Bioresponsive polymeric seal for protection

Abstract

In some aspects, the present disclosure is directed to polymeric coatings that may be used in a medical device such as a tampon or vaginal contraceptive to create a seal that prevents the transmission of sperm or infectious particles. In some embodiments, the seal may form when the polymeric coating is exposed to a physiological fluid such as seminal fluid.

Description

[0001] BIORESPONSIVE POLYMERIC SEAL FOR PROTECTION

[0002] This application claims the benefit of priority to United States Provisional Application No. 63 / 453,454, filed on March 20, 2023, the entire contents of which are hereby incorporated by reference.

[0003] BACKGROUND

[0004] 1. Field

[0005] This disclosure relates to the fields of medicine, pharmacology and chemistry. In particular, new compositions and methods of prevention of unwanted pregnancies and sexually transmitted infections are disclosed.

[0006] 2. Related Art

[0007] Sexually transmitted infections (STI) and unwanted pregnancies continue to challenge the lives of millions of women worldwide. It is estimated that 17 million women are currently infected with the HIV / AIDS virus, with more than 50% of those living in the sub-Saharan African region (Njororai & Njororai, 2010). Despite significant advances in contraception, women in developing countries are at greater risk of STIs and unwanted pregnancies due to limited access to preventive products that are socially acceptable and financially affordable (Ross et al., 2002).

[0008] Over the past decades, topical inventions for contraception and STI prevention via the vaginal route remained underutilized and unexplored partially due to archaic delivery systems that have not been adapted to the needs of today’s societies. Vaginal drug administration has been demonstrated to effectively decrease systemic side effects due to limited systemic exposure (e.g., progesterone), and to allow convenient self-administration (de Araujo Pereira et al., 2012). The majority of vaginal drug delivery systems are designed for topical administration of antifungals, microbicides, and spermicides despite possible interference with the vaginal equilibrium that can augment the likelihood of subsequent infections. In recent years, systemic delivery of drugs via the vaginal route has been explored. Therapeutic applications for systemic delivery include hormone replacement therapy and contraceptives. Nevertheless, cyclic variations in mucosal barrier properties may interfere with consistent drug delivery (de Araujo Pereira et al., 2012; Vermani et al., 2000).

[0009] Legally marketed vaginal products for female-initiated prevention of local vaginal infections and contraception are administered as semi-solid gels, polymeric films, tablets, creams, intra-vaginal rings, foams or suppositories. The shortcomings of these approaches include irritation, lack of retention inside the vaginal cavity, and variable efficacy (Vermani et al., 2000). Critical to future development of these female-initiated, on-demand technologies to prevent unintended pregnancies and STIs is the development of new compositions that fortify naturally occurring barrier properties of the cervicovaginal area. Previous research has shown that sperm motility and viability as well as infectivity of HIV / AIDS virions are significantly compromised under acidic conditions (Garg et al., 2001 ; Jay et al., 2009). Furthermore, viscous properties of the cervical mucus prevent sperm cells from entering the uterus and progressing towards the fallopian tube (Clift & Hart, 1953). Consequently, a combination of increased viscosity and maintenance of an acidic vaginal environment following exposure to seminal fluid are predicted to establish an effective barrier as a first-line defense against unwanted pregnancies and STIs.

[0010] Therefore, there remains a need to develop new compositions that may be used in the preparation of devices and materials to accomplish this objective.

[0011] SUMMARY

[0012] In some aspects, the present disclosure relates to the preparations of compositions and medical devices that maybe used to prevent pregnancies or infections such as sexually transmitted infections. In particular, these medical devices and compositions maybe used vaginally.

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0015] FIGS. 1A-1C shows polymeric compositions forming a bioresponsive seal for protection upon contact with physiological fluids (FIG. 1 A = hydrogel, FIG. IB = rod-shaped xerogel, FIG. 1C = non-woven fiber mat). FIG. 2 shows a representation of the bioresponsive seal formed upon contact of a medicated polymeric composition as claimed with physiological fluids to fortify natural contraceptive mechanisms and prevention of sexually transmitted infections.

[0016] FIGS. 3A & 3B show spreadability of a bioresponsive polymeric seal formed after exposure of a hydrated Carbopol® 974P / PVP (CP / PVP) polymer blend with Seminal Fluid Simulant, pH 7.6 (SFS). Experimental setup (FIG. 3A). Concentration-dependent work of shear of hydrogel (FIG. 3B).

[0017] FIG. 4 shows spreadability of a bioresponsive polymeric seal formed after exposure of a partially hydrated xerogel comprised of a Carbopol® 974P / PVP (CP / PVP) polymer blend with Seminal Fluid Simulant, pH 7.6 (SFS).

[0018] FIGS. 5A & 5B show spreadability of a bioresponsive polymeric seal formed after exposure of non-woven fiber mat comprised of a Carbopol® 974P / PVP (CP / PVP) polymer blend to phosphate buffer, pH 8.0. Experimental setup (FIG. 5A). Concentration-dependent work of shear of hydrated non-woven fiber mats comprised of different acidic / non-ionic polymer blends (FIG. 5B).

[0019] FIG. 6 shows spreadability of a bioresponsive polymeric seal formed after exposure of non-woven fiber mats comprised of a Carbopol® 974P / PVP (CP / PVP) polymer blend (50:50, w / w) to Vaginal Fluid Simulant, pH 4.3 (VFS) and Seminal Fluid Simulant, pH 7.6 (SFS), respectively.

[0020] FIGS. 7A & 7B show contraceptive efficacy in vitro of a bioresponsive polymeric seal formed after combining a Carbopol® 974P / PVP (CP / PVP) polymer blend with liquified human semen pH 7.8 - 8.5. Experimental setup (FIG. 7A). Composition-dependent barrier properties of hydrated CP / PVP polymer blends (FIG. 7B). Results are represented as mean + SD (n=3) and compared to filter only, 1 % (w / v) methylcellulose gel (MC gel), and the spermicidal VCF® gel product containing 4% (w / v) nonoxynol-9. Compositions were assessed at indicated volumetric dilutions using liquified human semen pH 7.8 - 8.5.

[0021] FIG. 8 shows the contraceptive efficacy in vivo. Pregnancy rate of rabbits after artificial insemination in the presence and absence of a bioresponsive polymeric seal formed intravaginally using a Carbopol® 974P / PVP (CP / PVP) polymer blend. Results are represented as mean ± SD (n=10) and compared to animals treated with an empty vaginal applicator only (i.e., sham-treated) or the spermicidal VCF® gel product containing 4% (w / v) nonoxynol-9 as positive control. CP = Carbopol® 974P, PVP = poly (N- vinylpyrrolidone). FIG. 9 shows drug release profile from a metronidazole-containing bioresponsive polymeric seal in vitro. Cumulative metronidazole (MTZ) released within 24 hrs in Vaginal Fluid Simulant, pH 4.3 (VFS) at 37°C from a hydrated Carbopol® 974P / PVP (CP / PVP) polymer blend containing 0.5 % (w / v) MTZ. Data are reported as mean ± SD (n>6).

[0022] FIG. 10 shows pharmacodynamic activity of metronidazole (MTZ) released from a medicated bioresponsive polymeric seal in vitro. Prevotella bivia growth pattern after a 6-hr incubation with a hydrated Carbopol® 974P / PVP (CP / PVP) polymer blend containing 0.5 % (w / v) MTZ was compared to media control, drug-free CP / PVP hydrogel and drug-free CP / PVP fiber mats as well as the antimicrobial vaginal NUVESSA® gel product containing 1.3% (w / v) MTZ as positive control. Data are reported as mean + SD (n>4).

[0023] DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0024] The present disclosure is directed, in part, to polymeric compositions forming a bioresponsive seal upon contact with physiological fluids exhibiting pH values between pH 4.0-8.9 to prevent, mitigate, or cure medical conditions in mammals. The bioresponsive polymeric seal may be formed in a number of ways but, preferably, at the site of administration following interaction of physiological fluid with said polymeric compositions, which is a blend comprised of at least of one acid and one non-ionic polymer. The polymeric seal may be effective in protecting underlying tissues and organs from exposure to unwanted external molecules as well as single- and multi-cell organisms using chemical and physical barrier properties. Polymeric compositions of the invention, biocompatible composites, and devices incorporating them may contain at least one pharmacologically active ingredient suitable to prevent, mitigate, or cure medical condition in mammals.

