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.

What is claimed is: 
     
         1 . A pharmaceutical composition for oral administration, which is self-emulsifiable on contact with a hydrophilic phase and a lipophilic phase, said composition comprising:
 an enzyme or enzyme mixture having at least lipolytic activity, and   (ii) a system comprising
 at least one surfactant, and 
 at least one co-surfactant. 
   
     
     
         2 . A pharmaceutical composition according to  claim 1 , wherein the hydrophilic phase used to form the final emulsion after ingestion is supplied by the physiological fluid of the digestive milieu. 
     
     
         3 . A pharmaceutical composition according to  claim 1 , 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. 
     
     
         4 . A pharmaceutical composition according to  claim 1 , wherein the system furthermore comprises a lipophilic phase. 
     
     
         5 . A pharmaceutical composition according to  claim 4 , wherein the system comprises
 as surfactant at least one agent having a hydrophilic-lipophilic balance value above 6 and below 18,   as co-surfactant at least one agent having a hydrophilic-lipophilic balance value below 10, and   as lipophilic phase a lipidic phase,   said system comprising surfactant, co-surfactant and lipophilic phase having a hydrophilic-lipophilic balance value of about 4 to 16, and a melting point of at least 20° C.   
     
     
         6 . A pharmaceutical composition according to  claim 5 , wherein said system has a melting point of at least 25° C. 
     
     
         7 . A pharmaceutical composition according to  claim 4 , wherein the system comprises
 a 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, ionic surfactants and mixtures thereof;   a co-surfactant selected from the group consisting of mono-acylglycerides, mono-ethers of glycerol, partial esters of propylenglycol, partial esters of polyglycerol, partial esters of ethyl diglycol and mixtures thereof, and   a lipophilic phase represented by di- and/or triacylglycerides.   
     
     
         8 . A pharmaceutical composition according to  claim 7 , wherein the system comprises
 a surfactant 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;   a co-surfactant selected from the group consisting of mono-acylglycerides 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   a lipophilic phase represented by di- and/or triacylglycerides with aliphatic C 6 -C 22  carboxylic acids.   
     
     
         9 . A pharmaceutical composition according to  claim 8 , wherein the system comprises
 as surfactant 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, whereby the polyethylene glycol comprises 6 to 60 ethylene oxide units per molecule,   as co-surfactant monoacylglycerides of aliphatic C 6 -C 22  carboxylic acids and/or monoethers of glycerol with aliphatic C 12 -C 22  alcohols, and   as lipophilic phase di- and triacylglycerides of aliphatic C 6 -C 22  carboxylic acids.   
     
     
         10 . A pharmaceutical composition according to  claim 9 , wherein a mixture of polyethylene glycol mono- and di-esters with aliphatic C 6 -C 22  carboxylic acids, whereby the polyethylene glycol comprises 6 to 40 ethylene oxide units per molecule, are used as surfactant, and monoacylglycerides of aliphatic C 6 -C 22  carboxylic acids are used as co-surfactant. 
     
     
         11 . A pharmaceutical composition according to  claim 4 , 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 lipophilic phase,   whereby the components surfactant, co-surfactant and the lipophilic 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.   
     
     
         12 . A pharmaceutical composition according to  claim 11 , wherein the system consisting of surfactant, co-surfactant and lipophilic phase makes up 10 to 70% by weight of the pharmaceutical composition. 
     
     
         13 . A pharmaceutical composition according to  claim 12 , wherein the system consisting of surfactant, co-surfactant and lipophilic phase makes up 20 to 50% by weight of the pharmaceutical composition. 
     
     
         14 . A pharmaceutical composition according to  claim 13 , wherein the system consisting of surfactant, co-surfactant and lipophilic phase makes up 25 to 40% by weight of the pharmaceutical composition. 
     
     
         15 . A pharmaceutical composition according to  claim 11 , wherein the system comprises
 40 to 90% by weight surfactants,   5 to 40% by weight co-surfactants, and   0 to 40% by weight of the lipophilic phase,   the total of co-surfactants and the lipophilic phase together being at least 10% by weight of the system.   
     
