Stable topical compositions for treating atrophic vaginitis

Abstract

A composition for treating atrophic vaginitis including sildenafil citrate USP (C22H30N6O4SC6H8O7), oxytocin USP (C43H66N12O12S2), boric acid, Chlorobutanol, Sodium phosphate monobasic and L arginine or L arginine HCI as a buffering system formulated in a suitable, non stainable and non leaky vaginal cream base. A method of treating atrophic vaginitis comprising topically administering the composition to a patient in need thereof.

Description

STABLE TOPICAL COMPOSITIONS FOR TREATING ATROPHIC VAGINITISFIELD OF THE INVENTION

[0001] In one of its aspects, the present disclosure relates generally to medicated topical compositions and topical compositions for treating atrophic vaginitis in particular.

[0002] In one of its aspects, the present invention is directed to pharmaceutical vaginal cream compositions comprising a synthetic peptide-based hormone known as oxytocin, a PDE-5 inhibitor selected from Sildenafil Citrate, Tadalafil, Vardenafil, and Avanafil. A combination of Sodium phosphate monobasic and an essential amino acid known as L-arginine or L-arginine HCI act as buffering agents to provide necessary micro-environmental conditions that favors the stability of the active ingredients in the vaginal cream composition. The present invention is also directed to a method of treating a menopausal condition in a female in need thereof, the method comprising vaginal administration of a pharmaceutical vaginal cream composition containing Oxytocin and Sildenafil citrate as active ingredients. It contains a combination of L arginine or L arginine HCI with sodium phosphate monobasic act as buffering agents to provide an essential micro-environmental condition that resists change in pH of the composition in the vaginal cavity of postmenopausal women. The buffering agents ensure that the active ingredients remain stable throughout the shelf life of the product. The vaginal cream is prescribed twice per week for at least 2 weeks.BACKGROUND

[0003] Vaginal atrophy (atrophic vaginitis) is thinning, drying and inflammation of the vaginal walls that may occur when your body has less estrogen. Vaginal atrophy occurs most often after menopause.

[0004] For many women, vaginal atrophy not only makes intercourse painful but also leads to distressing urinary symptoms. Since the condition causes both vaginal and urinary symptoms, doctors use the term "genitourinary syndrome of menopause (GSM)" to describe vaginal atrophy and its accompanying symptoms.

[0005] Sildenafil and L-arginine have been combined in a vaginal gel, and studies suggest this combination may improve sexual function in women with conditions like Vulvodynia,Dyspareunia, and female sexual arousal disorder. L-arginine plays a role in nitric oxide production, which is important for blood flow and sexual function.

[0006] Oxytocin, a peptide associated with bonding and social behavior. Oxytocin (generic name: Pitocin) has been FDA approved to be used in pregnant women to induce labor when there is a medical reason to do so (e.g., diabetes, high blood pressure, water breaks early) and to help get things moving when natural labor slows down. It can also help produce contractions during the third stage of labor and control bleeding in the mother after the birth. In addition, oxytocin (Pitocin) is an add-on therapy to help push out the pregnancy tissue after certain types of miscarriages (sudden, naturally-occuring loss of an unborn baby before week 20 of pregnancy).

[0007] FDA approved Oxytocin is given by injection.

[0008] Oxytocin has also been studied and used for many off label uses as well, including intractable pain, autism, fibromyalgia, migraine, social anxiety, sexual dysfunction, weight loss and vaginal atrophy. The most common dosage forms used in compounding are intranasal, sublingual and vaginal preparations.

[0009] Topical oxytocin has been shown to reverses vaginal atrophy in postmenopausal women in a double-blind randomized pilot study. Menopause International. Jonasson, A. F., Edwall, L., & Uvnas-Moberg, K. (2011) 17(4), 120-125.

[0010] Oxytocin and sildenafil are commonly sold as topical creams by pharmacies that compound these drugs. See for example: https: / / www.empowerpharmacy.com / compounding- pharmacy / sildenafil-oxytocin-odt / , accessed April 16, 2025. https: / / www.shieldspharmacy.com / men-s-health / sildenafil-oxytocin-compounded- trochelozenge, accessed April 16, 2025.

[0011] Oxytocin, sildenafil and arginine are also commonly sold as topical creams by pharmacies that compound these drugs. See for example: https: / / apollovh.com / resources / sexual-performance / and https: / / www.anazaohealth.com / sexual-health, both accessed April 15, 2025.

[0012] Prior art formulations, particularly if they include synthetic hormones, for treating atrophic vaginitis increase the risk of adverse side effects for the patient. In addition, compositions in the prior art are extremely unstable at room temperature and also unstablewith refrigeration. There is a need in the art to provide a stable, pharmaceutically acceptable topical formulation for the treatment of atrophic vaginitis.SUMMARY

[0013] In one aspect, the present disclosure relates to a composition for treating atrophic vaginitis including a cream base including sildenafil citrate and oxytocin. In certain embodiments the compositions of the invention comprise sildenafil citrate is in a dosage in the range of 25 mg / dose to 100 mg / dose, and oxytocin is in a dosage in the range of 40 lU / dose to 400 lU / dose. In another aspect, the composition further includes a buffering agent. In a further aspect, the buffering agent is Larginine. In a further aspect, the buffering agent is sodium phosphate monobasic.

