Pharmaceutical compositions of lipase-containing products, in particular of pancreatin

Abstract

Orally administrable pharmaceutical compositions of lipase-containing products, particularly pancreatin and pancreatin-containing products, or of enzyme products which contain at least one lipase of non-animal, especially microbial origin, which improve the lipolytic activity and particularly result in stabilization of the lipase in the acidic pH range. These oral pharmaceutical compositions contain a system which includes at least one surfactant and one co-surfactant and optionally a lipophilic phase, and are self-emulsifiable on contact with a hydrophilic and a lipophilic phase. The compositions according to the invention are suitable for treating or inhibiting maldigestion, especially maldigestion due to chronic exocrine pancreatic insufficiency, in mammals and humans.

1 - 50 . (canceled) 
     
     
         51 . A pharmaceutical composition for oral administration, which is self-emulsifiable on contact with a hydrophilic phase and a lipophilic phase, said composition comprising:
 (i) an enzyme or enzyme mixture comprising pancreatin or a microbial lipase, wherein the enzyme or enzyme mixture has lipolytic activity and exerts the lipolytic activity in the digestive tract upon oral administration, and   (ii) a system comprising:
 (a) at least one surfactant selected from the group consisting of polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polyethylene glycol alkyl ethers, polyethylene glycol sterol ethers, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block copolymers, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, alginate salts, propylene glycol alginate, alkylsulfates, sodium docusate, carnitines, and a combination thereof; and 
 (b) at least one co-surfactant which has a hydrophilic lipophilic balance value below 10; 
   wherein the pharmaceutical composition does not comprise any active substances to be absorbed into the bloodstream.   
     
     
         52 . The pharmaceutical composition of  claim 51 , wherein the hydrophilic phase used to form the final emulsion after ingestion is supplied by the physiological fluid of the digestive milieu. 
     
     
         53 . The pharmaceutical composition of  claim 51 , wherein the lipophilic phase used to form the final emulsion in the digestive tract after ingestion is at least partially supplied by the lipids present in ingested food. 
     
     
         54 . The pharmaceutical composition of  claim 51 , wherein the system further comprises a lipidic phase. 
     
     
         55 . The pharmaceutical composition of  claim 54 , wherein
 (a) the surfactant comprises at least one agent having a hydrophilic-lipophilic balance value above 6 and below 18, and   (b) the co-surfactant comprises at least one agent having a hydrophilic-lipophilic balance value below 10; and   wherein said system comprising surfactant, co-surfactant and lipidic phase has a hydrophilic-lipophilic balance value of about 4 to 16, and a melting point of at least 20° C.   
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein said system has a melting point of at least 25° C. 
     
     
         57 . The pharmaceutical composition of  claim 54 , wherein the system comprises
 (a) the surfactant is selected from the group consisting of polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polyethylene glycol alkyl ethers, polyethylene glycol sterol ethers, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof;   (b) the co-surfactant is selected from the group consisting of monoacylglycerides, mono-ethers of glycerol, partial esters of propylenglycol, partial esters of polyglycerol, partial esters of ethyl diglycol, and mixtures thereof, and   (c) the lipidic phase comprises di- and/or triacylglycerides.   
     
     
         58 . The pharmaceutical composition of  claim 57 , wherein
 (a) the surfactant is selected from the group consisting of polyethylene glycol fatty acid mono- and/or di-esters with aliphatic C 6 -C 22  carboxylic acids, polyethylene glycol glycerol fatty acid esters with aliphatic C 6 -C 22  carboxylic acids, polyethylene glycol alkyl mono- and/or di-ethers with aliphatic C 12 -C 18  alcohols, and mixtures thereof;   (b) the co-surfactant is selected from the group consisting of monoacylglycerides with aliphatic C 6 -C 22  carboxylic acids, mono-ethers of glycerol ethers with aliphatic C 12 -C 18  alcohols, partial esters of propylenglycol with aliphatic C 6 -C 22  carboxylic acids, partial esters of polyglycerol with aliphatic C 6 -C 22  carboxylic acids, and mixtures thereof; and   (c) the lipidic phase comprises di- and/or triacylglycerides with aliphatic C 6 -C 22  carboxylic acids.   
     
     
         59 . The pharmaceutical composition of  claim 58 , wherein
 (a) the surfactant comprises a mixture of polyethylene glycol mono- and di-esters with aliphatic C 6 -C 22  carboxylic acids and/or polyethylene glycol mono- and di-ethers with aliphatic C 12 -C 18  alcohols, wherein the polyethylene glycol comprises 6 to 60 ethylene oxide units per molecule,   (b) the co-surfactant comprises monoacylglycerides of aliphatic C 6 -C 22  carboxylic acids and/or monoethers of glycerol with aliphatic C 12 -C 22  alcohols, and   (c) the lipidic phase comprises di- and triacylglycerides of aliphatic C 6 -C 22  carboxylic acids.   
     
