Sustained-release theophylline formulation

• US 4,803,080 A
• Filed: 12/20/1985
• Issued: 02/07/1989
• Est. Priority Date: 12/21/1984
• Status: Expired due to Fees

• Current Assignee: BYK Gulden Lomberg Chemische Fabrik GMBH (Takeda Pharmaceutical Company Limited)
• Original Assignee: BYK Gulden Lomberg Chemische Fabrik GMBH (Takeda Pharmaceutical Company Limited)
• Inventors: Steinijans, Volker, Benedikt, Gerald
• Primary Examiner(s): LUSIGNAN, MICHAEL R
• Application Number:
  US06/811,742
• Time in Patent Office: 1,145 Days
• Field of Search: 424/458, 424/459, 424/461, 424/462, 424/490, 424/494, 424/495, 424/497, 424/475, 424/480, 424/486, 424/488, 514/263, 427/3
• US Class Current: 424/488
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077

Abstract

A sustained-release theophylline formulation, which comprises matrix pellets in which theophylline particles are embedded in a matrix of water-insoluble plastic and which are enclosed by a membrane of water-insoluble plastic containing embedded particles of lactose, produces and maintains plasma theophylline levels within the therapeutic range.

Claims

1. A pharmacologically-acceptable sustained-release theophylline formulation, which comprises matrix pellets in which theophylline particles are embedded in a matrix of water-insoluble plastic and which are enclosed by a membrane of water-insoluble plastic containing embedded particles of lactose.

2. A sustained-release theophylline formulation as claimed in claim 1, wherein the matrix pellets are built up from inert carrier pellets onto which the matrix containing the theophylline is applied.

3. A sustained-release theophylline formulation as claimed in claim 2, wherein the inert carrier pellets are sugar beads.

4. A sustained-release theophylline formulation as claimed in claim 1, wherein the theophylline particles have a particle size of less than 50 μ

m.

5. A sustained-release theophylline formulation as claimed in claim 1, wherein the water-insoluble plastic which forms the membrane is not swellable in water.

6. A sustained-release theophylline formulation as claimed in claim 5, wherein the water-insoluble plastic is a cellulose ether or a cellulose ester.

7. A sustained-release theophylline formulation as claimed in claim 1, wherein the particles of lactose embedded in the membrane have a particle size of less than 20 μ

m.

8. A sustained-release theophylline formulation as claimed in claim 1, which contains half a daily dose of theophylline.

9. A sustained-release theophylline formulation as claimed in claim 1, wherein a plastic in which lactose is insoluble is the p astic which forms the membrane.

10. A sustained-release theophylline formulation as claimed in claim 1, wherein some of the matrix pellets are in a slow form and some of the matrix pellets are in a rapid form.

11. A theophylline formulation as claimed in claim 10, wherein the matrix pellets of the slow form release more than 90%, of the theophylline present in the course of from 10 to 14 hours, preferably 11 to 13 hours in a USP paddle apparatus at pH 7.4, and the matrix pellets of the rapid form release more than 90%, of the theophylline present in the course of 4 to 8, hours in a USP paddle apparatus at pH 7.4.

12. A theophylline formulation as claimed in either claim 10 or claim 11, wherein 30 to 70 % of the theophylline is in the form of matrix pellets of the slow form.

13. A theophylline formulation as claimed in claim 11, which contains 50% of the theophylline as matrix pellets which release more than 95% of the theophylline present in the course of 12 hours in a USP paddle apparatus at pH 7.4, and 50% of the theophylline as matrix pellets which release more than 95% of the theophylline present in the course of 6 hours in a USP paddle apparatus at pH 7.4.

24. A process for establishing and maintaining plasma theophylline levels in the therapeutic range over an extended period of time by orally administering a sustained-release formulation, as claimed in claim 1, to a patient in need of such therapy.

25. A sustained-release theophylline formulation as claimed in claim 7, wherein the particles of lactose embedded in the membrane have a particle size of less than 10 μ

m.

26. A theophylline formulation as claimed in claim 10, wherein the matrix pellets of the slow form release more than 95% of the theophylline present in the course of from 11 to 13 hours in a USP paddle apparatus at pH 7.4, and the matrix pellets of the rapid form release more than 95% of the theophylline present in the course of from 5 to 7 hours in a USP paddle apparatus at pH 7.4.

27. A theophylline formulation according to claim 12 wherein from 40 to 60% of the theophylline is in the form of matrix pellets of the slow form.

28. A pharmacologically-acceptable sustained-release theophylline formulation as claimed in claim 1, wherein the membrane comprises as claimed in claim 1, wherein the membrance comprises a weight ratio of plastic to lactose within a range of from about 2:

1 to 1;

3.

14. A process for the preparation of a sustained-release theophylline formulation, which comprises shaping micronized theophylline into matrix pellets together with a water-insoluble plastic and coating the matrix pellets with a membrane of water-insoluble plastic containing embedded particles of lactose.

15. A process as claimed in claim 14, which comprises spraying a suspension of micronized theophylline in a solution of a water-insoluble plastic in an organic solvent onto carrier pellets to prepare the matrix pellets.

16. A process as claimed in claim 14, which comprises spraying the matrix pellets with a suspension of lactose in an organic-solvent solution of a water-insoluble plastic to coat said pellets.

17. A process as claimed in any one of claims 14, 15 and 16 for the preparation of a sustained-release theophylline formulation, wherein the membrane is a dialysis membrane, and which further comprises preparing the formulation in unit-dosage form.

18. A process as claimed in claim 17, which comprises combining matrix pellets which release the theophylline within 10 to 14 hours with matrix pellets which release the theophylline within 4 to 8 hours.

19. Enclosed-matrix theophylline pellets having 12-hour theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the ranges in the following table:

space="preserve" listing-type="tabular">__________________________________________________________________________Hour 1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th Percent 7-9 8-9 9-10 7-9 7-9 7-9 7-8 6-8 6-7 5-7 4-7 3-5 __________________________________________________________________________

and averaging from about 6.5 to 7.5 percent release per hour over a 12-hour period.

20. Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative ranges in the following table:

space="preserve" listing-type="tabular">______________________________________ Hour 1st 3rd 6th 9th Percent 8-16 30-50 65-85 >

85. ______________________________________

21. Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative values in the following table:

space="preserve" listing-type="tabular">______________________________________ Hour 1st 3rd 6th 9th Percent 12 38 73 >

90. ______________________________________

22. Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative ranges in the following table:

space="preserve" listing-type="tabular">______________________________________ Hour 1st 3rd 6th Percent 28-40 72-92 >

95. ______________________________________

23. Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative values in the following table:

space="preserve" listing-type="tabular">______________________________________ Hour 1st 3rd 6th Percent 34 82 100. ______________________________________