[0025] In some embodiments, sperm motility and movement of infectious particles such as HIV / AIDS virions may be hindered by this polymer coating, thus, augmenting contact time with contraceptive and / or anti-infective agents. In some embodiments, the present disclosure provides successful fabrication of tampon- like xerogel structures that may decrease pregnancy rate in rabbits by at least 40%. In some embodiments, the bioresponsive properties of the reconstituted polymer coating may translate into a more than 100% increased work of shear after exposure to seminal fluid stimulant (SFS) and may limit pH of the gel phase to less than pH 7 after dilution with equal volume of seminal fluid simulant, pH 7.6. In some embodiments the present disclosure may provide a hydrated, crosslinked polymeric network that has the capacity to hold water within its porous structure mainly due to the presence of polar functional groups and is intended for preventive and therapeutic women’s health applications. Utilizing pH-dependent changes in viscoelastic properties associated with selected acidic polymers (e.g., poly acrylic acid derivatives), we intended to engineer a bioresponsive system that creates a high viscosity barrier following exposure to alkaline seminal fluid, pH 7.0 - 8.9. As a consequence, it is predicted that movement of sperm cells and infectious particles such as HIV / AIDS virions will be hindered by this physical barrier, thus, creating a protective polymeric seal from unwanted pregnancies and mucosal infections. Critical to future development of these bioresponsive polymeric seals is the use of acidic polymers such as the acrylic acid-based polymer Carbopol® 974P NF, which effectively increases buffering capacity of reconstituted hydrogels in the acidic range below pH 5.0. Previous research has shown that sperm motility and viability as well as infectivity of HIV / AIDS virions are significantly compromised under acidic conditions. Following topical administration, such bioresponsive polymeric seals can also serve as a carrier or delivery system for a diverse array of pharmacologically active chemicals exhibiting anti-infective efficacy and / or negatively affect sperm cell motility / viability. Combined, increased viscoelastic properties and maintenance of an acidic vaginal environment following exposure to seminal fluid are predicted to establish an effective polymeric seal as a first-line defense against unwanted pregnancies and sexually transmitted infections.

[0026] In some embodiments, the present disclosure may provide a novel, tampon-like xerogel structure that may, in some aspects, be administered without the use of applicator and serve as bioresponsive vaginal devices for preventive and therapeutic women’s health applications. In contrast to conventional vaginal gels and creams, this tampon-like device may be administered digitally without an applicator and may convert into a bioadhesive hydrogel following exposure to vaginal fluid. In some embodiments, a bioresponsive tampon-like device may serve as a carrier or delivery system for a diverse array of pharmacologically active chemicals exhibiting contraceptive or anti-infective efficacy. Utilizing pH-dependent changes in viscosity associated with selected polymeric excipients (e.g., Carbopols), a bioresponsive device that creates a high viscosity barrier covering the vaginal mucosa following exposure to seminal fluid was engineered. A semisolid, bioresponsive polymeric seal comprised of hydrated Carbopol® 974P / PVP (CP / PVP) polymer blend (50:50, w / w) may effectively limit permeation of singlecell organisms as demonstrated by a significantly reduce fraction of sperm cells collected in the receiver compartment of a Transwell™ system (FIG. 7). I. Vaginal Drug Delivery Systems

[0027] Therapeutic efficacy of vaginally administered drugs is dependent on an appropriately designed intra-vaginal device that not only facilitates local deposition of the pharmacologically active agent inside the vaginal cavity but also affects pharmacokinetic properties of these agents as a consequence of selected excipients (Valenta, 2005). In general, a drug administered into the vaginal cavity can affect either local or systemic targets. To date, most commercial products focus on local action, predominantly for managing bacterial and antifungal infection as well as spermicides (de Araujo Pereira et al., 2012; Vermani et al., 2000).

[0028] Conventional delivery systems for these locally acting drugs include solutions, foams, gels, and creams that are mainly designed to allow uniform spreading over the mucosal surface. In contrast, vaginal administration of drugs designed for systemic treatment requires permeation of the active ingredient(s) across the vaginal epithelium. Among the few products approved for this purpose, controlled-release systems such as vaginal rings fabricated with silicon elastomers and polystyrene hold great promise as they significantly increase patient compliance due to decreased dosing frequency (Ndesendo et al., 2008).

[0029] Most vaginal gel dosage forms have been commonly designed, empirically on the lines of other available commercially accepted products mimicking their mechanical properties in order to achieve desired effectiveness and overall acceptability (Mahalingam et al., 2010). Administration of creams and gels via the vaginal route is most commonly used to manage local conditions such as infections. These delivery systems have the ability to physically interact with the mucosal surface, thereby prolonging contact time between the pharmacological agent and the desired therapeutic target due to mucoadhesive properties. Semi-solid formulations such as creams and gels are generally accepted because of their low cost and adequate therapeutic efficacy (De Araujo Pereira et al., 2012). Examples include metronidazole and itraconazole products that are approved for therapeutic management of bacterial vaginosis and vaginal candidiasis. Polyacrylic acid-based progesterone gel formulations (e.g., Noveon® AA1) are used for the treatment of hormonal imbalance (Hussain & Ahsan, 2005). As a consequence, vaginal gel dosage forms are also explored to deliver antiviral agents such as tenofovir and the pyrimidinedione analog IQP-0528 with the objective to prevent HIV-l / AIDS transmission (Mahalingam et al., 2010; Mahalingam et al., 2011). Major shortcomings associated with these preparations are the requirement for administration of these formulations using a disposable plastic applicator and limited retention inside the vaginal cavity due to reduced bioadhesive properties upon dilution with vaginal and / or seminal fluid, which may result in leakage and, thus, compromised therapeutic efficacy efficacy (Vermani et al., 2000).

[0030] Compressed tablets and suppositories are also used as delivery systems for vaginal interventions. Mucoadhesive tablets are mainly designed for sustained delivery of drugs over a prolonged period of time using conventional fabrication technologies established for oral solid dosage forms (Hussain & Ahsan, 2005). Main advantages associated with these systems are easy of manufacturing and simple insertion. Metronidazole and clotrimazole tablets are widely used for the treatment of the bacterial and anti-fungal infections (Alam et al., 2007). Vaginal tablet compositions are similar to those of conventional oral tablets, including incorporation of excipients such as disintegrants and binders (Hussain & Ahsan, 2005). Vaginal suppository formulations have decreased in clinical applications and are mainly limited for induction of cervical ripening and hormone replacement therapy with progesterone (Vukovich et al., 1977; Abrams & Weintraub, 1983). Short residence time and the need for correct placement within the vaginal cavity render this dosage form less desirable among all the commercially available options of vaginal products.

[0031] Vaginal rings represent the newest class of drug delivery systems specifically designed for women’s health applications. Vaginal rings are currently marketed for systemic or local therapy, predominantly as contraceptive products and for hormone replacement therapy (e.g., NuvaRing®) (Harwood & Mishell, 2001; Dezamaulds & Fraser, 2003). However, various pre- clinical and clinical trials focus on investigational assessment of vaginal rings for controlled- release application with microbicides (e.g., TMC 120 - dapivirine) (Romano et al., 2009; Malcolm et al., 2005). Microbicides are generally dispersed within elastomeric or thermoplastic materials (e.g., silicone) that allow simple molding and facilitate continuous release by diffusion (Kelly & Shattock, 2011). Johnson and co-workers recently introduced a novel, polyurethane-based vaginal ring design that was demonstrated to facilitate sustained release of the two hydrophilic antiretroviral agents dapivirine and tenofovir for 30 days (Johnson et al., 2010). Using a hot melt extrusion process, the same research group fabricated a polyurethane vaginal ring sustained, diffusion-controlled release of the potent non-nucleoside reverse transcriptase inhibitor UC781 (Clark et al., 2012). The circular shape of this device aids in facile, user-controlled positioning towards the posterior end of the vaginal cavity. Since the thin, flexible design does not interfere with the coitus and offers the potential for sustained drug release up to one-month, vaginal rings are predicted to offer unique advantages over conventional vaginal drug delivery systems (Hussain & Ahsan, 2005). Nevertheless, vaginal irritation, cold chain storage requirement, and limited dosing flexibility appear to limit rapid market expansion of this innovative vaginal dosage form. Furthermore, correct placement of a vaginal ring inside the vaginal cavity requires adequate instruction / training, which may not be readily available in developing countries with an insufficiently developed health care infrastructure.

