HK1231769A1 - Compositions and methods for stimulating hair growth - Google Patents

Description

Compositions and methods for stimulating hair growth

The present application is a divisional application of international application with application number PCT/US2010/055712 entitled "composition and method for stimulating hair growth" filed on 5/11/2010, which entered the chinese national phase at 6/2012, and with application number 201080055359.9.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application No. 61/259,368, filed on 9/11/2009, the entire disclosure of which is hereby incorporated by reference herein.

Technical Field

Disclosed herein are compositions and methods for stimulating hair growth and treating conditions caused by hair loss, wherein the compositions comprise a cyclopentane heptanoic acid, 2-cycloalkyl or aralkyl compound represented by formula I:

wherein the dashed bond indicates the presence or absence of a double bond, which may be in the cis or trans configuration, and A, B, Z, X, R₁And R₂As defined in the specification; and a penetration enhancer. Such compositions are useful for stimulating hair growth in human or non-human animals.

Background

Dermatologists have identified many different types of hair loss, the most common being "alopecia" or "baldness," in which hair loss in humans (mostly male) begins on the sideburns and the top of the head. However, hair loss can be caused by a number of other conditions.

Hair loss is often accompanied by changes in the hair growth cycle. All mammalian hair undergoes a life cycle including anagen, catagen and telogen phases. The anagen phase is the active anagen phase. On the scalp, this period lasts 3-5 years. The catagen phase is a transient 1-2 week transition between the anagen and telogen phases. The last resting period is considered to be the "resting period" in which all growth is stopped. This period is also relatively short lasting about 3-4 months, after which the hair is shed and new hair begins to grow. With the onset of baldness, the proportion of hair in the telogen phase becomes progressively greater, while the proportion of hair in the active growth phase becomes correspondingly less.

In addition, there are different types of hair, including terminal hair, vellus hair, and finished terminal hair. Terminal hair is a rough, pigmented long hair in which the hair follicle bulb is located deep in the dermis. Vellus hairs, on the other hand, are thin, non-pigmented short hairs in which the hair bulb is located on the surface of the dermis. Trimmed terminal hairs are found in the eyelashes and eyebrows. As alopecia progresses, a shift will occur in which the type of hair itself is changed from terminal to vellus hair. Thus, alopecia (baldness) also includes a lack of terminal hair.

One non-drug treatment of alopecia is hair transplantation. Skin plugs containing hair were transplanted from areas of the scalp where hair is growing to bald areas. While this approach is quite successful, it is costly, time consuming and painful. Other non-drug related methods of treating alopecia include ultraviolet radiation, massage, psychiatric treatment, and exercise therapy. However, the effectiveness of these methods has not been generally accepted. Even methods such as revascularization surgery or needle therapy are little, if any, effective.

Summary of The Invention

Disclosed herein are compositions and methods for topical application of an effective amount of at least one penetration enhancer and a cyclopentane heptanoic acid, 2 cycloalkyl or aralkyl compound represented by formula I:

wherein the dotted bond represents the presence or absence of a double bond which may be in cis or trans configuration, A is an alkylene or alkenylene group having 2 to 6 carbon atoms which may be interrupted by one or more oxo groups and may be substituted by one or more hydroxy, oxo, alkoxy or alkylcarboxy groups, wherein the groups are substituted by one or more hydroxy, oxo, alkoxy or alkylcarboxy groupsThe alkyl group contains 1 to 6 carbon atoms; b is cycloalkyl having 3 to 7 carbon atoms, or aryl selected from the group consisting of hydrogen, lower alkyl having 4 to 10 carbon atoms, wherein the heteroatom is selected from the group consisting of nitrogen, oxygen and sulfur atoms; x is-N (R)₄)₂Wherein R is₄Selected from the group consisting of hydrogen, lower alkyl having 1 to 6 carbon atoms,Group of (I) wherein R₅Is lower alkyl having 1 to 6 carbon atoms; z is ═ O; r₁And R₂One of which is ═ O, - - - -OH or- -O (co) R₆And the other is- -OH or- -O (CO) R₆Or R is₁Is ═ O and R₂Is H, wherein R₆Is a saturated or unsaturated acyclic hydrocarbon radical having from 1 to about 20 carbon atoms, or- - (CH)₂)mR₇Wherein m is 0 or an integer of 1 to 10, and R₇Is a cycloalkyl group having 3 to 7 carbon atoms, or an alkylaryl or heteroaryl group, as defined above, in free form or in pharmaceutically acceptable salt form, in combination with a penetration enhancer in a specific formulation suitable for topical application to mammalian skin.

