Material and method for treating internal cavities
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.
1. A thermoreversible hydrogel, comprising:
between 20% and 30% (w/w) of an ethylene oxide/propylene oxide triblock copolymer characterized by an average molar mass of 13000 and a general formula E106 P70 E106;
between 0.05% and 0.3% HPMC;
between 0.4and 2.5% 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% HPMC; and
between 0.4 and 1.8% PEG-400.
3. A thermoreversible hydrogel, comprising:
between 23% and 27% (w/w) of an ethylene oxide/propylene oxide triblock copolymer characterized by an average molar mass of 13000 and a general formula E106 P70 E106;
between 0.1% and 0.2% HPMC;
between 0.5% and 1% PEG-400; and
the balance water.
4. The thermoreversible hydrogel of any one of claims 1 , 2 , or 3 , 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, cellulose derivatives, low substituted hydroxypropylcellulose (L-HPC), dicalcium phosphate, lactose, PVP and sucrose, ethylcellulose, hydroxypropymethyleellulose 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 carboxymethylstarch, 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 carboxymethylstarch, 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, 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.
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 or starch derivatives, as well as gums like guar gum and xanthan gum and any combination thereof.
6. The thermoreversible hydrogel of 4 , 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, gluconie 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 derivatives, triethyl citrate, tributyl citrate, acetyl triethyl citrate, phthalic acid derivatives, 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 and derivatives, 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 any one of claims 1 , 2 , or 3 , 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 lactylatc, hydroxy-lanolin, and any combination thereof.
8. The thermoreversible hydrogel of any one of claim 1 , 2 , or 3 , comprising an active pharmaceutical ingredient selected from the group consisting of antineoplastic drugs; chemotherapeutic agents; anti-infective agents, antimicrobial drugs, antiparasitie 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, VEGF, inhibitory factors, 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 characterized by an average molar mass of 13000 and a general formula E106 P70 E106;
between 0.05% and 0.3% HPMC;
between 0.4% and 2.5% 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% HPMC; and
between 0.4% and 1.8% PEG-400.
17. The thermoreversible hydrogel of claim 15 , comprising:
between 23% and 27% (w/w) of an ethylene oxide/propylene oxide triblock copolymer characterized by an average molar mass of 13000 and a general formula E106 P70 E106;
between 0.1% and 0.2% HPMC;
between 0.5% and 1% 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, cellulose derivatives, low substituted hydroxypropylcellulose (L-HPC), dicalcium phosphate, lactose, PVP and sucrose, ethylcellulose, hydroxypropymethyleellulose 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 carboxymethylstarch, 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 carboxymethylstarch, 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, 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.
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 or starch derivatives, as well as gums like guar gum and xanthan gum and any combination thereof.
20. The thermoreversible hydrogel of 8 , 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, gluconie 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 derivatives, triethyl citrate, tributyl citrate, acetyl triethyl citrate, phthalic acid derivatives, 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 and derivatives, 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 lactylatc, hydroxy-lanolin, and any combination thereof.
22. The method of claim 11 , wherein the hydrogel provides for parenteral administration of the active pharmaceutical ingredient.