Extended release dosage forms of propranolol hydrochloride

• US 20040126427A1
• Filed: 12/31/2002
• Published: 07/01/2004
• Est. Priority Date: 12/31/2002
• Status: Active Grant

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Aptalis Pharmatech Incorporated
• Inventors: Venkatesh, Gopi M., Percel, Phillip J., Vishnupad, Krishna S.
• Granted Patent: US 8,367,111 B2
• Time in Patent Office: Days
• US Class Current: 424/469
• 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 9/5047 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 unit dosage form, such as a capsule or the like for delivering drugs into the body in a sustained release fashion similar to that produced by INDERAL® LA indicated for the treatment of cardiovascular diseases, comprises two populations of propranolol-containing particles (beads, pellets, granules, etc.). Each bead population exhibits a pre-designed rapid release profile (i.e., substantially complete release within 60 minutes) or sustained release profile over a period of 24 hours. Such a cardiovascular drug delivery system is designed by combining immediate release (IR) beads and sustained release (SR) beads. SR beads may be obtained by membrane coating IR beads with a water-insoluble polymer such as ethylcellulose or a mixture of a water insoluble polymer and a water-soluble polymer such as hydroxypropylcellulose at a ratio of from about 65/35 to 95/5.

Claims

1. An extended release pharmaceutical multi-particulate dosage form comprising immediate release (IR) beads and sustained release (SR) beads or SR beads without IR beads, wherein said IR beads comprise a core particle comprising propranolol or a pharmaceutically acceptable salt thereof and said SR beads comprise a core particle comprising propranolol or a pharmaceutically acceptable salt thereof and a first membrane comprising a water insoluble polymer or a combination of a water insoluble polymer and a water soluble polymer, said membrane providing for a sustained drug release;

wherein said dosage form when tested according to United States Pharmacopoeia dissolution test method for Propranolol Hydrochloride Extended Release Capsules (USP Apparatus 1, Baskets @ 100 rpm, Drug Release Test 1 using 900 mL of pH 1.2 buffer for 1.5 hours followed by testing in 900 mL of pH 6.8 at 4, 8, 14, and 24 hours) exhibits a dissolution profile substantially corresponding to the following pattern;

after 1.5 hours, not more than about 30% of the total propranolol is released;

after 4 hours, about 45±

15% of the total propranolol is released;

after 8 hours, about 65±

15% of the total propranolol is released;

after 14 hours, about 80±

15% of the total propranolol is released; and

after 24 hours, not less than about 85% of the total propranolol is released.

2. A dosage form as defined in claim 1 wherein said dissolution profile substantially corresponds to the following pattern:

after 1.5 hours, not more than about 30% of the total propranolol is released;

after 4 hours, about 45±

10% of the total propranolol is released;

after 8 hours, about 65±

10% of the total propranolol is released;

after 14 hours, about 80±

10% of the total propranolol is released; and

after 24 hours, not less than about 85% of the total propranolol is released.

3. A dosage form as defined in claim 1 wherein the immediate release (IR) beads and Sustained Release (SR) beads are present in said dosage form in a ratio of IR beads to SR beads up from about 30:

70 to 10;

90

4. A dosage form as defined in claim 1 wherein said IR beads release substantially all of the propranolol contained in said IR beads during the first hour of dissolution testing.

5. A dosage form as defined in claim 1 wherein said dosage form comprises SR beads without IR beads.

6. A dosage form as defined in claim 1 wherein said water insoluble polymer selected from the group consisting of ethylcellulose, cellulose acetate, ammonio methacrylic acid copolymers and mixtures thereof and said water soluble polymer is selected from the group consisting of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone.

7. A dosage form as defined in claim 6, wherein said water insoluble polymer and water soluble polymer are present in a weight ratio of from about 5:

5 to 65;

35 and the membrane comprises from about 1.5 to 6% of the weight of said SR beads.

8. A dosage form as defined in claim 1 wherein the core particle comprises a non-pareil seed coated with propranolol in a polymeric binder.

9. A dosage form as defined in claim 8 wherein said non-pareil seed is selected from the group consisting of sugar spheres, cellulose spheres, silicone dioxide spheroids, acidic buffer crystals and alkaline buffer crystals.

