments showed that the contraceptive gel compositions of the present disclosure exhibited spermicidal effects that were correlated to the concentration of gossypol acetate used.

[0039] Data has been accumulated on the research of gossypol as a male contraceptive in both of animal studies and clinical trials. Either in vitro or in vivo, gossypol can significantly inhibit sperm motility, making it a promising spermicidal candidate. In addition, Tenofovir is a first-line medication for the treatment and transmission reduction of HIV. It can inhibit the transcription and replication of viruses by inhibiting reverse transcription. Tenofovir has been reported to inhibit viral infection in vitro, which was determined by observing the efficiency of viral transfection in cells. Moreover, nitroglycerin, an FDA-approved drug, can produce nitric oxide (NO) transdermally to promote the mechanism of cGMP and the expansion of vascular smooth muscle, locally increasing blood flow. It is considered to be an effective male erectile enhancer. To take full advantage of all these functional agents, tenofovir (anti-viral), and nitroglycerin (male erectile enhancement), the contraceptive gel compositions of the present disclosure were modified by binding them together in one and verified their function in vitro and in vivo.

[0040] As described further herein, carbomer was used as the base material for fabricating the gel in part because the thickening effect of carbomer is related to the pH value. For example, this material can form a gel at pH 4.5, which is the same as the normal pH value in the vaginal environment. Thus, this property can effectively prevent the imbalance of the vaginal flora, or the destruction of the vaginal microecological balance, caused by pH changes. At present, there are many studies devoted to developing contraceptive tools that have multiple functions during sexual intercourse. Among them, the prevention of STDs has always been the focus of attention. Most STDs are caused by viruses invading the reproductive organs locally, including HIV and Herpes Simplex Virus (HSV). Therefore, a hydrogel was used as a topical drug release system, and the FDA-approved tenofovir fumarate was infused into it. In vitro experiments proved that under the effect of tenofovir, the degree of viral infection in human cervical cells was significantly reduced. With respect to the quality of sexual intercourse, nitroglycerin was used as another topical agent. This medicine can locally improve blood flow through the cGMP mechanism after transdermal diffusion. Therefore, nitroglycerin was added to the gel to improve the erection of male rats. After local application on the male genitals, the gel has the function of keeping the penis fully erect during the sexual intercourse, improving the quality of sex. Overall, the contraceptive gel compositions generated according to the materials and methods provided herein yielded higher contraceptive success rates than those on the market, and was formulated with the added benefits of protecting against STDs and improving male erectile function during sexual intercourse.

[0041] In accordance with the above, embodiments of the present disclosure include a contraceptive gel composition. In some embodiments, the composition includes an effective amount of gossypol or a pharmaceutically acceptable salt thereof, an effective amount of an anti-viral compound, and a gel-forming polymer. With respect to the gossypol component of the composition, gossypol acetate can be used in the composition, although other pharmaceutically acceptable salts of gossypol can also be used, provided the gossypol maintains function as a contraceptive when administered as part of the composition. The gossypol (e.g., gossypol acetate) can be present in the composition in various concentrations, depending on factors including, but not limited to, the desired dosage form, the particular medical condition of the subject, and the potency of the gossypol. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 100 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 90 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 80 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 70 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 60 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 50 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 40 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 30 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 20 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 2 mg/ml to about 20 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 4 mg/ml to about 20 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 8 mg/ml to about 20 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 2 mg/ml to about 18 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 4 mg/ml to about 16 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 5 mg/ml to about 15 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 6 mg/ml to about 14 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 7 mg/ml to about 13 mg/ml. In some embodiments, the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 8 mg/ml to about 12 mg/ml.

