# Patent

## Title
Topical compositions comprising bimatoprost and methods for stimulating hair growth therewith

## Abstract

Methods and compositions for stimulating the growth of hair are disclosed wherein said compositions include a cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compound represented by the formula I




    
    
        wherein the dashed bonds represent the presence or absence of a double bond which can be in the cis or trans configuration and A, B, Z, X, R1 and R2 are as defined in the specification and a penetration enhancer. Such compositions are used in stimulating hair growth of human or non-human animals.

## Background
RELATED APPLICATION
This application is a continuation of U.S. application Ser. No. 14/175,972 filed Feb. 7, 2014 which in turn claims priority to U.S. Provisional Application Ser. No. 61/783,962, filed on Mar. 14, 2013, and which is also a continuation-in-part of U.S. application Ser. No. 14/163,954, filed Jan. 24, 2014, which is a continuation of U.S. application Ser. No. 12/940,711, filed Nov. 5, 2010, which claims priority to U.S. Provisional Application Ser. No. 61/259,368, filed on Nov. 9, 2009, the disclosures of which are hereby incorporated herein by reference.


FIELD OF THE INVENTION
Disclosed herein are topical compositions and methods for stimulating the growth of hair and treating disorders resulting in hair loss wherein said compositions include a cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compound represented by the formula I:




wherein the dashed bonds represent the presence or absence of a double bond which can be in the cis or trans configuration and A, B, Z, X, R1 and R2 are as defined in the specification and a penetration enhancer. Such compositions are used in stimulating hair growth of human or non-human animals.

BACKGROUND OF THE INVENTION
Dermatologists recognize many different types of hair loss, the most common being “alopecia” or “baldness” wherein humans (mostly males) begin losing scalp hair at the temples and on the crown of their head. However, hair loss may be due to many other disorders.
Hair loss is often accompanied by a change in the hair growth cycle. All mammalian hair passes through a life cycle that includes the anagen phase, the catagen phase and the telogen phase. The anagen phase is the period of active hair growth. In the scalp, this phase lasts from 3-5 years. The catagen phase is a short 1-2 week transitional phase between the anagen phase and the telogen phase. The final telogen phase is considered a “resting phase” where all growth ceases. This phase is also relatively short-lived lasting about 3-4 months before the hair is shed and a new one begins to grow. With the onset of baldness, a successively greater proportion of hairs are in the telogen phase with correspondingly fewer in the active growth anagen phase.
Additionally, different types of hair exist including terminal hairs, vellus hairs and modified terminal hairs. Terminal hairs are coarse, pigmented, long hairs in which the bulb of the hair follicle is seated deep in the dermis. Vellus hairs, on the other hand, are fine, thin, non-pigmented short hairs in which the hair bulb is located superficially in the dermis. Modified terminal hairs are seen in eye lashes and eye brows. As alopecia progresses, a transition takes place wherein the hairs themselves change from the terminal to the vellus type. Accordingly, alopecia (baldness) also includes a deficiency in terminal hairs.
One non-drug treatment for alopecia is hair transplantation. Plugs of skin containing hair are transplanted from areas of the scalp where hair is growing to bald areas. This approach can be reasonably successful, however it is costly, time-consuming and painful. Other non-drug related approaches to treating alopecia include ultra-violet radiation, massage, psychiatric treatment and exercise therapy. None of these approaches, however, have been generally accepted as effective. Even such things as revascularization surgery or acupuncture have shown little, if any, effect.
SUMMARY OF THE INVENTION
Compositions and methods are disclosed herein for topical application of an effective amount of at least one penetration enhancer and cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compound represented by the formula I:




wherein the dashed bonds represent the presence or absence of a double bond which can be in the cis or trans configuration, A is an alkylene or alkenylene radical having from two to six carbon atoms, which radical can be interrupted by one or more oxo radicals and substituted with one or more hydroxy, oxo, alkyloxy or akylcarboxy groups wherein the alkyl radical comprises from one to six carbon atoms; B is 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, oxygen and sulfur atoms; X is —N(R4)2 wherein R4 is selected from the group consisting of hydrogen, a lower alkyl radical having from one to six carbon atoms,





wherein R5 is a lower alkyl radical having from one to six carbon atoms; Z is ═O; one of R1 and R2 is ═O, —OH or a —O(CO)R6 group, and the other one is —OH or —O(CO)R6, or R1 is ═O and R2 is H, wherein R6 is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms, or —(CH2)mR7 wherein m is 0 or an integer of from 1 to 10, and R7 is cycloalkyl radical, having from three to seven carbon atoms, or a hydrocarbyl aryl or heteroaryl radical, as defined above in free form or a pharmaceutically acceptable salt thereof, in association with a penetration enhancer in particular formulations adapted for topical application to mammalian skin.

