CN105263469B

CN105263469B - Including the topical composition of bimatoprost and the method for stimulating hair growth using it

Info

Publication number: CN105263469B
Application number: CN201480013418.4A
Authority: CN
Inventors: K·沃纳; K·普林; C·P·普贾瑞; P·萨博达尔; J·T·特罗格登; A·K·萨拉马; 陆光伟
Original assignee: Allergan Inc
Current assignee: Allergan Inc
Priority date: 2013-03-14
Filing date: 2014-02-07
Publication date: 2018-11-02
Anticipated expiration: 2034-02-07
Also published as: CN109106606A; AU2014242317B2; CN105263469A; KR20150129733A; HK1220384A1; EP2968093A1; WO2014158373A1; JP6082158B2; JP2016512246A; RU2015143409A; RU2703713C2; CA2900285A1; AU2014242317A1

Abstract

Disclosed herein is the method and compositions for stimulating hair growth, the wherein described composition includes the cyclopentane heptanoic acid indicated by Formulas I, 2- naphthenic base or aryl alkyl compound and penetration enhancer, wherein dotted line key is indicated presence or absence of double bond, the double bond can be in cis or trans configuration, and A, B, Z, X, R₁And R₂As defined in the description.Such composition is used to stimulate the hair growth of people or non-human animal.

Description

Including the topical composition of bimatoprost and the method for stimulating hair growth using it

Related application

This application claims the priority for the U.S. Provisional Application Serial No. 61/783,962 that on March 14th, 2013 submits, and And the part continuation application of U.S.Application Serial Number 14/163,954 that the application or on January 24th, 2014 submit, the U.S. Application serial no 14/163,954 is the continuation application for the U.S.Application Serial Number 12/940,711 submitted on November 5th, 2010, The U.S.Application Serial Number 12/940,711 requires the U.S. Provisional Application Serial No. 61/259,368 submitted on November 9th, 2009 Priority, these application disclosures be incorporated herein by reference herein.

Invention field

Disclosed herein is for stimulating hair growth and treating topical composition and the side of the illness for leading to trichomadesis Method, wherein the composition include that the cyclopentane heptanoic acid indicated by Formulas I, 2- naphthenic base or aryl alkyl compound and infiltration promote Agent：

Wherein dotted line key is indicated presence or absence of double bond, which can be in cis or trans configuration, and A, B, Z, X, R₁And R₂It is defined as in the description.Such composition is used to stimulate the hair growth of people or non-human animal.

Background of invention

Dermatologist confirmed many different types of trichomadesis, most commonly " baldness " or " alopecia ", wherein people Dropped hair at the temples on it and top of (most of is male) beginning.However, trichomadesis is attributable to many Other illnesss.

Trichomadesis is often accompanied by the variation of growth cycle of hair.The hair of all mammals is by including growth Phase (anagen phase), catagen (catagen phase) and the life cycle including stand-down (telogen phase). Growth period is the period of hair active growth.On scalp, this period continues 3-5.Catagen is to be in growth period and stop 1-2 weeks short transition phase when being between the phase only.Last stand-down is considered as all " resting stages " for growing and stopping.This Also relative brevity of a period lasts about 3-4 months, trichomadesis later and new hair starts to grow.With the breaking-out of baldness, place It is become larger in the ratio of the hair of stand-down, and the ratio for being in the hair of active growth phase then correspondingly becomes smaller.

Additionally, there are different types of hairs, including terminal hair, hair and the terminal hair of finishing.Terminal hair is coarse, coloured It becomes mildewed, wherein follicle bulb is located at deep dermis.On the other hand, hair is the thin and thin undercoat without color, and wherein ball top is located at Corium surface.Eyelashes and eyebrow are seen by the terminal hair of finishing.With the deterioration of alopecia, it will change, wherein hair from Body becomes hair type from terminal hair.Therefore, alopecia (baldness) further includes lacking for terminal hair.

A kind of non-drug therapy for alopecia is hair transplantation.Skin (Plugs of skin) containing hair is from hair The scalp region being growing is transplanted to bald areas.Although this method can be with successful, its high cost, consumption When and pain.Other non-drug correlation techniques of hair growth include ultraviolet radiation, massage, psychotherapy and kinesiatrics. However, these methods are not acknowledged as effectively.Even such as vascular reconstruction surgery or acupuncture therapy have shown that seldom (if If having) effect.

Summary of the invention

Disclosed herein is the cyclopentane heptanoics for applying a effective amount of at least one penetration enhancer for part and being indicated by Formulas I The composition and method of acid, 2- naphthenic base or aryl alkyl compound：

Wherein dotted line key indicates that, presence or absence of double bond, which can be in cis or trans configuration, and A is with 2 to 6 The alkylidene or alkenylene of carbon atom, the group can be interrupted by one or more oxo groups and by one or more hydroxyls, Oxo base, alkoxy or alkyl carboxyl (akylcarboxy) substitution, wherein alkyl include 1 to 6 carbon atom；B is with 3 to 7 The naphthenic base of a carbon atom, or the aryl selected from the group being made of hydrogen, the low-carbon alkyl with 4 to 10 carbon atoms, wherein miscellaneous Atom is selected from the group being made of nitrogen-atoms, oxygen atom and sulphur atom；X is -- N (R₄)₂, wherein R₄Selected from by hydrogen, have 1 to 6 The low-carbon alkyl of carbon atom,

The group of composition,

Wherein R₅For the low-carbon alkyl with 1 to 6 carbon atom；Z Wei ═ O；R₁And R₂In Ge Wei ═ O, -- OH or -- O(CO)R₆Group, and another is -- OH or -- O (CO) R₆Or R₁Wei ═ O and R₂For H, wherein R₆To have 1 to about 20 carbon The saturated or unsaturated acyclic hydrocarbon group of atom, or

--(CH₂)mR₇, wherein m is 0 or integer of 1 to 10, and R₇For naphthenic base or hydrocarbon with 3 to 7 carbon atoms Base aryl or heteroaryl, as hereinbefore defined, compound are free form or its pharmaceutically acceptable salt, are applied suitable for part It adds in the particular formulations of mammal skin and is combined with penetration enhancer.

In one embodiment, the cyclopentane heptanoic acid indicated by Formulas I, 2- naphthenic base or aryl alkyl compound are chemical combination Object bimatoprost.

Another embodiment includes a kind of composition, and composition includes the bimatoprost of following concentration：About 0.001- 1.5%w/w, 0.01%w/w are to 1.0%w/w, 0.02%w/w to 1.0%w/w, 0.03%w/w to about 1.0%w/w, 0.03% W/w is to 0.9%w/w, 0.04%w/w to 0.8%w/w, 0.05-0.7%w/w, 0.06%w/w to 0.6%w/w, 0.07%w/w To 0.5%w/w, 0.08-0.4%w/w, 0.09-0.3%w/w, 0.03%w/w to 5%w/w, 0.3%w/w to 3%w/w, 1% W/w to 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.Preferably than horse forefront Plain concentration range is about 2%w/w to 4%w/w, more preferably from about 2.5%w/w to 3.5%w/w.These preferred bimatoprosts Concentration range allows to realize between the required pharmacotoxicological effect and any unwanted side effect of composition unexpected good Good balance.It was previously believed that for stimulating the bimatoprost composition of hair growth that should have much lower bimatoprost Concentration；Have been surprisingly found out that situation is really not so now.

It can also include following excipient：The carbomer of a concentration of about 0.05-1.0%w/w, a concentration of about 0.01%w/w To the alkali of about 2.0%w/w, the ethyl alcohol of a concentration of about 10%w/w to about 90%w/w, a concentration of about 1.0%w/w to about 20%w/w Glycerine, a concentration of about 1.0%w/w to about 50%w/w diethylene glycol monoethyl ether, a concentration of about 0.1%w/w to about 5.0% The polysorbate20 of w/w, the polysorbate40 of a concentration of about 0.1%w/w to about 5.0%w/w, a concentration of about 0.1%w/w To the polysorbate60 of about 5.0%w/w, the polysorbate80, a concentration of of a concentration of about 0.1%w/w to about 5.0%w/w PPG-5 ceteths (ceteth) -20, a concentration of about 0.1%w/w to about 5.0% of about 0.1%w/w to about 5.0%w/w The oleic acid of w/w, the isostearyl isostearate ester of a concentration of about 0.1%w/w to about 10%w/w, a concentration of about 0.1%w/w are extremely The isopropyl myristate of about 10%w/w, a concentration of about 1%w/w to about 50%w/w dimethyl ether, it is a concentration of about The diethylene glycol of 1%w/w to about 50%w/w, the dipropylene glycol of a concentration of about 1%w/w to about 50%w/w, a concentration of about 0.1% The caprylic/capric (caprylic/capric) of w/w to about 10%w/w, the benzene first of a concentration of about 0.1%w/w to about 2.0%w/w 40 castors of PEG of alcohol, the polysiloxanes of a concentration of about 0.1%w/w to about 10%w/w, a concentration of about 0.1%w/w to 20%w/w Sesame oil, 35 castor oil of PEG of a concentration of about 0.1%w/w to 20%w/w, a concentration of about 0.1%w/w to 10%w/w oleyl alcohol, The water of the glyceryl monooleate of a concentration of about 0.1%w/w to 10%w/w and/or a concentration of about 0%w/w to about 90%w/w.