     
         60 . The pharmaceutical composition of  claim 59 , wherein the surfactant is a mixture of polyethylene glycol mono- and di-esters with aliphatic C 6 -C 22  carboxylic acids, wherein the polyethylene glycol comprises 6 to 40 ethylene oxide units per molecule, and wherein the co-surfactant comprises monoacylglycerides of aliphatic C 6 -C 22  carboxylic acids. 
     
     
         61 . The pharmaceutical composition of  claim 54 , wherein the system comprises
 2 to 90% by weight surfactants,   5 to 60% by weight co-surfactants, and   0 to 70% by weight of the lipidic phase,   
       wherein the components surfactant, co-surfactant and the lipidic phase together make up to 100% by weight of the system, and the system makes up 10% to 95% by weight of the pharmaceutical composition. 
     
     
         62 . The pharmaceutical composition of  claim 61 , wherein the system consisting of surfactant, co-surfactant and lipidic phase makes up 10 to 70% by weight of the pharmaceutical composition. 
     
     
         63 . The pharmaceutical composition of  claim 62 , wherein the system consisting of surfactant, co-surfactant and lipidic phase makes up 20 to 50% by weight of the pharmaceutical composition. 
     
     
         64 . The pharmaceutical composition of  claim 54 , wherein the composition contains at least one further pharmaceutically compatible auxiliary, carrier or excipient selected from the group consisting of polyethylene glycol, glycerol, C 1 -C 4 -alcohols, sugars, cellulosics and mixtures thereof. 
     
     
         65 . The pharmaceutical composition of  claim 64 , wherein said at least one further pharmaceutically compatible auxiliary, carrier, or excipient makes up a maximum of 20% by weight of the composition. 
     
     
         66 . The pharmaceutical composition of  claim 51 , wherein said composition is a solid pharmaceutical preparation in the form of a powder, granules, tablets, or pellets. 
     
     
         67 . The pharmaceutical composition of  claim 66 , wherein the enzyme or enzyme mixtures comprise pancreatin. 
     
     
         68 . The pharmaceutical composition of  claim 67 , wherein the pancreatin makes up 65-85% of the pharmaceutical composition. 
     
     
         69 . The pharmaceutical composition of  claim 66 , wherein the enzyme mixture comprises a mixture of at least one microbial lipase and at least one microbial enzyme selected from the group consisting of proteases and amylases. 
     
     
         70 . The pharmaceutical composition of  claim 69 , wherein microbial enzymes make up 5-80% by weight of the pharmaceutical composition. 
     
     
         71 . The pharmaceutical composition of  claim 51 , wherein the enzyme or enzyme mixture retains at least 90% of the lipolytic activity upon exposure to a buffer having pH 5 for 60 to 90 minutes. 
     
     
         72 . The pharmaceutical composition of  claim 51 , wherein the composition does not contain an enteric coating and wherein the enzyme or enzyme mixture retains at least 90% of the lipolytic activity upon exposure to a buffer having pH 5 for 60 to 90 minutes. 
     
     
         73 . A pharmaceutical composition for oral administration, which is self-emulsifiable on contact with a hydrophilic phase and a lipophilic phase, said composition comprising:
 (i) pancreatin, and   (ii) a system comprising:
 (a) at least one surfactant selected from the group consisting of polyethylene glycol sterol ethers, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block copolymers, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, alginate salts, propylene glycol alginate, alkylsulfates, sodium docusate, carnitines, and a combination thereof; and 
 (b) at least one co-surfactant which has a hydrophilic lipophilic balance value below 10; 
   wherein the pharmaceutical composition does not comprise any active substances to be absorbed into the bloodstream.   
     
     
         74 . The pharmaceutical composition of  claim 73 , wherein the hydrophilic phase used to form the final emulsion after ingestion is supplied by the physiological fluid of the digestive milieu. 
     
     
         75 . The pharmaceutical composition of  claim 73 , wherein the lipophilic phase used to form the final emulsion in the digestive tract after ingestion is at least partially supplied by the lipids present in ingested food. 
     
     
         76 . The pharmaceutical composition of  claim 73 , wherein the system further comprises a lipidic phase. 
     
     
         77 . The pharmaceutical composition of  claim 76 , wherein
 (a) the surfactant comprises at least one agent having a hydrophilic-lipophilic balance value above 6 and below 18, and   (b) the co-surfactant comprises at least one agent having a hydrophilic-lipophilic balance value below 10; and   wherein said system comprising surfactant, co-surfactant and lipidic phase has a hydrophilic-lipophilic balance value of about 4 to 16, and a melting point of at least 20° C.   
     
     
         78 . The pharmaceutical composition of  claim 73 , wherein said composition is a solid pharmaceutical preparation in the form of a powder, granules, tablets, or pellets. 
     
     
         79 . The pharmaceutical composition of  claim 73 , wherein the pancreatin makes up 65-85% of the pharmaceutical composition. 
     
     
         80 . The pharmaceutical composition of  claim 73 , wherein the composition does not contain an enteric coating and wherein at least 90% of the lipolytic activity of the pancreatin is retained upon exposure of the composition to a buffer having pH 5 for 60 to 90 minutes.