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 . A pharmaceutical composition comprising a therapeutically effective amount of rifaximin or polymorph thereof, one or more release controlling agents and at least one pharmaceutically acceptable excipient. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the composition is formulated to delay release of rifaximin in the gastrointestinal tract. 
     
     
         3 . The pharmaceutical composition according to  claim 2 , wherein the composition is formulated to delay release of rifaximin in the intestinal tract. 
     
     
         4 . The pharmaceutical composition according to  claim 2 , wherein the composition is formulated to give binding properties in the gastrointestinal tract. 
     
     
         5 . The pharmaceutical composition according to  claim 4 , wherein the binding properties are achieved with one or more binder compounds selected from the group consisting of cellulose, cellulose derivatives, starches, gums, synthetic gum, polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, gelatin, polypropylene glycol, alginic acid, alginate salts, sugars, and combinations thereof. 
     
     
         6 . The pharmaceutical composition according to  claim 5 , wherein said sugars are selected from the group consisting of sucrose, glucose, dextrose, and lactose. 
     
     
         7 . The pharmaceutical composition according to  claim 2 , wherein delay in release of rifaximin is achieved with excipients selected from the group consisting of proteins carbohydrates, polysaccharides, cellulose derivatives, acetylated glycerides, diethylphthalate, propylene glycol, polyethylene glycol, polysorbate, polyoxyethylenate esthers, poly vinylacetate phthalate, polyvinyl alcohol, acrylic polymer, acrylic methacrylic acid copolymers with an acrylic or methacrylic ester, polyvinyl alcohols, polyvinylpyrrolidone, polymers of acrylic and methacrylic esters, blends and copolymers or mixtures thereof, polyols, dextrans, sodium alginate, gums, xanthan gum, guar gum, and synthetic gum. 
     
     
         8 . The pharmaceutical composition according to  claim 7 , wherein said proteins are selected from the group consisting of pectin, zein, and gelatin. 
     
     
         9 . The pharmaceutical composition according to  claim 7 , wherein said carbohydrates are selected from the group consisting of starch and chitosan. 
     
     
         10 . The pharmaceutical composition according to  claim 7 , wherein said polysaccharide is cellulose. 
     
     
         11 . The pharmaceutical composition according to  claim 7 , wherein said cellulose derivatives are selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, and sodium carboxymethyl cellulose. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the release controlling agent is a hydrophilic polymer or hydrophobic polymer or combination thereof. 
     
     
         13 . The pharmaceutical composition according to  claim 1 , wherein the release controlling agent is a hydrophilic polymer. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , wherein the hydrophilic polymer is selected from the group consisting of carbohydrate, cellulose derivatives, gum, alginates, polyvinylacetate, polyvinylalcohol, povidone, polyvinylpyrrolidone, acrylic and methacrylic acid copolymers and mixtures thereof. 
     
     
         15 . The pharmaceutical composition according to  claim 14 , wherein the carbohydrate is cellulose. 
     
     
         16 . The pharmaceutical composition according to  claim 14 , wherein the cellulose derivative is ethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose. 
     
     
         17 . The pharmaceutical composition according to  claim 14 , wherein the gum is xanthan gum. 
     
     
         18 . The pharmaceutical composition according to  claim 12 , wherein the hydrophobic polymer is selected from the group consisting of waxes, fatty acids and their esters, glyceryl ester, hydrogenated oil, castor oil, mineral oil, paraffin, stearate salts, stearic acid, talc, and mixture thereof. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein the glyceryl ester is glyceryl monostearate or glyceryl distearate. 
     
     
         20 . The pharmaceutical composition according to  claim 18 , wherein the stearate salt is magnesium stearate or calcium stearate. 
     
     
         21 . The pharmaceutical composition according to  claim 1 , further comprising one or more solubilizing agents. 
     
     
         22 . The pharmaceutical composition according to  claim 21 , wherein the solubilizing agent is selected from the group consisting of surfactants, polysorbates, polyoxyethylene esters, dextrins, waxes, monohydric alcohol esters, trialkyl citrates, lower alcohol fatty acid esters, glycerol acetates, acetin, diacetin, triacetin, glycerol fatty acid esters, monoglycerides, diglycerides, triglycerides, acetylated mono and diglycerides, propylene glycol esters, ethylene glycol esters, and combinations thereof. 
     
     
         23 . The pharmaceutical composition according to  claim 1 , wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of binders, diluents, lubricants, surfactants, plasticizers, and glidants. 
     
     
         24 . The pharmaceutical composition according to  claim 23 , wherein the diluent is selected from the group consisting of cellulose or cellulose derivatives, polyhydric alcohol, sugar alcohols, sulphate or phosphate salts of inorganic metals, and mixtures thereof. 
     