Another embodiment includes a kind of composition, and composition includes the bimatoprost of about 0.1%w/w, about 0.10% The diethylene glycol monoethyl ether of the ethyl alcohol of the NaOH of the carbomer of w/w, about 0.035%w/w, about 15.0%w/w, about 10.0%w/w The water of about 74.8%w/w.

Another embodiment includes a kind of composition, and composition includes the bimatoprost of about 0.1%w/w, about 0.15% The triethylamine (TEA) of the carbomer of w/w, about 0.22%w/w, the diethylene glycol of the ethyl alcohol of about 15.0%w/w, about 10.0%w/w The water of the polysorbate20 of single ether, about 4.0%w/w and about 70.5%w/w.

Another embodiment includes a kind of composition, and composition includes the bimatoprost of about 0.1%w/w, about 0.125% The diethylene glycol monoethyl ether of the ethyl alcohol of the TEA of the carbomer of w/w, about 0.18%w/w, about 30.0%w/w, about 20.0%w/w and The water of about 49.59%w/w.

Another embodiment includes a kind of composition, and composition includes the bimatoprost of about 0.1%w/w, about 0.10% The propylene glycol of the ethyl alcohol of the TEA of the carbomer of w/w, about 0.15%w/w, about 30.0%w/w, about 20%w/w and about 49.7%w/w Water.

Another embodiment includes a kind of composition, and composition includes the bimatoprost of about 0.1%w/w, about 0.20% The glycerine of the ethyl alcohol of the TEA of the carbomer of w/w, about 0.22%w/w, about 60.0%w/w, about 5.0%w/w and about 34.48%w/w Water.

Another embodiment includes a kind of composition, and composition includes the bimatoprost of about 0.1%w/w, about 0.25% The polysorbate20 peace treaty of the ethyl alcohol of the TEA of the carbomer of w/w, about 0.38%w/w, about 60.0%w/w, about 4.0%w/w The water of 35.27%w/w.

Another embodiment includes a kind of composition, and composition includes the bimatoprost of about 0.1%w/w, about 0.25% The diethylene glycol monoethyl ether of the ethyl alcohol of the TEA of the carbomer of w/w, about 0.38%w/w, about 50.0%w/w, about 10%w/w, about The water of the polysorbate20 of 4.0%w/w and about 35.27%w/w.

In some embodiments, composition includes water；A concentration of about 1%w/w is to about 4%w/w, preferably from about 2-4%w/w And the bimatoprost of most preferably 2.5-3.5%w/w；With it is one or more in the group being made up of：It is a concentration of about The cetostearyl alcohol of 0.5%w/w to about 1%w/w；A concentration of about 1%w/w is to about 3%w/w, preferably from about 2%w/w Glyceryl monooleate；The oleyl alcohol of a concentration of about 1%w/w to about 3%w/w, preferably from about 2%w/w；A concentration of about 30%w/w is extremely The ethyl alcohol of about 75%w/w；The propylene glycol of a concentration of about 10%w/w to about 25%w/w；A concentration of about 0.5%w/w to about 2%w/ W, the preferably from about benzyl alcohol of 1%w/w；The ultrez of a concentration of about 0.15%w/w；The triethanolamine of a concentration of about 0.16%w/w； With the glycerine of a concentration of about 0.5%w/w to about 10%w/w, preferably 2%w/w.

In some embodiments, composition includes water；It is a concentration of about 1-5%w/w, preferably from about 2-4%w/w, more excellent Select about 2.5-3.5%w/w, the bimatoprost that most preferred value is 3%w/w；With one kind in the group being made up of Or it is a variety of：The transcutol of a concentration of about 1%w/w to about 25%w/w, preferably from about 10%w/w；A concentration of about 1%w/w is to about The propylene glycol of 25%w/w；The glyceryl monooleate of a concentration of about 1%w/w to about 3%w/w, preferably from about 2%w/w；It is a concentration of about The oleyl alcohol of 1%w/w to about 3%w/w, preferably from about 2%w/w；The ethyl alcohol of a concentration of about 30%w/w to about 75%w/w；It is a concentration of about The propylene glycol of 10%w/w to about 25%w/w；The benzyl alcohol of a concentration of about 0.5%w/w to about 2%w/w, preferably from about 1%w/w；It is dense Degree is the carbomer ultrez of about 0.15%w/w to about 0.2%w/w；The triethanolamine of a concentration of about 0.16%w/w；And concentration It is glycerine of the about 0.5%w/w to about 10%w/w, preferably 2%w/w.

Some embodiments also may include one or more other in addition to those of being described in detail in preceding paragraph Ingredient, one or more of which ingredient are selected from the group being made up of：A concentration of about 1%w/w is to about 5%w/w, preferably 2%w/w Linoleic acid；Concentration between 0.1%w/w between about 0.5%w/w, the preferred NaLS of 0.2%w/w；It is situated between with concentration In 0.1%w/w between about 0.5%w/w, the preferred docusate sodium of 0.2%w/w.

In some embodiments, composition includes water；A concentration of about 1-5%w/w, preferably from about 2-4%w/w, more preferably The bimatoprost that about 2.5-3.5%w/w, most preferred value are 3%w/w；With in the group being made up of one kind or It is a variety of：The transcutol of a concentration of about 1%w/w to about 25%w/w, preferably from about 10%w/w；A concentration of about 1%w/w is to about The propylene glycol of 25%w/w；The glyceryl monooleate of a concentration of about 1%w/w to about 3%w/w, preferably from about 2%w/w；It is a concentration of about The oleic acid of 1%w/w to about 3%w/w, preferably from about 2%w/w；A concentration of about 1%w/w is to the Asia of about 3%w/w, preferably from about 2%w/w Oleic acid；The ethyl alcohol of a concentration of about 30%w/w to about 75%w/w；The propylene glycol of a concentration of about 10%w/w to about 25%w/w；Concentration It is benzyl alcohols of the about 0.5%w/w to about 2%w/w, preferably from about 1%w/w；The card of a concentration of about 0.15%w/w to about 0.2%w/w Wave nurse ultrez；The triethanolamine of a concentration of about 0.16%w/w；A concentration of about 0.5%w/w to about 10%w/w, preferably from about 2% The glycerine of w/w；The terpinolene of a concentration of about 0.5%w/w to about 5%w/w, preferably from about 2%w/w；A concentration of about 0.5%w/w To the limonene of about 5%w/w, preferably from about 2%w/w；The flores aurantii of a concentration of about 0.5%w/w to about 5%w/w, preferably from about 2%w/w Alcohol；The cineol of a concentration of about 0.5%w/w to about 5%w/w, preferably from about 2%w/w；A concentration of about 0.5%w/w to about 5%w/ W, the preferably from about octyl salicylate of 2%w/w；The DMSO of a concentration of about 0.5%w/w to about 5%w/w, preferably from about 2%w/w；Concentration It is DDABs of the about 0.01%w/w to about 1%w/w, preferably from about 0.2%w/w；A concentration of about 0.01%w/w to about 5%w/w, preferably The sodium taurodeoxycholate of about 2%w/w；More library esters of a concentration of about 0.01%w/w to about 1%w/w, preferably from about 0.2%w/w Sodium；The Crodamol MM of a concentration of about 1%w/w to about 30%w/w, preferably from about 25%w/w；A concentration of about 1%w/w to about 5% The polysorbate80 of w/w, preferably from about 2%w/w；A concentration of about 40%w/w is to about 80%w/w's, preferably from about 73.5%w/w Dow ST-Elastomer 10；The Dow Silky Wax 10 of a concentration of about 1%w/w to about 20%w/w, preferably from about 8%w/w； The isopropyl myristate of a concentration of about 1%w/w to about 20%w/w, preferably from about 8%w/w.

In some embodiments, composition includes water；A concentration of for example, about 0.3%w/w is to about 5%w/w, preferably from about 1- The bimatoprost that 5%w/w or about 2-4%w/w, more preferably from about 2.5-3.5%w/w, most preferred value are 3%w/w；With selected from It is one or more in below：It is a concentration of for example between 0%w/w to the ethyl alcohol between about 89%w/w；Concentration is for example between 0% W/w is to the propylene glycol between about 89%w/w；Concentration is for example between 0%w/w to the diethylene glycol monoethyl ether between about 89%w/w； Concentration is for example between 0%w/w to the benzyl alcohol between about 89%w/w；And concentration is for example between 0%w/w between about 10%w/w One or more aliphatic acid and/or fatty ester excipient.In some embodiments, aliphatic acid may include one or more C₈-C₂₈Aliphatic acid, and it can be saturation, monounsaturated or how unsaturated.In some embodiments, saturated fat Fat acid can be stearic acid.In some embodiments, monounsaturated fatty acids can be oleic acid.In some embodiments, mostly not Saturated fatty acid can be linoleic acid.In some embodiments, fatty ester may include one or more C₈-C₂₈Aliphatic acid, and It can be saturation, monounsaturated or how unsaturated.In some embodiments, saturated fat ester can be monostearate Glyceride.In some embodiments, monounsaturated fatty acid ester can be glyceryl monooleate.In some embodiments, mostly not Saturated fat ester can be ethyl linoleate.

