Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof

Abstract

The present invention relates to rifaximin compositions comprising amino acids, characterized in that they increase rifaximin solubility in aqueous solutions and are useful in the treatment of disease wherein amino acids and rifaximin are efficacious. The present invention also relates to pharmaceutical compositions comprising rifaximin or one of the pharmaceutically acceptable salts thereof and one or more amino acid(s), wherein the molar ratio between the amino acid(s) and rifaximin is from 1:1 to 10:1, together with pharmaceutically acceptable excipients. The present invention further relates to rifaximin crystals obtained by dissolving rifaximin and amino acids in solutions formed by ethanol/water and evaporating the solution.

1 . A pharmaceutical composition comprising rifaximin or one of the pharmaceutically acceptable salts thereof and one or more amino acid(s), wherein the molar ratio between the amino acid(s) and rifaximin is from 1:1 to 10:1, together with pharmaceutically acceptable excipients. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the molar ratio between the amino acid(s) and rifaximin is from 1:1 to 5:1, 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the rifaximin is in the crystalline, polymorphous or amorphous form, in the form of a hydrate or solvate and/or in a mixture thereof. 
     
     
         4 . The pharmaceutical composition according to  claim 2 , wherein the crystalline form of rifaximin is selected from
 i) crystals having monoclinic space group P2 1  and cell parameters in the ranges:   a: 13.7(1)-13.8(1) Å; b: 19.7(1)-19.9(1) Å; c: 16.4(6)-16.6(6) Å; β: 92.1(1)-91.9(1) deg.,   ii) crystals having the features of i) and having 3 or 4.5 water molecules for each rifaximin molecule,   iii) crystals having monoclinic space group P2 1  and cell parameters in the ranges:   a: 14.2(1)-14.5(1) Å; b: 19.7(1)-20.1(1) Å; c: 16.1(1)-16.2(1) Å; β: 108.7(1)-111.4(1) deg.   iv) crystals having the features of iii) and having zero or 0.5 or 1.5 water molecules for each rifaximin molecule, or   v) α, β, γ, or δ.   
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein rifaximin is in a dosage from 20 mg to 1200 mg. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the amino acid(s) is/are selected from aliphatic amino acids, aromatic amino acids, basic amino acids, heterocyclic amino acids, branched amino acids, cyclic amino acids, acidic amino acids, hydroxyl or sulfur containing amino acids, amide amino acids or mixtures thereof. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the composition comprises at least one aromatic or heterocyclic amino acid. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the amino acid(s) is/are selected from serine, histidine, tryptophan, valine, leucine or isoleucine. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the amino acid(s) is/are selected from branched chain amino acids. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , comprising rifaximin and valine, leucine or isoleucine in a molar ratio of 10:1 with respect to rifaximin. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutically acceptable ingredients include diluting agents, binding agents, disintegregating agents, lubricating agents, release-controlling polymers or bioadhesive polymers. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the diluting agent is at least one selected from the group of: cellulose, microcrystalline cellulose, calcium phosphate, starch, kaolin, dehydrated calcium sulphate, calcium carbonate, lactose, saccharose, glucose, sorbitol and mannitol. 
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein the binding agent is at least one selected from the group of: cellulose, cellulose derivatives, carboxy methyl cellulose, microcrystalline cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, hydroxy propyl-methyl cellulose, starches, potato starch, maize starch, partially gelatinized starch, gums, synthetic gum, natural gums, polyvinyl pyrrolidone, polyethylene glycol, gelatin, polyols, propylene glycol, alginates and sugars. 
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein the disintegrating agent is at least one selected from the group of: sodium carboxy methyl cellulose, cross-linked sodium carboxy methyl cellulose, polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, starch, pre-gelatinized starch and silica. 
     
     
         15 . The pharmaceutical composition of  claim 11 , wherein the lubricating agent is at least one selected from the group of: silica, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oils, mineral oils, polyethylene glycols, sodium lauryl sulphate, glycerides, sodium benzoate, glyceryl dibehenate and glycerol stearate. 
     
     
         16 . The pharmaceutical composition of  claim 11 , wherein the release-controlling polymer is at least one selected from the group of: copolymers of acrylic acid, copolymers of methacrylic acid with an acrylic or methacrylic ester, polyvinyl acetate phthalate, hydroxy propyl methyl cellulose phthalate, cellulose acetate phthalate, Kollicoat®, Eudragit@, Aquateric®, Aqoat®; natural polymers and ethyl cellulose. 
     
     
         17 . The pharmaceutical composition of  claim 11 , wherein the bioadhesive polymer is at least one selected from the group of: pectins, zeins, casein, gelatin, albumin, collagen, kitosan, cellulose, dextran, polysaccharides from tamarind seeds, xanthan gum, arabic gum, hyaluronic acid, alginic acid, sodium alginate, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl pyrrolidone, polysiloxanes, polyurethanes, polystyrenes, polymers of acrylic acid and methacrylic esters, copolymers of methacrylic acid-ethyl acrylate, polylactides, barbituric polyacids, polyanhydrides, polyorthoesters, methyl cellulose, ethyl cellulose, hydroxy propyl cellulose, hydroxy butyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxy methyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, polymethyl methacrylate, poly isobutyl acrylate, poly octadecyl acrylate, polypropylene, polyethylene glycol, polyethylene oxide, polyethylene terephthalate, polyvinyl acetate, polyvinyl chloride, polystyrene, polyvinyl phenol, carboxylic acids, sulphonic acids, phosphonic acids, and neutral and positively charged amines, amides and imines. 
     
     
         18 . The pharmaceutical composition according to  claim 1 , wherein the composition is in the form of a powder, paste, tablet, capsule, ovules cream, foam, suspension, solution, aerosol, granulates, ointment or suppository suitable for human or animal administration. 
     
     
         19 . The pharmaceutical composition according to  claim 1 , wherein the composition is in a form for oral or vaginal or topical administration. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the composition includes rifaximin in an amount from 20 to 1200 mg. 
     
     
         21 - 51 . (canceled)