Compositions of digestive enzymes and salts of bile acids and process for preparation thereof

• US 5,578,304 A
• Filed: 05/04/1995
• Issued: 11/26/1996
• Est. Priority Date: 06/22/1992
• Status: Expired due to Term

• Current Assignee: Digestive Care, Inc.
• Original Assignee: Digestive Care, Inc.
• Inventors: Sipos, Tibor
• Primary Examiner(s): NOT, DEFINED
• Assistant Examiner(s): Larson, Kristin
• Application Number:
  US08/434,953
• Time in Patent Office: 572 Days
• Field of Search: 424/94.1, 424/94.2, 424/94.6, 424/94.64, 424/480, 424/490, 424/497, 424/94.65, 424/94.63, 424/94.3, 435/213
• US Class Current: 424/94.1
• 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 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 38/46 Hydrolases (3)
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1605 Excipients; Inactive ingredients
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings

Abstract

Disclosed are gastric acid-resistant polymer-coated, buffered digestive enzymes/ursodeoxycholate compositions, process for their preparations and methods for treating digestive disorders, pancreatic enzyme insufficiency, impaired liver function, and cystic fibrosis for regulating the absorption of dietary iron and cholesterol, and for dissolving gallstones by administering the compositions to a mammal in need of such treatment.

Claims

1. A buffered digestive enzyme/bile salt composition for the treatment of digestive enzyme/bile salt deficiency of mammals comprising, by weight per weight percentages based on the total weight of the composition:

a) from about 10 to about 90.0% of a concentrate of an enzyme selected from the group consisting of pancreatic proteases, pancreatic lipases, pancreatic nucleases and pancreatic amylases;

b) from about 0.3 to about 75% of a bile salt in powder form;

c) from about 7.35 to about 40.50% of a buffering agent selected from the group consisting of anhydrous sodium carbonate, sodium bicarbonate, potassium carbonate, ammonium carbonate, tromethamine, di(tris(hydoxymethyl)aminomethane) carbonate, tris-glycine, di-arginine in the molecular weight range of 350 to 50,000 daltons, tri-arginine in the molecular weight range of 350 to 50,000 daltons, poly-arginine in the molecular weight range of 350 to 50,000 daltons, di-lysine in the molecular weight range of 290 to 15,000 daltons, tri-lysine in the molecular weight range of 290 to 15,000 daltons, poly-lysine in the molecular weight range of 290 to 15,000 daltons, diethylamine and triethanolamine;

d) from about 0.9 to about 16% of a disintegrant selected from the group consisting of starch, modified starches, microcrystalline cellulose and propylene glycol alginate;

e) from about 0.3 to about 15.0% of an adhesive polymer selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, cellulose acetate phthalate, methyl cellulose and propylene glycol alginate; and

f) from about 7.0 to about 15% of an non-porous, gastric acid-resistant and pharmaceutically acceptable polymer-coating which contains from about 0.2 to about 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.

