FEMALES

AND TREATMENT METHODS THEREWITH

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.

62/255,059, filed November 13, 2015 and U.S. Provisional Application No. 62/169, 105, filed June 1, 2015, both of which are incorporated herein by reference in their entirety.

FIELD

[0002] This application relates to compositions for treatment of atrophic vaginitis, peri- and post-menopausal dyspareunia, and/or oopherectomized females prior to menopause, in particular compositions administered into the vagina that contain a selective estrogen receptor modulator, an intracellular carrier, and a cellular anti-inflammatory agent, and treatment methods using the same.

BACKGROUND

[0003] Atrophic vaginitis, peri- and post-menopausal dyspareunia, and/or

oopherectomized females prior to menopause can occur in women with the progression of aging or sometimes as a result of medical treatments, such as some cancer treatments. The symptoms related with both of these conditions include pain, itching, vaginal dryness, vaginal bleeding or mild spotting, and urogenital infections. Relief from these symptoms and a return to pleasant, non-painful intercourse are needed for these women.

[0004] Treatments using estrogen may be suitable for some women, but are not suitable for women who are at risk of breast, uterine, endometrial, ovarian, or fallopian tube cancer or have had such cancer(s). Accordingly, there is a need for an effective treatment of atrophic vaginitis and/or peri- and post-menopausal dyspareunia that is free of estrogen. SUMMARY

[0005] In one aspect, compositions for topical administration in a urogenital area and/or a vagina are disclosed herein, in particular compositions that are substantially free of estrogen. Such compositions provide a much needed alternative treatment for women who, for medical reasons, should not receive estrogen. The compositions have a therapeutically effective amount of a selective estrogen receptor modulator (SERM), an intracellular carrier for carrying the SERM into a cell, and a therapeutically effective amount of a cellular anti-inflammatory agent. The SERM is one or more of droloxifene, idoxifene, raloxifene, tamoxifen, toremifene, and TAT-59. In one embodiment, the SERM includes at least raloxifene, and is present as about 0.038 mg/ml to about 1.9 mg/ml of the

composition.

[0006] The intracellular carrier is a natural oil selected from the group consisting of almond oil, avocado oil, coconut oil, corn oil, flaxseed oil, mustard oil, olive oil, peanut oil, rice bran oil, soybean oil, walnut oil, and combinations thereof. In another embodiment, the intracellular carrier includes avocado oil, coconut oil, and/or olive oil. The intracellular carrier is present in the composition as about 15% by volume to about 54% by volume of the liquid ingredients.

[0007] The cellular anti-inflammatory agent is preferably a medicinal grade honey, for example Manuka honey or a honey from plants of the Leptospermum species. It is believed that the methylglyoxal content of honey made from plants of the Leptospermum species improves the antibacterial and immunostimulatory properties thereof. The medicinal grade honey is present in the composition as about 30% by volume to about 62% by volume of the total liquid ingredients.

[0008] The compositions may include a solute that dissolved the SERM. In another embodiment, the compositions may include a thickening agent, and/or one or more tocopherol and/or tocotrienols that have Vitamin E activity.

[0009] In another aspect, methods for treating atrophic vaginitis, peri- and postmenopausal dyspareunia, and/or oopherectomized females prior to menopause are disclosed herein. The method includes providing one of the compositions disclosed herein and topically applying about 2 ml to about 8 ml of the composition to the urogenital area and/or into the vagina daily, every other day, or at least once weekly. Topically applying the composition is performed just prior to a user lying down for at least four hours.

[0010] In another aspect, compositions for topical administration in a urogenital area and/or a vagina for treatment of atrophic vaginitis, peri- and post-menopausal dyspareunia, and/or oopherectomized females prior to menopause that are free of estrogen and free of a selective estrogen receptor modulator are also disclosed. The compositions include a therapeutically effective amount of a medicinal grade honey, a therapeutically effective amount of a natural oil, and are free of estrogen and free of a selective estrogen receptor modulator (SERM). The natural oil may be one or more of almond oil, avocado oil, coconut oil, corn oil, flaxseed oil, mustard oil, olive oil, peanut oil, rice bran oil, soybean oil, walnut oil, or other natural oils. The natural oil is preferably about 15% by volume to about 54% by volume of the composition. In one embodiment, the natural oil is avocado oil, coconut oil, and/or olive oil. In another embodiment, the natural oil is a 1 : 1 mixture of avocado oil and coconut oil. The medicinal grade honey includes Manuka honey, and is typically about 30% by volume to about 62% by volume of the composition. The composition may include one or more of a thickening agent, and/or one or more tocopherol and/or tocotrienols that have Vitamin E activity.

