Material and method for treating internal cavities

Abstract

A method of providing sustained-release topical treatment of a condition affecting an internal body cavity is provided. The method comprises administering a pharmaceutical composition comprising a thermoreversible hydrogel and an active pharmaceutical ingredient to an internal body cavity of the urinary tract. After administration, the concentration of the active pharmaceutical ingredient in urothelium of the internal body cavity is increased when compared to the concentration of the active pharmaceutical ingredient in urothelium of the internal body cavity following administration of a control composition comprising the same dose and concentration of active pharmaceutical ingredient in water.

What is claimed is: 
     
         1 . A method of providing sustained-release topical treatment of a condition affecting an internal body cavity, the method comprising administering a pharmaceutical composition comprising a thermoreversible hydrogel to an internal body cavity of the urinary tract, wherein the thermoreversible hydrogel comprises an active pharmaceutical ingredient, wherein the method comprises controlled release of the active pharmaceutical ingredient, wherein, after administration, the concentration of the active pharmaceutical ingredient in urothelium of the internal body cavity is increased when compared to the concentration of the active pharmaceutical ingredient in urothelium of the internal body cavity following administration of a control composition comprising the same dose and concentration of active pharmaceutical ingredient in water. 
     
     
         2 . The method of  claim 1 , wherein the concentration of the active pharmaceutical ingredient is increased 2 hours after the administration of the pharmaceutical composition. 
     
     
         3 . The method of  claim 1 , wherein the concentration of the active pharmaceutical ingredient is increased 6 hours after the administration of the pharmaceutical composition. 
     
     
         4 . The method of  claim 1 , wherein the concentration of the active pharmaceutical ingredient following administration of the pharmaceutical composition is at least 11-fold higher than the concentration of the active pharmaceutical ingredient following administration of the control composition. 
     
     
         5 . The method of  claim 1 , wherein the thermoreversible hydrogel has a gel point temperature of about 10° C. to about 37° C. 
     
     
         6 . The method of  claim 1 , wherein the thermoreversible hydrogel has a gel point temperature of about 4° C. to about room temperature. 
     
     
         7 . The method of  claim 1 , wherein the thermoreversible hydrogel has a gel point temperature of about 12° C. to about 22° C. 
     
     
         8 . The method of  claim 1 , wherein the thermoreversible hydrogel has a gel point temperature of about 14° C., about 15° C., or about 17° C. 
     
     
         9 . The method of  claim 1 , wherein the thermoreversible hydrogel has a gel point temperature of about 12° C. to about 17° C. 
     
     
         10 . The method of  claim 1 , wherein the thermoreversible hydrogel has a gel point below 20° C. 
     
     
         11 . The method of  claim 1 , wherein delivery of the thermoreversible hydrogel results in sustained release of the active pharmaceutical ingredient for at least 2 hours, at least 6 hours, at least 12 hours, at least 16 hours, at least 18 hours, over 12-24 hours, over 16-24 hours, or over 24 hours. 
     
     
         12 . The method of  claim 1 , wherein the active pharmaceutical ingredient 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. 
     
     
         13 . The method of  claim 1 , wherein the active pharmaceutical ingredient is selected from the group consisting of Mitomycin C, Deoxrubicin, Valrubicin, Gemcitabine, Thiotepa, Taxotere, Ethoglucid (Epodyl), Epirubicin, Pirarubicin, Apaziquone, Vicinium, Botulinum toxin, Lidocaine, Naproxen, Ibuprofen and combinations thereof. 
     
     
         14 . The method of  claim 1 , wherein the active pharmaceutical ingredient is a antineoplastic drug, a chemotherapeutic agent, or a combination thereof. 
     
     
         15 . The method of  claim 1 , wherein the active pharmaceutical ingredient is Mitomycin C. 
     
     
         16 . The method of  claim 9 , wherein the active pharmaceutical ingredient is mitomycin C. 
     
     
         17 . The method of  claim 1 , wherein the hydrogel is gradually diluted and expelled from the body within 24 hours after administration. 
     
     
         18 . The method of  claim 1 , wherein:
 a) the thermoreversible hydrogel has a gel point temperature of about 4° C. to about room temperature;   b) the hydrogel is gradually diluted and expelled from the body within 24 hours after administration; and   c) the thermoreversible hydrogel has a pH of 5.5-8.0.   
     
     
         19 . The method of  claim 18 , wherein the active pharmaceutical ingredient is mitomycin C. 
     
     
         20 . The method of  claim 18 , wherein the thermoreversible hydrogel has a gel point temperature of about 12° C. to about 17° C. 
     
     
         21 . The method of  claim 18 , wherein the active pharmaceutical ingredient is mitomycin C and the thermoreversible hydrogel has a gel point temperature of about 12° C. to about 17° C. 
     
