Controlled release pharmaceutical compositions for acid-labile drugs

Abstract

An enteric-coated oral dosage form comprising an acid labile active pharmaceutical ingredient where the composition is substantially free of monomeric phthalic acid esters and synthetic oils is described herein. Also provided are methods for making and using the enteric-coated oral dosage form. The disclosed pharmaceutical compositions comprise an enteric coating which includes at least one plasticizer, at least one film-forming agent and optionally at least one anti-sticking agent.

We claim: 
     
         1 . A process for the manufacture of pancreatin micropellets, comprising the steps of:
 a. providing pancreatin micropellet cores wherein the pancreatin micropellet cores are substantially free of synthetic oils;   b. providing an enteric-coating solution comprising
 i. one or more film-forming agents; 
 ii. a plasticizer in an amount greater than about 1.5% by weight relative to the one or more film-forming agents film-forming agents wherein the plasticizer is substantially free of monomeric phthalic acid esters; and 
 v. optionally, at least one anti-sticking agent, and 
 vi. one or more enzyme-friendly organic solvent(s); 
   c. coating the pancreatin micropellet cores with the enteric-coating solution wherein the temperature of the pancreatin micropellet cores during coating is kept at a temperature suitable for applying the enteric-coating solution; and   d. drying the coated pancreatin micropellet cores.   
     
     
         2 . The process of  claim 1  wherein the enteric coating is between about 20% and about 30% by weight of the pancreatin micropellets. 
     
     
         3 . The process of  claim 1  wherein the one or more film-forming agents is selected from the group consisting of: agar, carbomer polymers, carboxymethyl cellulose, carboxymethylethyl cellulose, carrageen, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimelliate, chitin, corn protein extract, ethyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid-ethyl methacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetate phthalate, polivinyl alcohol, shellac, sodium alginate, starch acetate phthalate, styrene/maleic acid copolymer and mixtures of said film-forming polymers. 
     
     
         4 . The process of  claim 1  wherein the plasticizer is selected from the group consisting of: saturated linear monohydric alcohols having 12 to 30 carbon atoms, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol, behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol, melissyl alcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acid esters of glycerol, glycerol, polyethylene glycol, propyleneglycol, sorbitan fatty acids, triacetin, triethyl citrate and mixtures of any of said plasticizers. 
     
     
         5 . The process of  claim 1  wherein the plasticizer is cetyl alcohol. 
     
     
         6 . The process of  claim 1  wherein the plasticizer is triethyl citrate present in an amount of between about 5% and about 20% by weight relative to the film-forming agent. 
     
     
         7 . The process of  claim 1  wherein the plasticizer is comprised of cetyl alcohol and triethyl citrate which are collectively present in an amount greater than about 3% by weight relative to the film-forming agent. 
     
     
         8 . The process of  claim 1  wherein the plasticizer is comprised of cetyl alcohol and triethyl citrate which are collectively present in an amount between about 4% and about 20% by weight relative to the film-forming agent. 
     
     
         9 . The process of  claim 8  wherein the ratio of cetyl alcohol to triethyl citrate is between about 0.05:1 and about 1:1 by weight. 
     
     
         10 . The process of  claim 1  wherein the anti-sticking agent is selected from the group consisting of: dimethicone and castor oil. 
     
     
         11 . The process of  claim 1  wherein the anti-sticking agent is present in an amount between about 1.5% and about 3% by weight relative to the film-forming agent. 
     
     
         12 . The process of  claim 1  wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 
     
     
         13 . A method of treating a medical condition in a mammalian subject, comprising the steps of:
 a. providing pancreatin micropellets manufactured according to the process of  claim 1  in a dosage form suitable for oral administration; and   b. orally administering the dosage form to the subject to provide pancreatin in an amount sufficient to treat the medical condition;   wherein the medical condition is selected from the group consisting of: pancreatic exocrine insufficiency, pancreatitis, cystic fibrosis, diabetes type I and diabetes type II.   
     
     
         14 . A pharmaceutical composition, comprising
 a. a pharmacologically effective amount of pancreatin wherein said pancreatin is in the form of pancreatin micropellets manufactured according to the process of  claim 1 ; and   b. a dosage form suitable for oral administration containing said pharmacologically effective amount of pancreatin.   
     
     
         15 . A pharmaceutical composition, prepared by a process comprising the steps of:
 a. preparing an extrudable mixture comprising:
 i. about 10% to about 95% pancreatin; 
 ii. about 5% to about 90% of at least one pharmaceutically acceptable binding agent; 
 iii. 0% to about 10% of at least one pharmaceutically acceptable excipient; and 
 iv. one or more enzyme-friendly organic solvents in an amount sufficient to form an extrudable mixture; 
 wherein the percentages of components are weight to weight of the extrudable mixture; 
   b. creating pancreatin micropellet cores from the extrudable mixture;   c. forming the pancreatin micropellet cores into approximately spherical or approximately ellipsoidal shape in the presence of additional enzyme-friendly organic solvent;   d. removing the one or more enzyme-friendly organic solvents from the pancreatin micropellet cores such that the pancreatin micropellet cores are substantially free of the one or more enzyme-friendly organic solvents;   wherein the pancreatin micropellet cores are substantially free of synthetic oils;   e. coating the pancreatin micropellet cores with an enteric-coating solution wherein the temperature of the pancreatin micropellet cores during coating is kept at a temperature suitable to apply the enteric-coating solution and wherein the enteric-coating solution is substantially free of monomeric phthalic acid esters;   f. drying the coated pancreatin micropellet cores; and   g. placing the coated pancreatin micropellet cores in a dosage form suitable for oral administration.   
     
