Material and method for treating internal cavities

Abstract

A hydrophilic biocompatible sustained-release material is disclosed. The material comprises amounts of an ethylene oxide/propylene oxide block copolymer, HPMC, and water, effective to produce a composition of sufficiently low viscosity at room temperature to be injectable into an internal body cavity via a tube inserted within a urinary catheter. At body temperature, the material exhibits a much higher viscosity and will stably adhere to the internal surface of a body cavity. As the material dissolves, a therapeutic agent incorporated therein is slowly released to the body cavity, while the material itself is excreted from the body.

What is claimed is: 
     
         1 . A thermoreversible hydrogel, comprising:
 between 20% and 30% (w/w) of an ethylene oxide/propylene oxide triblock copolymer;   between 0.05% and 0.3% hydroxypropylmethylcellulose (HPMC);   between 0.4 and 2.5% polyethylene glycol 400 (PEG-400);   a therapeutic agent; and water.   
     
     
         2 . The thermoreversible hydrogel of  claim 1 , comprising:
 between 0.1% and 0.3% hydroxypropylmethylcellulose (HPMC); and   between 0.4 and 1.8% polyethylene glycol 400 (PEG-400).   
     
     
         3 . The thermoreversible hydrogel of  claim 1 , comprising 0.2% hydroxypropylmethylcellulose (HPMC) or about 0.2% HPMC. 
     
     
         4 . The thermoreversible hydrogel of  claim 1 , comprising 1% polyethylene glycol 400 (PEG-400) or about 1% PEG-400. 
     
     
         5 . The thermoreversible hydrogel of  claim 1 , comprising about 0.2% hydroxypropylmethylcellulose (HPMC) or about 1% PEG-400. 
     
     
         6 . A thermoreversible hydrogel, comprising:
 between 23% and 27% (w/w) of an ethylene oxide/propylene oxide triblock copolymer;   between 0.1% and 0.2% hydroxypropylmethylcellulose (HPMC); and   between 0.5% and 1% polyethylene glycol 400 (PEG-400); and water.   
     
     
         7 . The thermoreversible hydrogel of  claim 6 , comprising 0.2% hydroxypropylmethylcellulose (HPMC) or about 0.2% HPMC. 
     
     
         8 . The thermoreversible hydrogel of  claim 6 , comprising 1% polyethylene glycol 400 (PEG-400) or about 1% PEG-400. 
     
     
         9 . The thermoreversible hydrogel of  claim 1 , comprising about 0.2% hydroxypropylmethylcellulose (HPMC) and about 1% polyethylene glycol 400 (PEG-400). 
     
     
         10 . The thermoreversible hydrogel of  claim 6 , comprising:
 27% of an ethylene oxide/propylene oxide triblock copolymer;   0.2% hydroxypropylmethylcellulose (HPMC); and   1% polyethylene glycol 400 (PEG-400).   
     
     
         11 . The thermoreversible hydrogel of  claim 1 , further comprising at least one component selected from the group consisting of:
 adhesive and thickening compounds;   at least one bonding agents selected from the group consisting of polycarbophil, cellulose, microcrystalline cellulose, low substituted hydroxypropylcellulose (L-HPC), dicalcium phosphate, lactose, polyvinylpyrrolidone (PVP) and 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 selected from swellable excipients group consisting of polyvinylpyrrolidones, crospovidones, crosslinked sodium carboxymethylcellulose, crosslinked sodium carboxymethyl starch, polyethylene oxides, polymethyacrylates, low-substituted hydroxypropylmethylcellulose (L-HPC), cellulose acetate, ethylcellulose and 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 selected 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;   at least one substance selected from matrix-forming polymers group 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.   
     
     
         12 . The thermoreversible hydrogel of  claim 11 , wherein the adhesive and thickening compounds are selected from the group consisting of polycarbophil, crosslinked acrylic acid, divinyl glycol, polyvinylpyrrolidone (PVP), methylcellulose (MC), hydroxy-propylcellulose (HPC), other hydroxyalkylcelluloses, hydroxyalkylmethylcelluloses, carboxy-methylcelluloses and salts thereof, polyacrylic acids, polymethacrylates, gelatin, starch, as well as gums like guar gum and xanthan gum and any combination thereof. 
     