Preferred composition includes bimatoprost, oleyl alcohol, ethyl alcohol and propylene glycol.Including the amount of bimatoprost be About 1-5%w/w, preferably from about 2-4%w/w, more preferably from about 2.5-3.5%w/w, most preferred value are 3%w/w.Including oil The amount of alcohol is about 1-10%w/w.Including the amount of ethyl alcohol be about 50-80%w/w.Including propylene glycol amount be 15- 15%w/w.

For making the example of the particularly preferred composition of hair growth include the ratio in free form by part application Bimatoprost or its pharmaceutically acceptable salt, included in the amount of bimatoprost be about 0.3%w/w to about 4%w/ w；At least one the first compound selected from aliphatic acid, fatty acid alcohol and fatty ester, wherein composition are prepared for part and apply With to skin.

In some embodiments, the first compound is aliphatic acid.The aliphatic acid can be saturated or unsaturated.? In some embodiments, aliphatic acid is selected from the group being made of stearic acid, oleic acid, linoleic acid and its mixture.In some embodiment party In case, the first compound is fatty ester.The fatty ester can be saturated or unsaturated.Fatty ester can be selected from by monostearate The group of glyceride, glyceryl monooleate and ethyl linoleate composition.In some embodiments, composition includes at least two the One compound.Composition may include the mixture of at least one aliphatic acid and at least one fatty ester.First compound can have 12-24 carbon atom.Composition can further include at least one selected from by ethyl alcohol, propylene glycol, diethylene glycol monoethyl ether and benzene The second compound of the group of methanol composition.Composition can further include at least one third selected from the group being made up of Close object：Terpene, occlusive agent, surfactant, sulfoxide, cyclic ethers, amide, amine and dimethylamino phenylpropionic acid derivatives.In some realities It applies in scheme, terpene is selected from the group being made of terpinolene, limonene, nerol and cineol.In some embodiments, it closes Suppository is selected from the group being made of polysiloxanes, mineral oil and insoluble polymer.In some embodiments, surfactant Selected from by polysorbate20, polysorbate40, polysorbate60, polysorbate80, lauryl sodium sulfate, bay The group of base sodium sulphate, DMSO and docusate sodium composition.In some embodiments, dimethylamino phenylpropionic acid derivatives are 2- diformazans Base alanine dodecyl ester.Composition can include about 1%w/w to the bimatoprost of the amount of about 4%w/w.It is highly preferred that Composition can include about 2.5%w/w to the bimatoprost of the amount of about 3.5%w/w.Most preferably, composition can include about 3% The bimatoprost of the amount of w/w.In some embodiments, composition is in the form of selected from one of group being made up of： Solution, gel, ointment, foam, film, liniment, emulsifiable paste, shampoo, lotion, paste, jelly, spraying and aerosol.One In a little embodiments, composition is packaged in for being applied to together with the giver of skin in kit.

In some preferred embodiments, the method for stimulating hair growth include to patient dermal administration it is effective The bimatoprost composition according to previously described any embodiment of amount, wherein application makes hair growth increase.Combination Object can be applied to scalp.Composition can at least be applied once a day.In some embodiments, composition is applied to scalp For treating the symptom for being selected from the group being made up of：It is alopecia areata, telogen effluvim, growth period alopecia, Cicatricial baldness, cicatrical Baldness；Hair Shaft Abnormalities, clastothrix (trichorrexis nodosa), the loose syndrome of anagen hair (trichorrexis nodosa), trichologia, traction property baldness；Infectious hair disorders, favus of the scalp (tiniea Capitis), seborrhea (sebohorreic dermatitis), scalp hair follicles inflammation (follicullitus of the ) and androgenetic alopecia scalp.In some embodiments, wherein composition is applied to due to the fact that and undergoing hair One or both of scalp and eyebrow of the patient of falling out：Chemotherapy, hormone imbalances, scalp fungal infection, anticoagulation Agent is used for gout, depression, hypertension and cardiopathic drug.

In one embodiment, include for trichogenous composition：At least one penetration enhancer；With in The bimatoprost of free form or its pharmaceutically acceptable salt, included in the amount of bimatoprost be about 1%w/w To 4%w/w；Wherein composition is prepared for local application to skin.In some embodiments, penetration enhancer be selected from by It is one or more in group consisting of：Alcohol, glycol, aliphatic acid, fatty ester, aliphatic ether, occlusive agent, surfactant, two Methylaminopropionic derivative, terpene, sulfoxide, cyclic ethers, amide and amine.

It will of course be understood that above and the literature in the whole text described in range also aim to the list covered within the scope of these One value.For example, for the preparation comprising the special component between 1-50%, also aim to disclose 5% or 49% percentage.

Composition is manufactured using following general procedure.Non-aqueous composition (such as bimatoprost, ethyl alcohol, glycol) is merged It is stirred in beaker and using the overhead mixer of propeller type (propeller type overhead mixer), until molten Liquid is clarified.Water is added in non-aqueous mixtures, adds thickener later.After thickener dispersion, addition alkali is poly- to neutralize It closes object and is gel or other required compositions by solution thickening.For example, ethyl alcohol and bimatoprost are incorporated in beaker And it is stirred using the overhead mixer of propeller type, until solution is clarified.Then the mixture is added in non-aqueous components To form non-aqueous mixtures.In a separate container, thickener is dispersed in water to form aqueous mixture, then should Aqueous mixture is added in non-aqueous mixtures.After so that non-aqueous mixtures and aqueous mixture is mixed, addition alkali is in It is gel with polymer and by solution thickening.

In yet another embodiment, for making the composition of hair growth include by part application

At least one penetration enhancer for including oleyl alcohol；With

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

Wherein the composition is prepared for local application to skin.

In some embodiments, composition include between about 0.3 weight % between about 10 weight % than horse forefront Element, preferably from about 1-5%w/w or about 2-4%w/w, more preferably from about 2.5-3.5%w/w, most preferred value are 3%w/w.At some In embodiment, composition includes the bimatoprost of about 1 weight %.In some embodiments, composition includes about 3 weights Measure the bimatoprost of %.Composition can include about the bimatoprost of 3 weight %, the oleyl alcohol of about 5 weight %, about 66 weight % Ethyl alcohol and about 22 weight % propylene glycol.Composition can be in the form of selected from one of group being made up of：Solution coagulates Glue, ointment, foam, film, liniment, emulsifiable paste, shampoo, lotion, paste, jelly, spraying and aerosol.Composition can with It is packaged together in kit in the giver for being applied to skin.

In another embodiment, the method for stimulating hair growth include to patient dermal administration it is a effective amount of such as Bimatoprost composition as described herein, wherein application makes hair growth increase.

In some embodiments, composition is applied to scalp.In some embodiments, at least apply once a day Composition.Composition can be applied to scalp for treating the symptom for being selected from the group being made up of：Alopecia areata, telogen effluvim, Growth period alopecia, Cicatricial baldness, alopecia cicatrisata；The loose syndrome of Hair Shaft Abnormalities, clastothrix, anagen hair, Trichologia, traction property baldness；Infectious hair disorders, favus of the scalp, seborrhea, scalp hair follicles inflammation and androgenetic alopecia. Composition can be applied to due to the fact that and one or both of undergoing scalp and the eyebrow of the patient of trichomadesis：Change Learn therapy, hormone imbalances, scalp fungal infection, anticoagulant, for gout, depression, hypertension and cardiopathic drug.

In some embodiments, the appropriate formulation for local application bimatoprost may include listed following in following table It is one or more in ingredient：

Specific implementation mode

Bimatoprost is intended for local delivery to skin to stimulate the moderate soluble compound of hair growth.Hair Occur long to include but not limited to that stimulation hair converts and is grown to serve as terminal hair and increases the growth rate of terminal hair.It is disclosed herein Embodiment provide the preparation of the bimatoprost containing penetration enhancer and similar compound.These penetration enhancers have Help infiltration and/or maintenance of the active component at their site of action in skin.Preparation disclosed herein can itself Anti-corrosion contains antimicrobial, such as benzyl alcohol.

According to embodiments disclosed herein, active component is expressed from the next：

Active component is provided in the particular formulations comprising penetration enhancer.It can be used for implementing implementation disclosed herein Some examples of the representative compound of scheme include compound shown in table 1：

1. representative compound of table

In one embodiment, compound is the cyclopentane heptanoic acid indicated by Formula II, 2- (phenylalkyl or phenoxy group alkane Base) or its pharmaceutically acceptable salt：

Wherein y is 0 or 1, and x is 0 or 1, and x and y are not that 1, Y is selected from the group being made up of：Alkyl, halogen (example Such as fluorine, chlorine), nitro, amino, sulfydryl, hydroxyl, alkoxy, alkyl carboxyl, halogen substitution alkyl, wherein alkyl include 1 to 6 carbon atoms etc., and n is 0 or integer of 1 to 3 and R₃Wei ═ O, -- OH or -- O (CO) R₆, wherein R₆As determined above Justice.

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

Wherein hacures indicate that α configurations, black triangle are used to indicate beta comfiguration.In another embodiment, y is 1 and x For 0 and R₁、R₂And R₃For hydroxyl.

One Exemplary active compound is the cis- -2- of pentamethylene N- ethyl heptamide -5- (3 Alpha-hydroxy -5- phenyl -1- Trans-pentenyl) -3,5- dihydroxy, [1_α,2_β,3_α,5_α], it is also known as bimatoprost, and by Allergan companies (California, the U.S.) withTitle sell.The compound has following structure：

The synthesis of above compound discloses in U.S. Patent number 5,607,978, and the United States Patent (USP) is by reference It is integrally incorporated.