     
         16 . The process of  claim 15  wherein the pancreatin is present between about 70% and about 90% weight to weight of the pancreatin micropellet cores. 
     
     
         17 . The process of  claim 15  wherein the binding agent is present between about 10% and about 30% weight to weight of the pancreatin micropellet cores. 
     
     
         18 . The process of  claim 15  wherein the binding agent is selected from the group consisting of: polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, hydroxypropyl methylcellulose, polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen and mixtures of said organic polymers. 
     
     
         19 . The process of  claim 15  wherein the binding agent is polyethylene glycol 4000. 
     
     
         20 . The process of  claim 15  wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of: magnesium stearate, calcium stearate, stearic acid, talcum, starch, calcium phosphate, corn starch, dextrans, dextrin, hydrated silicon dioxide, microcrystalline cellulose, kaolin, lactose, mannitol, polyvinyl pyrrolidone, precipitated calcium carbonate, sorbitol, silicic acid, alginic acid, amylose, calcium alginate, calcium carbonate, formaldehyde gelatin, pectic carbonate, sago starch, sodium bicarbonate and glycerol. 
     
     
         21 . The process of  claim 15  wherein the one or more enzyme-friendly organic solvents are present between about 15% and about 35% by weight relative to the amount of pancreatin. 
     
     
         22 . The process of  claim 15  wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 
     
     
         23 . The process of  claim 15  wherein the one or more enzyme-friendly organic solvents is 2-propanol. 
     
     
         24 . The process of  claim 15  wherein removing the one or more enzyme-friendly organic solvents from the pancreatin micropellet cores is by drying at a temperature between about 30° C. and about 75° C. 
     
     
         25 . A pharmaceutical composition, prepared by a process comprising the steps of:
 a. providing pancreatin micropellet cores wherein the pancreatin micropellet cores are substantially free of synthetic oils;   b. providing an enteric-coating solution comprising
 i. at least one film-forming agent 
 ii. a plasticizer in an amount of greater than about 1.5% by weight relative to the one or more film-forming agents film-forming agents wherein the plasticizer is substantially free of monomeric phthalic acid esters; and 
 iii. optionally at least one anti-sticking agent in one or more enzyme-friendly organic solvent; 
   c. coating the pancreatin micropellet cores with the enteric-coating solution wherein the temperature of the pancreatin micropellet cores during coating is kept at a temperature suitable to apply the enteric-coating solution; and   d. drying the coated pancreatin micropellet cores; and   e. placing the coated pancreatin micropellet cores in a dosage form suitable for oral administration.   
     
     
         26 . The composition of  claim 25  wherein the enteric coating is between about 20% and about 30% by weight of the pancreatin micropellets. 
     
     
         27 . The composition of  claim 25  wherein the one or more film-forming agents is selected from the group consisting of: agar, carbomer polymers, carboxymethyl cellulose, carboxymethylethyl cellulose, carrageen, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimelliate, chitin, corn protein extract, ethyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid-ethyl methacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetate phthalate, polivinyl alcohol, shellac, sodium alginate, starch acetate phthalate, styrene/maleic acid copolymer and mixtures of said film-forming polymers. 
     
     
         28 . The composition of  claim 25  wherein the plasticizer is selected from the group consisting of: saturated linear monohydric alcohols having 12 to 30 carbon atoms, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol, behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol, melissyl alcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acid esters of glycerol, glycerol, polyethylene glycol, propyleneglycol, sorbitan fatty acids, triacetin, triethyl citrate and mixtures of any of said plasticizers. 
     
     
         29 . The composition of  claim 25  wherein the plasticizer is cetyl alcohol. 
     
     
         30 . The composition of  claim 25  wherein the plasticizer is triethyl citrate present in an amount of between about 5% and about 20% by weight relative to the film-forming agent. 
     
     
         31 . The composition of  claim 25  wherein the plasticizer is a mixture of cetyl alcohol and triethyl citrate which are collectively present in an amount of greater than about 3% by weight relative to the film-forming agent. 
     
     
         32 . The composition of  claim 31  wherein the ratio of cetyl alcohol to triethyl citrate is between about 0.05:1 and about 1:1 by weight. 
     
     
         33 . The composition of  claim 25  wherein the anti-sticking agent is selected from the group consisting of: dimethicone and castor oil. 
     
