Pharmaceutical preparation for oral administration with controlled active ingredient release in the small intestine and method for its production

Abstract

Any pharmaceutical preparation for oral administration with controlled release of active ingredient in the small bowel, on the basis of active ingredient carriers provided with at least one active ingredient which are provided with an inner layer to control the release of active ingredient and with a gastro-resistant coating layer disposed thereon, which is characterized in that the inner layer is formed from at least two diffusion layers whose permeability for the diffusing active ingredient decreases from the inside to the outside, and a method for the production thereof, are described.

1 . A pharmaceutical preparation for oral administration with controlled release of active ingredient in the small bowel, on the basis of active ingredient carriers provided with at least one active ingredient which are provided with an inner layer to control the release of active ingredient and with a gastro-resistant coating layer disposed thereon, characterized in that the inner layer is formed from at least two diffusion layers whose permeability for the diffusing active ingredient decreases from the inside to the outside, the diffusion layers being formed from a matrix material which is insoluble in small bowel fluid and into which pore formers which control the permeability for the diffusing active ingredient and are soluble and/or swellable and/or water-absorbing in small bowel fluid are incorporated,
 the pore former of the diffusion layers is selected from the group comprising polyvinyl alcohol-polyethylene glycol copolymers, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, crosslinked polyvinylpyrrolidone, microcrystalline cellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, methylethylcellulose, methylhydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylpropylcellulose, polyethylene glycol, cellulose powder, sucrose, lactose, mannitol, sorbitol and polysorbate, and the active ingredient carriers comprise as active ingredient 4-diethylamino-2-butynyl α-phenylcyclo-hexaneglyconate hydrochloride, ethyldimethyl(1-methyl-3,3-diphenylpropyl)ammonium carrageenate, (+)-[R-2-[α-2-(diisopropylamino)ethyl]benzyl]-p-cresol tartrate, 8-(cyclopropylmethyl)-6β,7β-epoxy-3a-hydroxy-1αH,5α)-(S)-tropate bromide, (1R,3r,5S)-3-[(hydroxyl-diphenylacetyl)oxy]spiro[8-azoniabicyclo[3.2.1]octane-8,1′-pyrrolidinium] chloride, 2-diethylaminoethyl (bicyclohexyl)-1-carboxylate hydrochloride, 1-methyl-4-piperidyl diphenylpropoxyacetate hydrochloride, (3R)-1-azabicyclo[2.2.2]oct-3-yl (1S)-1-phenyl-3,4-dihydro-isoquinoline-2(1H)-carboxylate succinate, (S)-1-[2-(2,3-dihydro-5-benzofuranyl)ethyl]-α,α-diphenyl-3-pyrrolidineacetamide hydrobromide, (8R)-3α-hydroxy-5-isopropyl-1αH,5αH-tropanium bromide (±tropate), 8-butyl-6β,7β-epoxy-3α-[(S)-3-hydroxy-2-phenylpropanoyloxy]tropanium bromide, (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine, 2-[(1R)-3-(di-isopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl isobutyrate, 4-(diethylamino)-but-2-yn-1-yl (2S)-cyclohexyl (hydroxy)phenylacetate, ethyldimethyl(1-methyl-3,3-diphenylpropyl)ammonium bromide, 2-piperidinoethyl 3-methyl-4-oxo-2-phenyl-4H-chromene-8-carboxylate hydrochloride, benzyl(2-chloroethyl)-(1-methyl-2-phenoxyethyl)amine hydrochloride and/or a salt or another salt of these active ingredients.   
     
     
         2 . The pharmaceutical preparation according to  claim 1 , characterized in that the diffusion layers comprise identical or different types of matrix materials. 
     
     
         3 . The pharmaceutical preparation according to  claim 1 , characterized in that the diffusion layers comprise one or more pore formers which are identical or of different types. 
     
     
         4 . The pharmaceutical preparation according to  claim 1 , characterized in that the permeability of the diffusion layers for the diffusing active ingredient is controlled via the nature, the quantity and/or the particle size and/or the solubility and/or the swellability and/or the water-absorbing capacity of the pore formers. 
     
