WO2012126277A1 - 用于治疗脱发的外用逆向温敏可逆水凝胶组合物 - Google Patents

用于治疗脱发的外用逆向温敏可逆水凝胶组合物 Download PDF

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WO2012126277A1
WO2012126277A1 PCT/CN2012/000348 CN2012000348W WO2012126277A1 WO 2012126277 A1 WO2012126277 A1 WO 2012126277A1 CN 2012000348 W CN2012000348 W CN 2012000348W WO 2012126277 A1 WO2012126277 A1 WO 2012126277A1
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composition
hair loss
temperature
water
acid
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PCT/CN2012/000348
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English (en)
French (fr)
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吕绍祥
吕美博
刘乐天
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博任达生化科技（上海）有限公司
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    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
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    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C08G65/3324—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof cyclic
    • C08G65/3326—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof cyclic aromatic
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    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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    • C08J3/205—Compounding polymers with additives, e.g. colouring in the presence of a continuous liquid phase
    • C08J3/21—Compounding polymers with additives, e.g. colouring in the presence of a continuous liquid phase the polymer being premixed with a liquid phase
    • C08J3/212—Compounding polymers with additives, e.g. colouring in the presence of a continuous liquid phase the polymer being premixed with a liquid phase and solid additives
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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    • A61K2800/26—Optical properties
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    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/58—Ethylene oxide or propylene oxide copolymers, e.g. pluronics
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use

Definitions

  • the present invention relates to a reverse temperature-sensitive reversible hydrogel composition for treating and/or preventing hair loss, recovery and/or promoting hair growth, and a method of preparing and using such a composition.
  • the two hair loss boundaries continue to extend, and eventually develop into a half-moon shape.
  • the length and diameter of each hair in the adjacent hair loss area will be reduced, but the hair follicles will remain unchanged.
  • women's hair loss is characterized by the spread of thinning of the top, parietal and temporal areas of the hair, but the hairline of the hairline and the area of the occipital area are not affected.
  • Prior art techniques for treating hair loss and promoting hair growth include various pharmaceutical and health care products and/or oral medications. For example, minoxidil, commonly known as Luojian, causes hair growth and slows hair loss in some people by stimulating hair follicles on the scalp.
  • the efficacy of minoxidil is limited because only a relatively small proportion of patients have mild to moderate hair regeneration after use.
  • the commercially available drug under the trade name "Paul Law” (Merck Pharmaceuticals) is a drug containing the active ingredient of finasteride.
  • the law is "" an oral tablet.
  • the oral route is complicated by gastrointestinal irritation and complications associated with drug metabolism in the liver.
  • oral finasteride complications may result Side effects include mood disorders (Alto Mai et al., 2002, Dermatology, 29 (10): 665-9), Unilateral Breast Development (Faran et al., 2002, Dermatology Archives, 138 (4) ) : 543-4), loss of libido, erectile dysfunction and ejaculation disorders (McLealen et al., 1999, Drugs, 57 (1): 111-26).
  • compositions based on extracts from natural plants including Chinese herbal medicines for the treatment of hair loss There are also many compositions based on extracts from natural plants including Chinese herbal medicines for the treatment of hair loss. Hair-developing compositions prepared from different medicinal extracts are generally used as stimulants and accelerators for hair growth. However, these extracts generally do not exhibit a positive effect on hair growth. Even though some of the hair growth compositions have some effect, they are still defective, for example, due to skin irritation, unpleasant odors and other side effects, it is difficult to continue to use for a long time.
  • Another method of treating hair loss is hair transplantation. This method usually involves transplanting natural hair including the scalp area to the bald area. However, during hair movement, the transplanted hair usually falls after 2 to 4 weeks. Although most transplanted hair grows again after 3 to 4 months, it requires an extra hair transplant.
  • the transplantation method requires infinite cost and time, pain and limited effectiveness. Therefore, there is a need to develop an effective composition and simple method for treating and/or preventing hair loss, restoring and/or promoting hair growth, especially It is used in human hair and has a good therapeutic effect on hair loss in a short period of time. It promotes hair growth, is easy to use, and : has no side effects.
  • a reverse temperature-sensitive reversible hydrogel composition comprising: f, treating and/or preventing hair loss, restoring and/or promoting hair growth:
  • a water-soluble block comprising a mixture of at least two polyethylene oxide blocks and at least one polypropylene oxide block at a content of from 5 to 25%;
  • the present invention also relates to a reverse temperature-sensitive reversible hydrogel composition for treating and/or preventing hair loss, restoring and/or promoting hair growth, at about -45 ° C 3 ⁇ 43 ⁇ 4, preferably at about 8-40 ° C. Within the temperature range, there is a tunable transition temperature from solution to gel state.
  • the invention also relates to a reverse temperature-sensitive reversible hydrogel composition for treating and/or preventing hair loss, restoring and/or promoting hair growth, at about 4 to 50, preferably at about 8-45 It exists in a gel form in the temperature range of about °C.
  • the present invention also relates to a reverse temperature-sensitive reversible hydrogel composition having improved bioadhesion and skin permeability for treating and/or preventing hair loss, restoring and/or promoting hair growth.
  • the present invention also relates to the efficacy and efficacy of a retrograde thermosensitive reversible hydrogel composition having improved treatment for and/or prevention of hair loss, recovery and/or promotion of hair growth.
  • the invention further relates to a method for treating and/or preventing hair loss, restoring and/or promoting hair growth, wherein the method comprises applying a topical reverse temperature-sensitive reversible hydrogel composition to the scalp, followed by full massage
  • the composition is allowed to penetrate into the skin, contact the hair follicle, and then continue to allow the composition to reside on the scalp, or the composition can be rinsed off the scalp in a short period of time.
  • the invention is broadly applicable to common desorptions: the reverse temperature sensitivity defined above Reversible hydrogel compositions may be effective in treating androgenetic alopecia.
  • retrograde temperature-sensitive reversible hydrogel compositions have significant improvements in inducing and stimulating hair growth and preventing hair loss, as well as significantly increasing skin bioavailability and/or percutaneous penetration, the composition of which includes a water solubility a block copolymer, at least one associated gelling agent and at least one prophylactic or therapeutic anti-hair loss agent, the water-soluble block copolymer comprising at least two polyethylene oxide blocks and at least one polyepoxyhydrazine block 5 ⁇ /100 ⁇ A water soluble intermolecular complex.
  • the present invention is also advantageous in that the external reverse temperature-sensitive reversible hydrogel for treating hair loss can be applied to the affected part of the scalp for about 1-2 minutes and then rinsed or rinsed off like a shampoo. Even so, it can achieve equal or better efficacy as other existing resident hair loss prevention compositions.
  • a hydrogel composition herein, the term "gel” as used herein and in the appended claims means that the composition is a solid, gelatinous substance which may have a weak and soft To the hard and tough attributes.
  • a gel is a dilute system that exhibits no fluidity under steady state conditions. The transition temperature of the solution to gel or gel to solution is the observed gel melting temperature, which is determined visually by inverting the vial.
  • the vial is inverted and immersed in a water bath with a slowly rising or falling temperature.
  • the gel melting temperature is taken as the temperature point at which the gel begins to flow.
  • the so-called “reverse temperature-sensitive reversible” gel term used herein refers to a gelation process that occurs as the temperature increases rather than the temperature decreases. This is counterintuitive because the viscosity of the solution generally decreases with increasing temperature.
  • condition of use refers to all conditions under which the composition may be exposed during use, including transport and storage, and during use or treatment or personal care.
  • pharmaceutically acceptable refers to electrolytes (eg, salts).
  • alkalis, thinners, preservatives, buffers and other excipients are used interchangeably and indicate that the material can be used on human skin, esophagus, ear, vagina, rectum, and topical eyes without adverse effects such as adverse effects such as Inflammatory, itching, stinging, or systemic side effects such as nausea, dizziness, and so on.
  • resident product means that the product remains on the skin after application.
  • Resident products are products such as "anti-aging cream”, “body lotion/cream”, “deodorant”, and “hand lotion/cream”.
  • Flushing products as used herein and in the appended claims, means that the product is rinsed off in a short period of time after application and use. Flushing products are products such as “shampoo”, “hair conditioner”, “cleanser”. ⁇ All percentages mentioned in this document are percentages by weight unless otherwise stated. The following description includes a water-soluble block copolymer comprising at least two polycyclohexane blocks and at least one polypropylene oxide block. ⁇
  • polyethylene oxide polyethylene oxide
  • PE0 polyethylene glycol
  • PEG polyethylene glycol
  • Polyethylene oxide and polycyclopropene block copolymers refer to the synthesis of various molecular weights, different types of polyethylene oxide blocks (Chemical Formula 1) and polypropylene oxide blocks (Chemical Formula 2). Copolymers, from linear multi-block copolymers, side-linking branched block copolymers, and hyperbranched block copolymers and to star block copolymers. Polyepoxyethylene and polyepoxyfluorene block copolymers also include various end group modified and expanded block copolymers.
  • a and b are each an integer in the range of from about 10 to 150, representing the average number of monomer repeating units in the polymer.
  • An example of a water-soluble block copolymer of the present invention comprising at least two polyethylene oxide blocks and at least one polypropylene oxide block is a blue block copolymer commercially available under the trade name Plunik Also known as Polosham, it is available from BASF (Olive Hills, NJ).
  • a preferred poloxamer polymer is a Pluronic® F127 block copolymer as shown by the general formula HO-(E0) a (P0) b (E0) a -H (also known as mooring) Losham 407), correspondingly, the average of a is about 101 ⁇ and the average of b is about 56, and Pluronic® F108 (also known as poloxamer 338), correspondingly, a The average value is about 141 ⁇ , and the average value of -3 ⁇ 4 b is about 44.
  • Other water-soluble multi-block copolymers of the invention are chain extended, hyperbranched, or star chain block copolymers of the formula ⁇ [A originate (E0) a (P0) b (E0) human] ⁇ resort, wherein (E0) a is a polyethylene oxide block, and (P0) b is a polypropylene oxide block, a and b each An integer in the range of about 10-150', A is a monomeric repeating unit, E is an extended chain or crosslinker, and n is from 0 to 50, preferably from 1 to 20 (0 to 20 is non-living) Degradable material), more preferably 2 to 16 (0 to 16 in the case of non-biodegradable materials), an integer in the range, and m is the number of repeating units of the copolymer molecule, which is an integer equal to or greater than 2 (in practical In the range of up to about 10 million or more, preferably from about 2 to about 500, more preferably from about 3 to about 100.
  • the polymer structure formula envisaged by the present invention is ⁇ [(E0) a (P0) b (E0) a ]E ⁇ .
  • Other exemplary water-soluble block copolymers are end group modified. Block copolymer, having a general formula
  • R"G (E0) a (P0) b (E0) a -GR wherein (E0) a is a polyethylene oxide block, (P0) b is a polyepoxyhydrazine block, and G is selected from the group consisting of C"C, C-0, C(0)NH, SC, C(0)-0, a group consisting of Si-0 groups, R is a chain having a thiol chain length between C 8 _C 36 Indenyl and arylthio groups, a is between about 50 and about 150, and b is between about 35 and about 70.
