Immunomodulatory compositions

Abstract

Immunomodulator formulations for use in the treatment of disease of the GI tract. The formulations comprise a hydroxylase inhibitor and/or an immunosuppressant. Exemplary formulations comprise hydralazine as a hydroxylase inhibitor and/or cyclosporin A as an immunosuppressant.

We claim: 
     
         1 . A method of maintenance therapy of a patient who has suffered from or is suffering from an inflammatory and/or fibrotic intestinal disorder, the method comprising administering a hydroxylase inhibitor to the patient. 
     
     
         2 . The method of  claim 1 , wherein the maintenance therapy is for a patient who has suffered from or is suffering from an inflammatory intestinal disorder. 
     
     
         3 . The method of  claim 1 , wherein the maintenance therapy is for a patient who has suffered from or is suffering from a fibrotic intestinal disorder. 
     
     
         4 . The method of  claim 1 , wherein the disorder is selected from (i) inflammatory bowel disease and (ii) graft-versus-host disease following hematopoietic stem cell transplantation. 
     
     
         5 . The method of  claim 4 , wherein the disorder is colitis. 
     
     
         6 . The method of  claim 1 , wherein the hydroxylase inhibitor is at least one hydrolase inhibitor selected from DMOG, hydralazine, FG-4497, FG4095, AGN-2979, TM 6008, TM 6089, a siRNA against hydroxylases, and an antisense therapeutic against hydroxylases. 
     
     
         7 . The method of  claim 6 , wherein the hydroxylase inhibitor is hydralazine. 
     
     
         8 . The method of  claim 1 , wherein the hydroxylase inhibitor is in solution phase in a pharmaceutical composition. 
     
     
         9 . The method of  claim 8 , wherein the pharmaceutical composition is a multiple minibead composition, the minibeads comprising a water soluble polymer matrix in which the hydroxylase inhibitor is in solid solution. 
     
     
         10 . The method of  claim 9 , wherein the minibeads further comprise a hydrophobic dispersed phase in the matrix, the hydrophobic phase comprising a water immiscible liquid and being formed of material liquid at body temperature. 
     
     
         11 . The method of  claim 8 , wherein the pharmaceutical composition is adapted for at least a portion of the hydroxylase inhibitor to be released in the colon. 
     
     
         12 . The method of  claim 9 , wherein at least some of the minibeads have a controlled release coating adapted for the coated minibeads to release hydralazine in the colon. 
     
     
         13 . The method of  claim 12 , wherein the coated minibeads are coated with a coating comprising a pH independent polymer. 
     
     
         14 . The method of  claim 1 , wherein the disorder is selected from celiac disease, HIV or another enteropathy, pouchitis and cachexia. 
     
     
         15 . The method of  claim 1 , wherein the disorder is a disorder of, or at least suspected of being associated with, a leaky intestinal epithelial barrier. 
     
     
         16 . The method of  claim 15 , wherein the disorder is selected from celiac disease, a rheumatic disorder, rheumatoid arthritis, temporomandibular joint syndrome, type I diabetes, multiple sclerosis, atopic dermatitis, psoriasis, a chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, depressive disorders, affective disorders and attention disorders, gastroenteritis, duodenitis, jejunitis, ileitis, peptic ulcer, Curling's ulcer, appendicitis, colitis, pseudomembraneous colitis, irritable bowel syndrome, diverticulosis, diverticulitis, endometriosis, colorectal carcinoma, adenocarcinoma, and chronic heart failure. 
     
     
         17 . The method of  claim 1 , wherein the method is a method of reducing chemotherapy-induced or radiation therapy-induced gastrointestinal insult and inflammatory bowel disease, and combinations thereof. 
     
     
         18 . The method of  claim 1 , wherein the patient is suffering from Crohn's disease, ulcerative colitis, diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis, atypical colitis, pseudomembraneous colitis, fulminant colitis, autistic enterocolitis, interdeminate colitis, Behcet's disease, jejunoiletis, ileitis, ileocolitis, granulomatous colitis, irritable bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, mucositis, radiation-associated enteritis, short bowel disease, or chronic diarrhea. 
     
     
         19 . The method of  claim 1 , wherein the patient is suffering from collagenous colitis, lymphocytic colitis, and irritable bowel syndrome with constipation, irritable bowel syndrome with diarrhea and/or irritable bowel syndrome with pain symptoms. 
     
     
         20 . A method of treating or preventing a disorder of a leaky intestinal epithelial barrier, wherein the disorder is not irritable bowel disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, GVHD, or GI-GVHD, the method comprising administering to a patient a pharmaceutical composition for oral administration, comprising a water-soluble polymer matrix material in which matrix material are dispersed at least one water-insoluble active ingredient selected from calcineurin inhibitor, mTor inhibitor, macrolide immunosuppressant and macrolide antibiotic; and droplets of a water-immiscible liquid in which the water-insoluble active ingredient is soluble, wherein the composition is adapted to release the water-insoluble active ingredient in at least the colon. 
     
