RU2703713C2 - Compositions for local application containing bimatoprost, and methods for hair growth stimulation with help thereof - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.SUBSTANCE: invention relates to the pharmaceutical industry and is a topical hair growth composition containing bimatoprost in an unbound form or in form of a pharmaceutically acceptable salt thereof, wherein bimatoprost is contained in amount of 0.3–4 % wt/wt, ethanol, propylene glycol, diethylene glycol monoethyl ether, benzyl alcohol in amount of 0.5–2 % wt/wt and at least one compound selected from a group consisting of glycerylmonooleate in amount of 1–3 % wt/wt and oleic acid in amount of 1–3 % wt/wt; wherein said composition is made for local application on skin.EFFECT: invention provides a synergetic effect consisting in a much higher efficiency of bimatoprost infection through the skin.17 cl, 35 ex, 28 tbl

Description

[0001] This application claims priority to a provisional application for US patent with serial number 61/783962, filed March 14, 2013, and this application also represents a partial continuation of the application for US patent with serial number 14/163954, filed January 24, 2014 year, which is a continuation of the US patent application with serial number 12/940711, filed November 5, 2010, which claims priority on provisional US application with serial number 61/259368, filed November 9, 2009, descriptions of which are incorporated herein by links.

FIELD OF TECHNOLOGY

[0002] This document provides compositions for topical application, as well as methods for stimulating hair growth and treating disorders leading to hair loss, wherein said compositions comprise a cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compound represented by formula I:

where the dashed bonds indicate the presence or absence of a double bond, which 20 may be in a cis or trans configuration, and A, B, Z, X, R ₁ and R ₂ are as defined herein, and the penetration enhancer. Such compositions are used in promoting the growth of human hair or non-human animals.

BACKGROUND

[0003] Dermatologists recognize many different types of hair loss, the most common of which are "alopecia" or "baldness", while people (mostly men) begin to bald in the scalp on the temples and on the crown of the head. However, hair loss can be associated with many other disorders.

[0004] Hair loss is often accompanied by a change in the hair growth cycle. The hair of all mammals goes through a life cycle that includes the anagen phase, the catagen phase and the telogen phase. The anagen phase is a period of active hair growth. In the scalp, this phase lasts from 3 to 5 years. The catagen phase is a short 1-2 week intermediate phase between the anagen phase and the telogen phase. The last phase of telogen is considered the “resting phase”, at which all growth stops. This phase is also relatively short, lasting about 3-4 months, before the hair falls out and new ones begin to grow. With the onset of baldness, an increasing part of the hair is in the telogen phase, while a correspondingly smaller part is in the anagenic phase of active growth.

[0005] In addition, there are various types of hair, including terminal hair, fluffy hair and modified terminal hair. Terminal hair is hard, pigmented, long hair, in which the bulb of the hair follicle is located deep in the dermis layer. On the other hand, vellus hair is thin, sparse, unpigmented short hair, in which the hair follicle is not deep in the dermis. Modified terminal hair is found on eyelashes and eyebrows. As alopecia progresses, a transition occurs in which the hair itself changes from a terminal type to a fluff. Accordingly, alopecia (baldness) also includes the absence of terminal hair.

[0006] One of the methods of non-drug treatment of alopecia is hair transplantation. A skin graft containing hair is transplanted from areas of the scalp on which the hair grows in an area without hairline. This approach can be quite successful, however, it is expensive, time consuming and painful. Other non-drug approaches to treating alopecia include ultraviolet radiation, massage, psychiatric treatment, and exercise therapy. However, none of these approaches has been universally recognized as effective. Even methods such as revascularization surgery or acupuncture have shown a slight effect, if any.

SUMMARY OF THE INVENTION

[0007] This document provides compositions and methods for topical application of an effective amount of at least one penetration promoting substance and a compound of cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl represented by formula I:

where the dashed bonds indicate the presence or absence of a double bond, which may be in the cis or trans configuration, A represents an alkylene or alkenylene radical having from two to six carbon atoms, wherein the radical can be interrupted by one or more oxo radicals and replaced by one or more hydroxy, oxo, alkyloxy or alkyl carboxyl groups, wherein the alkyl radical contains from one to six carbon atoms; B represents a cycloalkyl radical having from three to seven carbon atoms, or an aryl radical selected from the group consisting of hydrogen, a lower alkyl radical having from four to ten carbon atoms, wherein the heteroatom is selected from the group consisting of nitrogen atoms, oxygen and sulfur; X represents —N (R ₄ ) ₂ , wherein R _{4 is} selected from the group consisting of hydrogen, a lower alkyl radical having from one to six carbon atoms,

и

and

where R ₅ represents a lower alkyl radical having from one to six carbon atoms; Z represents = O; one of R ₁ and R ₂ represents = O, —OH or —O (CO) R ₆ group, and the other represents —OH or —O (CO) R ₆ , or R ₁ represents = O and R ₂ represents H, wherein R ₆ represents a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms, or

- (CH ₂ ) mR ₇ , where m is 0 or an integer from 1 to 10, and R ₇ is a cycloalkyl radical having from three to seven carbon atoms, or a hydrocarbylaryl or heteroaryl radical, as defined above, in free form or in the form of a pharmaceutically acceptable salt thereof, in combination with a penetration enhancer, in certain compositions adapted for topical application to the skin of mammals.

[0008] In one embodiment of the invention, the cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compound represented by formula I is a bimatoprost compound.

[0009] Another embodiment of the invention includes a composition containing bimatoprost in a concentration of about 0.001-1.5% by weight, from 0.01-1.0% by weight, from 0.02-1.0% by weight, from 0.03 to about 1.0% wt., from 0.03 to 0.9% wt., from 0.04 to 0.8% wt., 0.05-0.7% wt., 0, 06% -0.6% mass., 0.07% -0.5% mass., 0.08-0.4% mass., 0.09-0.3% mass., 0.03-5% mass., 0.3-3% mass., 1-3% mass., 0.1% mass., 0.15% mass., 0.2% mass., 0.3% mass., 0.4 % wt., 0.5% wt., 0.6% wt., 0.7% wt., 0.8% wt., 0.9% wt., 1.0% wt., 1.5% mass., 2% mass., 3% mass., 3.5% mass., 4% mass., 5% mass., 5.5% mass., 6% mass., 6.5% mass., 7 % wt., 8% of the mass., 9% of the mass. and 10% of the mass. The preferred concentration range of bimatoprost is about 2-4% wt., More preferably about 2.5-3.5% of the mass. These preferred bimatoprost concentration ranges provide a surprisingly good balance between the desired pharmacological effects of the composition and any undesirable side effects. It was previously believed that bimatoprost compositions to stimulate hair growth should have a much lower concentration of bimatoprost; but it was unexpectedly found that this is not so.

[0010] The following excipients may also be contained: carbomer in a concentration of about 0.05-1.0% by weight .; the base in a concentration of from about 0.01 to about 2.0% of the mass .; ethanol in a concentration of from about 10 to about 90% of the mass .; glycerin in a concentration of from about 1.0 to about 20% of the mass .; diethylene glycol monoethyl ether in a concentration of from about 1.0 to about 50% of the mass .; polysorbate 20 in a concentration of from about 0.1 to about 5.0% of the mass .; polysorbate 40 in a concentration of from about 0.1 to about 5.0% of the mass .; polysorbate 60 in a concentration of from about 0.1 to about 5.0% of the mass .; polysorbate 80 in a concentration of from about 0.1 to about 5.0% of the mass .; PPG-5-cetet-20 in a concentration of from about 0.1 to about 5.0% of the mass .; oleic acid in a concentration of from about 0.1 to about 5.0% of the mass .; isostearyl isostearate in a concentration of from about 0.1 to about 10% of the mass .; isopropyl myristate in a concentration of from about 0.1 to about 10% of the mass .; dipropylene glycol dimethyl ether in a concentration of from about 1 to about 50% by weight .; diethylene glycol in a concentration of from about 1 to about 50% of the mass .; dipropylene glycol in a concentration of from about 1 to about 50% of the mass .; caprylic / capric triglycerides in a concentration of from about 0.1 to about 10% of the mass .; benzyl alcohol in a concentration of from about 0.1 to about 2.0% of the mass .; silicone in a concentration of from about 0.1 to about 10% of the mass .; PEG 40 castor oil in a concentration of from about 0.1 to 20% of the mass .; PEG 35 castor oil in a concentration of from about 0.1 to 20% of the mass .; oleyl alcohol in a concentration of from about 0.1 to 10% of the mass .; glyceryl monooleate in a concentration of from about 0.1 to 10% of the mass .; and / or water in a concentration of from about 0 to about 90% of the mass.