2. The composition of claim 1 wherein said bile salt is selected from the group consisting of:

sodium-ursodeoxycholate, sodium glycylursodeoxycholate,

potassium-ursodeoxycholate, potassium glycylursodeoxycholate,

ferrous-ursodeoxycholate, ferrous glycylursodeoxycholate,

ammonium-ursodeoxycholate, ammonium glycylursodeoxycholate,

sodium-tauroursodeoxycholate, sodium-N-methylglycylursodeoxycholate,

potassium-tauroursodeoxycholate, potassium-N-methyglycylursodeoxy-cholate,

ferrous-tauroursodeoxycholate, ferrous-N-methyglycylursodeoxycholate,

ammonium-tauroursodeoxycholate, ammonium-N-methyglycylursodeoxycholate,

sodium-N-methyltauroursodeoxycholate,

potassium-N-methyltauroursodeoxycholate,

ferrous-N-methyltauroursodeoxycholate,

ammonium-N-methyltauroursodeoxycholate,

sodium-cholate, sodium-deoxycholate,

potassium-cholate, potassium-deoxycholate,

ferrous-cholate, ferrous-deoxycholate,

ammonium-cholate, ammonium-deoxycholate,

sodium-chenodeoxycholate, sodium-glycylcholate,

potassium-chenodeoxycholate, potassium-glycylcholate,

ferrous-chenodeoxycholate, ferrous-glycylcholate

ammonium-chenodeoxycholate, ammonium-glycylcholate,

sodium-taurocholate, sodium-N-methylglycylcholate,

potassium-taurocholate, potassium-N-methylglycylcholate,

ferrous-taurocholate, ferrous-N-methylglycylcholate,

ammonium-taurocholate, ammonium-N-methylglycylcholate,

sodium-N-methyltaurocholate, sodium-glycyldeoxycholate,

potassium-N-methyltaurocholate, potassium-glycyldeoxycholate,

ferrous-N-methyltaurocholate, ferrous-glycyldeoxycholate,

ammonium-N-methyltaurocholate, ammonium-glycyldeoxycholate,

sodium-taurodeoxycholate, sodium-N-methylglycyldeoxycholate,

potassium-taurodeoxycholate, potassium-N-methylglycyldeoxycholate,

ferrous-taurodeoxycholate, ferrous-N-methyl glycyldeoxycholate,

ammonium-taurodeoxycholate, ammonium-N-methylglycyldeoxycholate,

sodium-N-methyltaurodeoxycholate, sodum-N-methylglycylchenodeoxycholate,

potassium-N-methyltaurodeoxycholate, potassium-N-methylglycylchenodeoxycholate,

ferrous-N-methyltaurodeoxycholate, ferrous-N-methylglycylchenodeoxycholate,

ammonium-N-methyltaurodeoxycholate, ammonium-N-methylglycylchenodeoxycholate,

sodium-N-methyltaurochenodeoxycholate,

potassium-N-methyltaurochenodeoxycholate,

ferrous-N-methyltaurochenodeoxycholate,

ammonium-N-methyltaurochenodeoxycholate, ethyl esters of

ursodeoxycholate, propyl esters of ursodeoxycholate,

sodium-glycylchenodeoxycholate,

potassium-glycylchenodeoxycholate,

ferrous-glycylchenodeoxycholate,

ammonium-glycylchenodeoxycholate,

sodium-taurochenodeoxycholate,

potassium-taurochenodeoxycholate,

ferrous-taurochenodeoxycholate, and

ammonium-taurochenodeoxycholate.

3. A method for treating a digestive enzyme/bile salt deficiency in mammals comprising:

orally administering to a mammal in need thereof an effective amount of the composition of claim 1, wherein said effective amount is sufficient to reduce the digestive enzyme/bile salt deficiency.

4. The method of claim 3 wherein said treatment reduces a digestive enzyme/bile salt deficiency present when the mammal has impaired liver function, absorbs dietary iron insufficiently, absorbs cholesterol insufficiently, has cystic fibrosis, or has gallstones.

5. The method of claim 3 wherein about 0.5 to 1.5 gms of the composition is administered to a digestive enzyme/bile salt deficient patient with each meal three times a day.

6. The method of claim 3 wherein said composition is administered in an acid soluble capsule containing from about 0.2 to about 0.5 grams of microspheres or microtablets.

7. The method of claim 3 wherein said treatment reduces a digestive enzyme/bile salt deficiency in digestive disorders.

8. A buffered digestive enzyme/bile salt composition for the treatment of digestive enzyme/bile salt deficiency of mammals comprising by weight per weight percentages based on the total weight of the composition:

a) from about 10 to about 90.0% of a concentrate of an enzyme selected from the group consisting of pancreatic proteases, pancreatic lipases, pancreatic nucleases and pancreatic amylases;

b) from about 0.3 to about 75% of a bile salt in powder form;

c) from about 5.10 to about 7.25% of a buffering agent selected from the group consisting of anhydrous sodium carbonate, sodium bicarbonate, potassium carbonate, ammonium carbonate, tromethamine di(tris(hydoxymethyl)aminomethane) carbonate, tris-glycine, di-arginine in the molecular weight range of 350 to 50,000 daltons, tri-arginine in the molecular weight range of 350 to 50,000 daltons, poly-arginine in the molecular weight range of 350 to 50,000 daltons, di-lysine in the molecular weight range of 290 to 15,000 daltons, tri-lysine in the molecular weight range of 290 to 15,000 daltons, poly-lysine in the molecular weight range of 290 to 15,000 daltons, diethylamine and triethanolamine;

d) from about 0.9 to about 16% of a disintegrant selected from the group consisting of starch, modified starches, microcrystalline cellulose and propylene glycol alginate;

e) from about 0.3 to about 15.0% of an adhesive polymer selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, cellulose acetate phthalate, methylcellulose and propyleneglycol alginate; and

f) from about 7.0 to about 15% of an non-porous, gastric acid-resistant and pharmaceutically acceptable polymer-coating which contains from about 0.2 to about 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.

