Topical compositions and methods for treating atrophic vaginitis

Abstract

A composition for treating astrophic vaginitis including a cream base including sildenafil citrate and oxytocin. The composition of claim 1, wherein the 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 IU / dose to 400 IU / dose. In another aspect, the composition further includes a buffering agent. In a further aspect, the buffering agent is L-arginine. In a further aspect, the buffering agent is sodium phosphate monobasic.

Description

TOPICAL COMPOSITIONS AND METHODS FOR TREATING ATROPHIC VAGINITISFIELD

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

[0002] Atrophic vaginitis is inflammation of the vagina as a result of tissue thinning due to insufficient Sildenafil citrate and Oxytocin and is a common condition in menopausal women. Atrophic vaginitis can lead to dyspareunia in women. Prior art formulations, particularly if they include synthetic hormones, for treating atrophic vaginitis increase the risk of adverse side effects for the patient. A composition to treat atrophic vaginitis that minimizes adverse side effects is desired.SUMMARY

[0003] In one aspect, the present disclosure relates to a composition for treating astrophic vaginitis including a cream base including sildenafil citrate and oxytocin. The composition of claim 1 , wherein the 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 L- arginine. In a further aspect, the buffering agent is sodium phosphate monobasic.

[0004] 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)CO2H, 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.

[0005] 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 L-arginine USP having the formula H2NC(=NH)NH(CH2)3CH(NH2)CO2H in theamount of 60 mg, sildenafil citrate USP having the formula C22H30N6O4S CeHsO? in the amount of 10mg, oxytocin API raw USP having the formula C43H66N12O12S2 in the amount of 40 IU, hyaluronic acid having the formula (Ci4H2iNOn)nin an amount of 2 mg / dose at a concentration of 0.2%-0.5%, a stabilizer in the amount of 1.5 mg, and a cream base in the amount of 726 mg. In one aspect, the stabilizer is boron citrate and / or chlorobutanol. In another aspect, the stabilizer is a suitable stabilizer that can keep oxytocin stable.

[0006] In one aspect, a base cream useful in compositions of the present disclosure, can be an anhydrous vaginal base. In one aspect, the anhydrous vaginal base can be the anhydrous vaginal base marketed under the trademark ELLAGE™. In another aspect, a base cream useful in compositions of the present disclosure can include dimethicone, chlorocresol, chlorobutanol, 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 hydroxy toluene, mineral oil, polysorbate 80, disodium EDTA, methylchloroisothaizoline, methylisothiazoline, chlorobutanol, Tocobiol and rosemary extract, and purified water.

[0007] 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.

[0008] 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.

[0009] In another aspect, the present disclosure relates to a method of treating atrophic vaginitis including topically applying 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, thelocation 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).BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Embodiments of the present invention will be described with reference to the accompanying drawings, wherein like reference numerals denote like parts, and in which:

[0011] Figure 1 is a process flowchart of a process for the manufacture of compositions according to embodiments of the present invention.DESCRIPTION

[0012] 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.

[0013] The description is not intended to be construed in a limiting sense. Thus, various modifications of the illustrative embodiments, as well as other 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.

[0014] In one embodiment, the present invention relates to a composition for treating atrophic vaginitis including L-arginine USP having the formula H2NC(=NH)NH(CH2)3CH(NH2)CO2H, 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 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.

[0015] 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 L-arginine USP having the formula H2NC(=NH)NH(CH2)3CH(NH2)CO2H in the amount of 60 mg, sildenafil citrate USP having the formula C22H30N6O4S CeHsO? in the amount of 10 mg, oxytocin API raw USP having the formulaC43H66N12O12S2 in the amount of 40 III, hyaluronic acid having the formula (Ci4H2iNOn)nin 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 in the amount of 726 mg.

[0016] In another embodiment, compositions of the present invention can be formulated by taking a base cream useful for embodiments of the present invention and blending non-cream ingredients disclosed herein into the cream. In one embodiment, 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.

