Reversely thermo-reversible hydrogel compositions

Abstract

A reversely thermo-reversible hydrogel composition comprising a water soluble block copolymer comprising at least two blocks of polyethylene oxide and at least one block of polypropylene oxide, and at least one associative gelling adjuvant having water solubility less than 0.5 g/100 ml, preferably less than 0.3 g/100 ml at 20° C., and being capable of forming water soluble inter-molecular complexes with the water soluble block copolymer in water. The hydrogel composition exhibits improved gelling efficiency, enhanced solubility and/or stability for water sparely soluble and insoluble pharmaceutical agents. The hydrogel compositions are useful in a variety of pharmaceutical and cosmetic products and applications, such as esophageal, otic, vaginal, rectal, ophthalmic, treatments of disorders and imperfections of the skin, and treating and/or preventing alopecia and restoring and/or promoting hair growth.

What is claimed is: 
     
         1 . A reversely thermo-reversible hydrogel composition, having a transparent gel form in the temperature range of from about 4-45° C., and a gel-sol transition temperature greater than 45° C., comprising:
 (a) a water soluble block copolymer comprising at least two blocks of polyethylene oxide and at least one block of polypropylene oxide, wherein the water soluble block copolymer is a linear multi-block copolymer, having the general formula of HO—[(PO) b (EO) a ] m (PO) c [(EO) a (PO) b ] m —H, where (EO) a  is a polyethylene oxide block, (PO) b  and (PO) c  are polypropylene oxide blocks, a is in the range of about 50 to about 150, b and c are in the range of about 35 to about 70, and m is an integer greater than 0; 
 (b) at least one associative gelling adjuvant having a water solubility of less than 0.5 g/100 ml being capable of forming water soluble inter-molecular complexes with said water soluble block copolymers in water; and 
 (c) water, 
 wherein the combined amount of the water soluble block copolymer (a) and the at least one associative gelling adjuvant (b) is 24 wt. % or less of the hydrogel composition. 
 
     
     
         2 . The composition of  claim 1 , having an adjustable sol-gel transition temperature in the range of from about 4-30° C., and a gel-sol transition temperature greater than 35° C. 
     
     
         3 . The composition of  claim 1 , wherein the water soluble block copolymer is presented at a concentration ranging from about 5% to about 20%. 
     
     
         4 . The composition of  claim 3 , wherein the water soluble block copolymer is presented at a concentration ranging from about 8% to about 16%. 
     
     
         5 . A reversely thermo-reversible hydrogel composition, having a transparent gel form in the temperature range of from about 4-45° C., and a gel-sol transition temperature greater than 45° C., comprising:
 (a) a water soluble block copolymer comprising at least two blocks of polyethylene oxide and at least one block of polypropylene oxide, wherein the water soluble block copolymer is a chain extended, hyper-branched, or star-shaped block copolymer of the formula {[A n (EO) a (PO) b (EO) a A n ]E} m , where A is a monomer selected from the group consisting of esters, hydroxyl add esters, carbonates, ethers, siloxanes, and amides, (EO) a  is a polyethylene oxide block, (PO) b  is a polypropylene oxide block, E is a chain extender or crosslinking agent, a is in the range of about 50 to about 150, b is in the range of about 35 to about 70, n is an integer ranging from 0 to 50, and m is the number of repeating units in the polymer molecule and is an Integer equal to or greater than 2, preferably ranging from about 2 to about 500, more preferably from about 3 to about 100; 
 (b) at least one associative gelling adjuvant having a water solubility of less than 0.5 g/100 ml being capable of forming water soluble inter-molecular complexes with said water soluble block copolymers in water; and 
 (c) water, 
 wherein the combined amount of the water soluble block copolymer (a) and the at least one associative gelling adjuvant (b) is 24 wt. % or less of the hydrogel composition. 
 