The range of compound is by about the 1 × 10 of usually composition^-7%w/w is to about 50%w/w, in one embodiment For composition about 0.001%w/w to about 50%w/w and be the about 0.1%w/w of composition in another embodiment to about 30%w/w.In some embodiments, the preferred scope of reactive compound can be about 0.03%w/w to about 5%, more preferably from about 0.3%w/w to about 3%w/w and even more preferably about 1%w/w to about 3%w/w.Further include 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；In about 30-40%w/w and about 35% Range and percentage.

Pharmaceutical preparation disclosed herein may include one or more penetration enhancers.Phrase " penetration enhancer " includes promoting Their site of action is shifted or be delivered into active component and/or any of active component is maintained at their site of action Reagent.The non-limiting examples of the classification of penetration enhancer appropriate include alcohol, glycol, aliphatic acid, ether, ester, occlusive agent and table Face activating agent.Provided hereinafter the representativeness of these classifications and non-limiting examples.It will of course be understood that one or more infiltrations promote It can be combined in various embodiments disclosed herein into agent or its classification.

In one embodiment, alcohol includes but not limited to fatty alcohol and aromatic alcohol, including ethyl alcohol, propyl alcohol, normal propyl alcohol, different Propyl alcohol, butanol, octanol, benzyl alcohol and acetyl alcohol, such as U.S. Patent number 5, described in 789,244, entire contents are with the side of reference Formula is incorporated herein.Fatty alcohol includes such as saturated fatty alcohol and unsaturated fatty alcohol, including for example with C₈-C₂₈The fat of chain length Alcohol, stearyl alcohol, oleyl alcohol, palmityl alcohol and laruyl alcohol and combinations thereof.In some embodiments, oleyl alcohol can be between about 0.5%w/w To between about 50%w/w, preferably in the range of about 1%w/w between about 10%w/w, and even more preferably between about 3%w/w to about It is used between 6%w/w.Be also contemplated by 1%w/w, 1.5%w/w, 2%w/w, 3%w/w, 3.5%w/w, 4%w/w, The percentage of 5%w/w, 5.5%w/w, 6%w/w, 7%w/w, 8%w/w, 9%w/w and 10%w/w.Most preferably, oleyl alcohol can Exist with the ratio of about 5%w/w.

Glycol includes but not limited to propylene glycol, (including such as molecular weight is the poly- of about 300-8000 dalton to polyethylene glycol Ethylene glycol), diol, derivatives and other low molecular weight diols, such as glycerine and thioglycerol.

Aliphatic acid, ester and ether include but not limited to C be saturated, monounsaturated and how unsaturated₈-C₂₈Aliphatic acid and fat Fat ester, such as C₄-C₂₀It is saturated monocarboxylic acid and dicarboxylic acids, straight chain fatty acid, stearic acid, oleic acid, linoleic acid, palmitoleic acid, octanoic acid With capric acid, methyl cinnamate, ethyl oleate, mono laurate macrogol ester, mono laurate propylene glycol ester, two bay of propylene glycerine Acid esters (propylene glycerol dilaurate), glyceryl monolaurate, glyceryl monooleate, glycerol monostearate Ester, ethyl linoleate, n-capric acid isopropyl ester, octyl dodecyl myristate, diethylene glycol monoethyl ether, diethylene glycol list first Ether, Crodamol MM, isopropyl myristate and wherein C₂-C₄Alkane diol or triol are through one or two aliphatic ether substituent group Substituted compound.

Occlusive agent include but not limited to polysiloxanes (including Dow ST-Elastomer 10, Dow Silky Wax 10), Mineral oil and grease, long chain acid, animal tallow and grease, plant fat and grease, insoluble polymer, paraffin, paraffin oil, Atoleine, vaseline, liquid petrolatum, white petrolatum, yellow petrolatum, microwax and ceresine.

Surfactant includes but not limited to nonionics, anionics and cationics and combinations thereof, such as poly- sorb Alcohol ester 20,40,60 and 80,(20,40,60,80) and optionally corresponding SPAN serial (20,40,60,80),(231,182,184), lauryl sodium sulfate (SDS), are gathered 15 hydroxy stearic acid esters of macrogol Vinyl caprolactam-polyvinyl acetate-polyethyleneglycol-graft copolymer, lecithin, lysolecithin, Nonylphenoxy polyoxy Ethylene, lysophosphatidyl choline, polyethylene glycol 400 (polyethylenglycol 400), polyoxyethylene ether, polyglycol ether table Face activating agent, sodium laurate, NaLS, cetyltrimethylammonium bromide, docusate sodium and benzalkonium chloride.

Workable other penetration enhancers include dimethylamino phenylpropionic acid derivatives, such as 2- dimethylaminos propionic acid ten Dialkyl ester (DDAIP)；Terpene, including terpinolene, limonene, nerol, cineol；Sulfoxide, such as DMSO；Cyclic ethers；Acyl Amine and amine, such as didecyldimethylammonium bromide (DDAB), sodium taurodeoxycholate, triethylamine；Octyl salicylate；With its group It closes.

Other penetration enhancer will be known to the those of ordinary skill of localized drug delivery field, and/or be described in phase It closes in textbook and document.

Embodiments disclosed herein may also include tackifier.Reagent appropriate include but not limited to methylcellulose, Ethyl cellulose, hydroxyethyl cellulose, acrylamide/acryloyl dimethyl tauric acid sodium copolymer, polyacrylic acid, polyethylene Alcohol, polyvinylpyrrolidone, hyaluronic acid and chondroitin sulfate.

Certain embodiments disclosed herein may include that preservative, including but not limited to Phenoxyethanol, benzyl alcohol, benzene are pricked Oronain, Chlorhexidine, methaform, methyl-, propyl-or butyl-P-hydroxybenzoic acid, phenyl mercuric salt (include but not limited to nitric acid Salt, chloride, acetate and borate) and glycine betaine.

In addition to those of above-identified, it also may include various other additives in the present compositions.These packets Include but be not limited to antioxidant, astringent, fragrance, softening agent, pigment, dyestuff, humidizer, propellant and sun-screening agent, Yi Jiqi In the presence of can be cosmetically, medically or other aspects need other materials classification.Composition and preparation can also with minots You and propecia are combined.

Composition can also be configured to " be sustained " preparation so that when the activity of active component continues longer between treatment Between.

Although particular embodiment disclosed herein may include each component as discussed above, may need other Specific embodiment is one or more in these components of substantially free in various combinations.It is " basic as used herein On be free of " mean that the component is not added into preparation and cannot exist with any amount for being greater than about 1%w/w.

Although not limiting the clear excluded ranges of aforementioned paragraphs, particular embodiment disclosed herein can substantially not Containing one or more in following：Bimatoprost, carbomer, NaOH, TEA, ethyl alcohol, glycerine, diethylene glycol, single ether, third Glycol, polysorbate20, polysorbate40, polysorbate60, polysorbate80, PPG-5 ceteths -20, The different stearyl ester of oleic acid, isostearic acid, isopropyl myristate, dimethyl ether, diethylene glycol, dipropylene glycol, glycerine three Ester, caprylic/capric, benzyl alcohol, polysiloxanes and water.

The all components of preparation described herein will with amount acceptable in dermatology by comprising.As used herein " acceptable in dermatology " means that composition or its component are suitable for contacting with human skin and toxicity without exception, incompatible Property, unstability, allergic reaction etc..Term " about " as used herein applied to activating agent and excipient refers to being considered as biology Equivalent concentration variation.

Embodiments disclosed herein can be used for mammalian species, including humans and animals.It is disclosed herein in people The compound of embodiment can be applied in (but not limited to) to scalp, face, beard, head, pubic region, upper lip, eyebrow and eye Eyelid.The composition of the present invention can be used for treating various trichomadesis illnesss, including but not limited to alopecia areata, telogen effluvim, growth Phase alopecia, Cicatricial baldness and alopecia cicatrisata；Hair Shaft Abnormalities, such as the loose syndrome of clastothrix, anagen hair, Trichologia and traction property baldness；Infectious hair disorders, such as favus of the scalp, seborrhea and scalp hair follicles are scorching；Inherited disorder, Such as androgenetic alopecia；Be undergoing the patient due to the fact that caused trichomadesis：Chemotherapy, hormone imbalances (for example, thyroid gland symptom such as hypothyroidism and hyperthyroidism, gestation, childbirth, deactivated contraceptive and menstruation Mechanical periodicity), scalp fungal infection (such as ringworm) causes the drug (such as anticoagulant) of trichomadesis, for gout, suppression The drug that strongly fragrant disease, hypertension and certain cardiac drugs are treated.The preparation of the present invention can be used for treating de- with following relevant hair It falls：Other diseases such as diabetes, lupus and malnutrition, for example, psychological stress caused by operation, disease and high fever and Somatic Stress.Environmental factor and the chemicals being used in hair treatment (dyeing (dying), dyeing (tinting) and bleaching).

For obtain fur and in domesticated animal (for example, ermine), can for business reason its body whole surface Upper application preparation is to improve whole fur.This method can also be used for animal for cosmetic reasons, such as be applied to by leading It causes on the mange of a degree of baldness or the skin of the dog of the bald spot caused by Other diseases and cat.