     
         13 . The thermoreversible hydrogel of  claim 11 , 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.   
     
     
         14 . The hydrogel of  claim 1 , 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), polypropylene fumarate) (PPF), polyurethane (PU), poly(organophosphazene) (POP), Poloxamers of the type (poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO-PPO-PEO), stearic acid, poly(acrylic acid), glyceryl stearate, cetearyl alcohol, sodium stearoyl lactylate, hydroxy-lanolin, and any combination thereof. 
     
     
         15 . The thermoreversible hydrogel of  claim 1 , wherein the therapeutic agent is an active pharmaceutical ingredient selected from the group consisting of antineoplastic drugs; chemotherapeutic agents; anti-infective agents, antimicrobial drugs, antiparasitic agents, antivirals; drugs acting on the blood and blood forming organs, antihemorrhagics, antithrombotic agents, antianemia drugs, dermatologic drugs, antifungals, antiseptics, genito-urinary system drugs, gastrointestinal system drugs, antiobesity drugs, drugs for treating acid related disorders, metabolism drugs, anti-inflammatory product, musculoskeletal system acting drugs; neurological drugs, respiratory drugs, gene therapy, cardio-vascular drugs, otological drugs, corticosteroids, analgesic and anesthetic drugs, growth factors, vascular endothelial growth factor (VEGF), inhibitory factors, interleukin 6 class cytokine (LIF) and any combination thereof. 
     
     
         16 . The thermoreversible hydrogel of  claim 15  wherein the active pharmaceutical agent is selected from the group consisting of Mitomycin C, Deoxrubicin, Valrubicin, Gemcitabine, Thiotepa, Taxotere, Ethoglucid (Epodyl), Epirubicin, Pirarubicin, Apaziquone, Vicinium, Botulinum toxin, Lidocaine, Naproxen and Ibuprofen. 
     
     
         17 . The thermoreversible hydrogel of  claim 15 , wherein the active pharmaceutical agent is antineoplastic drug, a chemotherapeutic agent, or a combination thereof. 
     
     
         18 . The thermoreversible hydrogel of  claim 15 , wherein the active pharmaceutical agent is Mitomycin C. 
     
     
         19 . A method of providing sustained-release topical treatment of a condition affecting an internal body cavity, the method comprising administering the hydrogel of  claim 15  to the internal body cavity. 
     
     
         20 . A method of providing sustained-release topical treatment of a condition affecting an internal body cavity, the method comprising administering the hydrogel of  claim 16  to the internal body cavity. 
     
     
         21 . The method of  claim 19 , wherein the internal body cavity is at least one selected from the group consisting of the urinary bladder, mouth, nasal and paranasal sinus, gallbladder, esophagus, rectum, lungs, vagina, uterus, stomach, renal pelvis, pleura, abdomen, peritoneum, pelvis, liver, kidney, heart, intestine, brain, vertebral column, and any combination thereof. 
     
     
         22 . The method of  claim 19 , wherein the internal body cavity is an internal body cavity of the urinary tract. 
     
     
         23 . The method of  claim 19 , wherein the internal body cavity is an upper urinary tract, urinary bladder, renal pelvis, kidney, or any combination thereof. 
     
     
         24 . The method of  claim 19 , wherein the internal body cavity is a kidney. 
     
     
         25 . The method of  claim 19 , wherein the internal body cavity is a urinary bladder. 
     
     
         26 . The method of  claim 19 , wherein the active pharmaceutical agent is an antineoplastic drug, a chemotherapeutic agent, or a combination thereof. 
     
     
         27 . The method of  claim 19 , wherein the condition affecting an internal body cavity is a cancer. 
     
     
         28 . The method of  claim 19 , wherein the condition affecting an internal body cavity is a urinary tract cancer. 
     
     
         29 . The method of  claim 19 , wherein the condition affecting an internal body cavity is a carcinoma of the upper urinary tract, transitional cell carcinoma in the upper urinary tract, urothelial carcinoma, urothelial carcinoma of the renal pelvis and ureter, ureteral cancer, bladder cancer, renal cancer, or any combination thereof. 
     