[0011] Another embodiment of the invention includes a composition containing about 0.1% of the mass. bimatoprost; about 0.10% of the mass. carbomer; about 0.035% of the mass. NaOH; about 15.0% of the mass. ethanol; about 10.0% of the mass. diethylene glycol monoethyl ether; and about 74.8% of the mass. water.

[0012] Another embodiment of the invention includes a composition containing about 0.1% of the mass. bimatoprost; about 0.15% of the mass. carbomer; about 0.22% of the mass. triethylamine (TEA); about 15.0% of the mass. ethanol; about 10.0% of the mass. diethylene glycol monoethyl ether; about 4.0% of the mass. polysorbate 20; and about 70.5% of the mass. water.

[0013] Another embodiment of the invention includes a composition containing about 0.1% of the mass. bimatoprost; about 0.125% of the mass. carbomer; about 0.18% of the mass. TEA; about 30.0% of the mass. ethanol; about 20.0% of the mass. diethylene glycol monoethyl ether; and about 49.59% of the mass. water.

[0014] Another embodiment of the invention includes a composition containing about 0.1% of the mass. bimatoprost; about 0.10% of the mass. carbomer; about 0.15% of the mass. TEA; about 30.0% of the mass. ethanol; about 20% of the mass. propylene glycol; and about 49.7% of the mass. water.

[0015] Another embodiment of the invention includes a composition containing about 0.1% of the mass. bimatoprost; about 0.20% of the mass. carbomer; about 0.22% of the mass. TEA; about 60.0% of the mass. ethanol; about 5.0% of the mass. glycerin; and about 34.48% of the mass. water.

[0016] Another embodiment of the invention includes a composition containing about 0.1% of the mass. bimatoprost; about 0.25% of the mass. carbomer; about 0.38% of the mass. TEA; about 60.0% of the mass. ethanol; about 4.0% of the mass. polysorbate 20; and about 35.27% of the mass. water.

[0017] Another embodiment of the invention includes a composition containing about 0.1% of the mass. bimatoprost; about 0.25% of the mass. carbomer; about 0.38% of the mass. TEA; about 50.0% of the mass. ethanol; about 10% of the mass. diethylene glycol monoethyl ether; about 4.0% of the mass. polysorbate 20; and about 35.27% of the mass. water.

[0018] In some embodiments of the invention, the composition comprises water, bimatoprost in a concentration of from about 1% of the mass. up to about 4% of the mass., preferably about 2-4% of the mass. and most preferably 2.5-3.5% by weight, and one or more components selected from the group consisting of: cetostearyl alcohol in a concentration of from about 0.5% by weight. up to about 1% wt., glyceryl monooleate in a concentration of from about 1% wt. up to about 3 wt. -%, preferably about 2 wt. -%, oleyl alcohol in a concentration of from about 1% of the mass. up to about 3% wt., preferably about 2% wt., ethanol in a concentration of from about 30% wt. up to about 75% of the mass., propylene glycol in a concentration comprising from about 10% of the mass. up to about 25% of the mass., benzyl alcohol in a concentration comprising from about 0.5% of the mass. up to about 2 wt. -%, preferably about 1 wt. -%, ultrez in a concentration of about 0.15 wt.%, trolamine in a concentration of about 0.16 wt. and glycerol in a concentration of from about 0.5% of the mass. up to about 10 wt. -%, preferably 2% of the mass.

[0019] In some embodiments of the invention, the composition comprises water, bimatoprost in a concentration of about 1-5% by weight, preferably about 2-4% by weight, more preferably about 2.5-3.5% by weight, most preferably, a value of 3% by weight and one or more components selected from the group consisting of: transcutol in a concentration of from about 1% by weight. up to about 25 wt. -%, preferably about 10 wt. -%, propylene glycol in a concentration of from about 1% of the mass. up to about 25% of the mass., glycerol monooleate in a concentration of from about 1% of the mass. up to about 3 wt. -%, preferably about 2 wt. -%, oleyl alcohol in a concentration of from about 1% of the mass. up to about 3% wt., preferably about 2% wt., ethanol in a concentration of from about 30% wt. up to about 75% of the mass., propylene glycol in a concentration comprising from about 10% of the mass. up to about 25% of the mass., benzyl alcohol in a concentration comprising from about 0.5% of the mass. up to about 2 wt. -%, preferably about 1 wt. -%, ultrez carbomer in a concentration of from about 0.15 wt. up to about 0.2% of the mass., triethanolamine in a concentration of about 0.16% of the mass. and glycerol in a concentration of from about 0.5% of the mass. up to about 10 wt. -%, preferably 2% of the mass.

[0020] Some embodiments of the invention may also include one or more additional components in addition to those indicated in the previous paragraph, while this one or more components is selected from the group consisting of linoleic acid in a concentration of from about 1% of the mass . up to about 5% wt., preferably 2% wt., sodium lauryl sulfate in a concentration of from 0.1% wt. up to about 0.5% by weight, preferably 0.2% by weight, and docusate sodium in a concentration of from 0.1% by weight. up to about 0.5% of the mass., preferably 0.2% of the mass.

[0021] In some embodiments of the invention, the composition comprises water, bimatoprost in a concentration of about 1-5% by weight, preferably about 2-4% by weight, more preferably about 2.5-3.5% by weight, most preferably, a value of 3% by weight and one or more components selected from the group consisting of: transcutol in a concentration of from about 1% by weight. up to about 25 wt. -%, preferably about 10 wt. -%, propylene glycol in a concentration of from about 1% of the mass. up to about 25% of the mass., glycerol monooleate in a concentration of from about 1% of the mass. up to about 3 wt. -%, preferably about 2 wt. -%, oleic acid in a concentration of from about 1% of the mass. up to about 3% wt., preferably about 2% wt., linoleic acid in a concentration of from about 1% wt. up to about 3% wt., preferably about 2% wt., ethanol in a concentration of from about 30% wt. up to about 75% of the mass., propylene glycol in a concentration comprising from about 10% of the mass. up to about 25% of the mass., benzyl alcohol in a concentration comprising from about 0.5% of the mass. up to about 2 wt. -%, preferably about 1 wt. -%, ultrez carbomer in a concentration of from about 0.15 wt. up to about 0.2% by weight, triethanolamine in a concentration of about 0.16% by weight, glycerin in a concentration of from about 0.5% by weight. up to about 10% wt., preferably about 2% wt., terpinolene in a concentration of from about 0.5% wt. up to about 5% wt., preferably about 2% wt., limonene in a concentration of from about 0.5% wt. up to about 5% wt., preferably about 2% wt., nerol in a concentration of from about 0.5% wt. up to about 5% wt., preferably about 2% wt., cineol in a concentration of from about 0.5% wt. up to about 5% wt., preferably about 2% wt., octyl salicylate in a concentration of from about 0.5% wt. up to about 5% wt., preferably about 2% wt., DMSO in a concentration of from about 0.5% wt. up to about 5 wt. -%, preferably about 2 wt. -%, DDAB (DDAB) in a concentration of from about 0.01% of the mass. up to about 1% wt., preferably about 0.2% wt., sodium taurodeoxycholate in a concentration of from about 0.01% wt. up to about 5% wt., preferably about 2% wt., docusate sodium in a concentration of from about 0.01% wt. up to about 1% wt., preferably about 0.2% wt., Crodamol MM in a concentration of from about 1% wt. up to about 30 wt. -%, preferably about 25 wt. -%, polysorbate 80 in a concentration of from about 1% of the mass. up to about 5 wt. -%, preferably about 2 wt. -%, Dow ST-Elastomer 10 in a concentration of from about 40% of the mass. up to about 80 wt. -%, preferably about 73.5 wt. -%, Dow Silky Wax 10 in a concentration of from about 1% of the mass. up to about 20% wt., preferably about 8% wt., isopropyl myristate in a concentration of from about 1% wt. up to about 20% of the mass., preferably about 8% of the mass.

[0022] In some embodiments of the invention, the composition comprises water; bimatoprost, for example, in a concentration of from about 0.3% of the mass. up to about 5 wt. -%, preferably about 1-5% of the mass. or about 2-4% by weight, more preferably about 2.5-3.5% by weight, most preferably a value of 3% by weight .; and one or more components selected from the following: ethanol, for example, in a concentration component of from 0% of the mass. up to about 89% of the mass .; propylene glycol, for example, in a concentration of from 0% of the mass. up to about 89% of the mass .; simple diethylene glycol monoethyl ether, for example, in a concentration component of from 0% of the mass. up to about 89% of the mass .; benzyl alcohol, for example, in a concentration of from 0% of the mass. up to about 89% of the mass .; and one or more auxiliary substances in the form of fatty acids and / or esters of fatty acids, for example, in a concentration of from 0% of the mass. up to about 10% of the mass. In some embodiments of the invention, fatty acids may include one or more fatty acids with carbon numbers from 8 to 28 (C ₈ -C ₂₈ ), and may be saturated, monounsaturated or polyunsaturated. In some embodiments, a saturated fatty acid may be. stearic acid. In some embodiments, the monounsaturated fatty acid may be oleic acid. In some embodiments, the polyunsaturated fatty acid may be linoleic acid. In some embodiments, fatty acid esters may include one or more C ₈ -C ₂₈ fatty acids, and may be saturated, monounsaturated, or polyunsaturated. In some embodiments, a saturated fatty acid ester may be glyceryl monostearate. In some embodiments, the monounsaturated fatty acid ester may be glyceryl monooleate. In some embodiments, the polyunsaturated fatty acid ester may be linoleic acid ethyl ester.