[0011] The features, functions, and advantages that have been discussed can be achieved independently in various embodiments or may be combined in yet other embodiments, further details of which can be seen with reference to the following description.

DESCRIPTION

[0012] Compositions for administration in the vagina are disclosed herein that include a therapeutically effective amount of a selective estrogen receptor modulator (SERM); an intracellular carrier for carrying the SERM into a cell; and a therapeutically effective amount of a cellular anti-inflammatory agent. Since the compositions use a SERM as the therapeutic agent, these compositions can be free of estrogen. As used herein, "free of estrogen" means that the composition includes no estrogen or less than 0.001 mg/ml by weight of an estrogen, more preferably less than 0.0001 mg/ml of an estrogen.

[0013] SERM [0014] The SERM may be one or more of droloxifene, idoxifene, raloxifene, tamoxifen, toremifene, TAT-59 ((E)-4-[l-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4-isopropy l) phenyl- l-butenyl]phenyl monophosphate), or derivatives thereof that retain the properties of a selective estrogen receptor modulator. In one embodiment, the SERM is at least raloxifene. In another embodiment, the SERM is only raloxifene. The SERM in total comprises about 0.038 mg/ml of the composition to about 1.9 mg/ml of the composition. In one embodiment, the SERM in total comprises about 0.15 mg/ml of the composition to about 1 mg/ml of the composition. In a preferred embodiment, the SERM in total comprises about 0.3 mg/ml of the composition to about 0.7 mg/ml of the composition.

[0015] The SERM may be dissolved in a solute. The solute may be glycerin, propylene glycol, butylene glycol, hexylene glycol or polyethylene glycol of various molecular weight and the like and/or combinations thereof.

[0016] Intracellular Carrier

[0017] The intracellular carrier is a natural oil selected from the group consisting of almond oil, avocado oil, coconut oil, corn oil, flaxseed oil, mustard oil, olive oil, palm oil, palm kernel oil, peanut oil, rice bran oil, soybean oil, theobroma oil, walnut oil, and combinations thereof. In one embodiment, the intracellular carrier included in the composition has one or more of avocado oil, coconut oil, and olive oil.

[0018] The intracellular carrier may be present in the composition, based liquid ingredients, i.e., all ingredients except for the SERM, as about 15% by volume to about 54%) by volume of the liquid ingredients. In another embodiment, the intracellular carrier may be present as about 23%> by volume to about 38%> by volume of the liquid ingredients. One example composition comprises equal amounts of avocado oil and coconut oil.

[0019] Cellular Anti-inflammatory Agent

[0020] The cellular anti-inflammatory agent is one that reduces inflammation resulting from a cytokine response, specifically a cytokine response from the release of cytokines from monocytes and macrophages. In one embodiment, the cellular anti-inflammatory agent includes a medicinal grade honey, such as a medicinal grade Manuka honey. The medicinal grade honey may be present as about 30%> by volume to about 62%> by volume of the total liquid ingredients. In another embodiment, the medicinal grade honey may be present as about 38% by volume to about 50% by volume of the total liquid ingredients.

[0021] Tocopherols and Tocotrienols

[0022] Tocopherols and/or tocotrienols having Vitamin E activity include, but are not limited to, alpha tocopherol, D alpha tocopherol, DL alpha tocopherol, or tocopheryl acetate, alpha, beta, gamma, and delta tocotrienols. The tocopherols and/or tocotrienols may be present as about 1% by volume to about 15% by volume of the total liquid ingredients. In another embodiment, the tocopherols and/or tocotrienols may be present as about 4% by volume to about 8% by volume of the total liquid ingredients.

[0023] Thickening Agent

[0024] Optionally, the vaginal compositions may include an effective amount of a thickening agent. The thickening agent may be any one or more of the following: pectin, algin, gum arabic, propylene glycol, methyl cellulose, and carnauba wax. The effective amount is determined based on a desired viscosity that makes the vaginal composition spreadable within the vagina without creating a vaginal discharge that would be excessive and/or undesirable to the end user. The thickening agent may be present as about 1% by volume to about 15% by volume of the total liquid ingredients. In another embodiment, the thickening agent may be present as about 4% by volume to about 8% by volume of the total liquid ingredients.