[0042] In some embodiments, the gel compositions of the present disclosure can also include an anti-viral compound. In some embodiments, the anti-viral compound is a nucleotide analogue reverse transcriptase inhibitor (NRTI). In some embodiments, the anti-viral compound is selected from the group consisting of abacavir, didanosine, emtricitabine, bictegravir, lamivudine, stavudine, tenofovir, zalcitabine, aciclovir and zidovudine, including any combinations, variants, and/or derivatives thereof. In some embodiments, the anti-viral compound is tenofovir or a derivative thereof. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 20 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 18 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 16 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 14 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 12 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 10 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 8 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 6 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 4 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.4 mg/ml to about 10 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.6 mg/ml to about 10 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.8 mg/ml to about 10 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 1.0 mg/ml to about 10 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 1.2 mg/ml to about 10 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 1.4 mg/ml to about 10 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 1.6 mg/ml to about 10 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 1.8 mg/ml to about 10 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.5 mg/ml to about 10 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.5 mg/ml to about 8.0 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.5 mg/ml to about 6.0 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.5 mg/ml to about 4.0 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 0.5 mg/ml to about 5.0 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 1.0 mg/ml to about 4.0 mg/ml. In some embodiments, the anti-viral compound is present in the composition at a concentration ranging from about 1.0 mg/ml to about 3.0 mg/ml.

[0043] In some embodiments, the gel-forming polymer that forms the base of the compositions of the present disclosure forms a matrix and facilitates the delivery or release of the contraceptive component, the anti-viral component, and/or the erectile enhancement component into a subject. In some embodiments, the gel-forming polymer is a hydrogel-based polymer that is biocompatible with a subject’s body (e.g., vaginal canal) In some embodiments, the gel-forming polymer is derived from acrylic acid. In some embodiments, the gel-forming polymer is carbomer or a derivative or variant thereof. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.1% to about 5.0%. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.2% to about 5.0%. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.4% to about 5.0%. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.8% to about 5.0%. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.1% to about 4.0%. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.1% to about 3.0%. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.1% to about 2.0%. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.5% to about 2.0%. In some embodiments, the gel-forming polymer is present in the composition at a concentration ranging from about 0.5% to about 1.5%.

[0044] In some embodiments, the gel-forming polymer that forms the base of the compositions of the present disclosure is a polymer that is responsive to changes in pH. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 3.0 to about 7.0. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 3.0 to about 6.5. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 3.0 to about 6.0. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 3.0 to about 5.5. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 3.0 to about 5.0. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 3.0 to about 4.5. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 3.0 to about 4.0. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 3.5 to about 4.5. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 4.0 to about 5.0. In some embodiments, the gel-forming polymer forms a gel at a pH ranging from about 4.5 to about 5.5.

[0045] In some embodiments, the contraceptive gel compositions of the present disclosure include other agents or components that address a medical need or improve one or more physical aspects of a subject. For example, in some embodiments, the gel compositions of the present disclosure can include an erectile enhancement agent. In some embodiments, the erectile enhancement agent is Sildenafil (VIAGRA), vardenafil (LEVITRA, STAXYN), tadalafil (CIALIS) and avanafil (STENDRA), and nitroglycerin, or any combinations, variants, or derivatives thereof. In some embodiments, the erectile enhancement agent is nitroglycerin. [0046] In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.1% to about 5.0%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.1% to about 4.0%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.1% to about 3.0%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.1% to about 2.0%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.5% to about 5.0%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.5% to about 4.5%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.5% to about 4.0%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.5% to about 3.5%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.5% to about 3.0%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.5% to about 2.5%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.5% to about 2.0%. In some embodiments, the erectile enhancement agent is present in the composition at a concentration ranging from about 0.5% to about 1.5%.

3. Therapeutic Methods and Kits

|0047] Embodiments of the present disclosure also include a kit comprising any of the compositions described herein, and at least one container. In some embodiments, the kit further includes instructions for administering the composition to a human, including such information as dosing regimens, frequency of administration, routes of administration, side effects, and the like. In some embodiments, the kit includes a device that can be used to administer any of the compositions described herein, including but not limited to, a syringe, an applicator, a depressor, and the like, into a body cavity of an individual (e.g., vaginal canal).

|0048] Embodiments of the present disclosure also include a methods of preventing pregnancy (e.g., contraception) using any of the compositions and/or kits described herein. In accordance with these embodiments, the method includes topically administering a pharmaceutically effective amount of the composition to a surface of a female subject’s vagina or vaginal canal, and/or to a surface of a male subject’s penis.