10. A dosage form as defined in claim 9 wherein said polymeric binder comprises polyvinylpyrrolidone.

11. A dosage form as defined in claim 1 wherein said core particle further comprises a seal coating substantially surrounding said core particle.

12. A dosage form as defined in claim 1 wherein said water insoluble polymer comprises ethyl cellulose and said water soluble polymer is selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose.

13. A dosage form as defined in claim 12 wherein said water insoluble polymer and water soluble polymer are present at a weight ratio of from about 85:

15 to 75;

25.

14. A dosage form as defined in claim 13 wherein the membrane coating comprises about 1.5% to 6% based on the weight of the coated particles.

15. A dosage form as defined in claim 12 wherein said ethylcellulose has a viscosity of not more than 30 cps at 25°

C. and said water soluble polymer has a viscosity of not more than 200 cps when tested on a 2% aqueous solution at 25°

C.

16. A dosage form as defined claim 1 wherein said dosage form contains a total of from 60 mg to 160 mg propranolol or a pharmaceutically acceptable salt thereof.

27. A method of providing a patient with a sustained release delivery of propranolol over a dosing period of 24 hours comprising administering to said patient a dosage form of claim 1 comprising a combination of IR and SR beads.

28. The method of claim 27 wherein said dosage form comprises a capsule and said capsule is administered orally.

17. A method of preparing a pharmaceutical multi-particulate dosage form comprising sustained release (SR) beads and optionally immediate release (IR) beads wherein said method comprises the steps of:

a. preparing IR beads by layering an aqueous solution comprising propranolol and a binder on non-pareil seeds;

b. preparing SR beads by applying a sustained release coating on IR beads, said sustained release coating comprising a water insoluble polymer or a water insoluble polymer in combination with a water soluble polymer, said sustained release coating comprising approximately 1.5% to approximately 6% by weight based on the total weight of the coated SR particles; and

c. filling capsules with IR beads and SR beads at a ratio ranging from about 0;

100 to 30;

70 (IR beads;

SR beads) to produce extended release propranolol-containing capsules, wherein said capsules when tested according to United States Pharmacopoeia dissolution test method for Propranolol Hydrochloride Extended Release Capsules (USP Apparatus 1, Baskets @ 100 rpm, Drug Release Test 1 using 900 mL of pH 1.2 buffer for 1.5 hours followed by testing in 900 mL of pH 6.8 at 4, 8, 14, and 24 hours), exhibit a dissolution profile substantially corresponding to the following pattern;

after 1.5 hours, not more than about 30% of the total propranolol is released

after 4 hours, about 45±

15% of the total propranolol is released;

after 8 hours, about 65±

15% of the total propranolol is released;

after 14 hours, about 80±

15% of the total propranolol is released; and

after 24 hours, not less than about 85% of the total propranolol is released.

18. The method of claim 17 wherein said IR beads release substantially all of the propranolol contained in said IR beads within the first hour of dissolution testing.

19. The method of claim 17 wherein said water insoluble polymer comprises ethylcellulose and said water soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose.

20. The method of claim 17 wherein step (a) further comprises:

applying a protective seal coat to said IR beads.

21. The method of claim 17 wherein said sustained release coating comprises ethylcellulose in combination with a water soluble polymer selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose, said water insoluble polymer and water soluble polymer being present at a weight ratio of from about 85:

15 to 75;

25, respectively.

22. The method of claim 21 wherein the ethylcellulose has a viscosity of not more than 30 cps at 25°

C. and said water soluble polymer has a viscosity of not more than 200 cps when tested on a 2% aqueous solution at 25°

C.

23. The method of claim 22 wherein said sustained release coating comprises approximately 1.5% to 6% based on the weight of the coated SR particles.

24. The method of claim 17 wherein said dosage form contains a total of from about 60 mg to 160 mg propranolol or a pharmaceutically acceptable salt thereof.

25. The method of claim 17 wherein said dissolution profile substantially corresponds to the following pattern:

after 1.5 hours, not more than about 30% of the total propranolol is released;

after 4 hours, about 45±

10% of the total propranolol is released;

after 8 hours, about 65±

10% of the total propranolol is released;

after 14 hours, about 80±

10% of the total propranolol is released; and

after 24 hours, not less than about 85% of the total propranolol is released.

26. A method of claim 17 wherein said dosage form comprises 100% sustained release (SR) beads.