     
     
         6 . A reversely thermo-reversible hydrogel composition, having a transparent gel form in the temperature range of from about 4-45° C., and a gel-sol transition temperature greater than 45° C., comprising:
 (a) a water soluble block copolymer comprising at least two blocks of polyethylene oxide and at least one block of polypropylene oxide, wherein the water soluble block copolymer is an end-modified block copolymer, having formula of R-G-(EO) a (PO) b (EO) a -G-R, where (EO) a  is a polyethylene oxide block, (PO) b  is a polypropylene oxide block, G is selected from the group consisting of C—C, C—O, C(O)NH, S—C, C(O)—O, or Si—O, R is alkyl or arylalkyl having an alkyl chain length in the range of C 8 -C 36 , a is in the range of about 50 to about 150, and b is in the range of about 35 to about 70; 
 (b) at least one associative gelling adjuvant having a water solubility of less than 0.5 g/100 ml being capable of forming water soluble inter-molecular complexes with said water soluble block copolymers in water; and 
 (c) water, 
 wherein the combined amount of the water soluble block copolymer (a) and the at least one associative gelling adjuvant (b) is 24 wt. %. or less of the hydrogel composition. 
 
     
     
         7 . A reversely thermo-reversible hydrogel composition, having a transparent gel form in the temperature range of from about 4-45° C., and a gel-sol transition temperature greater than 45° C., comprising:
 (a) a water soluble block copolymer comprising at least two blocks of polyethylene oxide and at least one block of polypropylene oxide, wherein the water soluble block copolymer is a grafted block copolymer, comprising a grafted side chain, comprising at least two blocks of polyethylene oxide, and at least one block of polypropylene oxide, and having the formula [A(EO) a (PO) b (EO) a ] m , where (EO) a  is a polyethylene oxide block, (PO) b  is a polypropylene oxide block, a and b are in the range of about 50 to about 150, A is selected from the group consisting of vinyl, ester, amide, imide, ether, and siloxane linkages, m is the number of repeating units in the polymer molecule and is an integer equal to or greater than 2; 
 (b) at least one associative gelling adjuvant having a water solubility of less than 0.5 g/100 ml being capable of forming water soluble inter-molecular complexes with said water soluble block copolymers in water; and 
 (c) water, 
 wherein the combined amount of the water soluble block copolymer (a) and the at least one associative gelling adjuvant (b) is 24 wt. % or less of the hydrogel composition. 
 
     
     
         8 . The composition of  claim 1 , wherein the at least one associative gelling adjuvant is presented at a concentration ranging from about 0.1% to about 12% by weight of the total composition. 
     
     
         9 . The composition of  claim 1 , wherein the at least one associative gelling adjuvant is selected from the group consisting of oxyalkylated fatty alcohol, esters of oxyalkylated fatty alcohol, oxyalkylated alkyl alcohol, esters of oxyalkylated alkyl alcohol, oxyalkylated alkylaryl alcohol, aliphatic hydroxy carboxylic acid, esters of aliphatic hydroxy carboxylic acid, aromatic hydroxy carboxylic acid, esters of aromatic hydroxy carboxylic acid, poly(hydroxy carboxylic acid), oxyalkylated sorbitan ester, oxyalkylated triglyceride, oxyalkylated glyceryl ester, esters of oxyalkylated sorbitol, polyol ester, sorbitan ester, and mixtures thereof. 
     
     
         10 . The composition of  claim 9 , wherein the oxyalkylated fatty alcohol is selected from the group consisting of laureth-2, laureth-3, laureth-4, laureth-5, and laureth-6; oleth-2, oleth-5, and oleth-10. 
     
     
         11 . The composition of  claim 9 , wherein the oxyalkylated alkyl alcohol is selected from the group consisting of C 12-13  pareth-2, C 12-13  pareth-3, C 12-13  pareth-4, C 12-13  pareth-5, and C 12-13  pareth-6. 
     
     
         12 . The composition of  claim 9 , wherein the esters of oxyalkylated fatty alcohol is selected from the group consisting of di-PPG-2 myreth-9 adipate, di-PPG-2 myreth-10 adipate, and dl-PPG-2 myreth-11 adipate. 
     
     
         13 . The composition of  claim 9 , wherein the aromatic hydroxy carboxylic acid is selected from the group consisting of salicylic acid or its derivatives. 
     
     
         14 . A method for preparing the composition of  claim 1 , comprising the steps of:
 (a) Dissolving the said water soluble block copolymer in water at the temperature below 20° C., and   (b) Then mixing the dissolved copolymer mixing the dissolved copolymer with at least one associative gelling adjuvant at a suitable temperature to form a reversely thermo-reversible hydrogel composition.   
     