[0049] In some embodiments, the method further includes simultaneously preventing and/or treating a viral infection in a female subject and/or a male subject and preventing pregnancy in the female subject. For example, the method can include administering any of the compositions described herein containing and a contraceptive component and an anti-viral component to a subject (male and/or female subject). In some embodiments, the method further includes simultaneously enhancing male erectile function and preventing pregnancy in a female subject. For example, the method can include administering any of the compositions described herein containing and a contraceptive component and an erectile enhancement agent to a subject (male and/or female subject). In some embodiments, the method further includes preventing pregnancy, treating and/or preventing a viral infection, and enhancing erectile function in the male subject, by administering any of the compositions described herein.

[0050] The various compositions of the present disclosure provide dosage forms, formulations, and methods that confer advantages and/or beneficial pharmacokinetic profiles. A composition of the disclosure can be utilized in dosage forms in pure or substantially pure form, in the form of its pharmaceutically acceptable salts, and also in other forms including anhydrous or hydrated forms. A beneficial pharmacokinetic profile may be obtained by administering a formulation or dosage form suitable for once, twice a day, or three times a day, or more administration comprising one or more composition of the disclosure present in an amount sufficient to provide the required concentration or dose of the composition to an environment of use to treat a disease disclosed herein, in particular a cancer.

|0051] Embodiments of the present disclosure relate to a dosage form comprising one or more compositions of the present disclosure that can provide peak plasma concentrations of the composition of between about 0.001 to 2 mg/ml, 0001 to 1 mg/ml, 0.0002 to 2 mg/ml, 0.005 to 2 mg/ml, 001 to 2 mg/ml, 0.05 to 2 mg/ml, 0.001 to 0.5 mg/ml, 0.002 to 1 mg/ml, 0.005 to

1 mg/ml, 0.01 to 1 mg/ml, 005 to 1 mg/ml, or 0.1 to 1 mg/ml. The disclosure also provides a formulation or dosage form comprising one or more compositions of the present disclosure that provides an elimination ti/2 of 0.5 to 20 h, 0.5 to 15 h, 0.5 to 10 h, 0.5 to 6 h, 1 to 20 h, 1 to 15 h, 1 to 10 h, or 1 to 6 h.

[0052] A subject may be treated with a composition of the present disclosure or composition or unit dosage thereof on substantially any desired schedule (e.g., prior to sexual intercourse). They may be administered one or more times per day, in particular 1 or 2 times per day, once per week, once a month or continuously. However, a subject may be treated less frequently, such as every other day or once a week, or more frequently. A composition or composition may be administered to a subject for about or at least about 24 hours, 2 days, 3 days, 1 week,

2 weeks to 4 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2 weeks to 12 weeks, 2 weeks to 14 weeks, 2 weeks to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, 2 weeks to 24 months, or for more than 24 months, periodically or continuously.

[0053] A beneficial pharmacokinetic profile can be obtained by the administration of a formulation or dosage form suitable for once, twice, or three times a day administration, or as often as needed, such as before sexual activity or sexual intercourse. The required dose of a composition of the disclosure administered once twice, three times or more daily is about 0.01 to 3000 mg/kg, 0.01 to 2000 mg/kg, 0.5 to 2000 mg/kg, about 0.5 to 1000 mg/kg, 0.1 to 1000 mg/kg, 0.1 to 500 mg/kg, 0.1 to 400 mg/kg, 0.1 to 300 mg/kg, 0.1 to 200 mg/kg, 0.1 to 100 mg/kg, 0.1 to 50 mg/kg, 0.1 to 20 mg/kg, 0.1 to 10 mg/kg, 0.1 to 6 mg/kg, 0.1 to 5 mg/kg, 0.1 to 3 mg/kg, 0.1 to 2 mg/kg, 0.1 to 1 mg/kg, 1 to 1000 mg/kg, 1 to 500 mg/kg, 1 to 400 mg/kg, 1 to 300 mg/kg, 1 to 200 mg/kg, 1 to 100 mg/kg, 1 to 50 mg/kg, 1 to 20 mg/kg, 1 to 10 mg/kg, 1 to 6 mg/kg, 1 to 5 mg/kg, or 1 to 3 mg/kg, or 1 to 2.5 mg/kg, or less than or about 10 mg/kg, 5 mg/kg, 2.5 mg/kg, 1 mg/kg, or 0.5 mg/kg twice daily or less.

