Material and method for treating internal cavities

Abstract

Disclosed herein are materials, means and methods for sustained release of therapeutic agents for topical treatments. In particular, disclosed are means and methods for topical treatment of diseases of internal body cavities by embedding therapeutic agents in a slowly degrading biocompatible mixture applied to affected tissue.

1 - 15 . (canceled) 
     
     
         16 . A thermoreversible hydrogel, comprising:
 between 18% and 40% (w/w) of an ethylene oxide/propylene oxide triblock copolymer;   a mucoadhesive polymer;   an effective amount of a therapeutic agent; and   the balance water,   wherein the thermoreversible hydrogel has a peel strength of 0.5-5.0 N −2  tested using ASTM D2256-03 at 37° C. and a flexibility such that a 3 cm 2×3  cm 2  section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm 2×9  cm 2  without detachment of the thermoreversible hydrogel from the bladder tissue.   
     
     
         17 . The thermoreversible hydrogel of  claim 16 , having a viscosity of less than 200 Pa·s at a temperature ranging from 10° C. to 25° C. and greater than 3000 Pa·s at a range of 35° C. to 37° C. 
     
     
         18 . The thermoreversible hydrogel of  claim 16 , having:
 a viscosity of less than 5 P·s over a temperature range of 4° C.-12° C., or   a viscosity of greater than 10 3  Pa·s at 37° C.   
     
     
         19 . The thermoreversible hydrogel of  claim 16 , having:
 a viscosity of less than 5 P·s over a temperature range of 4° C.-12° C., and   a viscosity of greater than 10 3  Pa·s at 37° C.   
     
     
         20 . The thermoreversible hydrogel of  claim 16 , having a gel point below 20° C. 
     
     
         21 . The thermoreversible hydrogel of  claim 16 , wherein the therapeutic agent is continuously released for at least 2 hours after administration. 
     
     
         22 . The thermoreversible hydrogel of  claim 16 , wherein the therapeutic agent has an average release of 80% (w/w) in a period from 3 to 18 hours and an initial release of 0 to 30% in the first 30 minutes after administration 
     
     
         23 . The thermoreversible hydrogel of  claim 16 , wherein 80% (w/w) of the therapeutic agent is released in a time range of between 3 and 30 hours over a temperature range of 36° C.-42° C. and a pH range of between 1 and 9.0. 
     
     
         24 . The thermoreversible hydrogel of  claim 16 , wherein if administered to the bladder of a patient, the thermoreversible hydrogel completely dissolves in less than 24 hours after administration. 
     
     
         25 . The thermoreversible hydrogel of  claim 16 , wherein the therapeutic agent is an antineoplastic drug, anticancer drug, chemotherapy drug, or immunotherapy drug. 
     
     
         26 . The thermoreversible hydrogel of  claim 16 , wherein the therapeutic agent is mitomycin C (MMC), gemcitabine, or  bacillus  Calmette-Guérin (BCG). 
     
     
         27 . The thermoreversible hydrogel of  claim 16 , wherein the ethylene oxide/propylene oxide triblock copolymer comprises Poloxamer 407. 
     
     
         28 . The thermoreversible hydrogel of  claim 16 , wherein the mucoadhesive agent is a cellulose derivative, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), a combination thereof, or a salt thereof. 
     
     
         29 . The thermoreversible hydrogel of  claim 16 , further comprising at least one component selected from the group consisting of:
 adhesive and thickening compounds;   at least one bonding agent selected from the group consisting of polycarbophil, cellulose, microcrystalline cellulose, low substituted hydroxypropylcellulose (L-HPC), dicalcium phosphate, lactose, polyvinylpyrrolidone (PVP), sucrose, ethylcellulose, hydroxypropylmethylcellulose acetate succinate (HPMCAS), PVP, vinylpyrrolidone/vinyl acetate copolymer, polyethylene glycol, polyethylene oxide, polymethacrylates, polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc), polysaccharides, fats, fatty acids, and any combination thereof;   pH-modifying substances;   at least one diffusion coating selected from the group consisting of ethylcelluloses and polymethacrylates, cellulose acetate, cellulose acetate butyrate and any combination thereof;   plasticizers;   at least one substance chosen from the group of swellable excipients consisting of polyvinylpyrrolidones, crospovidones, crosslinked sodium carboxymethylcellulose, crosslinked sodium carboxymethyl starch, polyethylene oxides, polymethyacrylates, low-substituted hydroxypropylmethylcellulose (L-HPC), cellulose acetate, ethylcellulose, polymethacrylates, high-molecular weight polyethylene oxides, xanthan gum, copolymers of vinylpyrrolidone and vinyl acetate, polyvinylpyrrolidones, crospovidones, crosslinked sodium carboxymethylcellulose, crosslinked sodium carboxymethyl starch, poly(hydroxyalkyl methacrylate), alginates, galactomannans, and any combination thereof;   at least one substance chosen from the group of water soluble polymers consisting of polyethylene glycols, PVP, PVA, hydroxypropylcelluloses (HPC), hydroxyethylcelluloses (HEC), methylcellulose (MC), carboxymethylcelluloses or their salts, dextrins, maltodextrins, cyclodextrins, dextrans, urea, salts, sodium chloride, potassium chloride, ammonium chloride, sugars, sucrose, lactose, glucose, fructose, maltose, sugar alcohols, mannitol, sorbitol, xylitol, lactitol, and any combination thereof; and   at least one substance chosen from the group of matrix-forming polymers consisting of hydroxyethylmethylcelluloses, hydroxypropylcelluloses (HPC), hydroxyethylcelluloses methylcelluloses (MC), ethylcelluloses, alkylcelluloses, hydroxy-alkylcelluloses hydroxyalkylmethylcelluloses, sodium carboxymethylcelluloses (NaCMC), alginates, galactomannans, xanthans, polyethylene oxides, polyacrylic acids, polymethacrylic acids, polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), agar, pectin, gum arabic, tragacanth, gelatin, starch, and any combination thereof.   
     
