Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/34—Alcohols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/361—Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/37—Esters of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/37—Esters of carboxylic acids
  • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/42—Amides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q7/00—Preparations for affecting hair growth

Definitions

• 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:
• 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, Ri and R 2 are as defined in the specification and a penetration enhancer.
• compositions are used in stimulating hair growth of human or non-human animals.
• hair loss 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.
• 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.
• terminal hairs are coarse, pigmented, long hairs in which the bulb of the hair follicle is seated deep in the dermis.
• Vellus hairs 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.
• 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 arylalkyi compound represented by the formula I:
• 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(R 4 ) 2 wherein R 4 is selected from the group consisting of hydrogen, a lower alkyl radical having from one to six carbon atoms,
• R 7 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.
• 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%
• 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.
• 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
• 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.
• TAA triethylamine
• 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.
• 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,
• 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%
• 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.
• 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
• 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, linole
• 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.
• ethanol for example at a concentration between
• the fatty acids may include one or more Cs-C 2 8 fatty acids, and which may be saturated, monounsaturated, or polyunsaturated.
• a saturated fatty acid may be stearic acid.
• a monounsaturated fatty acid may be oleic acid.
• a polyunsaturated fatty acid may be linoleic acid.
• the fatty ester may one or more include C8-C 2 8 fatty acids, and which may be saturated, monounsaturated, or polyunsaturated.
• a saturated fatty ester may be glyceryl monostearate.
• a monounsaturated fatty ester may be glyceryl monooleate.
• 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.
• 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.
• the first compound is a fatty acid.
• the fatty acid may be saturated or unsaturated.
• the fatty acid is selected from the group consisting of stearic acid, oleic acid, linoleic acid, and mixtures thereof.
• 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.
• 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.
• the terpene is selected from the group consisting of terpinolene, limonene, nerol, and cineol.
• the occlusive agent is selected from the group consisting of silicones, mineral oils, and water insoluble polymers.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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, follicul
• 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.
• 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.
• compositions were manufactured using the following general procedure.
• Non-aqueous components e.g. bimatoprost, ethanol, glycols
• Water was added to the non-aqueous mixture followed by the addition of the thickening agent.
• a base was added to neutralize the polymer and thicken the solution into a gel other desired composition.
• 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.
• the thickening agent was dispersed in water to form an aqueous mixture, which was then added to the non-aqueous mixture.
• a base was added to neutralize the polymer and to thicken the solution into a gel.
• 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;
• composition is formulated for topical administration to the skin.
• 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.
• the composition comprises about 1 % by weight of bimatoprost.
• 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.
• 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.
• 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.
• 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, anticoagulants, medicine for gout, depression, high blood pressure and heart disease.
• a suitable formulation for topical administration of bimatoprost may comprise one or more of the following ingredients listed in the table below:
• 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.
• 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 :
• the compound is a cyclopentane heptanoic acid, 2- (phenyl alkyi or phenyloxyalkyl) represented by the formula II:
• the compound is a compound of formula III:
• hatched lines indicate a configuration
• solid triangles are used to indicate ⁇ configuration.
• y is 1 and x is 0 and R-i , R 2 and R 3 are hydroxy.
• One exemplary active compound is cyclopentane N-ethyl heptanamide- 5-cis-2-(3a-hydroxy-5-phenyl-1 -trans-pentenyl)-3,5-dihy- droxy, [1 ⁇ ,2 ⁇ ,3 ⁇ ,5 ⁇ ], also known as bimatoprost and sold under the name of LUMIGAN by Allergan, Inc., California, USA. This compound has the following structure:
• the compound will generally range from about 1 x 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.
• 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.
• the pharmaceutical formulations disclosed herein can include one or more penetration enhancers.
• 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.
• 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 Cs-C 2 8 chain length, stearyl alcohol, oleyl alcohol, palmityl alcohol, and lauryl alcohol, and combinations thereof.
• 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 C 8 -C 2 8 fatty acids and fatty esters, such as C 4 -C 2 o 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
• 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.
• nonionic, anionic, and cationic agents 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
• lecithin lecithin, lysolecithin, nonylphenoxypolyoxyethylene, lysophosphatidylcholine, polyethylenglycol 400, polyoxyethylene ethers, polyglycol ether surfactants, sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, docusate sodium, and benzalkonium chloride.
• DDAIP 2-dimethylaminopropionic acid dodecyl ester
• terpenes including terpinolene, limonene, nerol, cineol
• sulfoxides such as DMSO
• cyclic ethers such as Didecyldimethylammonium bromide (DDAB), sodium taurodeoxycholate, triethylamine; octyl salicylate, and combinations thereof.
• DDAB Didecyldimethylammonium bromide
• 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.
• compositions of the present invention may be included 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.
• 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.
• compositions or components thereof are suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, and the like.
• 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.
• 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.
• the compounds of embodiments disclosed herein can be applied without limitation, to the scalp, face, beard, head, pubic area, upper lip, eyebrows, and eyelids.
• 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.
• alopecia areata,
• 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).
• 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.
• 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.
• compositions disclosed herein are formulated for topical administration.
• topical administration 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.
• 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.
• formulations described herein will be applied repeatedly for a sustained period of time to the part of the body to be treated.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 1 1 .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.
• 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.
• 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.
• compositions are similarly prepared substituting an equimolar amount of a compound of Table 1 A for the bimatoprost disclosed in the preceding Examples.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• bimatoprost solution 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
• 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.
• Transcutol® refers to a commercial product sold by Gattefosse, and which comprises diethylene glycol monoethyl ether.
• Example 19 bimatoprost gel formulation without oleyl alcohol
• 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
• the formulations described in Tables 7, 8, and 9 above were tested with an in vitro system comprising a 1 .0 cm 2 Franz Cell diffusion chamber.
• 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 ⁇ 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.
• 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
• 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
• Table 1 1 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.
• 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.
• 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.
• 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.
• 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 1 1 .
• 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 [00113] 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 1 1 .
• Example 31 Additional in vitro testing
• 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%).
• 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 1 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.
• 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 1 1 .
• 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.
• a base formulation from Table 25 will be combined with at least two ingredients from Table 26.
• the at least two ingredients from Table 26 are one fatty acid and one fatty ester.
• 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.
• 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
• DIA digital image analysis
• TAHC Target Area Hair Count
• THW Target Area Hair Width
• TAHD Target Area Hair Darkness
• Safety measures included adverse event monitoring, local tolerability assessment, clinical laboratory testing, vital signs, 12-lead electrocardiograms (ECGs), and physical examinations.
• DIA Digital image analysis
• Table 27 Summary of Treatment-Related Adverse Events (AEs)
• Topical Minoxidil 5% applied twice daily in an open-label manner showed efficacy higher than any of the bimatoprost doses tested.

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