[0054] The present disclosure also contemplates a formulation or dosage form comprising amounts of one or more composition of the disclosure that results in therapeutically effective amounts of the composition over a dosing period, in particular a 24 h dosing period. The therapeutically effective amounts of a composition of the disclosure are between about 0.1 to 1000 mg/kg, 0.1 to 500 mg/kg, 0.1 to 400 mg/kg, 0.1 to 300 mg/kg, 0.1 to 200 mg/kg, 0.1 to 100 mg/kg, 0.1 to 75 mg/kg, 0.1 to 50 mg/kg, 0.1 to 25 mg/kg, 0.1 to 20 mg/kg, 0.1 to 15 mg/kg, 0.1 to 10 mg/kg, 0.1 to 9 mg/kg, 0.1 to 8 mg/kg, 0.1 to 7 mg/kg, 0.1 to 6 mg/kg, 0.1 to 5 mg/kg, 0.1 to 4 mg/kg, 0.1 to 3 mg/kg, 0.1 to 2 mg/kg, or 0.1 to 1 mg/kg.

[0055] A medicament or treatment of the disclosure may comprise a unit dosage of at least one composition of the disclosure to provide therapeutic effects. A “unit dosage or “dosage unit” refers to a unitary (e.g., a single dose), which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active agents as such or a mixture with one or more solid or liquid pharmaceutical excipients, carriers, or vehicles.

4. Materials and Methods

[0056] Synthesis of the contraceptive gel. Carbomer (Fisher Scientific, Waltham, MA, USA) was added to deionized water at a ratio of 1:100 (w/w) and fully stirred into a solution. Then, tenofovir (Sigma- Aldrich, Missouri, USA) was added to the solution at a concentration of 2 mg/ml. Subsequently, gossypol acetate (Sigma- Aldrich, Missouri, USA) was dissolved in 70% ethanol and added to the get at a concentration of 10 mg/ml. The pH of the solution was adjusted to 3.5-4.5 (same as the intravaginal environment) with triethanolamine (Sigma- Aldrich, Missouri, USA) titration, which made the carbomer gelatinous. Finally, nitroglycerin (Sigma- Aldrich, Missouri, USA) was added at a concentration of 1% (by weight) and stirred thoroughly to yield the final contraceptive gel. In some cases, because the titration process may affect the chemical properties of gossypol and nitroglycerin (triethanolamine is alkaline), it can be important to adjust pH before adding gossypol and nitroglycerin. In order to observe the subtle morphological structures and properties of the gel, scanning electron microscopy (SEM) was used and the rheological properties of the gel were measured.

[0057] In vitro spermicidal capability test. All pig sperm samples were taken twice a week from boars at the Swine Unit of North Carolina State University’s College of Veterinary Medicine. The Androstar Premium extender (Minitube, Germany) was used to maintain the sperm’s viability at or above 90%. The gel was diluted into 3 concentration gradients of gossypol acetate in carbomer: Omg/ml, 5mg/ml, lOmg/ml. Fresh pig sperm was pipetted into the 1ml pipette tip. Then, gels with each of the three different concentrations were applied to different pipettes to cover the tips. The sperm in the pipette tip was shot onto a glass slide to simulate the ejaculation process. The sperm activity was immediately observed under a microscope and recorded, at three time points (30s, Imin, and 3min). As a control, pig sperm was shot onto the slide with a pipette without applying the gel. The experiment was repeated three times.