In one embodiment, the cyclopentane heptanoic acid, 2-cycloalkyl or aralkyl compound represented by formula I is the compound bimatoprost (bimatoprost).

Another embodiment includes a composition comprising a concentration of about 0.001-1.5% w/w, 0.01-1.0% w/w, 0.02-1.0% w/w, 0.03% w/w to about 1.0% w/w, 0.03-0.9% w/w, 0.04-0.8% 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, 0.1% 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, and the 0.1% w/w ratio of the starting horse essence. May also include excipients Carbomer (Carbomer) at a concentration of about 0.05 to 1.0% w/w, base at a concentration of about 0.01% w/w to about 2.0% w/w, ethanol at a concentration of about 10% w/w to about 90% w/w, glycerin at a concentration of about 1.0% w/w to about 20% w/w, diethylene glycol monoethyl ether at a concentration of about 1.0% w/w to about 50% w/w, polysorbate 20 at a concentration of about 0.1% w/w to about 5.0% w/w, polysorbate 40 at a concentration of about 0.1% w/w to about 5.0% w/w, polysorbate 60 at a concentration of about 0.1% w/w to about 5.0% w/w, polysorbate 80 at a concentration of about 0.1% w/w to about 5.0% w/w, cetyl alcohol at a concentration of about 0.1% w to about 5.0% w/w, Oleic acid at a concentration of about 0.1% w/w to about 5.0% w/w, isostearyl isostearate at a concentration of about 0.1% w/w to about 10% w/w, isopropyl myristate at a concentration of about 0.1% w/w to about 10% w/w, dipropylene glycol dimethyl ether at a concentration of about 1% w/w to about 50% w/w, diethylene glycol at a concentration of about 1% w/w to about 50% w/w, dipropylene glycol at a concentration of about 1% w/w to about 50% w/w, caprylic/capric acid at a concentration of about 0.1% w/w to about 10% w/w, benzyl alcohol at a concentration of about 0.1% w/w to about 2.0% w/w, silicone at a concentration of about 0.1% w/w to about 10% w/w, and/or water at a concentration of about 0% w/w to about 90% w/w.

Another embodiment includes a composition comprising about 0.1% w/w bimatoprost, about 0.10% w/w carbomer, about 0.035% w/w NaOH, about 15.0% w/w ethanol, about 10.0% w/w diethylene glycol monoethyl ether, and about 74.8% w/w water.

Another embodiment includes a composition comprising about 0.1% w/w bimatoprost, about 0.15% w/w carbomer, about 0.22% w/w Triethylamine (TEA), about 15.0% w/w ethanol, about 10.0% w/w diethylene glycol monoethyl ether, about 4.0% w/w polysorbate 20, and about 70.5% w/w water.

Another embodiment includes a composition comprising about 0.1% w/w bimatoprost, about 0.125% w/w carbomer, about 0.18% w/w TEA, about 30.0% w/w ethanol, about 20.0% w/w diethylene glycol monoethyl ether, and about 49.59% w/w water.

Another embodiment includes a composition comprising about 0.1% w/w bimatoprost, about 0.10% w/w carbomer, about 0.15% w/w TEA, about 30.0% w/w ethanol, about 20% w/w propylene glycol, and about 49.7% w/w water.