In one embodiment, the cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compound represented by the formula I is the compound bimatoprost.
Another embodiment includes a composition comprising bimatoprost at a concentration of about 0.001-1.5% w/w, from 0.01-1.0% w/w, from 0.02-1.0% w/w, 0.03 to about 1.0% w/w, 0.03 to 0.9% w/w, 0.04 to 0.8% w/w, 0.05-0.7% w/w, 0.06%-0.6% w/w, 0.07%-0.5% w/w, 0.08-0.4% w/w, 0.09-0.3% w/w, 0.03%-5% w/w, 0.3%-3% w/w, 1%-3% w/w, 0.1% w/w, 0.15% w/w, 0.2% w/w, 0.3% w/w, 0.4% w/w, 0.5% w/w, 0.6% w/w, 0.7% w/w, 0.8% w/w, 0.9% w/w, 1.0% w/w, 1.5% w/w, 2% w/w, 3% w/w, 3.5% w/w, 4% w/w, 5% w/w, 5.5% w/w, 6% w/w, 6.5% w/w, 7% w/w, 8% w/w, 9% w/w, and 10% w/w. The preferred bimatoprost concentration range is about 2-4% w/w, more preferably about 2.5-3.5% w/w. These preferred bimatoprost concentration ranges allow a surprisingly good balance to be achieved between the wanted pharmacologic effects of the composition and any unwanted side-effects. It had previously been thought that bimatoprost compositions for stimulating growth of hair should have a much lower bimatoprost concentration; this has now surprisingly been found not to be the case.
The following excipients may also be included: Carbomer at a concentration of about 0.05-1.0% w/w; base at a concentration of about 0.01 to about 2.0% w/w; ethanol at a concentration of about 10 to about 90% w/w; glycerin at a concentration of about 1.0 to about 20% w/w; diethylene glycol monoethyl ether at a concentration of about 1.0 to about 50% w/w; polysorbate 20 at a concentration of about 0.1 to about 5.0% w/w; polysorbate 40 at a concentration of about 0.1 to about 5.0% w/w; polysorbate 60 at a concentration of about 0.1 to about 5.0% w/w; polysorbate 80 at a concentration of about 0.1 to about 5.0% w/w; PPG-5 ceteth-20 at a concentration of about 0.1 to about 5.0% w/w; oleic acid at a concentration of about 0.1 to about 5.0% w/w; isostearyl isostearate at a concentration of about 0.1 to about 10% w/w; isopropyl myristate at a concentration of about 0.1 to about 10% w/w; dipropylene glycol dimethyl ether at a concentration of about 1 to about 50% w/w; diethylene glycol at a concentration of about 1 to about 50% w/w; dipropylene glycol at a concentration of about 1 to about 50% w/w; caprylic/capric at a concentration of about 0.1 to about 10% w/w; benzyl alcohol at a concentration of about 0.1 to about 2.0% w/w; silicone at a concentration of about 0.1 to about 10% w/w; PEG 40 castor oil at a concentration of about 0.1 to 20% w/w; PEG 35 castor oil at a concentration of about 0.1 to 20% w/w; oleyl alcohol at a concentration of about 0.1 to 10% w/w; glyceryl monooleate at a concentration of about 0.1 to 10% w/w; and/or water at a concentration of about 0 to about 90% w/w.
Another embodiment includes a composition comprising bimatoprost at about 0.1% w/w; carbomer at about 0.10% w/w; NaOH at about 0.035% w/w; ethanol at about 15.0% w/w; diethylene glycol monoethyl ether at about 10.0% w/w; and water at about 74.8% w/w.
Another embodiment includes a composition comprising bimatoprost at about 0.1% w/w; carbomer at about 0.15% w/w; triethylamine (TEA) at about 0.22% w/w; ethanol at about 15.0% w/w; diethylene glycol monoethyl ether at about 10.0% w/w; polysorbate 20 at about 4.0% w/w; and water at about 70.5% w/w.
Another embodiment includes a composition comprising bimatoprost at about 0.1% w/w; carbomer at about 0.125% w/w; TEA at about 0.18% w/w; ethanol at about 30.0% w/w; diethylene glycol monoethyl ether at about 20.0% w/w; and water at about 49.59% w/w.
Another embodiment includes a composition comprising bimatoprost at about 0.1% w/w; carbomer at about 0.10% w/w; TEA at about 0.15% w/w; ethanol at about 30.0% w/w; propylene glycol at about 20% w/w; and water at about 49.7% w/w.
Another embodiment includes a composition comprising bimatoprost at about 0.1% w/w; carbomer at about 0.20% w/w; TEA at about 0.22% w/w; ethanol at about 60.0% w/w; glycerin at about 5.0% w/w; and water at about 34.48% w/w.
Another embodiment includes a composition comprising bimatoprost at about 0.1% w/w; carbomer at about 0.25% w/w; TEA at about 0.38% w/w; ethanol at about 60.0% w/w; polysorbate 20 at about 4.0% w/w; and water at about 35.27% w/w.
Another embodiment includes a composition comprising bimatoprost at about 0.1% w/w; carbomer at about 0.25% w/w; TEA at about 0.38% w/w; ethanol at about 50.0% w/w; diethylene glycol monoethyl ether at about 10% w/w; polysorbate 20 at about 4.0% w/w; and water at about 35.27% w/w.
In some embodiments, the composition comprises water, bimatoprost at a concentration of about 1% w/w to about 4% w/w, preferably about 2-4% w/w and most preferably 2.5-3.5% w/w, and one or more selected from the group consisting of: cetostearyl alcohol at a concentration of about 0.5% w/w to about 1% w/w, glyceryl mono-oleate at a concentration of about 1% w/w to about 3% w/w, preferably about 2% w/w, oleyl alcohol at a concentration of about 1% w/w to about 3% w/w, preferably about 2% w/w, ethanol at a concentration of about 30% w/w to about 75% w/w, propylene glycol at a concentration of about 10% w/w to about 25% w/w, benzyl alcohol at a concentration of about 0.5% w/w to about 2% w/w, preferably about 1% w/w, ultrez at a concentration of about 0.15% w/w, trolamine at a concentration of about 0.16% w/w, and glycerol at a concentration of about 0.5% w/w to about 10% w/w, preferably 2% w/w.
In some embodiments, the composition comprises water, bimatoprost at a concentration of about about 1-5% w/w, preferably about 2-4% w/w, more preferably about 2.5-3.5% w/w, the most preferred value being 3% w/w, and one or more selected from the group consisting of: transcutol at a concentration of about 1% w/w to about 25% w/w, preferably about 10% w/w, propylene glycol at a concentration of about 1% w/w to about 25% w/w, glycerol monooleate at a concentration of about 1% w/w to about 3% w/w, preferably about 2% w/w, oleyl alcohol at a concentration of about 1% w/w to about 3% w/w, preferably about 2% w/w, ethanol at a concentration of about 30% w/w to about 75% w/w, propylene glycol at a concentration of about 10% w/w to about 25% w/w, benzyl alcohol at a concentration of about 0.5% w/w to about 2% w/w, preferably about 1% w/w, carbomer ultrez at a concentration of about 0.15% w/w to about 0.2% w/w, triethanolamine at a concentration of about 0.16% w/w, and glycerin at a concentration of about 0.5% w/w to about 10% w/w, preferably 2% w/w.
Some embodiments may also comprise one or more additional ingredients in addition to those specified in the paragraph above, wherein the one or more ingredients are selected from the group consisting of linoleic acid at a concentration of about 1% w/w to about 5% w/w, preferably 2% w/w, sodium lauryl sulfate at a concentration between 0.1% w/w to about 0.5% w/w, preferably 0.2% w/w, and docusate sodium at a concentration between 0.1% w/w to about 0.5% w/w, preferably 0.2% w/w.
In some embodiments, the composition comprises water, bimatoprost at a concentration of about 1-5% w/w, preferably about 2-4% w/w, more preferably about 2.5-3.5% w/w the most preferred value being 3% w/w, and one or more selected from the group consisting of: transcutol at a concentration of about 1% w/w to about 25% w/w, preferably about 10% w/w, propylene glycol at a concentration of about 1% w/w to about 25% w/w, glycerol monooleate at a concentration of about 1% w/w to about 3% w/w, preferably about 2% w/w, oleic acid at a concentration of about 1% w/w to about 3% w/w, preferably about 2% w/w, linoleic acid at a concentration of about 1% w/w to about 3% w/w, preferably about 2% w/w, ethanol at a concentration of about 30% w/w to about 75% w/w, propylene glycol at a concentration of about 10% w/w to about 25% w/w, benzyl alcohol at a concentration of about 0.5% w/w to about 2% w/w, preferably about 1% w/w, carbomer ultrez at a concentration of about 0.15% w/w to about 0.2% w/w, triethanolamine at a concentration of about 0.16% w/w, glycerin at a concentration of about 0.5% w/w to about 10% w/w, preferably about 2% w/w, terpinolene at a concentration of about 0.5% w/w to about 5% w/w, preferably about 2% w/w, limonene at a concentration of about 0.5% w/w to about 5% w/w, preferably about 2% w/w, nerol at a concentration of about 0.5% w/w to about 5% w/w, preferably about 2% w/w, cineol at a concentration of about 0.5% w/w to about 5% w/w, preferably about 2% w/w, octyl salicylate at a concentration of about 0.5% w/w to about 5% w/w, preferably about 2% w/w, DMSO at a concentration of about 0.5% w/w to about 5% w/w, preferably about 2% w/w, DDAB at a concentration of about 0.01% w/w to about 1% w/w, preferably about 0.2% w/w, sodium taurodeoxycholate at a concentration of about 0.01% w/w to about 5% w/w, preferably about 2% w/w, docusate sodium at a concentration of about 0.01% w/w to about 1% w/w, preferably about 0.2% w/w, Crodamol MM at a concentration of about 1% w/w to about 30% w/w, preferably about 25% w/w, polysorbate 80 at a concentration of about 1% w/w to about 5% w/w, preferably about 2% w/w, Dow ST-Elastomer 10 at a concentration of about 40% w/w to about 80% w/w, preferably about 73.5% w/w, Dow Silky Wax 10 at a concentration of about 1% w/w to about 20% w/w, preferably about 8% w/w, Isopropyl Myristate at a concentration of about 1% w/w to about 20% w/w, preferably about 8% w/w.
In some embodiments, the composition comprises water; bimatoprost, for example at a concentration from about 0.3% w/w to about 5% w/w, preferably about 1-5% w/w or about 2-4% w/w, more preferably about 2.5-3.5% w/w the most preferred value being 3% w/w; and one or more selected from the following: ethanol, for example at a concentration between 0% w/w to about 89% w/w; propylene glycol, for example at a concentration between 0% w/w to about 89% w/w; diethylene glycol monoethyl ether, for example at a concentration between 0% w/w to about 89% w/w; benzyl alcohol, for example at a concentration between 0% w/w to about 89% w/w; and one or more fatty acids and/or fatty ester excipients, for example at a concentration between 0% w/w to about 10% w/w. In some embodiments, the fatty acids may include one or more C8-C28 fatty acids, and which may be saturated, monounsaturated, or polyunsaturated. In some embodiments, a saturated fatty acid may be stearic acid. In some embodiments, a monounsaturated fatty acid may be oleic acid. In some embodiments, a polyunsaturated fatty acid may be linoleic acid. In some embodiments, the fatty ester may one or more include C8-C28 fatty acids, and which may be saturated, monounsaturated, or polyunsaturated. In some embodiments, a saturated fatty ester may be glyceryl monostearate. In some embodiments, a monounsaturated fatty ester may be glyceryl monooleate. In some embodiments, a polyunsaturated fatty ester may be ethyl ester of linoleic acid.
A preferred composition comprises bimatoprost, oleyl alcohol, ethanol and propylene glycol. Bimatoprost is comprised in an amount of about 1-5% w/w, preferably about 2-4% w/w, more preferably about 2.5-3.5% w/w the most preferred value being 3% w/w. Oleyl alcohol is comprised in an amount of about 1-10% w/w. Ethanol is comprised in an amount of about 50-80% w/w. Propylene glycol is comprised in an amount of 15-15% w/w.
Examples of particularly preferred compositions for growing hair by topical application comprise bimatoprost in free form or a pharmaceutically acceptable salt thereof, wherein the bimatoprost is contained in an amount of about 0.3% w/w to about 4% w/w; at least one first compound selected from a fatty acid, fatty acid alcohol and fatty ester, wherein said composition is formulated for topical administration to the skin.
In some embodiments, the first compound is a fatty acid. The 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 ester. The fatty ester may be saturated or unsaturated. The fatty ester may be selected from the group consisting of glyceryl monostearate, glyceryl monooleate, and ethyl ester of linoleic acid. In some embodiments, the composition comprises at least two first compounds. The composition may comprise a mixture of at last one fatty acid and at least one fatty 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 agents, surface active agents, 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 cineol. In some embodiments, the occlusive agent is selected from the group consisting of silicones, mineral oils, and water insoluble polymers. In some embodiments, the surface active agent is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium dodecyl sulfate, sodium lauryl sulfate, DMSO, and docusate sodium. In some embodiments, the dimethylaminopropionic acid derivative is 2-dimethylaminopropionic acid dodecyl ester. The composition may comprise bimatoprost in an amount of about 1% w/w to about 4% w/w. More preferably, the composition may comprise bimatoprost in an amount of about 2.5% w/w to about 3.5% w/w. Most preferably, the composition may comprise bimatoprost in an amount of about 3% w/w. In some embodiments, the composition is in the form of one selected from the group consisting of solutions, gels, ointments, foams, films, liniments, creams, shampoos, lotions, pastes, jellies, sprays and aerosols. In some embodiments, the composition is packaged in a kit with an applicator for application to the skin.
In some preferred embodiments, a method for stimulating hair growth comprises administering to the skin of a patient an effective amount of a bimatoprost composition according to any embodiment previously described, wherein the administration causes increased hair growth. The composition may be applied to the scalp. The composition may be applied at least once daily. In some embodiments, the composition is applied to the scalp for treatment of a condition selected from the group consisting of alopecia areata, telogen effluvium, anagen effluvium, cicatricial alopecia, scarring alopecia; hair shaft abnormalities, trichorrexis nodosa, loose anagen syndrome, trichotillomania, traction alopecia; infectious hair disorders, tiniea capitis, sebohorreic dermatitis, follicullitus of the scalp, and androgenetic alopecia. In some embodiments, wherein the composition is applied to one or both of the scalp and the eyebrows for patients experiencing hair loss due to chemotherapy, hormonal imbalance, fungal infection of the scalp, anti-coagulants, medicine for gout, depression, high blood pressure and heart disease.
In one embodiment, a composition for promoting the growth of hair comprises: at least one penetration enhancer; and bimatoprost in free form or a pharmaceutically acceptable salt thereof, wherein the bimatoprost is contained in an amount of about 1-4% w/w; wherein said composition is formulated for topical administration to the skin. In some embodiments, the penetration enhancer is selected from one or more of the group consisting of alcohols, glycols, fatty acids, fatty esters, fatty ethers, occlusive agents, surface active agents, dimethylaminoproprionic acid derivatives, terpenes, sulfoxides, cyclic ethers, amides, and amines.
It will of course be understood that the ranges described above, and throughout this document, are also intended to encompass single values contained within these ranges. For example, for a formulation comprising a particular ingredient in a range between 1-50%, a percentage of 5% or 49% is also intended to be disclosed.
The compositions were manufactured using the following general procedure. Non-aqueous components (e.g. bimatoprost, ethanol, glycols) were combined in a beaker and stirred using a propeller type overhead mixer until the solution was clear. Water was added to the non-aqueous mixture followed by the addition of the thickening agent. Upon dispersion of the thickening agent, a base was added to neutralize the polymer and thicken the solution into a gel other desired composition. For example, ethanol and bimatoprost were combined in a beaker and stirred using a propeller type overhead mixer until the solution was clear. This mixture was then added to the non-aqueous ingredients to form a non-aqueous mixture. In a separate vessel the thickening agent was dispersed in water to form an aqueous mixture, which was then added to the non-aqueous mixture. Upon mixing of the non-aqueous and aqueous mixtures, a base was added to neutralize the polymer and to thicken the solution into a gel.
In yet another embodiment, a composition for growing hair by topical application comprises
at least one penetration enhancer comprising oleyl alcohol; and
bimatoprost in free form or a pharmaceutically acceptable salt thereof;
wherein said composition is formulated for topical administration to the skin.
In some embodiments, the composition comprises from between about 0.3% to about 10% by weight of bimatoprost, preferably about 1-5% w/w or about 2-4% w/w, more preferably about 2.5-3.5% w/w the most preferred value being 3% w/w. In some embodiments, the composition comprises about 1% by weight of bimatoprost. In some embodiments, the composition comprises about 3% by weight of bimatoprost. The composition may comprise 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 the form of one selected from the group consisting of solutions, gels, ointments, foams, films, liniments, creams, shampoos, lotions, pastes, jellies, sprays and aerosols. The composition may be packaged in a kit with an applicator for application to the skin.
In another embodiment, a method for stimulating hair growth comprises administering to the skin of a patient an effective amount of a bimatoprost composition as described herein, wherein the administration causes increased hair growth.
In some embodiments, the composition is applied to the scalp. In some embodiments, the composition is applied at least once daily. The composition may be applied to the scalp for treatment of conditions selected from the group consisting of alopecia areata, telogen effluvium, anagen effluvium, cicatricial alopecia, scarring alopecia; hair shaft abnormalities, trichorrexis nodosa, loose anagen syndrome, trichotillomania, traction alopecia; infectious hair disorders, tiniea capitis, sebohorreic dermatitis, follicullitus of the scalp, and androgenetic alopecia. The composition may be applied to one or both of the scalp and the eyebrows for patients experiencing hair loss due to chemotherapy, hormonal imbalance, fungal infection of the scalp, anti-coagulants, medicine for gout, depression, high blood pressure and heart disease.
In some embodiments, a suitable formulation for topical administration of bimatoprost may comprise one or more of the following ingredients listed in the table below:















Bimatoprost
Bimatoprost


Ingredient (% w/w)
Function
solution 1
solution 2







Bimatoprost
Active
0.3-6% 
0.3-6% 


Oleyl Alcohol
Penetration
0
0.1-10% 


Ethanol
enhancer
40-80%
40-80%


Propylene

10-30%
10-30%


glycol


Thickener
Thickener
0-6%
0-6%


Carbopol or


other thickeners


(Sepineo,


cellulose, etc)


Triethanolamine
Neutralizing
QSAD
QSAD


or other
Agent


neutralizer as


appropriate


Purified water
Vehicle
QS 100%
QS 100%











DETAILED DESCRIPTION
Bimatoprost is a moderately soluble compound intended for topical delivery to the skin to stimulate hair growth. Hair growth includes, without limitation, stimulating the conversion of vellus hair to growth as terminal hair as well as increasing the rate of growth of terminal hair. Embodiments disclosed herein provide formulations of bimatoprost and similar compounds with penetration enhancers. These penetration enhancers facilitate active component penetration and/or maintenance at their site of action in the skin. Formulations disclosed herein can be self-preserved or contain an antimicrobial agent such as benzyl alcohol.
In accordance with embodiments disclosed herein, active components are represented by




The active components are provided in particular formulations that include penetration enhancers. Some examples of representative compounds useful in the practice of embodiments disclosed herein include the compounds shown in Table 1:







TABLE 1





Representative Compounds















cyclopentane heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-


pentenyl)-3,5-dihydroxy, [1α,2β,3α,5α] cyclopentane N,N-dimethyl-


heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-penten-yl)-3,5-


dihydroxy, [1α,2β,3α,5α]


cyclopentane heptenylamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-


1-trans-pent-enyl)-3,5-dihydroxy, [1α,2β,3α,5α]


cyclopentane heptenylamide-5-cis-2-(3α-hydroxy-4-trifluoromethylphen-


oxy-1-trans--pentenyl)-3,5-dihydroxy, [1α,2β,3α,5α]


cyclopentane N-isopropyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-


trans-pentenyl)-3,5-dihydroxy, [1α,2β,3α,5α]


cyclopentane N-ethyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-


trans-pentenyl)-3,5-dihydroxy, [1α,2β,3α,5α]


cyclopentane N-methyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-


trans-pentenyl)-3,5-dihydroxy, [1α,2β,3α,5α]


cyclopentane heptenamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-


trans-buteny-l)-3,5-dihydroxy, [1α,2β,3α,5α]









In one embodiment, the compound is a cyclopentane heptanoic acid, 2-(phenyl alkyl or phenyloxyalkyl) represented by the formula II:




wherein y is 0 or 1, x is 0 or 1 and x and y are not both 1, Y is selected from the group consisting of alkyl, halo, e.g. fluoro, chloro, etc., nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxy, halo substituted alkyl wherein said alkyl radical comprises from one to six carbon atoms, etc. and n is 0 or an integer of from 1 to 3 and R3 is ═O, —OH or —O(CO)R6 wherein R6 is as defined above or a pharmaceutically acceptable salt thereof.

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




wherein hatched lines indicate α configuration, solid triangles are used to indicate β configuration. In another embodiment, y is 1 and x is 0 and R1, R2 and R3 are hydroxy.

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




The synthesis of the above compounds has been disclosed in U.S. Pat. No. 5,607,978 which is incorporated by reference in its entirety.
The compound will generally range from about 1×10−7 to about 50% w/w of the composition, in one embodiment from about 0.001 to about 50% w/w of the composition and in another embodiment from about 0.1 to about 30% w/w of the composition. In some embodiments, a preferred range of the active compound may be about 0.03% w/w to about 5%, more preferably about 0.3% w/w to about 3% w/w, and even more preferably, about 1% w/w to about 3% w/w. Ranges and percentages within about 0.3% w/w, 0.5% w/w, 1% w/w, 1.5% w/w, 2% w/w, 3% w/w, 3.5% w/w, 4% w/w, 5% w/w, 5.5% w/w, 6% w/w, 6.5% w/w, 7% w/w, 8% w/w, 9% w/w, 10% w/w; 10-50% w/w; about 20-50% w/w; about 30-40% w/w and about 35% are also included.
The pharmaceutical formulations disclosed herein can include one or more penetration enhancers. The phrase “penetration enhancers” includes any agent that facilitates the transfer or delivery of active components to their site of action and/or maintains the active component at their site of action. Non-limiting examples of classes of appropriate penetration enhancers include alcohols, glycols, fatty acids, ethers, esters, occlusive agents and surface active agents. Representative and non-limiting examples of these classes are provided below. It will of course be understood that one or more penetration enhancers or classes thereof may be combined in the various embodiments disclosed herein.
Alcohols include, without limitation, aliphatic and aromatic alcohols, including ethanol, propanol, n-propanol, isopropanol, butyl alcohol, octanol, benzyl alcohol and acetyl alcohol, in one embodiment, as described in U.S. Pat. No. 5,789,244, the entire contents of which are incorporated by reference herein. Fatty alcohols include, for example, saturated and unsaturated fatty alcohols, including for example those with C8-C28 chain length, stearyl alcohol, oleyl alcohol, palmityl alcohol, and lauryl alcohol, and combinations thereof. In some embodiments, oleyl alcohol may be used in a range between about 0.5% w/w to about 50% w/w, preferably between about 1% w/w and about 10% w/w, and even more preferably between about 3% w/w and about 6% w/w. Percentages of 1% w/w, 1.5% w/w, 2% w/w, 3% w/w, 3.5% w/w, 4% w/w, 5% w/w, 5.5% w/w, 6% w/w, 7% w/w, 8% w/w, 9% w/w, and 10% w/w are also contemplated. Most preferably, oleyl alcohol may be present at about 5% w/w.
Glycols include, without limitation, propylene glycol, polyethylene glycols (including for example polyethylene glycols with a molecular weight from about 300-8000 Daltons), glycol derivatives, and other low molecular weight glycols such as glycerol and thioglycerol.
Fatty acids, esters and ethers include, without limitation, saturated, monounsaturated, and polyunsaturated C8-C28 fatty acids and fatty esters, such as C4-C20 saturated monocarboxylic and dicarboxylic acids, straight chain fatty acids, stearic acid, oleic acid, linoleic acid, palmitoleic acid, octanoic and decanoic acids, methyl laurate, ethyl oleate, polyethylene glycol monolaurate, propylene glycol monolaurate, propylene glycerol dilaurate, glycerol monolaurate, glyceryl monooleate, glyceryl monostearate, ethyl esters of linoleic acid, isopropyl n-decanoate, octyldodecyl myristate, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, Crodamol MM, Isopropyl myristate, and compounds wherein a C2-C4 alkane diol or triol is substituted with one or two fatty ether substituents.
Occlusive agents include, without limitation, 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, water insoluble polymers, paraffin, paraffin oil, liquid paraffin, petrolatum, liquid petrolatum, white petrolatum, yellow petrolatum, microcrystalline wax and ceresin.
Surface active agents include without limitation nonionic, anionic, and cationic agents, and combinations thereof, such as polysorbate 20, 40, 60 and 80, TWEEN® (20, 40, 60, 80) and optionally corresponding SPAN Series (20, 40, 60, 80), POLOXAMER® (231, 182, 184), sodium dodecyl sulfate (SDS), macrogol 15 hydroxystearate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer. lecithin, lysolecithin, nonylphenoxypolyoxyethylene, lysophosphatidylcholine, polyethylenglycol 400, polyoxyethylene ethers, polyglycol ether surfactants, sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, docusate sodium, and benzalkonium chloride.
Other penetration enhancers that may be useful include dimethylaminoproprionic acid derivatives, such as 2-dimethylaminopropionic acid dodecyl ester (DDAIP); terpenes, including terpinolene, limonene, nerol, cineol; sulfoxides such as DMSO; cyclic ethers; amides and amines, such as Didecyldimethylammonium bromide (DDAB), sodium taurodeoxycholate, triethylamine; octyl salicylate, and combinations thereof.
Additional penetration enhancers will be known to those of ordinary skill in the art of topical drug delivery, and/or are described in the pertinent texts and literature.
Embodiments disclosed herein can also include viscosity increasing agents. Appropriate agents include, without limitation, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, acrylamide/sodium acryloyldimethyltaurate copolymer, polyacrylic acid, polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid and chondroitin sulfate.
Certain embodiments disclosed herein can include preservatives including, without limitation, phenoxyethanol, benzyl alcohol, benzalkonium chloride, chlorhexidine, chlorobutanol, methyl-, propyl-, or butyl-parahydroxybenzoic acids, phenylmercuric salts including, without limitation, nitrate, chloride, acetate, and borate and betain.
Various other additives may be included in the compositions of the present invention in addition to those identified above. These include, but are not limited to, antioxidants, astringents, perfumes, emollients, pigments, dyes, humectants, propellants, and sunscreen agents, as well as other classes of materials whose presence may be cosmetically, medicinally or otherwise desirable. The compositions and formulations may also be taken in conjunction with minoxidil and propecia.
Compositions can also be formulated as “slow-releasing” formulations so that the activity of active components is sustained for a longer period of time between treatments.
While particular embodiments disclosed herein can include each of the components discussed above, other particular embodiments can be required to be “substantially free” of one or more of these components in various combinations. “Substantially free”, as used herein, means that the component is not added to a formulation and cannot be present in any amount greater than about 1% w/w.
While not limiting the scope of express exclusion of the preceding paragraph, particular embodiments disclosed herein can be substantially free of one or more of bimatoprost, carbomer, NaOH, TEA, ethanol, glycerin, diethylene glycol, monoethyl ether, propylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, PPG-5 ceteth-20, oleic acid, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, triglycerides, caprylic/capric, benzyl alcohol, silicone and water.
All components of formulations described herein will be included in amounts that are dermatologically-acceptable. As used herein, “dermatologically-acceptable” means that the compositions or components thereof are suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, and the like. As used in herein as applied to active agents and excipients, the term “about” refers to variations in concentrations which are considered to be bioequivalent.
Embodiments disclosed herein find application in mammalian species, including both humans and animals. In humans, the compounds of embodiments disclosed herein can be applied without limitation, to the scalp, face, beard, head, pubic area, upper lip, eyebrows, and eyelids. The compositions of the present inventions may be used for treating various hair loss disorders including but not limited to alopecia areata, telogen effluvium, anagen effluvium, cicatricial alopecia and scarring alopecia; hair shaft abnormalities such as trichorrexis nodosa, loose anagen syndrome, trichotillomania and traction alopecia; infectious hair disorders such as tiniea capitis, sebohorreic dermatitis, and follicullitus of the scalp; genetic disorders such as androgenetic alopecia and patients undergoing hair loss due to chemotherapy, hormonal imbalance (e.g., thyroid conditions such as hypothyroidism and hyperthyroidism, pregnancy, child birth, discontinuation of birth control pills and changes in menstrual cycle), fungal infection of the scalp such as ringworm, medicines which cause hair loss such as anti-coagulants, medicine for gout, depression, high blood pressure and certain heart medications. The formulations of the present invention may be used to treat hair loss related to other disease such as diabetes, lupus, and poor nutrition, mental and physical stress such as due to surgery, illness and high fever. Environmental factors and chemicals used in hair treatment (dying, tinting and bleaching).
In animals raised for their pelts, e.g., mink, the formulations can be applied over the entire surface of the body to improve the overall pelt for commercial reasons. The process can also be used for cosmetic reasons in animals, e.g., applied to the skin of dogs and cats having bald patches due to mange or other diseases causing a degree of alopecia.
The compositions and methods of the present invention may be applied to patients suffering from hair loss or in healthy patients simply wanting to increase hair growth in any part of the body.
The compositions disclosed herein are formulated for topical administration. The term “topical administration” as used herein includes applying a formulation as described herein to the outer skin or hair. The application will generally occur at or near the area of desired hair growth.
Accordingly, appropriate formulation or composition types include, without limitation, solutions, gels, ointments, foams, films, liniments, creams, shampoos, lotions, pastes, jellies, sprays and aerosols. Such formulation types can be applied in swaths, patches, applicators or through the use of impregnated dressings depending on the situation and part of the body to be treated.
Typically, the formulations described herein will be applied repeatedly for a sustained period of time to the part of the body to be treated. In particular embodiments, formulations disclosed herein can include one or more applications daily, one or more applications weekly, one or more applications monthly or one or more applications yearly for a period of treatment of at least one day, at least one week, at least one month, at least one year or until the treatment has achieved or achieved and maintained a desired result.
Formulations described herein will be administered in safe and effective amounts. As used herein, “safe and effective amounts” include an amount sufficient so that the composition provides the desired hair growth stimulation effect at a reasonable benefit/risk ratio attendant with any medical treatment. Within the scope of sound medical judgment, the amount of active components used can vary with the particular condition being treated, the severity of the condition, the cause of the condition, the duration of the treatment, the specific active component employed, its concentration, the specific vehicle utilized, the general health of the patient, the tolerance of the patient to various effects of the administration, other drugs being administered to the patient, and like factors within the specific knowledge and expertise of the patient or attending physician.
For daily administration, an appropriate dose can include, without limitation, about 0.1 ng to about 100 mg, about 1 ng to about 10 mg per day or in another embodiment about 10 ng to about 1 mg per day.
Non-limiting examples of some components with their appropriate concentration ranges and function are provided in Tables 1A and B below. Particular examples of non-limiting formulations or compositions are provided in Table 2.