     
         22 . The method of  claim 18 , wherein the internal body cavity is an upper urinary tract, urinary bladder, renal pelvis, kidney, or any combination thereof. 
     
     
         23 . The method of  claim 18 , wherein the internal body cavity is a kidney. 
     
     
         24 . The method of  claim 18 , wherein the internal body cavity is a urinary bladder. 
     
     
         25 . The method of  claim 1 , wherein the condition affecting an internal body cavity is a cancer. 
     
     
         26 . The method of  claim 1 , wherein the condition affecting an internal body cavity is a urinary tract cancer. 
     
     
         27 . The method of  claim 1 , 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. 
     
     
         28 . The method of  claim 1 , wherein the condition affecting an internal body cavity is a bladder cancer. 
     
     
         29 . The method of  claim 1 , wherein the internal body cavity is a kidney and the condition affecting an internal body cavity is upper urinary tract transitional cell carcinoma. 
     
     
         30 . The method of  claim 1 , wherein the internal body cavity is a urinary bladder and the condition affecting an internal body cavity is bladder cancer. 
     
     
         31 . The method of  claim 29 , wherein the active pharmaceutical ingredient is mitomycin C. 
     
     
         32 . The method of  claim 30 , wherein the active pharmaceutical ingredient is mitomycin C. 
     
     
         33 . The method of  claim 1 , wherein the thermoreversible hydrogel has a pH of 5.5-8.0. 
     
     
         34 . The method of  claim 18 , wherein the pharmaceutical composition has 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.   
     
     
         35 . The method of  claim 18 , wherein the thermoreversible hydrogel comprises a poloxamer. 
     
     
         36 . The method of  claim 35 , wherein the poloxamer is Poloxamer 407. 
     
     
         37 . The method of  claim 18 , wherein the thermoreversible hydrogel comprises an ethylene oxide/propylene oxide triblock copolymer. 
     
     
         38 . A pharmaceutical composition for providing sustained-release topical treatment of a condition affecting an internal body cavity of the urinary tract, comprising
 a thermoreversible hydrogel; and   an active pharmaceutical ingredient;   wherein the thermoreversible hydrogel is capable of effecting controlled release of the active pharmaceutical ingredient in the internal body cavity of the urinary tract, wherein, after administration, the concentration of the active pharmaceutical ingredient in urothelium of the internal body cavity is increased when compared to the concentration of the active pharmaceutical ingredient in urothelium of the internal body cavity following administration of a control composition comprising the same dose and concentration of active pharmaceutical ingredient in water.   
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the concentration of the active pharmaceutical ingredient is increased 2 hours after the administration of the pharmaceutical composition. 
     
     
         40 . The pharmaceutical composition of  claim 38 , wherein the concentration of the active pharmaceutical ingredient is increased 6 hours after the administration of the pharmaceutical composition. 
     
     
         41 . The pharmaceutical composition of  claim 38 , wherein the concentration of the active pharmaceutical ingredient following administration of the pharmaceutical composition is at least 11-fold higher than the concentration of the active pharmaceutical ingredient following administration of the control composition. 
     
     
         42 . The pharmaceutical composition of  claim 38 , wherein:
 a) the thermoreversible hydrogel has a gel point temperature of about 4° C. to about room temperature;   b) the hydrogel is gradually diluted and expelled from the body within 24 hours after administration; and   c) the thermoreversible hydrogel has a pH of 5.5-8.0.   
     
     
         43 . The pharmaceutical composition of  claim 38 , wherein the active pharmaceutical ingredient 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. 
     
     
         44 . The pharmaceutical composition of  claim 38 , wherein the active pharmaceutical ingredient is selected from the group consisting of Mitomycin C, Deoxrubicin, Valrubicin, Gemcitabine, Thiotepa, Taxotere, Ethoglucid (Epodyl), Epirubicin, Pirarubicin, Apaziquone, Vicinium, Botulinum toxin, Lidocaine, Naproxen, Ibuprofen and combinations thereof. 
     
     
         45 . The pharmaceutical composition of  claim 38 , wherein the active pharmaceutical ingredient is a antineoplastic drug, a chemotherapeutic agent, or a combination thereof. 
     
     
         46 . The pharmaceutical composition of  claim 38 , wherein the active pharmaceutical ingredient is Mitomycin C. 
     
     
         47 . The pharmaceutical composition of  claim 42 , wherein the active pharmaceutical ingredient is mitomycin C. 
     
     
         48 . The pharmaceutical composition of  claim 42 , wherein the thermoreversible hydrogel has a gel point temperature of about 12° C. to about 17° C. 
     
     
         49 . The pharmaceutical composition of  claim 42 , wherein the active pharmaceutical ingredient is mitomycin C and the thermoreversible hydrogel has a gel point temperature of about 12° C. to about 17° C.