Timed, sustained release systems for propranolol

• US 9,040,086 B2
• Filed: 08/09/2006
• Issued: 05/26/2015
• Est. Priority Date: 10/04/2001
• Status: Expired due to Fees

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Aptalis Pharmatech Incorporated
• Inventors: Percel, Phillip J., Vishnupad, Krishna S., Venkatesh, Gopi M.
• Primary Examiner(s): WESTERBERG, NISSA M
• Application Number:
  US11/500,892
• Publication Number:
  US 20060269607A1
• Time in Patent Office: 3,212 Days
• Field of Search: None
• US Class Current: 424/489
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• 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 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.

Claims

1. A timed, sustained-release (TSR) pharmaceutical formulation comprising timed, sustained release beads, wherein said TSR beads comprise:

a) a core comprising propranolol or a pharmaceutically acceptable salt thereof;

b) a first membrane comprising a first water insoluble polymer surrounding said core;

c) a second outer membrane comprising a mixture of a second water insoluble polymer and an enteric polymer;

wherein said formulation provides a lag time in propranolol blood plasma concentration of about 2 to about 6 hours,

wherein said formulation comprises about 80 mg, about 120 mg, or about 160 mg of propranolol or a pharmaceutically acceptable salt thereof,

wherein said formulation provides a maximum blood plasma concentration (C_max) between about 10 and about 14 hours following administration.

2. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation comprises about 160 mg of propranolol or a pharmaceutically acceptable salt thereof, and provides a maximum blood plasma concentration (C_max) within the range of 80% to 125% of about 177 ng/mL of propranolol between about 10 and about 14 hours following administration and an AUC_0-T within the range of 80% to 125% of about 3417 ng·

hr/mL.

3. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation comprises about 120 mg of propranolol or a pharmaceutically acceptable salt thereof, and provides a maximum blood plasma concentration (C_max) within the range of 80% to 125% of about 130 ng/ml, of propranolol between about 10 and about 14 hours following administration and an AUC_0-T within the range of 80% to 125% of about 2270 ng·

hr/mL.

4. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation comprises about 80 mg of propranolol or a pharmaceutically acceptable salt thereof, and provides a maximum blood plasma concentration (C_max) within the range of 80% to 125% of about 81 ng/mL of propranolol between about 10 and about 14 hours following administration and an AUC_0-T within the range of 80% to 125% of about 1443 ng·

hr/mL.

5. The pharmaceutical formulation of claim 1 wherein the first and second water insoluble polymers are independently selected from the group consisting of ethylcellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methylmethacrylate, and copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups.

6. The pharmaceutical formulation of claim 1 wherein the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methamethacrylate copolymers and shellac.

7. The pharmaceutical formulation of claim 1 whereby the first and second water insoluble polymers are ethylcellulose and the enteric polymer is a pH sensitive methacrylic acid-methamethacrylate copolymer.

8. A method of propranolol therapy which comprises administering orally to a human in need thereof the pharmaceutical formulation of claim 1.

9. A method of propranolol therapy which comprises administering orally to a human in need thereof the pharmaceutical formulation of claim 2.

10. A method of propranolol therapy which comprises administering orally to a human in need thereof the pharmaceutical formulation of claim 3.

11. A method of propranolol therapy which comprises administering orally to a human in need thereof the pharmaceutical formulation of claim 4.

12. A method of decreasing blood pressure during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 1.

13. A method of decreasing blood pressure during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 2.

14. A method of decreasing blood pressure during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 3.

15. A method of decreasing blood pressure during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 4.

16. A method of preventing angina during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 1.

17. A method of preventing angina during the early waking hours comprising orally administering once daily before bed time to a human in need thereof the pharmaceutical formulation of claim 2.

18. A method of preventing angina during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 3.

19. A method of preventing angina during the early waking hours comprising orally administering once daily before bedtime to a human in need thereof the pharmaceutical formulation of claim 4.