Stable low digestive enzyme content formulation
The present invention is directed to a pharmaceutical composition or dosage form having a stable, low (diluted) digestive enzyme content comprising at least one digestive enzyme and at least one carrier, or a dosage form thereof. The invention is also directed to a process of preparation of the composition or the dosage form. In addition the invention is directed to the treatment and prevention of disorders or conditions associated with a digestive enzyme deficiency in a patient in need thereof, comprising administering to said patient a pharmaceutically acceptable amount of the composition having a stable low digestive enzyme content or dosage form thereof.
1. A process for the preparation of a pharmaceutical composition comprising a blend of at least one digestive enzyme and at least one carrier, the process comprising the following steps:
a) mixing the at least one digestive enzyme and the at least one carrier, and optional further excipients;
b) compressing the mixture into beads; and
c) optionally coating the beads with an enteric polymer,
wherein a total amount of the at least one digestive enzyme in the pharmaceutical composition is from 4% to 19% by weight, and the at least one carrier comprises microcrystalline cellulose having an average particle size greater than 100 μm.
2. The process of claim 1 , wherein the process comprises step c).
3. The process of claim 1 , wherein the steps are carried out in a low moisture environment and the moisture of the carrier or carriers is equal to or less than 5%.
4. The process of claim 2 , wherein the at least one digestive enzyme is in the form of enterically coated pancrelipase beads.
5. The process of claim 4 , wherein the total amount of the at least one digestive enzyme in the pharmaceutical composition is from 10% to 15% by weight.
6. The process of claim 4 , wherein the enterically coated pancrelipase beads comprise from 4 wt. % to 19 wt. % of pancrepliase based on a total weight of uncoated beads and from 70 wt. % to 96 wt. % of the at least one carrier based on the total weight of the uncoated beads.
7. The process of claim 4 , wherein the enterically coated pancreplipase beads comprise from 10 wt. % to 15 wt. % of pancrelipase based on a total weight of uncoated beads and from 75 wt. % to 90 wt. % of the at least one carrier based on the total weight of the uncoated beads.
8. The process of claim 4 , wherein the enterically coated pancrelipase beads comprise from 10 wt. % to 15 wt. % of pancrelipase based on a total weight of uncoated beads and from 80 wt. % to 85 wt. % of the at least one carrier based on the total weight of the uncoated beads.
9. The process of claim 4 , wherein the enterically coated pancrelipase beads comprise 15 wt. % of pancrelipase based on a total weight of uncoated beads, 80 wt. % of the at least one carrier based on the total weight of the uncoated beads, and 5 wt. % of further excipients based on the total weight of the uncoated beads.
10. The process of claim 4 , wherein the enterically coated pancrelipase beads comprise 10 wt. % of pancrelipase based on a total weight of uncoated beads, 85 wt. % of the at least one carrier based on the total weight of the uncoated beads, and 5 wt. % of further excipients, based on the total weight of the uncoated beads.
11. The process of claim 1 , wherein the at least one carrier comprises the microcrystalline cellulose having a moisture content equal to or less than 5%, a nominal mean particle size of 160 μm, mesh size 38: amount retained: S 1.0%, mesh size 94: amount retained: S 50.0%, and mesh size 300: amount retained: S 70.0%.
12. The process of claim 1 , wherein the at least one carrier comprises the microcrystalline cellulose having a moisture content equal to or less than 5%, a nominal mean particle size of 180 μm, mesh size 60: amount retained: S 10.0%, and mesh size 100: amount retained: S 50.0%.
13. The process of claim 1 , wherein the at least one carrier comprises a first microcrystalline cellulose having a moisture content equal to or less than 5%, a nominal mean particle size of 160 μm, mesh size 38: amount retained: S 1.0%, mesh size 94: amount retained: S 50.0%, and mesh size 300: amount retained: S 70.0%, and a second microcrystalline cellulose having a moisture content equal to or less than 5%, a nominal mean particle size of 50 μm, mesh size 60: amount retained: S 1.0%, and mesh size 200: amount retained: S30.0%, and a weight ratio of the first and second microcrystalline cellulose is 16:1.
14. The process of claim 1 , wherein the at least one carrier comprises a mixture of the microcrystalline cellulose and trehalose.
15. The process of claim 13 , wherein the at least one carrier comprises the microcrystalline cellulose having a moisture content equal to or less than 5%, a nominal mean particle size of 160 μm, mesh size 38: amount retained: S 1.0%, a mesh size 94: amount retained: S 50.0%, and mesh size 300: amount retained: S 70.0% and trehalose, and a weight ratio of the microcrystalline cellulose and the trehalose is 1:1.
16. The process of claim 14 , wherein the at least one carrier comprises the microcrystalline cellulose having a moisture content equal to or less than 5%, a nominal mean particle size of 180 μm, mesh size 60: amount retained: S 10.0%, mesh size 100; amount retained: S 50.0%, and trehalose, and a weight ratio of the microcrystalline cellulose and the trehalose is 1:1.
17. A process for the preparation of a dosage form comprising a pharmaceutical composition comprising a blend of at least one digestive enzyme and at least one carrier, the process comprising the following steps:
a) mixing the at least one digestive enzyme and the at least one carrier, and optional further excipients;
b) compressing the mixture into beads;
c) optionally coating the beads with an enteric polymer; and
d) preparing the dosage form with the optionally coated beads,
wherein a total amount of the at least one digestive enzyme in the pharmaceutical composition is from 4% to 19% by weight, and the at least one carrier comprises microcrystalline cellulose having an average particle size greater than 100 μm.
18. The process of claim 17 , wherein the dosage form is a capsule.
19. The process of claim 18 , wherein the at least one digestive enzyme is lipase from 500 to 5,000 USP units.
20. The process of claim 19 , wherein the at least one digestive enzyme is lipase from 675 to 825 USP units.
21. The process of claim 19 , wherein the at least one digestive enzyme is lipase from 675 to 825 USP units, protease from 1,250 to 3,850 USP units, and amylase from 1,600 to 6,575 USP units.
22. The process of claim 17 , wherein the dosage form is a capsule having a residual moisture content below 5%.
23. The process of claim 17 , wherein the process further comprises step e) packaging the dosage form.