[0058] Cytotoxicity assay. Human HeLa cells (ATCC®, Manassas, VA) were seeded in two 96- well plates at a density of 5,000 cells per well, and then incubated at 37°C in a 5% CO2 incubator until cells attached. The gel was diluted with culture medium adjusted to a pH of 4.5 (same pH as vaginal secretions) to concentrations of 10 mg/ml, 5 mg/ml, 1 mg/ml, 0.2 mg/ml, 0.1 mg/ml, 0 mg/ml. The culture medium in the 96-well culture plates was replaced with the gel-infused medias at different concentrations. Each group had six duplicates. After 2 h and 6 h of incubation, respectively, 10 pL of Cell Counting Kit-8 (Sigma-Aldrich, Missouri, USA) solution were added to each well and incubated for another 2 hours. The 450 nm absorbance for each group was measured with a microplate reader and the viability /proliferation data was analyzed to calculate the 50% cytotoxicity concentration (CC50). GraphPad (GraphPad Software, California, USA) software was used to graph the data. Cytotoxicity was also examined with a Live/Dead imaging kit (ThermoFisher Scientific, Waltham, MA). In short, 500,000 cells per well were seeded in a 12-well plate and incubated overnight. The next day, the gel was diluted with culture medium to concentrations of 10 mg/ml, 6 mg/ml, 4 mg/ml, 0 mg/ml. Each group had three replicates. After a 2-hour incubation, components A and B of the Live/Dead imaging kit were mixed and added to each well, followed by a 15-min incubation. The plate was then put under a fluorescence microscope for observation and cell counting.

[0059] In vitro virus infection. Hela cells were seeded in three 4-well plates at a density of 50,000 cells per well and then incubated overnight at 37°C in a 5% CO2 incubator. The gel was diluted in cell culture medium to achieve the following concentrations of tenofovir: 20 pg/ml, 40 pg/ml, 75 pg/ml. Three of the wells were used to test each of the tenofovir concentrations stated, and one well was used as a blank control. The cell culture medium in the three test wells was replaced with tenofovir-infused gels diluted in medium. The cell culture medium in the last well was simply replaced with fresh cell culture medium. Then, GFP-Lentiviruses (Cellomics Technology LLC, Halethorpe, MD) were used to transduce the cells (MOI=2). After incubating for 4 hours to complete the lentiviral transduction, the cells were washed with PBS and then incubated in cell culture medium for another 48 hours. After incubation, the fluorescence intensity of GFP was observed with a confocal microscope. Cell numbers were counted using Image J software.

[0060] Determination of the rat estrous cycle. Female SD rats (Charles River Laboratories, Wilmington, MA) were anesthetized via isoflurane inhalation, and then affixed to a rodent operating table. A small cotton swab, moistened with saline, was placed at the vaginal orifice, gently inserted into the rat's vagina, slowly rotated, and then slowly removed. The mucus picked up by the small cotton swab was evenly spread onto a glass slide to make a vaginal smear. It was dried and then stained with hematoxylin and eosin (H&E). Under the microscope, the estrous cycle of female rats was determined by the type and proportion of the cells observed.

[0061] Rat mating experiment. Female rats in the estrous phase were randomly divided into a treatment group and a control group, with 6 rats in each group. A total volume of 0.3 mL of contraceptive gel was placed in a 1 mL syringe and administrated into the distal vagina. The rats in the control group received blank carbomer gel as a placebo. After the gel was applied, the rats were continuously monitored for 2 hours for any vaginal leaks. Female rats and fertile male SD rats were placed in the same cage for mating (1:1). The termination of mating was determined by the presence of sperm in vaginal lavage fluid or the occurrence of the vaginal plug.

[0062] Recording the frequency of rat mating. The male rats were randomly divided into a treatment group and a control group, each consisting of six rats. The gel containing 1% nitroglycerin or the blank carbomer gel was applied to the surface of the rat penises in the treatment group or the control group, respectively. Five minutes after administration, the male rats were placed in mating cages alone to give them time to adapt to the new environment. After another 5 minutes, an adult female rat was added to each cage. The following indicators were recorded: (1) The incubation latency, which is the span of time from when the female rat is added to the cage to when the male mated with the female for the first time; (2) The number of erections, which is counted as the number of times the male rat pounced on the female rat, or the number of visible times that the male rat had penile erections (penis exposed over the foreskin) over a 20 minute period.