     
         15 . The composition of  claim 1 , further comprising an effective amount of at least one pharmaceutical medicament or diagnostic compound. 
     
     
         16 . The composition of  claim 15 , wherein the at least one pharmaceutical medicament or diagnostic compound is selected from the group consisting of anti-bacterial substances, anti-histamines, decongestants, anti-inflammatories, miotics, anti-cholinergics, mydriatics, anti-glaucoma compounds, anti-parasitics, anti-viral compounds, carbonic anhydrase inhibitors, diagnostic agents, ophthalmic agents, chelating agents, immunosuppressive agents, anti-metabolites, anesthetics, anti-fungal agents, amoebacidal compounds, trichomonacidal agents, analgesics, anti-arthritics, anti-asthmatics, anti-coagulants, anti-convulsants, anti-depressants, anti-diabetics, anti-neoplastics, anti-psychotics, anti-hypertensive agents, muscle relaxants, proteins, peptides, acne treatment agents, lubricating agents, and mixtures thereof. 
     
     
         17 . The composition of  claim 15 , wherein the at least one pharmaceutical medicament or diagnostic compound is incorporated in a micropartculate drug delivery system. 
     
     
         18 . The composition of  claim 15 , wherein the at least one pharmaceutical medicament or diagnostic compound is presented at a concentration ranging from about 0.001% to about 70% by weight of the total composition. 
     
     
         19 . The composition of  claim 15 , further comprising one or more pharmaceutically and/or dermatologically acceptable humectants, emollients, surfactants, rheology modifiers, skin penetration enhancers, flavorings, water soluble film forming polymers, preservatives, pH regulators, or fragrances. 
     
     
         20 . The composition of  claim 15 , wherein the pharmaceutical and/or dermatological compositions take a form selected from the group consisting of soft or hard gel, liquid, lotion, cream, roll-on formulations, sprays, aerosols, pad-applied formulations, film-forming formulations, and masks. 
     
     
         21 . The composition of  claim 15 , wherein the at least one pharmaceutical medicament is absorbable through skin or mucosal membranes. 
     
     
         22 . The composition of  claim 15 , wherein the at least one pharmaceutical medicament is absorbable through a vaginal mucosal membrane, a nasal mucosal membrane, a rectal mucosal membrane, an otic mucosal membrane, an ophthalmic mucosal membrane, an esophageal mucosal membrane or an oral cavity membrane. 
     
     
         23 . The composition of  claim 15 , wherein the pharmaceutical composition is in the form of drops, spray, tablets or injectable. 
     
     
         24 . The composition of  claim 15 , comprising an acne treatment pharmaceutical hydrogel composition. 
     
     
         25 . The composition of  claim 24 , wherein the acne treatment pharmaceutical hydrogel composition comprising at least one acne treatment agent is selected from the group consisting of salicylic acid or its derivatives, sulfur, lactic acid, glycolic acid, pyruvic acid, azelaic acid, benzoyl peroxide, urea, resorcinol, N-acetylcysteine, retinoids and their derivatives, and mixtures thereof. 
     
     
         26 . The composition of  claim 25 , wherein the acne treatment agent is salicylic acid, or its derivatives. 
     
     
         27 . The composition of  claim 24 , wherein the acne treatment pharmaceutical hydrogel comprising an alcohol-free composition. 
     
     
         28 . The composition of  claim 15 , comprising a reversely thermo-reversible anti-fungal pharmaceutical hydrogel composition. 
     
     
         29 . The composition of  claim 28 , wherein the anti-fungal pharmaceutical hydrogel composition comprising an anti-fungal agent is selected from the group consisting of clotrimzole, fluconazole, flucytosine, itraconazole, ketoconazole, miconazole, ciclopirox, econazole, nystatin, oxiconazole, terbinafine hydrochloride, tioconazole, butoconazle, terconazole, miconazole nitrate, metronidazole, isoconazole nitrate, and tolnaftate. 
     
     
         30 . The composition of  claim 28 , wherein the anti-fungal agent is terbinafline hydrochloride. 
     
     
         31 . The composition of  claim 15 , wherein the at least one pharmaceutical medicament comprising at least one herb medicine or herb extract. 
     
