Gastroresistant pharmaceutical formulations containing rifaximin

Abstract

The object of the invention consists of pharmaceutical formulations containing rifaximin in the shape of microgranules made gastroresistant by an insoluble polymer at pH values between 1.5 and 4.0 and soluble at pH values between 5:0 and 7.5, by their preparation and by their use in the manufacture of medicinal preparations useful in the treatment of inflammatory bowel diseases (IBD) and mainly Crohn's disease.

1 .- 17 . (canceled) 
     
     
         18 . A method for preparing gastroresistant microgranule of rifaximin, the method comprising spraying on rifaximin microgranules an aqueous suspension containing a gastroresistant polymer insoluble over a pH range of from 1.5 to 4.0 and soluble over a pH range from 5.0 to 7.5 together with pharmaceutically acceptable excipients, the spraying performed in a fluid apparatus, in which air flows, to obtain the gastroresistant microgranule of rifaximin directly coated with the gastroresistant polymer in which the rifaximin is retained at pH lower than 4.0 and is released at pH higher than 5. 
     
     
         19 . The method of  claim 18 , wherein the air flow is in entrance at a temperature between 50° C. and 75° C. and with an output 450 and 650 m 3  per hour under a pressure between 1.0 and 1.5 bar and a flow speed between 150 and 300 g/min through a nozzle on the mixture of rifaximin maintained in a suspension fluid bed apparatus. 
     
     
         20 . The method of  claim 18  wherein the product temperature during the spraying is maintained at a value between 20° C. and 40° C. 
     
     
         21 . The method according of  claim 19  wherein the air temperature in entrance is at a temperature between 60° C. and 70° C. 
     
     
         22 . The method of  claim 18 , wherein the gastroresistant polymer is selected in the group consisting of cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, co-polymers of methacrylic acid and combinations thereof. 
     
     
         23 . The method of  claim 18  wherein the gastroresistant microgranules have a delayed release. 
     
     
         24 . The method of  claim 18 , wherein the pharmaceutically acceptable excipients are selected from the group consisting of plasticizer, diluent, anti-sticking, anti-agglomerative, glidants, anti-foam and colouring substances. 
     
     
         25 . The method according to  claim 24 , wherein the pharmaceutically acceptable excipients are in an amount from 1% to 50% by the weight of the gastroresistant microgranule of rifaximin. 
     
     
         26 . The method of  claim 18 , wherein the spraying provides a film coating on the rifaximin microgranules. 
     
     
         27 . The method of  claim 18 , wherein the gastroresistant polymer is in an aqueous suspension at a concentration between 15 and 30% (V/V). 
     
     
         28 . The method of  claim 18 , wherein rifaximin is in a polymorphous form selected from form a, form 3, form y, form 6 and form c. 
     
     
         29 . The method of  claim 18 , wherein the aqueous suspension is prepared by suspending said gastroresistant polymers in demineralized water and homogenised before spraying on the rifaximin powder. 
     
     
         30 . The method of  claim 18 , wherein the gastroresistant polymer is from 5% to 75% of the gastroresistant microgranule of rifaximin, from 10% to 60%, from 20% to 55%, from 30 to 80%, or from 25% to 50% of weight of the gastroresistant microgranule of rifaximin. 
     
     
         31 . The method of  claim 24 , wherein the plasticizer is selected from the group consisting of acetylated monoglycerides, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin, ethylene glycol, propylene glycol, triacetin citrate, triacetin, tripropinoin, diacetin, dibutyl phthalate, acetyl monoglyceride, polyethylene glycols, castor oil, triethyl citrate, polyhydric alcohols, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-1-octyl phthalate, di-1-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, glyceryl monocaprylate, glyceryl monocaprate and combinations thereof. 
     
     
         32 . The method of  claim 31 , wherein the plasticizer is in an amount from 10% to 50%, by weight, based on the weight of the dry polymer. 
     
     
         33 . The method of  claim 18 , further comprising coating the gastroresistant microgranule of rifaximin with a semipermeable polymer. 
     
     
         34 . The method of  claim 33 , wherein the semipermeable polymer is selected between cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acid and their esters, waxes, and/or zein. 
     
     
         35 . The method of  claim 34 , wherein the semipermeble polymers are combined with hydrophilic polymers 
     
     
         36 . The method of  claim 35 , wherein the hydrophilic polymer is selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinipyrrolidone. 
     
     
         37 . A gastroresistant microgranule of rifaximin comprising a rifaximin microgranule directly coated with a gastroresistant polymer insoluble over a pH range of from 1.5 to 4 and soluble over a pH range from 5.0 to 7.5, in which the rifaximin is retained at pH lower than 4.0 and is released at pH higher than 5. 
     
     
         38 . The gastroresistant microgranule of  claim 37 , further comprising a protective layer over the gastroresistant polymer, the protective layer containing a semi-permeable polymer. 
     
     
         39 . A pharmaceutical composition comprising the gastroresistant microgranule of  claim 37 , together with pharmaceutically acceptable excipients.