[0014] In one aspect, the present disclosure relates to a composition for treating atrophic vaginitis including L-arginine USP having the formula H2NC(=NH)NH(CH2)3CH(NH2)CC>2H, sildenafil citrate USP having the formula C22H30N6O4S CeHsO?, oxytocin API raw USP having the formula C43H66N12O12S2, hyaluronic acid having the formula (Ci4H2iNOn)n, and a cream base. In one aspect, the composition can include a stabilizer, and in another aspect, the stabilizer is boron citrate and / or chlorobutanol. In another aspect, the stabilizer is a suitable stabilizer that can keep oxytocin stable.

[0015] In another aspect, compositions according to aspects of the present disclosure can be dispensed using a pump. In one aspect, the pump can dispense 0.5 g of the composition with each dispensation.

[0016] The viscosity of conventional vaginal cream compositions decreases by about 70% to 80% at human body temperature, which is 37°C. Due to the loss in viscosity, the conventional creams liquefy and exude from the vaginal cavity. In one aspect, the unique composition of the compositions of the present invention maintain a high viscosity even when the temperature of the cream is raised to 37° C.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Embodiments of the present invention will be described with reference to the accompanying drawings.

[0018] Figure 1 is a process flowchart of a process for the manufacture of compositions according to embodiments of the present invention.DESCRIPTION

[0019] Various compositions will be described below to provide an example of an embodiment of each claimed invention. No embodiment described below limits any claimed invention and any claimed invention may cover compositions that differ from those described below.

[0020] The description is not intended to be construed in a limiting sense. Thus, various modifications of the illustrative embodiments, as well as others While the teaching herein include illustrative embodiments and examples of some embodiments of an embodiment of the invention, may be apparent to persons skilled in the art upon reference to this description. It is therefore contemplated that the appended claims will cover any such modifications or embodiments.

[0021] In one embodiment, the present invention relates to a composition for treating atrophic vaginitis including L-arginine USP (H2NC(=NH) NH(CH2)3CH(NH2)CC>2H), sildenafil citrate USP (C22H30N6O4SC6H8O7), oxytocin USP (C43H66N12O12S2), hyaluronic acid ((C14H21NO11)n) and a cream base. In one embodiment, the composition can include a stabilizer, and in another aspect, the stabilizer is boron citrate and / or Chlorobutanol. In another embodiment, the stabilizer is a suitable stabilizer that can keep oxytocin stable.

[0022] In another embodiment, the present invention relates to a composition for treating atrophic vaginitis where the composition is in the amount of 1.0 g (which in one embodiment is a single dose), including sildenafil citrate USP (C22H30N6O4S CeHsO?) in the amount of 10 mg, oxytocin USP (C43H66N12O12S2 ) in the amount of 40 IU, hyaluronic acid ((Ci4H2iNOn)n) in an amount of 2 mg / dose at a concentration of 0.2%-0.5%, boron citrate in the amount of 1.5 mg and 0.5% Chlorobutanol, and a cream base to make 1000 mg.

[0023] According to one embodiment of the present invention, there is provided a viscous vaginal cream composition comprising aliphatic alcohols, an ester which is preferably a fatty acid ester, a surfactant, emulsifier, pH modifier, antimicrobial agent, antioxidant, a synthetic peptide hormone known as Oxytocin, a PDE-5 Inhibitor selected from a group of PDE-5 Inhibitor such as Sildenafil Citrate, an essential amino acid such as L-Arginine or L-arginineHCI, a substituted methoxyphenol which acts as an antioxidant, and water. The PDE-5 Inhibitor is preferably selected from the group consisting of Sildenafil Citrate, Tadalafil, Vardenafil and Avanafil.

[0024] In certain embodiments the cream composition of the present invention is an oil in water (O / W) emulsion in which the oil phase is considered the internal or dispersed phase while the aqueous phase is considered the external or continuous phase. The oil phase of the composition preferably comprises Cetyl Ester (Crodamol SS), Ceto stearyl alcohol and Octylodecanol. While the aqueous phase preferably comprises of Polysorbate 60, Sorbitan monooleate 60, Sorbitan sesquioleate (Span 83), Butylated Hydroxyanisole, Sodium phosphate monobasic, Chlorobutanol Hemihydrate, Boric acid and water. A PDE-5 Inhibitor compound, which is sparingly soluble in water, is homogenized with a surfactant and boric acid using high shear homogenizer to get a water-soluble solution to uniformly disperse throughout the cream. Oxytocin is water soluble and maintains stability of solution. Addition of oxytocin to the cream base is only done after cooling the cream to below 10oC using a suitable chiller during manufacturing.

[0025] In certain embodiments a mixture of Cetyl Ester and Ceto stearyl alcohols, which act as auxiliary emulsifiers, impart to the oil phase of the cream an HLB (hydrophilic hydrophobic balance) value of about 15.2.

[0026] In certain embodiments an ester, which acts as an emollient and lubricant, is included in the composition. The ester preferably is a fatty acid ester and is selected from the group consisting of isopropyl stearate, isopropyl myristate, isopropyl palmitate and isopropyl laurate. Most preferably, the ester is isopropyl myristate. The ester provides the cream with smoothness and lubricity which, in turn, facilitates the loading of the cream into and dispensing of the cream from a vaginal applicator.

