Claims for Patent: 9,950,069

Summary for Patent: 9,950,069

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):	Holzer; Asher (Raanana, IL), Daniel; Dorit (Raanana, IL), Mullerad; Michael (Tel Aviv, IL), De La Zerda; Jaime (Haifa, IL), Shpolansky; Uri (Pardes Hana, IL), Malchi; Nadav (Pardes Hanna-Karkur, IL), Dollberg; Yosh (Raanana, IL), Tal; Dor (Hadera, IL), Yavin; Yossi (Mikhmoret, IL), Konorty; Marina (Hertzyla, IL)
Assignee:	UROGEN PHARMA LTD. (Raanana, IL)
Application Number:	15/366,256
Patent Claims:	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); an effective amount of a therapeutic agent; and the balance 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. A thermoreversible hydrogel, comprising: between 23% and 27% (w/w) of an ethylene oxide/propylene oxide triblock copolymer having a general formula E101 P56 E101; between 0.1% and 0.2% hydroxypropylmethylcellulose (HPMC); between 0.5% and 1% polyethylene glycol 400 (PEG-400); and the balance water. 4. 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 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; 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. 5. The thermoreversible hydrogel of claim 4, 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. 6. The thermoreversible hydrogel of 18, 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. 7. 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), poly(propylene 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. 8. The thermoreversible hydrogel of claim 1, comprising 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. 9. The thermoreversible hydrogel of claim 8 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, Fibrin, Lidocaine, Thrombin, Collagen, Naproxen and Ibuprofen. 10. A method for providing sustained-release topical treatment of a condition affecting an internal body cavity, comprising administering the hydrogel of claim 8 to the internal body cavity. 11. A method for providing sustained-release topical treatment of a condition affecting an internal body cavity, comprising administering the hydrogel of claim 9 to the internal body cavity. 12. The method of claim 10, 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. 13. The method of claim 11, 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. 14. The method of claim 10, wherein the hydrogel provides for parenteral administration of the active pharmaceutical ingredient. 15. 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); an effective amount of a therapeutic agent selected from the group consisting of Mitomycin C, Deoxrubicin, Valrubicin, Gemcitabine, Thiotepa, Taxotere, Ethoglucid (Epodyl), Epirubicin, Pirarubicin, Apaziquone, Vicinium, Botulinum toxin, Fibrin, Lidocaine, Thrombin, Collagen, Naproxen and Ibuprofen; and the balance water. 16. The thermoreversible hydrogel of claim 15, comprising: between 0.1% and 0.3% hydroxypropylmethylcellulose (HPMC); and between 0.4% and 1.8% polyethylene glycol 400 (PEG-400). 17. The thermoreversible hydrogel of claim 15, comprising: between 23% and 27% (w/w) of an ethylene oxide/propylene oxide triblock copolymer having a general formula E101 P56 E101; between 0.1% and 0.2% hydroxypropylmethylcellulose (HPMC); between 0.5% and 1% polyethylene glycol 400 (PEG-400); and the balance water. 18. The thermoreversible hydrogel of claim 15, 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 chosen 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 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. 19. The thermoreversible hydrogel of claim 15, 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. 20. The thermoreversible hydrogel of 22, 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. 21. The hydrogel of claim 15, 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), 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. 22. The method of claim 11, wherein the hydrogel provides for parenteral administration of the active pharmaceutical ingredient. 23. 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 Ps over a temperature range of 4.degree. C.-12.degree. C.; a viscosity of greater than 10.sup.3 Pas over at 37.degree. C.; a peel strength of 0.5-5.0 N.sup.-2 tested using ASTM D2256-03 at 37.degree. C.; and a flexibility such that a 3 cm.sup.2.times.3 cm.sup.2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm.sup.2.times.9 cm.sup.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 Ps over a temperature range of 4.degree. C.-12.degree. C.; a viscosity of greater than 10.sup.3 Pas over at 37.degree. C.; a peel strength of 0.5-5.0 N.sup.-2 tested using ASTM D2256-03 at 37.degree. C.; and a flexibility such that a 3 cm.sup.2.times.3 cm.sup.2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm.sup.2.times.9 cm.sup.2 without detachment of the thermoreversible hydrogel from the bladder tissue. 25. The thermoreversible hydrogel of claim 23, having three or more of the following: a viscosity of less than 5 Ps over a temperature range of 4.degree. C.-12.degree. C.; a viscosity of greater than 10.sup.3 Pas over at 37.degree. C.; a peel strength of 0.5-5.0 N.sup.-2 tested using ASTM D2256-03 at 37.degree. C.; and a flexibility such that a 3 cm.sup.2.times.3 cm.sup.2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm.sup.2.times.9 cm.sup.2 without detachment of the thermoreversible hydrogel from the bladder tissue. 26. The thermoreversible hydrogel of claim 23, having the following: a viscosity of less than 5 Ps over a temperature range of 4.degree. C.-12.degree. C.; a viscosity of greater than 103 Pas over at 37.degree. C.; a peel strength of 0.5-5.0 N.sup.-2 tested using ASTM D2256-03 at 37.degree. C.; and a flexibility such that a 3 cm.sup.2.times.3 cm.sup.2 section of bladder tissue layered with the thermoreversible hydrogel at room temperature can be stretched to 9 cm.sup.2.times.9 cm.sup.2 without detachment of the thermoreversible hydrogel from the bladder tissue. 27. 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. 28. The thermoreversible hydrogel of claim 1, wherein the therapeutic agent is mitomycin C and the thermoreversible hydrogel has a viscosity of less than 200 Pas at a temperature ranging from 8.degree. C. to 25.degree. C., and greater than 3000 Pas at a range of 35.degree. C. to 37.degree. C. 29. The thermoreversible hydrogel of claim 28, wherein the mitomycin C is present in an amount which is therapeutically effective for treating superficial bladder cancer. 30. 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.