9. The composition of claim 8 wherein said bile salt is selected from the group consisting of:

sodium-ursodeoxycholate, sodium glycylursodeoxycholate,

potassium-ursodeoxycholate, potassium glycylursodeoxycholate,

ferrous-ursodeoxycholate, ferrous glycylursodeoxycholate,

ammonium-ursodeoxycholate, ammonium glycylursodeoxycholate,

sodium-tauroursodeoxycholate, sodium-N-methylglycylursodeoxycholate,

potassium-tauroursodeoxycholate, potassium-N-methyglycylursodeoxy-cholate,

ferrous-tauroursodeoxycholate, ferrous-N-methyglycylursodeoxycholate,

ammonium-tauroursodeoxycholate, ammonium-N-methyglycylursodeoxycholate,

sodium-N-methyltauroursodeoxycholate,

potassium-N-methyltauroursodeoxycholate,

ferrous-N-methyltauroursodeoxycholate,

ammonium-N-methyltauroursodeoxycholate,

sodium-cholate, sodium-deoxycholate,

potassium-cholate, potassium-deoxycholate,

ferrous-cholate, ferrous-deoxycholate,

ammonium-cholate, ammonium-deoxycholate,

sodium-chenodeoxycholate, sodium-glycylcholate,

potassium-chenodeoxycholate, potassium-glycylcholate,

ferrous-chenodeoxycholate, ferrous-glycylcholate

ammonium-chenodeoxycholate, ammonium-glycylcholate,

sodium-taurocholate, sodium-N-methylglycylcholate,

potassium-taurocholate, potassium-N-methylglycylcholate,

ferrous-taurocholate, ferrous-N-methylglycylcholate,

ammonium-taurocholate, ammonium-N-methylglycylcholate,

sodium-N-methyltaurocholate, sodium-glycyldeoxycholate,

potassium-N-methyltaurocholate, potassium-glycyldeoxycholate,

ferrous-N-methyltaurocholate, ferrous-glycyldeoxycholate,

ammonium-N-methyltaurocholate, ammonium-glycyldeoxycholate,

sodium-taurodeoxycholate, sodium-N-methylglycyldeoxycholate,

potassium-taurodeoxycholate, potassium-N-methylglycyldeoxycholate,

ferrous-taurodeoxycholate, ferrous-N-methylglycyldeoxycholate,

ammonium-taurodeoxycholate, ammonium-N-methylglycyldeoxycholate,

sodium-N-methyltaurodeoxycholate, sodum-N-methylglycylchenodeoxycholate,

potassium-N-methyltaurodeoxycholate, potassium-N-methylglycylchenodeoxycholate,

ferrous-N-methyltaurodeoxycholate, ferrous-N-methylglycylchenodeoxycholate,

ammonium-N-methyltaurodeoxycholate, ammonium-N-methylglycylchenodeoxycholate,

sodium-N-methyltaurochenodeoxycholate,

potassium-N-methyltaurochenodeoxycholate,

ferrous-N-methyltaurochenodeoxycholate,

ammonium-N-methyltaurochenodeoxycholate, ethyl esters of

ursodeoxycholate, propyl esters of ursodeoxycholate,

sodium-glycylchenodeoxycholate,

potassium-glycylchenodeoxycholate,

ferrous-glycylchenodeoxycholate,

ammonium-glycylchenodeoxycholate,

sodium-taurochenodeoxycholate,

potassium-taurochenodeoxycholate,

ferrous-taurochenodeoxycholate, and

ammonium-taurochenodeoxycholate.

10. A method for treating a digestive enzyme/bile salt, deficiency in mammals comprising:

orally administering to a mammal in need thereof an effective amount of the composition of claim 8, wherein said effective amount is sufficient to reduce the digestive enzyme/bile salt deficiency.

11. The method of claim 10 wherein said treatment reduces a digestive enzyme/bile salt deficiency present when the mammal has impaired liver function, absorbs dietary iron insufficiently, absorbs cholesterol insufficiently, has cystic fibrosis, or gallstones.

12. The method of claim 10 wherein about 0.5 to 1.5 gms of the composition is administered to a digestive enzyme/bile salt deficient patient with each meal three times a day.

13. The method of claim 10 wherein said composition is administered in an acid soluble capsule containing from about 0.2 to about 0.5 grams of microspheres or microtablets.

14. The method of claim 10 wherein said treatment reduces a digestive enzyme/bile salt deficiency in digestive disorders.