     
         21 . A method according to  claim 20  wherein the disorder is selected from celiac disease, a rheumatic disorder, rheumatoid arthritis, temporomandibular joint syndrome, type I diabetes, multiple sclerosis, atopic dermatitis, psoriasis, a chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, depressive disorders, affective disorders and attention disorders, gastroenteritis, duodenitis, jejunitis, ileitis, peptic ulcer, Curling's ulcer, appendicitis, colitis, pseudomembraneous colitis, diverticulosis, diverticulitis, endometriosis, colorectal carcinoma, adenocarcinoma, and chronic heart failure. 
     
     
         22 . The method of  claim 9 , wherein the composition comprises gelatin as the water-soluble polymer. 
     
     
         23 . The method of  claim 9  wherein the water-soluble matrix material is selected from a hydrocolloid, a non-hydrocolloid gum, chitosan and a derivative thereof. 
     
     
         24 . The method of  claim 9  wherein the unit solid is a minibead having a diameter of not more than 10 mm, the composition optionally comprising a plurality of said minibeads. 
     
     
         25 . The method of  claim 24  wherein the one or more minibeads comprise a controlled-release polymer. 
     
     
         26 . The method of  claim 25  in which the minibead has a coat which comprises the controlled release polymer. 
     
     
         27 . The method of  claim 25  wherein the controlled-release polymer is ethylcellulose comprised in a coating on the minibead and optionally in association with an emulsification agent. 
     
     
         28 . The method of  claim 8  wherein the composition further comprises a hydrophilic surfactant. 
     
     
         29 . The method of  claim 28 , wherein the hydrophilic surfactant is an anionic surfactant. 
     
     
         30 . The method of  claim 29 , wherein the anionic surfactant comprises sodium dodecyl sulfate or another alkyl sulfate salt. 
     
     
         31 . The method of  claim 29  in which the water-soluble polymer matrix material further contains a non-ionic surfactant having an HLB value of at least 10 but less than that of the hydrophilic surfactant. 
     
     
         32 . The method of  claim 31  wherein the non-ionic surfactant comprises a glycerol polyethylene glycol ricinoleate, or another non-ionic surfactant comprising a poly(oxyethylene) group. 
     
     
         33 . The method of  claim 10  in which the water-immiscible liquid comprises a liquid lipid and a solvent miscible therewith, in which solvent the water-insoluble active ingredient is soluble. 
     
     
         34 . The method of  claim 33  in which the water-soluble polymer matrix material further contains a non-ionic surfactant having an HLB value of at least 10 but less than that of the hydrophilic surfactant and wherein the ratio of liquid lipid to non-ionic surfactant is in the range 1-4:1 by weight. 
     
     
         35 . The method of  claim 33  in which the liquid lipid is a medium chain triglyceride composition, the medium chain triglyceride(s) being one or more triglycerides of at least one fatty acid selected from C6-C12 fatty acids. 
     
     
         36 . The method of  claim 33  in which the solvent is 2-(2-ethoxy)ethanol, or another solvent miscible with both the liquid lipid and with water. 
     
     
         37 . The method of  claim 13  wherein the water-insoluble active ingredient is comprised in a pharmaceutical formulation adapted to release the active ingredient in at least the colon. 
     
     
         38 . The method of  claim 20 , wherein the composition is a capsule comprising a population of minibeads which have a diameter of at most 10 mm and which comprise the water-soluble polymer matrix material and a coating on the matrix material, the water-soluble polymer matrix material further including the hydroxylase inhibitor, wherein the hydrophilic surfactant has an HLB value of at least 15, and wherein the coating comprises a controlled-release polymer, optionally wherein the coating is a barrier membrane for extended release of the water-insoluble active ingredient and of the hydroxylase inhibitor and/or is a coating which resists becoming degraded or becoming of increased permeability in the conditions of the GI tract above the colon but which becomes degraded or of increased permeability in the conditions of the colon. 
     
     
         39 . The method of  claim 20  wherein the water-insoluble active ingredient is a macrolide immunosuppressant. 
     
     
         40 . A multiple minibead unit dosage form, wherein the minibeads comprise a water soluble polymer matrix comprising hydralazine dispersed in the matrix. 
     
     
         41 . The unit dosage form of  claim 40 , further comprising a dispersed phase composed of a material selected from a hydrophobic material, an amphiphilic material, and a combination thereof, the unit dosage form comprising hydralazine in an amount of from 2.5 mg-100 mg. 
     
     
         42 . The dosage form of  claim 40  wherein the hydralazine is in an amount of from 5 mg-100 mg. 
     
     
         43 . The dosage form of  claim 40 , wherein the hydralazine is in solid solution in the matrix. 
     
     
         44 . The dosage form of  claim 40  which is for once a day administration. 
     