The compositions and methods of the invention can be applied to the patient for suffering from trichomadesis or just want to increase body times The healthy patients of hair growth in what position.

The compositions disclosed herein is prepared for local application.Term " local application " as used herein includes will Preparation as described herein is applied on crust or hair.Apply by usually at or near the region of desired hair growth into Row.

Therefore, preparation appropriate or types of compositions include but not limited to solution, gel, ointment, foam, film, liniment, Emulsifiable paste, shampoo, lotion, paste, jelly, spraying and aerosol.Such preparation type can in strip (swath), patch, apply It applies in medicine device or is applied by using impregnated dressings, this depends on the situation of body to be treated and position.

In general, preparation as described herein will be repeatedly applied in one section of sustained period to body part to be treated.? In particular embodiment, preparation disclosed herein may include at least one day, at least one week, at least one moon, at least a year Treatment phase in apply daily it is one or many, apply weekly it is one or many, monthly apply one or many or annual application It is one or many, until treatment has realized expected result or realization and has maintained expected result.

Preparation as described herein will be applied with safe and efficient amount." safe and efficient amount " includes as used herein It is enough to make composition to provide desired hair growth effect of stimulation with rational interests/Hazard ratio of any therapeutic treatment Amount.Within a reasonable range of medical judgment, the amount of active component used can be with following change：Very pathology, the symptom treated Seriousness, the cause of disease of symptom, the duration for the treatment of, used concrete activity component, its concentration, the specific matchmaker utilized The other medicines that Jie's object, the general health of patient, patient apply the tolerance of the various influences of application, positive patient, And the similar factor within patient or attending physician's concrete knowledge and professional knowledge.

For daily administration, dosage appropriate may include but be not limited to daily about 0.1ng to about 100mg, it is daily about 1ng is to about 10mg, or is daily about 10ng to about 1mg in another embodiment.

The following table 1 A and B provide the non-limiting examples of some components and their debita spissitudo range and function.Table 2 carries The particular instance of non-limiting preparation or composition is supplied.

Table 1A:Exemplary compositions and function and concentration range

Table 1B:Exemplary compositions and function and concentration range

Table 2:Exemplary composition

Embodiment 1：The preparation of bimatoprost natural on-off cycles of hair growth gel combination

Ethyl alcohol is weighed to assembly in mixed suitable media bottle, then bimatoprost to be added in ethyl alcohol, And with medium speed's stirring until bimatoprost dissolves.Into individual blending tank add glycerine, diethylene glycol monoethyl ether and Propylene glycol simultaneously mixes until solvent disperses.Then ethyl alcohol/bimatoprost solution is added in the non-aqueous mixtures and is mixed It closes until component uniformly mixes (mixing about 5 minutes).The carbomer thickening being previously dispersed in water is added into said mixture Agent simultaneously mixes until fully dispersed, once disperseing, i.e., addition alkali is so that solution thickening is gel.The generation prepared according to the above method Table preparation is shown in the following table 3.

3. bimatoprost natural on-off cycles of hair growth topical gel formulation of table

Embodiment 2：Interior therapeutic

It begins one's study systematically to assess hair and eyebrow on the scalp using the bimatoprost gel preparation in table 3 Appearance.Research is related to 10 subjects, i.e. 5 males, 5 women, average age 70 years old (range is 50-94 Sui).It is daily logical It crosses and bimatoprost is locally applied by the 0.3%w/w bimatoprosts preparation in table 3 to treat every subject.

Research is limited to have applied the subject that bimatoprost is more than 3 months.It is evaluating between control and research eye Hair or eyebrow growth parameter before, the average duration for being exposed to 0.3%w/w bimatoprost gel preparations is (range is 90-254 days) on the 129th.It is observed with high magnification under slit lamp biomicroscope.Using especially suitable for crack Difference between the camera record control zone and treatment region of lamp biomicroscope.

It is as follows to observe result：

The length of hair and eyebrow：The hair length of routine observation to two groups all increases.Difference in length is about 10% Change between up to 30%.

Hair and eyebrow number：Observe that hair and the eyebrow number on every patient scalp increase.Hair and eyebrow number Purpose difference changes between about 5% up to 30%.Whether statistically significant, before the ratio horse containing penetration enhancer Row element all will have more preferable and/or faster effect than the bimatoprost without penetration enhancer.

Foregoing observations obtain：0.03%w/w bimatoprost composition skin permeations simultaneously make hair growth.

Embodiment 3：Topical cream.

0.2%w/w bimatoprost topical creams prepare as follows：Make Tegacid and spermaceti molten at a temperature of 70-80 DEG C Change together.Methyl p-hydroxybenzoate is dissolved in about 500gm water, and adds propylene glycol, polysorbate80, ratio successively Bimatoprost and penetration enhancer maintain 75-80 DEG C of temperature.Methyl p-hydroxybenzoate mixture is delayed with continuous stirring Slowly it is added in the melt of Tegacid and spermaceti.The addition continues at least 30 minutes under outer plus stirring until temperature declines To 40-45 DEG C.Finally, add enough water so that final weight reaches 1000gm, and stir prepared product with maintain uniformly until Cooling and condensation.

Embodiment 4：Topical cream.

0.1%w/w bimatoprost topical creams prepare as follows：Make Tegacid and spermaceti molten at a temperature of 70-80 DEG C Change together.Methyl p-hydroxybenzoate is dissolved in the water, and adds propylene glycol, polysorbate80 successively, than horse forefront Element and penetration enhancer maintain 75-80 DEG C of temperature.Methyl p-hydroxybenzoate mixture is slowly added with continuous stirring To in the melt of Tegacid and spermaceti.The addition continues at least 30 minutes under outer plus stirring until temperature drops to 40-45 ℃.Finally, enough water is added so that final weight reaches 1000gm, and stirs prepared product to maintain uniformly until cooling and solidifying Knot.

Embodiment 5：Topical ointment.

Ointment containing 2.0%w/w bimatoprosts prepares as follows：

White petrolatum and lanolin are melted, filtering, and liquid petrolatum is added thereto.Bimatoprost, infiltration are promoted Agent, zinc oxide and calamine are added in remaining liquid petrolatum, and pulverize the mixture up to powder is fine crushing and uniformly divides It dissipates.It stirs the mixture for into white petrolatum, makes its fusing and cooling under stiring until ointment condenses.In other variants, oxygen Change zinc and/or calamine can be omitted so that preparation is substantially free of zinc oxide or calamine.

Embodiment 6：Ointment.

Promoted containing 5%w/w bimatoprosts and infiltration to prepare by adding reactive compound into light liquid petrolatum Into the ointment of agent.White petrolatum and lanolin are consequently flowed together, filtered, and the temperature was then adjusted to 45-50 DEG C.Adding liquid vaseline Slurries, and ointment is stirred until condensation.The ointment can be packaged in 30gm pipes.

Embodiment 7：Spray formulation.

The aqueous spray formulation preparation for containing 0.03%, w/w bimatoprosts and penetration enhancer is as follows.It will be than horse forefront Element and penetration enhancer are dissolved in the water, and are sterilized to acquired solution by filtering.The solution is aseptically filled into sterile In container, band is useful for the nozzle applied on the top of container.Preparation is shown in the following table 4 A.Table 4B also lists replacement system Agent.

The bimatoprost spray formulation of table 4A. embodiments 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	--
		Glycerine	1
Carbomer (Ultrez 10)	--
		Triethanolamine	--
Purified water	24
		Hydrofluorocarbons, hydrocarbon propellant, CO₂Or nitrogen	49.97

The alternative bimatoprost spray formulations of table 4B.

Ingredient (%w/w)	Spray formulation (w/w%)
		Bimatoprost	0.03
Propylene glycol	5
		Diethylene glycol monoethyl ether	5
Ethyl alcohol	15
		Glycerine	1
PVP or cellulose	0.1-1%

Purified water	24
		Hydrofluorocarbons, hydrocarbon propellant, CO₂Or nitrogen	49.97

Embodiment 8：Lotion.

The sample of bimatoprost and penetration enhancer is dissolved in the medium of N-Methyl pyrrolidone and propylene glycol 0.5%w/w bimatoprost lotions are made, lotion is for being applied in scalp or other body parts so that hair growth.

Embodiment 9：Aerosol

Compare horse containing about 0.1%w/w by the way that bimatoprost and penetration enhancer to be dissolved in absolute alcohol to prepare The aerosol of forefront element and penetration enhancer.Acquired solution is filtered to remove particle and the end of a thread.The solution is refrigerated to About -30 DEG C.Then the freezing of dicholorodifluoromethane and dichlorotetra-fluoroethane is added in the solution.11.5gm can be used The cold filled plastics coating of each acquired solution 13ml amber bottles, and amber bottle is covered.Aerosol can be sprayed into scalp Or so that hair growth in other body parts.

Embodiment 10：Topical foams preparation

0.1%w/w bimatoprost topical foams preparations prepare as follows：Methyl p-hydroxybenzoate is dissolved in about In 500gm water, and propylene glycol, polysorbate80, bimatoprost and penetration enhancer are added successively, maintain 75-80 DEG C Temperature.Methyl p-hydroxybenzoate mixture is added slowly in Tegacid and spermaceti with continuous stirring.The addition is outside Add and continues under stirring at least 30 minutes until temperature drops to 40-45 DEG C.Finally, enough water is added so that final weight reaches 1000gm, and prepared product is stirred to maintain uniformly until cooling and condensation.