  • An exemplary water soluble end group modified block copolymer is a mercapto or arylsulfonyl end group modified block copolymer comprising at least two polyethylene oxide blocks and at least one polyepoxyanthene block
  • the end group-modified block copolymer is a product of condensation reaction with a terminal mercapto or aralkyl alcohol.
  • the thiol group should have a hydrophobic group such as butyl or n-hexyl.
  • the hydrazino poloxamer may have the general formula R- [(E0) a (P0) b (E0) ⁇ - R' , wherein (E0) a is a polyethylene oxide block, and ⁇ is a polyglycol
  • the hydrazine block, R and R' are non-polar pendant groups, such as fluorenyl and aryl fluorenyl groups having a chain length C 6 - C 36 , and m is in the range of 1-10.
  • exemplary side-chain branch copolymers comprising at least two polyethylene oxide blocks and at least one polyglycidylene block are of the formula ⁇ , wherein (E0) a is a polyethylene oxide block, (P0) b polypropylene oxide block, a and b are each an integer in the range of about 10 to 150, and A is a main chain monomer repeating unit, which may be selected from Repeating unit linking such as ethylene, ester, amide, acylamine, polyether, siloxane, m is the number of repeating units of the copolymer molecule, and is an integer equal to or greater than 2.
  • the water-soluble multi-block polymer of the present invention is a chain-expanded polyester block copolymer of the formula ⁇ [A an (E0) a (P0) b (E0) human] E ⁇ 0 , wherein (E0) a is a polyethylene oxide block, and (P0) b is a polypropylene oxide block, and A is a monomer repeating unit, as defined above, wherein (E0) a is a 1- polyethylene oxide block, And (P0) b is a polyepoxyhydrazine block, E is an extended chain or crosslinker, n is from 0 50, preferably from 1 to 20 (0 to 20 is a non-biodegradable material), more preferably 2 to 16 (0 to 16 in the case of a non-biodegradable material), an integer in the range, and m is the number of repeating units of the copolymer molecule, which is an integer equal to or greater than 2 (in the practical range, up to about 100, 10
  • the above monomer repeating unit may be derived from an aliphatic hydroxycarboxylic acid or related ester, a lactone, a diester, a carbonate, an acid anhydride, a dioxanone, an amide, or a phase monomer, and is preferably derived from Aliphatic ⁇ -hydroxycarboxylic acid derivatives or related esters, these repeating units may be derived from the following examples: including, for example, lactic acid, lactate, glycolic acid, glycolate, or related aliphatic hydroxycarboxylic acid, ester (lactone), dimer acid or related compound, such as propiolactone, ⁇ -caprolactone, ⁇ -glutaractone, ⁇ -valerolactone, ⁇ -butyrolactone, ⁇ , ⁇ - Diethyl propiolactone, ethylene carbonate, trimethylene carbonate, ⁇ -butyrolactone, ⁇ -dioxanone, 1,5-dioxepin-2-one, trimethyl-
  • a-hydroxy acids and their corresponding cyclic dimer esters especially lactide, glycolide and hexyl esters
  • the monomers produced do not specifically refer to esters, but may include, for example, carbonates (polycarbonates), amino acids (used to produce poly Amides) and from the monomers described above or comprising nucleophilic groups and electrophilic group polymerizable related groups.
  • polyester should include copolymers derived from all of the above monomers, which are actually preferred to produce ester units.
  • poly(hydroxy carboxylic acid)' or "poly(a-hydroxycarboxylic acid)" is used to describe the multiblock UA n (E0) a .(P0) b (E0) of the polymer composition according to the invention.
  • polyester A blocks in EL wherein A is derived from a hydroxycarboxylic acid or related ester, or a dimer ester, preferably derived from an S aliphatic alpha hydroxy carboxylic acid or related ester, including a polyester, such as, for example, lactic acid, lactide, glycolic acid, glycolic acid, or an associated aliphatic hydroxy acid or ester (lactone), for example, like ⁇ -caprolactone, ⁇ -pentanelactone , ⁇ -valerolactone, ⁇ -butyrolactone and mixtures, many of which are specified herein.
  • a polyester such as, for example, lactic acid, lactide, glycolic acid, glycolic acid, or an associated aliphatic hydroxy acid or ester (lactone), for example, like ⁇ -caprolactone, ⁇ -pentanelactone , ⁇ -valerolactone, ⁇ -butyrolactone and mixtures, many of which are specified herein.
  • Suitable end group modifying compounds may include, but are not limited to, ionic polymers.
  • the ionic polymer in the present invention includes linear, branched and/or crosslinked polymers.
  • carboxyvinyl polymer monomers such as acrylic acid, methacrylic acid; ethacrylic acid, phenylacrylic acid, pentenoic acid and the like.
  • Poly(acrylic acid) and its salts are preferred for carboxyvinyl polymers.
  • One or more polycarboxyvinyl polymers can be used in the polyether compositions of the present invention.
  • Preferred reverse temperature-sensitive reversible hydrogel compositions of the present invention may comprise from about 5% to 25%, preferably from 8% to 18%, most preferably from 10% to 15% by weight, including at least two poly A water soluble block copolymer of an ethylene oxide block and at least one polypropylene oxide block. Needless to say, those skilled in the art will select a suitable water-soluble block copolymer comprising at least two polyethylene oxide blocks and at least one polyglycolide block, so that it is in accordance with the invention.
  • the advantageous properties of the reverse temperature-sensitive reversible hydrogel composition are either absent or have no significant adverse effects of S.
  • associated gel adjuvant is meant an adjuvant selected from the group consisting of a gel that can modify other gelling agents, and at the same time, when they are present alone, have almost any direct effect on the viscosity of the ice solution. 5 ⁇ /100 ⁇ , and its own in the essence, the gel adjuvant itself has a very limited solubility in water, and usually less than 0. 5 g / 100 ml, preferably less than 0.3 g / 100 ml, and it is There is no ability to thicken or gel the water.
  • the reverse temperature-sensitive reversible hydrogel of the present invention comprises a water-soluble block copolymer comprising at least two polyethylene oxide blocks and at least one polypropylene oxide block.
  • the solution to the gel transition temperature is It is regulated by the addition of an effective amount of at least one associated gel adjuvant or over a relatively large range of use temperatures.
  • the present invention provides pharmaceutical, cosmetic and personal care product compositions having the properties set forth above for the controlled release or sustained release of an effective amount of the active ingredient.
  • associated gel adjuvants include, but are not limited to, ethoxylated fatty alcohols, alkoxylated fatty alcohol esters, decyloxydecyl alcohols, decyloxydecyl alcohol esters; alkoxylated aromatics Alkyl alcohol, aliphatic hydroxycarboxylic acid, aliphatic hydroxycarboxylic acid ester, aromatic hydroxycarboxylic acid, poly(hydroxycarboxylic acid), alkoxylated sorbitan ester, ethoxylated triglyceride, alkoxylation Glyceryl esters, alkoxylated sorbitan esters, polyol esters, sorbitan esters, and the like.
  • Suitable for use with the present gel adjuvant include, but are not limited to, laureth-2, laureth-3, laureth-4, lauryl-5, laureth-6, and the like; oleth -2, oleth - 5 and oleth-10, and similar articles; C 12-13 pareth -2, C 12 - 13 alcohol polyether chain alkyl -3, C 12-13 pareth -4, C 12 - 13 alcohol polyether chain alkyl -5, C 12-13 pareth - 6, and the like; dipropylene glycol myristyl -2 Alcohol-9 adipate, dipropylene glycol-2 myristyl ⁇ polyether-10 adipate, dipropylene glycol-2 myristate-11 adipate, and the like; Acids and derivatives thereof; paraben methyl, paraben ethyl, paraben propyl, paraben, and the like.
  • the solubility of the gel adjuvant in the water at 20 ° C is less than 0.5 g / 100 ml, preferably less than 0.3 g / 100 ml, and can be embedded with the above water-soluble
  • the segment copolymer forms a water soluble intermolecular complex.
  • the unrecognized person in the field will choose a suitable water-soluble block copolymer comprising at least two polyethylene oxide blocks and at least one polyglycolide block to form a water-soluble solution.
  • the associated gel adjuvant of the sexual complex is such that there is no, or substantially no significant, adverse effect on the advantageous properties of the retrograde temperature-sensitive hydrogel composition in accordance with the present invention.
  • the following describes the prevention or treatment of anti-hair loss agents.
  • the reverse temperature-sensitive reversible hydrogel composition comprises at least one prophylactic or therapeutic anti-hair loss agent.
  • prophylactic or therapeutic anti-hair loss agents may be selected from the group consisting of, but not limited to: benzalkonium chloride, benzethon chloride, phenol, estradiol, diphenhydramine hydrochloride, Chlorpheniramine, chlorophyll derivative, cholesterol, salicylic acid or salicylic acid derivative, p-hydroxybenzoic acid and its ester derivatives, acetaminophen, ibuprofen, cystine, red pepper, niacin Benzyl ester, DL menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, eucalyptus, steroids, resorcinol, minoxidil, crotacin, pinacidil, nanonidil, two Phenylcyclopropyl ketone, copper peptide, antiandrogen drugs such as cyproterone acetate, danazol, flutamide, 5-alpha reductarate, 5-alpha
  • a prophylactic or therapeutic anti-hair loss agent which is particularly suitable for use herein may include, but is not limited to, salicylic acid or a salicylic acid derivative, a hydroxybenzoic acid hydrazine derivative thereof, menthol, minoxidil, flurazepam Amine, finasteride, or the like.
  • the prophylactic or therapeutic hair loss prevention agents listed above are merely exemplary.
  • the retrograde temperature sensitive reversible gel compositions of the present invention are particularly suitable for use in treating and/or preventing hair loss, restoring and/or promoting hair growth.
  • the reverse temperature sensitive reversible hydrogel composition will be in the form of a gel or a liquid, most preferably, the reverse temperature sensitive reversible hydrogel composition will be in a gel state or a A liquid form having gelling ability after contact with skin or mucosal tissue. 01% ⁇ 15 ⁇ Anti-hair loss agent for prevention or treatment.
  • a suitable effective amount of a prophylactic or therapeutic anti-hair loss agent selected at a composition temperature and pH is simply added to the hydrogel combination.
  • the selected prophylactic or therapeutic anti-hair loss agent will dissolve in the solution or will be uniformly dispersed.
  • the pharmaceutical retrograde reversible hydrogel composition of the present invention may comprise pharmaceutically and/or physiologically acceptable excipients including, but not limited to, physiologically acceptable surfactants, solvents, humectants, emollients. , penetration enhancers, colorants, perfumes, and the like, which are well known in the art, some of which are described in the following context.