[0027] In certain embodiments propylene glycol is included as a humectant to prevent the cream from drying out and forming a crust. The humectant also improves the cream's consistency and spreadability, enhances solubility of the PDE-5 Inhibitors and acts as an antimicrobial agent.

[0028] In certain embodiments either polysorbate 60 or polysorbate 80 is included as a surfactant. The surfactant efficiently emulsifies the cream and imparts a high and stable viscosity even at a temperature of 37°C when used at a preferred concentration of about 1 .0%to 4.0%. Unlike commercially available state-of-the-art creams, the present composition requires the use of two surfactants. One surfactant (Tween 60), having an HLB of 15.0 (which is close to the HLB value of the oil phase of the composition) and second one (Span 60) having an HLB 4.0, has been found to impart to the cream, giving its novel long-lasting viscous characteristics.

[0029] In certain embodiments the composition further comprises a substituted methoxyphenol, preferably butyl hydroxyanisole, which acts as an antioxidant.

[0030] In certain embodiments the composition further comprises chlorobutanol, which acts as an antibacterial.

[0031] In one aspect, the present invention disclosure relates to a composition for treating atrophic vaginitis, where a vaginal cream provides a necessary buffering environment in which Oxytocin remains stable in the vaginal cavity. The vaginal cream maintains a stable pH despite fluctuations in the vaginal cavity environment and remains physically and chemically stable under both room temperature and accelerated storage conditions. The buffering agent comprises L-arginine or L arginine HCI and sodium phosphate monobasic to maintain the stability of oxytocin in vaginal cream.

[0032] In another aspect, 1 mg of Oxytocin contains Oxytocic activity not less than 400 USP units. In one aspect, 1.42 mg of Sildenafil citrate equivalent to Sildenafil base 1 mg. The present invention's disclosure relates to a stable vaginal cream composition including a stable composition of Oxytocin and Sildenafil citrate. The micro-environmental pH (3.5-4.0) condition that favors the healthy condition of vaginal cavity as well as provide stability of the drug substance is provided by combination of buffering system comprises L-arginine or L arginine HCI and Sodium phosphate monobasic. This buffer system resists change in pH and is required to maintain the stability of oxytocin in the vaginal cream.

[0033] In various aspects, each gram of vaginal cream contains: Oxytocin equivalent to 40, 100, 200, 300 or 400 USP units and Sildenafil citrate equivalent to Sildenafil base 25 mg, 50 mg, or 100mg.

[0034] In one aspect, oxytocin is stabilized with a buffering system composed of L- arginine or L-arginine HCL and Sodium phosphate monobasic. The addition of Boron citrate or boric acid buffer provides buffering capacity while chelating metal ions that catalyze oxidation.

[0035] In one aspect, the micro-environmental pH around the drug substances is very critical to keep them stable in the cream composition. Additionally, physiologically the vaginal cavity needs to maintain an acidic pH (3.0-4.5) to be healthy and promote growth of Lactobacillus. Lactobacillus species metabolize glycogen to help maintain an acidic vaginal environment; without their activity the pH can become alkaline, promoting the growth of yeast, mold and harmful bacteria.

[0036] In one aspect, when formulating a vaginal cream, it's essential to use buffer salts that maintain the pH within the physiological range of the vaginal environment (typically pH 3.8-4.5). This pH range helps maintain the natural flora (e.g., Lactobacillus species) and prevents the growth of pathogens. In certain embodiments suitable buffer salts for vaginal creams include Lactic Acid and Sodium Lactate, Citric Acid and Sodium Citrate, Acetic Acid and Sodium Acetate, Boric Acid and Sodium Borate, Phosphate Buffers (e.g., Monobasic Sodium Phosphate and Dibasic Sodium Phosphate).

[0037] In one aspect, when formulating the vaginal cream, select one or more buffer salts specified above to maintain a required pH between 3.0 to 4.5.

[0038] In another aspect, the present disclosure relates to a composition for treating atrophic vaginitis where the composition is in the amount of 1.0 g (which in one aspect is a single dose), including sildenafil citrate USP (C22H30N6O4S CeHsO?) in the amount of 25mg, oxytocin USP (C43H66N12O12S2) in the amount of 40 IU, hyaluronic acid (C14H21 NO11)n in an amount of 2 mg / dose at a concentration of 0.2%-0.5%, a stabilizer in the amount of 1.5 mg, and the remaining weight is adjusted by the cream base to achieve 1000 mg. In one aspect, the stabilizer is boron citrate and / or Chlorobutanol Hemihydrate. In another aspect, the stabilizer is a suitable stabilizer that can keep oxytocin stable.

[0039] In one aspect, a base cream useful in compositions of the present disclosure, can be an anhydrous vaginal base. In another aspect, a base cream useful in compositions of the present disclosure can include dimethicone, chlorocresol, Chlorobutanol anhydrous and Hemihydrate, butylated hydroxy toluene, Ceto stearyl alcohol, Ceto macrogol 1000, disodium EDTA, light liquid paraffin, polyethylene glycol 40 hydrogenated castor oil, propylene glycol, white soft paraffin, citric acid, sodium dihydrogen phosphate, Tocobiol-vitamin E- rosemary extract and purified water. In another aspect, a base cream useful in compositions of the present disclosure can include petrolatum, Cetyl alcohol, stearyl alcohol, butylated hydroxytoluene, mineral oil, polysorbate 80, disodium EDTA, methylchloroisothaizoline, methylisothiazoline, Chlorobutanol, Tocobiol and rosemary extract, and purified water.