The following table 5 A-B describe by with taught in embodiment 10 in a manner of similar mode prepare alternative foam formulations In.

Table 5A:

Ingredient (%w/w)	Foam formulations (w/w%)
		Bimatoprost	0.03

Propylene glycol	--
		Diethylene glycol monoethyl ether	5
Ethyl alcohol	10
		Light mineral oil	6
Ceteareth 12	5
		Glycerine	--
Carbomer (Ultrez 10)	--

Table 5B:

Ingredient (%w/w)	Foam formulations (w/w%)
		Bimatoprost	0.03
Propylene glycol	--
		Diethylene glycol monoethyl ether	5
Ethyl alcohol	10
		Light mineral oil	6
Myrj 45	5
		Glycerine	--

Embodiment 11：Conspergative

The pulvis of compound bimatoprost and penetration enhancer by by their dried forms and talcum powder with 1:1: 10 weight/weight ratio mixes to prepare.

Embodiment 12：Related compound

According to the program of previous embodiment, replace comparing disclosed in previous embodiment with the compound of the table 1A of equimolar amounts Bimatoprost is similarly prepared composition.

Unless otherwise stated, the quantity of the expression composition used in specification and claims, property such as molecule All numbers of amount, reaction condition etc. are interpreted as all being modified by term " about " in all cases." about " refer to according to FDA and Other regulatory agencies are considered as the variation of the excipient concentration and excipient type of bioequivalence.

Embodiment 13

One 44 years old Caucasian male that trichomadesis is undergoing because of alopecia areata applies before sleeping in a table 3 daily 0.1%w/w bimatoprost compositions, continue 6 months.After applying 3 months, which never has hair before will be noted that There are new hair growth, and the hair follicle blackening of old hair in the place of hair.By slit lamp biomicroscope under high magnification and logical Cross computer assisted image analysis observation new hair growth.Utilize the camera note especially suitable for slit lamp biomicroscope Record the difference between control zone and treatment region.

Embodiment 14

One 37 years old Spain male that male pattern alopecia is suffered from because of androgenetic alopecia is obviously thinning in hair daily Few region applies the 0.2%w/w bimatoprost compositions in table 3 twice.After applying 63 days, it will be noted that hair growth increases Add, the virgin wool such as measured by slit lamp biomicroscope under high magnification and by computer assisted image analysis occurs It is long.After observing satisfactory hair growth level, which only applies weekly 0.2%w/w bimatoprosts group twice Close object.

Embodiment 15

It is hoped that there will be denser hair and more hair growths for one 29 years old white race healthy women, although not by doctor It is diagnosed to be disease or trichomadesis symptom.The 0.3%w/w bimatoprost compositions that the patient will daily apply in a table 3, Until observing more hair growths after using about three months.The patient continues to apply weekly a composition to tie up Hold hair growth increase.

Embodiment 16

One 35 years old Black American male for being diagnosed with hair follicle regresses syndrome and related trichomadesis is by application table 3 In 0.03%w/w bimatoprost compositions.It is daily to apply the composition twice, it is primary after morning shower, it is primary at night. After applying 46 days, it will be noted that hair growth increases and the remission of hair follicle regresses syndrome.The patient is further continued for applying 6 Month.

The other embodiments of preparation containing bimatoprost are also possible, and can be used for further stimulating hair to give birth to It is long.In some embodiments, some preparations can be particularly useful for the hair growth in stimulation scalp.

Embodiment 17：Bimatoprost pharmaceutical solutions containing oleyl alcohol

The bimatoprost pharmaceutical solutions of penetration enhancer containing 0.3%w/w bimatoprosts and comprising oleyl alcohol can be made It is standby as follows.It weighs the ingredient of the following table 7 and is distributed in the suitable medium bottle to assembly for mixing.Preferably, horse will be compared Forefront element is dissolved in ethyl alcohol, then simultaneously with oleyl alcohol, propylene glycol and hydration.Various components are mixed until uniformly mixed It closes.It should be understood that the preparation provided in table 7 is non-limiting, and other preparations are certainly possible to and are contemplated to.With The ratio of bimatoprost and oleyl alcohol is 0.06 in lower bimatoprost solution, and the ratio of bimatoprost and ethyl alcohol is 0.005, And the ratio of oleyl alcohol and ethyl alcohol is 0.083.

Bimatoprost pharmaceutical solutions of the table 7. containing oleyl alcohol

Ingredient (%w/w)	Bimatoprost solution
		Bimatoprost	0.3
Oleyl alcohol	5
		Ethyl alcohol	60
Propylene glycol	20
		Purified water	14.97

Embodiment 18：Bimatoprost pharmaceutical solutions without oleyl alcohol

Certainly, it is considered serving as the oleyl alcohol of penetration enhancer although above example includes, some compositions still may be used Not include the compound.The following table 8 illustrates the other non-limiting examples of such preparation.In bimatoprost solution below The ratio of bimatoprost and ethyl alcohol is 0.005 in 8A and 8B.

Table 8. is free of the bimatoprost pharmaceutical solutions of oleyl alcohol

Above in full text,Refer to being sold by Gattefoss é and includes diethylene glycol monoethyl ether Commercial product.

Embodiment 19：Bimatoprost gel preparation without oleyl alcohol

Other than the gel preparation provided in example 1 above, include the gel preparation of 0.3%w/w bimatoprosts Ingredient listed in the following table 9 also can be used to manufacture.

The ingredient in table 9 is configured to gel according to following procedure.First, ascorbic acid and EDTA are dissolved in total water In a part.Then, carbopol 974P are added in the solution to disperse and soak carbopol.Next, independent Container in poloxamer188 be added in another part of total water and mix to disperse.Then by carbopol Part is added in the part and mixes.Next polysorbate80, hexylene glycol and PEG 400 are incorporated in another container And it mixes until uniformly.BHA, BHT and bimatoprost are weighed into another container, add benzyl alcohol later.Ingredient is mixed It is combined until uniformly.Then, which is added in polysorbate80 part and is mixed.All parts are blended in Together, it is mixed in later in remaining water and tromethamine (its be pre-mixed together with) to neutralize gel.

Table 9:Bimatoprost gel preparation

Ingredient (%w/w)	Bimatoprost gel
		Bimatoprost	0.3
Benzyl alcohol	1
		Tromethamine	0.8
Hexylene glycol	2
		PEG 400	45
Carbomer (Ultrez 10)	1.25
		Poloxamer188	0.2
Polysorbate40	0.2
		Ascorbic acid	0.5
BHT	0.5
		BHA	0.5
EDTA	0.5
		Purified water	47.66

Embodiment 20：Testing in vitro

Using including 1.0cm²The vitro system test table 7 above of the ponds Franz diffuser casing, the preparation described in 8 and 9.? During the test, the ponds Franz include body skin sample after the in vitro people's corpse of corium (dermatomized), and sample covering is filled out Diffusion cell filled with the receptor solution fluid for simulated body fluid.

The preparation of test is applied to the skin samples of covering diffusion cell.Using two tool donor cadavers, the first tool comes from 43 Year negro male, second tool come from 59 years old Caucasian male.The preparation of each donor and test is tested in triplicate.Every square li Rice skin applies 10 μ l and tests solution.With 2 hours, 4 hours, 7 hours, 24 hours and 48 hours for interval, at every point of time Receptor solution fluid is collected, and the amount of bimatoprost is quantified.It, will be above-mentioned in order to obtain accumulation receptor solution concentration The amount of the bimatoprost calculated at each time interval is added together.Keratodermas and corium are carried out in 48 hours terminals Analysis and bimatoprost are quantitative.

10. vitro skin Permeation Results of table are summarized

As shown in upper table 10, the novel formulation of 0.3% bimatoprost preparation and table 7,8 and 9 described in table 3 is carried out Compare.In addition to the gel preparation for showing minimum Cutaneous permeation, novel formulation (all containing 0.3% bimatoprost) all shows Go out to penetrate through skin samples and enters the bigger cumulant of the bimatoprost in receptor solution.Unexpectedly, it comes from The preparation containing the oleyl alcohol as skin penetrant of table 7 shows unexpected higher relative to the preparation of other tests The accumulation receptor solution fluid concentrations of Cutaneous permeation (concentration of cuticula/epidermis and corium) and bigger.

Embodiment 21：In addition 1% and 3% bimatoprost preparation

Other preparation is prepared in a manner of similar to having been described.Table 11 illustrates the example of such preparation, illustrates this Preparation is not necessarily required to include oleyl alcohol.The ratio of bimatoprost and ethyl alcohol in bimatoprost solution A below is 0.03.Than The ratio of bimatoprost and ethyl alcohol in Bimatoprost solution B is 0.01.Bimatoprost in bimatoprost solution C with The ratio of ethyl alcohol is 0.005.The ratio of bimatoprost and ethyl alcohol in bimatoprost solution D is 0.0167.Than horse forefront The ratio of bimatoprost and ethyl alcohol in plain solution E is 0.05.

The bimatoprost preparation of table 11. 1% and 3%

Embodiment 22：Testing in vitro

The preparation of table 11 is compared with 0.3% pharmaceutical solutions of bimatoprost of table 3.Using with above example 20 Identical equipment and conventional arrangement are tested.However, here, cadaver skin sample comes from 44 years old Caucasian female and 60 years old white man Women.