  • the hydrogel composition has a preferred pH in the range of from about 1 to about 12. Other preferred embodiments may be in the pH range of about 3.5 to 10.
  • the hydrogel compositions of the present invention further comprise one or more ingredients that function to promote penetration through the upper stratum corneum barrier to the underlying layer of the skin.
  • skin penetration enhancers include, but are not limited to, propylene glycol, azone, ethoxylated dipropylene glycol, isosorbide dinitrate, urea, ethanol, dimethyl sulfoxide, and the like.
  • the hydrogel composition of the present invention further comprises a pharmaceutically and/or physiologically acceptable humectant, preferably at a concentration of from about 0.01% to about 40%, preferably from about 0. From 1% to about 30%, preferably from about 0.5% to about 25%.
  • Preferred humectant compounds include, but are not limited to, selected from the group consisting of polyhydric alcohols, sorbitol, glycerin, urea, betaine, D-panthenol, DL-panthenol, calcium pantothenate, royal jelly, dipyridylthioethylamine, pantethein Ethylamine, panthenol ethyl ether, guanidine acid, pyridoxine, pantosyl lactate complex vitamin 8, sodium pyrrolidone carboxylate, hexan-1,2,6-triol, hydrazine or its derivatives And their mixtures.
  • Polyols suitable for use herein include, but are not limited to, polyalkylene glycol, preferably olefin polyols and derivatives thereof, including propylene glycol, dipropylene glycol, poly(3); alcohols, polyethylene glycols and derivatives thereof, Sorbitol, hydroxypropyl sorbitol, erythritol, threitol, 'pentaerythritol, xylitol, sorbitol, mannitol, pentanediol, ethylene glycol, butylene glycol (eg 1, 3-butadiene) Alcohol), hexanetriol (eg 1,2,6-ethylenetriol), trimethylolpropane, neopentyl glycol, glycerol, ethoxyglycerol, 1, 3-propanediol, propoxyglycerol And mixtures thereof.
  • polyalkylene glycol preferably olefin polyols
  • polyol oxirane derivatives are also suitable for use herein.
  • Preferred polyols of the invention are selected from the group consisting of glycerin, butylene glycol, propylene glycol, pentanediol, ethylene glycol, dipropylene glycol, polyethylene glycol, hexanetriol, glycerin and propoxy glycerol, and mixtures thereof.
  • Humectants suitable for use herein also include sodium 2-pyrrolidone-5-carboxylic acid (NaPCA), hydrazine; glycolic acid and glycolate (such as ammonium and quaternary ammonium decyl ammonium), lactic acid and lactate ( Such as ammonium and quaternary ammonium decyl ammonium; various forms (eg, aloe vera gel) hyaluronic acid and its derivatives ' (such as salt derivatives, such as sodium hyaluronate); lactine amine ethanolamine, ethanolamine acetamide , urea, betaine, panthenol and its derivatives; and mixtures thereof.
  • NaPCA sodium 2-pyrrolidone-5-carboxylic acid
  • hydrazine such as ammonium and quaternary ammonium decyl ammonium
  • lactic acid and lactate Such as ammonium and quaternary ammonium decyl ammonium
  • the hydrogel composition of the present invention comprises a pharmaceutically and/or physiologically acceptable emollient, preferably at a concentration of from about 0.01% to about 20%, preferably from about 0. 1% ⁇ 15%, preferably from 0.5% to about 10%.
  • emollients are lanolin, castor oil, mineral oil, silicon products and petrolatum.
  • Other ingredients used as emollients include high oleic sunflower oil and its derivatives, macadamia nut oil and its derivatives, grape seed oil, hazelnut oil, olive oil, sesame oil and other natural seeds and nut oils, such as jojoba Oil, and its derivatives.
  • emollients include corn oil, cottonseed oil, rose water, almond oil, avocado oil, cocoa butter, almond oil, and myristyl alcohol.
  • fatty acids derived from plants or animals are used as emollients.
  • Fatty acids used in cosmetic formulations include stearic acid, oil Acid, myristic acid and palmitic acid.
  • Other typical fatty acids include linoleic acid, moringhisic acid, palmitoleic acid.
  • Fatty alcohols are also used as emollients. Examples of fatty alcohols used as emollients are lauryl alcohol, cetyl alcohol, stearyl alcohol, jojobaol and oleyl alcohol.
  • the hydrogel composition of the present invention further comprises a surfactant, preferably at a concentration of from about 0.01% to about 15%, preferably from about 0.1% to about 10%.
  • the surfactant may be an anionic, or cationic, or amphoteric, or non-subsurfactant.
  • nonionic surfactants include polyhydric alcohol fatty acid esters such as sorbitol or glycerol mono, di, tri or tetraoleate or stearic acid, glycerol and polyethylene glycol laurate; polyethylene glycol fatty acid Ester (polyethylene glycol monostearate or monolaurate) '; polyoxyethylene etherified sorbitol fatty acid ester (stearate or oleate); polyoxyethylene etherified decyl ether (12 ⁇ ;.16, ⁇ or ⁇ ).
  • polyhydric alcohol fatty acid esters such as sorbitol or glycerol mono, di, tri or tetraoleate or stearic acid, glycerol and polyethylene glycol laurate
  • polyethylene glycol fatty acid Ester polyethylene glycol monostearate or monolaurate
  • polyoxyethylene etherified sorbitol fatty acid ester stearate or oleate
  • anionic surfactant examples include a carboxylate (salt) (sodium 2(2-hydroxyalkoxy)acetate), an amino acid derivative (N-acylglutamic acid, N-acetylglycine or an acylamino acid), Sulfhydryl sulfate, mercaptoether sulfate and oxyethylene ether etherified derivatives, sulfonates, isethionates and N-acyl isethionates, taurates and N-acyl N-methyl Taurine, sulfosuccinate, mercaptosulfonate, phosphate and sulfhydryl phosphate.
  • carboxylate salt
  • amino acid derivative N-acylglutamic acid, N-acetylglycine or an acylamino acid
  • Sulfhydryl sulfate mercaptoether sulfate and oxyethylene ether etherified derivatives
  • sulfonates isethionate
  • the 3 ⁇ 4 ⁇ 7 gum composition further comprises a rheology modifier, the concentration of which is preferably from about
  • examples of rheology modifiers include, but are not limited to, carbomers, acrylate copolymers, polyacrylamides, polysaccharides, natural gums, clays such as South Clay Products ( Gonzalez, Texas) Laponite®, and more.
  • the inventive hydrogel compositions further include a preservative.
  • physiologically tolerated preservatives include, but are not limited to, bacteriostatic, preservatives, inhibitors, and the like; such as p-hydroxybenzoic acid (paraben) methyl ester, ethyl ester, propyl ester and butyl ester; Propyl gallate, sorbic acid and its sodium and potassium salts; propionic acid and its calcium and sodium salts; 6-acetyl-2,4-dimethyl-o-dioxin; 2 : bromo-2-nitro -1,3-diol; salicyl such as dibromo salicyl and tribromo salicyl; hexachlorophenol; sodium benzoic acid; ethylenediaminetetraacetic acid (EDTA), citric acid, alkali metal salts thereof, phenols a compound such as t-butyl-p-hydroxyphene Ethyl ether, butyl hydroxymethyl, chloro and bromocresol, and oxyleno
  • the hydrogel compositions of the present invention further comprise a pH adjusting agent such as lactic acid, citric acid, glycolic acid, succinic acid, tartaric acid, DL-malic acid, potassium carbonate, sodium hydrogencarbonate and ammonium hydrogencarbonate; Acid or base can also be used to adjust the pH of these formulations.
  • a pH adjusting agent such as lactic acid, citric acid, glycolic acid, succinic acid, tartaric acid, DL-malic acid, potassium carbonate, sodium hydrogencarbonate and ammonium hydrogencarbonate
  • Acid or base can also be used to adjust the pH of these formulations.
  • Different pH adjusting agents and pH adjusting means can be used as long as the resulting product is pharmaceutically and cosmetically acceptable.
  • the pH of the hydrogel composition is preferably in the range of from about 1 to about 12.
  • the other preferred embodiment may be in the range of about 3.5 to 10.
  • the present hydrogel compositions further include colorants including, but not limited to, acid dyes, neutral dyes, cationic dyes, and mixtures, in accordance with the present invention, the total amount of colorant in the hydrogel composition.
  • the concentration is from about 0.001% to about 5%, preferably from about '0.01% to about 4%, more preferably from about 0.1% to about 3%, most preferably from 0.1% to 1%. %, by weight.
  • the invention further relates to a method for preparing a topical reverse temperature-sensitive reversible hydrogel composition for treating hair loss, comprising the steps of:
  • At least one associated gel adjuvant is mixed at a suitable temperature to form a topical reverse temperature-sensitive reversible hydrogel composition for the desired treatment of hair loss.
  • the invention still further relates to a method for treating and/or preventing hair loss, restoring and/or promoting hair growth, the method comprising applying an aerosol, a spray, a pump, a brush, a cotton swab, or other applicator
  • the hydrogel composition is administered topically, and then thoroughly massaged to allow the composition to penetrate the skin, contact the hair follicle, and then continue to allow the composition to reside on the scalp, or to rinse the composition from the skin in a short period of time. Drop it.
  • Example 1 The following preparations for topical reverse temperature-sensitive reversible hydrogel compositions for the treatment of hair loss:
  • Preparation method Mix component A, stir to a homogeneous solution at a temperature below 10 ° C; then heat to 55-60 ° C, add B, continue to stir until completely dissolved; at 55-60 ° C temperature Add C, stir until dissolved; Finally, add D at a temperature of 55-60 ° C, stir until homogeneous, and cool to room temperature.
  • the resulting preparation was a clear gel at room temperature.
  • the external hydrogel composition can be applied to the affected part of the head as a resident product or as a rinse-off product to the affected part of the head.
  • Example 1 The formulation of Example 1 was used as a rinsing treatment product for experimental research.
  • Six healthy male volunteers with a history of 10-20 years of hair loss with a history of 10-20 years old and having baldness and most of the pre-hairline hair loss were used for testing.
  • Each subject applied 1-4 ml of the Formula 1 hydrogel composition of Example 1 to the affected area of the scalp and massaged on the scalp for 1-2 minutes, then rinsed off in the shower.
  • the treatment time is 12 weeks. Take pictures every week before and after treatment. The primary therapeutic effect was assessed by artificial hair counting of specific scalp areas. We were surprised to find that after a week of use, the two volunteer testers had new hair on the scalp that was originally on the top of the hair and the hairline of the front hairline.
  • Example 2 Preparation of a rinse-off external reverse temperature-sensitive reversible hydrogel composition for treating hair loss:
  • Preparation method mixing component A, stirring to a homogeneous solution at a temperature below 10 ° C; then heating to 55-60 ° C, adding B, continuing to stir until completely dissolved; adding at a temperature of 55-60 ° C C, stir until dissolved; Finally, add D at 55-60 °C, mix until homogeneous, and cool to room temperature.