[0040] In another aspect, compositions of the present disclosure can be formulated by taking a base cream useful for compositions of the present disclosure and blending non-cream ingredients disclosed herein into the cream. In one aspect, standard compounding methods can be used for the blending. In another aspect, the pH of the composition after blending is adjusted to be acidic. In another aspect, the pH of the composition after blending is adjusted to a pH in the range of pH 3.5-4.5.

[0041] In another aspect, compositions according to aspects of the present disclosure can be dispensed using a pump. In one aspect, the pump can dispense 0.5 g of the composition with each dispensation.

[0042] In another aspect, the present disclosure relates to a method of treating atrophic vaginitis including topically administering a composition according to an aspect of the present disclosure to a patient in need thereof. In one aspect, the topical application is to the area around the entrance to the vagina. In another aspect, the topical application is to the clitoris. In another aspect, the topical application is to the anterior vaginal wall. In another aspect, the location of topical application on the anterior vaginal wall is the area of the vaginal erogenous zone (commonly referred to as the 'G-spot' or Grafenberg spot).

[0043] In another embodiment, compositions of the present invention are formulated by taking a various Functional Excipients such as Ceto stearyl Alcohol, Octyldodecanol, Cetyl Ester, Polysorbate 60, Sorbitan Monostearate, Sorbitan Sesquioleate (Span 83), Sorbitan monooleate 60 (Span 60), Cetyl Ester, as components of the vaginal cream base. To achieve desired Physico-chemical properties, various components are added in the cream composition which are buffering agents, pH adjuster, antioxidants, stabilizers, etc.

[0044] In certain embodiments of the invention the cream base is characterized by performing various studies such as homogeneity, colour, odour, and feel to touch. The chemical properties of the cream base are critical for its function as a drug delivery system, ensuring the effective delivery of a therapeutic dose to achieve the desired clinical outcome. The following properties were evaluated and based on these properties, the components and their respective concentrations were determined for the final composition. Chemical propertiessuch as pH, buffering capacity, Osmolality, Firmness and Adhesiveness, Bio adhesion and Viscosity affect the stability of the cream composition and performance of the products. The buffer capacity of vaginal creams plays a crucial role in maintaining the pH balance of the vaginal environment. Here's how it works:

[0045] pH Regulation: The vagina naturally maintains an acidic pH, typically between 3.8 and 4.5, which helps prevent the growth of harmful bacteria and yeast. Vaginal creams often contain buffers, such as lactate or acetate, which help to regulate and maintain this acidic pH.

[0046] Protective Barrier: Buffering agents in vaginal creams help to maintain the stability of the pH level despite changes caused by menstrual cycles, sexual activity, or the use of certain medications. This stability creates a protective barrier against infections and other imbalances.

[0047] Prevention of Infections: By maintaining the acidic environment of the vagina, vaginal creams with adequate buffer capacity can help prevent the overgrowth of harmful microorganisms like yeast (such as Candida) and bacteria (like Gardnerella vaginalis), which can lead to infections like bacterial vaginosis or yeast infections.

[0048] Comfort and Symptom Relief: Vaginal creams with appropriate buffer capacity can also provide relief from symptoms like itching, burning, or irritation, which may occur due to pH imbalances.

[0049] Enhanced Efficacy of Active Ingredients: Some vaginal creams contain active ingredients such as antifungals or antibiotics. Optimal pH conditions, facilitated by buffer capacity, can enhance the efficacy of these active ingredients, making the treatment more effective.

[0050] In certain compositions according to the invention, buffering agents are composed of L-arginine and a buffer salt, monobasic sodium phosphate. The presence and level of buffering agent is critical to maintain the required buffering capacity of the vaginal cream and it is well balanced in composition. The level of buffering agent is critically balanced and the pH is adjusted with other pH adjusting components such as boric acid, which is an acidifier as well as antifungal.

[0051] In certain embodiments of the invention the base cream employed in the present invention is suitable for incorporating the active ingredients disclosed herein. In oneembodiment, standard compounding methods can be used for blending. In another embodiment, after blending, the pH of the composition is adjusted to be acidic. In another embodiment, the pH of the composition is adjusted to a pH in the range of pH 3.5-4.5. The stability of oxytocin is pH dependent, and it degrades faster at pH 1.2 and slowest at pH 3.5. Therefore, in one embodiment, the composition is maintained at a preferred pH of 3.5 by the inclusion of citric acid, Boric acid, or boron citrate.

[0052] In another embodiment, compositions according to the present invention can be dispensed using a pump. In one embodiment, the pump can dispense 0.5 g of the composition with each dispensation.

[0053] In another embodiment, the present invention relates to a method of treating atrophic vaginitis including topically administering a composition according to an embodiment of the present disclosure to a patient in need thereof. In one embodiment, the topical application is to the area around the entrance to the vagina. In another embodiment, the topical application is to the clitoris. In another embodiment, the topical application is to the anterior vaginal wall. In another embodiment, the location of topical application on the anterior vaginal wall is the area of the vaginal erogenous zone (commonly referred to as the ‘G-spot’ or Grafenberg spot).