12. vitro skin Permeation Results of table are summarized

The above result shows that the bimatoprost preparation with higher ethyl alcohol and propylene glycol relative amount is (that is, come from table 10 solution C, D and E) relative to other preparations show higher receptor solution and corium concentration.

Embodiment 23：Other bimatoprost preparation

Also further preparation is prepared using similar to the manufacturing technology previously described.Here, it has manufactured in upper table 13 The preparation for including the oleyl alcohol as skin penetrant.In table 13, bimatoprost in bimatoprost solution A with The ratio of oleyl alcohol is 0.6, and the ratio of bimatoprost and ethyl alcohol is 0.045, and the ratio of oleyl alcohol and ethyl alcohol is 0.076.Than The ratio of bimatoprost and oleyl alcohol in Bimatoprost solution B is 0.6, and the ratio of bimatoprost and ethyl alcohol is 0.05, and And the ratio of oleyl alcohol and ethyl alcohol is 0.083.The ratio of bimatoprost and oleyl alcohol in bimatoprost solution C is 0.6, compares horse The ratio of forefront element and ethyl alcohol is 0.05, and the ratio of oleyl alcohol and ethyl alcohol is 0.083.

The other bimatoprost preparation of table 13.

Embodiment 24：Other bimatoprost gel preparation

Also the other gel containing 10%w/w bimatoprosts is prepared using similar to the manufacturing technology previously described Preparation.The ratio of bimatoprost and ethyl alcohol in bimatoprost gel preparation below is 0.33.The following table 14 describes packet Said preparation containing special component.

The other bimatoprost gel preparation of table 14.

Embodiment 25：Testing in vitro

The preparation of table 13 and 14 is compared with 0.03% pharmaceutical solutions of bimatoprost of table 3.Using with the above reality Identical equipment and conventional arrangement used in example 20 and 22 is applied to be tested.Here, cadaver skin sample is from three tool donor corpse 54 years old Caucasian male of body-, 42 years old negro male and 26 years old Caucasian male.

15. vitro skin Permeation Results of table are summarized

Relative to the control formulation of table 3, the 3% bimatoprost solution containing oleyl alcohol show high Cutaneous permeation and Thief zone in receptor solution.Solution A goes out extra high receptor fluid concentration relative to other oleyl alcohol preparation exhibits.

In addition, the 10%w/w bimatoprost gel preparations not comprising any oleyl alcohol from table 14 show it is high true Skin concentration, but the infiltration in receptor solution with 3%w/w bimatoprosts solution as many is not shown.However, all 4 The test characteristic of kind novel formulation is superior to virgin control preparation.

Embodiment 26：Other bimatoprost preparation

The example of preparation containing bimatoprost and one or more penetration enhancers is found in the following table 16, and root It is manufactured according to previously described technology.

Table 16:In addition 3% bimatoprost preparation

Embodiment 27：Other testing in vitro

Preparation from upper table 16 is tested using vitro skin penetration testing method.Using in above example 20 and 22 Identical equipment and conventional arrangement used are tested.

Table 17:Vitro skin Permeation Results are summarized

Compared to preparation F-7, it is found that preparation F-2 to F-6 shows in receptor fluid comparable or greater compares horse Forefront element infiltration.Preparation F-2 to F-6 is also shown with higher bimatoprost amount in the dermis.Preparation F-6 containing oleyl alcohol With the highest bimatoprost concentration in corium and receptor solution respectively.

Embodiment 28：Other bimatoprost preparation

The example of preparation containing bimatoprost and one or more penetration enhancers is found in the following table 18, and root It is manufactured according to previously described technology.It should be noted that preparation F-1 and F-2 is identical as preparation shown in table 11.

Table 18:Other bimatoprost preparation

Embodiment 29：Other testing in vitro

Preparation from upper table 18 is tested using vitro skin penetration testing method.Using in above example 20 and 22 Identical equipment and conventional arrangement used are tested.

Table 19:Other testing in vitro

Compared to preparation F-1 (it has 3% bimatoprost concentration), the preparation of the bimatoprost containing 1% concentration F-3 to F-10 has to the comparable or greater bimatoprost infiltration in receptor fluid.In addition, relative to preparation F-1, system Agent F-3 and F-5 to F-10 shows higher bimatoprost amount in the dermis.Should researches show that in vitro study in compared to Preparation F-1 and F-2, glyceryl monooleate and oleic acid can be respectively used to enhancing bimatoprost and enter skin and oozing across skin Thoroughly.

Embodiment 30：Other bimatoprost preparation

The example of preparation containing bimatoprost and one or more penetration enhancers is found in the following table 20, and root It is manufactured according to previously described technology.It should be noted that preparation F-1 and F-2 is identical as preparation shown in table 11.

Table 20:Other bimatoprost preparation

Embodiment 31：Other testing in vitro

Preparation from upper table 20 is tested using vitro skin penetration testing method.Using in above example 20 and 22 Identical equipment and conventional arrangement used are tested.

Table 21:Other testing in vitro

Relative to preparation F-1, when using bimatoprost (1% relative to 3%) of relatively low percentage, preparation F- 3 to F-9 have to bimatoprost infiltration comparable or greater in receptor fluid.The combination (preparation F-4) of GMO and oleic acid And linoleic acid (preparation F-9) shows that the highest bimatoprost in receptor solution permeates.

Embodiment 32：Other bimatoprost preparation

The example of preparation containing bimatoprost and one or more penetration enhancers is found in the following table 22, and root It is manufactured according to previously described technology.It should be noted that preparation F-1 is identical as preparation shown in table 11.

Table 22:Other bimatoprost preparation

Embodiment 33：Other testing in vitro

Preparation from upper table 22 is tested using vitro skin penetration testing method.Using in above example 20 and 22 Identical equipment and conventional arrangement used are tested.

Table 23:Other testing in vitro

Compared to preparation F-1, even if when the total concentration of bimatoprost is relatively low, preparation F-2 to F-9 is still shown Receptor solution is neutralized to comparable or greater bimatoprost infiltration in corium.

Embodiment 34：Other bimatoprost preparation

The example of preparation containing bimatoprost and one or more penetration enhancers is found in the following table 24, and root It is manufactured according to previously described technology.It should be noted that preparation F-1 is identical as preparation shown in table 11.

Table 24:Other bimatoprost preparation

Embodiment 35：Other bimatoprost preparation

In some embodiments, can be manufactured as described in following two table it is several can carry out superior Cutaneous permeation can It can preparation.Using the basic preparation described in table 25, one or more aliphatic acid or fatty ester can be added thereto (in such as table 26 It is described) mixture.Preferably, basic preparation from table 25 by at least two from table 26 at subassembly.Even more Preferably, at least two ingredients from table 26 are a kind of aliphatic acid and a kind of fatty ester.It should be understood, of course, that being not regarded as this A little preparations have any specific manufacturing sequence, therefore are intended merely to facilitate understanding and present.Appoint although basic preparation is available Prepared by the bimatoprost of what debita spissitudo, but the concentration is preferably in the range of about between 0.3%w/w and about 5%w/w, more preferably About 1%w/w is to about 3%w/w, and even more preferably about 3%w/w.

Table 25:Basic preparation

Table 26:Exemplary fatty acid and fatty ester excipient

Ingredient	Example	It forms (%w/w)
			Aliphatic acid (C₈-C₂₈)
Saturation	Stearic acid	0-10
			It is monounsaturated	Oleic acid	0-10
How unsaturated	Linoleic acid	0-10
			Fatty ester (C₈-C₂₈)
Saturation	Glycerin monostearate	0-10
			It is monounsaturated	Glyceryl monooleate	0-10
How unsaturated	Ethyl linoleate	0-10

Embodiment 35：To assess the office once a day of the natural on-off cycles of hair growth for increasing the male with androgenetic alopecia The clinical trial of the effect of portion's bimatoprost solution and safety

In 2 phase multiple center trials, with 1:1:1:1:1 ratio is randomly assigned with slightly to moderate androgenetic alopecia (AGA) 18-49 Sui male, to receive the bimatoprost for being applied to scalp top area once a day with double-blind fashion (BIM) 0.3%, 0.1%, 0.03% or medium, or twice daily it is applied to the open label over the counter of scalp top area 5% solution of minoxidil (MIN), continues 6 months.It assesses within every 2 months and 2 months after completing to treat during treatment tested Person.For the BIM preparations in the research as described in upper table 3.

Utilize digital image analysis (DIA；By microdot tatoo (microdot tattoo) identification scalp at the top of it is thinning Predetermined 1-cm at the front forward position in few region²The enlarged photograph of annular region) it is carried out using the software by verification of customization It evaluates below：With terminal hair/cm²The target area hair of measurement counts (TAHC)；With mm/cm²The target area hair width of measurement (TAHW)；With the target area hair darkness (TAHD) measured with volume unit；

Other evaluations include that subject's self-assessment (SSA), researcher's overall evaluation (IGA) and whole group examine (Global Panel Review) (GPR), whole group examine the independent group that is made of 3 dermatologists in baseline (the 1 day) and observe in current interview the standardized whole photo of scalp and (or carried out in current interview in the case of IGA Field evaluation).To measure natural on-off cycles of hair growth variation from 7 grades of ordinal scales of -3 (significant decreases) to+3 (dramatically increasing).

