Claims for Patent: 10,039,832

Summary for Patent: 10,039,832

Title:	Material and method for treating internal cavities
Abstract:	A hydrophilic biocompatible sustained-release material is disclosed. The material comprises amounts of Pluronic F-127, PEG-400, 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.
Inventor(s):	Asher Holzer, Dorit Daniel, Michael MULLERAD, Jaime De La Zerda, Uri SHPOLANSKY, Nadav MALCHI, Yosh DOLLBERG, Dor TAL, Yossi YAVIN, Marina KONORTY
Assignee:	Urogen Pharma Ltd
Application Number:	US14/720,676
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,039,832
Patent Claims:	1. A method of treating a urinary tract cancer comprising: obtaining a pharmaceutical composition comprising a therapeutically effective amount of an effective amount of a therapeutic agent and a thermoreversible hydrogel; wherein the thermoreversible hydrogel comprises: (i) 18% (w/w) to 40% (w/w) ethylene oxide/propylene oxide block copolymer, (ii) 0.05% (w/w) to 0.5% (w/w) HPMC, and (iii) water; wherein the therapeutic agent is Mitomycin C and is 0.025% to 0.3% (w/v) of the pharmaceutical composition; and administering the pharmaceutical composition to a human in need thereof. 2. The method of claim 1, wherein the urinary tract cancer is selected from the group consisting of a bladder cancer, an upper urinary tract cancer and a renal pelvis cancer. 3. The method of claim 1, wherein the thermoreversible hydrogel further comprises at least one component that is not HPMC 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, cellulose derivatives, low substituted hydroxypropylcellulose (L-HPC), dicalcium phosphate, lactose, PVP and sucrose, ethylcellulose, hydroxypropymethylcellulose acetate succinate PVP, vinylpyrrolidone/vinyl acetate copolymer, polyethylene glycol, polyethylene oxide, polymethacrylates, polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc), polysaccharides, fats and fatty acid derivatives 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 carboxymehylstarch, polyethylene oxides, polymethyacrylates, low-substituted hydroxypropylmethylcellulose (LHPC), 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 polymer consisting of polyethylene glycols, PVP, PV A, 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 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, polymethacrylic acid derivatives, polyvinyl alcohols (PV A), partially hydrolysed polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), agar, pectin, gum arable, tragacanth, gelatin, starch, starch derivatives and any combination thereof. 4. The method of claim 1, wherein the therapeutic agent is 0.05% to 0.2% (w/v) of the pharmaceutical composition. 5. A pharmaceutical composition comprising a therapeutically effective amount of a therapeutic agent and a thermoreversible hydrogel; wherein the thermoreversible hydrogel comprises: (i) 18% to 40% ethylene oxide/propylene oxide block copolymer, (ii) 0.05% to 0.15% HPMC, and (iii) water; wherein the therapeutic agent is Mitomycin C and is 0.025% to 0.3% (w/v) of the pharmaceutical composition. 6. The pharmaceutical composition of claim 5, further comprising at least one component that is not HPMC 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, cellulose derivatives, low substituted hydroxypropylcellulose (L-HPC), dicalcium phosphate, lactose, PVP and sucrose, ethylcellulose, hydroxypropyrnethyleellulose acetate succinate (HPMCAS), PVP, vinylpyrrolidone/vinyl acetate copolymer, polyethylene glycol, polyethylene oxide, polymethacrylates, polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc), polysaccharides, fats and fatty acid derivatives 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 (LHPC), 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 polymer consisting of polyethylene glycols, PVP, PVA, 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 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, polymethacrylic acid derivatives, polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), agar, pectin, gum arabic, tragacanth, gelatin, starch, starch derivatives and any combination thereof. 7. The pharmaceutical composition of claim 5, wherein the therapeutic agent is 0.05% to 0.2% (w/v) of the pharmaceutical composition. 8. The pharmaceutical composition of claim 5, 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 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 cm2×3 cm2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm2×9 cm2 without detachment of the thermoreversible hydrogel from the bladder tissue. 9. The pharmaceutical composition of claim 8, 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 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 cm2×3 cm2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm2×9 cm2 without detachment of the thermoreversible hydrogel from the bladder tissue. 10. The pharmaceutical composition of claim 8, 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 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 cm2×3 cm2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm2×9 cm2 without detachment of the thermoreversible hydrogel from the bladder tissue. 11. The pharmaceutical composition of claim 8, 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 cm2×3 cm2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm2×9 cm2 without detachment of the thermoreversible hydrogel from the bladder tissue. 12. The pharmaceutical composition of claim 5, wherein 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. 13. The pharmaceutical composition of claim 8, 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. 14. The pharmaceutical composition of claim 13, wherein the mitomycin C is present in an amount which is therapeutically effective for treating superficial bladder cancer. 15. The pharmaceutical composition of claim 5, wherein after administration the therapeutic agent is continuously released for at least 16 hours. 16. The method of claim 1, wherein the pharmaceutical composition has 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 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 cm2×3 cm2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm2×9 cm2 without detachment of the thermoreversible hydrogel from the bladder tissue. 17. The method of claim 16, wherein the pharmaceutical composition has 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 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 cm2×3 cm2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm2×9 cm2 without detachment of the thermoreversible hydrogel from the bladder tissue. 18. The method of claim 16, wherein the pharmaceutical composition has 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 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 cm2×3 cm2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm2×9 cm2 without detachment of the thermoreversible hydrogel from the bladder tissue. 19. The method of claim 16, wherein the pharmaceutical composition has 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 cm2×3 cm2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm2×9 cm2 without detachment of the thermoreversible hydrogel from the bladder tissue. 20. The method of claim 1, wherein the ethylene oxide/propylene oxide triblock copolymer of the pharmaceutical composition 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. 21. The method 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. 22. The method of claim 21, wherein the mitomycin C is present in an amount which is therapeutically effective for treating superficial bladder cancer. 23. The method of claim 1, wherein after administration the therapeutic agent is continuously released for at least 16 hours.