[0063] Rats blood tests. After administration of the gel overnight, whole blood and serum from all female rats in the gel group and the control group were harvested for a biochemical combination test and a complete blood count.

5. Examples

[0064] It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods of the present disclosure described herein are readily applicable and appreciable, and may be made using suitable equivalents without departing from the scope of the present disclosure or the aspects and embodiments disclosed herein. Having now described the present disclosure in detail, the same will be more clearly understood by reference to the following examples, which are merely intended only to illustrate some aspects and embodiments of the disclosure, and should not be viewed as limiting to the scope of the disclosure. The disclosures of all journal references, U.S. patents, and publications referred to herein are hereby incorporated by reference in their entireties.

[0065] The present disclosure has multiple aspects, illustrated by the following non-limiting examples.

Example 1

|0066] Characterization of the contraceptive gel compositions. Three different functional agents were used to fabricate the gel (FIG. 1A). As show in FIG. 1C, a yellow trifunctional contraceptive gel was prepared. At room temperature, when settled at the bottom of a small glass vial that is subsequently turned upside down, the gel does not fall, demonstrating the required viscosity and rigidity for its application. As shown in the SEM micrograph (FIG. IB), the gel has a compact structure with few, tiny holes. The dependence of the gel’s viscosity on shear rate, a key rheological property, is shown (FIG. ID). These are the steady shear viscosities calculated from the torque measured after 30 min of continuous shear. The gel exhibited shear thinning behavior over the range of shear rates studied, with the viscosity reduced by about two orders of magnitude as the shear rate was increased from 0.01 to 1,000 s. The slope of the curve was relatively stable, indicating that the gel was a nonNewtonian fluid. The rheological properties of the gel demonstrate that it exhibits the characteristics of an effective sexual lubricant. Moreover, when the gel reaches the distal vagina, it will not flow out of the vagina on its own. Instead, unless mechanically forced out, it will stay in place, which is important if it is to be used as a contraceptive gel in the vagina.

[0067] In some embodiments, the carbomer component of the compositions of the present disclosure can facilitate the formation of a gel at certain concentrations. For example, a concentration of about 1% produced a gel composition that exhibited a desired strength. Subsequent experiments were conducted to dilute the carbomer in water at a ratio of about 1 : 100 (w/w). Next, to optimize the concentration of gossypol acetate in the gel, a concentration of about 5 mg/ml and a concentration of about lOmg/ml were tested, and it was found that at 10 mg/ml, the efficiency had reached a desired level. That is, all sperm was inactivated within 30s, which was the same as higher concentrations. Thus, a concentration of 10 mg/ml was an optimal concentration of gossypol acetate in the gel compositions. Furthermore, with respect to the antivirus experiments, as the concentration of Tenofovir was gradually increased, the virus inhibition rate gradually approached 100%. But for the in vitro optimization, cells could die easily when the drug concentration was too high. However, it is possible that Tenofovir will be eventually diluted by body fluids and lower concentrations of Tenofovir could be used (e.g., 2mg/ml). Additionally, it has been reported that when the concentration of nitroglycerin exceeded 1.5%, its promotion for erectile function began to decrease. So a 1% final concentration was used in the gel compositions.

Example 2

[0068] The spermicidal effect of the gel on pig sperm in vitro. The gossypol acetate infused carbomer gel composition had a significant inhibitory effect on pig sperm (FIG. 2). Under the microscope, when sperm cells made contact with the gel, they lost their forwardmoving motility (FIG. 2A), which demonstrated that the gel not only had an inhibiting effect on sperm, but also had a spermicidal effect. Moreover, the spermicidal intensity of the gel increased with higher concentrations of gossypol acetate, showing a dose-dependent relationship (FIG. 2B). When compared to the blank control group without gossypol acetate, the difference was statistically significant (P<0.05).