     
         5 . The pharmaceutical preparation according to  claim 4 , characterized in that the inner layer for controlling the release of active ingredient includes an inner and an outer diffusion layer. 
     
     
         6 . The pharmaceutical preparation according to  claim 5 , characterized in that in the case of identical pore former material the particle size and/or the concentration of the pore formers in the inner diffusion layer is greater than in the outer diffusion layer. 
     
     
         7 . The pharmaceutical preparation according to  claim 6 , characterized in that in the case of pore formers which are soluble in small bowel fluid the ratio of the pore former concentration in the inner diffusion layer to the pore former concentration in the outer diffusion layer is in the range from 20:1 to 1:1. 
     
     
         8 . The pharmaceutical preparation according to  claim 1 , characterized in that the matrix material of the diffusion layers is selected from the group comprising ethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, shellac, hydroxypropyl-methylcellulose acetate succinate, cellulose acetate, cellulose acetate propionate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate, polyvinyl acetate phthalate, cellulose acetate butyrate, butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymers, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl methacrylate copolymers, methacrylic acid-ethyl acrylate copolymers, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymers, silicone elastomer latex suspensions, hydrogenated castor oil, stearic acid, glycerol monostearate, glycerol distearate, glycerol dibehenate, stearyl alcohol, white wax, yellow wax, hydrogenated vegetable oil and microcrystalline wax. 
     
     
         9 . The pharmaceutical preparation according to  claim 1 , characterized in that the matrix material of the diffusion layers additionally comprises plasticizers and antitack agents. 
     
     
         10 . The pharmaceutical preparation according to  claim 9 , characterized in that the matrix material of the diffusion layers comprises polyethylene glycol, propylene glycol, triethyl citrate, triacetin, acetyl tributyl citrate, polysorbates, 2-pyrrolidone, dibutyl sebacate, stearic acid, castor oil and/or medium-chain triglycerides as plasticizer, and talc, stearic acid and salts thereof, fatty alcohols, mono-, di- or triglycerides with straight- and/or branched-chain fatty acids, colloidal silicon dioxide, precipitated silicon dioxide, aluminium oxide, kaolin, maize starch, wheat starch, rice starch, potato starch, titanium dioxide, silicone emulsions and/or a magnesium aluminium silicate dispersion as antitack agent. 
     
     
         11 . The pharmaceutical preparation according to  claim 1 , characterized in that the active ingredient is present in an amount of from 1 to 250 mg per dose unit on the active ingredient carriers. 
     
     
         12 . The pharmaceutical preparation according to  claim 1 , characterized in that the active ingredient is present in the form of a coating on the active ingredient carriers. 
     
     
         13 . The pharmaceutical preparation according to  claim 1 , characterized in that the active ingredient carriers are in the form of neutral pellets and/or crystalline substances and/or granulated or extruded carrier substances. 
     
     
         14 . The pharmaceutical preparation according to  claim 13 , characterized in that the active ingredient carriers have a particle size of from 0.1 to 3.0 mm. 
     
     
         15 . The pharmaceutical preparation according to  claim 13 , characterized in that the active ingredient carriers include as carrier material sugar, starch, microcrystalline cellulose, dicalcium phosphate, sodium chloride, citric acid, tartaric acid, malic acid, sucrose, lactose, sorbitol, mannitol, cellulose, calcium hydrogen phosphate, sodium citrate, tricalcium phosphate, maize starch, wheat starch, potato starch, rice starch and/or mixtures thereof. 
     
     
         16 . The pharmaceutical preparation according to  claim 1 , characterized in that the active ingredient carriers provided with the active ingredient additionally have, besides the active ingredient, on their surface a binder and optionally an antitack agent and/or buffer substances. 
     
     
         17 . The pharmaceutical preparation according to  claim 16 , characterized in that the active ingredient carriers provided with the active ingredient comprise per dose unit from 1 to 250 mg active ingredient, from 10 to 500 parts by weight of carrier material, from 1 to 100 parts by weight of binder, from 1 to 100 parts by weight of antitack agent and from 1 to 100 parts by weight of buffer substance. 
     
