Gastrointestinal mucosa-adherent matrixes, pharmaceutical preparations and a coating composition

Abstract

A solid matrix composition which is solid at ambient temperature, which comprises a viscogenic agent, such as an acrylic acid polymer, capable of developing viscosity on contact with water, as dispersed at least in the neighborhood of the surface layer of a matrix particle containing a polyglycerol fatty acid ester or a lipid and an active ingredient. The matrix may be such that a matrix particle containing a polyglycerol fatty acid ester or a lipid and an active ingredient has been coated with a coating composition containing at least one viscogenic agent. Such composition can adhere to the digestive tract and remain there for a prolonged period of time, thereby increasing the bioavailability of the active ingredient. Solid preparations, such as fine granules and granules, contain the above matrix composition.

What is claimed is:  
     
         1 . A gastrointestinal mucosa-adherent matrix which is solid at ambient temperature, which comprises a viscogenic agent capable of developing viscosity on contact with water, as dispersed at least in the neighborhood of the surface layer of a matrix particle containing a polyglycerol fatty acid ester or a lipid and an active ingredient.  
     
     
         2 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said viscogenic agent is one member selected from the group consisting of polymers containing carboxyl groups or salts thereof, cellulose ethers, polyethylene glycols having molecular weights not less than 200,000 and naturally-occurring mucous substances.  
     
     
         3 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said viscogenic agent is an acrylic acid polymer and/or a salt thereof.  
     
     
         4 . A gastrointestinal mucosa-adherent matrix composition according to  claim 2  wherein said polymers containing carboxyl groups or salts thereof are acrylic acid polymers obtainable from acrylic acid or a salt thereof as their constituent monomer.  
     
     
         5 . A gastrointestinal mucosa-adherent matrix according to  claim 4  wherein said acrylic acid polymers or salts thereof each contains 58.0 to 63.0 percent by weight of carboxyl groups and has a molecular weight of 200,000 to 6,000,000.  
     
     
         6 . A gastrointestinal mucosa-adherent matrix according to  claim 2  wherein said cellulose ethers are carboxymethylcellulose sodium, hydroxypropylmethylcellulose, methylcellulose and crystalline cellulose-carboxymethylcellulose sodium.  
     
     
         7 . A gastrointestinal mucosa-adherent matrix according to  claim 2  wherein said naturally-occurring mucous substances are mucin, agar, gelatin, pectin, carrageenan, sodium alginate, locust beam gum, xanthan gum, tragacanth gum, arabic gum, chitosan, pullulan and waxistarch.  
     
     
         8 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein the content of said visco genic agent is 0.005 to 95 percent by weight based on the total weight of said matrix particle.  
     
     
         9 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said polyglycerol fatty acid ester is an ester of a polyglycerol of the formula  
       
         
           
           
               
               
           
         
         wherein n represents the degree of polymerization which is an integer of not less than 2, with a saturated or unsaturated higher fatty acid.  
       
     
     
         10 . A gastrointestinal mucosa-adherent matrix according to  claim 9  wherein n is 2 to 50.  
     
     
         11 . A gastrointestinal mucosa-adherent matrix according to  claim 9  wherein said fatty acid is a saturated or unsaturated higher fatty acid containing 8 to 40 carbon atoms.  
     
     
         12 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said polyglycerol fatty acid ester is behenyl hexa(tetra)glyceride, stearyl penta(tetra)glycerid, stearyl mono(tetra)glyceride, stearyl penta(hexa)glyceride, stearyl sesqui(hexa) glyceride, stearyl mono(deca)glyceride or a mixture thereof.  
     
     
         13 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said polyglycerol fatty acid ester has an HLB (hydrophile-lipophile balance) of 1 to 22.  
     
     
         14 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said polyglycerol fatty acid ester has a melting point of 15 to 80° C.  
     
     
         15 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said lipid has a melting point of 40 to 120° C.  
     
     
         16 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said lipid is a C 14-22  saturated fatty acid or a salt thereof, a C 16-22  higher alcohol, a fatty acid glycerol ester, an oil, a wax, a hydrocarbon or a phospholipid.  
     
     
         17 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said active ingredient is an antiulcer agent or a therapeutic drug for gastritis.  
     
     
         18 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said active ingredient is a compound of the following formula (II) or a physiologically acceptable salt thereof:  
       
         
           
           
               
               
           
         
         wherein R 1  means hydrogen, an alkyl, a halogen, cyano, carboxy, an alkoxycarbonyl, an alkoxycarbonylalkyl, carbamoyl, a carbamoyalkyl, hydroxy, an alkoxy, a hydroxyalkyl, trifluoromethyl, an acyl, carbamoyloxy, nitro, an acyloxy, an aryl, an aryloxy, an alkylthio or an alkylsufinyl; R 2  means hydrogen, an alkyl, acryl, an alkoxycarbonyl, carbamoyl, an alkylcarbamoyl, a dialkylcarbamoyl, an alkylcarbonylmethyl, an alkoxycarbonylmethyl or an alkylsulfonyl; R 3  and R 5  may be the same or different and each means hydrogen, an alkyl, an alkoxy or an alkoxyalkoxy; R 4  means hydrogen, an alkyl, an alkoxy which may be fluorinated, an alkoxyalkoxy, an alkenyloxy which may be fluorinated or an alkynyloxy which may be fluorinated and m means an integer of 0 to 4.  
       