  • the external water gel composition can be applied to the affected part of the head as a rinse-off product.
  • Example 3 The following preparations for the treatment of hair loss for topical reverse temperature sensitive reversible hydrogel compositions:
  • Preparation method mixing component A, stirring to a homogeneous solution at a temperature below 10 ° C; then raising the temperature to 55-60 ° C, adding B, continuing to stir until completely dissolved; adding at a temperature of 55-60 ° C C, stir until dissolved; Finally, add D at a temperature of 55-60 ° C, stir until homogeneous, and then cool to room temperature.
  • the external hydrogel composition can be applied to the affected area of the head as a resident product.
  • Example 4 The following preparations for the treatment of hair loss topical reverse temperature-sensitive reversible hydrogel compositions :
  • Preparation method mixing component A, stirring to a homogeneous solution at a temperature below 10 ° C; then heating to 55-60 ° C, adding B, continuing to stir until completely dissolved; adding at a temperature of 55-60 ° C C, stir until dissolved; Finally, add D at a temperature of 55-60 ° C, stir until homogeneous, and then cool to room temperature.
  • the external hydrogel composition can be applied to the affected area of the head as a resident product.

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Description

说 明 书
用于治疗脱发的外用逆向温敏可逆水凝胶组合物
技术领域 本发明涉及一种用于治疗和 /或防止脱发、恢复和 /或促进头发生长的逆向温敏可逆水凝胶 组合物， 以及这种组合物的制备及使用方法。
背景技术 虽然脱发的病因还不能很好地确定，但是多种因素特有的形成机制理论己被提出，这意味 着脱发是多个基因与多种环境因素相互作用的结果。 雄激素性脱发或常见脱发占所有脱发案 例的 99% (博得兰和穆勒， 皮肤， 47 : 173-176, 1991 ) 。 常见脱发是许多成年男性常见的脱发 症状， 被认为是生理和老化过程的一部分。 虽然男性常见脱发的几种模式己有描述， 前额发 际线区域头发的后退是迄今为止最常见的早期症状。 随着脱发延伸到头顶， 两个脱发边界的 不断延伸 ·， 最终发展成半月形脱发形态。 除了脱发， 邻近脱发区域每根头发的长度和直径将 减少， 但毛囊保持不变。 另一方面， 妇女脱发的特征是头发顶部、 顶叶和颞区扩散变薄， 但 额发际线和枕区头发不受影响。 治疗脱发和促进头发生长的现有技术包括各种药品和保健品和 /或口服药治疗。 例如， 米 诺地尔， 通称为落健， 在头皮上时会通过刺激毛囊导致一些人头发生长和减缓脱发。 米诺 地尔的疗效是有限的， 因为只有相对比例较小的部分患者在使用后有轻至中等程度的毛发再 生。 商品名为 "保法止" （默克制药公司） 的市售药物是一种含非那雄胺活性成分的药物。 保法止是"^种口服药片。 然而， 口服给药途径因为胃肠道刺激及药物在肝脏内代谢相关的并 发症而变得更复杂。 据裉道： 口服非那雄胺并发症可能导致的副作用包括情绪障碍 （奥拓麦 等人， 2002年， 皮肤病学 ^志， 29 ( 10) : 665-9) ， 单侧乳房发育 （法然都等人， 2002年， 皮肤科档案， 138 (4) : 543-4)， 性欲减退， 勃起功能障碍和射精障碍（麦克莱伦等人， 1999 年， 药品， 57 (1) : 111-26)。
确认本 也有很多基于从天然植物包括中药材提取物的组合物用于治疗脱发。不同药材提取物制备 的生发组合物一般被用来作为头发生长的刺激剂和促进剂。 然而， 通常这些提取物不能表现 出对头发生长的积极作用。 即使其中一些生发组合物有一些效果， 但仍然有缺陷， 例如， 由 于对皮肤的刺激性， 难闻的气味和其他副作用等， 它很难在很长一段时间内持续使用。 治疗脱发的另一种 法是毛发移植。这种方法通常是将包括头皮区域的自然头发移植到秃 头部位生长。 然而， 在头发移楦期间， 移植头发通常会在 2- 4周后掉落。 虽然大部分移植头 发 3- 4个月后重新长出， 但这需要额外的头发移植手术。 因 ^(， 这种移植方法需要无限的成 本和吋间， 痛苦并且收效有限。 因此，有需要开发一种治疗 /或防止脱发，恢复和 /或促进头发生长的有效组合物和简单 方法， 特别是用于人类头发， 并能在较短的时间内， 具有很好的治疗脱发 ¾ ^促进头发生长的 效果， 易于使用, 同时 :， 无副作用的组合物。
发明内容 依据'本发明提供了一种用 f、冶疗和 /或防止脱发， 恢复和 /或促进头发生长的逆向温敏可 逆水凝胶组合物^括: '
(a) 一种含量为 ^ 5-25%包括至少两个聚环氧乙烷嵌段和至少一个聚环氧丙垸嵌段组 成的水溶性嵌段共¾物； 和
(b) 至少一种含量为约 0. 05-10%关联凝胶佐剂， 所述关联凝胶佐剂具有一种在 20摄 氏度下水中的溶解度小于 0. 5克 /100毫升， 优选是小于 0. 3克 /100毫升,并能与 上述水溶性嵌段共聚物形成水溶性分子间复合物；
(c) 至少一种含量为约 0. 05-10%预防或治疗用防脱发剂。 本发明还涉及一种用于治疗和 /或防止脱发， 恢复和 /或促进头发生长的逆向温敏可逆水 凝胶组合物， 在约 -45°C¾¾, 优选是在约 8-40°C左右的温度范围内， 具有一种可调控的从 溶液到凝胶态的转变温度。 ' ' 本发明还涉及一种用于治疗和 /或防止脱发， 恢复和 /或促进头发生长的逆向温敏可逆水 凝胶组合物， 在约 4- 50 左右，'优选是在约 8- 45°C左右的温度范围内以一种凝胶形态存在。 本发明还涉及到一种具有改进的生物粘附性和皮肤渗透性， 用于治疗和 /或防止脱发， 恢 复和 /或促进头发生长的逆向温敏可逆水凝胶组合物。 本发明还涉及到具有改善用于治疗和 /或防止脱发， 恢复和 /或促进头发生长逆向温敏可 逆水凝胶组合物的效力和疗效。 本发明还涉及到一种用于治疗和 /或防止脱发， 恢复和 /或促进头发生长的方法， 其中所 述方法包括， 涂抹外用逆向温敏可逆水凝胶组合物至头皮上， 然后充分按摩使组合物渗入皮 肤， 接触毛囊， 然后既可以继续让组合物驻留在头皮上， 也可以在短时间内将组合物从头皮 冲洗掉 本发明广泛适用于常见脱 ：， 上述定义的逆向温敏可逆水凝胶组合物可能对治疗雄激素 性脱发 别有效。'我们假设一种活跃的组织雄激素， 如 5-a-二氢睾酮， 随着时间的推移在某 些头皮毛囊中积累， 导致这些头皮毛囊头发生长蒌缩。 在此， 不希望被任何特定的理论约束， 我们相信， 局部涂抹本发明逆向温敏可逆水凝胶组合物于头皮患处, 已被证明导致新的头发 生长， 可能和消除多余的雄激素或清理毛囊有关。 申请人令人惊讶地发现逆向温敏可逆水凝胶组合物具有明显改善、 诱导和刺激头发生长 及防止脱发， 以及显著增加皮肤生物利用度和 /或经皮渗透， 其组成包括一种水溶性嵌段共聚 物， 至少一种关联凝胶 剂和至少一种预防或治疗用防脱发剂， 所述水溶性嵌段共聚物包括 至少两个聚环氧乙 嵌段和至少一个聚环氧丙垸嵌段， 所述关联凝胶佐剂， 在 20摄氏度下水 中的溶解度小于 0. 5克 /100毫升， 优选是小于 0. 3克 /100毫升， 并能与上述水溶性嵌段共聚 物形成'水溶性分子间复合物。 ： ' 我们发现用于治疗和 /或防 ih脱发， 恢复和 /或促进头发生长的逆向温敏可逆水凝胶组合 物无论是作为驻留型产品涂抹于'头皮或香波类冲洗型产品使用都具有优越的功效。 本发明逆 向温敏可逆水凝胶组合物可以在三个月的疗程内被外用于头皮患处， 每天一次， 每次约 0. 01 毫升到 5毫升， 优选是约 0. 05毫升到 3. 