[0023] A preferred composition comprises bimatoprost, oleyl alcohol, ethanol and propylene glycol. Bimatoprost is contained in an amount of about 1-5% by weight, preferably about 2-4% by weight, more preferably about 2.5-3.5% by weight, most preferably a value of 3% by weight. Oleyl alcohol is contained in an amount of about 1-10% of the mass. Ethanol is contained in an amount of about 50-80% of the mass. Propylene glycol is contained in an amount of 15-15% of the mass.

[0024] Examples of particularly preferred topical hair growth compositions include bimatoprost in free form or in the form of a pharmaceutically acceptable salt thereof, wherein bimatoprost is contained in an amount of about 0.3% by weight. up to about 4% of the mass .; at least one first compound is selected from fatty acid, fatty acid alcohol and a fatty acid ester, the composition being formulated for topical application to the skin.

[0025] In some embodiments of the invention, the first compound is a fatty acid. Fatty acid may be saturated or unsaturated. In some embodiments, the fatty acid is selected from the group consisting of stearic acid, oleic acid, linoleic acid, and mixtures thereof. In some embodiments, the first compound is a fatty acid ester. The fatty acid ester may be saturated or unsaturated. The fatty acid ester may be selected from the group consisting of glyceryl monostearate, glyceryl monooleate and ethyl linoleic acid ester. In some embodiments, the composition comprises at least two first compounds. The composition may comprise a mixture of at least one fatty acid and at least one fatty acid ester. The first compound may have 12-24 carbon atoms. The composition may further comprise at least one second compound selected from the group consisting of ethanol, propylene glycol, diethylene glycol monoethyl ether and benzyl alcohol. The composition may further comprise at least one third compound selected from the group consisting of terpenes, occlusive substances, surfactants, sulfoxides, cyclic ethers, amides, amines, and dimethylaminopropionic acid derivatives. In some embodiments, the terpene is selected from the group consisting of terpinolene, limonene, nerol, and cineole. In some embodiments, the occlusive substance is selected from the group consisting of silicones, mineral oils, and water-insoluble polymers. In some embodiments, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium dodecyl sulfate, sodium lauryl sulfate, DMSO and sodium docusate. In some embodiments, the dimethylaminopropionic acid derivative is a 2-dimethylaminopropionic acid dodecyl ester. The composition may contain bimatoprost in an amount of from about 1% of the mass. up to about 4% of the mass. More preferably, the composition may contain bimatoprost in an amount of about 2.5% by weight. up to about 3.5% of the mass. Most preferably, the composition may contain bimatoprost in an amount of about 3% of the mass. In some embodiments of the invention, the composition is in one of the forms selected from the group consisting of solutions, gels, ointments, foams, films, liniments, creams, shampoos, lotions, pastes, jellies, sprays and aerosols. In some embodiments of the invention, the composition is packaged in a kit with an applicator for application to the skin.

[0026] In some preferred embodiments of the invention, a method of stimulating hair growth comprises administering to the patient's skin an effective amount of a bimatoprost composition according to any of the above embodiments, wherein administration results in increased hair growth. The composition may be applied to the scalp. The composition may be applied at least once a day. In some embodiments, the composition is applied to the scalp to treat a condition selected from the group consisting of focal alopecia, telogen alopecia, anagen alopecia, cicatricial alopecia, scar alopecia; disturbances of the hair shaft, nodular trichorexis, a syndrome of weakened anagen hair, trichotillomania, traction alopecia; infectious lesions of hair, ringworm, seborrheic dermatitis, folliculitis of the scalp and androgenic alopecia. In some embodiments of the invention, the composition is applied to one or both of the scalp and eyebrow in patients suffering from hair loss due to chemotherapy, hormonal imbalance, fungal infection of the scalp, anticoagulants, drugs for the treatment of gout, depression, high arterial pressure and diseases of the cardiovascular system.

[0027] In one embodiment, the composition for promoting hair growth comprises: at least one penetration promoting substance; and bimatoprost in free form or in the form of its pharmaceutically acceptable salt, while bimatoprost is contained in an amount of about 1-4% of the mass .; wherein said composition is formulated for topical application to the skin. In some embodiments of the invention, the penetration enhancer is selected from one or more of the group consisting of alcohols, glycols, fatty acids, fatty acid esters, fatty acid ethers, occlusive substances, surfactants, dimethylaminopropionic acid derivatives, terpenes , sulfoxides, cyclic ethers, amides and amines.

[0028] Of course, it should be understood that the intervals described above and throughout the text of this document are also intended to cover the individual values contained in these intervals. For example, for a composition containing a specific component in the range between 1-50%, disclosure of a percentage of 5% or 49% is also intended.

[0029] The compositions were prepared using the following general procedure. Non-aqueous components (for example, bimatoprost, ethanol, glycols) were combined in a beaker and mixed using a vertical propeller stirrer until the solution became clear. Water was added to the non-aqueous mixture followed by a thickener. After dispersing the thickener, a base was added in order to neutralize the polymer and gel the solution into a gel of another desired composition. For example, ethanol and bimatoprost were combined in a beaker and mixed using a vertical propeller stirrer until the solution became clear. This mixture was then added to non-aqueous components to form a non-aqueous mixture. In a separate vessel, the thickener was dispersed in water to form an aqueous mixture, which was then added to the non-aqueous mixture. After mixing non-aqueous and aqueous mixtures, a base was added in order to neutralize the polymer and gel the solution.

[0030] In yet another embodiment, a topical hair growth composition comprises

at least one penetration promoting agent, including oleyl alcohol; and

bimatoprost in free form or in the form of its pharmaceutically acceptable salt;

wherein said composition is formulated for topical application to the skin.

[0031] In some embodiments, the composition comprises from about 0.3% to about 10% by weight of bimatoprost, preferably about 1-5% by weight. or about 2-4% by weight, more preferably about 2.5-3.5% by weight, most preferably a value of 3% by weight. In some embodiments of the invention, the composition comprises about 1% by weight of bimatoprost. In some embodiments of the invention, the composition comprises about 3% by weight of bimatoprost. The composition may contain about 3% by weight of bimatoprost, about 5% by weight of oleyl alcohol, about 66% by weight of ethanol and about 22% by weight of propylene glycol. The composition may be in one of the forms selected from the group consisting of solutions, gels, ointments, foams, films, liniment, creams, shampoos, lotions, pastes, jellies, sprays and aerosols. The composition may be packaged in a kit with an applicator for application to the skin.

[0032] In another embodiment, a method of stimulating hair growth comprises administering to the patient's skin an effective amount of the bimatoprost composition described herein, wherein administration results in increased hair growth.

[0033] In some embodiments of the invention, the composition is applied to the scalp. In some embodiments of the invention, the composition is applied at least once a day. The composition can be applied to the scalp for treating conditions selected from the group consisting of focal alopecia, telogen alopecia, anagen alopecia, cicatricial alopecia, scar alopecia; disturbances of the hair shaft, nodular trichorexis, a syndrome of weakened anagen hair, trichotillomania, traction alopecia; infectious lesions of hair, ringworm, seborrheic dermatitis, folliculitis of the scalp and androgenic alopecia. The composition may be applied to one or both of the scalp and eyebrow in patients suffering from hair loss due to chemotherapy, hormonal imbalance, fungal infection of the scalp, anticoagulants, medications for the treatment of gout, depression, high blood pressure and diseases of cardio-vascular system.

[0034] In some embodiments of the invention, a suitable composition for topical application of bimatoprost may contain one or more of the following components listed in the table below:

DETAILED DESCRIPTION OF THE INVENTION

[0035] Bimatoprost is a sparingly soluble compound intended for local topical delivery to stimulate hair growth. Hair growth includes, but is not limited to, stimulating the transformation of vellus hair to growth as terminal hair, as well as increasing the growth rate of terminal hair. The embodiments disclosed herein provide combinations of bimatoprost and similar compounds with penetration enhancers. These penetration aids promote the penetration of the active component and / or preservation at the site of their action in the skin. The compositions described herein may be self-preserving or contain an antimicrobial substance, such as gasoline alcohol.