[0032] To increase patient compliance and enhance vaginal retention of conventional dosage forms after administration, bioadhesive polymers were explored as suitable excipients in vaginal drug delivery systems. Among the most commonly used bioadhesive polymers are polycarbophil, Carbopol®, sodium alginate, and various cellulose derivatives such as sodium carboxymethylcellulose, hydroxypropyl cellulose, and hydroxypropylmethylcellulose, respectively (Hussain & Ahsan, 2005). Incorporation of these excipients into vaginal formulations was demonstrated to induce desirable bioadhesive properties, swelling upon interaction with biological fluids and, in some instances, pH-responsive behavior that provided greater selectivity in therapeutic interventions (Ferguson & Rohan, 2011). Bioadhesive polymers prolong vaginal residence time by forming molecular interactions, including hydrogen bonds and ionic forces, between the epithelial layer and the formulation. In addition, hydration of these polymers establishes a three-dimensional network that can create an effective diffusion layer to control drug release (Das Neves & Bahia, 2006). Recent in vitro and in vivo studies using a UC781- and tenofovir-containing combination product prepared in a hydroxyethylcellulose / Carbopol 974P gel showed effective local deposition of the microbicides on the vaginal tissue (Kiser etal., 2012) However, clinical studies performed with tenofovir- containing hydroxyethylcellulose gel in South Africa (CAPRISA 004) only revealed a disappointing 39% reduction in HIV-1 transmission (Karim et al., 2010). Incorporation of ionizable polymers such as Carbopols® provide an opportunity for controlling the pH value within the vaginal cavity, which can positively impact the management of infections by fortifying the natural acidic defense barrier produced by lactobacillus bacteria. More importantly, it is scientifically established that an acidic pH environment within the vaginal cavity reduces motility and viability of sperms, thereby contributing to contraceptive protection (Garg el al., 2001). This concept has been commercially translated into the carboxymethylcellulose-based contraceptive gel Gynol II™.

[0033] IL Human Immunodeficiency Virus

[0034] Today, more than 30 years after initial discovery, modern medicine is still searching for an effective strategy to prevent HIV infections. It is established; however, that exposure of the vaginal mucosa during coitus to seminal fluid carrying HIV virions significantly increases the risk for contracting HIV / AIDS. More than 50% of the female population infected worldwide with HIV / AIDS lives in the sub-Saharan African region, where limited genital health and sexual intercourse with multiple partners are believed to contribute to increased risk of HIV infection (Ferguson & Rohan, 2011). Since heterosexual male to female transmission accounts for the majority of HIV infections, short-term prevention strategies focusing on women-controlled barrier methods to minimize exposure of the vulnerable cervicovaginal mucosa to HIV-infected seminal fluid appear more advantageous. The most effective approach to prevent HIV infections, however, is the development of a vaccine. Unfortunately, this still remains a distant dream due to unresolved scientific challenges, intellectual property issues, and regulatory compliance questions (Rohan & Sassi, 2009).

[0035] Current HIV / AIDS treatment strategies involving a diverse array of anti-retroviral drugs are effective in reducing mortality while, simultaneously, increasing the quality of life of patients diagnosed with HIV / AIDS. Unfortunately, this successful therapeutic approach is not equally accessible throughout the world. Especially in the sub-Saharan African region, challenges such as socio-economic status and limited drug stability under elevated temperatures prevent effective implementation HIV / AIDS drug management (Turpin J. A., 2002; Krishnan et al., 2008). Since STIs generally increase the risk of HIV infection by 10- fold due to compromised mucosal defense mechanisms ( / .<?., increased vaginal pH and epithelial damage), preventive strategies targeting STIs are considered effective approaches to limit HIV infection (Ndesendo et al., 2008). Consequently, the focus of HIV prevention programs broadly includes protection against STIs using adequate, safe approaches that are affordable and socially acceptable to the female population worldwide.

[0036] Maintenance of an acidic vaginal environment is of prime importance in order to prevent HIV infections because the virulence of HIV virions is dramatically reduced under acidic conditions (Jay et al., 2009). Earlier studies demonstrated that HIV virions are fully infective at pH 7.4 but lose their pathogenic activity when the environmental pH is maintained below pH 5.0. Currently, the most effective strategies to prevent STIs and HIV infections rely on various microbicides. These chemical agents interfere with vital functions of the pathogens upon interaction, thus, preventing or at least reducing the occurrences of the STIs and HIV / AIDS. Topical administration of vaginal microbicides for local intervention is facilitated by various delivery systems such as gels, tablets, and vaginal rings (Jay et al., 2009). Microbicides currently investigated in clinical trials are classified as follows: first generation microbicides that inactivate the virus by disrupting the HIV protein envelope structure (e.g., nonoxynol-9), second generation microbicides, which includes fusion inhibitors that block cell entry of HIV virions by competing for endocytosis receptor binding (e.g., PR02000, carrageenan), and third generation microbicides that inhibit reverse transcriptase activity, a viral DNA polymerase, which is a crucial enzyme required for viral replication (e.g., tenofovir, UC781) (Weber et al., 2005). Large-scale clinical trials in developing country using bioadhesive, vaginal microbicide delivery systems that comprise polymers such as Carbopols® or hydroxyethylcellulose demonstrated promising results against HIV infection (e.g., Buffer Gel, PR02000) (Karim et al., 201 1).

[0037] In mammals, the skin and a diverse array of mucous membranes constitute complex protective barriers that guard underlying anatomical structures from exposure to external factors. The epidermis is the outermost layer of skin and forms a protective barrier over the body’s surface. The mucous membranes (or mucosae) line cavities that are exposed to the external environment and internal organs. They can be attached to skin such as at the nostrils, mouth, lips, eyelids, and genital area, but are also located within the body cavities, such as in the stomach, anus, trachea, and ears. Most mucous membranes secrete a sticky, thick fluid called mucus, which facilitates several barrier functions and provides a moist environment. The mucosae are highly specialized in each organ to deal with different conditions. The most variation is seen in the epithelium lining the mucous membrane. Together, the skin and mucosae form the barrier immune system, which is considered a component of the innate immune system. These structures represent physical or mechanical barriers that prevent chemical molecules as well as single- and multi-cell organisms from entering the body through a variety of methods. While the skin simply prevents penetration into underlying tissues, more specialized mechanisms like the mucociliary clearance in the trachea exist to actively protect internal organs from exposure to external factors. In addition, the barrier immune system also constitutes chemical barriers that contribute to protective mechanisms. Notable examples include stomach acidity which kills most microbes and secretion of antimicrobial peptides on mucosal epithelial tissue.

[0038] The barrier immune system is the first line of defense protecting underlying tissues and organs from exposure to unwanted external molecules as well as single- and multi-cell organisms. However, this natural barrier can be broken through cuts or abrasions. In addition, infections with pathogens can weaken mechanical and / or chemical properties of the barrier immune system and, thus, allowing unwanted external molecules as well as single- and multicell organisms to reach undesired internal areas within the body. III. Therapies

[0039] A. Pharmaceutical Formulations and Routes of Administration

[0040] In some aspects, for administration to a patient in need of such treatment, pharmaceutical formulations (also referred to as a pharmaceutical preparations, pharmaceutical compositions, pharmaceutical products, medicinal products, medicines, medications, or medicaments) comprise a therapeutically effective amount of a composition of the present disclosure formulated with one or more excipients and / or drug carriers appropriate to the indicated route of administration. In some embodiments, the compositions disclosed herein are formulated in a manner amenable for the treatment of human and / or veterinary patients. In some embodiments, formulation comprises admixing or combining one or more of the compositions disclosed herein with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol. In some embodiments, e.g., for oral administration, the pharmaceutical formulation may be tableted or encapsulated. In some embodiments, the compositions may be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. In some embodiments, the pharmaceutical formulations may be subjected to pharmaceutical operations, such as sterilization, and / or may contain drug carriers and / or excipients such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents such as lipids, dendrimers, polymers, proteins such as albumin, nucleic acids, and buffers.