5毫升。 本发明的优越性还在于用于治疗脱发的外用 逆向温敏可逆水凝胶 合物可涂抹于头皮患处， 保持约 1-2分钟， 然后就像使用洗发水一样 漂洗或冲洗掉。 即使这样， 它仍然可以像其它现有驻留型防脱发组合物一样达到同等或更好 的效力。 在谈到本文中水凝胶组合物时， 本文中和所附的权力要求书中所使用的术语 "凝胶"意 味着组合物是一种固态， 胶状物质， 它可以具有从弱和软到硬和坚韧的属性。 凝胶是一种稀 释体系， .在稳态状态下， 表现为无流动性。 溶液到凝胶或凝胶到溶液的转变温度为观察到的一种凝胶熔化温度， 该凝胶熔化温度是 通过将小瓶倒置方法目测确定。 样品瓶被倒置浸在温度缓慢上升或下降的水浴中。 凝胶熔化 温度被取作为凝胶开始流动的温度点。 用于此处的所谓 "逆向温敏可逆 "凝胶术语， 它是指随着温度的升高而不是温度的降低 而发生的凝胶化过程。 这是违反常理的， 因为通常溶液粘度随温度的增加而降低。 用于此处的所谓 "使用条件"一词是指组合物在使用时所有可能被暴露的条件下， 包括 运^和储存以及治疗或个人护理使用期间。 本文中和所附的权 j要求书中所使用的术语"药学上可接受的" "生理学上可以接受的" 和 "美容 上可接受的"和文法变体等， 他们是指电解质 （如盐） ， 碱， 稀释剂， 防腐剂， 缓冲剂和其他辅料可以互换使用， 并表示该材料可用于人体皮肤， 食道， 耳， 阴道， 直肠， 眼局部使用， 不会产生不良的生 效应， 如剌激性， 瘙痒， 刺痛， 或全身性副作用， 如恶心， 头晕， 等等。 本文中和所附的权力要求书中所使用的术语 "驻留"类产品， 它们是指该产品在涂抹后 留在皮肤上。 驻留型产品是像 "抗老化霜"、 "身体乳液 /霜"、 "除臭剂"、 和 "护手液 / 霜"等一类产品。 而本文中和所附的权力要求书中所使用的术语 "冲洗"类产品， 它们是指 该产品在涂抹和使用后很短的时间内被冲洗掉。 冲洗型产品是像 "洗发水"、 "护发素"、 "洗面奶" .等一类产品。 · 本文'提及的所有百分比均为重量百分比， 除非另有说明。 下面 包括至少两 聚环 乙烷嵌段和至少一个聚环氧丙垸嵌段的水溶性嵌段共聚物进 行说明。 ·
术语 "聚环氧乙烷 "， "PE0"， "E0" ， "聚乙二醇"和 "PEG"是可以用来互换描述 本发明， 指下列化学结构表示的环氧乙烷合成高分子：
HO-tCH2CH20+H 、 其中 a是整数， 表 单体重复单元的平均数目。 术语 "聚环氧丙垸 "， "PP0"， "P0" ， "聚丙二醇"和 "PPG"是可以用来互换描述 本发明， 指下列化学结构表示的环氧丙垸合成高分子：
CH3
HO CH2CHO¾H ( 2 ) 其中 b是整数， .表示单体重复单元的平均数目。 聚环氧乙烷和聚环^丙垸嵌段共聚物是指各种不同分子量， 不同类型的聚环氧乙烷嵌段 ^ (化学式 1 )和聚环氧丙烷嵌段（化学式 2) 的合成共聚物， 从线性多嵌段共聚物， 侧链接枝 嵌段共聚物， 和超支嵌段共聚物和到星形嵌段共聚物。 聚环氧乙垸和聚环氧丙垸嵌段共聚物 还包括各类端基改性和 扩展嵌段共聚物。 ： 牢发明中特另 U令人感 趣的包括至少两个如通式 -[E0L-所示的嵌段聚环氧乙垸和至少 ： 一个如通式 -[P0]b-所示的嵌段聚环氧丙垸组成的水溶性嵌段共聚物， 如通式
HO- (E0)a(P0) b (E0)a-H所示， 其中 a和 b各自为在约 10-150范围内的整数, 代表聚合物中单 体重复单元的平均数目。 包括至少两个聚环氧乙烷嵌段和至少一个聚环氧丙烷嵌段组成的本发明所述水溶性嵌段 共聚物的例子是兰嵌段共聚物， 其市售商品名为普朗尼克， 也被称为泊洛沙姆， 可从巴斯夫 公司 (橄榄山， 新泽西州）获得。 一种优选的泊洛沙姆聚合物是如通式 HO- (E0) a(P0) b (E0) a-H 所示的普朗尼克 （Pluronic®) F127嵌段共聚物 （也称为泊洛沙姆 407) ， 相应地， a的平均 值约为 101 ^及 b的平均值约为 56， 和普朗尼克（Pluronic®) F108 (也称为泊洛沙姆 338) ， 相应地， a的平均值约为 141·， - ¾ b平均值约为 44。 其它示范性的包括至少两个聚环氧乙烷嵌段和至少一个聚环氧丙垸嵌段的本发明所述水 溶性嵌段共聚物的 子 通式为 H0-[ (P0) b (E0)丄 (P0)。[ (E0) a(P0) - H的线性多嵌段共聚物， 其中 (E0)a是聚环氧乙垸嵌段， （P0)b和 (P0)。是聚环氧丙垸嵌段， a， b和 c各自为约 10-150 范围内的整数， 并且 m是大于 0的整数。 其它本发明水溶性多嵌段共聚物是化学式为 { [A„ (E0) a (P0) b (E0)人] Ε}„的链延伸、超支链、 或星形链嵌段共聚物， 其中 (E0) a是聚环氧乙垸嵌段， 和 (P0) b是聚环氧丙烷嵌段， a和 b各自 为约 10-150 '范围内的整数， A是 种单体重复单元， E是一个扩展链或交联剂， n是一个从 0 到 50， .优选是 1到 20 (0到 20为非生物降解材料） ， 更优选是 2到 16 (0到 16如果是非生 物降解材料的情况下） ， 范围内的整数， 和 m是共聚物分子重复单元数目， 是一个等于或大 于 2的整数（在实用范围内， 高达约 100, 000万或更高） ， 最好是从约 2至约 500， 更优选为 约 3至约 100。 因此， 如果 n为 0， 本发明设想的聚合物结构式为 {[(E0)a(P0)b(E0)a]E}„。 其它示范性水溶性嵌段共聚物是一种端基改性嵌段共聚物， 具有通式
R"G (E0)a(P0)b(E0)a-G-R， 其中 (E0)a是聚环氧乙烷嵌段， （P0)b是聚环氧丙垸嵌段， G系选自 包括 C"C, C-0, C(0)NH， S-C, C(0)-0， Si-0基团组成的组群， R为具有一种垸基链长在 C8_C36 之间的垸基和芳垸基， a是在约 50到约 150之间， b是在约 35到约 70之间。 示范性的水溶性端基改性嵌段共聚物是垸基或芳垸基端基改性嵌段共聚物， 其包括至少 两个聚环氧乙垸嵌段和至少一个聚环氧丙垸嵌段， 该端基改性嵌段共聚物是一个与终端垸基 或芳烷基醇缩合反应的产物。 该垸基集团应该有如丁基， 正己基之类的疏水基团。 垸基泊洛 沙姆可能具有通式 R- [(E0)a(P0)b(E0)丄- R' ，其中 (E0)a是聚环氧乙烷嵌段， 和 ^ 是聚环氧 丙垸嵌段， R和 R '是非极性侧基， 如具有链长 C6-C36范围内垸基和芳垸基， 以及 m是在 1-10 的范围内。 . 其它示范性的包括至少两个聚环氧乙烷嵌段和至少一个聚环氧丙垸嵌段组成的侧链接枝 嵌段共聚物通式为^^^^^^丄， 其中 (E0)a是聚环氧乙烷嵌段， （P0)b 聚环氧丙烷嵌 段， a和 b各自为约 10- 150范围内的整数， A是一种主链单体重复单元，可以是选自乙烯，酯， 酰胺， 酰 i胺， 聚醚， 硅氧垸等重复单元链接， m是共聚物分子重复单元数目， 是一个等于或 大于 2的整数。 其它本发明水溶性多嵌段 ^聚物是化学式为 { [A„ (E0) a (P0) b (E0)人] E} 0的链扩展聚酯嵌段 共聚物， 其中（E0)a是聚环氧乙烷嵌段，. 和 (P0)b是聚环氧丙烷嵌段， A是一种单体重复单元， 如前定义， 其中 (E0)a是1聚环氧乙烷嵌段， 和 (P0)b是聚环氧丙垸嵌段， E是一个扩展链或交联 剂, n是一个从 0 50， 优选是 1到 20 (0到 20为非生物降解材料） ， 更优选是 2到 16 (0 到 16如果是非生物降解材料的情况下） ， 范围内的整数， 和 m是共聚物分子重复单元数目， 是一个等于或大于 2的整数（在实用范围内， 高达约 100, 000万或更高） ， 最好是从约 2至 约 500， 更优选为约 3至约 100。 因此， 如果 n为 0， 本发明设想的聚合物结构式为 {[(E0)a(P0)b(E0)a]E}mo
：上述单体重复单元可能是来源于脂肪族羟基羧酸或相关酯， 内酯， 二聚酯， 碳酸脂， 酸 酐， 二氧环己酮，酰胺， 或相^^单体， 并且优选来源于脂肪族 α_羟基羧酸衍生物或相关酯类， 这些重复单元可源自下例： 包括， 例如， 乳酸， 乳酸酯， 乙醇酸， 乙醇酸酯， 或相关的脂肪 族羟基羧酸， 酯 （内酯） ， 二聚酸或相关的化合物， 例如 丙内酯， ε-己内酯， δ-戊二内 酯， δ -戊内酯， β-丁内 新戊内酯， α， α-二乙基丙内酯， 碳酸乙烯酯， 三亚甲基碳酸 酯， γ -丁内酯， ρ_二氧环己酮， 1,5-二氧杂环庚垸 -2-酮， 三甲基 -1,4-二氧- 2,5-二酮， 3， 3， -二甲基 -1-4-二氧 -2, 5-二酮， α-羟丁酸， α-羟戊酸环酯， a-羟异戊酸， a -羟基酸， a- 羟基- a-乙塞酸， a-羟异己酸， a-羟基 -a-甲基戊酸， a -羟庚酸， α-羟基硬脂酸酸， a- 羟廿四酸， 水杨酸酸及其混合物等等。 在本发明中对 a-羟基酸及其相应环状二聚体酯， 尤其 是丙交酯, 乙交酯和已 酯的使用是优选的。 值得注意的是在使用根据本发明所描述的单体 时， 所产生的单体单^ &并不特指酯类， 而可能包括像碳酸酯 （聚碳酸酯） ， 氨基酸类（用来 生产聚酰胺）及源自上面描述的单体或包含亲核基团和亲电基团可聚合相关基团。 不言而喻， 术语聚酯应包括由所有上述这些单体派生的共聚物， 这些实际上产生酯单元为优选。 术语' "聚（羟基羧酸) "或 "聚（ a -羟基羧酸） "是用来描述根据本发明聚合物组成的 多嵌段 UAn(E0)a.(P0)b(E0) ] EL中某些聚酯 A嵌段， 其中 A是来源于羟基羧酸或相关的酯， 或二聚体酯， 优选是源自 S肪族 α_羟基羧酸或相关的酯， 包括」种环状二聚酯， 例如， 像乳 酸， 丙交酯， 乙醇酸， 甘醇酸， 或相关的脂肪族羟基酸或酯 （内酯） ， 例如， 像 ε -己内酯， δ -戊二内酯， δ-戊内酯， γ-丁内酯和混合物， 其中， 许多其它的在此处所述规定。 使用 α
