Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
  • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7007—Drug-containing films, membranes or sheets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
  • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
  • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
  • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof

Definitions

• This disclosure relates to the fields of medicine, pharmacology and chemistry.
• new compositions and methods of prevention of unwanted pregnancies and sexually transmitted infections are disclosed.
• 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.
• 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).
• 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.
• 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.
• these medical devices and compositions maybe used vaginally.
• 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.
• 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).
• 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).
• CP/PVP Carbopol® 974P/PVP
• 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).
• 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.
• CP/PVP Carbopol® 974P/PVP
• 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.
• Compositions were assessed at indicated volumetric dilutions using liquified human semen pH 7.8 - 8.5.
• FIG. 8 shows the contraceptive efficacy in vivo.
• 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).
• FIG. 10 shows pharmacodynamic activity of metronidazole (MTZ) released from a medicated bioresponsive polymeric seal in vitro.
• MTZ metronidazole
• 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.
• 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.
• the present disclosure provides successful fabrication of tampon- like xerogel structures that may decrease pregnancy rate in rabbits by at least 40%.
• 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.
• 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.
• selected acidic polymers e.g., poly acrylic acid derivatives
• alkaline seminal fluid pH 7.0 - 8.9
• bioresponsive polymeric seals 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.
• 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.
• sperm motility and viability as well as infectivity of HIV/AIDS virions are significantly compromised under acidic conditions.
• 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.
• 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
• 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.
• this tampon-like device may be administered digitally without an applicator and may convert into a bioadhesive hydrogel following exposure to vaginal fluid.
• 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.
• 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 TranswellTM system (FIG. 7).
• 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).
• a drug administered into the vaginal cavity can affect either local or systemic targets.
• 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).
• vaginal administration of drugs designed for systemic treatment requires permeation of the active ingredient(s) across the vaginal epithelium.
• 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).
• 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).
• 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).
• 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 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 e.g., TMC 120 - dapivirine
• 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).
• elastomeric or thermoplastic materials e.g., silicone
• bioadhesive polymers were explored as suitable excipients in vaginal drug delivery systems.
• 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).
• 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).
• 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)
• third generation microbicides that inhibit reverse transcriptase activity
• mucous membranes 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.
• compositions for administration to a patient in need of such treatment, 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.
• the compositions disclosed herein are formulated in a manner amenable for the treatment of human and/or veterinary patients.
• 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.
• the pharmaceutical formulation may be tableted or encapsulated.
• 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.
• 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.
• compositions may be administered by a variety of methods, e.g., orally or by injection e.g. subcutaneous, intravenous, and intraperitoneal).
• 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.
• 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.
• CGF com gluten feed
• 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.
• 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.
• the effective dose range for the therapeutic compound can be extrapolated from effective doses determined in animal studies for a variety of different animals.
• 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):
• HED Animal dose (mg/kg) x (Animal K m /Human K m )
• K m factors in conversion results in HED values based on body surface area (BSA) rather than only on body mass.
• BSA body surface area
• K m values for humans and various animals are well known. For example, the K m for an average 60 kg human (with a BSA of 1.6 m 2 ) is 37, whereas a 20 kg child (BSA 0.8 m 2 ) would have a K m of 25.
• mice K m of 3 (given a weight of 0.02 kg and BSA of 0.007); hamster K m of 5 (given a weight of 0.08 kg and BSA of 0.02); rat K m of 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey K m of 12 (given a weight of 3 kg and BSA of 0.24).
• HED dose 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.
• 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.
• 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.
• the amount is less than 10,000 mg per day with a range of 750 mg to 9,000 mg per day.
• 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.
• 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.
• patients may be administered two doses daily at approximately 12-hour intervals.
• the agent is administered once a day.
• the agent(s) may be administered on a routine schedule.
• 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.
• 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.
• 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.
• 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.
• the agent can be taken every morning and/or every evening, regardless of when the patient has eaten or will eat.
• compositions that may be used in treating a disease or disorder in a 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.
• 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.
• 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.
• 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.
• the therapeutic methods of the disclosure 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).
• 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.
• compositions and at least one other therapy are 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.
• the compounds described herein may precede or follow the other treatment by intervals ranging from minutes to weeks.
• 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.”
• active ingredient 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.
• “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.
• 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.
• 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
• 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.
• the patient or subject is a primate.
• Non-limiting examples of human patients are adults, juveniles, infants and fetuses.
• “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
• 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).
• 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 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.
• 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.
• 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.
• a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
• Treatment 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.
• 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.
• 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.
• 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.
• 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.
• Combination of the gel composition with SFS results in a volumetric dilution of the acidic CP polymer from 4% to 1%.
• the work of shear required to spread the hydrogel increases, which demonstrates increasing viscoelastic properties after exposure to alkaline SFS.
• 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.
• 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, b poly(V- vinylpyrrolidone)
• 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, b poly(A- vinylpyrrolidone)
• 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.
• frozen gel cylinders 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).
• 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 NasalTM Intranasal Mucosal Atomization nozzle (Teleflex, Wayne, PA) that creates a fine mist of fluid particles ranging from 30-100 pm in size.
• 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).
• 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 NasalTM 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 mm 2 .
• 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 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.
• an alkaline buffer solution such as phosphate buffer, pH 8.0
• 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).
• 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 TranswellTM 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.
• 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.
• 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.
• 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.
• MTZ antibacterial drug metronidazole
• 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
• Valenta C. The use of mucoadhesive polymers in vaginal delivery. Advanced Drug Delivery Reviews, 2005. 57(11): p. 1692-1712.
• TDS-730 Viscosity of Carbopol®* Polymers in Aqueous Systems 2010 (www.lubrizol.com/-/media/Lubrizol/Health/TDS/TDS- 730_Viscosity_Carbopol_in_Aqueous-Systems.pdf, accessed last on February 23, 2024).
• Aquaporin3 is a sperm water channel essential for postcopulatory sperm osmoadaptation and migration. Cell Research, 2011. 21(6): p. 922-933.

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