     
         18 . The pharmaceutical preparation according to  claim 16 , characterized in that the binder of the active ingredient carriers provided with active ingredient is selected from the group comprising hydroxy-propylmethylcellulose, butyl methacrylate-(2-dimethyl-aminoethyl) methacrylate-methyl methacrylate copolymers, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl methacrylate copolymers, methacrylic acid-ethyl acrylate copolymers, methyl acrylate-methyl methacrylate-methacrylic acid copolymers, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate chloride copolymers, ethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, methylethylcellulose, hydroxyethylmethylpropylcellulose, polyvinylpyrrolidone, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol, gelatin, maize starch, wheat starch, rice starch and potato starch and mixtures thereof. 
     
     
         19 . The pharmaceutical preparation according to  claim 16 , characterized in that the antitack agent of the active ingredient carriers provided with the active ingredient is selected from the group comprising talc, stearic acid and salts thereof, mono-, di-, triglycerides with straight- and/or branched-chain fatty acids, fatty alcohols, colloidal silicon dioxide, precipitated silicon dioxide, aluminium oxide, hydrogenated castor oil, and macrogol (polyethylene glycol) and mixtures thereof. 
     
     
         20 . The pharmaceutical preparation according to  claim 16 , characterized in that the buffer substances of the active ingredient carriers provided with the active ingredient are selected from the group comprising sodium hydroxide, citric acid, tartaric acid, phosphoric acid, ascorbic acid, succinic acid, adipic acid, fumaric acid and their pharmaceutically acceptable salts and mixtures thereof. 
     
     
         21 . The pharmaceutical preparation according to  claim 1 , characterized in that the gastro-resistant coating layer disposed on the active ingredient carrier provided with the active ingredient and the diffusion layers is formed from the group comprising ethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, shellac, hydroxypropylmethylcellulose acetate succinate, cellulose acetate, cellulose acetate propionate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate butyrate, butyl methacrylate-(2-dimethylaminoethyl methacrylate-methyl methacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methyl acrylate-methyl methacrylate-mthacrylic acid copolymer, ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate chloride copolymer and/or mixtures thereof. 
     
     
         22 . The pharmaceutical preparation according to  claim 1 , characterized in that the active ingredient carriers provided with the active ingredient, the diffusion layers and where appropriate the optional gastro-resistant coating are provided with a saliva-resistant outer layer. 
     
     
         23 . The pharmaceutical preparation according to  claim 22 , characterized in that the active ingredient carriers provided with the active ingredient, the diffusion layers and the optional gastro-resistant coating are provided with a saliva-resistant outer layer from the group comprising ethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, shellac, hydroxypropylmethylcellulose acetate succinate, cellulose acetate, cellulose acetate propionate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate, polyvinyl acetate phthalate, polyvinyl alcohol-polyethylene glycol copolymer, cellulose acetate butyrate, butyl methacrylate-2-dimethylaminoethyl methacrylate-methyl methacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate chloride copolymer and/or mixtures thereof. 
     
     
         24 . The pharmaceutical preparation according to  claim 23 , characterized in that the saliva-resistant outer layer comprises aromatizing substances, flavourings and/or sweeteners. 
     
     
         25 . The pharmaceutical preparation according to  claim 1 , characterized in that the active ingredient carriers which have been provided with the active ingredient, the diffusion layers, the gastro-resistant coating layer, and, optionally, the saliva-resistant outer layer, are compressed to tablets using conventional excipients, or packed into capsules made of gelatin, cellulose, starch or starch derivatives, or are in the form of liquids or semisolid or solid preparations for preparing a suspension or a suspension gel. 
     
     
         26 . A method for producing the pharmaceutical preparation according to  claim 1 , characterized in that the active ingredient carriers are coated with a solution or suspension which comprises the active ingredient, the binder, the antitack agent and, optionally, buffer substances, then the at least two diffusion layers whose permeability for the diffusing active ingredient decreases from the inside to the outside are successively applied, the gastro-resistant coating layer is applied and, optionally, a saliva-resistant outer layer is provided.