TABLE 1A







Example Components with Function and Concentration Ranges









Ingredient
Function
Composition (% w/w)





bimatoprost
Active
0.03-1.0 


carbomer
Thickener
0.05-1.0 


base
Neutralizing Agent
0.01-2.0 


ethanol
Penetration
10-90


glycerin
enhancers
1.0-20 


diethylene glycol

1.0-50 


monoethyl ether


propylene glycol

 1-50


polysorbate 20

0.1-5.0


polysorbate 40

0.1-5.0


polysorbate 60

0.1-5.0


polysorbate 80

0.1-5.0


PPG-5 ceteth-20

0.1-5.0


oleic acid

0.1-5.0


isostearyl isostearate

0.1-10 


isopropyl myristate

0.1-10 


dipropylene glycol

 1-50


dimethyl ether


diethylene glycol

 1-50


dipropylene glycol

 1-50


caprylic/capric triglycerides

0.1-10 


benzyl alcohol
Preservative
0.1-2.0


silicone
Occlusive Agent
0.1-10 


water
Vehicle
 0-90
















TABLE 1B







Example Components with Function and Concentration Ranges









Ingredient
Function
Composition (% w/w)





bimatoprost
Active
0.03-1.0 


carbomer
Thickener
0.05-1.0 


base
Neutralizing Agent
0.01-2.0 


ethanol
Penetration
10-90


glycerin
enhancers
1.0-20 


diethylene glycol

1.0-50 


monoethyl ether


propylene glycol

 1-50


polysorbate 20

0.1-5.0


polysorbate 40

0.1-5.0


polysorbate 60

0.1-5.0


polysorbate 80

0.1-5.0


PPG-5 ceteth-20

0.1-5.0


oleic acid

0.1-5.0


isostearyl isostearate

0.1-10 


isopropyl myristate

0.1-10 


dipropylene glycol

 1-50


dimethyl ether


diethylene glycol

 1-50


dipropylene glycol

 1-50


caprylic/capric triglycerides

0.1-10 


oleyl alcohol

0.1-10 


benzyl alcohol
Preservative
0.1-2.0


silicone
Occlusive Agent
0.1-10 


water
Vehicle
 0-90
















TABLE 2







Example Compositions









Ingredient
Function
Composition (% w/w)


















bimatoprost
Active
0.1
0.1
0.1
0.1
0.1
0.1
0.1


carbomer
Thickener
0.10
0.15
0.125
0.10
0.20
0.25
0.25


NaOH (s)
Neutralizing
0.035



Agent


TEA
Neutralizing

0.22
0.18
0.15
0.22
0.38
0.38



Agent


ethanol
Penetration
15.0
15.0
30.0
30.0
60.0
60.0
50.0


glycerin
enhancers




5.0


diethylene glycol

10.0
10.0
20.0



10


monoethyl ether


propylene glycol




20


polysorbate 20


4.0



4.0
4.0


water
Vehicle
74.8
70.5
49.595
49.7
34.48
35.27
35.27









Example 1: Preparations of Bimatoprost Scalp Hair Growth Gel Compositions
Ethyl alcohol is weighed into a suitable media jar equipped for mixing, bimatoprost is then added to the ethyl alcohol and stirred at moderate speed until bimatoprost is dissolved. Into separate mixing tank, glycerin, diethylene glycol monoethyl ether, and propylene glycol are added and mixed until the solvents are dispersed. Ethyl alcohol/bimatoprost solution is then added into the non-aqueous solution and mixed until the components are homogenously mixed (about 5 minutes of mixing). To the above mixture the carbomer thickener previously dispersed in water is added and mixed until well dispersed, once dispersed a base is added to thicken the solution into a gel. Representative formulations made according to the method above are shown in Table 3 below.







TABLE 3







Bimatoprost Scalp Hair Growth Topical Gel Formulations












Bimatoprost 0.03%
Bimatoprost 0.1%
Bimatoprost 0.3%
Bimatoprost 0.2%



(Propylene Glycol)
(Propylene Glycol)
(Propylene Glycol)
(Propylene Glycol)