Another embodiment includes a composition comprising about 0.1% w/w bimatoprost, about 0.20% w/w carbomer, about 0.22% w/w TEA, about 60.0% w/w ethanol, about 5.0% w/w glycerin, and about 34.48% w/w water.

Another embodiment includes a composition comprising about 0.1% w/w bimatoprost, about 0.25% w/w carbomer, about 0.38% w/w TEA, about 60.0% w/w ethanol, about 4.0% w/w polysorbate 20, and about 35.27% w/w water.

Another embodiment includes a composition comprising about 0.1% w/w bimatoprost, about 0.25% w/w carbomer, about 0.38% w/w TEA, about 50.0% w/w ethanol, about 10% w/w diethylene glycol monoethyl ether, about 4.0% w/w polysorbate 20, and about 35.27% w/w water.

The compositions were prepared using the following general procedure. The water components (e.g., bimatoprost, ethanol, ethylene glycol) were combined in a beaker and stirred using a propeller-type overhead mixer until the solution became clear. Water is added to the non-aqueous mixture, followed by the addition of a thickener. After dispersing the thickener, a base is added to neutralize the polymer to thicken the solution into a gel, i.e., the desired composition.

Detailed Description

Bimatoprost is a moderately soluble compound intended for topical delivery to the skin to stimulate hair growth. Hair growth includes, but is not limited to, stimulating the conversion of vellus hair to grow terminal hair and increasing the growth rate of terminal hair. Embodiments disclosed herein provide formulations comprising bimatoprost and similar compounds and a penetration enhancer. These penetration enhancers help the active ingredient to penetrate and/or maintain its site of action in the skin. The formulations disclosed herein may be preserved themselves or contain an antimicrobial agent such as benzyl alcohol.

According to embodiments disclosed herein, the active component is represented by the formula:

the active ingredient is provided in a specific formulation that includes a penetration enhancer. Some examples of representative compounds that may be used to practice embodiments disclosed herein include the compounds shown in table 1:

TABLE 1 representative Compounds

In one embodiment, the compound is cyclopentane heptanoic acid, 2- (phenylalkyl or phenoxyalkyl) represented by formula II:

wherein Y is 0 or 1, x is 0 or 1 and x and Y are not simultaneously 1, Y is selected from the group consisting of alkyl, halo (e.g., fluoro, chloro, etc.), nitro, amino, thiol, hydroxy, alkoxy, alkylcarboxy, halo-substituted alkyl, and the like, wherein the alkyl contains 1 to 6 carbon atoms, and n is 0 or an integer from 1 to 3, and R is₃Is ═ O, - - -OH or- -O (CO) R₆Wherein R is₆As defined above.

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

wherein the hatched lines indicate the α configuration and the solid triangles are used to indicate the β configuration in another embodiment, y is 1 and x is 0, and R is₁、R₂And R₃Is a hydroxyl group.

An exemplary compound is cyclopentylAlkane N-ethylheptanamide-5-cis-2- (3 α -hydroxy-5-phenyl-1-trans-pentenyl) -3, 5-dihydroxy, [1 ]_α，2_β，3_α，5_α]Also known as bimatoprost, by Allergan Inc. of California, USATrade names are sold. Such compounds have the following structure:

the synthesis of the above compounds is disclosed in U.S. patent No. 5,607,978, which is incorporated by reference in its entirety.

An effective amount of the active compound can be determined by one of ordinary skill in the art, but will vary depending on the compound employed, the frequency of application, and the desired result, the concentration of the compound in the composition will generally range from about 1 × 1^0-7% w/w to about 50% w/w, in one embodiment about 0.001% w/w to about 50% w/w, and in another embodiment about 0.1% w/w to about 30% w/w. Ranges within the range of about 10-50% w/w, about 20-50% w/w, about 30-40% w/w, and about 35% w/w are also included.