[0036] In accordance with the embodiments described herein, active components are provided

[0037] The active components are given in certain compositions that contain penetration enhancing substances. Some examples of typical compounds used in the practice of the embodiments of this invention described herein include the compounds shown in Table 1:

[0038] In one embodiment, the compound is cyclopentane heptanoic acid, 2- (phenylalkyl or phenyloxyalkyl) and is represented by formula II:

where y is 0 or 1, x is 0 or 1, and both x and y are not 1, Y is selected from the group consisting of alkyl, halogen, e.g. fluorine, chlorine, etc., nitro, amino, thiol, hydroxy , alkoxy, alkylcarboxy, halogen substituted alkyl, wherein said alkyl radical contains from one to six carbon atoms, etc., and n is 0 or an integer from 1 to 3, and R ₃ is = O, --OH or --O (CO) R ₆ , where R ₆ is as defined above, or a pharmaceutically acceptable salt thereof.

[0039] In another embodiment, the compound is a compound of formula III:

where the dotted lines indicate the α configuration, the filled triangles are used to indicate the β configuration. In another embodiment, y is 1 and x is 0, and R ₁ , R ₂ and R ₃ are hydroxy.

[0040] One typical active compound is cyclopentane N-ethyl heptanamide-5-cis-2- (3α-hydroxy-5-phenyl-1-trans-pentenyl) -3,5-dihydroxy, [1 _α , 2 _β , 3 _α , 5 _α ], also known as bimatoprost and sold under the name LUMIGAN® by Allergan, Inc., California, USA. This compound has the following structure:

[0041] The synthesis of the above compounds has been described in US patent No. 5607978, which is incorporated by reference in full.

[0042] The compound will typically be in the range of from about 1 × 10 ^-7 to about 50% by weight of the composition, in one embodiment of the invention, from about 0.001 to about 50% by weight of the composition, and in another embodiment - from about 0.1 to about 30% of the mass of the composition. In some embodiments, a preferred range of active compound may be from about 0.03% by weight, to about 5% by weight, more preferably from about 0.3% by weight, to about 3% by weight, and even more preferably from about 1 % of the mass, up to about 3% of the mass. Also included are intervals and percentages within about 0.3% of the masses, 0.5% of the masses, 1% of the masses, 1.5% of the masses, 2% of the masses, 3% of the masses, 3.5% of the masses, 4% of the masses, 5 % mass, 5.5% mass, 6% mass, 6.5% mass, 7% mass, 8% mass, 9% mass, 10% mass; 10-50% of the mass; about 20-50% of the mass; about 30-40% of the mass, and about 35% of the mass.

[0043] The pharmaceutical compositions described herein may contain one or more penetration promoting substances. The definition of “penetration enhancing substances” includes any substance that facilitates the transfer or delivery of active components to their site of action and / or preserves the active component at its site of action. Non-limiting examples of classes of suitable penetration enhancers include alcohols, glycols, fatty acids, ethers, esters, occlusive substances, and surfactants. Typical and non-limiting examples of these classes are given below. Of course, it should be understood that one or more penetration enhancing substances, or classes thereof, can be combined in various embodiments of the invention described herein.

[0044] Alcohols include, but are not limited to, aliphatic and aromatic alcohols, including ethanol, propanol, n-propanol, isopropanol, butyl alcohol, octanol, benzyl alcohol and cetyl alcohol, in one embodiment of the invention, as described in US Pat. No. 5789244, the entire contents of which are incorporated herein by reference. Fatty alcohols include, for example, saturated and unsaturated fatty alcohols, including, for example, fatty alcohols with chain length of component C ₈ -C _28, stearyl alcohol, oleyl alcohol, lauryl alcohol, palmitic alcohol and combinations thereof. In some embodiments of the invention, oleyl alcohol can be used in the range of from about 0.5% to about 50% by weight, preferably from about 1% by weight, and to about 10% by weight, and even more preferably from about 3% by weight , and up to about 6% of the mass. Also considered are percentages of 1% mass, 1.5% mass, 2% mass, 3% mass, 3.5% mass, 4% mass, 5% mass, 5.5% mass, 6% mass, 7% masses, 8% of the masses, 9% of the masses and 10% of the masses. Most preferably, oleic alcohol may be present in an amount of about 5% of the mass.

[0045] Glycols include, but are not limited to, propylene glycol, polyethylene glycols (including, for example, polyethylene glycols with a molecular weight of about 300-8000 daltons), glycol derivatives, and other low molecular weight glycols such as glycerol and thioglycerol.

[0046] Fatty acids, esters and ethers include, but are not limited to, saturated, monounsaturated and polyunsaturated C ₈ -C ₂₈ fatty acids and fatty acid esters such as C ₄ -C ₂₀ saturated monocarboxylic and dicarboxylic acids, unbranched fatty acids , stearic acid, oleic acid, linoleic acid, palmitoleic acid, octanoic and decanoic acids, methyl laurate, ethyl oleate, polyethylene glycol monolaurate, propene glycol monolaurate, propylene glycerol dilaurate, glycerol monolaurate, glycerol monol lyceryl monostearate, ethyl esters of linoleic acid, isopropyl n-decanoate, octyl dodecyl myristate, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, Crodamol MM, isopropyl myristate and compounds in which C ₂ -C _{4 are} tri-alkanediols or acids.

[0047] Occlusive substances include, but are not limited to, silicones (including Dow ST-Elastomer 10, Dow Silky Wax 10), mineral oils and greases, long chain acids, animal fats and greases, vegetable fats and greases, insoluble in water, polymers, paraffin, paraffin oil, liquid paraffin, petroleum jelly, liquid petrolatum, white petrolatum, yellow petrolatum, microcrystalline wax and ceresin.

[0048] Surfactants include, but are not limited to, nonionic, anionic and cationic substances, as well as combinations thereof, such as Polysorbate 20, 40, 60 and 80, TWEEN® (20, 40, 60, 80) and optionally appropriate SPAN series (20, 40, 60, 80), POLOXAMER® (231, 182, 184), sodium dodecyl sulfate (SDS), macrogol 15 hydroxystearate, grafted copolymer polyvinylcaprolactam - polyvinyl acetate-polyethylene glycol, lecithin, lysolecithin, nonolithylene glycol polyethylene glycol , polyoxyethylene ethers, surfactants based polyglycol ethers, sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, sodium docusate and benzalkonium chloride.

[0049] Other penetration agents that may be used include dimethylaminopropionic acid derivatives such as 2-dimethylaminopropionic acid dodecyl ester (DDAIP); terpenes, including terpinolen, limonene, nerol, cineole; sulfoxides such as DMSO; cyclic ethers; amides and amines such as didecyldimethylammonium bromide (DCAB), sodium taurodeoxycholate, triethylamine; octyl salicylate, as well as combinations thereof.

[0050] Additional penetration enhancers will be known to those of ordinary skill in the art of drug delivery in topical application and / or described in the texts and literature relating to the prior art.

[0051] Embodiments of the invention described herein may also include thickeners. Suitable materials include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, acrylamide / acryloyl dimethyl taurate copolymer, polyacrylic acid, polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid and chondroitin sulfate.

[0052] Some embodiments described herein may include preservatives, including, but not limited to, phenoxyethanol, gasoline alcohol, benzalkonium chloride, chlorhexidine, chlorobutanol, methyl, propyl or butyl parahydroxybenzoic acids, phenylmercury salts, including, without limitation, nitrate, chloride, acetate and borate, as well as betaine.

[0053] Various other additives may be included in the compositions of the present invention in addition to those defined above. These include, but are not limited to, antioxidants, astringents, perfumes, emollients, pigments, colorants, moisturizers, propellants and sunscreens, as well as other classes of materials whose presence may be desirable for cosmetic, medical or other purposes. Compositions and preparations can also be taken in combination with minoxidil and propecia (Propecia).

[0054] Compositions can also be formulated as “sustained release” compositions so that the activity of the active components between treatments is maintained for a longer period of time.

[0055] Although in certain embodiments described herein each of the components described above may be contained, it may be necessary for other specific embodiments to be “substantially free” of one or more of these components in various combinations. "Essentially free," when used in the text of this document, means that the component is not added to the composition and cannot be present in any amount exceeding about 1% of the mass.

[0056] At the same time, without limiting the scope of the clear exception in the previous paragraph, in certain embodiments described herein, one or more components of bimatoprost, carbomer, NaOH, TEA, ethanol, glycerol, diethylene glycol, monoethyl ether, may not be present, propylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, PPG-5-ceteta-20, oleic acid, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropi langlycol, caprylic / capric triglycerides, gasoline alcohol, silicone and water.