Ingredient (% w/w)
Solution
Solution
Solution
Solution














Bimatoprost
0.03
0.1
0.3
0.2


Propylene glycol
10.0
10.0
10.0
10.0


Diethylene glycol
10.0
10.0
10.0
10.0


monoethyl ether


Ethyl alcohol
30.0
30.0
30.0
30.0


Glycerin
2.0
2.0
2.0
2.0


Carbomer (Ultrez 10)
0.15
0.15
0.15
0.15


Triethanolamine
0.16
0.16
0.16
0.16


Purified water
47.66
47.59
47.39
47.49









Example 2: In Vivo Treatment
A study is initiated to systematically evaluate the appearance of hair on the scalp and eyebrows who are administered bimatoprost gel formulations as in Table 3. The study involves 10 subjects, 5 male, 5 female, average age 70 years, (ranging from 50-94 years). Each subject is treated daily by the topical application of bimatoprost by the 0.3% w/w bimatoprost formulation of Table 3.
The study is limited to subjects who have administered bimatoprost for more than 3 months. The mean duration of exposure to the 0.3% w/w bimatoprost gel formulation prior to assessing the parameter of hair or eyebrow growth between the control and study eye is 129 days (range 90-254 days). Observations are made under high magnification at a slit lamp biomicroscope. Documentation of differences between the control and treatment areas is accomplished using a camera specially adapted for use with a slit lamp biomicroscope.
The Results of the Observations Will Be as Follows:
Length of hair and eyebrows: Increased length of hair in both groups is regularly observed. The difference in length varies from approximately 10% to as much as 30%.
Number of hairs and eyebrows: Increased numbers of hairs are observed on the scalp and eyebrows of each patient. The difference in number of hair and eyebrows varies from approximately 5% to as much as 30%. Whether statistically significant or not, bimatoprost with a penetration enhancer will provide better and/or faster results than bimatoprost without a penetration enhancer.
The foregoing observations will establish that 0.03% w/w bimatoprost composition penetrates skin and grows hair.
Example 3: Topical Cream
A topical 0.2% w/w bimatoprost cream is prepared as follows: Tegacid and spermaceti are melted together at a temperature of 70-80° C. Methylparaben is dissolved in about 500 gm of water and propylene glycol, polysorbate 80, bimatoprost and a penetration enhancer are added in turn, maintaining a temperature of 75-80° C. The methylparaben mixture is added slowly to the Tegacid and spermaceti melt, with constant stirring. The addition is continued for at least 30 minutes with additional stirring until the temperature has dropped to 40-45° C. Finally, sufficient water is added to bring the final weight to 1000 gm and the preparation stirred to maintain homogeneity until cooled and congealed.
Example 4: Topical Cream
A 0.1% w/w bimatoprost 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 in turn, maintaining a temperature of 75-80° C. The methylparaben mixture is added slowly to the Tegacid and spermaceti melt, with constant stirring. The addition is continued for at least 30 minutes with additional stirring until the temperature has dropped to 40-45° C. Finally, sufficient water is added to bring the final weight to 1000 gm and the preparation stirred to maintain homogeneity until cooled and congealed.
Example 5: Topical Ointment
An Ointment Containing 2.0% w/w Bimatoprost is Prepared as Follows:
White petrolatum and wool fat are melted, strained and liquid petrolatum is added thereto. Bimatoprost, a penetration enhancer, zinc oxide, and calamine are added to the remaining liquid petrolatum and the mixture milled until the powders are finely divided and uniformly dispersed. The mixture is stirred into the white petrolatum, melted and cooled with stirring until the ointment congeals. In other variants, the zinc oxide and/or calamine can be omitted such that the formulation is substantially free of the zinc oxide or calamine.
Example 6: Ointment
An ointment containing 5% w/w bimatoprost and a penetration enhancer is prepared by adding the active compound to light liquid petrolatum. White petrolatum is melted together with wool fat, strained, and the temperature adjusted to 45-50° C. The liquid petrolatum slurry is added and the ointment stirred until congealed. The ointment can be packaged in 30 gm tubes.
Example 7: Spray Formulation
An aqueous spray formulation containing 0.03%, w/w bimatoprost and a penetration enhancer are prepared as follows. Bimatoprost and a penetration enhancer are dissolved in water and the resulting solution is sterilized by filtration. The solution is aseptically filled into sterile containers with a spray nozzle for application on top of the head. The formulation is presented in Table 4A below. An alternative formulation is also listed in Table 4B.







TABLE 4A







Bimatoprost Spray Formulation of Example 7










Ingredient (% w/w)
Spray formulation (w/w %)














Bimatoprost
0.03



Propylene glycol
5



Diethylene glycol monoethyl ether
5



Ethyl alcohol
15



Light mineral oil
—



Ceteareth 12
—



Glycerin
1



Carbomer (Ultrez 10)
—



Triethanolamine
—



Purified water
24



Hydrofluoro carbon, hydrocarbon
49.97



propellant, CO2, or, Nitrogen

















TABLE 4B







Alternative bimatoprost Spray Formulation










Ingredient (% w/w)
Spray formulation (w/w %)














Bimatoprost
0.03



Propylene glycol
5



Diethylene glycol monoethyl ether
5



Ethyl alcohol
15



Glycerin
1



PVP or Cellulose
0.1-1%



Purified water
24



Hydrofluoro carbon, hydrocarbon
49.97



propellant, CO2, or, Nitrogen










Example 8: Lotion
A sample of bimatoprost and a penetration enhancer is dissolved in the vehicle of N-methyl pyrrolidone and propylene glycol to make a 0.5% w/w bimatoprost lotion for application to the scalp or other parts of the body for growing hair.
Example 9: Aerosol
An aerosol containing approximately 0.1% w/w bimatoprost and a penetration enhancer is prepared by dissolving the bimatoprost and a penetration enhancer in absolute alcohol. The resulting solution is filtered to remove particles and lint. This solution is chilled to about −30° C. A chilled mixture of dichlorodifluoromethane and dichlorotetrafluoroethane is then added to the solution. Thirteen ml plastic-coated amber bottles can be cold filled with 11.5 gm each of the resulting solution and capped. The aerosol may be sprayed onto the scalp or other parts of the body to grow hair.
Example 10: Topical Foam Formulation
A 0.1% w/w bimatoprost topical foam formulation is prepared as follows: Methylparaben is dissolved in about 500 gm of water and propylene glycol, polysorbate 80, bimatoprost and a penetration enhancer are added in turn, maintaining a temperature of 75-80° C. The methylparaben mixture is added slowly to Tegacid and spermaceti, with constant stirring. The addition is continued for at least 30 minutes with additional stirring until the temperature has dropped to 40-45° C. Finally, sufficient water is added to bring the final weight to 1000 gm and the preparation stirred to maintain homogeneity until cooled and congealed.
Alternative foam formulations prepared in a similar manner as taught in Example 10 are described below in Tables 5A-B.










TABLE 5A







Ingredient (% w/w)
Foam formulation (w/w %)



















Bimatoprost
0.03



Propylene glycol
—



Diethylene glycol
5



monoethyl ether



Ethyl alcohol
10



Light mineral oil
6



Ceteareth 12
5



Glycerin
—



Carbomer (Ultrez 10)
—




















TABLE 5B







Ingredient (% w/w)
Foam formulation (w/w %)



















Bimatoprost
0.03



Propylene glycol
—



Diethylene glycol
5



monoethyl ether



Ethyl alcohol
10



Light mineral oil
6



Myrj 45
5



Glycerin
—










Example 11: Dusting Powder
A powder of the compound bimatoprost and a penetration enhancer is prepared by mixing in dry form with talcum powder at a weight/weight ratio of 1:1:10.
Example 12: Related Compounds
Following the procedures of the preceding Examples, compositions are similarly prepared substituting an equimolar amount of a compound of Table 1A for the bimatoprost disclosed in the preceding Examples.
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, etc. used in the specification and claims are to be understood as being modified in all instances by the term “about.” “About” refers to variations in concentrations of excipients and types of excipients which are considered to be bioequivalent according to the FDA and other regulatory authorities.
Example 13
A 44 year old Caucasian male undergoing hair loss due to alopecia areata applies once daily before sleeping the 0.1% w/w bimatoprost composition of Table 3 for a period of 6 months. After 3 months of application, the subject will notice new hair growth where there previously had been none and darkening of the follicles of old hair. Observations of new hair growth are made under high magnification at the slit lamp biomicroscope and by computer assisted image analysis. Documentation of differences between the control and treatment areas is accomplished using a camera specially adapted for use with the slit lamp biomicroscope.
Example 14
A 37 year old Hispanic male suffering from male pattern baldness due to androgenetic alopecia applies the 0.2% w/w bimatoprost composition of Table 3 twice daily in areas where hair is noticeably thinning. After 63 days of application, increased growth of hair will be noticed as will be new hair growth as measured by high magnification at the slit lamp biomicroscope and by computer assisted image analysis. After satisfactory levels of hair growth are observed, the patient applies the 0.2% w/w bimatoprost composition only twice a week.
Example 15
A 29 year old Caucasian healthy female wishes to have fuller hair and more hair growth even though no disease or hair loss condition has been diagnosed by doctors. The patient will apply the 0.3% w/w bimatoprost composition of Table 3 once daily until more hair growth is observed after approximately three months of use. The patient continues to apply the composition once a week to maintain the increased hair growth.
Example 16
A 35 year old African American male diagnosed with follicular degeneration syndrome and associated hair loss will apply the 0.03% w/w bimatoprost composition of Table 3. The composition will be applied twice daily, once in the morning after showering and once in the evening. After 46 days of application, increased hair growth will be noticed and easing of the symptoms of follicular degeneration syndrome. The patient continues application for another 6 months.
Further examples of formulations containing bimatoprost are also possible, and may be used to further stimulate hair growth. In some embodiments, some formulations may be particularly beneficial to stimulate hair growth in the scalp.
Example 17: Bimatoprost Solution Formulation with Oleyl Alcohol
A formulation of bimatoprost solution containing 0.3% w/w bimatoprost and a penetration enhancer comprising oleyl alcohol may be prepared as follows. The ingredients of Table 7 below are weighed and dispensed into a suitable media jar equipped for mixing. Preferably, bimatoprost is dissolved into the ethanol, and then combined with oleyl alcohol, propylene glycol and water. The various components are mixed together until homogenously mixed. It will be understood that the formulation provided in Table 7 is non limiting and that other formulations are of course possible and envisioned. The bimatoprost solution below had a ratio of bimatoprost to oleyl alcohol of 0.06, a ratio of bimatoprost to ethanol of 0.005, and a ratio of oleyl alcohol to ethanol of 0.083.







TABLE 7







bimatoprost solution formulation with oleyl alcohol











Bimatoprost



Ingredient (% w/w)
solution














Bimatoprost
0.3



Oleyl Alcohol
5



Ethanol
60



Propylene glycol
20



Purified water
14.97










Example 18: Bimatoprost Solution Formulation without Oleyl Alcohol
Of course, while the example above comprises oleyl alcohol, which is believed to act as a penetration enhancer, some compositions may nevertheless not comprise this compound. Table 8 below illustrates additional non-limiting examples of such formulations. The bimatoprost solutions 8A and 8B below had a ratio of bimatoprost to ethanol of 0.005.