[0041] Pharmaceutical formulations may be administered by a variety of methods, e.g., orally or by injection e.g. subcutaneous, intravenous, and intraperitoneal). Depending on the route of administration, the compositions disclosed herein may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. To administer the active compound by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. In some embodiments, the active compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in- oil-in-water com gluten feed (CGF) emulsions as well as conventional liposomes. The compositions disclosed herein may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

[0042] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

[0043] In some embodiments, it may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. In some embodiments, the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient. In some embodiments, active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient. For example, the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in a human or another animal.

[0044] In some embodiments, the effective dose range for the therapeutic compound can be extrapolated from effective doses determined in animal studies for a variety of different animals. In some embodiments, the human equivalent dose (HED) in mg / kg can be calculated in accordance with the following formula (see, e.g., Reagan-Shaw et al., FASEB J., 22(3):659- 661, 2008, which is incorporated herein by reference):

[0045] HED (mg / kg) = Animal dose (mg / kg) x (Animal Km / Human Km)

[0046] Use of the Kmfactors in conversion results in HED values based on body surface area (BSA) rather than only on body mass. Kmvalues for humans and various animals are well known. For example, the Kmfor an average 60 kg human (with a BSA of 1.6 m2) is 37, whereas a 20 kg child (BSA 0.8 m2) would have a Kmof 25. Kmfor some relevant animal models are also well known, including: mice Kmof 3 (given a weight of 0.02 kg and BSA of 0.007); hamster Kmof 5 (given a weight of 0.08 kg and BSA of 0.02); rat Kmof 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey Kmof 12 (given a weight of 3 kg and BSA of 0.24).

[0047] Precise amounts of the therapeutic composition depend on the judgment of the practitioner and are specific to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment and the potency, stability and toxicity of the particular therapeutic formulation.

[0048] The actual dosage amount of a compound of the present disclosure or composition comprising a compound of the present disclosure administered to a patient may be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual patient. The dosage may be adjusted by the individual physician in the event of any complication.

[0049] In some embodiments, the therapeutically effective amount typically will vary from about 0.001 mg / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 100 mg / kg to about 500 mg / kg, from about 1 mg / kg to about 250 mg / kg, from about 10 mg / kg to about 150 mg / kg in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above). Other suitable dose ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day. In some embodiments, the amount is less than 10,000 mg per day with a range of 750 mg to 9,000 mg per day. In some embodiments, the amount of the active compound in the pharmaceutical formulation is from about 2 to about 75 weight percent. In some of these embodiments, the amount if from about 25 to about 60 weight percent.

[0050] Single or multiple doses of the agents are contemplated. Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, patients may be administered two doses daily at approximately 12-hour intervals. In some embodiments, the agent is administered once a day.

[0051] The agent(s) may be administered on a routine schedule. As used herein a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical, or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration three times a day, twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks therebetween. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc. In other embodiments, the invention provides that the agent(s) may be taken orally and that the timing of which is or is not dependent upon food intake. Thus, for example, the agent can be taken every morning and / or every evening, regardless of when the patient has eaten or will eat.

[0052] B. Methods of Treatment

[0053] In particular, the compositions that may be used in treating a disease or disorder in a subject (e.g., a human subject) are disclosed herein. The compositions described above are preferably administered to a mammal (e.g., rodent, human, non-human primates, canine, bovine, ovine, equine, feline, etc.) in an effective amount, that is, an amount capable of producing a desirable result in a treated subject (e.g. , slowing, stopping, reducing or eliminating one or more symptoms or underlying causes of disease). Toxicity and therapeutic efficacy of the compositions utilized in methods of the disclosure can be determined by standard pharmaceutical procedures. As is well known in the medical and veterinary arts, dosage for any one animal depends on many factors, including the subject's size, body surface area, body weight, age, the particular composition to be administered, time and route of administration, general health, the clinical symptoms and other drugs being administered concurrently. In some embodiments, amount of the compounds used is calculated to be from about 0.01 mg to about 10,000 mg / day. In some embodiments, the amount is from about 1 mg to about 1,000 mg / day. In some embodiments, these dosings may be reduced or increased based upon the biological factors of a particular patient such as increased or decreased metabolic breakdown of the drug or decreased uptake by the digestive tract if administered orally. Additionally, the compounds may be more efficacious and thus a smaller dose is required to achieve a similar effect. Such a dose is typically administered once a day for a few weeks or until sufficient achieve clinical benefit.

[0054] The therapeutic methods of the disclosure (which include prophylactic treatment) in genera] include administration of a therapeutically effective amount of the compositions described herein to a subject in need thereof, including a mammal, particularly a human. Such treatment will be suitably administered to subjects, particularly humans, suffering from, having, susceptible to, or at risk for a disease, disorder, or symptom thereof. Determination of those subjects "at risk" can be made by any objective or subjective determination by a diagnostic test or opinion of a subject or health care provider (e.g., genetic test, enzyme or protein marker, family history, and the like).

[0055] C. Combination Therapies

[0056] It is envisioned that the compositions described herein may be used in combination therapies with one or more additional therapies or a compound which mitigates one or more of the side effects experienced by the patient. It is common in the field of medicine to combine therapeutic modalities. The following is a general discussion of therapies that may be used in conjunction with the therapies of the present disclosure.

[0057] To treat diseases or disorders using the methods and compositions of the present disclosure, one would generally contact a cell or a subject with a composition and at least one other therapy. These therapies would be provided in a combined amount effective to achieve a reduction in one or more disease parameter. This process may involve contacting the cells / subjects with the both agents / therapies at the same time, e.g. , using a single composition or pharmacological formulation that includes both agents, or by contacting the cell / subject with two distinct compositions or formulations, at the same time, wherein one composition includes the compound and the other includes the other agent.

[0058] Alternatively, the compounds described herein may precede or follow the other treatment by intervals ranging from minutes to weeks. One would generally ensure that a significant period of time did not expire between the times of each delivery, such that the therapies would still be able to exert an advantageously combined effect on the cell / subject. In such instances, it is contemplated that one would contact the cell with both modalities within about 12-24 hours of each other, within about 6-12 hours of each other, or with a delay time of only about 1-2 hours. In some situations, it may be desirable to extend the time period for treatment significantly; however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations.

[0059] It also is conceivable that more than one administration of either the compound or the other therapy will be desired. Various combinations may be employed, where a compound of the present disclosure is “A,” and the other therapy is “B,” as exemplified below:

[0060] A / B / A B / A / B B / B / A A / A / B B / A / A A / B / B B / B / B / A B / B / A / B A / A / BZB A / B / A / B A / BZB / A B / B / A / A B / A / B / A B / A / A / B B / B / B / A A / A / A / B B / A / A / A A / B / A / A A / A / B / A A / B / B / B B / A / B / B B / B / A / B

[0061] Other combinations are also contemplated. A discussion of other potential therapies that may be used combination with the compounds of the present disclosure is presented elsewhere in this document.

[0062] IV. Definitions

[0063] The use of the word “a” or “an,” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0064] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects or patients. Unless otherwise noted, the term “about” is used to indicate a value of ±10% of the reported value, preferably a value of ±5% of the reported value. It is to be understood that, whenever the term “about” is used, a specific reference to the exact numerical value indicated is also included.”

[0065] An “active ingredient” (Al) or active pharmaceutical ingredient (API) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, agent, biologically active molecule, or a therapeutic compound) is the ingredient in a pharmaceutical drug that is biologically active.

[0066] The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps. The term “effective,” as that term is used in the specification and / or claims, means adequate to accomplish a desired, expected, or intended result. “Effective amount,” “Therapeutically effective amount” or “pharmaceutically effective amount” when used in the context of treating a patient or subject with a compound means that amount of the compound which, when administered to the patient or subject, is sufficient to effect such treatment or prevention of the disease as those terms are defined below.

[0067] An “excipient” is a pharmaceutically acceptable substance formulated along with the active ingredient(s) of a medication, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, to bulk up the composition (thus often referred to as “bulking agents,” “fillers,” or “diluents” when used for this purpose), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable versions of anti adherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles. The main excipient that serves as a medium for conveying the active ingredient is usually called the vehicle. Excipients may also be used in the manufacturing process, for example, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The suitability of an excipient will typically vary depending on the route of administration, the dosage form, the active ingredient, as well as other factors.