     
         30 . The method of  claim 19 , wherein the condition affecting an internal body cavity is a bladder cancer. 
     
     
         31 . The method of  claim 19 , wherein the internal body cavity is a kidney and the condition affecting an internal body cavity is upper urinary tract transitional cell carcinoma. 
     
     
         32 . The method of  claim 19 , wherein the internal body cavity is a urinary bladder and the condition affecting an internal body cavity is bladder cancer. 
     
     
         33 . The method of  claim 19 , wherein the active pharmaceutical ingredient is mitomycin C. 
     
     
         34 . The method of  claim 31 , wherein the active pharmaceutical ingredient is mitomycin C. 
     
     
         35 . The method of  claim 32 , wherein the active pharmaceutical ingredient is mitomycin C. 
     
     
         36 . The method of  claim 20 , wherein the internal body cavity is at least one selected from the group consisting of the urinary bladder, mouth, nasal and paranasal sinus, gallbladder, esophagus, rectum, lungs, vagina, uterus, stomach, renal pelvis, pleura, abdomen, peritoneum, pelvis, liver, kidney, heart, intestine, brain, vertebral column, and any combination thereof. 
     
     
         37 . The method of  claim 19 , wherein the hydrogel provides for parenteral administration of the active pharmaceutical ingredient. 
     
     
         38 . The thermoreversible hydrogel of  claim 16 , comprising:
 between 0.1% and 0.3% hydroxypropylmethylcellulose (HPMC); and   between 0.4% and 1.8% polyethylene glycol 400 (PEG-400).   
     
     
         39 . The thermoreversible hydrogel of  claim 16 , comprising:
 between 23% and 27% (w/w) of an ethylene oxide/propylene oxide triblock copolymer;   between 0.1% and 0.2% hydroxypropylmethylcellulose (HPMC);   between 0.5% and 1% polyethylene glycol 400 (PEG-400); and water.   
     
     
         40 . The thermoreversible hydrogel of  claim 17 , wherein the active pharmaceutical agent is Mitomycin C. 
     
     
         41 . 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 agents selected from the group consisting of polycarbophil, cellulose, microcrystalline cellulose, low substituted hydroxypropylcellulose (L-HPC), dicalcium phosphate, lactose, polyvinylpyrrolidone (PVP) and 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 selected from swellable excipients group consisting of polyvinylpyrrolidones, crospovidones, crosslinked sodium carboxymethylcellulose, crosslinked sodium carboxymethyl starch, polyethylene oxides, polymethyacrylates, low-substituted hydroxypropylmethylcellulose (L-HPC), cellulose acetate, ethylcellulose and 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 selected from the group of water soluble polymers consisting of polyethylene glycols, PVP, PVA, hydroxypropylcelluloses (HPC), hydroxyethylcelluloses (HEC), MC, carboxymethylcelluloses or their salts, dextrins, maltodextrins, cylcodextrins, 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   at least one substance selected from matrix-forming polymers group 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.   
     
     
         42 . The thermoreversible hydrogel of  claim 16 , wherein the adhesive and thickening compounds are selected from the group consisting of polycarbophil, crosslinked acrylic acid, divinyl glycol, polyvinylpyrrolidone (PVP), methylcellulose (MC), hydroxy-propylcellulose (HPC), other hydroxyalkylcelluloses, hydroxyalkylmethylcelluloses, carboxy-methylcelluloses and salts thereof, polyacrylic acids, polymethacrylates, gelatin, starch, as well as gums like guar gum and xanthan gum and any combination thereof. 
     
     
         43 . The thermoreversible hydrogel of  claim 15 , 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.   
     
     
         44 . The hydrogel of  claim 16 , further comprising at least one component selected from the group consisting of polypropylene oxide) (PPO), poly(lactide-co-glycolic acid) (PLGA), poly(N-isopropylacrylamide) (PNIPAM), polypropylene fumarate) (PPF), polyurethane (PU), poly(organophosphazene) (POP), Poloxamers of the type (poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO-PPO-PEO), stearic acid, poly(acrylic acid), glyceryl stearate, cetearyl alcohol, sodium stearoyl lactylate, hydroxy-lanolin, and any combination thereof. 
     