Example 3

[0069] The nontoxicity of the gel in human cells. The results of the cck8 cytotoxicity assay are shown in FIG. 2C. After two time points, 2 hours and 6 hours of incubation with the gel, the viability of HeLa cells remained stable. The CC50 value confirmed that the working concentration of the gel in vagina (approximately 2 mg/ml) is significantly less than the concentration (6.975 mg/ml) that could cause 50% cytotoxicity (FIG. 2D). Verified with fluorescence microscopy, the Live/Dead assay yielded large areas of live cells (green) and few dead cells (red) (FIG. 2E). While the proportion of dead cells increased with the concentration of the gel in the medium, it had a minimal effect on cell viability at low concentrations. At lower concentrations, the rate of increase in cell death was also relatively slow, showing safety and translation feasibility.

Example 4

[0070] Inhibitory effect of the gel on viral infection. After having undergone GFP- lentiviral transduction, HeLa cells expressed different levels of fluorescence intensity (FIG. 3 A). The percentage of cells expressing GFP was determined as a fraction of the total number of cells, and this was used to measure the degree viral infection. The degree of infection of the blank group (without gel) was used as the negative control, and the inhibitory efficiency on viral transduction of gel dilutions containing different concentrations of tenofovir was calculated (FIG. 3B). The curve suggested that within a certain range, as the concentration increased, the inhibitory efficiency also increased significantly, which indicated the potential of the gel to become a drug release system. This system is likely able to interfere with the viral infection process by releasing functional agents, and has the potential to prevent STD transmission during sexual intercourse.

Example 5

[0071] Determination of estrus cycle and mating success. Vaginal smears of female rats at different stages of the physiological cycle were performed, and the rat estrous cycle was determined based on the proportion of the observed cell types (FIG. 4A). If a large number of white blood cells and a small number of nucleated epithelial cells were observed under the microscope, then the rats were in the diestrus stage, which was not suitable for mating experiments. If a large number of elliptical nucleated epithelial cells were observed, accompanied by a small number of keratinocytes, then they were in the proestrus stage. If irregular keratinized epithelial cells, nucleated epithelial cells, and white blood cells were observed, and their proportions were equal, they were in the metestrus stage. When a large number of irregularly shaped keratinocytes was observed, they were in the estrus stage and ready for mating. Female rats at the estrus stage were selected as experimental subjects and had gel inserted in their vaginas. The gel continued to exist stably in the vagina for 2 hours, which proved the feasibility of its application. Rat sperm was obtained from the seminal vesicles of male rats. Through sperm smears, the morphology of rat sperm was determined under the microscope (FIG. 4D). Male and female rats were placed in the same cage for mating (FIG. 4C). The observation of a vaginal plug indicated successful mating (FIG. 4C). In addition, vaginal lavage fluid was collected and male rat sperm was found (which had similar morphology as observed in vitro) (FIG. 4D), which further proved the successful mating of rats.

Example 6

[0072] The contraceptive effect of the gel. Rats in the estrus phase were selected for mating experiments. Before mating, the gel was evenly applied in the rats’ vaginas (FIG. 4B), which effectively inhibited sperm motility after mating. There was no pregnancy recorded in the experimental group (FIG. 5A). By contrast, the rats in the control group all completed normal delivery within one trimester of pregnancy after mating (FIG. 5C). Ultrasound imaging was used to monitor their pregnancies after successfully mating. In the female rats that were given the gel, the ultrasound images of the uterus did not show any pregnancy, while in the control group, the ultrasound images showed the existence of a fetus (FIG. 5B). After 22 days after successful mating, no pregnancy cases were observed in the experimental group, which indicated the effective contraceptive function of the gel.

Example 7

|0073] Improvement of male erectile function. In a separate animal experiment, the gel was applied to the penis of male rats to determine its effect on male libido and erectile function. After application, the male and female rats were in the same cage (FIG. 6C). The gel composition containing 1% nitroglycerin helped the male penis become fully erect (expos over the foreskin) (FIG. 6D). There was visible difference between the signs of erection and nonerection in rats. In addition, the use of the gel composition significantly shortened the incubation period for male rats (amount of time the male took to mate once placed in a cage with a female), and increased the number of times male rats mated with females, compared with the rats without gel application (FIGS. 6A- 6B) (P<0.05).