[0025] Pain Reliever

[0026] Optionally, the vaginal compositions may include a pain reliever as about 1% to about 7%) by weight of the composition, or more preferably about 1% to about 4% by weight of the composition. The pain reliever may be benzocaine, which may be provided as a powder. The benzocaine may be added to the raloxifene Phase B mixture, as explained in the Examples, and then incorporated into Phase A.

[0027] pH Adjuster

[0028] The vaginal compositions may also include a pH adjuster, in particular a pharmaceutically acceptable pH adjuster. The pH adjuster may be an acid, base, or buffer. In one embodiment, the pH adjuster is an acid, such as a weak acid. The weak acid may be but is not limited to, lactic acid, citric acid, ascorbic acid, and the like and combinations thereof. The acid is added to adjust the pH of the composition to within a range of about 4.5 to about 6. In one embodiment, aloe vera juice was added to correct the pH to within the range of about 4.5 to about 6. In another embodiment, additional tocopherols and/or tocotrienols and/or medicinal grade honey were added to adjust the pH.

[0029] Additives

[0030] The vaginal compositions may also include other additives or inactive ingredients, such as, but not limited to, purified, sterile water, fillers, preservatives, absorption enhancers, colorants, and emulsifiers. The fillers may include, but are not limited to, titanium dioxide, anhydrous lactose, lactose monohydrate, and magnesium stearate, and combinations thereof. The preservatives may include, but are not limited to,

methylparaben, propylparaben, potassium sorbate, benzalkonium chloride, and

benzethonium chloride, of which one or more may be present in the vaginal suppository compositions. The absorption enhancers include, but are not limited to crospovidone. The colorants include, but are not limited to, FD&C Blue #3 (alum lake). The emulsifiers include, but are not limited to, povidone, and polysorbate 80.

[0031] The compositions for administration in the vagina disclosed herein are effective at soothing and reducing symptoms of atrophic vaginitis. In the compositions, the cellular anit-inflammatory agent, such as medicinal grade honey, is a non-irritant to menopausal or atrophic urogenital cells, and decreases the cellular inflammation inherent to atrophic cells so that these cells can begin to heal. Once the atrophic urogenital cells have decreased inflammation, it is possible for the intracellular carrier to facilitate passage of the SERM into the urogenital cells at an intracellular level. The SERMs are typically lipophilic and the intracellular carrier is preferably a natural oil, which increases the bioavailability of the SERM, so that the SERM can intracellularly bind with estrogen receptor sites, in particular estrogen response DNA elements (ERE _S ). Moreover, the solvent selected and Vitamin E synergistically help the intracellular carrier transport the SERM by decreasing cellular and tissue inflammation and increase the bioavailability of the SERM as it is delivered to urogenital tissue. [0032] The compositions may also include a minimal amount of lemon oil or peppermint oil. The compositions as used in the working examples below have 130 ml of liquid ingredients. The lemon oil and/or peppermint oil may be added thereto, in total, in an amount of 2-6 drops, which is about 0.1 ml to about 0.3 ml.

[0033] In operation, the composition reverses much of the urogenital atrophy of the urogenital cells so that dryness and inflammation are reduced and homeostasis and integrity return to the urogenital tissue. This allows women using the composition, as directed, to return to pleasant and non-painful intercourse, as supported by the Study included herein as Example 3. The composition also relieves vaginal pain associated with atrophic vaginitis, as well as decreases itching, vaginal dryness, vaginal bleeding and mild spotting, and the occurrence of urogenital infections.

[0034] In another aspect, compositions for topical administration in a urogenital area and/or a vagina for treatment of atrophic vaginitis, peri- and post-menopausal dyspareunia, and/or oopherectomized females prior to menopause that are free of estrogen and free of a selective estrogen receptor modulator are also disclosed. In other words, a sexual lubricant composition is disclosed that has similar compositions to those disclosed above, but without the SERM and without estrogen (i.e., they are estrogen free). The sexual lubricant composition is useful for vaginal or anal sex. Vaginal application of the sexual lubricant composition has shown some of the same beneficial effects on atrophic vaginitis, peri- and post-menopausal dyspareunia, and/or oopherectomized females prior to menopause as the compositions disclosed above.