The pharmaceutical formulations disclosed herein may include one or more penetration enhancers. The phrase "penetration enhancer" includes any agent that facilitates the transfer of an active ingredient to its site of action or maintains an active ingredient at its site of action. Non-limiting examples of suitable classes of penetration enhancers include alcohols, glycols, fatty acids, ethers, esters, occlusion agents, and surfactants. Representative examples of these categories are given below.

In one embodiment, alcohols include, but are not limited to, ethanol, propanol, N-propanol, isopropanol, butanol, octanol, benzyl alcohol, and acetyl alcohol (acetyl alcohol), as described in U.S. patent No. 5,789,244, the entire contents of which are incorporated herein by reference. Fatty alcohols include, for example, stearyl alcohol and oleyl alcohol.

Diols include, without limitation, glycerol, propylene glycol, polyethylene glycol, and other low molecular weight diols, such as glycerol and thioglycerol.

Fatty acids, esters and ethers include, but are not limited to, oleic acid, palmitoleic acid, straight chain C₄-C₂₀Saturated monocarboxylic and dicarboxylic acids, octanoic and decanoic acids, methyl laurate, ethyl oleate, polyethylene glycol monolaurate, propylene glycol dilaurate (propyleneglycol dilaurate), propylene glycol monolaurate, propylene glycol monooleate, isopropyl n-decanoate, octyldodecyl myristate, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, and wherein C is₂-C₄Compounds in which the alkane diol or triol is substituted with one or two aliphatic ether substituents.

Occlusion agents include, without limitation, silicones, mineral oils and greases, long chain acids, animal fats and greases, vegetable fats and greases, water insoluble polymers, paraffin oil, liquid paraffin, petrolatum, liquid petrolatum, white petrolatum, yellow petrolatum, microcrystalline wax, and ceresin wax.

Surfactants include but are not limited to polysorbates 20, 40, 60 and 80,(20、40、60、80)，(231, 182, 184), Sodium Dodecyl Sulfate (SDS), lecithin, lysolecithin, nonylphenoxypolyoxyethylene, lysophosphatidylcholine, polyethylene glycol 400, polyoxyethylene ether, polyglycol ether surfactant, DMSO, sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, and benzalkonium chloride.

Additional penetration enhancers are known to those of ordinary skill in the art of topical drug delivery and/or are described in the relevant text and literature.

Embodiments disclosed herein may also include a tackifier. Suitable agents include, without limitation, methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, and chondroitin sulfate.

Certain embodiments disclosed herein may include preservatives including, without limitation, benzyl alcohol, benzalkonium chloride, chlorhexidine (chlorohexidine), chlorobutanol, methyl, propyl or butyl parabens, phenyl mercury salts including, without limitation, nitrates, hydrochlorides, acetates, and borates and betaines.

In addition to the agents listed above, the compositions of the present invention may also include various other additives. These additives include, without limitation, antioxidants, astringents, perfumes, emollients, pigments, dyes, humectants, propellants, sunscreens, and other classes of materials whose presence may be cosmetically, medically or otherwise desirable. The compositions and formulations may also be used in combination with minoxidil (minoxidil) and captopril (propecia).

The compositions may also be formulated as "sustained release" formulations, so that the activity of the active ingredient lasts longer between treatments.

While particular embodiments disclosed herein may include each of the components discussed above, other particular embodiments may be required to be "substantially free" of one or more of these components in various combinations. As used herein, "substantially free" means that no component is added to the formulation and that the component cannot be present in an amount greater than about 1% w/w.

While not limiting the scope of the explicit exclusions of the preceding paragraphs, particular embodiments disclosed herein may be substantially free of one or more of the following: bimatoprost, carbomer, NaOH, TEA, ethanol, glycerol, diethylene glycol, diethyl ether, propylene glycol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, PPG-5 ceteth-20, oleic acid, isostearyl alcohol isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, triglycerides, caprylic/capric acid, benzyl alcohol, silicone and water.

All components of the formulations described herein are present in dermatologically acceptable amounts. As used herein, "dermatologically acceptable" means that the composition or components thereof are suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, and the like. The term "about" as used herein in reference to active agents and excipients refers to a change in concentration that is considered to be bioequivalent.