[0057] All components of the composition described herein will be contained in amounts that are dermatologically acceptable. As used herein, “dermatologically acceptable” means that the compositions or their components are suitable for use in contact with human skin without excessive toxicity, incompatibility, instability, allergic reaction, and the like. When used throughout the text of this document for active substances and excipients, the term "about" refers to changes in concentrations that are considered bioequivalent.

[0058] The embodiments described herein are used in mammals, including humans and animals. In humans, the compounds of the embodiments described herein can be applied without limitation to the scalp, face, beard, head, pubic region, upper lip, eyebrows and eyelids. The compositions of the present invention can be used to treat various disorders leading to hair loss, including, but not limited to, focal alopecia, telogen alopecia, anagen alopecia, cicatricial alopecia and scar alopecia; hair shaft disorders such as nodular trichorexis, weakened anagen hair syndrome, trichotillomania and traction alopecia; infectious hair lesions, such as ringworm, seborrheic dermatitis, and folliculitis of the scalp; hereditary diseases such as androgenetic alopecia, and the conditions of patients who have experienced hair loss due to chemotherapy, hormonal imbalances (for example, thyroid diseases such as hypothyroidism and hyperthyroidism, pregnancy, childbirth, discontinuation of birth control pills and changes in the menstrual cycle), fungal infections of the scalp, such as dermatomycosis, taking medications that cause hair loss, such as anticoagulants, medications for treatment I have gout, depression, high blood pressure and cardiovascular system. The compositions of the present invention can be used to treat hair loss associated with another disease, such as diabetes, lupus, as well as malnutrition, mental and physical stress, for example, due to surgery, illness and high fever. Environmental factors and chemicals used for hair care (dyeing, shading and lightening).

[0059] In animals raised for their skins, such as minks, compositions can be applied over the entire surface of the body to improve the entire skin for commercial purposes. In animals, this method can also be used for cosmetic purposes, for example, for application to the skin of dogs and cats having bald spots due to scabies or other diseases causing the degree of alopecia.

[0060] The compositions and methods of the present invention can be used in patients suffering from hair loss, or healthy patients who want to simply increase hair growth on any part of the body.

[0061] The compositions described herein are formulated for topical application. The term "topical application", as used herein, includes applying the composition described herein to the epidermis or hair. Application, as a rule, occurs in the area of the desired hair growth or near it.

[0062] Accordingly, suitable forms of a preparation or composition include, but are not limited to, solutions, gels, ointments, foams, films, liniments, creams, shampoos, lotions, pastes, jellies, sprays, and aerosols. These types of preparations can be used in the form of strips, patches, applicators, or through the use of impregnated dressings, depending on the situation and the part of the body to be treated.

[0063] Typically, the compositions described herein will be applied several times over an extended period of time to the body part to be treated. In specific embodiments of the invention, the compositions described herein may include one or more applications per day, one or more applications per week, one or more applications per month or one or more applications per year for a treatment period of at least one day, at least one week, at least one month, at least one year or until a cure or achieve and maintain the desired result.

[0064] The compositions described herein can be applied in safe and effective amounts. As used herein, the term “safe and effective amounts” includes an amount sufficient to provide the desired hair growth stimulation effect with an acceptable benefit / risk ratio inherent in any medical treatment. As part of a medical assessment, the amount of active components used may vary depending on the particular condition being treated, the severity of the condition, the cause of the condition, the duration of treatment, the specific active component used, its concentration, the specific carrier medium used, the patient’s general health status, patient tolerance to various effects of administration, other drugs administered to the patient, and similar factors within the specific knowledge and experience of the patient or when treating his doctor.

[0065] For daily application, the appropriate dose may include, without limitation, from about 0.1 ng to about 100 mg, from about 1 ng to 10 mg per day, or in another embodiment, from about 10 ng to about 1 mg in a day.

[0066] Non-limiting examples of certain components and suitable ranges of their concentrations and function are shown below in Tables 1A and B. Specific examples of non-limiting preparations or compositions are shown in Table 2.

EXAMPLE 1: Obtaining gel compositions of bimatoprost for hair growth in the scalp

[0067] Ethyl alcohol is metered into a suitable mixing vessel for the medium, then bimatoprost is added to the ethyl alcohol and mixed at moderate speed until the bimatoprost is dissolved. Glycerin, diethylene glycol monoethyl ether and propylene glycol are added to a separate mixing tank and mixed until the solvents are dispersed. Ethyl alcohol / bimatoprost solution is then added to the non-aqueous solution and stirred until the components are homogeneous (about 5 minutes of mixing). A thickener carbomer, previously dispersed in water, is added to the above mixture and mixed until a good dispersion occurs, after dispersion, a base for thickening the solution is added to the gel. Typical compositions made in accordance with the above method are shown below in Table 3.

EXAMPLE 2: In vivo Treatment

[0068] The study was initiated to systematically assess the appearance of hair on the scalp and eyebrows, which are applied to the bimatoprost gel compositions shown in Table 3. The study involves 10 subjects, 5 men, 5 women, whose average age is 70 years ( in the range of 50-94 years). Each subject is daily treated by topical application of 0.3% of the mass. the bimatoprost composition shown in Table 3.

[0069] The study is limited to subjects who have been applied bimatoprost for a period of time exceeding 3 months. The average exposure time of 0.3% of the mass. bimatoprost gel composition before evaluating the parameter of hair or eyebrow growth between the control and the examined eye is 129 days (interval 90-254 days). Observations are performed at high magnification during biomicroscopy using a slit lamp. The differences between the control area and the treatment area are documented using a camera specially adapted for use in biomicroscopy using a slit lamp.

[0070] The observation results will be as follows:

[0071] Hair and Eyebrow Length: In both groups, a regular increase in hair length was observed. The difference in length is from about 10% to as much as 30%.

[0072] Hair and Eyebrow Number: An increase in hair number is observed on the scalp and eyebrows of each patient. The difference in the number of hair and eyebrows is from about 5% to as much as 30%. Regardless of whether it is statistically significant or not, bimatoprost with a penetration enhancer will provide better and / or faster results than bimatoprost without a penetration enhancer.

[0073] The above observations will confirm that 0.03% of the mass, the bimatoprost composition penetrates the skin and causes hair growth.

EXAMPLE 3: Topical Cream

[0074] A 0.2% mass bimatoprost cream for topical application is prepared as follows: Tegacid and spermaceti are melted together at a temperature of 70-80 ° C. Methylparaben is dissolved in about 500 g of water and propylene glycol, polysorbate 80, bimatoprost and penetration enhancer are added alternately, maintaining the temperature at 75-80 ° C. A mixture of methyl paraben is slowly added to the molten Tegacid and sperm acetate, with constant stirring. Addition is continued for at least 30 minutes with additional stirring until the temperature drops to 40-45 ° C. At the end, enough water is added to bring the final mass to 1000 g, and the composition is mixed to maintain uniformity until it cools and solidifies.

EXAMPLE 4: Topical Cream

[0075] 0.1% of the mass. bimatoprost in the form of a topical cream is prepared as follows: Tegacid and spermaceti are melted together at a temperature of 70-80 ° C. Methylparaben is dissolved in water and propylene glycol, polysorbate 80, bimatoprost and a penetration enhancer are added alternately, maintaining the temperature at 75-80 ° C. A mixture of methyl paraben is slowly added to the molten Tegacid and sperm acetate, with constant stirring. Addition is continued for at least 30 minutes with additional stirring until the temperature drops to 40-45 ° C. At the end, enough water is added to bring the final mass to 1000 g, and the composition is mixed to maintain uniformity until it cools and solidifies.

EXAMPLE 5: Topical Ointment

[0076] An ointment containing 2.0% of the mass. bimatoprost receive as follows:

[0077] White petrolatum and lanolin are melted, filtered and liquid petrolatum is added to them. Bimatoprost, a penetration enhancer, zinc oxide and calamine are added to the remaining liquid petrolatum and the mixture is ground until the powders are finely divided and evenly distributed. The mixture is mixed in white petrolatum, melted and cooled with stirring until the ointment solidifies. In other embodiments, zinc oxide and / or calamine can be eliminated so that the composition does not essentially contain zinc oxide or calamine.

EXAMPLE 6: Ointment

[0078] An ointment containing 5% of the mass. bimatoprost and penetration enhancer are prepared by adding the active compound to a light liquid petrolatum. White petrolatum is melted together with lanolin, filtered and the temperature is set at 45-50 ° C. A suspension of liquid petroleum jelly is added and the ointment is mixed until it solidifies. The ointment can be packaged in 30 g tubes.

EXAMPLE 7: Composition in the form of a spray

[0079] An aqueous composition in the form of a spray containing 0.03% of the mass. bimatoprost and a penetration enhancer are prepared as follows. Bimatoprost and penetration enhancer are dissolved in water and the resulting solution is sterilized by filtration. The solution is poured under aseptic conditions into sterile containers with a spray tip for application to the parietal part of the head. The composition is presented below in Table 4A. Also in Table 4B, an alternative composition is indicated.