Common main (Co-primary) efficacy endpoint measured includes variations and natural on-off cycles of hair growth variation of the TAHC from baseline SSA.Secondary efficacy terminal includes the IGA/GPR of the variation and natural on-off cycles of hair growth variation of TAHW and TAHD from baseline.

Safety measure includes Adverse event monitoring, local tolerance evaluation, clinical labororatory's test, vital sign, 12 leads Electrocardiogram (ECG) and physical examination.

Statistical power analysis, group are carried out to treatment of purpose (modified intent-to-treat) group of improvement It is treated including all receiving researchs being randomly assigned and has carried out the subject of base line measurement.It was led jointly at 6th month Efficiency analysis is wanted, analyze TAHC, TAHW and TAHD using Wilcoxon rank sum tests changes from the percentage of baseline.Using to year The Cochran-Mantel-Haenszel of age group (18-34 years old to 35-49 years old) layering examines to analyze SSA, IGA and GPR scoring Frequency distribution, and using last observation value carry down (last-observation-carried-forward) method will lack Data are attributed to 6th month.Safety measure is assessed in all subjects for receiving research drug therapy；Using card side or take uncommon You are accurate to examine the group for carrying out adverse events incidence to neutralize in pairs relatively.

As a result

307 males with AGA receive research and treat and be included in effect and safety analysis in total.With regard to people Treatment group generally fully balances for mouth statistical property and baseline characteristics.

Digital image analysis (DIA) show, compared with medium, bimatoprost 0.3% produce TAHC from baseline to 6th month notable (11.1% pair 3.3% larger of mean change percentage；P=0.008).DIA is also shown, at the 6th Month, compared with medium, had a significant improvement using the TAHW rather than TAHD of bimatoprost 0.3%；It was also seen at 4th month TAHW's significantly improves.Stop treating latter two moon, the variation using the TAHC and TAHW of bimatoprost is no longer dramatically different In medium.

6th month SSA is distributed in and has no difference between bimatoprost and medium.GPR evaluations in 6th month Rather than IGA evaluation displays, compared with medium, using bimatoprost 0.3% have >=1 grade improve (that is, scoring for+3 ,+ 2 or+1) significantly larger (21.1% pair 8.9% of the percentage of subject；P=0.030).Use bimatoprost 0.3% The improvement of GPR evaluations is maintained (16.4% pair 0% for 2 months after the treatment；P=0.017)

In 5% treatment group of open label minoxidil twice daily applied, treatment makes TAHC at 6th month from baseline Increase 18.4%.This is higher than 13% increased publications of the ≈ report after TAHC was treated at 4 months and 12 months.Most of applications Subject's (67.3%) of minoxidil 5% show hair growth >=1 grade improvement.It is any to compare horse under the dosage of test The effect of forefront element group respectively less than MIN groups the effect of

With reference to the following table 27, compared with medium, when using bimatoprost, the incidence of treatment-related adverse events is omited Height, but it is less than incidence when using minoxidil.

Table 27:The summary of treatment-related adverse events (AE)

With reference to the following table 28, most common skin-tolerant symptom is itching based on subjects reported and is based on dermatologist Drying/decortication of report；Compared with minoxidil, when using bimatoprost 0.3%, the equal smaller of frequency of the two.However, In dermatologist report, compared with using minoxidil, when using bimatoprost 0.3%, epifolliculitis is more conventional.

Table 28:The skin-tolerant reported based on subject and dermatologist

* P=0.028；P=0.001；P=0.01；§ P=0.003, relative to medium.

When using bimatoprost, clinical labororatory's parameter, vital sign, ECG or physical examination are without clinically intentional Justice or dose-dependent variation.

Conclusion

Research confirms that compared with medium, the local bimatoprost 0.3% applied once a day significantly increases trouble There is the natural on-off cycles of hair growth of the slightly subject to moderate AGA.The topical minoxidil 5% twice daily applied in a manner of open label The effect of showing the bimatoprost dosage higher than any test.Local bimatoprost shows to be used for head with fixed Long local treatment consistent safety and tolerance characteristics occurs.

Although above-mentioned specific implementation mode has shown that, is described and pointed out novel feature applied to various embodiments, It should be understood that under the premise of not departing from the spirit of present disclosure, it can be to the form and details of illustrated device or method Carry out various omissions, substitutions and changes.In addition, above-mentioned various features and method can be used independently of each other, or can be with various sides Formula combines.All possible combination and sub-portfolio are intended to and fall within the scope of the present disclosure.Above-mentioned many embodiment packets Similar component is included, and therefore, these similar components are interchangeable in different implementation scenarios.Although in certain realities Apply scheme and embodiment it is disclosed in the context that the present invention, it is understood by one skilled in the art that the present invention can exceed it is specific Disclosed embodiment extends to other alternate embodiments and/or application and its apparent modification and equivalent.Therefore, The present invention is not intended to be limited by the specific disclosure of this paper preferred embodiments.

Claims

1. a kind of composition for making hair growth by part application, it includes：

In the bimatoprost of free form or its pharmaceutically acceptable salt, included in the amount of bimatoprost be 0.3%w/w to 4%w/w；And oleic acid and glyceryl monooleate；

The wherein described composition is prepared for local application to skin,

The wherein described composition also includes ethyl alcohol and benzyl alcohol；And

The wherein described composition also includes propylene glycol and diethylene glycol monoethyl ether.

2. composition as described in claim 1, wherein the composition include bimatoprost 1%w/w, ethyl alcohol 67%w/w, Diethylene glycol monoethyl ether 10%w/w, propylene glycol 10%w/w, benzyl alcohol 1%w/w, oleic acid 2%w/w, glyceryl monooleate 2%w/ W and water 7%w/w.

3. composition as described in claim 1 further includes at least one third selected from the group being made up of Close object：Terpene, occlusive agent, surfactant, sulfoxide, cyclic ethers, amide, amine and dimethylamino phenylpropionic acid derivatives.

4. composition as claimed in claim 3, wherein the terpene is selected from by terpinolene, limonene, nerol and eucalyptus oil The group of alcohol composition.

5. composition as claimed in claim 3 is made of wherein the occlusive agent is selected from mineral oil and insoluble polymer Group.

6. composition as claimed in claim 3, wherein the occlusive agent is selected from polysiloxanes.

7. composition as claimed in claim 3, wherein the surfactant is selected from by polysorbate20, polysorbate 40, the group of polysorbate60, polysorbate80, lauryl sodium sulfate and docusate sodium composition.

8. composition as claimed in claim 3, wherein sulfoxide are DMSO.

9. composition as claimed in claim 3, wherein the dimethylamino propanoic derivatives are 2- dimethylamino propionic acid Dodecyl ester.

10. composition as described in claim 1, wherein the composition includes the amount of 1%w/w to 4%w/w than horse forefront Element.

11. composition as claimed in claim 10, wherein the composition includes the ratio of the amount of 2.5%w/w to 3.5%w/w Bimatoprost.

12. composition as claimed in claim 10, wherein the composition includes the bimatoprost of the amount of 3%w/w.

13. such as claim 1-2 any one of them compositions, wherein the composition be in the group being made up of it One form：Solution, gel, foam, film, emulsifiable paste and aerosol.

14. such as claim 1-2 any one of them compositions, wherein the composition be in the group being made up of it One form：Liniment, lotion, paste and spraying.

15. such as claim 1-2 any one of them compositions, wherein the composition be in the group being made up of it One form：Ointment, shampoo and jelly.

16. such as claim 1-2 any one of them compositions, wherein the composition and the giver for being applied to skin It is packaged in kit together.

17. being used to prepare the purposes of medicament according to claim 1-16 any one of them compositions, the medicament is for stimulating Hair growth comprising to a effective amount of bimatoprost composition of dermal administration of patient, wherein the application makes hair give birth to It is long to increase.

18. purposes as claimed in claim 17, wherein the composition is applied to scalp.

19. the purposes as described in any one of claim 17-18, wherein the composition is applied at least once a day.

20. the purposes as described in any one of claim 17-18, wherein the composition be applied to scalp for treat choosing The symptom of free group consisting of：Alopecia areata, telogen effluvim, growth period alopecia, alopecia cicatrisata；Hair Shaft Abnormalities, nodositas Trichorrhexis disease, the loose syndrome of anagen hair, trichologia, traction property baldness；Infectious hair disorders, favus of the scalp, seborrheica skin Scorching, scalp hair follicles inflammation and androgenetic alopecia.

21. the purposes as described in any one of claim 17-18, wherein the composition be applied to due to the fact that and Undergo one or both of scalp and the eyebrow of the patient of trichomadesis：Chemotherapy, hormone imbalances, scalp fungal infection, Anticoagulant is used for gout, depression, hypertension and cardiopathic drug.

22. one kind being used for trichogenous composition, the composition includes：

Oleic acid and glyceryl monooleate are as penetration enhancer；With

In the bimatoprost of free form or its pharmaceutically acceptable salt, included in the amount of bimatoprost be 1- 4%w/w；

The wherein described composition is prepared for local application to skin,

23. composition as claimed in claim 22 is also oozed comprising one or more be used as in the group being made up of Saturating accelerating agent：Occlusive agent, surfactant, dimethylamino phenylpropionic acid derivatives, terpene, sulfoxide, cyclic ethers, amide and amine.