[0035] The sexual lubricant composition may comprise any of the substances discussed above, including the additives. In its simplest form, the composition has a therapeutically effective amount of a medicinal grade honey, a therapeutically effective amount of a natural oil, and is free of estrogen and free of selective estrogen receptor modulators. The natural oil may be one or more of almond oil, avocado oil, coconut oil, corn oil, flaxseed oil, mustard oil, olive oil, peanut oil, rice bran oil, soybean oil, walnut oil, or other natural oils. The natural oil is preferably about 15% by volume to about 54% by volume of the composition. In one embodiment, the natural oil is avocado oil, coconut oil, and/or olive oil. In another embodiment, the natural oil is a 1 : 1 mixture of avocado oil and coconut oil. The medicinal grade honey includes Manuka honey, and is typically about 30% by volume to about 62% by volume of the composition. The composition may include one or more of the thickening agents, one or more tocopherol and/or tocotrienols that have Vitamin E activity, one or more pain relievers, one or more pH adjusters, and one or more additives discussed above.

[0036] The sexual lubricant comprises ingredients that will not deteriorate the material of a condom, including non-latex condoms.

[0037] Method of Making

[0038] The compositions for topical vaginal application may be made by warming and mixing the intracellular carrier, the cellular anti-inflammatory agent, and the tocopherols and/or tocotrienols. In one embodiment, the warming of the components may be performed using a double boiler. This may be within a temperature range about 95°F (35°C) to about 120°F (49°C). This portion of the composition is referred to as Phase A. Phase B of the composition includes the primary active agent, the SERM, in powder form dissolved in a solvent. The method may include grinding the primary active agent into a powder before dissolving in the solvent.

[0039] Next, the warmed ingredients of Phase A are mixed with the dissolved primary active agent of Phase B to form the composition. In one embodiment, the composition is an emulsion, which may have a cream consistency for topical application of the

composition. In another embodiment, the composition may be in the form of a suppository or a softgel encapsulating the composition. The softgel may be a gelatin based shell filled with the composition using encapsulation processes known in the art. The softgel shell may be a combination of gelatin, water, and a plasticizer such as glycerin and/or sorbitol(s) or other polymer such as starch and carrageenan rather than gelatin.

[0040] A thickening agent, if present, may be added to Phase B of the composition before mixing with Phase A, or may be added to the composition after Phase A and Phase B are mixed together. If needed, the pH of the composition may be adjusted by adding a pH adjuster thereto with mixing. The pH of the composition is preferably in a range of about 4.5 to about 6. Accordingly, enough pH adjuster is added to the composition to adjust the pH to be within this range. [0041] If a pain reliever is present in the composition, it is preferably added into the solvent in Phase A before Phase A is mixed with Phase B. Other additives may be added to either Phase A or Phase B as appropriate or even to the composition after Phase A and Phase B are mixed together.

[0042] The method of making the compositions that are free of estrogen and free of SERM includes carrying out just Phase A above. If needed, the pH of the composition may be adjusted by adding a pH adjuster to Phase A with mixing. The pH of the composition is preferably in a range of about 4.5 to about 6. Accordingly, enough pH adjuster is added to the composition to adjust the pH to be within this range. If a pain reliever or other additives are present, they are also added to Phase A.

[0043] Method of Treatment

[0044] Methods for treating atrophic vaginitis include providing a composition for administration in the vagina that includes a therapeutically effective amount of a selective estrogen receptor modulator (SERM), an intracellular carrier for carrying the SERM into a cell, and a therapeutically effective amount of a cellular anti-inflammatory agent in any of the variations disclosed herein for topical application. About 2 ml to about 8 ml of the composition is topically applied to the urogenital area and/or into the vagina. The topical application may be daily, every other day, or at least once weekly. In one embodiment, the composition is topically applied as about 3 ml to about 5 ml to the urogenital area and/or into the vagina.

[0045] The topical application of the composition is preferably performed just prior to the user lying down to rest for at least about four hours. In one embodiment, the topical application of the composition is performed just prior to lying down to go to sleep, and is typically performed once daily, but is not limited thereto.

[0046] The dosage for the SERM free compositions is the same as noted above when the SERM is present.