-羟基羧类及其相应环状二聚酯， 特别是本发明中乳酸和乙醇酸酯是首选。 其他合适的端基改性化合物可能包括， 但不仅限于， 离子型聚合物。 本发明中的离子型 聚合物包括线性， 分支和 /或交联型聚合物。 特别令人感兴趣的是羧基乙烯基聚合物单体如丙 烯酸， 甲基丙烯酸； 乙基丙烯酸， 苯基丙烯酸， 戊烯酸等等。 聚 （丙烯酸）及其盐类是羧基 乙烯基聚合物的首选。 个或多个聚羧基乙烯基聚合物， 可用于本发明聚醚组合物中。 如仅 举例; 共聚物仅仅含丙烯酸和甲基丙烯酸共聚物也可以考虑。 优选的本发明逆向温敏可逆水凝胶组合物可以包括从约 5%至 25 %， 优选是从 8 %至 18 %， 最优选是从 10%到 15 %按重量计的包括至少两个聚环氧乙烷嵌段和至少一个聚环氧丙垸 嵌段的水溶性嵌段共聚物。 不用说， 所属领域的技术人员将会选择合适的包括至少两个聚环氧乙烷嵌段和至少一个 聚环氧丙'垸嵌段组成的水溶性嵌段共聚物， 以至于对符合本发明逆向温敏可逆水凝胶组合物 的有利特性没有， 或没有大幅 S的不利影响。 下文就关联凝胶佐剂进行说明。 ' 所谓 "关联凝胶佐剂 "是指选自一组可改性其它胶凝剂的凝胶作用， 同时， 当他们单独 存在时， 对氷溶液的粘度几乎 有任何直接影响的佐剂。 从本质上讲， 关联凝胶佐剂自身在 水中具有非常有限的溶解度， 且通常在 2CTC水中的溶解度小于 0. 5克 /100毫升， 优选是小于 0. 3克 /100毫升， 并且它自身在水中并没有增稠或凝胶的能力。 用目前市售泊^沙姆聚合物， 想获得在低于室温下的溶液到凝胶转变温度， 同时保持聚 合物在相对较低浓度下的能力是有限的。 与此同时， 在一个低固含量的组合物中， 至关重要 的是系统要能够承载并稳定有效剂量的， 可用于控释和缓释的活性成分。 例如，在 7J中需要约 20%重量百分比的普朗尼克 F127才能具有在约 25°C左右的溶液至凝 胶转变温度。为了扩展至远低于 25°C的溶液至凝胶转变温度，必须使用高浓度的嵌段共聚物。 事实上， 需要高达 35%重量百分比的會朗尼克 F127才能具有约 8°C左右的溶液至凝胶转变温 度。 相反地， 仅仅需要约 18. 5%的普朗尼克 F127结合约 8%重量百分比的月桂醇聚醚 4， 就具 有相同的溶液至凝胶转变温度。 由于聚合物浓度大大减少， 溶液粘度低得多， 以及由此产生 的逆向温敏可逆水凝胶是不发粘的， 更少残留物， 更好的剪切敏感特性和美容效果。 根据本发明， 令人惊讶地发现， 通过添加少量至少一种关联凝胶佐剂， 包括至少两个聚 环氧乙烷嵌段和至少一个聚环氧丙垸嵌段组成的水溶性嵌段共聚物的胶凝效率大大提高。 己 经发现， 虽然用来形成理想 ^度的逆向温敏可逆水凝胶的聚合物的相对用量己大大减少， 由 此产生的水凝胶组合物在溶解和 /或稳定有效剂量的微水溶性或非水溶性药物和化妆品活性 成分的能力却得以改进。 令人惊讶地发现还有， 本发明所述这种包括至少两个聚环氧乙垸嵌段和至少一个聚环氧 丙烷嵌段组成的水溶性嵌段共聚物的逆向温敏可逆水凝胶组合物的溶液到凝胶转变温度是可 以通过添加有效剂量的至少一种关联凝胶佐剂或在相对较大的使用温度范围内来调控。 这种 在相对较低高分子浓度的条件下， 调控逆向温敏可逆水凝胶组合物溶液到凝胶转变温度的能 力， 克服了现有技术的限制， 并且， 在一种理想的液态或凝胶态， 无论是从性能或处理的角 度考虑都是重要的和非常有用的。 特别是， 本发明提供药品， 化妆品和个人护理用品组合物， 具有以上提出的性能， 用来控释或缓释有效剂量的活性成分。 虽然不希望被任何特定的理论约束， 此处现建议： 关联凝胶佐剂和包括至少两个聚环氧 乙垸嵌段和至少一个聚环氧丙垸嵌段水溶性嵌段共聚物之间的分子间的相互作用， 如氢键相 互作用， 导致在水中形成水溶性分子间复合物， 这是本发明中观察到的凝胶效率提高的原因。 关联凝胶佐剂的例子包括， 但不仅限于， 垸氧基化脂肪醇， 烷氧基化脂肪醇酯， 垸氧基 化垸基醇， 垸氧基化垸基醇酯； 烷氧基化芳烷基醇， 脂肪族羟基羧酸， 脂肪族羟基羧酸酯， 芳香族羟基羧酸， 聚 （羟基羧酸） ， 烷氧基化山梨醇酯， 垸氧基化甘油三酯， 烷氧基化甘油 基酯， 烷氧基化山 醇酯， 多元醇酯， 失水山梨醇酯， 及类似品。 适合于使用本关联凝胶佐剂包括， 但不仅限于， 月桂醇聚醚 -2， 月桂醇聚醚 -3， 月桂醇 聚醚 -4， 桂醇聚醚- 5， 月桂醇聚醚 -6， 及类似品； 油醇聚醚 -2， 油醇聚醚- 5， 油醇聚醚 -10， 及类似品； C12-13链烷醇聚醚 -2， C12-13链垸醇聚醚 -3， C12-13链烷醇聚醚 -4， C12-13链垸醇聚醚 -5， C12-13链烷醇聚醚- 6, 及类似品； 二聚丙二醇 -2肉豆蔻醇聚醚 -9己二酸酯， 二聚丙二醇 -2肉豆 蔻^聚醚 -10己二酸酯， 二聚丙二醇- 2肉豆蔻醇聚醚 -11己二酸酯， 及类似品； 水杨酸及其衍 生物； 尼泊金甲基， 尼泊金乙基， 尼泊金丙基， 尼泊金丁酯， 及类似品。 优选的本发明逆向 敏可逆水凝胶组合物可以包括从约 0. 01 %至 12 %， 优选是从 0. 05 %至 10%， 最优选是从 0. 1%到 8%按重量计的至少一种关联凝胶佐剂， 述关联凝胶佐剂在 20°C下水中的溶解度小于 0. 5克 /100毫升， 优选是小于 0. 3克 /100毫升,并能与上述水溶性 嵌段共聚物形成水溶性分子间复合物。 · 不用说， 所属领域 fefe未人'员将会选择合适的、 能和包括至少两个聚环氧乙烷嵌段和至 少一个聚环氧丙垸嵌段组成的水溶性嵌段共聚物形成水溶性复合物的关联凝胶佐剂， 以至于 对符合本发明的该逆向温敏可埤水凝胶组合物的有利特性没有， 或没有大幅度的不利影响。 下文就预防或治疗用防脱发剂进行说明。 根据本发明， 该逆向温敏可逆水凝胶组合物包括至少一种预防或治疗用防脱发剂。例如， 可以从以下化合物中选出一种或几种预防或治疗用防脱发剂组合， 包括， 但不仅限于： 苯扎 氯铵， 苄索氯， 酚， 雌二醇， 盐酸苯海拉明， 扑尔敏， 叶绿素衍生物， 胆固醇， 水杨酸或水 杨酸衍生物， 对羟基苯甲酸及其酯类衍生物， 对乙酰氨基酚， 布洛芬， 胱氨酸， 红辣椒酊， 烟酸苄酯， DL薄荷醇， 薄荷油， 泛酸钙， 泛醇， 蓖麻油， 桧木醇， 类固醇， 间苯二酚， 米诺 地尔， 克罗卡林， 吡那地尔， 纳米尼地尔， 二苯基环丙稀酮， 铜胜肽， 抗雄激素药物如醋酸 环丙孕酮， 达那唑， 氟他胺， 5- α还原酶抑制剂如非那雄胺， 妥罗雄脲， LY-191704, ΜΚ-306 和度他雄胺（美国专利号 4, 377, 584)， 以及从下列 S-三嗪类，苯并吡喃类， pyridinopyrans, 和氧化 -1-硫杂环己烷类化合物或前面提到的任何一种药学上可接受的盐或衍生物及类似物 中选出。 特别适合此处使用的预防或治疗用防脱发剂可以是包括， 但不仅限于， 水杨酸或水杨酸 衍生物， 对羟基苯甲酸犮其衍生物， 薄荷醇， 米诺地尔， 氟他胺， 非那雄胺， 或类似品。 所属领域的技术人员 理解，' 上述列出的预防或治疗用防脱发剂仅是示范。 因为本发明 逆向温敏可逆 凝胶组合物特别适合被用于治疗和 /或防止脱发， 恢复和 /或促进头发的生长。 优选的逆向温敏可逆水凝胶组合物将是以一种凝胶或一种液体形态存在， 最优选是， 逆 向温敏可逆水凝胶组合物将是以一种凝胶态存在或一种经与皮肤或粘膜组织接触后具有胶凝 ^能力的液体形态存在。 优选的本发明逆向温敏可逆水凝胶组合物可以包括从约 0. 01 %至 50% , 优选是从 0. 05 %至30%.， 最优选是从 0. 1 %到 15%按重量计的预防或治疗用防脱发剂。 要制备根据本发明 教导的逆向温敏可逆水凝胶组舍物， 在组合物配方温度和 PH值下 将选择的适当有效剂量的 预防或治疗用防脱发剂简竽地添加到水凝胶组合物中。 最好是， 选择的预防或治疗用防脱发 剂在溶液 会溶解或将被均匀地分散。. 本发明药物逆向温 可逆水凝胶组合物可以包含药学上和 /或生理学上可接受的辅料，包 括， 但不仅限于， 如生理上能承受的表面活性剂， 溶剂， 保湿剂， 润肤剂， 促渗剂， 着色剂， 香料， 等等， 这些都是在该领域众所周知的， 其中有些在后面的上下文中会被描述。 水凝胶 组合物具有一个优选的为约 1到 12范围内的 pH值。其他优选实施例可能在约 3. 5到 10的 pH 值范围内。 在一些实施例中， 本发明水凝胶组合物还进一步包括一个或多个成分， 其作用是促进通 过上层角质层屏障到皮肤下层的渗透。 皮肤渗透促进剂的例子包括， 但不仅限于， 丙二醇， 氮酮， 乙氧基化二丙二醇， 二硝酸异山梨， 尿素， 乙醇， 二甲基亚砜， 等等。 在一些实施例中， 本发明水凝胶组合物还包括药学上和 /或生理学上可以接受的保湿剂， 其浓度优选是在从约 0. 01 %到约 40 %， 优选是从约 0. 1 %到约 30 %， 优选是从约 0. 5 %到约 25%的水平上。 优选保湿剂化合物包括， 但不仅限于， 选自多元醇， 山梨醇， 甘油， 尿素， 甜菜碱， D-泛醇， DL-泛醇， 泛酸钙， 蜂王浆， 双泛酰硫乙胺， 泛酰巯基乙胺， 泛醇基乙基醚， 泮加酸， 吡哆醇， 泛酰乳糖复合维生素8， 吡咯垸酮羧酸钠， 己垸 -1， 2, 6, -三醇， 胍或它 的衍生物， 及其混合物。 适合此处使用的多元醇包括， 但不仅限于聚亚垸基二醇， 优选是烯多元醇及其衍生物， 包括丙二醇， 二丙二醇， 聚¾;'醇， 聚乙二醇及其衍生物， 山梨糖醇， 羟丙基山梨醇， 赤藓， 苏糖醇，'季戊四醇，. 木糖醇， 山梨醇， 甘露醇， 戊二醇， 乙二醇， 丁二醇（如 1， 3-丁二醇）， 己烷三醇 （例如， 1， 2， 6-乙三醇） ， 三羟甲基丙垸， 新戊二醇， 甘油， 乙氧基甘油， 1， 3- 丙二醇， 丙氧基甘油及其混合物。 上述多元醇垸氧基衍生物也适合此处使用。 本发明首选多 元醇均选自甘油， 丁二醇， 丙二醇， 戊二醇， 乙二醇， 二丙二醇， 聚乙二醇， 己三醇， 甘油 和丙氧基甘油及其混合物。