[0017] In other embodiments, compositions of the present invention are formulated by including functional excipients selected from the group consisting of cetostearyl alcohol, Octyldodecanol, Cetyl Ester, Polysorbate 60 and Sorbitan Monostearate the cream base. In other embodiments, in order to achieve desired physico-chemical properties, various components selected from the group consisting of buffering agents, pH adjuster, antioxidant and stabilizer are added to the composition.

[0018] Cream bases according to embodiments of the present invention were characterized by performing various studies including homogeneity, colour, odour, and feel to touch. The chemical properties of a cream base govern how a cream acts as a drug delivery system to deliver a therapeutic dose to a patient to achieve desired therapeutic effectiveness. Chemical properties which affect the stability of a cream composition and its use as a drug delivery system include pH and buffering capacity, osmolality, firmness and adhesiveness, bioadhesion, and viscosity. For cream bases according to embodiments of the present invention, the amount or level of various components in the composition were set according to the chemical properties achieved after testing.

[0019] The buffer capacity of vaginal creams plays a crucial role in maintaining the pH balance of the vaginal environment. Without being bound by theory, this can be achieved through the following:

[0020] 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 environment.

[0021] 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.

[0022] 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 (such as Gardnerella vaginalis), which can lead to infections like bacterial vaginosis or yeast infections.

[0023] Comfort and Symptom Relief: Vaginal creams with appropriate buffer capacity can also provide relief from symptoms such as itching, burning, or irritation, which may occur due to pH imbalances.

[0024] 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.

[0025] Certain embodiments of the present composition include buffering agents composed of L-arginine and monobasic sodium phosphate. The presence and level of the buffering agent maintains the desired buffering capacity of vaginal cream compositions according to embodiments of the present invention to achieve a well balanced in composition. Levels of the buffering agent is balanced and pH adjusted with another pH adjusting component such as boric acid which is an acidifier as well as having antifungal properties.

[0026] In certain embodiments, compositions of the present invention are made by blending one or more non-cream ingredients disclosed herein into a cream base. In one embodiment, 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 oneembodiment, the composition is maintained at a preferred pH of 3.5 by the inclusion of citric acid, boric acid, or boron citrate.

[0027] In another embodiment, compositions according to embodiments of 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.

[0028] 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).

[0029] 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.

[0030] In some embodiments, the composition of the present invention further includes 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 / ordosage 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.

[0031] 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 semisolid 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.

[0032] 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, forexample 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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 presentinvention. 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).

[0037] The pH of compositions 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.

[0038] 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.

[0039] 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, 20thed. (2000).

[0040] 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 vaginal ointment, 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)). Insome 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.

[0041] The amount of active agent or agents in a dosage form 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 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.

[0042] Various amounts of Sildenafil citrate and Oxytocin in compositions of the present invention can be present in a dosage form. In some embodiments, compositions of the present invention are in a dosage form, wherein the dosage form is in the range of 25 mg / dose to 100 mg / dose of Sildenafil citrate, and 40 1 ll / dose to 400 1 ll / 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. In some embodiments, the composition of the present invention is in a dosage form, wherein the dosage form is 25 mg / dose of Sildenafil citrate and 40 lll / dose of Oxytocin.

[0043] Compositions for treating atrophic vaginitis according to certain embodiments of the present invention include the ingredients as set out in Table 1.Table 1Formulary 1 :Formulary 2:Formulary 3:Formulary 4:Formulary 5:Formular 6:Formulary 7:Formulary 8:Formulary 9:Formulary 10:Formulary 11:Formulary 12:Stability study of Representative Prototype:Manufacturing process of Vaginal cream

[0044] A process flowchart of a process according to one embodiment for the manufacture of the formulations of Table 1 is presented in Figure 1.

[0045] Preparation of Phase A (Aqueous Phase): Transfer calculated amount of purified water in a suitable container fitted with mechanical stirrer and add boric acid to dissolve under stirring conditions and the dispersed Sildenafil citrate under stirring conditions and continue mixing till ready to add to next phase.