EXAMPLE 8: Lotion

[0080] A bimatoprost sample and penetration enhancer are dissolved in a carrier medium of N-methylpyrrolidone and propylene glycol to obtain 0.5% by weight, bimatoprost in the form of a lotion for application to the scalp or other parts of the body for hair growth.

EXAMPLE 9: Aerosol

[0081] An aerosol containing about 0.1% by weight of bimatoprost and a penetration promoting substance is obtained by dissolving bimatoprost and a penetration promoting substance in absolute alcohol. The resulting solution is filtered to remove particles and fibers. The solution is cooled to a temperature of about -30 ° C. Then, a chilled mixture of dichlorodifluoromethane and dichlorotetrafluoroethane is added to the solution. Thirteen-milliliter polymer-coated yellow glass bottles can be cold-filled with 11.5 g of each solution obtained and closed with a lid. Aerosol can be sprayed onto the scalp or other parts of the body for hair growth.

EXAMPLE 10: Foam compositions for topical application

[0082] A composition of 0.1% by weight, topical bimatoprost foam for topical application is prepared as follows: Methylparaben is dissolved in about 500 g of water and propylene glycol, polysorbate 80, bimatoprost and penetration enhancing agent are added, keeping the temperature at 75-80 ° C. A mixture of methylparaben is slowly added to Tegacid and spermaceti, with constant stirring. Addition is continued for at least 30 minutes with additional stirring until the temperature drops to 40-45 ° C. At the end, enough water is added to bring the final mass to 1000 g, and the composition is mixed to maintain uniformity until it cools and solidifies.

[0083] Alternative foam compositions obtained by a method similar to that described in Example 10 are described below in Tables 5A-B.

EXAMPLE 11: Powder

[0084] The powder of the bimatoprost compound and the penetration enhancer is obtained by mixing in a dry form with talcum powder in a weight / weight ratio of 1: 1: 10.

EXAMPLE 12: Related Compounds

[0085] Following the procedures of the previous Examples, the compositions are prepared in a similar manner by replacing the equimolar amount of the compound of Table 1A with the bimatoprost described in the previous Examples.

[0086] Unless otherwise indicated, all numbers expressing the amounts of components, properties, such as molecular weight, reaction conditions, etc., used in the description and claims, should be understood as modified in all cases by the term "about". "About" refers to options for concentrations of excipients and types of excipients that are considered bioequivalent according to the FDA and other regulatory authorities.

EXAMPLE 13

[0087] A 44-year-old Caucasian man who suffered hair loss due to focal alopecia applies 6% of the weight once a day at bedtime before bedtime, the bimatoprost composition shown in Table 3. After 3 months of application, the subject will notice new growth hair where it was not previously, and darkening of the follicles of old hair. Observation of new hair growth is performed at high magnification during biomicroscopy using a slit lamp and through computerized image analysis. The differences between the control area and the treatment area are documented using a camera specially adapted for use in biomicroscopy using a slit lamp.

EXAMPLE 14

[0088] 37-year-old Hispanic man suffering from male pattern baldness due to androgenetic alopecia, causes 0.2% of the mass twice a day. the bimatoprost composition shown in Table 3, in the area in which the hair is noticeably thinned. After 63 days of application, with a large increase during biomicroscopy using a slit lamp and through computerized image analysis, an increase in hair growth in the form of new hair growth will be noticeable. After observing satisfactory levels of hair growth, the patient applies 0.2% of the mass. bimatoprost composition only twice a week.

EXAMPLE 15

[0089] A 29-year-old healthy Caucasian woman wants to have more voluminous hair and stronger hair growth, despite the fact that the doctors did not diagnose any disease or condition associated with hair loss. The patient will apply 0.3% of the mass once a day. the bimatoprost composition shown in Table 3 until more hair growth is observed after almost three months of use. The patient continues to apply the composition once a week to maintain increased hair growth.

EXAMPLE 16

[0090] A 35-year-old African-American man who has been diagnosed with follicular degeneration syndrome and associated hair loss will use 0.03% of the mass. the bimatoprost composition shown in Table 3. The composition will be applied twice a day, once in the morning after a shower and once in the evening. After 46 days of use, an increase in hair growth and a weakening of the symptoms of follicular degeneration syndrome will become noticeable. The patient continues to use for another 6 months.

[0091] Additional examples of compositions containing bimatoprost are also possible and may be used to further stimulate hair growth. In some embodiments of the invention, some compositions may be particularly useful for promoting hair growth on the scalp.

EXAMPLE 17: The composition of the solution of bimatoprost with oleyl alcohol

[0092] the Composition of a solution of bimatoprost containing 0.3% of the mass. bimatoprost and a penetration enhancer that contains oleyl alcohol can be prepared as follows. The components shown in Table 7 below are dispensed and dispensed into a suitable mixing vessel for the medium. Preferably, bimatoprost is dissolved in ethanol and then combined with oleyl alcohol, propylene glycol and water. Different components are mixed until a homogeneous state is achieved. It should be understood that the composition shown in Table 7 is not limiting and that, of course, other compositions are possible and provided. The bimatoprost solution below had a bimatoprost to oleic alcohol ratio of 0.06, a bimatoprost to ethanol ratio of 0.005, and an oleyl alcohol to ethanol ratio of 0.083.

EXAMPLE 18: The composition of the solution bimatoprost without oleyl alcohol

[0093] Of course, although the above example contains oleyl alcohol, which is believed to function as a penetration enhancer, however, some compositions may not contain this compound. Table 8 below illustrates further non-limiting examples of such compositions. The bimatoprost solutions 8A and 8B below had a bimatoprost to ethanol ratio of 0.005.

Above and throughout the text of this document, Transcutol® refers to a commercial product sold by Gattefosse and containing diethylene glycol monoethyl ether.

EXAMPLE 19: Bimatoprost gel composition without oleyl alcohol

[0094] In addition to the gel composition shown in Example 1 above, a gel composition containing 0.3% by weight of bimatoprost can also be made using the components listed in Table 9 below.

[0095] The components in Table 9 are gelled according to the following procedure. First, ascorbic acid and EDTA are dissolved in parts of the total amount of water. Carbopol 974P is then added to this solution to disperse and wet the carbopol. Next, poloxamer 407 is added to another part of the total amount of water in a separate container and mixed to disperse. Then part of carbopol is added to this part and mixed. Next, Polysorbate 80, hexylene glycol and PEG 400 are combined in another container and mixed until a homogeneous state is achieved. BHA, BHT and bimatoprost are dosed in another container, followed by the addition of benzyl alcohol. The components are mixed until a homogeneous state is achieved. Subsequently, this part is added to the part of Polysorbate 80 and mixed. All parts are mixed, followed by stirring in the remaining part of water and tromethamine (which were mixed previously) to neutralize the gel.

EXAMPLE 20: In vitro Tests

[0096] The compositions described above in Tables 7, 8 and 9 were tested using an in vitro system comprising a diffusion chamber with 1.0 cm ² Franz diffusion cell. During this test, the Franz diffusion cell contains a dermatome ex-vivo sample of a flap of the skin of a human corpse from the back of the body, covering a diffusion cell filled with a receptor solution capable of simulating biological fluid.

[0097] The test compositions were applied to skin samples covering a diffusion cell. Two donor corpses were used, the first being a 43-year-old black man, and the second a 59-year-old white man. The test was performed in triplicate for each donor and test composition. Ten μl of the test solution was applied per square centimeter of skin. At 2, 4, 7, 24, and 48-hour intervals, the receptor solution was collected at each time point and a bimatoprost assay was performed. To obtain the total concentration of the receptor solution, the amount of bimatoprost determined at each of the above time intervals was summarized. Analysis and quantification of bimatoprost for the stratum corneum of the skin and dermis was performed at an endpoint of 48 hours.

[0098] As shown in Table 10 above, the 0.3% bimatoprost composition described in Table 3 was compared with the new compositions shown in Tables 7, 8, and 9. All new compositions (all containing 0.3% bimatoprost) showed higher overall the amount of bimatoprost penetrating through the skin sample and in the receptor solution, with the exception of the gel composition, which showed minimal penetration through the skin. Surprisingly, the composition shown in Table 7, which contained oleyl alcohol as a skin penetrating substance, showed surprisingly higher penetration through the skin (concentration in the stratum corneum / epidermis and dermis layer) and a higher total concentration of the receptor solution compared to other test compositions .

