# US 9,040,074 B2 · Material and method for treating internal cavities

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- Number: US 9,040,074 B2
- Document ID: US9040074B2
- Status: Granted
- Kind: B2
- Application number: 13/553,198
- Filed: 2012-07-19
- Published: 2013-02-21
- Granted: 2015-05-26
- Earliest claimed: 2010-01-20
- Assignees: Theracoat Ltd.
- Applicants: Asher Holzer; Dorit Daniel; Michael Mullerad; Jaime De La Zerda; Uri Shpolansky; Nadav Malchi; Yosh Dollberg; Dor Tal; Yossi Yavin; Marina Konorty
- Inventors: Asher Holzer; Dorit Daniel; Michael Mullerad; Jaime De La Zerda; Uri Shpolansky; Nadav Malchi; Yosh Dollberg; Dor Tal; Yossi Yavin; Marina Konorty
- Web page: https://patentgrep.com/patent/US9040074B2

## CPC

- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61K 9/0024: {Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L)}
- A61K 9/0034: {Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants}
- A61K 9/006: {Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 31/07: Retinol compounds, e.g. vitamin A (retinoic acids A61K31/203)
- A61K 31/122: having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/59: Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/79: Polymers of vinyl pyrrolidone
- A61K 38/2013: {IL-2}
- A61K 38/4893: {Botulinum neurotoxin (3.4.24.69)}
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/38: Cellulose; Derivatives thereof
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 25/00: Drugs for disorders of the nervous system
- C12Y 304/24069: Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Y: ENZYMES

## 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.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

The thermoreversible hydrogel of claim 1, comprising:
between 0.1% and 0.3% HPMC; and
between 0.4 and 1.8% PEG-400.

### Claim 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.

### Claim 4 (depends on 1, 2)

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.

### Claim 5 (depends on 4)

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.

### Claim 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.

### Claim 7 (depends on 1, 2)

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.

### Claim 8 (depends on 1, 2)

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.

### Claim 9 (depends on 8)

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.

### Claim 10 (depends on 8)

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.

### Claim 11 (depends on 9)

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.

### Claim 12 (depends on 10)

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.

### Claim 13 (depends on 11)

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.

### Claim 14 (depends on 10)

The method of claim 10,
wherein the hydrogel provides for parenteral administration of the active pharmaceutical ingredient.

### Claim 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.

### Claim 16 (depends on 15)

The thermoreversible hydrogel of claim 15, comprising:
between 0.1% and 0.3% HPMC; and
between 0.4% and 1.8% PEG-400.

### Claim 17 (depends on 15)

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.

### Claim 18 (depends on 15)

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.

### Claim 19 (depends on 15)

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.

### Claim 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.

### Claim 21 (depends on 15)

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.

### Claim 22 (depends on 11)

The method of claim 11, wherein the hydrogel provides for parenteral administration of the active pharmaceutical ingredient.