适合此处使用的保湿剂还包括钠 2-吡咯垸酮 -5-羧酸 （NaPCA) ， 胍； 乙醇酸及乙醇酸盐 (如铵和季铵盐垸基铵） ， 乳酸和乳酸盐 （如铵和季铵盐垸基铵） ； 各种形式的 （如， 芦荟 凝胶） 透明质酸及其衍生物'（如盐衍生物， 如透明质酸钠） ； 乳酸胺乙醇胺， 乙醇胺乙酰 胺， 尿素， 甜菜碱， 泛醇及其衍生物;及其混合物。 在一些实 ½例中， 本发明水凝胶组合物包括还药学上和 /或生理学上可以接受的润肤剂， 其浓度优选是从约 0. 01 %到约 20%， 优选是从约 0. 1 %到约 15%， 优选是从 0. 5%到约 10% 的水平。 润肤剂的例子有羊毛脂， 蓖麻油， 矿物油， 硅产品和凡士林。 作为润肤剂使用的其 他成分包括高油酸葵花籽油及其衍生物， 澳洲坚果油及其衍生物， 葡萄籽油， 榛果油， 橄榄 油， 芝麻油等天然种子和坚果油， 如霍霍巴油， 及其衍生物。 最后， 作为润肤剂使用的其他 成分包括玉米油， 棉籽油， 玫瑰水膏， 杏仁油， 鳄梨油， 可可油， 杏仁油， 肉豆寇醇。 此外， 一些从植物或动物来源的脂肪酸被用作润肤剂。 用于化妆品配方中的脂肪酸包括硬脂酸， 油 酸， 肉豆蔻酸和棕榈酸。 其他典型的脂肪酸包括亚油酸， 辣木子油酸， 棕榈油酸。 脂肪醇也 被用作润肤剂。作为润肤剂使用的脂肪醇的例子是月桂醇， 鲸蜡醇， 硬脂醇， 霍霍巴醇和油 醇。 此外， 脂肪酯用作润肤剂。 脂肪酯的例子包括棕榈酸异丙酯， 肉豆蔻酸异丙酯和硬脂酸 甘油酯。 此外， 非生物降解的润肤剂如碳氢化合物或有机硅 （如甲基硅） 是众所周知， 并在 化妆品和个人护理中用作润肤剂使用。 在一些实施例中，本发明水凝胶组合物还进一步包括表面活性剂，其浓度优选是从约 0. 01 %到约 15%， 优选是从约 0. 1 %到约 10%的水平。表面活性剂可能是一种阴离子， 或阳离子， 或两性， 或非 子表面活性剂。 非离子表面活性剂的例子包括多元醇脂肪酸酯， 例如山梨醇 或甘油单， 双， 三或四油酸盐或硬脂酸， 甘油和聚乙二醇月桂酸酯； 聚乙二醇脂肪酸酯 （聚 乙二醇单硬脂酸酯或单月桂酸酯) '； 聚氧乙烯醚化山梨醇脂肪酸脂 （硬脂酸脂或油酸脂） ； 聚氧乙烯醚化垸基醚 （十二垸基;.十六， 十八垸基或辛垸基) 。 阴离子表面活性剂的例子包 括羧酸脂 （盐） （钠 2^ (2-羟烷氧基） 醋酸盐） ， 氨基酸衍生物 （N-酰基谷氨酸， N-乙酰甘 氨酸或酰基氨基酸） ， 垸基硫酸盐， 垸基醚硫酸盐及氧乙烯醚醚化衍生物， 磺酸盐， 羟基乙 磺酸盐和 N-酰基羟乙磺酸盐， 牛磺酸盐和 N-酰基 N ―甲基牛磺酸盐， 磺基琥珀酸酯， 垸基 磺基乙酸盐， 磷酸盐和垸基磷酸盐。 多肽， 垸基多糖苷 （酰基 D-半乳糖苷糖醛酸脂） ， 和脂 肪酸肥皂， 及其混合物。 两性和两性离子的例子包括甜菜碱， N-烷基酰胺甜菜碱及其衍生物， 甘氨酸衍生 ¾ (， 垸基酰氨基丙基羟基磺基， 垸基聚氨基羧酸和烷基苯丙胺醋酸酯， 及其混合 物。 · . 在一些实施^中， 本¾^7 胶组合物还进一步包括流变学改性剂， 其浓度优选是从约
0. 01 %到约 6%的水平， 流变学改性剂的例子包括， 但不仅限于， 卡波姆， 丙烯酸酯共聚物， 聚丙烯酰胺， 多糖， 天然树胶， 黏土如南粘土制品公司 （冈萨雷斯， 德克萨斯州） 出品的 Laponite®, 等等。 在一些实施例中， 发明水凝胶组合物还包括防腐剂。生理学上耐受的防腐剂例子包括， 但不仅限于， 抑菌 ， 防腐剂， 抑制剂， 以及类似品； 如对羟基苯甲酸 （尼泊金类） 甲酯， 乙酯， 丙酯和丁酯; 五倍子酸丙酯， 山梨酸及其钠和钾盐; 丙酸及其钙和钠盐类； 6-乙酰 -2， 4-二甲基-邻-二恶垸； 2:溴- 2-硝基 -1, 3-二醇； 水杨酰如二溴水杨酰和三溴水杨酰； 六氯酚； 钠苯甲酸； 乙二胺四乙酸 （EDTA) ， 柠檬酸， 其碱金属盐类， 酚类化合物如叔丁基对羟基茴 香醚， 丁基羟基甲 ， 氯和溴甲酚， 和氯和溴 oxylenols; 季铵盐如苯扎氯铵； 如 2-苯乙醇 和苯甲醇； 氯丁醇； 喹啉衍生物如氯碘喹 (啉）； 等等。 在一些实施例中， 本发明水凝胶组合物还包括 pH调节剂， 如乳酸， 柠檬酸， 乙醇酸， 琥 珀酸， 酒石酸， DL-苹果酸， 碳酸钾， 碳酸氢钠和碳酸氢铵； 根据需要， 酸或碱也可用于调整 这些配方的 pH值。 不同 pH值的调节剂和 pH值调节手段都可以使用， 只要由此产生的制备产 物是药学上和美容上可以接受的。 水凝胶组合物的 pH值优选在约 1到 12的范围内。 其他首 选实施例可能在约 3. 5到 10的范围内。 在一些实施例中， 本发明水凝胶组合物还包括着色剂， 包括但不仅限于， 酸性染料， 中 性染料， 阳离子染料， 及混合物， 根据本发明， 水凝胶组合物中着色剂的总浓度由约 0. 001 %至约 5%左右，优选是从约' 0. 01 %到约 4%，更优选是约 0. 1 %至 3%左右，最优选是从 0. 1 %到 1 %， 按重量计。 . . 不用说， 所属领域^技术人员将会选择合适的这个或这些可选的其他组份和 /或用量， 以 至于对符合本发明水凝胶组合物的有利特性没有， 或没有大幅度的不利影响。 本发明进一步涉及一种用于治疗脱发的外用逆向温敏可逆水凝胶组合物的制备方法， 包 括以下步骤:
(a) 在低于 2Q°C温度下,.将包括至少两个聚环氧乙垸嵌段 至少一个聚环氧丙烷嵌段的 水溶性嵌段共聚物溶于水中；
(b) . 然后， 在合适温度下混合其它辅料和 /或至少一种有效剂量的预防或治疗用防脱发 剂， 直至溶解或分散均匀；
(c) 最后, 在合适温度下混合至少一种关联凝胶佐剂， 以形成所需治疗脱发的外用逆向 温敏可逆水凝胶组合物。
： 本发明还进一步涉及到一种用于治疗和 /或防止脱发， 恢复和 /或促进头发生长的方法， 所述方法包括运用气雾^、 喷雾、 泵、 刷子， 棉签、 或其他涂敷器将所述水凝胶组合物外用 给药， 然后充分按摩使组合物渗入皮肤， 接触毛囊， 然后既可以继续让组合物驻留在头皮上， 也可以在短时间内将组合物从 ^皮冲洗掉。
； 除另有注明外， 所有数字表达的成分数量， 反应条件， 等等用在说明和权利要求书中， 在所有情况下， 被修改定义的这个词的理解都被视为是 "约" 。 因此， 除非有相反的表示， 数值参数中规定的下列规范和所附的权力要求是近似， 这可能因本发明设法获得所需的属性 而定。
具体实施方式 以下提供非限制性的例子是为了对本发明示范组合物的属性说明。 在下面的例子中， 浓 度均以重量百分比 （wt. % ) ¾示， 和去离子水被用来制备配方。 除非另有说明， 配方制备温 度为 22°C左右的室温。
实施例一 下列用于治疗脱发的外用逆向温敏可逆水凝胶组合物的制备:
相 成分 wt. %
去离子水 76. 5
聚乙二醇- 400 3. 2
A
二丙二醇 3. 0
普朗尼克 F 127 12. 0
B 水杨酸 2. 0
C · 薄荷醇 0. 3
D- Λ 月桂醇聚醚 -4 3. 0
：制备方法：将成分 A相混合，在低于 10°C的温度下搅拌至均匀溶液；然后升温至 55-60 °C， 加入 B， 继续搅拌至完全溶解； 在 55-60°C温度下加入 C，搅拌至溶解； 最后， 在 55-60 °C温 度下加入 D， 搅拌至均匀后， 冷却至室温。 由此产生的制备物在室温下是透明凝胶。 该外用水凝胶组合物既可作为驻留型产品涂抹于头部患处， 也可以作为冲洗型产品施用 于头部患处。
实施例 1配方被用作冲洗类治疗产品进行了试验研究。 6个年龄在 40 5 &岁己有 10- 20 年脱发历史， 并且具有秃顶和大部分前发际线头发脱落的健康男性志愿者被用于测试。 每个 受试者每天将 1-4毫升的实施例 1配方水凝胶组合物涂抹于头皮患处， 并在头皮上按摩 1-2 分钟， 然后淋浴冲洗掉。 治疗的时间为 12周。 治疗前及治疗后的每个星期拍照。 主要治疗效 果评价是通过对特定头皮区域进行人工头发计数。 我们惊讶地发现， 在使用一星期后， 两个 志愿测试者在原本是脱发的头顶和前发际线部位头皮上有新的头发长出。 在使用两到三个星 期后， 其余的四个志愿测试者都有新的头发长出。 经过 12周的测试试验研究后表明， 四个志 愿测试者有显著的头发苒生， 两个志愿测试者有中度头发再生。 实施例二 下列用于治疗脱发的冲洗型外用逆向温敏可逆水凝胶组合物的制备:
相 , 成分 wt. %
去离子水 75.3
聚乙二醇- 400 4.2
A
二丙二醇 3.0
