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 - 40 . (canceled) 
     
     
         41 . A controlled release rifaximin pharmaceutical composition comprising:
 rifaximin coated by:   an enteric polymeric material insoluble at pH values between 1.5 and 4.0 and soluble at pH values between 5.0 and 7.5; and   a water semipermeable polymer over the enteric polymeric material;   
       wherein the water semipermeable polymer is in an amount effective to increase a lag time for rifaximin release of the enteric polymeric material. 
     
     
         42 . The controlled release rifaximin pharmaceutical composition of  claim 41 , wherein the rifaximin comprises one or more of polymorphous forms of rifaximin, a raw form of rifaximin or a combination thereof in combination with at least one excipient. 
     
     
         43 . The controlled release rifaximin pharmaceutical composition of  claim 41 , wherein the rifaximin is in a rifaximin based mixture which comprises one or more of a diluent, a plasticizer, an anti-agglomerative agent, an anti-sticking agent, a glidant, an anti-foam agent and a coloring substance, 
     
     
         44 . The controlled release rifaximin pharmaceutical composition of  claim 41 , wherein the enteric polymeric material is selected from one or more of acrylic polymers, methacrylic acid copolymers, methacrylic acid copolymers with an acrylic or methacrylic ester, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid ethylacrylate copolymer, and methacrylic acid methylmethacrylate copolymer. 
     
     
         45 . The controlled release rifaximin pharmaceutical composition of  claim 41 , wherein the water semipermeable polymer is selected from one or more of cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and their esters, waxes, zein, EUDRAGIT RS and RL 30D, EUDRAGIT® NE 30D, EUDRAGIT® 40, AQUACOAT®, SURELEASE®, and cellulose acetate latex. 
     
     
         44 . The controlled release rifaximin pharmaceutical composition of  claim 41 , wherein polymeric material comprising the enteric polymeric material and the water semipermeable polymer is comprised in the composition in an amount of about 1% to about 50% by weight relative to the weight of the rifaximin based mixture. 
     
     
         46 . The controlled release rifaximin pharmaceutical composition of  claim 41  further comprising an agent to improve processability of the barrier polymer. 
     
     
         47 . The controlled release rifaximin pharmaceutical composition of  claim 46 , wherein the agent to improve processability of the barrier polymer is selected from one or more of talc, colloidal silica, polyvinyl alcohol, titanium dioxide, micronized silica, fumed silica, glycerol monostearate, magnesium trisilicate, and magnesium stearate. 
     
     
         48 . The controlled release rifaximin pharmaceutical composition of  claim 41  wherein the composition further comprises a diluent, a plasticizer, an anti-agglomerative, an anti-sticking agent, a glidant, an anti-foam agent, a coloring substance, a sweetener, a binder, a lubricant, or a disintegrant, or a combination thereof. 
     
     
         49 . A multilayer controlled release rifaximin pharmaceutical composition comprising:
 a mixture comprising an effective amount of rifaximin within a plurality of coating layers, the plurality of coating layers comprising:
 an enteric coating layer comprising a polymer insoluble at pH values between 1.5 and 4.0 and soluble at pH values between 5.0 and 7.5; and 
 a barrier coating layer over the enteric coating layer; 
   
       wherein the barrier coating is configured to reduce water penetration through the enteric coating layer. 
     
     
         50 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 49 , wherein rifaximin comprises one or more rifaximin polymorph forms selected from the group consisting of form α, form β, form γ, form δ, form ε, and mixtures thereof in combination with one or more excipients. 
     
     
         51 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 50 , wherein the one or more excipients comprise a diluents, plasticizer, anti-agglomerative, anti-sticking, glidants, anti-foam surfactants, or coloring substances. 
     
     
         52 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 49 , wherein the enteric coating layer comprises at least one gastroresistent polymer and at least one plasticizer, the plasticizer in an amount of from about 10% to about 50%, for based on the weight of the dry polymer. 
     
     
         53 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 52 , wherein the at least one gastroresistent polymer is selected from acrylic polymers, methacrylic acid copolymers, methacrylic acid copolymers with an acrylic or methacrylic ester, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid ethylacrylate copolymer or methacrylic acid methylmethacrylate copolymer, and mixtures thereof. 
     
     
         54 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 52 , 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, glyceryl monocaprate, and mixtures thereof. 
     
     
         55 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 49 , wherein the barrier coating layer comprises one or more water semi-permeable polymers and one or more hydrophilic polymers. 
     
     
         56 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 55 , wherein
 the one or more water semipermeable polymers comprise cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and their esters, waxes, zein, EUDRAGIT RS and RL 30D, EUDRAGIT® NE 30D, EUDRAGIT® 40, AQUACOAT®, SURELEASE® or cellulose acetate latex, and mixtures thereof and   the one or more hydrophilic polymers comprise hydroxyethyl cellulose, hydroxypropyl cellulose hydroxypropyl methylcellulose, polyvinylpyrrolidone.   
     