     
         30 . The thermoreversible hydrogel of  29 , wherein
 the pH-modifying substances are selected from the group consisting of acids, bases and buffer, adipic acid, malic acid, L-arginine, ascorbic acid, aspartic acid, benzenesulphonic acid, benzoic acid, succinic acid, citric acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, fumaric acid, gluconic acid, glucuronic acid, glutamic acid, potassium hydrogen tartrate, maleic acid, malonic acid, methanesulphonic acid, toluenesulphonic acid, trometamol, tartaric acid, and any combination thereof; and   the plasticizers are selected from the group consisting of citric acid, triethyl citrate, tributyl citrate, acetyl triethyl citrate; phthalic acid, dimethyl phthalate, diethyl phthalate, dibutyl phthalate; benzoic acid and benzoic esters, other aromatic carboxylic esters, trimellithic esters, aliphatic dicarboxylic esters, dialkyl adipates, sebacic esters, in particular diethyl sebacate, tartaric esters, glycerol monoacetate; glycerol diacetate or glycerol triacetate, polyols, glycerol, 1,2-propanediol, polyethylene glycol of varying chain length, fatty acids, glycerol monostearates, acetylated fatty acid glycerides, castor oil and other natural oils, Miglyol, fatty acid alcohols, cetyl alcohol, cetylstearyl alcohol and any combination thereof.   
     
     
         31 . The thermoreversible hydrogel of  claim 16 , further comprising at least one component selected from the group consisting of poly(propylene oxide) (PPO), poly(lactide-co-glycolic acid) (PLGA), poly(N-isopropylacrylamide) (PNIPAM), poly(propylene fumarate) (PPF), polyurethane (PU), poly(organophosphazene) (POP), stearic acid, poly(acrylic acid), glyceryl stearate, cetearyl alcohol, sodium stearoyl lactylate, hydroxy-lanolin, and any combination thereof. 
     
     
         32 . A thermoreversible hydrogel, comprising:
 between 18% and 40% (w/w) of an ethylene oxide/propylene oxide triblock copolymer;   a mucoadhesive polymer;   an effective amount of a therapeutic agent; and   the balance water,   wherein the thermoreversible hydrogel has a gel point below 23° C. and a viscosity greater than 3000 Pa·s at a range of 35° C. to 37° C.   
     
     
         33 . The thermoreversible hydrogel of  claim 32 , having a peel strength of 0.5-5.0 N −2  tested using ASTM D2256-03 at 37° C. 
     
     
         34 . The thermoreversible hydrogel of  claim 32 , having a flexibility such that a 3 cm 2×3  cm 2  section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm 2×9  cm 2  without detachment of the thermoreversible hydrogel from the bladder tissue. 
     
     
         35 . The thermoreversible hydrogel of  claim 32 , wherein the therapeutic agent is continuously released for at least 3 hours after administration. 
     
     
         36 . The thermoreversible hydrogel of  claim 32 , wherein 80% (w/w) of the therapeutic agent is released in a time range of between 3 and 30 hours over a temperature range of 36° C.-42° C. and a pH range of between 1 and 9.0. 
     
     
         37 . The thermoreversible hydrogel of  claim 32 , wherein the therapeutic agent has an average release of 80% (w/w) in a period from 3 to 18 hours and an initial release of 0 to 30% in the first 30 minutes after administration. 
     
     
         38 . The thermoreversible hydrogel of  claim 32 , wherein if administered to the bladder of a patient, the thermoreversible hydrogel completely dissolves in less than 24 hours after administration. 
     
     
         39 . The thermoreversible hydrogel of  claim 32 , wherein the therapeutic agent is an antineoplastic drug, anticancer drug, chemotherapy drug, or immunotherapy drug. 
     
     
         40 . The thermoreversible hydrogel of  claim 32 , wherein the therapeutic agent is mitomycin C (MMC), gemcitabine, or  bacillus  Calmette-Guérin (BCG). 
     
     
         41 . The thermoreversible hydrogel of  claim 32 , wherein the ethylene oxide/propylene oxide triblock copolymer comprises Poloxamer 407. 
     
     
         42 . The thermoreversible hydrogel of  claim 32 , wherein the mucoadhesive agent is a cellulose derivative, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), a combination thereof, or a salt thereof. 
     
     
         43 . A method of treating urinary tract cancer, bladder cancer, or upper tract urothelial carcinoma (UTUC), the method comprising administering locally a therapeutically effective amount of the thermoreversible hydrogel of  claim 16  to a patient in need thereof, wherein the therapeutic agent is MMC, and wherein the MMC is continuously released for at least 3 hours after administration. 
     
     
         44 . A method of treating urinary tract cancer, bladder cancer, or upper tract urothelial carcinoma (UTUC), the method comprising administering locally a therapeutically effective amount of the thermoreversible hydrogel of  claim 32  to a patient in need thereof, wherein the therapeutic agent is MMC, and wherein the MMC is continuously released for at least 3 hours after administration.