Material and method for treating internal cavities

1. A method for treating a patient with a bladder disorder characterized by bladder spasms, comprising:

preparing a pharmaceutical composition by incorporating into a biocompatible mucoadhesive thermoreversible hydrogel a therapeutically effective amount of at least one pharmaceutically active agent selected from the group of neurological blocking agents comprising botulinum toxin, botulinum toxin A, botulinum toxin B, botulinum toxin Cl, botulinum toxin D, botulinum toxin E, botulinum toxin F, botulinum toxin G;

and

instilling said pharmaceutical composition into the urinary tract of the patient suffering from the bladder disorder;

wherein said instilling is at a temperature at which the pharmaceutical composition is liquid; whereby the pharmaceutical composition gels in contact with an internal wall of the urinary tract;

wherein the method does not comprise any step of injecting a pharmaceutically active agent into a wall of the bladder; and

wherein the pharmaceutical composition has a viscosity of greater than 3000 Pa·s at 37° C.

2. The method according to claim 1 , wherein the step of incorporating is performed up to two weeks prior to the step of applying.

3. The method according to claim 1 , wherein the disorder is selected from the group consisting of urinary incontinence or urge due to unstable bladder or unstable detrusor sphincter; voiding complications; spinal cord injury; stroke or multiple sclerosis; bladder pathologies wherein a spasms are involved; interstitial cystitis; stress incontinence; urge incontinence; and neurogenic bladder.

4. The method according to claim 2 , wherein the disorder is selected from the group consisting of urinary incontinence or urge due to unstable bladder or unstable detrusor sphincter; voiding complications; spinal cord injury; stroke or multiple sclerosis; bladder pathologies wherein a spasms are involved; interstitial cystitis; stress incontinence; urge incontinence; and neurogenic bladder.

5. The method according to claim 1 , wherein the amount of the pharmaceutically active agent applied is about 0.2-20 U/kg body weight of botulinum toxin.

6. The method according to claim 1 , wherein the pharmaceutical composition comprises at least one reverse thermal gelation agent and at least one component selected from the group consisting of mucoadhesive enhancers and thickening compounds.

7. The method according to claim 6 , wherein the thermal reverse gelation agent comprises polymers and copolymers selected from the group consisting of: Chitosan, Polycarboxylic acids, polyglycolic acid polylactic acid and polyacrylic acid; polyurethanes; polyesters, poly(ethylene terephthalate); polyamides, nylon; polyacrylonitriles; polyphosphazenes; polylactones, polycaprolactone; polyanhydrides, poly[bis(pcarboxyphenoxy) propane anhydride; polyethylene; polyvinyl chloride; ethylene vinyl acetate; polyvinyl alcohol and polyvinyl acetate; Polylactide (PLA) and Poly(Lactide-co-Glycolide) (PLGA); Poloxamer block copolymers of the type polyethylene oxide-polypropyleneoxide, Poloxamer 407, Poloxamer 188, Poloxamer 338; cellulose polymers, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, and hydroxymethylcellulose.

8. The method according to claim 6 , wherein the mucoadhesive enhancers and thickening compounds are selected from:

the group consisting of polycarbophil, polyacrylic acids, crosslinked acrylic acid, polymethacrylates, divinyl glycol, vinylpyrrolidone/vinyl acetate copolymer, polyethylene glycol, cellulose, microcrystalline cellulose, gelatin, starch, gums, dicalcium phosphate, lactose, sucrose, PVP, PVA, PVAc, polysaccharides, waxes, fats, hyaluronic acid, k-carrageenan, carbomers, and Eudragitor;

cellulose derivatives selected from the group consisting of methylcellulose, ethylcellulose, hydroxypropylmethylcellulose HPMC, methoxy-substituted HPMC with any possible degree of methoxy substitution (from 0 to 3), HPC, hydroxyalkylcelluloses, hydroxyalkylmethylcelluloses, L-HPC, HPMCAS, carboxymethylcelluloses, and salts thereof;

starch derivatives selected from the group consisting of mono- and diphosphate ester starches;

gums selected from the group consisting of gums selected from the group consisting of guar gum, locust beam gum, xanthan gum, and any combination thereof; and,

polysaccharides selected from the group consisting of alginic acid, alginates, alginate esters, dextrin, cyclodextrin, and galactomannans.

