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Claims for Patent: 6,500,454

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Claims for Patent: 6,500,454

Title: Timed, sustained release systems for propranolol
Abstract:A unit dosage form, such as a capsule or the like for delivering drugs into the body in a circadian release fashion, is comprising of one or more populations of propranolol-containing particles (beads, pellets, granules, etc.). Each bead population exhibits a pre-designed rapid or sustained release profile with or without a predetermined lag time of 3 to 5 hours. Such a circadian rhythm release cardiovascular drug delivery system is designed to provide a plasma concentration--time profile, which varies according to physiological need during the day, i.e., mimicking the circadian rhythm and severity/manifestation of a cardiovascular disease, predicted based on pharmaco-kinetic and pharmaco-dynamic considerations and in vitro/in vivo correlations.
Inventor(s): Percel; Phillip J. (Troy, OH), Vishnupad; Krishna S. (Dayton, OH), Venkatesh; Gopi M. (Dayton, OH)
Assignee: Eurand Pharmaceuticals Ltd. (IE)
Application Number:09/971,167
Patent Claims: 1. A pharmaceutical dosage form comprising timed, sustained release (TSR) beads, wherein said TSR beads comprise: a. a core particle comprising propranolol or a pharmaceutically acceptable salt thereof; b. a first membrane comprising ethylcellulose surrounding said core to sustain drug release; and c. a second outer membrane comprising a mixture of ethylcellulose and an enteric polymer, said second membrane providing a lag time before drug release; d. wherein said TSR beads when tested in a USP type II apparatus at 50 rpm using a 2-stage dissolution medium (first two hours in 700 ml 0.1N HC1 at 37.degree. C. followed by dissolution in a pH of 6.8 obtained by the addition of 200 ML of pH modifier) exhibit a dissolution profile substantially corresponding to the following pattern: after 2 hours, 0-20% of the total propranolol is released; after 4 hours, 5-35% of the total propranolol is released; after 6 hours, 10-60% of the total propranolol is released; after 10 hours, 40-90% of the total propranolol is released; and after 16 hours, not less than 60% of the total propanolol is released.

2. A pharmaceutical dosage form as defined in claim 1, wherein said dissolution profile substantially corresponds to the following pattern: after 2 hours, 0-10% of the total propranolol is released; after 4 hours, 5-25% of the total propranolol is released; after 6 hours, 20-45% of the total propranolol is released; after 10 hours, 50-80% of the total propranolol is released; and after 16 hours, not less than 70% of the total propranolol is released.

3. A pharmaceutical dosage form as defined in claim 2, wherein the dissolution profile substantially corresponds to the following pattern: after 2 hours, 0-5% of the total propanolol is released; after 4 hours, 5-15% of the total propranolol is released; after 6 hours, 25-35% of the total propranolol is released; after 10 hours, 55-70% of the total propranolol is released; and after 16 hours, not less than 75% of the total propranolol is released.

4. A pharmaceutical dosage form as defined in claim 1, wherein the core particle is a non-pareil sugar seed coated with propranolol in a polymeric binder or the core particle is particle prepared by granulation and milling or extrusion/spheronization to form a core particle containing propranolol.

5. A pharmaceutical dosage form as defined in claim 1 wherein said enteric polymer is selected from the group consisting of esters of cellulose, polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methylmethacrylate copolymers and shellac.

6. A pharmaceutical dosage form as defined in claim 5 wherein said enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate and combinations thereof.

7. A pharmaceutical dosage form as defined in claim 1 wherein at least one of said first and second membranes further comprises a plasticizer.

8. A pharmaceutical dosage form as defined in claim 7 wherein said plasticizer is selected from the group consisting of triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil and acetylated mono- and di-glycerides and mixtures thereof.

9. A pharmaceutical dosage form as defined in claim 1 wherein said ethylcellulose and said enteric polymers are present in said outer membrane at a ratio from 10:1 to 1:2.

10. A pharmaceutical dosage form as defined in claim 9 wherein said ratio of ethylcellulose to enteric polymer is from 2:1 to 1:1.

11. A pharmaceutical dosage form as defined in claim 10 wherein said enteric polymer is hydroxypropyl methylcellulose phthalate.

12. A pharmaceutical dosage form as defined in claim 11 wherein said ratio is approximately 1:1.

13. A pharmaceutical dosage form as defined in claim 1 wherein said dosage form further comprises immediate release (IR) beads, said IR beads comprising a core particle comprising propranolol.

14. A pharmaceutical dosage form as defined in claim 13 wherein said IR beads provide a loading dose by releasing substantially all of the propranolol contained in said IR beads within the first hour after administration of the dosage form.

15. A pharmaceutical dosage form as defined in claim 1 wherein the total coating weight of said membranes is from about 10 to 60% of the total weight of said TSR beads.

16. A pharmaceutical dosage form as defined in claim 15 wherein said first membranes comprises from about 1.5 to 4% of the total weight of said TSR beads and said second membrane comprises from about 10 to 56% total weight of said TSR beads.

17. A pharmaceutical dosage form as defined in claim 1 wherein said dosage form contains a total of from 80 mg to 160 mg propranolol or pharmaceutically acceptable salt thereof.

18. A method for the preparation of the dosage form of claim 1, comprising the steps of: a. preparing a propranolol-containing core; b. coating said core with a plasticized ethylcellulose to form an ethylcellulose membrane around said core; c. coating said ethylcellulose coated core with a mixture of plasticized ethylcellulose and an enteric polymer to form a Timed, Sustained Release (TSR) coated drug particle; and d. filling capsules with said TSR beads.

19. The method of claim 18 wherein said propranolol-containing core is produced by coating a particle selected from the group consisting of non-pareil seeds, acidic buffer crystals and alkaline buffer crystals with a water soluble film-forming composition comprising propranolol and a polymeric binder.

20. The method of claim 18 wherein said propranolol-containing core is produced by granulating and milling and/or by extrusion and spheronization of a polymer composition containing propranolol.

21. A method of providing a patient with a timed, sustained release of propranolol which comprises administering to said patient a dosage form of claim 1.

22. The method according to claim 21, wherein said dosage form is administered orally.

23. The method according to claim 22, wherein said dosage form is administered in the late evening.

24. The method according to claim 22, wherein said dosage form provides a therapeutically effective amount of propranolol by early morning and thereafter provides for sustained release of therapeutic amounts of propranolol.

25. The method according to claim 21, wherein said dosage form provides a T.sub.max at about 12 hours after administration of said dosage form.
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