TABLE 8







bimatoprost solution formulation without oleyl alcohol












Bimatoprost
Bimatoprost



Ingredient (% w/w)
solution 8A
solution 8B















Bimatoprost
0.3
0.3



Ethanol
60
60



Propylene glycol
20
0



Transcutol ®
0
20



Benzyl Alcohol
0
2.5



Purified water
19.97
17.47










In the preceding and throughout, Transcutol® refers to a commercial product sold by Gattefossé, and which comprises diethylene glycol monoethyl ether.
Example 19: Bimatoprost Gel Formulation without Oleyl Alcohol
In addition to the gel formulation provided in Example 1 above, a gel formulation comprising 0.3% w/w bimatoprost may also be manufactured using the ingredients listed in Table 9 below.
The ingredients in Table 9 are formulated into a gel according to the following procedure. First, ascorbic acid and EDTA are dissolved in a portion of the total water. Then, carbopol 974P is added to this solution to disperse and wet the carbopol. Next, poloxamer 407 is added to another portion of the total water in a separate container and mixed to disperse. The carbopol portion is then added to this part and mixed. Polysorbate 80, hexylene glycol and PEG 400 are next combined in another container and mixed until homogeneous. BHA, BHT and bimatoprost are weighed into another container, followed by the addition of benzyl alcohol. The ingredients are mixed together until homogeneous. Subsequently, this part is added to the Polysorbate 80 part and mixed. All parts are mixed together, followed by mixing in the remaining water and tromethamine (which have been previously mixed together) so as to neutralize the gel







TABLE 9







bimatoprost gel formulation











Bimatoprost



Ingredient (% w/w) 
Gel














Bimatoprost
0.3



Benzyl alcohol
1



Tromethamine
0.8



Hexylene Glycol
2



PEG 400
45



Carbomer (Ultrez
1.25



10)




Poloxamer 407
0.2



Polysorbate 40
0.2



Ascorbic Acid
0.5



BHT
0.5



BHA
0.5



EDTA
0.5



Purified water
47.66










Example 20: In Vitro Testing
The formulations described in Tables 7, 8, and 9 above were tested with an in vitro system comprising a 1.0 cm2 Franz Cell diffusion chamber. During this testing, the Franz Cell comprises a sample of dermatomized ex-vivo human cadaver posterior trunk skin overlaying a diffusion cell filled with receptor solution fluid configured to simulate body fluid.
The tested formulations were applied to the skin samples overlaying the diffusion cell. Two donor cadavers were used, the first from a 43-year old black male, and the second from a 59-year old white male. Testing was performed in triplicate for each donor and formulation tested. Ten μl of tested solution was applied per square centimeter of skin. At 2, 4, 7, 24, and 48 hour intervals, receptor solution fluid was collected at each time point, and the amount of bimatoprost was quantified. To obtain the cumulative receptor solution concentration, the amount of bimatoprost calculated at each time interval above were added together. Analysis and bimatoprost quantification for the skin stratum corneum and dermis was performed at the 48 hour endpoint.







TABLE 10







Summary of in vitro skin penetration results













Cumulative 



Stratum

Receptor



Corneum
Dermis 
Solution Fluid



and Epidermis 
Conc. at 48
Concentration 



Conc. at 48 hrs. 
hrs. (ng 
at 48 hrs. (ng. 


Formulation
(ng bimatoprost)
bimatoprost)
bimatoprost)













Bimatoprost 0.3%
700
18.8
6.95


(Propylene Glycol)





Solution, Table 3





Bimatoprost 
1600
164
2390


solution, Table 7





Bimatoprost solution 
410
41.3
28.9


8A, Table 8





Bimatoprost solution 
200
51.4
30.2


8B, Table 8





Bimatoprost gel, 
64
14.2
BLQ


Table 9









As shown in Table 10 above, the 0.3% bimatoprost formulation described in Table 3 was compared to the new formulations of Tables 7, 8, and 9. The new formulations (all containing 0.3% bimatoprost) all exhibited greater cumulative amounts of bimatoprost permeating through the skin sample and into the receptor solution, with the exception of the gel formulation which exhibited minimal skin penetration. Unexpectedly, the formulation from table 7 that contained oleyl alcohol as a skin penetrant showed a surprisingly higher skin penetration (stratum corneum/epidermis and dermis concentration), and greater cumulative receptor solution fluid concentration relative to the other tested formulations.
Example 21: Additional 1% and 3% Bimatoprost Formulations
Additional formulations were prepared in a similar manner to what has already been described. Table 11 illustrates examples of such formulations, illustrating that the formulations do not necessarily need to comprise oleyl alcohol. The bimatoprost solution A below had a ratio of bimatoprost to ethanol of 0.03. The bimatoprost solution B had a ratio of bimatoprost to ethanol of 0.01. The bimatoprost solution C had a ratio of bimatoprost to ethanol of 0.005. The bimatoprost solution D had a ratio of bimatoprost to ethanol of 0.0167. The bimatoprost solution E had a ratio of bimatoprost to ethanol of 0.05.







TABLE 11







1% and 3% bimatoprost formulations













Bima-
Bima-
Bima-
Bima- 
Bima-



toprost
toprost
toprost
toprost
toprost


Ingredient 
solution A
solution B
solution C
solution D
solution E


(% w/w)
1%
3%
0.3%
1%
3%















Bimatoprost
1
3
0.3
1
3


Transcutol ®
10
10
0
0
0


Ethanol
30
30
60
60
60


Propylene
10
10
20
20
20


glycol







Glycerin
2
2
0
0
0


Carbomer
0.15
0.15
0
0
0


(Ultrez 10)







Triethanolamine
0.16
0.16
0
0
0


Purified water
46.69
44.69
19.7
19
17









Example 22: In Vitro Testing
The formulations of Table 11 were compared to the Bimatoprost 0.3% Solution formulation of Table 3. Testing was done using the same apparatus and general setup as Example 20 above. Here, however, the cadaver skin samples came from a 44 year old white female, and a 60 year old white female.







TABLE 12







Summary of in vitro skin penetration results










Dermis 
Cumulative Receptor



Conc. at 48
Solution Fluid



hrs. (ng 
Concentration at 48


Formulation
bimatoprost)
hrs. (ng. bimatoprost)












Bimatoprost 0.3%
69.1
28.7


(Propylene Glycol)




Solution, Table 3




Bimatoprost solution A 
35.3
58.3


1%, Table 11




Bimatoprost solution B
787
133


3%, Table 11




Bimatoprost solution C 
139
83.1


0.3%, Table 11




Bimatoprost solution D
1060
175


1%, Table 11




Bimatoprost solution E
1410
230


3%, Table 11









The results above indicate that the bimatoprost formulations with a higher relative ethanol and propylene glycol content, i.e., the solutions C, D, and E from Table 10, showed higher receptor solution and dermis concentration relative to the other formulations.
Example 23: Additional Bimatoprost Formulations
Further formulations were also prepared using similar manufacturing techniques as have been previously described. Here, the formulations described below in Table 13 were manufactured comprising oleyl alcohol as a skin penetrating agent. In table 13, bimatoprost solution A had a ratio of bimatoprost to oleyl alcohol of 0.6, a ratio of bimatoprost to ethanol of 0.045, and a ratio of oleyl alcohol to ethanol of 0.076. The bimatoprost solution B had a ratio of bimatoprost to oleyl alcohol of 0.6, a ratio of bimatoprost to ethanol of 0.05, and a ratio of oleyl alcohol to ethanol of 0.083. The bimatoprost solution C had a ratio of bimatoprost to oleyl alcohol of 0.6, a ratio of bimatoprost to ethanol of 0.05, and a ratio of oleyl alcohol to ethanol of 0.083.







TABLE 13







Additional bimatoprost formulations













Bimatoprost
Bimatoprost
Bimatoprost



Ingredient
solution A
solution B
solution C



(% w/w)
3%
3%
3%
















Bimatoprost
3
3
3



Oleyl alcohol
5
5
5



Ethanol
66
60
60



Propylene
22
20
20



glycol






Cremophor
0
5
0



RH40 (PEG






40 castor oil)






Cremophor
0
0
8



ELP






(PEG 35






castor oil)






Purified water
4
7
4










Example 24: Additional Bimatoprost Gel Formulation
An additional gel formulation containing 10% w/w bimatoprost was also prepared using similar manufacturing techniques as have been previously described. The bimatoprost gel formulation below had a ratio of bimatoprost to ethanol of 0.33. Table 14 below describes the specific ingredients comprising this formulation.







TABLE 14







Additional bimatoprost gel formulation










Ingredient (%




w/w)
Bimatoprost Gel














Bimatoprost
10



Ethanol
30



Transcutol ®
10



Propylene Glycol
10



Glycerin
2



Carbomer Ultrez 10
0.15



Triethanolamine
0.16



Purified water
37.69










Example 25: In Vitro Testing
The formulations of Tables 13 and 14 were compared to the bimatoprost 0.03% Solution formulation of Table 3. Testing was done using the same apparatus and general setup as used in Examples 20 and 22 above. Here, the cadaver skin samples were from three donor cadavers—a 54 year old white male, a 42 year old black male, and a 26 year old white male.







TABLE 15







Summary of in vitro skin penetration results










Dermis 
Cumulative Receptor



Conc. at 48
Solution Fluid



hrs. (ng 
Concentration at 48


Formulation
bimatoprost)
hrs. (ng. bimatoprost)












Bimatoprost 0.3%
79.1
250


(Propylene Glycol)




Solution, Table 3




Bimatoprost solution A
1970
17200


3%, Table 13




Bimatoprost solution B
1240
8100


3%, Table 13




Bimatoprost solution C
2900
5640


3%, Table 13




Bimatoprost 10% gel
2820
646


formulation, Table 14









Relative to the control formulation of Table 3, the 3% bimatoprost solutions containing oleyl alcohol demonstrated high skin permeation and permeation into the receptor solution. Solution A demonstrated a particularly high receptor fluid concentration relative to the other oleyl alcohol formulations.
Additionally, the 10% w/w bimatoprost gel formulation from Table 14, which did not include any oleyl alcohol, showed a high dermal concentration, but did not exhibit as much penetration into the receptor solution as the 3% w/w bimatoprost solutions. Nevertheless, the tested characteristics of all four new formulations were superior compared to the original control formulation.
Example 26: Additional Bimatoprost Formulations
Examples of formulations containing bimatoprost and one or more penetration enhancers may be found in Table 16 below, and were manufactured in accordance with the techniques described previously.