[0068] The term “hydrate” when used as a modifier to a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water

[0069] As used herein, the term “patient” or “subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients are adults, juveniles, infants and fetuses.

[0070] As generally used herein “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio. “Pharmaceutically acceptable salts” means salts of compounds disclosed herein which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1 ,2-ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene- 1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-l -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesul fonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, / V-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0071] A “pharmaceutically acceptable carrier,” “drug carrier,” or simply “carrier” is a pharmaceutically acceptable substance formulated along with the active ingredient medication that is involved in carrying, delivering and / or transporting a chemical agent. Drug carriers may be used to improve the delivery and the effectiveness of drugs, including for example, controlled-release technology to modulate drug bioavailability, decrease drug metabolism, and / or reduce drug toxicity. Some drug carriers may increase the effectiveness of drug delivery to the specific target sites. Examples of carriers include: liposomes, microspheres (e.g., made of poly(lactic-co-glycolic) acid), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers. “Prevention” or “preventing” includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and / or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and / or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and / or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.

[0072] “Prodrug” means a compound that is convertible in vivo metabolically into an active pharmaceutical ingredient of the present invention. The prodrug itself may or may not have activity within its prodrug form. For example, a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Non-limiting examples of suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-P-hydroxynaphthoate, gentisates, isethionates, di- -toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, and esters of amino acids. Similarly, a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.

[0073] “Treatment” or “treating” includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and / or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and / or symptomatology), and / or (3) effecting any measurable decrease in a disease or symptom thereof in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.

[0074] The term “unit dose” refers to a formulation of the compound or composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active ingredient to a patient in a single administration. Such unit dose formulations that may be used include but are not limited to a single tablet, capsule, or other oral formulations, or a single vial with a syringeable liquid or other injectable formulations.

[0075] The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention.

[0076] V. Examples

[0077] The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0078] EXAMPLE 1 - Semisolid Bioresponsive Polymeric Seal Analysis

[0079] A semisolid, bioresponsive polymeric seal comprised of hydrated Carbopol® 974P / PVP (CP / P VP) polymer blend creates a significant physical barrier in response to alkaline seminal fluid simulant, pH 7.6 (SFS) as demonstrated by increasing work of shear required to spread the semisolid composition (see Figure 3). A standard batch of bioresponsive hydrogel is prepared by gradually suspending the CP / P VP polymer mixture under stirring in 0.01 N NaOH. Final concentrations of CP was 4% (w / w) and PVP ranged from 0-40% (w / w), respectively. To quantify changes in structural and viscoelastic gel properties under various simulated intravaginal conditions, spreadability of fully hydrated gel formulations was measured using the T'A.-XT'Plus texture analyzer (Stable Microsystems, UK). Fully hydrated gel formulations were assessed using the cone-cap assembly (Figure 3A). For a single measurement, 0.5 g of the hydrogel was fdled into the 45° acrylic cap and combined at various volumetric ratios with SFS (Owen & Katz, 2005). After a 60-second incubation at room temperature, the coaxially aligned 45° cone was lowered at a test speed of 1 mm / s (i.e., compression mode) until a maximum load force of 5 N was reached. This value was selected as it represents the average physiological intravaginal pressure exerted by soft tissue surrounding the vaginal pelvic floor in supine position (Morgan et al., 2008). The area under the force-distance curve is equivalent to the total work done to spread (or shear) the gel formulation. Consequently, the work of shear is a suitable quantitative in vitro parameter for comparing the dynamics of gel spreading under various simulated vaginal conditions.

[0080] Combination of the gel composition with SFS results in a volumetric dilution of the acidic CP polymer from 4% to 1%. During this dilution process, the work of shear required to spread the hydrogel increases, which demonstrates increasing viscoelastic properties after exposure to alkaline SFS. In the absence of PVP, the maximum work of shear recorded after gel dilution to 1% CP was 6.49 ± 0.01 Nxs (Figure 3B). Increasing concentrations of PVP in the composition significandy increased the work of shear required to spread the gel composition at the same CP levels. In comparison the 4%CP gel only, the work of shear of the hydrogel supplemented with 40% of PVP was increased by almost 40% (8.88 ± 0.87 Nxs vs. 6.49 ± 0.01 Nxs). These results underline the additive effect of PVP in augmenting the pH-dependent increase in viscoelastic properties of this hydrogel composition upon interactions with alkaline SFS. In parallel to spreadability assessments, quantitative determination of the gel phase pH value using the DeltaTrak® Pocket ISFET pH Meter, which is equipped with an ion-sensitive field effect transistor pH sensor and an integrated temperature sensor (DeltaTrak, Inc., Pleasanton, CA), revealed that hydrated CP / PVP polymer blends create a significant chemical barrier in response to alkaline SFS as demonstrated by strong buffering capacity (see Table 1). Dilution of a CP4% / PVP4% hydrogel with greater volume fractions of SFS gradually increased the pH value of the gel phase from pH 3.4 ± 0.1 to pH 4.5 ± 0.1 at volumetric unity. Maintenance of such an acidic vaginal environment despite the presence of alkaline SFS is predicted to significantly compromise sperm motility and viability as well as infectivity of HIV / AIDS virions (Garg et al., 2001; Jay et al., 2009). This critical buffering capacity is dependent on the CP / PVP polymer blend composition and, consequently, can be tailored to the intended preventive and / or therapeutic objective.

[0081] Table 1: Buffering Capacity of a Bioresponsive Polymeric Seal Formed after Exposure of a Hydrated Acidic / Non-ionic Polymer Blend with Seminal Fluid Simulant, pH 7.6 (SFS) a Carbopol® 974P,bpoly(V- vinylpyrrolidone)

[0082] To estimate mucoadhesive properties of fully hydrated CP / PVP polymeric blends, 0.5 g of the hydrogel was placed onto a microscope glass and was brought in contact with a parallel microscope glass assembly that was attached in perpendicular alignment the TA-XTPlus texture analyzer. After a 10 s contact time using a maximum load force of 5 N, the top plate was removed at a test speed of 0.1 mm / s and the work of adhesion measured from the force-distance plot. The results summarized in Table 2 demonstrate that mucoadhesive properties of CP / PVP hydrogels under simulated vaginal conditions significantly increase using a greater mass ratio of PVP in the polymer blend. Moreover, the work of adhesion consistently increases upon dilution in the hydrogel with alkaline SFS, which implies effective vaginal retention of the hydrated CP / PVP polymer blend after forming a bioresponsive contraceptive seal in the presence of seminal fluid.

[0083] Table 2: Mucoadhesive Properties of a Bioresponsive Polymeric Seal Formed after Exposure of a Hydrated Acidic / Non-ionic Polymer Blend with Seminal Fluid Simulant, pH 7.6 (SFS). a Carbopol® 974P,bpoly(A- vinylpyrrolidone)