     
         32 . A method for preparing the composition of  claim 15 , comprising the steps of:
 (a) Dissolving the said water soluble block copolymer in water at the temperature below 20° C.,   (b) Then mixing the dissolved copolymer with other excipients and/or at least one effective amount of pharmaceutical medicament or diagnostic compound at a suitable temperature to substantially dissolve or disperse uniformly the pharmaceutical medicament or diagnostic compound in the aqueous solution, and   (c) Finally mixing the dissolved copolymer with at least one associative gelling adjuvant at a suitable temperature to form a reversely thermo-reversible pharmaceutical and/or diagnostic hydrogel composition.   
     
     
         33 . A method for making up or treatment of the skin and/or mucosa, comprising applying the pharmaceutical composition of  claim 15  to the skin and/or mucosa. 
     
     
         34 . A kit for making up or treatment of the skin and/or mucosa, comprising the pharmaceutical composition of  claim 15 . 
     
     
         35 . A composition comprising:
 (a) the hydrogel of  claim 1 ; and   (b) an effective amount of at least one prophylactically or therapeutically anti-alopecia agent.   
     
     
         36 . The composition of  claim 35 , wherein the at least one prophylactically or therapeutically anti-alopecia agent is selected from the group consisting of benzalkonlum chloride, benzethonium chloride, phenol, estradiol, diphenhydramine hydrochloride, chlorpheniramine maleate, chlorophyllin derivatives, cholesterol, salicylic acid or its derivatives, p-hydroxy benzoic acid or its ester derivatives, acetaminophen, Ibuprofen, cystine, red pepper tincture, benzyl nicotinate, dl-menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, hinokitiol, prednisolone, resorcinol, minoxidil, cromakalin, pinacidil, naminidil, diphenylcyclopropenone, tricomin, antiandrogen agents, cyproterone acetate, danazol and flutamide, 5-alpha reductase inhibitors, finasteride, turosteride, LY-191704, MK-306, dutasteride, s-triazines, benzopyrans, pyridinopyrans, thiane-1-oxides, and pharmaceutically acceptable salts or derivatives of any one of the aforementioned. 
     
     
         37 . The composition of  claim 35 , wherein the at least one prophylactically or therapeutically anti-alopecia agent is salicylic acid, or its derivatives. 
     
     
         38 . The composition of  claim 35 , wherein the at least one prophylactically or therapeutically anti-alopecla agent is 5-alpha reductase inhibitors. 
     
     
         39 . The composition of  claim 38 , wherein the 5-alpha reductase inhibitors is finasteride. 
     
     
         40 . The composition of  claim 35 , wherein the at least one prophylactically or therapeutically anti-alopecia agent is an antiandrogen. 
     
     
         41 . The composition of  claim 40 , wherein the antiandrogen is flutamide. 
     
     
         42 . The composition of  claim 35 , wherein the at least one prophylactically or therapeutically anti-alopecia agent is minoxidil. 
     
     
         43 . The composition of  claim 35 , wherein the at least one prophylactically or therapeutically anti-alopecia agent is present at a concentration ranging from about 0.01% to about 15% by weight of the total composition. 
     
     
         44 . The composition of  claim 35 , further comprising one or more dermatologically acceptable humectants, emollients, surfactants, rheology modifiers, skin penetration enhancers, preservatives, pH regulators, or fragrances. 
     
     
         45 . The composition of  claim 35 , wherein the anti-alopecia hydrogel composition is an alcohol-free composition. 
     
     
         46 . A method for preparing the composition of  claim 35 , comprising the steps of:
 (a) Dissolving the said water soluble block copolymer in water at the temperature below 20° C.,   (b) Then mixing the dissolved copolymer with other excipients and/or at least one effective amount prophylactically or therapeutically anti-alopecia agent at a suitable temperature to substantially dissolve or disperse uniformly the prophylactically or therapeutically anti-alopecia agent in the aqueous solution, and   (c) Finally mixing the dissolved copolymer with at least one associative gelling adjuvant at a suitable temperature to form the topical reversely thermo-reversible hydrogel composition for the treatment of hair loss.   
     
     
         47 . The composition of  claim 1 , further comprising an effective amount of at least one cosmetic active ingredient. 
     