TABLE 16







Additional 3% bimatoprost formulations














Formulation #
1
2
3
4
5
6
7







Ingredient (% w/w)

















Bimatoprost
3
3
3
3
3
3
3


Water
2
2
2
6
4
QS
QS








100
100


cetostearyl
0.5
1
—
—
—
—
—


alcohol


glyceryl
—
—
2
2
2
—
—


mono-oleate


Oleyl alcohol
—
—
—
—
—
2
—


Ethanol
73.5
73
72
68
68.25
68.25
30


Propylene Glycol
10
10
10
10
22.75
22.75
10


Transcutol P
10
10
10
10
—
—
10


Benzyl alcohol
1
1
1
1
—
—
—


Ultrez
—
—
—
—
—
—
0.15


Trolamine
—
—
—
—
—
—
0.16


Glycerol
—
—
—
—
—
—
2









Example 27: Additional In Vitro Testing
The formulations from Table 16 above were tested in an in vitro skin penetration testing method. Testing was done using the same apparatus and general setup as used in Examples 20 and 22 above.







TABLE 17







Summary of in vitro skin penetration results










Cumulative



Formulation 
amount in
Dermis


# (from
receptor
Concentration at


Table 16)
solution (ng)
48 hours. (ng)





F-1
 567 ± 722
 278 ± 73


F-2
 907 ± 554
 861 ± 395


F-3
2050 ± 660
 685 ± 108


F-4
2740 ± 260
 894 ± 615


F-5
3110 ± 230
 819 ± 356


F-6
4080 ± 1640
1480 ± 980


F-7
 365 ± 317
 757 ± 123









Compared to the formulation F-7, formulations F-2 through F-6 were found to have demonstrated comparable or higher bimatoprost permeation into the receptor fluid. Also formulations F-2 through F-6 were shown to have a higher amount of bimatoprost in the dermis. Formulation F-6, which contains oleyl alcohol, had the highest bimatoprost concentration in the dermis and receptor solution, respectively.
Example 28: Additional Bimatoprost Formulations
Examples of formulations containing bimatoprost and one or more penetration enhancers may be found in Table 18 below, and were manufactured in accordance with the techniques described previously. It will be noted that the formulations F-1 and F-2 are the same as those shown in Table 11.







TABLE 18







Additional bimatoprost formulations

















Formulation #
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10







Ingredient (% w/w)




















Bimatoprost
3
1
1
1
1
1
1
1
1
1


Glycerin
2
2

2





2


Ethanol
30
30
69.4
69.4
70
46
45
69.4
69.4
69.4


Transcutol
10
10

21.1
10
10
4


21.1


Propylene Glycol
10
10
23.1

10
10
4
23.1
23.1


Benzyl Alcohol




1
1
1


Carbomer Ultrez 10
0.15
0.15




0.2


Triethanolamine
0.16
0.16




0.3


Oleyl Alcohol


0.5
0.5


Oleic Acid







0.5
2
2


Glycerol




2
2
2


monooleate (GMO)


Water
44.69
46.69
6
6
6
30
42.5
6
4.5
4.5









Example 29: Additional In Vitro Testing
The formulations from Table 18 above were tested in an in vitro skin penetration testing method. Testing was done using the same apparatus and general setup as used in Examples 20 and 22 above.







TABLE 19







Additional in vitro testing










Cumulative 




amount in




receptor
Dermis



solution 
Concentration at


Description
(ng)
48 hours. (ng)





F-1
45.7 ± 6.5
449 ± 231


F-2
36.6 ± 36.3
132 ± 70


F-3
 209 ± 41
618 ± 457


F-4
 104 ± 32
145 ± 126


F-5
 328 ± 183
476 ± 56


F-6
 178 ± 41
830 ± 25


F-7
66.7 ± 29.7
452 ± 6


F-8
66.0 ± 28.1
391 ± 227


F-9
 193 ± 134
935 ± 680


F-10
 206 ± 155
229 ± 72









Compared to the formulation F-1 (which has a 3% bimatoprost concentration), formulations F-3 through F-10 have comparable or higher bimatoprost permeation into the receptor fluid while containing bimatoprost at a 1% concentration. Additionally, formulations F-3, and F-5 through F-10 demonstrate a higher amount of bimatoprost in the dermis versus formulation F-1. This study shows that glycerol monooleate and oleic acid, respectively, may be useful in enhancing the penetration of bimatoprost into and through the skin in an in vitro study compared to formulations F-1 and F-2.
Example 30: Additional Bimatoprost Formulations
Examples of formulations containing bimatoprost and one or more penetration enhancers may be found in Table 20 below, and were manufactured in accordance with the techniques described previously. It will be noted that the formulations F-1 and F-2 are the same as those shown in Table 11.







TABLE 20







Additional bimatoprost formulations















Formulation
1
2
3
4
6
7
8
9







Ingredient (% w/w)


















Bimatoprost
3
1
1
1
1
1
1
1


Glycerin
2
2


Ethanol
30
30
69.4
68.25
68.25
68.25
68.25
68.25


Transcutol
10
10


Propylene Glycol
10
10
23.1
22.75
22.75
22.75
22.75
22.75


Benzyl Alcohol


Carbomer Ultrez 10
0.15
0.15


Triethanolamine
0.16
0.16


Oleyl Alcohol


0.5


Oleic Acid



2


GMO



2

2


Linoleic Acid







2


Sodium Lauryl




0.2
0.2


Sulfate


Docusate Sodium






0.2


Water
44.69
46.69
6
4
7.8
5.8
7.8
6









Example 31: Additional In Vitro Testing
The formulations from Table 20 above were tested in an in vitro skin penetration testing method. Testing was done using the same apparatus and general setup as used in Examples 20 and 22 above.







TABLE 21







Additional in vitro testing










Cumulative




amount in 
Dermis



receptor
Concentration at


Formulation ID
solution (ng)
48 hours (ng)





F-1
 42.7 ± 3.1 
348 ± 57


F-2
 55.3 ± 31.7
135 ± 54


F-3
  594 ± 301
202 ± 35


F-4
 1070 ± 530 
514 ± 168


F-6
  101 ± 58
387 ± 435


F-7
  624 ± 394
331 ± 156


F-8
  171 ± 93
377 ± 204


F-9
  936 ± 419
378 ± 62









Compared to the formulation F-1, formulations F-3 through F-9 have comparable or higher bimatoprost permeation into the receptor fluid while using a comparatively lower percentage of bimatoprost (1% versus 3%). A combination of GMO and oleic acid (Formulation F-4) and linoleic acid (Formulation F-9), showed the highest permeation of bimatoprost into the receptor solution.
Example 32: Additional Bimatoprost Formulations
Examples of formulations containing bimatoprost and one or more penetration enhancers may be found in Table 22 below, and were manufactured in accordance with the techniques described previously. It will be noted that the formulation F-1 is the same as those shown in Table 11.







TABLE 22







Additional bimatoprost formulations
















Formulation
1
2
3
4
5
6
7
8
9







Ingredient (% w/w)



















Bimatoprost
3
1
1
1
1
1
1
1
1


Glycerin
2


Ethanol
30
68.25
68.25
68.25
68.25
68.25
68.25
68.25
67


Transcutol
10







10


Propylene Glycol
10
22.75
22.75
22.75
22.75
22.75
22.75
22.75
10


Benzyl Alcohol








1


Oleic Acid

2
2
2
2
2
2
2
2


glycerol monooleate

2
2
2
2
2
2
2
2


Linoleic Acid

2


Terpinolene


2


Limonene



2


Nerol




2


Cineol





2


Octyl Salicylate






2


DMSO







2


Carbomer Ultrez 10
0.15


triethylamine
0.16


Water
44.69
2
2
2
2
2
2
2
7









Example 33: Additional In Vitro Testing
The formulations from Table 22 above were tested in an in vitro skin penetration testing method. Testing was done using the same apparatus and general setup as used in Examples 20 and 22 above.







TABLE 23







Additional in vitro testing










Cumulative
Dermis



amount in
Concentration



receptor
at 48 hours


Formulation ID
solution (ng)
(ng)





F-1
 10.5 ± 2.1
 72 ± 27


F-2
 1360 ± 360
581 ± 360


F-3
 2030 ± 2170
183 ± 107


F-4
 5200 ± 2720
251 ± 172


F-5
 3570 ± 1100
538 ± 583


F-6
 4650 ± 1010
362 ± 163


F-7
 5890 ± 4150
678 ± 644


F-8
 6810 ± 1020
632 ± 314


F-9
 3640 ± 2020
279 ± 48









Compared to the formulation F-1, formulations F-2 through F-9 have demonstrated comparable or higher bimatoprost permeation into receptor solution and into the dermis, even with a lower overall concentration of bimatoprost.
Example 34: Additional Bimatoprost Formulations
Examples of formulations containing bimatoprost and one or more penetration enhancers may be found in Table 24 below, and were manufactured in accordance with the techniques described previously. It will be noted that the formulation F-1 is the same as those shown in Table 11.







TABLE 24







Additional bimatoprost formulations
















Formulation
1
2
3
4
5
6
7
8
9







Ingredient (% w/w)



















Bimatoprost
3
1
1
1
1
1
1
1
0.5


Glycerin
2


Ethanol
30
46
68.25
68.25
68.25
68.25
68.25

10


Transcutol
10
10


Propylene Glycol
10
10
22.75
22.75
22.75
22.75
22.75


Benzyl Alcohol

1


Oleic Acid

2
0.8
3.2
2

2


GMO

2
3.2
0.8
2

2


Sodium Lauryl

0.2



0.2


Sulfate


DDAB






0.2


Sodium





2


Taurodeoxycholate


Docusate Sodium

0.2


Polysorbate 80







2


Crodamol MM







25


Dow ST-Elastomer 10








73.5


Dow Silky Wax 10








8


Isopropyl Myristate








8


Carbomer Ultrez 10
0.15


Trolamine
0.16


Water
QS
QS
QS
QS
QS
QS
QS
QS









Example 35: Additional Bimatoprost Formulations
In some embodiments, several possible formulations capable of superior skin penetration may be manufactured as set forth in the two following tables. Using a base formulation set forth in Table 25, a mixture of one or more fatty acids or fatty esters (as set forth in Table 26) may be added thereto. Preferably, a base formulation from Table 25 will be combined with at least two ingredients from Table 26. Even more preferably, the at least two ingredients from Table 26 are one fatty acid and one fatty ester. Of course, it will be understood that these formulations do not presume any particular order of manufacture, and are only presented thusly for ease of understanding. While the base formulations may be prepared with any appropriate concentration of bimatoprost, this concentration is preferably between about 0.3% w/w and about 5% w/w, more preferably about 1% w/w to about 3% w/w, and even more preferably about 3% w/w.