[0054] Various stabilizers can be used in the present invention. The term “stabilizer” refers to any substance that keeps Sildenafil citrate and Oxytocin chemically stable. Alternatively, the term “stabilizer” refers to any substance that slows or retards the degradation or alteration of Sildenafil citrate and Oxytocin. For example, a stabilizer can protect Sildenafil citrate and Oxytocin from instability caused by light, moisture, heat, or oxidation. In some embodiments, the stabilizer is lipophilic. In some embodiments, the stabilizer is hydrophilic. In some embodiments, the stabilizer can prevent or retard the oxidation of the oil. In some embodiments, the stabilizer can be, but is not limited to, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid and its esters, vitamin E and its esters, e.g., vitamin E acetate, sodium bisulfite, sodium metabisulfite, 3-dehydroshikimic acid (DHS), tocopherols and their esters, alkyl gallates, chelating agents, EDTA (ethylenediaminetetraacetic acid; edetate disodium), citric acid, benzyl alcohol, or combinations thereof. In some embodiments, the stabilizer can be edetate disodium, butylated hydroxy anisole, butylated hydroxytoluene, or combinations thereof.

[0055] In some embodiments, the composition of the present invention further comprises a pharmaceutically acceptable excipient. As used herein, “excipient” refers to a substance, or mixture of substances, that is used in the formulation of vaginal cream compositions to give desirable physical characteristics to the formulation. As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit / risk ratio. In some embodiments, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized international pharmacopeia for use in animals, and more particularly in humans. Various pharmaceutically acceptable excipients can be used. In some embodiments, the pharmaceutically acceptable excipient can be, but is not limited to, a stiffening agent, an oil, a solvent, an emulsifier, a humectant, a buffering agent, a filler, an emollient, a stabilizer, or combinations thereof.

[0056] In some embodiments, compositions of the present invention further include a "stiffing agent". The term “stiffening agent” refers to a substance, or mixture of substances, added to make a vaginal cream composition more viscous at room temperature. In some embodiments, a stiffening agent is any substance that promotes formation of a formulation having a semi- solid consistency. The stiffening agent can be hydrophilic (e.g., CARBOPOL, carboxymethylcellulose, hydroxypropyl methylcellulose, alginate, polyethylene glycol). In some embodiments, the stiffening agent has low hydrophilic-lipophilic balance (HLB). In some embodiments, the hydrophilic-lipophilic (HLB) value is less than 7. In some embodiments, the HLB value is less than 5. In some embodiments, the HLB value is about 4. Examples of suitable stiffening agents include, but are not limited to, hydrogenated vegetable oil, cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, lauryl alcohol, myristal alcohol, cetostearyl alcohol, white wax, yellow wax, beeswax, candelilla wax, cotton wax, carnauba wax, bayberry wax, rice-bran wax, and combinations thereof. In some embodiments, the stiffening agent is a mixture of cetyl esters wax, cetyl alcohol, and beeswax.

[0057] In some embodiments, compositions of the present invention further include an "oil". The term “oil” refers to any pharmaceutically acceptable hydrophobic liquid. In some embodiments, an oil is an ester of glycerol (1 ,2,3-propanetriol) and fatty acids. Generally, the fatty acid hydrocarbon chains each contain greater than 8 carbons. In some embodiments,each hydrocarbon chain can contain from about 12 to about 36 carbon atoms. In some embodiments, the hydrocarbon chains can contain a variety of functional groups. In some embodiments, the hydrocarbon chain can be branched. In some embodiments, the hydrocarbon chains are unsaturated or polyunsaturated. In some embodiments, the hydrocarbon chains are saturated. The degree of saturation can affect the physical state, for example viscosity, of the oil. In some embodiments, the oil can be, but is not limited to, vegetable, nut, and seed oils (e.g., almond oil, castor oil, coconut oil, corn oil, cotton seed oil, jojoba oil, linseed oil, grape seed oil, rape seed oil, mustard oil, olive oil, palm and palm kernel oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower-seed oil, crambe oil, wheat germ oil, and cocoa butter), hydrocarbon and petroleum oils (e.g., petrolatum, mineral oil, and liquid paraffin). In some embodiments, the term “oil” refers to higher fatty acids (e.g., lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, 12-hydroxystearic acid, undecylenic acid, tall acid, lanolin fatty acid, isostearic acid, linoleic acid, and linolenic acid) and combinations thereof. In some embodiments, the oil is not an ester of glycerol, e.g., mineral oil and silicone oil.

[0058] In some embodiments, compositions of the present invention further include a "solvent". The term “solvent” refers to any substance capable of dissolving or dispersing one or more of the conjugated Sildenafil citrate and Oxytocin or the excipients of the present invention. The solvent can be aqueous or non-aqueous. In some embodiments, the solvent is hydrophilic, and is 10% to 75% by weight, or 20% to 60% by weight, of the total composition. In some embodiments, the solvent is lipophilic, and is 20% to 60% by weight, or 25% to 50% by weight, of the total composition. In some embodiments, the solvent is water, a polyol (e.g., glycerol) or combinations thereof. In some embodiments, the solvent is an oil as described above.

