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;   between 0.05% and 0.3% hydroxypropylmethylcellulose (HPMC) and/or carboxymethylcellulose or a salt thereof;   between 0.4 and 2.5% polyethylene glycol 400 (PEG-400); and   
       an effective amount of a therapeutic agent; and the balance water. 
     
     
         17 . The thermoreversible hydrogel of  claim 16 , wherein the therapeutic agent is 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. 
     
     
         18 . The thermoreversible hydrogel of  claim 16 , wherein the therapeutic agent is an antineoplastic drug. 
     
     
         19 . The thermoreversible hydrogel of  claim 16 , wherein the ethylene oxide/propylene oxide triblock copolymer is Poloxamer 407. 
     
     
         20 . The thermoreversible hydrogel of  claim 19 , comprising:
 between 0.1% and 0.3% HPMC; and   between 0.4 and 1.8% PEG-400.   
     
     
         21 . The thermoreversible hydrogel of  claim 20 , comprising:
 between 0.1% and 0.2% HPMC;   between 0.5% and 1% PEG-400.   
     
     
         22 . The thermoreversible hydrogel of  claim 19 , comprising between 30% and 40% (w/w) of Poloxamer 407; 
     
     
         23 . The thermoreversible hydrogel of  claim 19 , having one or more of the following:
 a viscosity of less than 5 P·s over a temperature range of 4° C.-12° C.;   a viscosity of greater than 10 3  Pa·s over at 37° C.;   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.   
     
     
         24 . The thermoreversible hydrogel of  claim 23 , having two or more of the following:
 a viscosity of less than 5 P·s over a temperature range of 4° C.-12° C.;   a viscosity of greater than 10 3  Pa·s over at 37° C.;   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.   
     
     
         25 . The thermoreversible hydrogel of  claim 24 , having three or more of the following:
 a viscosity of less than 5 P·s over a temperature range of 4° C.-12° C.;   a viscosity of greater than 10 3  Pa·s over at 37° C.;   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.   
     
     
         26 . The thermoreversible hydrogel of  claim 25 , having the following:
 a viscosity of less than 5 P·s over a temperature range of 4° C.-12° C.;   a viscosity of greater than 103 Pa·s over at 37° C.;   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.   
     
     
         27 . The thermoreversible hydrogel of  claim 19 , wherein if administered to the bladder of a patient, the thermoreversible hydrogel completely degrades in less than 24 hours after administration. 
     
     
         28 . The thermoreversible hydrogel of  claim 16 , wherein 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. 
     
     
         29 . The thermoreversible hydrogel of  claim 16 , wherein if administered to the bladder of a patient, the therapeutic agent is continuously released for at least 16 hours after administration. 
     
     
         30 . 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) 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 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 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.   
     
     
         31 . The thermoreversible hydrogel of  claim 30 , 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. 
     
     
         32 . The thermoreversible hydrogel of  30 , 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.   
     
     
         33 . 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. 
     
     
         34 . The thermoreversible hydrogel of  claim 19 , wherein the therapeutic agent is an antineoplastic drug. 
     
     
         35 . The thermoreversible hydrogel of  claim 34 , comprising:
 between 0.1% and 0.3% HPMC; and   between 0.4 and 1.8% PEG-400.