     
         16 . A pharmaceutical composition according to  claim 15 , wherein the system comprises
 60 to 85% by weight surfactants,   15-30% by weight co-surfactants, and   15-30% by weight of the lipophilic phase,   the total of co-surfactants and the lipophilic phase together being between 15 and 40% by weight of the system.   
     
     
         17 . A pharmaceutical composition according to  claim 4 , 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. 
     
     
         18 . A pharmaceutical composition according to  claim 17 , wherein said at least one further pharmaceutically compatible auxiliary, carrier, or excipient makes up a maximum of 20% by weight of the composition. 
     
     
         19 . A pharmaceutical composition according to  claim 4 , wherein macrogolglycerides represent the system comprising surfactant, co-surfactant and lipophilic phase and optionally also small proportions of glycerin and free polyethylene glycol, wherein the macrogolglycerides are a mixture of mono-, di- and triacylglycerides and polyethylene glycol mono- and diesters of aliphatic C 6 -C 22  carboxylic acids, with the polyethylene glycol comprising about 6 to about 32 ethylene oxide units per molecule. 
     
     
         20 . A pharmaceutical composition according to  claim 19 , wherein the system comprising surfactant, co-surfactant and lipophilic phase has a hydrophilic-lipophilic balance value of at least 10, and a melting point of at least 30° C. 
     
     
         21 . A pharmaceutical composition according to  claim 20 , wherein the system has a hydrophilic-lipophilic ratio of 10 to 16, and a melting point of between 30 and 60° C. 
     
     
         22 . A pharmaceutical composition according to  claim 21 , wherein the system has a hydrophilic-lipophilic ratio of 12 to 15, and a melting point of between 40 and 50° C. 
     
     
         23 . A pharmaceutical composition according to  claim 21 , wherein the system contains a mixture of mono-, di- and triacylglycerides and polyethylene glycol mono- and diesters of aliphatic C 8 -C 18  carboxylic acids, and optionally small proportions of glycerol and/or free polyethylene glycol, and has a melting point between 42° C. and 48° C. and an HLB value of around 14. 
     
     
         24 . A pharmaceutical composition according to  claim 21 , wherein the system contains a mixture of mono-, di- and triacylglycerides and polyethylene glycol mono- and diesters of aliphatic C 8 -C 18  carboxylic acids and optionally small proportions of glycerol and free polyethylene glycol, the system having a melting point between 46° C. and 51° C. and an HLB value of around 13. 
     
     
         25 . A pharmaceutical composition according to  claim 19 , wherein the system contains a mixture of mono-, di- and triacylglycerides and polyethylene glycol PEG-32 mono- and diesters mainly of aliphatic C 8 -C 16  carboxylic acids, a mixture of mono-, di- and triacylglycerides and polyethylene glycol PEG-8 mono- and diesters mainly of aliphatic C 6 -C 10  carboxylic acids and optionally small proportions of glycerol and free polyethylene glycol. 
     
     
         26 . A pharmaceutical composition according to  claim 7 , wherein the surfactant is an ionic surfactant. 
     
     
         27 . A pharmaceutical composition according to  claim 26 , wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, lysophosphatidic acid, lysophosphatidylserine, and mixtures thereof. 
     
     
         28 . A pharmaceutical composition according to  claim 27 , wherein the ionic surfactant is lysophosphatidylcholine. 
     
     
         29 . A pharmaceutical composition according to  claim 27 , wherein the system comprises
 as surfactant lysophosphatidylcholine,   as co-surfactant a mixture of mono-acylglycerides with aliphatic saturated and/or unsaturated C 16 -C 20  carboxylic acids, and   a lipophilic phase represented by di- and/or triacylglycerides with aliphatic C 16 -C 20  carboxylic acids.   
     
     
         30 . A pharmaceutical composition according to  claim 29 , wherein
 the co-surfactant is a mixture of mono-acylglycerides with oleic and/or linoleic acid, and   the lipophilic phase is represented by di- and/or triacylglycerides with oleic and/or linoleic acid.   
     