[0059] In some embodiments, compositions of the present invention further include an "emulsifier". The term “emulsifier” refers to any substance that promotes formation and stabilization of an emulsion or suspension. In some embodiments, the emulsifier includes, but is not limited to, sodium lauryl sulfate, propylene glycol monostearate, methyl stearate, glyceryl monostearate, Cetyl Ester, Ceto Stearyl Alcohol and combinations thereof.

[0060] In some embodiments, compositions of the present invention further include a "humectant". The term “humectant” refers to any substance that promotes retention of moisture in the composition of the present invention. In some embodiments, the humectant includes,but is not limited to, polyethylene glycol, propylene glycol, glycerin, polyol, polyol derivatives, and combinations thereof.

[0061] In some embodiments, compositions of the present invention further include a "buffering agent". The term “buffering agent” refers to any substance capable of neutralizing both acids and bases and thereby maintaining the desired pH of the composition of the present invention. In some embodiments, the buffering agent affects the emulsifying properties. For example, different buffering agents can be provided to increase or decrease the emulsification of the conjugated Sildenafil citrate and Oxytocin or the excipients of the present invention. In some embodiments, the buffer can be, but is not limited to, Tris buffers (Tris EDTA (TE), Tris acetate (TAE), Tris phosphate (TPE), Tris glycine), phosphate buffers (e.g., monobasic sodium phosphate, potassium phosphate), bicarbonate buffers, acetate buffers (e.g., sodium acetate), ammonium buffers, citrate buffers, and derivatives, L arginine, L-arginine HCI and combinations thereof. In some embodiments, an organic acid buffer is used. In some embodiments, an acetate buffer, a phosphate buffer, or a citrate buffer can be used. In some embodiments, a zwitterionic buffer can be used. In some embodiments, the buffering agent is a phosphate buffer (e.g., sodium phosphate monobasic).

[0062] The pH of embodiments of the invention can be physiologically compatible and / or sufficient to maintain stability of the composition. In some embodiments, the composition of the present invention can have a pH of 3.5 to 4.5.

[0063] In some embodiments, compositions of the present invention further include an "emollient". As defined herein, an “emollient” is a substance that moisturizes and increases the pliability of the vaginal epithelium. In some embodiments, the emollient can be, but is not limited to, lanolin, isopropyl myristate, palmitate, oleyl alcohol, beeswax, mineral oil, silicone oil, Octyldodecanol, Cetostearyl Alcohol or combinations thereof.

[0064] In some embodiments, compositions of the present invention further include a "filler". As defined herein, a “filler” is a substance used to give bulk to the composition without chemically reacting with the Sildenafil citrate and Oxytocin of the present invention. Fillers are known to those in the art, see e.g., Remington: The Science and Practice of Pharmacy, 20th ed. (2000).

[0065] As defined herein, a “vaginal cream” is a semi-solid preparation suitable for application to the vaginal tract. In some embodiments, a vaginal cream can be a vaginalointment, vaginal gel or vaginal emulsion. Various classes of vehicle bases can be used in the vaginal cream and are known to those in art. For example, suitable vehicle bases include, but are not limited to, hydrocarbon bases or oleaginous bases, absorption bases, water-removable bases and water-soluble bases (Remington: The Science and Practice of Pharmacy, 20thed. (2000)). In some embodiments, the vehicle base is non-irritating, non-staining, stable, non-pH dependent and / or compatible with the conjugated Sildenafil citrate and Oxytocin of the present invention.

[0066] The amount of active agents or agents in a dosage form according to the invention can vary. The exact dosage amount can be selected depending upon the needs of the female to which the active agent is being administered, as determined by a relevant person. In some embodiments, one of skill in the art can perform pharmacokinetic studies and use the results of the study to adjust the dosage amount for a female, or a group of females, to a suitable level. In some embodiments, one skill in the art can determine an appropriate dosage amount based on varying dosage amounts and comparing it to symptomatic relief. In some embodiments, appropriate animal studies may be performed to determine an appropriate dosage amount. A “relevant person” as used herein, includes, for example, a physician, physician assistant, nurse practitioner, pharmacist, and customer service representative.

[0067] Various amounts of Sildenafil citrate and Oxytocin in the compositions of the present invention can be present in a dosage form. In some embodiments, the composition of the present invention is in a dosage form, wherein the dosage form comprises 25 mg / dose to 100 mg / dose of Sildenafil citrate and 40 lll / dose to 400 lll / dose of Oxytocin. As used herein, unless a specific Sildenafil citrate and Oxytocin is identified, amounts of “Sildenafil citrate and Oxytocin” refer to a summation of the amounts of Sildenafil citrate equivalent to Sildenafil and Oxytocin equivalent to Oxytocic activity expressed as USP units. In some embodiments, the composition of the present invention is in a dosage form, wherein the dosage form comprises 25 mg / dose of Sildenafil citrate and 40 lll / dose of Oxytocin.In another aspect, the present disclosure relates to a composition for treating atrophic vaginitis where the composition includes the ingredients as set out in Table 1 , 2 and 3. A process flowchart of the process for the manufacture of the formulations of Table 1 , 2 and 3 is presented in Figure 1.Table 1Table 2:Table 3:EXAMPLESExample 1.

[0068] The following manufacturing procedure was used to create batch SAOR-2 used in stability testing.