EXAMPLE 21: Additional 1% and 3% of the bimatoprost composition

[0099] Additional compositions were prepared in a manner similar to that already described. Table 11 illustrates examples of such compositions, illustrating that the compositions need not necessarily contain oleyl alcohol. The bimatoprost A solution below had a bimatoprost to ethanol ratio of 0.03. The bimatoprost B solution had a bimatoprost to ethanol ratio of 0.01. The bimatoprost B solution had a bimatoprost to ethanol ratio of 0.005. The bimatoprost G solution had a bimatoprost to ethanol ratio of 0.0167. The bimatoprost D solution had a bimatoprost to ethanol ratio of 0.05.

EXAMPLE 22: In vitro Tests

[00100] The compositions shown in Table 11 were compared with the composition of Table 3 of a 0.3% bimatoprost solution. The test was performed using the same devices and general settings as in Example 20 above. However, in this case, corpse skin samples were taken from a 44-year-old white woman and a 60-year-old white woman.

[00101] The above results show that bimatoprost compositions with a higher relative ethanol and propylene glycol content, that is, solutions B, D and D from Table 10, showed a higher concentration of the receptor solution and the concentration in the dermis layer compared to other compositions.

EXAMPLE 23: Additional bimatoprost compositions

[00102] Additional compositions were also prepared using production methods similar to those described previously. In this case, the compositions described in Table 13 below were made with oleyl alcohol included as a substance penetrating the skin. In Table 13, the bimatoprost A solution had a bimatoprost to oleic alcohol ratio of 0.6, a bimatoprost to ethanol ratio of 0.045, and an oleyl alcohol to ethanol ratio of 0.076. The bimatoprost B solution had a bimatoprost to oleic alcohol ratio of 0.6, a bimatoprost to ethanol ratio of 0.05, and an oleyl alcohol to ethanol ratio of 0.083. The bimatoprost B solution had a bimatoprost to oleyl alcohol ratio of 0.6, a bimatoprost to ethanol ratio of 0.05, and an oleyl alcohol to ethanol ratio of 0.083.

EXAMPLE 24: Additional gel composition of bimatoprost

[00103] Also received an additional gel composition containing 10% of the mass. bimatoprost, using production methods similar to those described previously. The bimatoprost gel composition below had a bimatoprost to ethanol ratio of 0.33. Table 14 below describes the specific components contained in this composition.

EXAMPLE 25: Tests in vitro

[00104] The compositions shown in Tables 13 and 14 were compared with the composition of a 0.03% bimatoprost solution shown in Table 3. The test was performed using the same devices and general settings as in Examples 20 and 22 above. In this case, the skin samples of the corpse were from three donor corpses - a 54-year-old white man, 42-year-old black man and 26-year-old white men.

[00105] Compared to the control composition shown in Table 3, 3% bimatoprost solutions containing oleyl alcohol showed high percutaneous penetration and penetration into the receptor solution. Solution A showed a particularly high concentration of receptor fluid compared to other oleyl alcohol compositions.

[00106] In addition, shown in Table 14 10% of the mass. the bimatoprost gel composition, which did not contain oleyl alcohol at all, showed a high concentration in the skin, but did not show the same penetration of the receptor solution as 3% of the mass. bimatoprost solutions. However, the tested characteristics of all four new compositions were higher compared to the original control composition.

EXAMPLE 26: Additional bimatoprost compositions

[00107] Examples of compositions containing bimatoprost and one or more penetration promoting agents can be found in Table 16 below, and were made in accordance with the methods previously described.

EXAMPLE 27: Additional in vitro tests

[00108] The compositions of Table 16 above were tested using an in vitro skin penetration test method. The test was performed using the same devices and general settings as in the above Examples 20 and 22.

[00109] It was found that, compared to the F-7 composition, the F-2-F-6 compositions showed a comparable or higher penetration of bimatoprost into the receptor fluid. Also, compositions F-2-F-6 have demonstrated that they have a higher amount of bimatoprost in the dermis layer. Composition F-6, which contains oleyl alcohol, had a higher concentration of bimatoprost in the dermis layer and receptor solution, respectively.

EXAMPLE 28: Additional compositions bimatoprost

[00110] Examples of compositions containing bimatoprost and one or more penetration promoting agents can be found in Table 18 below, and were made in accordance with the methods previously described. It should be noted that the compositions F-1 and F-2 are the same as the compositions shown in Table 11.

EXAMPLE 29: Additional in vitro tests

[00111] The compositions of Table 18 above were tested using an in vitro skin penetration test method. The test was performed using the same devices and general settings as in the above Examples 20 and 22.

[00112] Compared to F-1 (with a bimatoprost concentration of 3%), F-3-F-10 compositions have a comparable or higher penetration of bimatoprost into the receptor fluid, despite the fact that they contain bimatoprost at a concentration of 1 % In addition, the compositions F-3 and F-5-F-10 show a higher amount of bimatoprost in the dermis layer compared to the composition F-1. This study shows that glycerol monooleate and oleic acid, respectively, can be used to improve the penetration of bimatoprost into and through the skin in an in vitro study compared to compositions F-1 and F-2.

EXAMPLE 30: Additional compositions bimatoprost

[00113] Examples of compositions containing bimatoprost and one or more penetration promoting agents can be found in Table 20 below, and have been manufactured in accordance with the methods previously described. It should be noted that the compositions F-1 and F-2 are the same as the compositions shown in Table 11.

EXAMPLE 31: Additional in vitro tests

[00114] The compositions of Table 20 above were tested using an in vitro skin penetration test method. The test was performed using the same devices and general settings as in the above Examples 20 and 22.

[00115] Compared to the F-1 composition, the F-3-F-9 compositions have a comparable or higher penetration of bimatoprost into the receptor fluid, although a relatively lower percentage of bimatoprost is used (1% compared to 3%) . The combination of GMO and oleic acid (composition F-4) and linoleic acid (composition F-9) showed the highest penetration of bimatoprost into the receptor solution.

EXAMPLE 32: Additional compositions bimatoprost

[00116] Examples of compositions containing bimatoprost and one or more penetration promoting agents can be found in Table 22 below, and have been manufactured in accordance with the methods previously described. It should be noted that the composition F-1 is the same as the composition shown in Table 11.

EXAMPLE 33: Additional in vitro tests

[00117] The compositions of Table 22 above were tested using an in vitro skin penetration test method. The test was performed using the same devices and general settings as in the above Examples 20 and 22.

[00118] Compared to the F-1 composition, the F-2 to F-9 compositions showed comparable or higher penetration of bimatoprost into the receptor fluid and into the dermis layer even at a lower total bimatoprost concentration.

EXAMPLE 34: Additional bimatoprost compositions

[00119] Examples of compositions containing bimatoprost and one or more penetration promoting agents can be found in Table 24 below, and were made in accordance with the methods previously described. It should be noted that the composition F-1 is the same as the composition shown in Table 11.

EXAMPLE 35: Additional bimatoprost compositions

[00120] In some embodiments of the invention, several possible compositions capable of superior penetration through the skin are shown in the following two tables. Using the base composition shown in Table 25, you can add a mixture of one or more fatty acids or fatty acid esters (shown in Table 26). Preferably, the base composition shown in Table 25 should be combined with at least two of the components shown in Table 26. Even more preferably, at least two of the components shown in Table 26 are one fatty acid and one fatty acid ester. Of course, it should be understood that these compositions do not imply any specific order of manufacture, and, thus, are presented only for ease of understanding. Despite the fact that the base composition can be obtained with any suitable concentration of bimatoprost, this concentration is preferably from about 0.3% to about 5% by weight, more preferably from about 1% to about 3% by weight, and even more preferably about 3% of the mass.

EXAMPLE 35: Clinical trials to evaluate the effectiveness and safety of topical application of bimatoprost solution once a day to increase hair growth in the scalp in men with androgenetic alopecia

[00121] In a multicenter study of 2 phases of men aged 18-49 years with mild to moderate androgenic alopecia (AHA), they were randomly distributed in a 1: 1: 1: 1: 1 ratio to obtain the following groups in a double-blind manner: bimatoprost (BIM ) 0.3%, 0.1%, 0.03% or a once-daily carrier medium, or the open application of an over-the-counter 5% solution of minoxidil (MIN), applied twice a day to the parietal region of the scalp for 6 months. Subjects were examined every 2 months during treatment and 2 months after completion of treatment. The BIM compositions used in this study were as described in Table 3 above.

[00122] The following evaluations were performed using digital image analysis (DIA; macro photographs of a predefined 1 cm ² circular region on the leading edge of the thinning parietal region of the scalp indicated by a micro dot tattoo) using specially approved software: Hair count in target area (TANS), measured in terminal hair / cm ² ; The thickness of the hair in the target area (TAHW), measured in mm / cm ² ; and Darkness of the hair in the target area (TAHD), measured in units of color saturation;

[00123] Other evaluations included Subjective Evaluation (SSA), General Researcher Evaluation (JA), and General Panel Analysis (GPR), performed by an independent group of 3 dermatologists while viewing standardized general scalp photographs of the scalp at baseline (1 day) and during the current visit (or direct assessment during the current visit in the case of IGA). The change in hair growth in the scalp was measured on a 7-point ordinal scale from -3 (significantly reduced) to +3 (significantly increased).

