Compositions comprising cyclosporin

Abstract

The present invention relates to a formulation comprising a pharmaceutically active ingredient and coating. The invention also relates to the use of the formulation in the treatment and prevention of disorders of the gastrointestinal tract. Also disclosed are methods for preparing the formulations.

1 - 119 . (canceled) 
     
     
         120 . A method of treating a condition of the gastrointestinal tract in a subject, wherein the method comprises administering to the subject a composition comprising cyclosporin, a hydrogel forming polymer matrix, a surfactant and an oil phase being dispersed in the hydrogel forming polymer matrix, wherein the surfactant comprises a medium chain or long chain fatty acid mono- or di-glyceride or a combination thereof and does not comprise a polyethyleneglycol ether or ester; wherein the hydrogel-forming polymer is in an amount of at least 25% by weight based upon the dry weight of the composition. 
     
     
         121 . The method of  claim 120 , wherein the condition of the gastrointestinal tract is selected from: inflammatory bowel disease, irritable bowel disease, Crohn's disease, ulcerative colitis, celiac disease, graft vs host disease, gastrointestinal graft-versus-host disease, gastroenteritis, duodenitis, jejunitis, ileitis, peptic ulcer, Curling's ulcer, appendicitis, colitis, pseudomembraneous colitis, diverticulosis, diverticulitis, collagenous colitis, endometriosis, colorectal carcinoma and adenocarcinoma. 
     
     
         122 . The method of  claim 121 , wherein the condition of the gastrointestinal tract is ulcerative colitis. 
     
     
         123 . The method of  claim 120 , wherein the oil phase comprises a solution of the cyclosporin. 
     
     
         124 . The method of  claim 120 , wherein the surfactant is present in an amount of more than 6 wt % of the dry weight of the composition. 
     
     
         125 . The method of  claim 120 , wherein the surfactant is selected from: glyceryl monocaprate, glyceryl dicaprate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl caprate, glyceryl monocaprylate/caprate, glyceryl caprylate/caprate glyceryl dicaprylate/caprate, glyceryl monooleate/dioleate, glyceryl monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitostearate, glyceryl dipalmitostearate, glyceryl monobehenate, glyceryl dibehenate, glyceryl monolinoleate, glycerol monolinoleate, glyceryl dilinoleate, polyglyceryl dioleate, propylene glycol monoheptanoate, polyglycerol dioleate, or a combination thereof. 
     
     
         126 . The method of  claim 120 , wherein the surfactant is selected from: glyceryl monocaprylate/caprate, glyceryl dicaprylate/caprate, glyceryl monooleate, glycerol monolinoleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitostearate, glyceryl dipalmitostearate, glyceryl monobehenate, glyceryl dibehenate, glyceryl monolinoleate, glyceryl dilinoleate, polyglyceryl dioleate or a combination thereof. 
     
     
         127 . The method of  claim 120 , wherein the surfactant is selected from: glyceryl caprylate/caprate (Capmul MCM), glyceryl monooleate/dioleate (Capmul GMO-50), glycerol monolinoleate (Maisine 35-1) or a combination thereof. 
     
     
         128 . The method of  claim 120 , wherein the surfactant is glyceryl caprylate, glyceryl caprate, glyceryl monooleate, glyceryl dioleate, glycerol monolinoleate or a combination thereof. 
     
     
         129 . The method of  claim 120 , wherein the oil phase comprises a liquid lipid, wherein the liquid lipid comprises a medium chain fatty acid triglyceride or a combination thereof, or the liquid lipid comprises a caprylic/capric triglyceride composition. 
     
     
         130 . The method of  claim 120 , wherein the composition further comprises a solvent, wherein the solvent is miscible with the oil phase and water. 
     
     
         131 . The method of  claim 120 , wherein the composition further comprises a high HLB surfactant having an HLB value of at least 10. 
     
     
         132 . The method of  claim 130 , wherein the high HLB surfactant is selected from a fatty acid salt or a bile salt. 
     
     
         133 . The method of  claim 120 , wherein the hydrogel forming polymer or hydrogel forming polymer matrix comprises a reversible hydrocolloid. 
     
     
         134 . The method of  claim 120 , wherein the hydrogel forming polymer or hydrogel forming polymer matrix comprises a hydrocolloid selected from carrageenan, gelatin, agar and pectin, or a combination thereof. 
     
     
         135 . The method of  claim 120 , wherein the composition is a solid composition and has the characteristics of a composition formed by mixing an aqueous phase premix with an oil phase premix to form a mixture, the aqueous phase premix comprising the hydrogel forming polymer matrix and the oil phase premix comprising the oil phase in which the cyclosporin is dissolved and the surfactant. 
     
     
         136 . The method of  claim 135 , wherein the composition further comprises a surfactant having an HLB value of at least 10 which is present in the aqueous phase premix. 
     
     
         137 . The method of  claim 120 , wherein the composition is a solid composition and further comprises at least one coating. 
     
     
         138 . The method of  claim 137 , wherein the at least one coating is adapted to release the cyclosporin in at least the colon. 
     
     
         139 . The method of  claim 138 , wherein the coating comprises ethylcellulose. 
     
     
         140 . The method of  claim 137 , wherein the at least one coating is present in an amount corresponding to a weight gain due to the coating of from 2% to 40%. 
     
     
         141 . The method of  claim 137 , wherein the composition comprises two coatings, a first coating and a second coating. 
     
     
         142 . The method of  claim 141 , wherein the first coating comprises a water-soluble cellulose ether and the second coating comprises ethylcellulose. 
     
     
         143 . The method of  claim 142 , wherein the water-soluble cellulose ether is hydroxypropylmethyl cellulose. 
     
     
         144 . The method of  claim 120 , wherein the composition is a solid composition that is in the form of a minibead having a size of from 0.5 mm to 5 mm. 
     
     
         145 . The method of  claim 137 , wherein the composition provides a mean whole blood cyclosporin A AUC0-inf of from about 140 to about 420 ng·hr/ml. 
     
     
         146 . The method of  claim 137 , wherein the composition provides a Cmax of cyclosporin A of from about 15 to about 60 ng/ml. 
     
     
         147 . The method of  claim 137 , wherein the time taken to reach maximum whole blood concentration of cyclosporin A following oral administration of a single dose of the composition (Tmax) is between about about 3 hours to about 10 hours. 
     
     
         148 . The method of  claim 137 , wherein the cyclosporin A absolute bioavailability following oral administration of the composition is less than 15%. 
     
     
         149 . The method of  claim 137 , wherein the composition releases less than 15% of the cyclosporin A after 2 hours; releases 10% to 40% of the cyclosporin A at 4 hours; and releases from about 30% to 70% of the cyclosporin A between 4 hours and 12 hours, when measured in a two stage dissolution test using a USP Apparatus II with a paddle speed of 75 rpm and a dissolution medium temperature of 37° C.; wherein for the first 2 hours of the dissolution test the dissolution medium is 750 ml of 0.1 N HCl, and at 2 hours 250 ml of 0.2M tribasic sodium phosphate containing 2% SDS is added to the dissolution medium and the pH is adjusted to pH 6.8. 
     
     
         150 . The method of  claim 137 , wherein the composition provides a concentration of cyclosporin A in colonic tissue of at least 250 ng/g following oral administration of the composition to a human. 
     
     
         151 . The method of  claim 150 , wherein the total daily dose of cyclosporin A administered to the human is in the range of from 1 mg to 500 mg. 
     
     
         152 . The method of  claim 120 , wherein the composition further comprises a P450 inhibitor or a PgP inhibitor, or a combination thereof.