[0069] Preparation of Phase A (Aqueous Phase): Transfer calculated amount of purified water into a suitable container fitted with a mechanical stirrer and add boric acid to dissolve under stirring conditions. Add Sildenafil citrate under stirring conditions and continue mixing. During mixing process, maintained the temperature between 65oC-70°C to assist in dissolving Sildenafil citrate and maintained the temperature till added to High Pressure Vacuum Homogenizer where Vaginal cream manufacturing takes place.

[0070] Preparation of Phase B (Aqueous Phase): Transfer calculated amount of purified water into jacketed tank of Homogenizer and set the speed of mixer to 100 rpm and set the temperature to 65°C-70°C. Add L arginine or L arginine HCI, Octyldodecanol, Polysorbate 60, Sorbitan Sesquioleate, Sorbitan Monooleate and sodium phosphate monobasic. Finally Add Chlorobutanol as antimicrobial or Preservative and mix well and maintained temperature.

[0071] Mixing of Phase A and B: Mix both Phase A and B in a mixing tank where cream formation takes place and maintain the temperature between 65-70°C.

[0072] Preparation of Phase C (Oil Phase): Transfer calculated amount of Cetyl Ester wax, Ceto Stearyl Alcohol into a separate suitable container equipped with mixer and heat the container to 65°C-70°C to assist in melting of Oil phase components and mix well to achieve a homogenous mixture and maintained temperature between 65°C-70°C to keep in molten condition till it is added to aqueous phase in High Pressure Vacuum Homogenizer. Add Butylated Hydroxytoluene as Antioxidant to prevent oxidation of Oil phase components.

[0073] Oxytocin Solution: Transfer a calculated amount of purified water into a suitable container and add Oxytocin under stirring conditions and continue mixing till a clear solution is formed. Maintain the solution at controlled room temperature until use.

[0074] Homogenization: Start the homogenizer after setting mixer speed to 2500-2800 rpm and start adding slowly Phase C (Oil Phase) to the mixture of Phase A & B and homogenize to achieve the cream base. Allow the cream base to cool down to a temperature range between 10-15°C using suitable chilling mechanism or running chilled water through the jacket of the mixing tank. Once the temperature has reached the recommended range, add the Oxytocin solution under stirring conditions and apply vacuum if necessary to remove any air bubbles from the cream base. Finally, check the pH of cream base whether it is between the range of 3.5-4.5 and if not then adjust to 3.5-4.5 using either Boric acid or Lactic acid. Allow the cream to cool to room temperature.Example 2. Stability Testing

[0075] Exemplary batches of creams according to the invention created using the procedure outlined in Example 1 were stored at various temperature and humidity levels to determine stability. Batches were prepared without L-arginine (Table 4) and with L-arginine (Table 5).Table 4. Stability of batch prepared without L-arginineTable 5. Batch prepared with using of L-arginine (B.N.: SAOR-2.5,0.25, 100-2402-023)Example 3.

[0076] Two examples of compounded sildenafil , oxytocin, l-arginine were obtained from a pharmacy and stored for two weeks at 25°C / 60% RH for comparison to formulations according to the instant invention. The results are tabulated in Table 6. As expected the formulations according to the invention were more stable for 3 months than the compounded formulations were at two weeks.Table 6. Comparative stability data of Vaginal cream of Oxytocin and Sildenafil citrate with L- arginine compounded by a pharmacy

Claims

What is claimed is:

1. A stabilized topical vaginal composition comprising oxytocin, sildenafil citrate, boric acid, chlorobutanol, and butylated hydroxy toluene.

2. A composition according to claim 1 further comprising L arginine or L arginine HCI,3. A composition according to claim 1 or 2 further comprising an emollient, a spreading agent, an emulsifier, a stabilizer a thickener a pH adjuster, an antimicrobial agent, a preservative, a buffering agent; an antioxidant; and a base.

4. A composition according to claim 3 comprising octyldodecanol, sorbitan monooleate and sorbitan sesquioleate, cetyl ester wax, cetyl stearyl alcohol, sodium phosphate monobasic, polysorbate 60, and purified water.

5. A composition according to claim 4 in a cream dosage form.

6. A composition according to claim 5 wherein the oxytocin is in the amount of 1 to 400 USP units / g.

7. A composition according to claim 6 wherein the sildenafil citrate is in the amount of amount of 10 to 100 mg / g.

8. A composition according to claim 7 wherein the octyldodecanol is present in the amount of 10-15% w / w; the sorbitan monooleate is present in the amount of 1-2.0% w / w; sorbitan sesquioleate is present in the amount of 2-3.5% w / w; the cetyl ester wax is present in the amount of 2-3% w / w; the cetyl stearyl alcohol is present in the amount of 10-15% w / w; boric acid is present in the amount of 0.5-1.0% w / w; the chlorobutanol is present in the amount of 0.05-0.1% w / w; the sodium phosphate monobasic is present in the amount of 0.2-0.5% w / w; the I arginine or I arginine HCL is present in the amount of 0.2-0.5% w / w; the polysorbate 60 is present in the amount of 1.0-2.0% w / w; and the butylated hydroxy toluene is present in the amount of 0.1% w / w.

9. A composition according to claim 8 wherein the sildenafil citrate is present in the amount of 25 mg, 50 mg or 100 mg and the oxytocin is present in the amount of 40 lll / g 100 lll / g 200 lU / g or 400 lU / g.