TABLE 25







Base formulations











Function
Ingredient
Composition (% w/w)







Active Ingredient
Bimatoprost
0.3-5%



Excipients
Ethanol
  0-89




Propylene glycol
  0-89




Diethylene glycol
  0-89




monoethyl ether 
  




Benzyl alcohol
  0-89




Water
  0-89

















TABLE 26







Example fatty acid and fatty ester excipients









Ingredient
Example
Composition (% w/w)





Fatty acids (C8-C28)




Saturated
stearic acid
0-10


Monounsaturated
oleic acid
0-10


Polyunsaturated
linoleic acid
0-10


Fatty esters (C8-C28)




Saturated
glyceryl monostearate
0-10


Monounsaturated
glyceryl monooleate
0-10


Polyunsaturated
ethyl ester of linoleic acid
0-10









Example 35: Clinical Testing to Evaluate the Efficacy and Safety of Once-Daily Topical Bimatoprost Solution for Increasing Scalp Hair Growth in Men with Androgenic Alopecia
In a phase 2 multicenter trial, men 18-49 years of age with mild to moderate androgenic alopecia (AGA) were randomized in a 1:1:1:1:1 ratio to receive in a double-blind manner bimatoprost (BIM) 0.3%, 0.1%, 0.03%, or vehicle applied once daily, or open label over-the-counter minoxidil 5% solution (MIN) applied twice daily to the vertex area of the scalp for 6 months. Subjects were evaluated every 2 months during treatment and at 2 months after completing treatment. The BIM formulations used in this study were as described in Table 3 above.
The following assessments were made with digital image analysis (DIA; macrophotographs of a prespecified 1-cm2 circular area at the anterior leading edge of the vertex thinning area of the scalp identified by microdot tattoo) using customized validated software: Target Area Hair Count (TAHC) measured in terminal hairs/cm2; Target Area Hair Width (TAHW) measured in mm/cm2; and, Target Area Hair Darkness (TAHD) measured in intensity units;
Other assessments included Subject Self Assessment (SSA), Investigator Global Assessment (IGA), and Global Panel Review (GPR) by an independent panel of 3 dermatologists while viewing standardized global photographs of the scalp at baseline (day 1) and at the current visit (or live assessment at the current visit in the case of IGA) Change in scalp hair growth was measured on 7-point ordinal scale from −3 (greatly decreased) to +3 (greatly increased).
Co-primary efficacy endpoints measured included the change from baseline in TAHC and the SSA of change in scalp hair growth. Secondary efficacy endpoints included changes from baseline in TAHW and TAHD, and IGA/GPR of changes in scalp hair growth.
Safety measures included adverse event monitoring, local tolerability assessment, clinical laboratory testing, vital signs, 12-lead electrocardiograms (ECGs), and physical examinations.
Statistical efficacy analyses were performed on the modified intent-to-treat population, which included all randomized subjects who received study treatment and had baseline measurements The co-primary efficacy analyses were conducted at month 6. Percent changes from baseline in TAHC, TAHW, and TAHD were analyzed using the Wilcoxon rank-sum test. Frequency distributions of SSA, IGA, and GPR scores were analyzed using a Cochran-Mantel-Haenszel test stratified for age group (18-34 vs 35-49 years), and missing data were imputed to month 6 using a last-observation-carried-forward approach. Safety measures were evaluated in all subjects who received study medication; among-group and pairwise comparisons of the incidence of adverse events were performed using a chi-square or Fisher's exact test
Results
A total of 307 men with AGA received study treatment and were included in the efficacy and safety analyses. Treatment arms were generally well balanced with respect to demographic and baseline characteristics
Digital image analysis (DIA) showed that bimatoprost 0.3% produced a significantly greater mean percentage change from baseline to month 6 in TAHC compared with vehicle (11.1% vs 3.3%; P=0.008). DIA also revealed a significant improvement in TAHW, but not in TAHD, with bimatoprost 0.3% in comparison to the vehicle at month 6; significant improvements were also seen at month 4 for TAHW. Two months after stopping treatment, the changes in TAHC and TAHW with bimatoprost were no longer significantly different from vehicle.
The distribution of SSA scores at month 6 did not differ between bimatoprost and vehicle. GPR assessments at month 6, but not IGA assessments, showed that the percentage of subjects with 1-grade improvement (i.e., scores of +3, +2, or +1) was significantly greater with bimatoprost 0.3% compared with vehicle (21.1% vs 8.9%; P=0.030). The improvement in GPR assessment with bimatoprost 0.3% was maintained at 2 months post-treatment (16.4% vs 0%; P=0.017)
In the open-label minoxidil 5% treatment arm with twice-daily application, treatment resulted in an increase in TAHC of 18.4% from baseline at month 6. This was higher than published reports of an ≈13% increase in TAHC after 4 and 12 months of treatment. A majority of subjects (67.3%) on minoxidil 5% indicated ≧1-grade improvement in hair growth. At the doses tested, the efficacy of any bimatoprost group was less than that of the MIN group
With reference to Table 27 below, the incidence of treatment-related adverse events was slightly higher with bimatoprost compared with vehicle, but lower than the rate with minoxidil.







TABLE 27







Summary of Treatment-Related Adverse Events (AEs)














Bima-
Bima- 
Bima-





toprost
toprost
toprost
Minoxidil 


Incidence, n
Vehicle
0.03%
0.1%
0.3%
5%


(%)
(n = 62)
(n = 62)
(n = 61)
(n = 61)
(n = 61)





Subjects with
3 (4.8)
3 (4.8)
7 (11.5)
5 (8.2)
13 (21.3)


≧1 treatment-







related AEs










Most common treatment-related AEs (reported by ≧2% of 


subjects in any group)















Application-
1 (1.6)
0
0
2 (3.3)
 2 (3.3) 


site dryness







Application-
0
0
4 (6.6) 
1 (1.6)
 7 (11.5)


site pruritus







Application-
0
0
3 (4.9) 
1 (1.6)
 2 (3.3) 


site pain









With reference to Table 28 below, the most common dermal tolerability symptoms were itching based on subject report and dryness/scaling based on dermatologist report; both were less frequent with bimatoprost 0.3% compared with minoxidil. However, folliculitis was more common with bimatoprost 0.3% than with minoxidil on the dermatologist report.







TABLE 28







Dermal Tolerability Based on Subject and 


Dermatologist Reports












Subjects 







With







≧1 Severity







Grade







Increase 







From

Bima-
Bima-
Bima-
Minox-


Baseline at

toprost
toprost
toprost
idil 


Any Visit, n
Vehicle
0.03%
0.1%
0.3%
5%


(%)
(n = 62)
(n = 62)
(n = 61)
(n = 61)
(n = 61)










Subject assessment












Burning
0
1 (1.6)
3 (4.9)
5 (8.2)*
3 (4.9)


Itching
2 (3.2)
2 (3.2)
3 (4.9)
7 (11.5)
14 (23.0)†


Stinging
0
1 (1.6)
2 (3.3)
5 (8.2)*
2 (3.3)







Dermatologist assessment












Dryness/
8 (12.9)
9 (14.5)
7 (11.5)
9 (14.8)
20 (32.8)‡


scaling







Erythema
4 (6.5)
5 (8.1)
7 (11.5)
9 (14.8)
7 (11.5)


Edema
0
0
1 (1.6)
2 (3.3)
3 (4.9)


Pigmentation
0
1 (1.6)
2 (3.3)
2 (3.3)
3 (4.9)


Folliculitis
0
3 (4.8)
2 (3.3)
8 (13.1)§
2 (3.3)





*P = 0.028;


†P = 0.001;


‡P = 0.01;


§P = 0.003 versus vehicle.






There were no clinically meaningful or dose-dependent changes in clinical laboratory parameters, vital signs, ECGs, or physical examinations with bimatoprost
CONCLUSIONS
The study demonstrated that topical bimatoprost 0.3% applied once daily significantly increased scalp hair growth compared with vehicle in subjects with mild-to-moderate AGA. Topical Minoxidil 5% applied twice daily in an open-label manner showed efficacy higher than any of the bimatoprost doses tested. Topical bimatoprost exhibited a safety and tolerability profile that was consistent with that of an established topical treatment for scalp hair growth
While the above detailed description has shown, described, and pointed out novel features as applied to various embodiments, it will be understood that various omissions, substitutions, and changes in the form and details of the device or process illustrated may be made without departing from the spirit of the disclosure. Additionally, the various features and processes described above may be used independently of one another, or may be combined in various ways. All possible combinations and subcombinations are intended to fall within the scope of this disclosure. Many of the embodiments described above include similar components, and as such, these similar components can be interchanged in different embodiments. Although the invention has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and obvious modifications and equivalents thereof. Accordingly, the invention is not intended to be limited by the specific disclosures of preferred embodiments herein.

## Claims

1. A composition for topical administration to a patient's skin, the composition comprising:
bimatoprost in free form or a pharmaceutically acceptable salt thereof;
ethanol;
propylene glycol;
diethylene glycol monoethyl ether;
benzyl alcohol; and,
at least one compound selected from the group consisting of glycerol monooleate and oleic acid.

2. The composition of claim 1, wherein the composition comprises about 0.3% w/w to about 5% w/w bimatoprost.

3. The composition of claim 1, wherein the composition comprises 70% w/w ethanol, 10% w/w propylene glycol, 10% w/w diethylene glycol monoethyl ether, 1% w/w benzyl alcohol, 2% w/w glycerol monooleate, and water.

4. The composition of claim 1, wherein the composition comprises 67% w/w ethanol, 10% w/w propylene glycol, 10% diethylene glycol monoethyl ether, 1% w/w benzyl alcohol, 2% w/w glycerol monooleate, 2% w/w oleic acid, and water.

5. The composition of claim 3 or 4, wherein the composition comprises about 1% to about 3% w/w bimatoprost.

6. The composition of claim 5, wherein the composition comprises 1% bimatoprost.

7. The composition of claim 5, wherein the composition comprises 2% bimatoprost.

8. The composition of claim 5, wherein the composition comprises 3% bimatoprost.

9. A method of stimulating hair growth, comprising administering the composition of claim 1 to the patient's skin.

10. The method of claim 9, wherein the method stimulates the conversion of vellus hair to terminal hair.

11. The method of claim 9, wherein the method stimulates the rate of growth of terminal hair.

12. The method of claim 9, wherein the composition is administered once daily.

13. The method of claim 9, wherein the composition is administered twice daily.

14. The method of claim 9, wherein the composition is administered to at least one region of skin selected from the group consisting of scalp, eyebrow, eyelid, and face.