[0084] EXAMPLE 2 - Xerogel Bioresponsive Polymeric Seal Analysis

[0085] A semisolid, bioresponsive polymeric seal is also established following hydration of a xerogel comprised of equal weight of Carbopol® 974P and PVP (CP / PVP) polymer blend. Bioresponsive xerogel devices are generally fabricated by lyophilization. Briefly, a volumetric aliquot of a fully hydrated CP / PVP gel formulation was filled into a polypropylene syringe barrel and frozen for 6 hrs at -80°C. Prior to lyophilization, frozen gel cylinders were expelled from the syringe barrel onto a pre-cooled aluminum pan and subjected to a conventional lyophilization cycle at 40 mTorr (i.e., primary drying phase for 6 hrs at -20°C followed by a secondary drying phase at +25°C for 3 hrs after a linear temperature gradient of 3.5°C / min) using the VirTis Advantage 2.0 freeze dryer (SP Industries, Gardiner, NY, U.S.A.). Spreadability of xerogel devices after incubation with different buffer solutions was quantified as outlined for hydrogels (see Example 1). Due to the rigid structure of cylindrical xerogel devices, the experimental design was modified from a cone-cap to a parallel glass plate assembly that allowed perpendicular alignment of the top plate with the cylindrical surface of the lyophilized device. Reproducible fluid administration was accomplished by spraying defined volumes of acidic VFS and alkaline SFS from a constant distance of 16 mm on the surface of a 1 cm xerogel device using a plastic syringe fitted with a MAD Nasal™ Intranasal Mucosal Atomization nozzle (Teleflex, Wayne, PA) that creates a fine mist of fluid particles ranging from 30-100 pm in size. After a 2-min incubation period at room temperature, excess fluid present on the device surface was removed by blotting before the upper glass plate was lowered at a test speed of 0.2 mm / s until a maximum load force of 5 N was reached. Each experiment was performed in triplicate using a fresh gel sample. Following vaginal administration, it is assumed that initial exposure of this xerogel device is limited to vaginal fluid only, which provides the baseline spreadability value of 2.43 ± 0.20 Nxs (Figure 4). Incremental addition of alkaline SFS transformed the xerogel device into a partially hydrated, bioresponsive CP / PVP polymer composition exhibiting increased spreadability properties. After combination of the xerogel device with 4-times the volume of SFS as compared to the initial VFS exposure, the work of shear recorded to spread the partially hydrated CP / PVP polymer blend under a simulated intravaginal pressure of 5 N was almost 70% greater than the corresponding value measured after interaction with acidic VFS (4.13 ± 0.13 Nxs vs. 2.43 ± 0.20 Nxs). These results demonstrate an increase in viscoelastic properties of partially hydrated CP / PVP xerogel devices in response to alkaline SFS. The presence of this bioresponsive seal is predicted to effectively limit movement of sperm cells as well as HIV / AIDS virions that are deposited intravaginally during ejaculation, thereby preventing pregnancy and STIs. The semisolid, bioresponsive polymeric seal established following exposure of a CP / PVP xerogel device with alkaline SFS also creates a significant chemical barrier. Similar to the experimental outline described for CP / PVP hydrogel compositions (see Example 1), the pH value of the partially hydrated gel phase of CP / PVP xerogel devices was quantified using the DeltaTrak® Pocket ISFET pH Meter. The data compiled in Table 3 underline the strong buffering capacity of CP / PVP xerogel devices in response to SFS (see Table 3). Even in the presence of a 4-fbld greater volume fraction of alkaline SFS, the gel pH value measured was 4.2 ± 0.1, which is within the pH range of the healthy vaginal environment reported for humans and, most importantly, compromises sperm motility and viability as well as infectivity of HIV / AIDS virions are significantly compromised under acidic conditions (Garg et al., 2001; Jay et al., 2009).

[0086] Table 3: Buffering Capacity of a Bioresponsive Polymeric Seal Formed after a partially hydrated xerogel comprised of an equal weight of Acidic / Non-ionic Polymer Blend is exposed to Seminal Fluid Simulant, pH 7.6 (SFS)

[0087] EXAMPLE 3 - Non-woven Fiber Mat Bioresponsive Polymeric Seal Analysis

[0088] A bioresponsive polymeric seal is also established following hydration of non-woven fiber mats comprised of a 50:50 (w / w) Carbopol® 974P / PVP (CP / PVP) polymer blend that are fabricated by single nozzle electrospinning using protocols described elsewhere (Moyers- Montoya et al., 2016). Spreadability of non-woven CP / PVP fiber mats after incubation with different buffer solutions was quantified as outlined in Example 2 but with the following modifications. Polymeric fiber mats were cut in 3 cm x 3 cm squares and deposited as a single layer onto a circular glass surface within a custom-made platform as shown in Figure 5A. Reproducible fluid administration was accomplished by spraying defined volumes of phosphate buffer, pH 8.0 from a constant distance of 37 mm onto the fiber mat surface using a plastic syringe fitted with a MAD Nasal™ Intranasal Mucosal Atomization nozzle. The defined distance between the fiber mat and syringe nozzle enabled uniform distribution of the fine buffer fluid mist across a constant fiber mat surface of 380 mm2. After a 5-min incubation period at room temperature, the upper glass plate was lowered at a test speed of 0.1 mm / s until a maximum load force of 5 N was reached. Each experiment was performed in triplicate using a fresh polymeric fiber mat sample. The results summarized in Figure 5B demonstrate that the spreadability profiles of non-woven fiber mats fabricated with CP / PVP polymer blends ranging from 1 : 1 to 1 : 10 (w / w) after incubation with various volume fractions of phosphate buffer, pH 8, remained within a narrow baseline value of 4-5 Nxs until the gel CP concentration reaches -10% (w / v). Further dilution with this alkaline buffer solution increased the resistance of the gel phase to spreading, which was most pronounced at CP concentrations below 3.5% (w / v). It is noted that spreadability of hydrogel compositions comprised of similar CP concentrations but different PVP concentrations was positively correlated with the increasing presence of PVP. These results are consistent with spreadability data shown in Figure 3B underlining the additive effect of the nonionized PVP polymer in creating a significant physical barrier after exposure to alkaline solutions. These findings are unique when compared to pH-dependent rheological data for CP gel compositions where spreadability proportionally increases with CP concentration (Lubrizol 2010).

[0089] Similar to the performance of CP / PVP xerogel and hydrogel compositions described in Examples 1 and 2, the bioresponsive polymeric seal established after exposure of non-woven CP / PVP fiber mats to an alkaline buffer solution such as phosphate buffer, pH 8.0, also constitutes a significant chemical barrier exhibiting a substantial acidic buffering capacity. In comparison to fiber mats fabricated with PVP only, the pH value of the partially hydrated gel phase that was quantified after combination of the fiber mat with various volume fractions of phosphate buffer, pH 8, using the DeltaTrak® Pocket ISFET pH Meter remained below pH 6.4 even in the presence of a 1 :20 volumetric dilution (Table 4). Incorporation of a grater CP mass fraction into electrospun fiber mats significantly amplified this essential buffering capacity that correlates with compromised sperm motility and viability as well as reduced infectivity of HIV / AIDS virions (Garg et al., 2001 ; Jay et al. , 2009). At an equal CP / PVP fiber mat mass ratio, the pH value of the reconstituted gel phase measured at the same 1 :20 volumetric dilution with phosphate buffer, pH 8, was equivalent to the critical pH threshold value reported where human sperm fail WHO fertility standards within 15 min of exposure (Zhou et al., 2015).

[0090] Table 4: Buffering Capacity of a Bioresponsive Polymeric Seal Formed after a non-woven fiber mat layer comprised of a an Acidic / Non-ionic Polymer Blend is exposed to alkaline phosphate buffer, pH 8.0 (PB8). a Carbopol® 974P,bpoly (N- vinylpyrrolidone), PB8 = phosphate buffer, pH 8

[0091] To explore dose-dependent bioresponsive changes in spreadability under simulated intravaginal conditions, eight layers of non-woven CP / PVP (50:50, w / w) from two different fabrication batches were combined with increasing volume fractions of VFS or SFS using the same experimental design as described above. This resulted in gel compositions with CP concentrations ranging from -95% to -10% (w / v). In the presence of acidic VFS, the work of shear recorded for the reconstituted gel phase consistently decreased after combination of the dry CP / PVP fiber mat with increasing volume fractions of VFS (Figure 6). This rheological behavior seems directly correlated with decreasing CP concentration in the gel phase and appears to result from increasingly diluted dispersion of coiled polymer particles. In contrast, interaction of the dry CP / PVP fiber mat with increasing volume fractions of alkaline SFS consistently increased the work of shear required to spread the gel phase and, thus, fortifying the physical barrier properties of this polymeric seal. This result is consistent with the hypothesized uncoiling of polymer particles due to electrostatic repulsion of deprotonated carboxylate groups as explained in Example 1. Interestingly, viscoelastic properties of the bioresponsive gel phase when reconstituted from multiple CP / PVP fiber mat layers appear quite constant within a CP concentration range from -80% to 20% (w / w). It is conceivable that slow penetration rate of the alkaline SFS across the different fiber mat layers may be responsible for this stable plateau effect. Consistent with results obtained with a single fiber mat layer (see Figure 5B), the most effective physical barrier established after hydration of multiple CP / PVP fiber mat layers with alkaline SFS is associated with the lowest CP concentration present in the gel phase as demonstrated by the greatest work of shear measured.