Embodiments disclosed herein are applicable to mammalian species, including humans and animals. In humans, the compounds of the embodiments disclosed herein can be applied to (without limitation) the scalp, face, beard, head, pubic area, upper lip, eyebrows, and eyelids. The compositions of the present invention may be used to treat a variety of hair loss disorders, including but not limited to alopecia areata, telogen effluvium, anagen effluvium, cicatricial alopecia, and cicatricial alopecia; hair shaft disorders such as tuberous brittle disease, anagen loose hair syndrome, trichotillomania, and traction alopecia; infectious hair disorders, such as tinea capitis, seborrheic dermatitis, and scalp folliculitis; genetic disorders such as androgenetic alopecia and patients suffering from hair loss due to: chemotherapy, hormonal imbalances (e.g., thyroid conditions such as hypothyroidism and hyperthyroidism, pregnancy, childbirth, pill withdrawal, and menstrual cycle changes), scalp fungal infections such as ringworm, drugs that cause hair loss such as anti-coagulant, drugs for gout, depression, hypertension, and certain cardiac medications. The formulations of the invention may be used to treat other diseases such as hair loss associated with psychological and physiological stresses such as diabetes, lupus and malnutrition, as well as from surgery, illness and high fever. Environmental factors and chemicals used for hair treatment (dyeing, coloring and bleaching).

For animals, such as mink, which are kept for their fur, the formulation can be applied for commercial reasons to the entire surface of the animal's body in order to improve the overall fur. The procedure can also be used for cosmetic reasons in animals, for example, on the skin of dogs and cats with baldness caused by mange or other diseases that lead to some degree of alopecia.

The compositions and methods of the present invention may be suitable for use in patients suffering from hair loss or in healthy patients who simply want to accelerate hair growth anywhere in the body.

The compositions disclosed herein are formulated for topical administration. The term "topical application" as used herein includes application of the formulations described herein to the cuticle or hair. The application is typically in or near the area where hair growth is desired.

Thus, suitable formulation or composition types include, without limitation, solutions, gels, ointments, foams, films, liniments, creams, shampoos, lotions, pastes, gels, sprays, and aerosols. Such formulation types may be applied in strips (swath), patches, applicators or by using impregnated dressings, depending on the condition and location of the body to be treated.

Typically, the formulations described herein are repeatedly applied to the body part to be treated for a period of time. In particular embodiments, the formulations disclosed herein may include one or more daily applications, one or more weekly applications, one or more monthly applications, or one or more yearly applications for a treatment period 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 the desired result.

The formulations disclosed herein will be administered in safe and effective amounts. As used herein, a "safe and effective amount" includes an amount sufficient for the composition to provide the desired hair growth stimulating effect at a reasonable benefit/risk ratio with any medical treatment. The amount of active ingredient used may vary within the scope of sound medical judgment from: the particular condition being treated, the severity of the condition, the cause of the condition, the duration of the treatment, the particular active ingredient employed and its concentration, the particular vehicle utilized, the overall health of the patient, the patient's tolerance to various effects of the administration, other drugs being administered to the patient, and similar factors within the specific knowledge and expertise of the patient or attending physician.

For daily administration, a suitable dose may include, without limitation, from about 0.1ng to about 100mg per day, from about 1ng to about 10mg per day, or in another embodiment from about 10ng to about 1mg per day.

Non-limiting examples of some components and their suitable concentration ranges and functions are given in table 1 below. Specific examples of non-limiting formulations or compositions are given in table 2.

Table 1: exemplary Components and functional and concentration ranges

Table 2: exemplary compositions

Example I

Preparation of bimatoprost hair growth gel compositions

The ethanol is weighed into a suitable medium bottle equipped for mixing, and bimatoprost is then added to the ethanol and stirred at moderate speed until bimatoprost is dissolved. In a separate mixing tank of water for injection, glycerol, diethylene glycol monoethyl ether and propylene glycol were added and mixed until the solvent was dispersed. The ethanol/bimatoprost solution was then added to the water mixture and mixed until the components were uniformly mixed (mixing for about 5 minutes). To the above mixture is added a carbomer thickener and mixed until well dispersed, and once dispersed, a base is added to thicken the solution into a gel. Representative formulations prepared according to the above-described methods are given in table 3 below.