     
         45 . The method of  claim 20 , wherein the hydrogel provides for parenteral administration of the active pharmaceutical ingredient. 
     
     
         46 . The thermoreversible hydrogel of  claim 1 , wherein the therapeutic agent is mytomycin C, and having one or more of the following:
 a viscosity of less than 5 Pa·s over a temperature range of 4° C.-12° C.;   a viscosity of greater than 10 3  Pa·s at 37° C.;   a peel strength of 0.5-5.0 N·cm -2  tested using ASTM D2256-03 at 37° C.; and   a flexibility such that a 3 cm×3 cm section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm×9 cm without detachment of the thermoreversible hydrogel from the bladder tissue.   
     
     
         47 . The thermoreversible hydrogel of  claim 46 , having two or more of the following:
 a viscosity of less than 5 Pa·s over a temperature range of 4° C.-12° C.;   a viscosity of greater than 10 3  Pa·s at 37° C.;   a peel strength of 0.5-5.0 N·cm -2  tested using ASTM D2256-03 at 37° C.; and   a flexibility such that a 3 cm×3 cm section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm×9 cm without detachment of the thermoreversible hydrogel from the bladder tissue.   
     
     
         48 . The thermoreversible hydrogel of  claim 46 , having three or more of the following:
 a viscosity of less than 5 Pa·s over a temperature range of 4° C.-12° C.;   a viscosity of greater than 10 3  Pas at 37° C.;   a peel strength of 0.5-5.0 N·cm -2  tested using ASTM D2256-03 at 37° C.; and   a flexibility such that a 3 cm×3 cm section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm×9 cm without detachment of the thermoreversible hydrogel from the bladder tissue.   
     
     
         49 . The thermoreversible hydrogel of  claim 46 , having the following:
 a viscosity of less than 5 Pa·s over a temperature range of 4° C.-12° C.;   a viscosity of greater than 10 3  Pa·s at 37° C.;   a peel strength of 0.5-5.0 N·cm -2  tested using ASTM D2256-03 at 37° C.; and   a flexibility such that a 3 cm×3 cm section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm×9 cm without detachment of the thermoreversible hydrogel from the bladder tissue.   
     
     
         50 . The thermoreversible hydrogel of  claim 1 , wherein the therapeutic agent is mitomycin C, the ethylene oxide/propylene oxide triblock copolymer has the general formula E101 P56 E101, and the thermoreversible hydrogel completely degrades in less than 24 hours after administration to the bladder of a patient. 
     
     
         51 . The thermoreversible hydrogel of  claim 1 , wherein the therapeutic agent is mitomycin C and the thermoreversible hydrogel has a viscosity of less than 200 Pa·s at a temperature ranging from 8° C. to 25° C., and greater than 3000 Pa·s at a range of 35° C. to 37° C. 
     
     
         52 . The thermoreversible hydrogel of  claim 51 , wherein the mitomycin C is present in an amount which is therapeutically effective for treating superficial bladder cancer; and
 the thermoreversible hydrogel has 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.   
     
     
         53 . The thermoreversible hydrogel of  claim 1 , wherein the therapeutic agent is mitomycin C and after administration the therapeutic agent is continuously released for at least 16 hours. 
     
     
         54 . A thermoreversible hydrogel, comprising:
 between 23% and 30% of an ethylene oxide/propylene oxide triblock copolymer having a general formula E101 P56 E101;   0.1 % to 0.2% HPMC;   0.4% to 1.8% PEG-400; and   water;   in combination with a composition comprising MMC.   
     
     
         55 . A sustained-release thermoreversible hydrogel prepared by mixing the thermoreversible hydrogel and composition comprising MMC of  claim 54 . 
     
     
         56 . The sustained-release thermoreversible hydrogel of  claim 54 , wherein after mixing the amount of MMC is 0.05% to 0.2%. 
     
     
         57 . A thermoreversible hydrogel, comprising:
 about 27% of an ethylene oxide/propylene oxide triblock copolymer having a general formula E101 P56 E101;   0.1 % to 0.2% HPMC;   0.4% to 1.8% PEG-400; and   water.