High buffer-containing enteric coating digestive enzyme bile acid compositions and method of treating digestive disorders therewith

• US 5,750,104 A
• Filed: 05/29/1996
• Issued: 05/12/1998
• Est. Priority Date: 05/29/1996
• Status: Expired due to Term

• Current Assignee: Digestive Care, Inc.
• Original Assignee: Digestive Care, Inc.
• Inventors: Sipos, Tibor
• Primary Examiner(s): Kulkosky, Peter F.
• Application Number:
  US08/654,900
• Time in Patent Office: 713 Days
• Field of Search: 424/94.21
• US Class Current: 424/94.21
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/465 acting on ester bonds (3.1), e.g. lipases, ribonucleases
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 38/48 acting on peptide bonds (3.4)
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Abstract

Disclosed are gastric acid-resistant polymer-coated buffered digestive enzymes/bile acid compositions, process for their preparations and methods of treating digestive disorders and cystic fibrosis by administering said compositions to a mammal in need of such treatment.

Claims

1. In an improved buffered digestive enzyme composition in the form of microencapsulated particles having a diameter of from about 10 mesh to about 40 mesh for the treatment of digestive enzyme/buffer deficiency of a mammal comprising:

a) from about 10 to about 70% w/w of an enzyme selected from the group consisting of pancreatic proteases, lipases, nucleases and amylases;

b) from about 0.5 to about 16% of a disintegrant selected from the group consisting of ursodiol, starch, modified starches, microcrystalline cellulose and propylene glycol alginate;

c) from about 1 to about 19% w/w of an adhesive polymer selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, cellulose acetate phthalate, ethyl cellulose and hydroxypropylmethyl cellulose; and

d) from about 7.0 to about 25% w/w of an non-porous, gastric acid-resistant and pharmaceutically acceptable polymer-coating which contains less than 2% talc and which is insoluble in the pH range of from about 1.5 to about 5 but is soluble in the pH range of from about 5.5 to about 9, said polymer-coating comprises a polymer selected from the group consisting of hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, diethyl phthalate, dibutyl phthalate, an enteric coating polymeric dispersion, and an acrylic based polymeric dispersion,

the improvement consisting essentially of;

from about 45 to 60% w/w of a buffering agent selected from the group consisting of;

anhydrous sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, tromethamine, di(tris(hydroxymethyl)amino-methane)carbonate, tris-glycine, di-arginine, tri-arginine, poly-arginine, di-lysine, tri-lysine, poly-lysine, diethylamine and triethanolamine, said buffering agent providing a pH of from 7 to 9 in the small intestine of said mammal, and said lipase having an activity of from 24% to 100% at said pH of from 7 to 9.

2. In an improved buffered digestive enzyme-bile acid composition in the form of microencapsulated particles having a diameter of from about 10 mesh to about 40 mesh for the treatment of digestive enzyme-bile acid-buffer deficiency of a mammal comprising:

a) from about 10 to about 70% w/w of a pancreatic enzyme selected from the group consisting of pancreatic proteases, lipases, nucleases and amylases;

b) from about 0.1 to about 15% w/w of a micropulverized, buffered bile acid in powder form, said buffer/bile acid forming a mixture of a 1 to 1 neutralization equivalent ratio, said buffer is selected from the group consisting of anhydrous sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, tromethamine, di(tris(hydroxymethyl)amino-methane)carbonate, tris-glycine, di-arginine, tri-arginine, poly-arginine, di-lysine, tri-lysine, poly-lysine, diethylamine and triethanolamine;

c) from about 0.5 to about 16% w/w of a disintegrant selected from the group consisting of ursodiol, starch, modified starches, microcrystalline cellulose and propylene glycol alginate;

d) from about 1 to about 19% w/w of an adhesive polymer selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, cellulose acetate phthalate, ethyl cellulose and hydroxypropylmethyl cellulose; and

e) from about 7.0 to about 25% w/w of an non-porous, gastric acid-resistant and pharmaceutically acceptable polymer-coating which contains less than 2% talc and which is insoluble in the pH range of from about 1.5 to about 5 but is soluble in the pH range of from about 5.5 to about 9, said polymer-coating comprises a polymer selected from the group consisting of hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, diethyl phthalate, dibutyl phthalate, an enteric coating polymeric dispersion, and an acrylic based polymeric dispersion;

the improvement consisting essentially of;

from about 45 to 60% w/w of a buffering agent selected from the group consisting of anhydrous sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, tromethamine, di(tris(hydroxymethyl)aminomethane)carbonate, tris-glycine, di-arginine, tri-arginine, poly-arginine, di-lysine, tri-lysine, poly-lysine, diethylamine and triethanolamine, said buffering agent providing a pH of from 7 to 9 in the small intestine of said mammal, and said lipase having an activity of from 24% to 100% at said pH of from 7 to 9.

3. The improved buffered digestive enzyme-bile acid composition of claim 2 wherein 0.25 to 10% w/w of said micropulverized, buffered bile acid is present in the composition.

4. In an improved method for treating digestive enzyme, bile acid and buffer deficiency in a mammal comprising orally administering an effective amount of a composition comprising:

a) from about 10 to about 70% w/w of a concentrate of an enzyme selected from the group consisting of pancreatic proteases, lipases, nucleases and amylases;

b) from about 0.5 to about 16% of a disintegrant selected from the group consisting of ursodiol, starch, modified starches, microcrystalline cellulose and propylene glycol alginate;

c) from about 1 to about 19% w/w of an adhesive polymer selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, cellulose acetate phthalate, ethyl cellulose and hydroxypropylmethyl cellulose; and

d) from about 7.0 to about 25% w/w of an non-porous, gastric acid-resistant and pharmaceutically acceptable polymer-coating which contains less than 2% talc and which is insoluble in the pH range of from about 1.5 to about 5 but is soluble in the pH range of from about 5.5 to about 9, said polymer-coating comprises a polymer selected from the group consisting of hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, diethyl phthalate, dibutyl phthalate, an enteric coating polymeric dispersion, and an acrylic based polymeric dispersion;

the improvement consisting essentially of;

from about 45 to 60% w/w of a buffering agent selected from the group consisting of;

anhydrous sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, tromethamine, di(tris(hydroxymethyl)aminomethane)carbonate, tris-glycine, di-arginine, tri-arginine, poly-arginine, di-lysine, tri-lysine, poly-lysine, diethylamine and triethanolamine, said buffering agent providing a pH of from 7 to 9 in the small intestine of said mammal, and said lipase having an activity of from 24% to 100% at said pH of from 7 to 9.

5. The improved method of claim 4 wherein said digestive enzyme, bile acid and buffer deficiency treatment is to reduce or modify conditions in a mammal selected from the group consisting of:

digestive enzyme deficiency, digestive disorders, impaired liver function, cystic fibrosis and presence of gallstones.