9. The method according to claim 1 , wherein the biocompatible mucoadhesive thermoreversible hydrogel is selected from the group consisting of:

i. ethylene oxide-propylene oxide triblock copolymer; at least one substance selected from the group consisting of CMC and HPMC; and the balance water;

ii. ethylene oxide-propylene oxide triblock copolymer; at least one substance selected from the group consisting of CMC and HPMC; polyethylene glycol; and the balance water;

iii. between 20% and 30% ethylene oxide-propylene oxide block copolymer; between 0.05% and 0.5% HPMC; between 0.1% and 2.5% PEG; and the balance water

iv. between 20% and 30% ethylene oxide-propylene oxide block copolymer; between 0.1% and 0.3% HPMC; between 0.1% and 1.8% PEG; and the balance water;

v. 27% Poloxamer 407; 0.2% HPMC; 1% PEG; and the balance water;

vi. 20% Poloxamer 407; 0.2% sodium carboxymethylcellulose, 0.5% polyethylene glycol MW 20,000; citric acid-citrate buffer (50 mmol L-1 pH 5.2); and the balance water;

vii. between 20% and 30% Poloxamer 407; between 0.05% and 0.8% CMC; between 0.1% and 2.5% PEG; and the balance water;

viii. between 20% and 30% Poloxamer 407; between 10% and 20% Poloxamer 188;

between 0.05% and 2% CMC; between 0.1% and 2.5% PEG; and the balance water;

ix. 20% Poloxamer 407, 16% Poloxamer 188, 0.2%; sodium carboxymethylcellulose, 1% polyethylene glycol MW 3000, and the balance water;

x. between 20% and 30% Poloxamer 407; between 10% and 20% Poloxamer 188; between 0.05% and 0.8% k-carrageenan; between 0.1% and 2.5% PEG; and the balance water;

xi. 20% Poloxamer 407; 10% Poloxamer 188; 0.3% k-carrageenan; 1% PEG-400; and the balance water;

xii. between 18% and 30% (w/w) of an ethylene oxide/propylene oxide triblock copolymer, 0.05-10% PVP (polyvinylpyrrolidones), between 0% and 2.5% PEG-400, between 1-10% sodium caprylate, 1M-20 mM Tris HCl buffer and the balance water; and

xiv. between 18% and 30% (w/w) of an ethylene oxide/propylene oxide triblock copolymer, 0.05-10% PVP (polyvinylpyrrolidones), between 0% and 2.5% PEG-400, 0.5-20% silica oxide 1M-20 mM Tris HCl buffer and the balance water; and xiv. 18% and 30% (w/w) of an ethylene oxide/propylene oxide triblock copolymer, 0.05-10% PVP (polyvinylpyrrolidones), between 0% and 2.5% PEG-400, 0.5-20% micronized cellulose 1M-20 mM Tris HCl buffer and the balance water.

10. A method for treating urinary incontinence, overacting bladder, interstitial cystitis, urge incontinence, and any bladder pathologies which involve bladder disorders, the method comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a biocompatible mucoadhesive thermoreversible hydrogel and a therapeutically effective amount of an active agent comprising at least one neurological blocking agent selected from the group consisting of botulinum toxin of botulinum toxin A, botulinum toxin B, botulinum toxin Cl, botulinum toxin D, botulinum toxin E, botulinum toxin F, and botulinum toxin G;

wherein the step of administering comprises: instilling into the urinary tract of the subject the biocompatible mucoadhesive thermoreversible hydrogel at a temperature at which the pharmaceutical composition is liquid; whereby the pharmaceutical composition gels at body temperature in contact with an internal wall of urinary tract;

and wherein the mucoadhesive thermoreversible hydrogel composition has a viscosity of less than 200 Pa s at 10° C. and greater than 3000 Pa s at 37° C.

11. The method according to claim 1 or claim 10 , wherein the biocompatible mucoadhesive thermoreversible hydrogel comprises between 20% and 30% ethylene oxide/propylene oxide triblock copolymer; between 0.05% and 0.5% HPMC; between 0.1% and 2.5% PEG; and the balance water.

12. The method according to claim 11 , wherein the thermoreversible hydrogel comprises between 20% and 30% ethylene oxide/propylene oxide triblock copolymer; between 0.1% and 0.3% HPMC; between 0.1% and 1.8% PEG; and the balance water.

13. The method of claim 12 , wherein the ethylene oxide/propylene oxide triblock copolymer is Poloxamer 407.