[0046] Preparation of Phase B (Aqueous Phase): Transfer calculated amount of purified water in a suitable container fitted with mechanical stirrer and heat water to 65°C and add L arginine and mix to dissolve under stirring conditions and continue mixing till ready to add to next phase.

[0047] Preparation of Phase C (Oil Phase): Transfer calculated amount of Cetyl Ester (Crodamal SS) Ceto Stearyl Alcohol, Octyldodecanol (Kollicream OD), Polysorbate 60, Sorbitan Monostearate 60, Monobasic Sodium Phosphate and mix well in a jacketed tank of Homogenizer and heat to 65oC to melt and mix well. Add Hydroxytoluene and Chlorobutanol as Antioxidant and preservative and mix till earlier phase added.

[0048] Water Phase: Transfer calculated amount of purified water in a suitable container and heated to 65oC temperature and maintain temperature till it is used.

[0049] Homogenization: Start homogenizer after setting predetermined operating conditions and add phase A, B and Water phase and homogenized to cream base and add Oxytocin and finally check pH and adjust in case needed to 3.5 and allow the material to cool to room temperature and send sample for QC analysis.

[0050] In certain embodiments, compositions of Table 1 are in the dosage forms set out in Table 2.Table 2

Claims

What is claimed is:

1. A composition for topical application to a human patient comprising: a semi-solid preparation comprising sildenafil citrate and oxytocin.

2. The composition of claim 1 , wherein the semi-solid preparation is selected from the group consisting of a cream, a gel, an ointment and an emulsion.

3. The composition of claim 1 , wherein the semi-solid preparation is selected from the group consisting a hydrocarbon base, an oleaginous base, an absorption base, a water-removable base and a water-soluble base.

4. The composition of any one of claims 1 to 3, wherein the 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 lll / dose to 400 lll / dose.

5. The composition of any one of claims 1 to 4, further comprising a buffering agent.

6. The composition of claim 5, wherein the buffering agent is L-arginine.

7. The composition of claim 6, further comprising hyaluronic acid.

8. The composition of claim 7, further comprising boric acid.

9. The composition of claim 8, further comprising chlorobutanol.

10. The composition of claim 5, wherein the buffering agent is sodium phosphate monobasic.

11. The composition of claim 6, wherein L arginine is present in the amount of 2.5mg / g and monobasic sodium phosphate is present in the amount of 0.47 mg / g.

12. The composition of any one of claims 1 to 3, further comprising L-arginine and sodium phosphate monobasic.

13. The composition of claim 5, wherein the buffering agent is selected from the group consisting of Tris buffers (Tris EDTA (TE), Tris acetate (TAE), Tris phosphate (TPE), Tris glycine), a phosphate buffer, a bicarbonate buffer, an acetate buffer, an ammonium buffer, a citrate buffer, a zwitterionic buffer, and combinations thereof.

14. The composition of any one of claims 1 to 4, further comprising chlorobutanol.

15. The composition of any one of claims 1 to 4, further comprising cetostearyl alcohol, octyldodecanol, boric acid, cetyl ester, polysorbate 60, sorbitan monostearate, sodium phosphate monobasic, hyaluronic acid, chlorobutanol hemihydrate, butylated hydroxytoluene and water.

16. The composition of any one of claims 1 to 15, wherein the composition is at a pH of 3.5 to 4.5.

17. The composition of any one of claims 1 to 15, wherein the semi-solid preparation is of a consistency suitable for topical application on a human patient.

18. A method of treating atrophic vaginitis comprising topically applying the composition according to any one of claims 1 to 17 to a human patient in need thereof.

19. The method of claim 18, wherein the topical application is to the area around the entrance to the patient's vagina.

20. The method of claim 18, wherein the topical application is to an area selected from the group consisting of the clitoris, the anterior vaginal wall and the Grafenberg spot of the patient.

21. Use of the composition of any one of claims 1 to 17 for treating atrophic vaginitis.

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