     
         25 . The pharmaceutical composition according to  claim 23 , wherein the lubricant is selected from the group consisting of magnesium or calcium stearate, polyethylene glycol, stearic acid, hydrogenated vegetable oil, glyceryl stearate, cornstarch, talc, magnesium silicate, colloidal silicon dioxide, silicon hydrogel, and mixtures thereof. 
     
     
         26 . The pharmaceutical composition according to  claim 23 , 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, epoxydised 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, and glyceryl monocaprate. 
     
     
         27 . The pharmaceutical composition according to  claim 23 , wherein the glidant is selected from the group consisting of silicon dioxide, colloidal silica, powdered cellulose, talc, dicalcium phosphate, and mixtures thereof. 
     
     
         28 . A pharmaceutical composition according to  claim 1 , wherein the composition is a one or multiple daily dose form comprising from 1 to 3000 mg of rifaximin in one or more polymorph forms or raw form. 
     
     
         29 . A pharmaceutical composition according to  claim 28 , comprising 50 to 800 mg of rifaximin in one or more polymorph forms or raw form. 
     
     
         30 . A pharmaceutical composition according to  claim 28 , wherein the unit dosage is 200 mg, or 400 mg or 550 mg or 600 mg or 800 mg of rifaximin in one or more polymorph forms or raw form. 
     
     
         31 . A method of treating or preventing a gastrointestinal disorder in a subject in need thereof comprising administering to said subject the pharmaceutical composition of  claim 1 , wherein said gastrointestinal indication is selected from the group consisting of traveler's diarrhea, infectious diarrhea, an antibacterial prophylactic prior to colon surgery, Crohn's disease, small intestinal bacterial overgrowth, traveler's diarrhea prophylaxis, inflammation of intestinal mucous membrane, surgical prophylaxis and gastric dyspepsia. 
     
     
         32 . The method according to  claim 31 , wherein the composition is used for the treatment of gastrointestinal inflammatory diseases. 
     
     
         33 . The method according to  claim 31 , wherein the composition is used for the treatment of disease caused by  E. coli.    
     
     
         34 . The method according to  claim 31 , wherein said composition is further coated with a coating which includes a film coating, a sugar coating, and/or an enteric coating. 
     
     
         35 . The method according to  claim 34 , wherein the coating comprises coating agents, plasticizers, antisticking agents, surfactants, coloring agents, or mixtures thereof. 
     
     
         36 . A pharmaceutical composition according to  claim 1 , wherein the composition is formulated as a tablet, granule, capsule, microcapsule, tablet in capsule, or microgranules for suspension. 
     
     
         37 . A pharmaceutical composition comprising a therapeutically effective amount of rifaximin or polymorph thereof, one or more release controlling agents and one or more pharmaceutically acceptable excipients, wherein said release controlling agents or excipients are selected from the group consisting of methacrylic acid ethylacrylate copolymer (1:1), methacrylic acid methylmethacrylate copolymer (1:2), polyvinyl acetate phthalate, polyvinylpyrrolidone, cellulose, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose acetate phthalate/cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate latex, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, acetylated glycerides, diethylphthalate, ethylene glycol, propylene glycol, polyethylene glycol, polysorbate, polyoxyethylenate esthers, amylose, chitosan, chondroitin sulphate, dextran, guar gum, inulin, adipates, azelates, benzoates, citrates, isoebucates, phthalates, sebacates, stearates, glycols, acetylated monoglycerides, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin, triacetin citrate, triacetin, tripropinoin, diacetin, dibutyl phthalate, acetyl monoglyceride, 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, epoxydized 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, fatty acids, fatty acid esters, waxes, zein, simethicone, polyvinyl alcohol, titanium dioxide, micronized silica, silica gel, fumed silica, colloidal silica, colloidal silicon dioxide, glycerol monostearate, magnesium trisilicate, magnesium stearate, sucrose, sorbitol, mannitol, glucose, dextrose, lactose, saccharine, acesulfame, neohesperedine, pectin, xanthan gum, agar, dicalcium phosphate, calcium sulphate, kaolin, sodium chloride, dry starch, starch, corn starch, potato starch, gelatin, synthetic gum, sodium alginate, talc, calcium stearate, stearic acid, hydrogenated vegetable, oils, croscarmelose, crospovidone, sodium starch glycolate, coloring agents, acetylated monoglycerides, citrate esters, albumin lake, iron oxide, and mixtures thereof. 
     
     
         38 . A pharmaceutical composition comprising a therapeutically effective amount of rifaximin or polymorph thereof, one or more release controlling agents and one or more pharmaceutically acceptable excipients, wherein said composition is multi-layered. 
     
     
         39 . A pharmaceutical composition according to  claim 38 , wherein at least one enteric layer is present. 
     
     
         40 . A pharmaceutical composition according to  claim 39 , further comprising a hydrophilic film.