     
         57 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 55 , wherein the barrier coating layer further comprises an agent to improve processability of the barrier polymer selected from the group consisting of talc, colloidal silica, polyvinyl alcohol, titanium dioxide, micronized silica, fumed silica, glycerol monostearate, magnesium trisilicate, and magnesium stearate, and mixtures thereof. 
     
     
         58 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 49 , the plurality of layers further comprises a film coating layer over the barrier coating layer, the film coating layer comprising one or more of cellulose and its substitutes such as hydropropylcellulose hydromethylcellulose, hydropropyl-ethylcellulose. 
     
     
         59 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 58 , wherein the film coating layer further comprises a plasticizer. 
     
     
         60 . The multilayer controlled release rifaximin pharmaceutical composition of  claim 49 , wherein the composition further comprises a diluent a plasticizer an anti-agglomerative an anti-sticking agent, a glidant, an anti-foam agent a coloring substance, a sweetener, a binder, a lubricant, a disintegrant or a combination thereof. 
     
     
         61 . A controlled release rifaximin pharmaceutical composition comprising:
 rifaximin as an active ingredient;   one or more release-controlling polymers; and   one or more pharmaceutical excipients;   
       wherein the one or more release controlling polymers comprise
 at least one gastoresistant polymer configured to release the rifaximin at pH values between 5.0 and 7.5 with a lag time for rifaximin release following water penetration through the gastroresistant polymer; and 
 at least one water semipermeable polymer in an amount to decrease the water penetration through the gastroresistant polymer and to increase the lag time for rifaximin release. 
 
     
     
         62 . The controlled release rifaximin pharmaceutical composition of  claim 61 , wherein the gastroresistant polymer is selected from the group consisting of acrylic polymers, methacrylic acid copolymers, methacrylic acid copolymers with an acrylic or methacrylic ester, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid ethylacrylate copolymer, methacrylic acid methylmethacrylate copolymer, and mixtures thereof. 
     
     
         63 . The controlled release rifaximin pharmaceutical composition of  claim 61 , wherein the gastroresistant polymer is selected from the group consisting of cellulose acetate phthalate, methacrylic acid copolymers, methacrylic acid copolymers with an acrylic or methacrylic ester, and mixtures thereof. 
     
     
         64 . The controlled release rifaximin pharmaceutical composition of  claim 61 , wherein the water semi permeable polymer is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, fatty acids and their esters, waxes, zein, EUDRAGIT RS and RL 30D, EUDRAGIT® NE 30D, EUDRAGIT@ 40, AQUACOAT®, SU RELEASE®, cellulose acetate latex. 
     
     
         65 . The controlled release rifaximin pharmaceutical composition of  claim 61 , wherein the water semi permeable polymer is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, ethyl cellulose, fatty acids and their esters, zein, EUDRAGIT RS and RL 30D, EUDRAGIT® NE 30D, and EUDRAGIT® 40. 
     
     
         66 . The controlled release rifaximin pharmaceutical composition of  claim 61 , wherein the water semi permeable polymer is in combination with one or more hydrophilic polymers. 
     
     
         67 . The controlled release rifaximin pharmaceutical composition of  claim 61 , wherein the one or more hydrophilic polymers comprise hydroxyethyl cellulose, hydroxypropyl cellulose hydroxypropyl methylcellulose, polyvinylpyrrolidone. 
     
     
         68 . The controlled release rifaximin pharmaceutical composition of  claim 61 , wherein the one or more hydrophilic polymers comprise hydroxypropyl cellulose hydroxypropyl methylcellulose, polyvinylpyrrolidone. 
     
     
         69 . A controlled release rifaximin pharmaceutical composition obtainable by a process comprising the steps of:
 spraying an aqueous suspension through a nozzle under pressure into a fluid bed apparatus in which a rifaximin mixture is kept in suspension, wherein the aqueous suspension contains a gastroresistant polymeric formulation, to obtain a gastroresistant preparation and   mixing the gastroresistant preparation with one or more pharmaceutically acceptable excipient   
     
     
         70 . The rifaximin pharmaceutical composition of  claim 69 , further comprising coating the gastroresistant preparation with one or more polymeric layers before the mixing. 
     
     
         71 . The rifaximin pharmaceutical composition of  claim 70 , wherein the one or more polymeric layers comprise a water penetration barrier layer comprising one or more water semipermeable polymers. 
     
     
         72 . The rifaximin pharmaceutical composition of  claim 70 , wherein the one or more polymeric layers comprise a film coating layer comprising one or more cellulose and its substitutes.