     
         45 . A method of maintenance therapy by monotherapy with the hydralazine, the method comprising administering to a patient a multiple minibead unit dosage form according to  claim 38 . 
     
     
         46 . A method of maintenance therapy of a patient who has suffered from or is suffering from an inflammatory intestinal disorder, the method comprising administering to the patient a multiple minibead unit dosage form wherein the minibeads comprise a water soluble polymer matrix in which a water soluble hydroxylase inhibitor is in solid solution. 
     
     
         47 . The method of  claim 46 , wherein the minibeads further comprise a hydrophobic phase dispersed in the matrix, the hydrophobic phase being formed of material liquid at body temperature. 
     
     
         48 . A method of treating or delaying the progression of, a fibrotic intestinal disorder of a patient, the method comprising administering a pharmaceutical composition comprising a hydroxylase inhibitor to a patient in need thereof. 
     
     
         49 . The method of  claim 48 , wherein the treatment is preventing or delaying the appearance of clinical symptoms of a state. 
     
     
         50 . The method of  claim 48 , wherein the fibrotic disorder is gastrointestinal fibrosis. 
     
     
         51 . The method of  claim 48 , wherein the hydroxylase inhibitor is in solution phase. 
     
     
         52 . The method of  claim 48 , wherein the composition comprises a polymeric matrix and the hydralazine is in particulate form. 
     
     
         53 . The method of  claim 48 , wherein the hydroxylase inhibitor is in solution phase in a pharmaceutical composition; wherein the pharmaceutical composition is a multiple minibead composition, the minibeads comprising a water soluble polymer matrix in which the hydroxylase inhibitor is in solid solution. 
     
     
         54 . The method of  claim 53 , wherein the minibeads further comprise a hydrophobic dispersed phase in the matrix, the hydrophobic phase comprising a water immiscible liquid and being formed of material liquid at body temperature. 
     
     
         55 . A method of treating a warm-blooded animal to treat, or delay the progression, of a fibrotic intestinal disorder, or for maintenance therapy of an animal which has suffered from or is suffering from a fibrotic intestinal disorder, the method comprising administering to said animal simultaneously, sequentially or separately an immunosuppressant and a hydroxylase inhibitor. 
     
     
         56 . The method of  claim 55 , wherein the treatment is preventing or delaying the appearance of clinical symptoms of a state. 
     
     
         57 . The method of  claim 55 , wherein the fibrotic disorder is gastrointestinal fibrosis. 
     
     
         58 . The method of  claim 55 , wherein the disorder is selected from celiac disease, HIV or another enteropathy, pouchitis, and cachexia. 
     
     
         59 . The method of  claim 55 , wherein the method is maintenance therapy of a patient who has suffered from or is suffering from an inflammatory intestinal disorder, is the prevention or reduction of chemotherapy-induced or radiation therapy-induced gastrointestinal insult and inflammatory bowel disease, and combinations thereof, or the method is the treatment of a patient suffering from Crohn's disease, ulcerative colitis, diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis, atypical colitis, pseudomembraneous colitis, fulminant colitis, autistic enterocolitis, interdeminate colitis, Behcet's disease, jejunoiletis, ileitis, ileocolitis, granulomatous colitis, irritable bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, mucositis, radiation-associated enteritis, short bowel disease, or chronic diarrhea. 
     
     
         60 . The method of  claim 55 , wherein the patient is suffering from collagenous colitis, lymphocytic colitis, and irritable bowel syndrome with constipation, irritable bowel syndrome with diarrhea and/or irritable bowel syndrome with pain symptoms. 
     
     
         61 . The method of  claim 55 , wherein the weight ratio of hydroxylase inhibitor:immunosuppressant is from 0.8:1 to 5:1. 
     
     
         62 . The method of  claim 61 , wherein the hydroxylase inhibitor is hydralazine and the immunosuppressant is cyclosporin. 
     
     
         63 . The method of  claim 55 , wherein the immunosuppressant is selected from cyclosporin, tacrolimus, sirolimus, pimecrolimus, an angiotensin II inhibitor, an ACE inhibitor, a dicarboxylate-containing agent, a phosphate-containing agent, a casokinin, a lactokinin, a lactotripeptide, and/or the hydroxylase inhibitor is selected from DMOG, hydralazine, FG-4497, FG4095, AGN-2979, TM 6008, TM 6089, a siRNA against hydroxylases and an antisense therapeutic against hydroxylases. 
     
     
         64 . The method of  claim 63 , wherein the hydroxylase inhibitor is in solution phase in a pharmaceutical composition; wherein the pharmaceutical composition is a multiple minibead composition, the minibeads comprising a water soluble polymer matrix in which the hydroxylase inhibitor is in solid solution. 
     
     
         65 . The method of  claim 64 , wherein the minibeads further comprise a hydrophobic dispersed phase in the matrix, the hydrophobic phase comprising a water immiscible liquid and being formed of material liquid at body temperature.