[0092] As the efficacy of polymeric seal compositions described in this disclosure for preventing unintended pregnancies and STIs depends on prolonged residence time of sperm and infectious particles within the bioresponsive gel phase, intravaginal retention of the reconstituted gel phase was estimated by quantifying mucoadhesive properties of partially hydrated non-woven CP / PVP fiber mats using the same experimental design as described above for spreadability assessment. After a 10 s contact time of the reconstituted gel phase using a load force of 5 N, which represents the average physiological intravaginal pressure exerted by soft tissue surrounding the vaginal pelvic floor in supine position (Morgan et al., 2008), the top plate was removed at a test speed of 0.1 mm / s and the work of adhesion measured from the force-distance plot. The results summarized in Table 5 demonstrate that mucoadhesive properties of CP / PVP hydrogels reconstituted under simulated vaginal conditions significantly increase in the presence of increasing SFS volume. The inverse correlation between the work of adhesion measured and the polymer concentrations in the reconstituted gel phase suggests more effective interactions of uncoiled polymer particles with the polar vaginal mucus layer, which is predicted to facilitate favorable vaginal retention of the hydrated CP / PVP polymer blend after forming a mucoadhesive contraceptive seal in the presence of seminal fluid. Table 5: Mucoadhesive Properties of a Bioresponsive Polymeric Seal Formed after Non-woven Fiber Mats Comprised of a Carbopol® 974P / PVP (CP / PVP) Polymer Blend (50:50, w / w) are Combined with Different Volume Fractions of Seminal Fluid Simulant, pH 7.6 (SFS). aCarbopol® 974P,bpoly (V- vinylpyrrolidone)

[0093] EXAMPLE 4 -Bioresponsive Polymeric Seal for Prevention of Pregnancy

[0094] To determine whether favorable biophysical properties of said polymer compositions measured under simulated vaginal conditions translate into contraceptive efficacy, the fraction of viable human sperm capable of traversing such a bioresponsive polymeric seal was quantified in vitro following a protocol described earlier by Chen and co-workers (Chen et al., 2011). Briefly, a sample of human liquified semen, pH 7.8-8.5, was added to the donor compartment of a Transwell™ dual chamber system (Figure 7A). The basolateral receiver compartment was filled with human tubular fluid buffer, pH 7.4. Both compartments were separated by a semipermeable polycarbonate membrane with an average pore size of 8 pm that provided physical support for deposition of bioresponsive polymer composition. The fraction of human spermatozoa migrating from the donor to the receiver compartment in the presence and absence of a reconstituted gel phase comprised of bioresponsive polymer blends was quantified microscopically after 60 min at 37°C using the conventional Makler™ counting chamber. Total motility of sperm in donor and receiver compartments was assessed in duplicate by blinded technicians according to the WHO Manual (WHO, 2021). Results were normalized to control experiments performed with the semipermeable filter membrane only and are summarized in Figure 7B. Inclusion of a 1% (w / v) methylcellulose gel barrier, which represents the viscoelastic properties of the cervical mucus during ovulation (Ivie et al., 2002), moderately reduces the fraction of viable sperm appearing in the receiver compartment on average by -33% from 99.0 + 7.6% to 66.7 ± 18.8%, while total motility of sperm before and after traversing the gel barrier was comparable (73.8 ± 10.0% vs. 56.6 ± 18.2%). In contrast, the fraction of sperm recovered from the receiver compartment after moving across a gel phase barrier comprised of a reconstituted bioresponsive CP / PVP polymer blend was dramatically reduced by more than 90%. In parallel, the motility of sperm cells capable of overcoming the bioresponsive gel barrier was less than 10%. According to WHO standards, these results are strong indicators of infertility in vivo (WHO, 2021). Direct comparison with the spermicidal VCF® gel reveals that inclusion of a pharmacological agent such as nonoxynol-9, which negatively affects sperm viability, has only a marginal additive benefit for contraceptive efficacy.

[0095] Further evaluation of contraceptive efficacy was performed in vivo using virgin New Zealand rabbits that were randomly assigned to four treatment groups of 10 animals each. In addition, four proven male breeder rabbits of the same source and strain were used as semen donors as described previously (Zeitlin et al., 2001). On the day of the experiment, the vaginal cavity of animals was flushed with 5 mL of VFS to lower the pH value to the physiological acidic environment of humans. After the vaginal douche, a 1 cm long, rabbit-sized xerogel device or 2 mL of a hydrogel composition prepared from bioresponsive CP / PVP polymer blends as outline in Examples 1 and 2 was administered vaginally to female rabbits using a blunted 1 mL tuberculin syringe without needle tip as applicator. Other treatment groups included a “positive control” receiving 2 mL of the contraceptive VCF® Gel containing 4% (w / v) nonoxynol-9 and a “sham control” where animals were only exposed to an empty syringe applicator. Within 15 min, artificial insemination of female rabbits in each treatment group was performed using 0.25 mL of pooled semen obtained from male breeder rabbits within 1 hr of collection and adjustment to 2.5-3.5xl07sperm cells / mL. Immediately after artificial insemination, each female rabbit received 20 USP units / kg of human chorionic gonadotropin via the marginal ear vein. After 12 days, female rabbits were euthanized using an intravenous dose of sodium pentobarbital. The reproductive tract was dissected from the abdominal cavity to count embryos within the uterine horns. The results summarized in Figure 8 establish a 90% pregnancy rate for rabbits in the negative control group that were only treated with an empty vaginal applicator (i.e., sham-treated). Intravaginal administration of a CP / PVP xerogel device fabricated by lyophilization from a bioresponsive CP 4% / PVP 4% hydrogel provided significant contraceptive efficacy as demonstrated by a 40% reduction in pregnancy rate when compared to sham- treated control animals. Further improvement in contraceptive efficacy was observed when a bioresponsive CP / PVP polymer blend was administered intravaginally as fully hydrated gel composition comprised of 8% (w / v) of each acidic and non-ionic polymer component. In comparison to the results obtained with the VCF® Gel that accomplishes contraceptive efficacy by killing sperm cells using nonoxynol-9 as the pharmacologically active agent, the contraceptive failure rate associated with the drag-free, bioresponsive polymeric seal established by the CP8% / PVP8% hydrogel was only 10% greater than after administration of the spermicidal VCF® Gel.

[0096] EXAMPLE 5 -Bioresponsive Polymeric Seal for Prevention of STIs

[0097] The ability of a bioresponsve polymeric seal to serve as an on-demand multipurpose prevention technology that provides contraceptive efficacy in parallel to protection from vaginally transmitted STIs hinges on tailored drug release properties for antimicrobial agents that are incorporated in said bioresponsive polymer compositions after intravaginal administration. To assess this requirement experimentally, the antibacterial drug metronidazole (MTZ), which has an established clinical safety and efficacy profile in the therapeutic management of highly prevalent vaginal infections in women, including bacterial vaginosis and trichomoniasis (Brandt et al., 2008; Augostini et al., 2023), was incorporated at 0.5 % (w / w) into a CP4% / PVP4% hydrogel that was prepared as described earlier in Example 1. Time-dependent release of MTZ from the bioresponsive phase was measured at 37°C in VFS using the dual-chamber Transwell™ design (see Figure 5A). Briefly, an aliquot of the MTZ-containing CP4% / PVP4% hydrogel was added onto the filter insert and 1 mL of VFS to the receiver compartment. Drag release kinetics were determined by periodically removing a 50 pL aliquot from the receiver compartment that was processed for quantitative drug analysis using a validated HPLC method for MTZ with UV detection. Figure 9 shows the cumulative drag amount released over 24 hours at 37 °C that was normalized to the total drag dose administered at t=0 min. The profile demonstrates that MTZ can successfully dissociate at a sustained release rate from the bioresponsive gel phase under physiologically relevant acidic conditions. After this 24-hr incubation period, only 5% of the total drug dose added to the system at t=0 min was still remaining in the gel phase suggesting almost quantitative release of this antibacterial drag. More importantly, the initial release rates measured under these simulated intravaginal conditions imply that drag concentrations in vaginal fluid will exceed pharmacodynamically effective microbicide concentrations >50 pg / mL (Augostini et al., 2023) within 60 s after vaginal administration.