普朗尼克 F 127 11.5
B 水杨酸 2.5
C 薄荷醇 0.5
月桂醇聚醚- 4 2.0
D i '
Sepigel 305 1.0
制备方法:将成分 A相混合，在低于 10°C的温度下搅拌至均匀溶液；然后升温至 55-60 °C， 加入 B， 继续搅拌至完全溶解； 在 55-60°C温度下加入 C,搅拌至溶解； 最后， 在 55- 60 °C温 度下加入 D， ^拌至均匀后， 冷却至室温。 外用水凝胶组合物可作为冲洗型产品施用于头部患处。
实施例三 下列用于治疗脱发外用逆向温敏可逆水凝胶组合物的制备:
相 成分 t. %
去离子水 75. 2
聚乙二醇- 400 3. 2
A
二丙二醇 3. 0
普朗尼克 F 127 13. 5
B 米诺地尔 1. 5 ,
C 薄荷醇 0. 2
D " " 月桂醇聚醚 -4 3. 4
制备方法：将成分 A相混合，在低于 10°C的温度下搅拌至均匀溶液；然后升温至 55-60 °C， 加入 B， 继续搅拌至完全溶解； 在 55- 60°C温度下加入 C，搅拌至溶解； 最后， 在 55- 60 °C温 度下加入 D， 搅拌至均匀后， 冷却至室温。 外用水凝胶组合物可作为驻留型产品施用于头部患处。
实施例四 下列用于治疗脱发外用逆向温敏可逆水凝胶组合物的制备:
Phase Ingredients wt. %
去离子水 74. 6
聚乙二醇 -400 3. 2
A
二丙二醇 3. 0
普朗尼克 F 127 12. 5
B 米诺地尔 1. 5
C 水杨酸 2. 0
D 薄荷醇 0. 2
E 月桂醇聚醚- 4 3. 0
制备方法：将成分 A相混合，在低于 10°C的温度下搅拌至均匀溶液；然后升温至 55-60 °C， 加入 B， 继续搅拌至完全溶解； 在 55-60°C温度下加入 C,搅拌至溶解； 最后， 在 55- 60 °C温 度下加入 D, 搅泮至均匀后， 冷却至室温。 外用水凝胶组合物可作为驻留型产品施用于头部患处。
本发明结合上述典型实施例进行了详细描述， 各种选择、 修改、 变化、 改进和 /或基本的 等同技术， 目前已知的或者是 （可能） 未知的内容， 对本领域的普通技术人员是熟知的。 因 此， 本发明的上述的典型实施例， 在与阐明而不在于限制本发明。 在不脱离本发明的精祌和 范围之内可以做多种改变。 因此， 本发明可以包含所有已知的或者以后发展的选择、 修改、 变化、 改进和 /或基本的等同技术。

Claims

权利要求书
1. 一种用于治疗脱发的外用逆向温敏可逆水凝胶组合物包括：
(a) 一种包括至少两个聚环氧乙垸嵌段和至少一个聚环氧丙垸嵌段的水溶性嵌段共聚 物； 和
' (b) 至少一种关联凝胶佐剂， 所述关联凝胶佐剂能与上述水溶性嵌段共聚物形成水溶 性分子间复合物。
(c) 至少一种有效剂量的预防或治疗用防脱发剂。
2. 权利要求 1所述组合物， 在为约 4-40摄氏度温度范围内具有一个可调节的溶液到凝胶的 转变温度和一个为约大于 45摄氏度的凝胶到溶液的转变温度。
3. 权利要求 1所述组合物， 在为约 4-35摄氏度温度范围内具有一个可调节的溶液到凝胶的 转变温度和一个为约大于 40摄氏度的凝胶到溶液的转变温度。
4. 权利要求 1所述组合物， 在为约 4-30摄氏度温度范围内具有一个可调节的溶液到凝胶的 转变温度和一个为约大于 35摄氏度的凝胶到溶液的转变温度。
5. 权利要求 1所述组合物， 其中所述水溶性嵌段共聚物占该组合物重量为约 5-25%。
6. 权利要求 5所述组合物，：其中所述水溶性嵌段共聚物占该组合物重量为约 8-20%。
7. 权利要求 6所述组合物， 其中所述水溶性嵌段共聚物占该组合物重量为约 10-16%。
8. 权利要求 1所 组合物， 其中所述水溶性嵌段共聚物是一个三嵌段共聚物， 如通式
H0-(E0) a (P0) b (E0) a-H所示， 其中（E0) a是聚环氧乙垸嵌段， （P0) b是聚环氧丙垸嵌段， a 是在约 50到约 150之间， b是在约 35到约 70之间。
9. 权利要求 8所述组合物， 其中 a是约 101， b是约 56。
10. 权利要求 8所述组合物， 其中 a是约 141， b是约 44。
11. 权利要求 1所述组合物， 其中所述至少一种关联凝胶佐剂占该组合物重量为约
0. 05-10%。
12. 权利要求 11所述组合物，其中所述至少一种关联凝胶佐剂占该组合物重量为约 0. 1-8%。
13. 权利要求 1所述组合物， 其中所述至少一种关联凝胶佐剂在 20°C下水中的溶解度小于 0. 5克 /100毫升。
14. 权利要求 13所述组合物， 其中所述至少一种关联凝胶佐剂在 20°C下水中的溶解度小于 0. 3克 /100毫升。
15. 权利要求 1所述组^ "物， 其中所述至少一种关联凝胶佐剂系选自包括垸氧基化脂肪醇， 烷氧基化脂肪醇 ^， 烷氧基化垸基醇， 垸氧基化垸基醇酯， 烷氧基化芳垸基醇， 脂肪族 羟基羧酸， 脂肪族羟基羧酸酯， 芳香族羟基羧酸， 芳香族羟基羧酸酯， 聚（羟基羧酸）， 垸氧基化失水山梨醇酯， 垸氧基化甘油三酯， 垸氧基化甘油基酯， 烷氧基化山梨醇酯， 多元醇酯， 失水山梨醇酯， 及混合物组成的组群。
16. 权利要求 15所述组合物， 其中所述垸氧基化脂肪醇系选自包括月桂醇聚醚 -2， 月桂醇 聚醚 -3， 月桂醇聚醚 -4， 月桂醇聚醚 -5, 和月桂醇聚醚 -6; 油醇聚醚 -2， 油醇聚醚 -5， 和油醇聚醚- 10等组成的组群。
17. 权利要求 15所述组合物，其中所述垸氧基化垸基醇系选自包括(：12-13链垸醇聚醚- 2，C12_13 链烷醇聚醚 -3， C12-13链垸醇聚醚- 4， C12-13链垸醇聚醚 -5，和( 12-13链垸醇聚醚 -6等组成的 组群。
18. 权利要求 15所述组合 ¾)， 其中所述烷氧基化脂肪醇酯系选自包括二聚丙二醇- 2肉豆蔻 油醇聚醚 -9己二酸酯， 二聚丙二醇- 2肉豆蔻油醇聚醚 -10己二酸酯， 和二聚丙二醇- 2 肉豆蔻油醇聚醚 -11己二酸酯等组成的组群。
19. 权利要求 1所述组合物，其中所述至少一种有效剂量的预防或治疗用防脱发剂占该组合 物重量为约 0. 05_10%%。 ,
20. 权利要求 1所述组合物，其中所述至少一种预防或治疗用防脱发剂系从下列化合物中选 出： 苯扎氯铵， 苄索氯， 酚， 雌二醇， 盐酸苯海拉明， 扑尔敏， 叶绿素衍生物， 胆固醇， 水杨酸或水杨酸衍生物， 对羟基苯甲酸及其酯类衍生物， 对乙酰氨基酚， 布洛芬， 胱氨 酸， 红辣椒酊， 烟酸苄酯， DL-薄荷醇， 薄荷油， 泛酸! ¾， 泛醇， 蓖麻油， 桧木醇， 类 固醇， 间苯二酚， 米诺地尔， 克罗卡林， 吡那地尔， 纳米尼地尔， 二苯基环丙稀酮， 铜 胜肽， 抗雄激素药物如醋酸环丙孕酮， 达那唑， 氟他胺， 5- α还原酶抑制剂如非那雄 胺， ¾罗雄脲， LY- 191704， ΜΚ-306和度他雄胺 （美国专利号 4, 377, 584) ， 以及从下 列 S-三嗪类 苯并吡喃类， pyridinopyrans, 和氧化 -1-硫杂环己烷类化合物或前面提到 的任何一种药学上可接受的盐或衍生物及类似物中选出。
21. 权利要求 20所述 ka合物， 其中所述至少一种预防或治疗用防脱发剂是水杨酸， 或水杨 酸衍生物。
22. 权利要求 20所述组合物， 其中所述至少一种预防或治疗用防脱发剂是 5- α还原酶抑制 剂。
23. 权利要求 22所述组合物， 其中所述 5- α还原酶抑制剂是非那雄胺。
24. 权利要 20所述组合物, 其中所述至少一种预防或治疗用防脱发剂是抗雄激素。
25. 权利要求 24所述组合物， 其中所述抗雄激素是氟他胺。
26. 权利要求 20所述组合物， 其中所述至少一种预防或治疗用防脱发剂是米诺地尔。
27. 权利要求 1所述组合物，还进一步包括一个或多个皮肤病学上可以接受的保湿剂，润肤 剂， 表面活性剂， 流变学改性剂， 皮肤渗透促进剂， 防腐剂， ρΗ值调节剂， 或香精。
28. 权利要求 1所述组合物，其中用于治疗脱发的外用逆向温敏可逆水凝胶组合物包括一种 不含酒精组合物。
29^ —种用于制备权利要求 1所述组合物的方法， 其中包括以下步骤：
(a) 在低于 20°C温度下， 将包括至少两个聚环氧乙垸嵌段和至少一个聚环氧丙垸嵌段 的水溶性嵌段共聚物溶于水中； (b) 然后，在合适温度下 合其它辅料及至少一种有效剂量的预防或治疗用防脱发剂, 直至溶解或将不溶性药剂分散均匀；
(c) 最后， 在合适温度下混合至少一种关联凝胶佐剂， 以形成所需治疗脱发的外用逆 向温敏可逆水凝胶组合物。
一种用于治疗和 /或防 i脱发， 恢复和 /或促进头发生长的方法， 其中所述方法包括运用 权利要求 L所述用于治疗脱发的外用逆向温敏可逆水凝胶组合物涂抹到头皮上， 然后， 在短时间内将组合物从头皮上冲洗掉。
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US9592295B2 (en) 2017-03-14
CN106474051B (zh) 2022-07-08
WO2012126278A1 (zh) 2012-09-27
CN102639097A (zh) 2012-08-15
US20170128574A1 (en) 2017-05-11
EP2689774B1 (en) 2019-01-30

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