Example 8

[0074] Biosafety of the gel. Determined by complete blood count test, the liver and kidney function indexes of the female rats exposed to the gel overnight were not significantly different from those of the control group, indicating that the gel had not been metabolized by the rats’ liver and kidneys, or that it had no effect on liver and kidney function (FIGS. 7A-7C). The number and type of white blood cells in the experimental group were not significantly different from those in the control group, which proved that the use of the gel did not cause acute or chronic inflammation in the rats (FIG. 7B). Thus, the use of the gel in rats is safe.

Claims

CLAIMS What is claimed is:

1. A contraceptive gel composition comprising: an effective amount of gossypol or a pharmaceutically acceptable salt thereof; an effective amount of an anti-viral compound; and a gel-forming polymer.

2. The composition according to claim 1, wherein the gossypol or pharmaceutically acceptable salt thereof is gossypol acetate.

3. The composition according to claim 1 or claim 2, wherein the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 1 mg/ml to about 100 mg/ml.

4. The composition according to claim 1 or claim 2, wherein the gossypol or gossypol acetate is present in the composition at a concentration ranging from about 5 mg/ml to about 15 mg/ml.

5. The composition according to any of claims 1 to 4, wherein the anti-viral compound is a nucleotide analogue reverse transcriptase inhibitor (NRTI).

6. The composition according to any of claims 1 to 4, wherein the anti-viral compound is selected from the group consisting of abacavir, didanosine, emtricitabine, bictegravir, lamivudine, stavudine, tenofovir, zalcitabine, aciclovir and zidovudine.

7. The composition according to any of claims 1 to 4, wherein the anti-viral compound is tenofovir or a derivative thereof.

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8. The composition according to any of claims 1 to 7, wherein the anti-viral compound is present in the composition at a concentration ranging from about 0.2 mg/ml to about 20 mg/ml.

8. The composition according to any of claims 1 to 7, wherein the anti-viral compound is present in the composition at a concentration ranging from about 0.5 mg/ml to about 4.0 mg/ml.

9. The composition according to any of claims 1 to 8, wherein the gel-forming polymer is responsive to changes in pH.

10. The composition according to any of claims 1 to 9, wherein the gel-forming polymer is derived from acrylic acid.

11. The composition according to any of claims 1 to 10, wherein the gel-forming polymer is carbomer or a derivative thereof.

12. The composition according to any of claims 1 to 11, wherein the gel-forming polymer is present in the composition at a concentration ranging from about 0.1% to about 5.0%.

13. The composition according to any of claims 1 to 11, wherein the gel-forming polymer is present in the composition at a concentration ranging from about 0.5% to about 2.0%.

14. The composition according to any of claims 1 to 13, wherein the gel-forming polymer forms a gel at a pH ranging from about 4.0 to about 5.0.

15. The composition according to any of claims 1 to 15, wherein the composition further comprises an erectile enhancement agent.

16. The composition according to claim 15, wherein the erectile enhancement agent is selected from the group consisting of sildenafil, vardenafil, tadalafil, avanafil, and nitroglycerin.

17. The composition according to claim 15 or claim 16, wherein the erectile enhancement agent is nitroglycerin, and wherein the nitroglycerin is present in the composition at a concentration ranging from about 0.1% to about 5.0%.

18. The composition according to claim 15 or claim 16, wherein the erectile enhancement agent is nitroglycerin, and wherein the nitroglycerin is present in the composition at a concentration ranging from about 0.5% to about 2.0%.

19. A kit comprising any of the compositions of claims 1 to 18, and at least one container.

20. The kit according to claim 19, further comprising instructions for administering the composition to a human.

21. A method of preventing pregnancy using any of the compositions of claims 1 to 18, wherein the method comprises topically administering a pharmaceutically effective amount of the composition to a surface of a female subject’s vagina and/or to a surface of a male subject’s penis.

22. The method according to claim 21, wherein the method further comprises simultaneously preventing viral infection in the female subject and/or the male subject.

23. The method according to claim 21 or claim 22, wherein the method further comprises simultaneously enhancing erectile function in the male subject.