TABLE 3 Bimatprost gel formulations for topical hair growth

Example II in vivo treatment

A study was conducted to systematically evaluate the appearance of hair and eyebrows on the scalp to which the bimatoprost gel formulations in table 3 were applied. The study involved 10 subjects, 5 males, 5 females, with a mean age of 70 years (range 50-94 years). Each subject was treated daily by topical application of bimatoprost from a 0.3% w/w bimatoprost formulation in Table 3.

The study was limited to subjects who had been administered bimatoprost for more than 3 months. The average duration of exposure to the 0.3% w/w bimatoprost gel formulation was 129 days (range 90-254 days) before evaluating the parameters for hair or eyebrow growth between control and study eyes (eye). The observation was performed under a slit-lamp biomicroscope with high magnification. The difference between the control area and the treated area is recorded with a camera particularly suitable for slit-lamp biomicroscopy.

The observations were as follows:

length of hair and eyebrow: an increase in hair length was observed for both groups at regular intervals. The length difference varies between about 10% up to 30%.

Number of hairs and eyebrows: an increase in the number of hairs and eyebrows on the scalp of each patient was observed. The difference in the number of hairs and eyebrows varies between about 5% and up to 30%. Whether statistically significant or not, bimatoprost with a penetration enhancer will have better and/or faster results than bimatoprost without a penetration enhancer.

The foregoing observations lead to: the 0.03% w/w bimatoprost composition penetrated the skin and allowed hair growth.

Example III topical cream

A bimatoprost topical cream at 0.2% w/w is prepared as follows: tegacid and spermaceti were melted together at 70-80 ℃. Methylparaben was dissolved in about 500gm of water and propylene glycol, polysorbate 80, bimatoprost and a penetration enhancer were added sequentially, maintaining the temperature at 75-80 ℃. The methylparaben mixture was slowly added to the melt of Tegacid and spermaceti wax with constant stirring. This addition was continued for at least 30 minutes and stirring was continued until the temperature had dropped to 40-45 ℃. Finally, enough water was added to reach a final weight of 1000gm and the preparation was stirred to remain homogeneous until cooled and coagulated.

Example IV topical cream

A bimatoprost topical cream at 0.1% w/w is prepared as follows: tegacid and spermaceti were melted together at 70-80 ℃. Dissolving methylparaben in water, sequentially adding propylene glycol, polysorbate 80, bimatoprost and penetration enhancer, and maintaining the temperature at 75-80 deg.C. The methylparaben mixture was slowly added to the melt of Tegacid and spermaceti wax with constant stirring. This addition was continued for at least 30 minutes and stirring was continued until the temperature had dropped to 40-45 ℃. Finally, enough water was added to reach a final weight of 1000gm and the preparation was stirred to remain homogeneous until cooled and coagulated.

Example v topical ointment

A paste containing 2.0% w/w bimatoprost was prepared as follows:

white petrolatum and lanolin are melted, filtered, and liquid petrolatum is added thereto. Bimatoprost, penetration enhancer, zinc oxide and calamine (calamine) are added to the remaining liquid petrolatum and the mixture is ground until the powder is finely divided and uniformly dispersed. The mixture was mixed with stirring into the white petrolatum, allowed to melt and cooled with stirring until the paste coagulated. In other variations, the zinc oxide and/or calamine may be omitted such that the formulation is substantially free of zinc oxide or calamine.

Example VI ointment

A paste containing 5% w/w bimatoprost and a penetration enhancer was prepared by adding the active compound to light liquid petrolatum. White petrolatum was melted together with lanolin, filtered, and the temperature was adjusted to 45-50 ℃. Liquid petrolatum slurry was added and stirred until the paste coagulated. The paste may be packaged in 30gm tubes.