     
         34 . The composition of  claim 25  wherein the anti-sticking agent is present in an amount between about 1.5% and about 3% by weight relative to the film-forming agent. 
     
     
         35 . The composition of  claim 25  wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 
     
     
         36 . A pharmaceutical composition comprising:
 enteric-coated pancreatin micropellets having a gastric acid resistance of about 75% or more at about pH 1 wherein the pancreatin micropellets are substantially free of both synthetic oils and monomeric phthalic acid esters.   
     
     
         37 . A pharmaceutical composition comprising:
 enteric-coated pancreatin micropellets having a gastric acid resistance of about 75% or more at about pH 5 wherein the pancreatin micropellets are substantially free of both synthetic oils and monomeric phthalic acid esters.   
     
     
         38 . A pharmaceutical composition comprising:
 a. pancreatin micropellet cores wherein the pancreatin micropellet cores are substantially free of synthetic oils;   b. at least one film-forming agent;   c. a plasticizer in an amount greater than about 1.5% by weight relative to the one or more film-forming agents wherein the enteric coating is substantially free of monomeric phthalic acid esters; and   d. optionally at least one anti-sticking agent in one or more enzyme-friendly organic solvent.   
     
     
         39 . A composition comprising enteric coated pancreatin micropellets wherein the percent lipase activity present in a phosphate buffer solution is greater than 0% after 10 minutes, greater than about 30% after 20 minutes, greater than about 50% after 30 minutes and greater than about 65% after 60 minutes as measured according to the United States Pharmacopoeia using a phosphate buffer solution at pH 6 wherein pancreatin micropellets are substantially free of synthetic oils. 
     
     
         40 . A composition comprising enteric coated pancreatin micropellets wherein the percent lipase activity present in a phosphate buffer solution is greater than 0.1% after 10 minutes, greater than about 15% after 20 minutes, greater than about 45% after 30 minutes and greater than about 65% after 60 minutes as measured according to the United States Pharmacopoeia but using a Mcllvain buffer solution at pH 6 wherein the pancreatin micropellets are substantially free of synthetic oils. 
     
     
         41 . A composition comprising enteric-coated pancreatin micropellets having a lipase activity of greater than about 75% after five months in an environment of about 30° C. and about 65% relative humidity wherein the pancreatin micropellets are substantially free of synthetic oils. 
     
     
         42 . A pharmaceutical composition comprising:
 enteric-coated pancreatin micropellets having a gastric acid resistance of about 75% or more at about pH 1 after five months in an environment of about 30° C. and about 65% relative humidity wherein the pancreatin micropellets are substantially free of synthetic oils.   
     
     
         43 . A pharmaceutical composition comprising:
 enteric-coated pancreatin micropellets having a gastric acid resistance of about 75% or more at about pH 5 after five months in an environment of about 30° C. and about 65% relative humidity wherein the pancreatin micropellets are substantially free of synthetic oils.   
     
     
         44 . A pharmaceutical composition, prepared by a process comprising the steps of:
 a. preparing an extrudable mixture comprising:
 i. about 10% to about 95% of an acid labile active pharmaceutical ingredient; 
 ii. about 5% to about 90% of at least one pharmaceutically acceptable binding agent; 
 iii. 0% to about 10% of at least one pharmaceutically acceptable excipient; and 
 iv. one or more enzyme-friendly organic solvents in an amount sufficient to form an extrudable mixture; 
 wherein the percentages of components are weight to weight of the extrudable mixture; 
   b. creating micropellet cores from the extrudable mixture;   c. forming the micropellet cores into approximately spherical or approximately ellipsoidal shape in the presence of additional enzyme-friendly organic solvent;   d. removing the one or more enzyme-friendly organic solvents from the micropellet cores such that the micropellet cores are substantially free of the one or more enzyme-friendly organic solvents;   wherein the micropellet cores are substantially free of synthetic oils;   e. coating the micropellet cores with an enteric-coating solution wherein the temperature of the micropellet cores during coating is kept at a temperature suitable to apply the enteric-coating solution and wherein the enteric-coating solution is substantially free of monomeric phthalic acid esters;   f. drying the coated micropellet cores; and   g. placing the coated micropellet cores in a dosage form suitable for oral administration.   
     
     
         45 . A pharmaceutical composition comprising pancreatin
 wherein the pharmaceutical composition has a dissolution profile with a similarity factor (f 2 ) greater than 50 when compared to the dissolution profile of composition G in Table 1;   wherein f 2  is determined by the formula:
     f   2 =50 log{[1+1/ nΣ   n   t=1 ( R   t   −T   t ) 2 ] −0.5 *100}. 
   
     
     
         46 . A pharmaceutical composition comprising pancreatin
 wherein the pharmaceutical composition has a dissolution profile with a similarity factor (f 2 ) greater than 50 when compared to the dissolution profile of composition 13 in Table 1;   wherein f 2  is determined by the formula:
     f   2 =50 log{[1+1/ nΣ   n   t=1 ( R   t   −T   t ) 2 ] −0.5 *100}.