     
         31 . A pharmaceutical composition according to  claim 29 , wherein the system comprises
 2 to 10% by weight lysophosphatidylcholine,   28 to 51% by weight mono-acylglycerides mainly of oleic acid and linoleic acid, and   36 to 54% by weight di-acylglycerides and 4 to 20% by weight tri-acylglycerides mainly of oleic acid and linoleic acid,   whereby the system consisting of surfactant, co-surfactant and the lipophilic phase together makes up 10% to 30% by weight of the pharmaceutical composition.   
     
     
         32 . A pharmaceutical composition according to  claim 31 , wherein the system comprises
 5%, by weight lysophosphatidylcholine,   28 to 51% by weight mono-acylglycerides mainly of oleic acid and linoleic acid, and   36 to 54% by weight di-acylglycerides and 4 to 20% by weight tri-acylglycerides mainly of oleic acid and linoleic acid,   whereby the system consisting of surfactant, co-surfactant and the lipophilic phase together makes up 20% by weight of the pharmaceutical composition.   
     
     
         33 . A pharmaceutical composition according to  claim 1 , wherein said composition is a solid pharmaceutical preparation in the form of a powder, granules, tablets, or pellets. 
     
     
         34 . A pharmaceutical composition according to  claim 1 , wherein the lipolytic activity of the enzymes or enzyme mixtures is provided by a microbial lipase. 
     
     
         35 . A pharmaceutical composition according to  claim 1 , wherein the microbial lipase is a bacterial or fungal lipase. 
     
     
         36 . A pharmaceutical composition according to  claim 1 , wherein the enzymes or enzyme mixtures also have proteolytic or amylolytic activity. 
     
     
         37 . A pharmaceutical composition according to  claim 36 , wherein the enzymes or enzyme mixtures comprise pancreatin. 
     
     
         38 . A pharmaceutical composition according to  claim 36 , wherein the enzyme mixture is a pancreatin-containing mixture of digestive enzymes. 
     
     
         39 . A pharmaceutical composition according to  claim 36 , wherein the pancreatin or pancreatin-containing mixture of digestive enzymes makes up 65-85% of the pharmaceutical composition. 
     
     
         40 . A pharmaceutical composition according to  claim 39 , wherein the pancreatin or pancreatin-containing mixture of digestive enzymes makes up 75-80% by weight of the pharmaceutical composition. 
     
     
         41 . A pharmaceutical composition according to  claim 36 , 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. 
     
     
         42 . A pharmaceutical composition according to  claim 41 , wherein microbial enzymes make up 5-80% by weight of the pharmaceutical composition. 
     
     
         43 . A pharmaceutical composition according to  claim 42 , wherein microbial enzymes make up 20-60% by weight of the pharmaceutical composition. 
     
     
         44 . A pharmaceutical composition according to  claim 36 , wherein the enzyme or enzyme mixture is pancreatin or a pancreatin-containing mixture of digestive enzymes, additionally containing at least one microbial enzyme selected from the group consisting of lipases, proteases and amylases. 
     
     
         45 . A pharmaceutical composition according to  claim 34 , wherein the microbial lipase is a recombinantly produced fungal or bacterial lipase. 
     
     
         46 . A pharmaceutical composition according to  claim 34 , wherein the lipase is a lipase variant or a mutated lipase. 
     
     
         47 . A method of stabilizing the lipolytic activity of a lypolytically active solid enzyme composition under acid pH conditions, said method comprising incorporating in said composition a stabilizing system comprising
 at least one surfactant,   at least one co-surfactant, and   optionally a lipophilic phase.   
     
     
         48 . A method according to  claim 47 , wherein said composition comprises pancreatin or a pancreatin-containing mixture of digestive enzymes. 
     
     
         49 . A process for preparing a solid pharmaceutical preparation containing an enzyme or enzyme mixture with lipolytic activity, said process comprising converting the enzymes or enzyme mixture into a suitable medicament form with a system comprising
 a 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, ionic surfactants and mixtures thereof;   a co-surfactant selected from the group consisting of mono-acylglycerides, mono-ethers of glycerol, partial esters of propylenglycol, partial esters of polyglycerol, partial esters of ethyl diglycol and mixtures thereof, and   a lipophilic phase represented by di- and/or triacylglycerides.   
     
     
         50 . A process according to  claim 49 , wherein said system further comprises at least one pharmaceutically compatible auxiliary, carrier or excipient.