Example VII spray formulation

An aqueous spray formulation containing 0.03% w/w bimatoprost and a penetration enhancer was prepared as follows. Bimatoprost and a penetration enhancer are dissolved in water, and the resulting solution is filter sterilized. The solution is aseptically filled into sterile containers with a nozzle at the top for application. The formulation is as follows:

TABLE 4 bimatoprost spray formulation of example VII

Example VIII lotion

A bimatoprost sample and a penetration enhancer were dissolved in a vehicle of N-methyl pyrrolidone and propylene glycol to produce a 0.5% w/w bimatoprost lotion for application to the scalp or other body parts for hair growth.

Example IX. Aerosol

An aerosol containing about 0.1% w/w bimatoprost and a penetration enhancer is prepared by dissolving bimatoprost and the penetration enhancer in anhydrous alcohol. The resulting solution was filtered to remove particulates and lint. This solution was frozen to about-30 ℃. A frozen mixture of dichlorodifluoromethane and dichlorotetrafluoroethane was then added to the solution. 11.5gm of each of the resulting solutions was liquid-cooled filled into 13ml plastic-coated ampere bottles, which were capped. The aerosol can be sprayed onto the scalp or other parts of the body to grow hair.

Example X. topical foam formulation

A0.1% w/w bimatoprost topical foam formulation was prepared as follows: methylparaben was dissolved in about 500gm of water and propylene glycol, polysorbate 80, bimatoprost and a penetration enhancer were added sequentially, maintaining the temperature at 75-80 ℃. The methylparaben mixture was added slowly to Tegacid and spermaceti wax with constant stirring. This addition was continued for at least 30 minutes and stirring was continued until the temperature had dropped to 40-45 ℃. Finally, enough water was added to reach a final weight of 1000gm and the preparation was stirred to remain homogeneous until cooled and coagulated.

The alternative foam formulations in table V, prepared in a similar manner to that taught in example X, are as follows:

example XI powder spray

Powders of the compound bimatoprost and penetration enhancer are prepared by mixing their dry form with talc in a weight/weight ratio of 1: 10.

Example xii. related compounds

The compositions were prepared analogously to the procedures of the preceding examples, replacing bimatoprost disclosed in the preceding examples with equimolar amounts of the compounds listed in table 1.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". "about" refers to the variation in excipient concentration and excipient type that is considered bioequivalent according to FDA and other regulations.

Example XIII

A44 year old caucasian male with alopecia areata who had developed hair loss was administered a 0.1% w/w bimatoprost composition of Table 3 once daily for 6 months prior to bedtime. After 3 months of application, the subject will notice new hair growth where there was no hair before and the old hair follicles darken. New hair growth was observed by slit lamp biomicroscopy at high magnification and by computer-assisted image analysis. The difference between the control area and the treated area is recorded with a camera particularly suitable for slit-lamp biomicroscopy.

Example XIV

A 37 year old spanish male suffering from male pattern baldness due to androgenic alopecia was twice daily administered the 0.2% w/w bimatoprost composition of table 3 in an area of significantly reduced hair. After 63 days of application, a rapid increase in hair growth will be noted, as well as new hair growth, as measured by slit lamp biomicroscopy at high magnification and by computer-assisted image analysis. After a satisfactory level of hair growth was observed, the patient applied the 0.2% w/w bimatoprost composition only twice a week.

Example XV

A 29 year old caucasian healthy female would like to have thicker hair and more hair growth, although no disease or hair loss condition was diagnosed by the physician. 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 continued to apply the composition once per week to maintain increased hair growth.

Example XVI

A35 year old American black male diagnosed with follicular degeneration syndrome and associated hair loss will be administered the 0.03% w/w bimatoprost composition of Table 3. The composition was applied twice daily, once in the morning after a shower and once in the evening. After 46 days of application, a reduction in symptoms of increased hair growth and degenerative hair follicle syndrome will be noted. The patient continued application for an additional 6 months.