     
         48 . The composition of  claim 47 , wherein the at least one cosmetic active Ingredient is selected from the group consisting of essential oils, moisture retention agents, skin-beautifying agents, sun screens, antiperspirants, vitamins, amino adds, anti-acne agents, antiseptics, antibacterial agents, zinc salts, tooth whitening agents, depilatory agents, fragrance oils, insect repellants, antioxidants, chelating agents, refrigerants, anti-inflammatory agents, salts, colorants, particulate fillers, and mixtures thereof. 
     
     
         49 . The composition of  claim 47 , wherein the at least one cosmetic active Ingredient is present at a concentration ranging from about 0.01% to about 70% by weight of the total composition. 
     
     
         50 . The composition of  claim 47 , further comprising one or more physiologically acceptable humectants, emollients, surfactants, rheology modifiers, skin penetration enhancers, flavorings, water soluble film forming polymers, silicone components, preservatives, pH regulators, fragrances, or mixtures thereof. 
     
     
         51 . The composition of  claim 47 , wherein the cosmetic composition takes a form selected from the group consisting of soft or hard gel, liquid, lotion, cream, roll-on formulations, sprays, aerosols, pad-applied formulations, film-forming formulations, and masks. 
     
     
         52 . The composition of  claim 47 , wherein the cosmetic composition is selected from the group consisting of skincare, color cosmetic, tooth whitening, antiseptic and antibacterial, depilatory, antiperspirant or deodorant, insect repellant, perfume, sunscreen, baby diaper rash, shaving, hair coloring, and anti-acne cosmetic hydrogel compositions. 
     
     
         53 . The composition of  claim 47 , wherein the at least one cosmetic active Ingredient is an anti-acne agent selected from the group consisting of salicylic acid and its derivatives, sulfur, lactic acid, glycolic acid, pyruvic acid, azelaic acid, benzoyl peroxide, urea, tea tree oil, resorcinol and N-acetylcysteine, retinoids and their derivatives, and mixtures thereof. 
     
     
         54 . The composition of  claim 53 , wherein the anti-acne agent (s) is salicylic acid or its derivatives. 
     
     
         55 . The composition of  claim 47 , wherein the cosmetic hydrogel composition comprising an alcohol-free composition. 
     
     
         56 . A method for preparing the composition of  claim 47 , comprising the steps of:
 (a) Dissolving the said water soluble block copolymer in water at the temperature below 20° C.,   (b) Then mixing the dissolved copolymer with other ingredients and/or an effective amount of at least one cosmetic active ingredient at a suitable temperature to substantially dissolve or disperse uniformly the cosmetic active ingredients in the aqueous solution, and   (c) Finally mixing the dissolved copolymer with at least one associative gelling adjuvant at a suitable temperature to form a reversely thermo-reversible cosmetic hydrogel composition.   
     
     
         57 . A method for making up, or caring, or treatment of a keratin material, comprising applying the cosmetic hydrogel composition of  claim 47  to the keratin material. 
     
     
         58 . The method of  claim 57 , wherein the keratin material comprises skin. 
     
     
         59 . The method of  claim 57 , wherein the keratin material comprises lip. 
     
     
         60 . The method of  claim 57 , wherein the keratin material comprises keratinous fibers. 
     
     
         61 . A kit for making up, or caring, or treatment of a keratin material, comprising the cosmetic composition of  claim 47 . 
     
     
         62 . A reversely thermo-reversible hydrogel composition, having a transparent gel form in the temperature range of from about 4-45° C., and a gel-sol transition temperature greater than 45° C., comprising:
 (a) a water soluble block copolymer comprising at least two blocks of polyethylene oxide and at least one block of polypropylene oxide, wherein the water soluble block copolymer is a tri-block copolymer, having the general formula of HO-(EO) a (PO) b (EO) a —H, where (EO) a  is a polyethylene oxide block, (PO) b  is a polypropylene oxide blocks, a is in the range of about 50 to about 150, and b is in the range of about 35 to about 70, and m is an integer greater than 0; 
 (b) at least one associative gelling adjuvant having a water solubility of less than 0.5 g/100 ml being capable of forming water soluble inter-molecular complexes with said water soluble block copolymers in water; and 
 (c) water, 
 wherein the combined amount of the water soluble block copolymer (a) and the at least one associative gelling adjuvant (b) is 24 wt. % or less of the hydrogel composition.