[0047] Example 1: Vaginal Cream/Emulsion [0048] Table 1 : Formula 1

[0049] The avocado oil, the Manuka honey, and the tocopherol were warmed in a double boiler until the temperature was about 95°F (35°C) to about 120°F (49°C) to make Phase A. The 90 mg of raloxifene was ground into a powder, and thereafter dissolved in the glycerin to make Phase B. The warmed ingredients of Phase A were blended with the dissolved raloxifene of Phase B to form an emulsion having a pH of about 6. The emulsion was stored in a glass container at room temperature away from sunlight.

[0050] Example 2: Vaginal Cream/Emulsion

[0051] Table 2: Formula 2

[0052] The avocado oil, the Manuka honey, and the tocopherol were warmed in a double boiler until the temperature was about 95°F (35°C) to about 120°F (49°C) to make Phase A. The 60 mg of raloxifene was ground into a powder, and thereafter dissolved in the glycerin and propylene glycol to make Phase B. The warmed ingredients of Phase A were mixed or blended with the dissolved raloxifene of Phase B to form an emulsion having a pH of about 6. The emulsion was stored in a glass container at room temperature away from sunlight. [0053] Example 3: Study

[0054] Ten women participated in a volunteer study to compare the effectiveness of the composition of Example 2 against a representative formulation from U.S. Patent No. 5,610,167, in particular the topical composition of formulation 10, set forth below, but modified to include the same amount of raloxifene as present in the formulation of Example 2. The amount of the active ingredient was adjusted to be the same so that the difference in performance of the two formulations, in particular the carrier and other ingredients, is shown to contribute significantly to the performance of the formulations disclosed herein.

[0055] Table 3 : Prior Art: Formulation 10

*amount of active equal to the amount of active in Example 2

[0056] Five women were give formulation 10 (Group I), reproduced above, with instructions to apply 4 ml of formulation 10 onto the urogenital area and into the vagina daily generally proximate to bedtime, i.e., a period of lying down for at least four hours. The other five women were given the formulation of Example 2 (Group II) above with instructions to apply 4 ml of the emulsion into the vagina daily generally proximate to bedtime, i.e., a period of lying down for at least four hours. The study was conducted over a five-week period with weekly follow-up consultations.

[0057] Group I included women between the ages of 45 and 60, all of which are experiencing menopause or peri-menopause. The younger women were experiencing early menopause as a result of cancer treatments and/or the removal of the ovaries. Three out of the five women in Group I were told by a health care provider that they cannot use products that include estrogen and the other two expressed a fear of using hormones. All the women experienced urinary incontinence and all the women were diagnosed with atrophic vaginitis. Each woman attested to pain with intercourse, vaginal pain and/or itching, vaginal dryness, and vaginal bleeding and/or mild spotting. [0058] Table 4:

[0059] Group II included women between the ages of 34 and 70, all of which are experiencing menopause or peri-menopause. The younger women were experiencing menopause as a result of cancer treatments and/or the removal of the ovaries. Four out of the five women in Group II were told by a health care provider that they cannot use products that include estrogen. Four out of the five women experienced urinary incontinence and all the women were diagnosed with atrophic vaginitis. Each woman attested to pain with intercourse, vaginal pain and/or itching, vaginal dryness, and vaginal bleeding and/or mild spotting. [0060] Table 5:

[0061] According to the study, the composition of Example 2, disclosed herein, was much more effective than formulation 10 from U.S. Patent No. 5,610, 167. Here, the women experienced improvement of symptoms of atrophic vaginitis (reduced symptoms) within 4-7 days and continual improvement over the five weeks. Even more important to the women and their spouses or partners was the improvement in their sex life—

penetration without pain, increased moisture, and elastic feel to the tissue. Further, some women even reported an improvement in their libido, which further enhanced their sex life. [0062] Example 4: SERM Free - Vaginal Cream/Emulsion [0063] Table 6: Formula 3

Composition A

[0064] Table 7: Formula 4

Composition B

[0065] The embodiments of this invention described in detail and by reference to specific exemplary embodiments of the prebiotic containing compositions are within the scope of the appended claims. It is contemplated that numerous other modifications and variations of the compositions may be created taking advantage of the disclosed approach. In short, it is the Applicant's intention that the scope of the patent issuing herefrom be limited only by the scope of the appended claims.