[00124] Measured combined primary endpoints for evaluating efficacy included a change from baseline in TANS and SSA changes in hair growth in the scalp. Secondary endpoints for evaluating efficacy included a change from baseline in TAHW and TAHD, as well as IGA / GPR changes in hair growth in the scalp.

[00125] Security measures included monitoring for adverse events, assessing local tolerance, clinical laboratory tests, examining key body condition indicators, 12-lead electrocardiograms (ECGs), and physical parameters.

[00126] Statistical efficacy analysis was performed on a modified ITT population (population formed according to the initially prescribed treatment), which included all randomized subjects treated in the study and measured at baseline. Combined primary efficacy analyzes were performed at 6 months. Using the Wilcoxon rank sum criterion, percent changes relative to baseline in TANS, TAHW and TAHD were analyzed. The frequency distributions of SSA, IGA and GPR indicators were analyzed using the Cochran-Mantel-Hansel criterion stratified by age group (18-34 compared to 35-49 years old), and the missing data was replaced by 6 months using the method of transferring the data of the last observation forward . Safety measures were evaluated in all subjects receiving the study drug; Intergroup and pairwise comparisons of the incidence of adverse events were performed using the chi-square test or Fisher's exact test.

results

[00127] A total of 307 men with AHA were treated as part of the study and were included in efficacy and safety analyzes. Treatment groups, as a rule, were well balanced in terms of demographic and baseline characteristics.

[00128] Digital Image Analysis (DIA) showed that 0.3% of bimatoprost caused a significantly larger average percentage change from baseline at 6 months in TANS compared with the carrier medium (11.1% compared to 3.3%; P = 0.008). The DIA also showed significant improvement in TAHW, but not in TAHD, when using 0.3% bimatoprost compared with the carrier medium for 6 months; significant improvements were seen at 4 months with respect to TAHW. Two months after cessation of treatment, changes in TANS and TAHW with bimatoprost did not differ significantly from the results of the carrier medium.

[00129] At 6 months, there was no difference between bimatoprost and the carrier medium in the distribution of SSA indicators. GPR scores at 6 months, but not IGA scores, showed that the percentage of subjects with a ≥1-point improvement (i.e., scores of +3, +2, or +1) was significantly higher with 0.3% bimatoprost compared with a carrier medium (21.1% compared with 8.9%; P = 0.030). The improvement in GPR score with 0.3% bimatoprost was maintained 2 months after treatment (16.4% compared with 0%; P = 0.017).

[00130] In the open-label treatment group, 5% minoxidil twice daily, treatment resulted in an increase in TANS of 18.4% from the baseline at 6 months. This is higher than published reports of a -13% increase in TANS after 4 and 12 months of treatment. Most subjects (67.3%) taking 5% minoxidil showed a ≥1-point improvement in hair growth. At the tested doses, the effectiveness of any bimatoprost group was less than the effectiveness of the MIN group.

[00131] With reference to Table 27 below, the incidence of treatment-related adverse events with bimatoprost was slightly higher than the carrier medium, but lower than that with minoxidil.

[00132] With reference to Table 28 below, the most common symptoms of skin tolerance were itching according to the subject's report and dryness / peeling according to the report of the dermatologist; both were less common with 0.3% bimatoprost compared with minoxidil. However, according to a dermatologist’s report, folliculitis was more common with 0.3% bimatoprost than with minoxidil.

[00133] When applying bimatoprost, there were no clinically significant or dose-dependent changes in the clinical laboratory parameters, the main indicators of the state of the body, ECG or the study of physical parameters.

findings

[00134], The study showed that 0.3% topical bimatoprost applied once a day significantly increased hair growth in the scalp compared to the carrier medium in mild to moderate AHA. Topical topical 5% minoxidil, openly applied twice daily, has been shown to be more effective than any of the tested doses of bimatoprost. Bimatoprost for topical application has demonstrated a safety and tolerance profile comparable to the established topical treatment for hair growth in the scalp.

[00135] Although the above detailed description has shown, described and noted new features that apply to various embodiments of the invention, it should be understood that various omissions, replacements and changes in the shape and details of the shown device or method can be made without departing from the essence of this description . In addition, the various features and methods described above can be applied independently of each other or can be combined in various ways. All possible combinations and subcombinations suggest falling within the scope of this description. Many of the above embodiments of the invention include similar components, and accordingly, these similar components can be used interchangeably in various embodiments. Although the invention has been described in the context of certain embodiments and examples, those skilled in the art should understand that the invention is beyond the scope of the specifically disclosed embodiments, extending to other alternative embodiments and / or applications, as well as their obvious modifications and equivalents. Accordingly, the invention should not be limited to specific descriptions of preferred embodiments herein.

Claims (29)

1. Composition for hair growth for local application, containing: bimatoprost in unbound form or in the form of its pharmaceutically acceptable salt, while bimatoprost is contained in an amount of 0.3-4% wt./wt., ethanol propylene glycol diethylene glycol monoethyl ether, benzyl alcohol in an amount of 0.5-2% wt./wt. and at least one compound selected from the group consisting of glyceryl monooleate in an amount of 1-3% w / w. and oleic acid in an amount of 1-3% w / w; wherein said composition is formulated for topical application to the skin. 2. The composition according to p. 1, characterized in that it contains bimatoprost in an amount of 1-4% wt./wt. 3. The composition according to p. 2, characterized in that it contains bimatoprost in an amount of 2.5-3.5% wt./wt. 4. The composition according to p. 3, characterized in that it contains bimatoprost in an amount of 3% wt. 5. The composition according to p. 1, characterized in that it exists in one of the forms selected from the group consisting of solutions, gels, ointments, foams, films, liniment, creams, shampoos, lotions, pastes, jellies, sprays and aerosols. 6. The composition according to p. 1, characterized in that it is packaged in a kit with an applicator for application to the skin. 7. A method of stimulating hair growth, comprising applying to the patient's skin an effective amount of a bimatoprost composition according to any one of paragraphs. 1-6, while the application leads to enhanced hair growth. 8. The method according to p. 7, characterized in that the composition is applied to the scalp. 9. The method according to p. 7, characterized in that the composition is applied at least once a day. 10. The method according to p. 7, characterized in that the composition is applied to the scalp to treat a condition selected from the group consisting of focal alopecia, telogen alopecia, anagen alopecia, cicatricial alopecia, scar alopecia; disturbances of the hair shaft, nodular trichorexis, a syndrome of weakened anagen hair, trichotillomania, traction alopecia; infectious lesions of hair, ringworm, seborrheic dermatitis, folliculitis of the scalp and androgenic alopecia. 11. The method according to p. 7, characterized in that the composition is applied to the scalp and / or eyebrow in patients suffering from hair loss due to chemotherapy, hormonal imbalance, fungal infection of the scalp, taking anticoagulants, drugs for the treatment of gout , depression, high blood pressure and diseases of the cardiovascular system. 12. A composition for stimulating hair growth, comprising: at least one penetration enhancing substance comprising the combination of: a first group of penetration enhancers including ethanol, propylene glycol and diethylene glycol monoethyl ether, and the second group of penetration enhancers, comprising at least two compounds selected from the group consisting of glyceryl monooleate in an amount of 1-3% w / w, oleic acid in an amount of 1-3% w / w. and benzyl alcohol in an amount of 0.5-2% w / w, and bimatoprost in free form or in the form of its pharmaceutically acceptable salt, while bimatoprost is contained in an amount of 1-4% wt./wt .; wherein said composition is formulated for topical application to the skin. 13. The composition according to p. 12, comprising ethanol in an amount of 70% w / w, diethylene glycol monoethyl ether in an amount of 10% w / w, propylene glycol in an amount of 10% w / w, glyceryl monooleate in an amount of 2% wt./wt., benzyl alcohol in an amount of 1% wt./wt. 14. The composition of claim 12, comprising ethanol in an amount of 67% w / w, diethylene glycol monoethyl ether in an amount of 10% w / w, propylene glycol in an amount of 10% w / w, glyceryl monooleate in an amount of 2% w / w, oleic acid in an amount of 2% w / w, benzyl alcohol in an amount of 1% w / w 15. The composition according to any one of paragraphs. 13 or 14, where bimatoprost is contained in an amount of 1% wt./wt. 16. The composition according to any one of paragraphs. 13 or 14, where bimatoprost is contained in an amount of 3% w / w. 17. The composition according to p. 2, containing bimatoprost in an amount of 1% wt./wt.