10. A composition according to claim 9 wherein the sildenafil citrate is degraded less than 2% and the oxytocin less than 5% after 3 months at 30°C and 65% relative humidity when no L arginine or L arginine HCI is present.

11. A composition according to claim 9 wherein the sildenafil citrate is degraded less than 2% and the oxytocin less than 10% after 3 months at 30°C and 65% relative humidity when L arginine or L arginine HCI is present.

12. A composition according to claim 9 that is stable at room temperature for at least three months.

13. A method of treating vaginal atrophy comprising administering a composition according to claim 12.

14. A method according to claim 13 wherein the treatment enhances vaginal mucosal repair and regeneration.

15. A method according to claim 13 wherein the treatment Improves blood circulation to the vaginal area.

16. A method according to claim 13 wherein the treatment supports hormonal balance in the vaginal tissues.

17. A method according to claim 13 wherein the treatment maintains the optimal vaginal pH for microbial health.

18. A method according to claim 13 wherein the treatment promotes vaginal tissue healing; enhancing vaginal elasticity and lubrication; and reduces the symptoms of vaginal dryness, irritation, and discomfort.

19. A composition according to claim 12 that has a stable pH within the range of 3.8 to 4.5.

20. A composition of claim 12 wherein the ratio between sorbitan sesquioleate, sorbitan monooleate, and polysorbate 60 is about 2:1 :1.

21. A method of treating vaginal dryness, irritation, or hormonal imbalance in a subject comprising administering a therapeutically effective amount of the composition of claim 12 to the vaginal area of the subject.

22. A method of preparing the vaginal cream composition of claim 1 comprising: a) dispersing boric acid in purified water to form a first aqueous phase; b) adding sildenafil citrate to the first aqueous phase; c) homogenizing the first aqueous phase at high speed to mill down active ingredients and promote to dissolution until the first aqueous phase is clear; d) dissolving octyldodecanol, chlorobutanol hemihydrate, sorbitan sesquioleate, sodium phosphate monobasic, l-arginine and polysorbate 60 in purified water to form a second aqueous phase; e) combining the two aqueous phases in a vessel fitted with a high-speed mixer and a vacuum pump to form a final aqueous phase; f) mixing the final aqueous phase at 3500-3800 rpm while maintaining the temperature between 65-70°C; g) combining butylated hydroxytoluene, cetyl ester wax and cetyl stearyl alcohol to form an oil phase; h) dissolving oxytocin in purified water while maintaining the temperature at room temperature to form an oxytocin solution; i) combining the oil phase with the final aqueous phase while stirring at 3500-3800 rpm and applying vacuum until a smooth homogenous cream is formed; j) cool ling the cream to 10-15°C; k) adding the oxytocin solution to the cream while mixing to achieve a homogenous and uniform, smooth cream; and l) cooling the emulsion to room temperature while mixing to obtain the final cream composition.

23. A method according to any one of claims 13 or 21 wherein the composition is administered twice daily in a therapeutically effective amount consisting of 10 USP units of oxytocin and sildenafil citrate equivalent to sildenafil base 20 mg / g per application, with a dose of 0.5 g / application.

24. A method according to any one of claims 13 or 21 wherein the composition is administered twice daily in a therapeutically effective amount consisting of 40 USP units of oxytocin and sildenafil citrate equivalent to sildenafil base 20 mg / g per application, with a dose of 0.5 g / application.

25. A method according to any one of claims 13 or 21 wherein the composition is administered twice daily in a therapeutically effective amount consisting of 100 USP units of oxytocin and sildenafil citrate equivalent to sildenafil base 20 mg / g per application, with a dose of 0.5 g / application.

26. A method according to any one of claims 13 or 21 wherein the composition is administered twice daily in a therapeutically effective amount consisting of 200 USP units of oxytocin and sildenafil citrate equivalent to sildenafil base 20 mg / g per application, with a dose of 0.5 g / application.

27. A method according to any one of claims 13 or 21 wherein the composition is administered twice daily in a therapeutically effective amount consisting of 300 USP units of oxytocin and sildenafil citrate equivalent to sildenafil base 20 mg / g per application, with a dose of 0.5 g / application.

28. A method according to any one of claims 13 or 21 wherein the composition is administered twice daily in a therapeutically effective amount consisting of 400 USP units of oxytocin and sildenafil citrate equivalent to sildenafil base 20 mg / g per application, with a dose of 0.5 g / application.

29. A vaginal cream composition comprising: a) a therapeutically effective amount of synthetic oxytocin; b) a therapeutically effective amount of sildenafil citrate; andc) a pharmaceutically acceptable cream base comprising at least one emollient, emulsifier, stabilizer, pH adjuster, preservative, buffering agent, antioxidant and aqueous phase.

30. A composition of any one of claims 1 to 12 further comprising hyaluronic acid, vitamin E, aloe vera, or panthenol.

31. A composition of any one of claims 1to 12, wherein the concentration of oxytocin ranges from 0.01% to 0.08% w / w and the concentration of sildenafil citrate ranges from 0.25% to 1 % w / w.

32. A composition according to any of claims 1 to 12 wherein the total amount of impurities created by degradation at 25 °C and 60% relative humidity after 3 months is less than 0.1% for sildenafil and 1.0% for oxytocin.

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