[0098] Following experimental demonstration of clinically relevant drag release rates of MTZ from a medicated CP / PVP hydrogel composition exhibiting bioresponsive properties under simulated vaginal conditions, the pharmacodynamic effect of the released antimicrobial drug on microorganisms associated with STIs was evaluated using a human-derived ex vivo co-culture model for bacterial vaginosis. Briefly, immortalized human vaginal epithelial Vk2 / E6E7B cells were colonized at a 10:1 bacterial / epithelial cell ratio with suspensions of Prevotella bivia isolates that were originally collected from human subjects and are highly prevalent in the microflora of patients diagnosed with bacterial vaginosis (Fichorova et al., 2011). The co-cultures were incubated under anaerobic conditions for 24 hours before loosely attached bacteria were removed by washing. Viable bacteria associated with epithelial cells were quantified by conventional colony-forming unit (CFU) counts. Figure 10 summarizes the number of viable Prevotella bivia recovered from this coculture model after a 6-hr treatment using different compositions, hi comparison to the results obtained following media treatment (= negative control), only MTZ-containing compositions, including the medicated CP4% / PVP4% hydrogel containing 0.5% (w / v) and the marketed NUVESSA® gel products containing 1.3% (w / v) of MTZ, significantly decreased the bacterial count of Prevotella bivia. These data underline the validity of this human-derived ex vivo co-culture model for assessing preventive opportunities against vaginal pathogens associated with STIs. It is noted that the MTZ-containing CP / PVP hydrogel was more successful in suppressing growth of this Prevotella bivia strain after a 6-hr incubation time than the vaginal NUVESSA® gel. These results suggest different drug release kinetics of MTZ from these two gel compositions favoring a pharmacodynamic benefit for the fast-releasing MTZ-containing CP / PVP hydrogel.

[0099] All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and / or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims. VI. References

[0100] The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference:

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Claims

WHAT IS CLAIMED:

1. A medical device comprising a polymer composition where the polymer composition comprises a polycarboxylic acid containing polymer and a polylactone containing polymer, wherein the polymer coating is essentially free of any cellulosic polymer.

2. The medical device of claim 1, wherein the polycarboxylic acid containing polymer comprises two or more carboxylic acid or carboxylic esters per repeating units.

3. The medical device of either claim 1 or claim 2, wherein the polycarboxylic acid containing polymer comprises from one or carboxylic acid or carboxylic ester containing acrylate or methacrylate repeating unit.

4. The medical device according to any one of claims 1-3, wherein the polycarboxylic acid containing polymer comprises from about 50% w / w to about 75% w / w carboxylic acid or carboxylic ester groups.

5. The medical device according to any one of claims 1-3, wherein the polycarboxylic acid containing polymer further comprises one or more cross linking agents.

6. The medical device of claim 5, wherein the cross-linking agent is a sugar or sugar alcohol.

7. The medical device of claim 6, wherein the sugar is polysaccharide.

8. The method device of claim 6, wherein the polysaccharide is sucrose.

9. The medical device of claim 6, wherein the sugar alcohol is erythritol.

10. The medical device according to any one of claims 1-9, wherein the polylactone containing polymer is a polypyrrolidone containing polymer.1 1. The medical device according to any one of claims 1-10, wherein the polypyrrolidone containing polymer is polyvinylpyrrolidone.

12. The medical device according to any one of claims 1-11, wherein the polycarboxylic acid containing polymer and the polypyrrolidone containing polymer are present in a ratio of 15:1 to 1 :15.

13. The medical device of claim 12, wherein the ratio is 10: 1 to 1 :10.

14. The medical device of claim 13, wherein the ratio is 5:1 to 1:5.

15. The medical device of either claim 12 or claim 13, wherein the ratio is 1: 1.

16. The medical device of claim 12, wherein the ratio is 15:1 to 1 : 1.

17. The medical device of claim 16, wherein the ratio is 15: 1 to about 5:1.

18. The medical device according to any one of claims 1-17, wherein the polymer composition is anhydrous.

19. The medical device according to any one of claims 1-17, wherein the polymer composition is a hydrate.

20. The medical device according to any of claims 1- 19, wherein the medical device is used to prevent pregnancy.

21. The medical device according to any one of claims 1-20, wherein the medical device is used to prevent the transmission of a sexually transmitted diseases.

22. The method device according to any one of claims 1-21 , wherein the medical device is used to treat an infection.

23. The medical device according to any one of claims 1-22, wherein the medical device is designed to be inserted into the vagina.

24. The medical device according to any one of claims 1-23, wherein the medical device forms barrier between the inside of the vagina and the outside of the body.

25. The medical device of claim 24, wherein the barrier is formed upon exposure of the polymer composition of the medical device to physiological fluids.

26. The medical device of either claim 24 or claim 25, wherein the barrier is formed upon exposure of the polymer coating of the medical device to a fluid with a pH of at least 7.

27. The medical device of claim 26, wherein the pH is from about 7 to about 8.9.

28. The medical device of either claim 26 or claim 27, wherein the pH is from about 7.6.

29. The medical device according to any one of claims 1-28, wherein the polymer composition of the medical device forms a barrier is formed upon exposure to seminal fluid.

30. The medical device according to any one of claims 1-29, wherein the polymer composition further comprises one or more excipients.

31. The medical device of claim 30, wherein the excipient is a pore forming excipient.

32. The medical device of claim 31 , wherein the pore forming excipient is a sugar or sugar alcohol.

33. The medical device of claim 31, wherein the sugar or sugar alcohol is mannitol.

34. The medical device according to any one of claims 30-33, wherein the polymer composition comprises an amount from about 0.1% w / w to 25% w / w of the polymer composition.

35. The medical device of claim 34, wherein the amount is from about 1% w / w to about36. The medical device according to any one of claims 1-35, wherein the medical device further comprises an active pharmaceutical ingredient.

37. The medical device of claim 36, wherein the active pharmaceutical ingredient is a hormone, a contraceptive, an anti-inflammatory agent, an anti-microbial agent, or a spermicide.

38. The medical device of claim 37, wherein the active pharmaceutical ingredient is a hormone.

39. The medical device of claim 37, wherein the active pharmaceutical ingredient is a contraceptive.

40. The medical device of claim 37, wherein the active pharmaceutical ingredient is an antiinflammatory agent.

41. The medical device of claim 40, wherein the anti-inflammatory agent is a nonsteroidal anti-inflammatory drug (NSAID).

42. The medical device of claim 37, wherein the active pharmaceutical ingredient is an antimicrobial agent.

43. The medical device of claim 42, wherein the anti-microbial agent is an antibiotic.

44. The medical device of claim 42, wherein the anti-microbial agent is an antiviral.

45. The medical device of claim 42, wherein the anti-microbial agent is an antifungal.

46. The medical device of claim 37, wherein the active pharmaceutical ingredient is a spermicide.

47. The medical device according to any one of claims 1 -30, wherein the cellulosic polymer is a non-ionic cellulose.

48. The medical device of claim 47, wherein the non-ionic cellulose is hydropropyl methyl cellulose.

49. The medical device according to any one of claims 1-48, wherein the medical device is coated with the polymer composition to form a polymer coating.

50. The medical device of claim 49, wherein the polymer coating is present at a thickness of at least 1 nm.

51. The medical device of claim 50, wherein the thickness is at least 10 nm.

52. A method of preventing an infection comprises inserting the medical device according to any one of claims 1-51 into the vagina of a patient.

53. The method of claim 52, wherein the infection is a sexually transmitted disease or disorder.

54. The method of claim 53, wherein the sexually transmitted disease or disorder is HIV or AIDS.

55. The method of claim 52, wherein the infection is an infection of the vagina.

56. The method of either claim 52 or claim 55, wherein the infection is a yeast infection.

57. The method according to any one of claims 52-56, wherein the medical device is inserted into the vagina without the use of an applicator.

58. The method of claim 57, wherein the medical device is inserted into the vagina digitally.

59. A kit comprising a medical device according to any one of claims 1-51.

60. A polymer composition comprising:(A) a polycarboxylic acid containing polymer, wherein the polycarboxylic acid containing polymer comprises from about 55% w / w to about 70% w / w carboxylic acid groups and comprises an acrylate backbone; and(B) a polyvinyl pyrrolidone polymer, wherein the polymer composition comprises a ratio of 5:1 to about 1:5 of the polycarboxylic acid and the polyvinyl pyrrolidone polymer and is essentially free of any cellulosic material.

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