     
     
         19 . A gastrointestinal mucosa-adherent matrix according to  claim 18  wherein, in said compound of the formula (II), R 1 , R 2  and R 5  each is hydrogen and R 3  is hydrogen or methyl.  
     
     
         20 . A gastrointestinal mucosa-adherent matrix according to  claim 18  wherein, in said compound of the formula (II), R 4  is a fluorinated C 1-4  alkoxy group.  
     
     
         21 . A gastrointestinal mucosa-adherent matrix according to  claim 18  wherein, in said compound of the formula (II), R 1  is hydrogen, fluorine, methoxy or trifluoromethyl as substituted in position-5; R 2  is hydrogen; R 3  is hydrogen or methyl; R 4  is a C 1-4  alkoxy which may be fluorinated, 2-propenyloxy or allyl; R 5  is hydrogen or methyl and m=1.  
     
     
         22 . A gastrointestinal mucosa-adherent matrix according to  claim 1  which comprises a water-insoluble or sparingly water-soluble solid base together with an acidic active ingredient.  
     
     
         23 . A gastrointestinal mucosa-adherent matrix according to  claim 1  which comprises an enteric polymer together with a basic active ingredient.  
     
     
         24 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein the content of said polyglycerol fatty acid ester and/or said lipid in said matrix particle is 0.001 to 10,000 parts by weight relative to one part by weight of said active ingredient.  
     
     
         25 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein, in the matrix particle containing said ester of a polyglycerol of formula (I), wherein n is 2 to 50, with a saturated or unsaturated higher fatty acid of 8 to 40 carbon atoms and/or said lipid, said active ingredient and said viscogenic agent, the content of said polyglycerol fatty acid ester and/or lipid is 0.001 to 10,000 parts by weight relative to one part by weight of said active ingredient and said viscogenic agent comprises an acrylic acid polymer and/or a salt thereof.  
     
     
         26 . A gastrointestinal mucosa-adherent matrix according to  claim 1  wherein said matrix has a melting point of 30 to 120° C.  
     
     
         27 . A gastrointestinal mucosa-adherent matrix which is solid at ambient temperature, which comprises a matrix particle containing a polyglycerol fatty acid ester or a lipid and an active ingredient, said particle having a coating layer formed from a coating composition containing a viscogenic agent which develops viscosity on contact with water.  
     
     
         28 . A gastrointestinal mucosa-adherent matrix according to  claim 27  wherein said coating layer contains at least one member selected from the group consisting of polyglycerol fatty acid esters, lipids, enteric polymers and water-insoluble polymers.  
     
     
         29 . A gastrointestinal mucosa-adherent matrix according to  claim 27  wherein the content of said viscogenic agent in the coating layer is 0.005 to 100 percent by weight based on the total weight of the coating layer.  
     
     
         30 . A gastrointestinal mucosa-adherent matrix according to  claim 27  wherein the coating amount of said coating composition is 0.1 to 100 percent by weight based on the weight of said matrix particle.  
     
     
         31 . A solid pharmaceutical preparation comprising (1) a gastrointestinal mucosa-adherent matrix which is solid at ambient temperature, which comprises a viscogenic agent capable of developing viscosity on contact with water, as dispersed at least in the neighborhood of the surface layer of a matrix particle containing a polyglycerol fatty acid ester or a lipid and an active ingredient or (2) a gastrointestinal mucosa-adherent matrix which is solid at ambient temperature which is such that a matrix particle containing a polyglycerol fatty acid ester or a lipid and an active ingredient has been coated with a coating composition containing a viscogenic agent which develops viscosity on contact with water.  
     
     
         32 . A solid pharmaceutical preparation according to  claim 31  which is in a dosage form selected from the group consisting of fine granules, granules, pills, tablets obtainable by compression-molding said fine granules or granules, and capsules obtainable by filling said fine granules or granules in capsules.  
     
     
         33 . A coating composition comprising at least a viscogenic agent which develops viscosity on contact with water.  
     
     
         34 . A coating composition according to  claim 33  which contains at least one component selected from the group consisting of polyglycerol fatty acid esters, lipids, enteric polymers and water-insoluble polymers.  
     
     
         35 . A coating composition according to  claim 33  which, on a nonvolatile matter basis, contains 0.005 to 100 percent by weight of said viscogenic agent.