Claims (21)

1. A composition for use in hair growth by topical application comprising:

at least one penetration enhancer; and

0.01% to 5% w/w bimatoprost;

wherein the composition is formulated for topical application to the skin;

wherein the at least one penetration enhancer comprises a compound selected from the group consisting of propylene glycol, diethylene glycol monoether, ethanol, and glycerin, and further comprises a compound selected from the group consisting of benzyl alcohol, oleic acid, and glycerol monooleate.

2. The composition of claim 1, wherein the penetration enhancer comprises at least two compounds selected from the group consisting of propylene glycol, diethylene glycol monoether, ethanol, and glycerin.

3. The composition of claim 1, wherein the penetration enhancer consists of: propylene glycol, diethylene glycol monoether, ethanol, glycerol, benzyl alcohol, oleic acid, and glycerol monooleate.

4. The composition of any one of claims 1-3, wherein the diethylene glycol monoether is diethylene glycol monoethyl ether.

5. The composition of claim 1, comprising from 0.03% to 5% w/w bimatoprost.

6. The composition of claim 5, wherein the composition comprises 0.3% w/w bimatoprost.

7. The composition of claim 5, wherein the composition comprises 1% w/w bimatoprost.

8. The composition of claim 5, wherein the composition comprises 2% w/w bimatoprost.

9. The composition of claim 5, wherein the composition is in a form selected from the group consisting of a solution, a gel, an ointment, a foam, a film, a liniment, a cream, a shampoo, a lotion, a paste, a gel, a spray, and an aerosol.

10. The composition according to claim 9, wherein said composition is packaged in a kit with an applicator for application to the skin.

11. Use of a composition in the manufacture of a medicament for stimulating hair growth, wherein the composition comprises:

at least one penetration enhancer; and

bimatoprost;

wherein the medicament is formulated for topical application to the skin;

wherein the at least one penetration enhancer comprises a compound selected from the group consisting of propylene glycol, diethylene glycol monoether, ethanol, and glycerin, and further comprises a compound selected from the group consisting of benzyl alcohol, oleic acid, and glycerol monooleate.

12. The use of claim 11, wherein the composition comprises bimatoprost at a concentration of about 0.03% w/w to about 5% w/w.

13. The use according to claim 11, wherein the penetration enhancer comprises at least two compounds selected from the group consisting of propylene glycol, diethylene glycol monoether, ethanol and glycerin.

14. The use according to claim 11, wherein the penetration enhancer consists of the following compounds: propylene glycol, diethylene glycol monoether, ethanol, glycerol, benzyl alcohol, oleic acid, and glycerol monooleate.

15. The use according to any one of claims 11-14, wherein the diethylene glycol monoether is diethylene glycol monoethyl ether.

16. The use of claim 11, wherein the composition comprises 0.3% w/w bimatoprost.

17. The use of claim 11, the composition comprising 1% w/w bimatoprost.

18. The use of claim 11, wherein the composition comprises 2% w/w bimatoprost.

19. The use according to claim 11, wherein the medicament is applied to the scalp at least once daily.

20. The use according to claim 11, wherein the medicament is applied to the scalp at least once daily to treat one of the following conditions selected from the group consisting of: alopecia areata, telogen phase alopecia, anagen phase alopecia, cicatricial alopecia, and cicatricial alopecia; hair shaft abnormality, nodular brittle disease, anagen hair loosening syndrome, trichotillomania, and alopecia tractalis; infectious hair disorders, tinea, seborrheic dermatitis, scalp folliculitis, and androgenetic alopecia.

21. Use according to claim 11, wherein the medicament is applied at least once a day to the scalp and eyebrows of a patient suffering from hair loss due to: chemotherapy, hormone imbalance, scalp fungal infection, and anticoagulant, and can be used for treating gout, depression, hypertension, and heart disease.