Timed, sustained release systems for propranolol

• US 20060269607A1
• Filed: 08/09/2006
• Published: 11/30/2006
• Est. Priority Date: 10/04/2001
• Status: Active Grant

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Eurand Incorporated (Abbvie Incorporated)
• Inventors: Venkatesh, Gopi M., Percel, Phillip J., Vishnupad, Krishna S.
• Granted Patent: US 9,040,086 B2
• Time in Patent Office: Days
• US Class Current: 424/473
• 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) formulation comprising about 160 mg of propranolol or a pharmaceutically acceptable salt thereof and TSR formulation excipients including one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 3417 ng·

hr/mL.

2. A formulation comprising timed, sustained release (TSR) beads wherein each of said TSR beads comprises:

(a) a core particle comprising about 160 mg propranolol or a pharmaceutically acceptable salt thereof;

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

(c) a second, outer membrane comprising a mixture of a second water insoluble polymer and an enteric polymer, wherein the first and second water insoluble polymers are the same or different;

whereby said formulation provides a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 3417 ng·

hr/mL.

3. The formulation of claim 2 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.

4. The formulation of claim 3 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.

5. The formulation of claim 2 whereby the first and second water insoluble polymers are ethylcellulose and the enteric polymer is a pH sensitive methacrylic acid-methamethacrylate copolymer.

6. A timed, sustained-release (TSR) formulation comprising about 120 mg of propranolol or a pharmaceutically acceptable salt thereof and TSR formulation excipients including one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 2270 ng·

hr/mL.

7. A formulation comprising timed, sustained release (TSR) beads wherein each of said TSR beads comprises:

(a) a core particle comprising about 120 mg propranolol or a pharmaceutically acceptable salt thereof;

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

(c) a second, outer membrane comprising a mixture of a second water insoluble polymer and an enteric polymer, wherein the first and second water insoluble polymers are the same or different;

whereby said formulation provides a lag time in propranolol blood plasma concentration of about 2 to about 6 hours followed by 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, whereby the AUC_0-T is within the range of 80% to 125% of about 2270 ng·

hr/mL.

8. The formulation of claim 7 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.

9. The formulation of claim 8 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.

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

11. A timed, sustained-release (TSR) formulation comprising about 80 mg of propranolol or a pharmaceutically acceptable salt thereof and TSR formulation excipients including one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 1443 ng·

hr/mL.

12. A formulation comprising timed, sustained release (TSR) beads wherein each of said TSR beads comprises:

(a) a core particle comprising about 80 mg propranolol or a pharmaceutically acceptable salt thereof;

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

(c) a second, outer membrane comprising a mixture of a second water insoluble polymer and an enteric polymer, wherein the first and second water insoluble polymers are the same or different;

whereby said formulation provides a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 1443 ng·

hr/mL.

13. The formulation of claim 12 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.

14. The formulation of claim 13 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 methaerylic acid-methamethacrylate copolymers and shellac.

15. The formulation of claim 12 whereby the first and second water insoluble polymers are ethylcellulose and the enteric polymer is a pH sensitive methacrylic acid methamethacrylate copolymer.

16. A method of propranolol therapy which comprises administering orally to a human in need thereof about 160 mg of propranolol or a pharmaceutically acceptable salt thereof in a timed sustained release (TSR) formulation including one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 3417 ng·

hr/mL.

17. A method of propranolol therapy which comprises administering orally to a human in need thereof a timed sustained release (TSR) formulation, said formulation comprising beads, each of which comprises:

(a) a core particle comprising about 160 mg propranolol or a pharmaceutically acceptable salt thereof;

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

(c) a second, outer membrane comprising a mixture of a second water insoluble polymer and an enteric polymer, wherein the first and second water insoluble polymers are the same or different;

whereby following a lag time in propranolol blood concentration of about 2 to about 6 hours a maximum blood plasma concentration (C_max) within the range of 80% to 125% of about 177 ng/mL propranolol is reached between about 10 and about 14 hours after administration and the AUC_0-T is within the range of 80% to 125% of about 3417 ng·

hr/mL.

18. The method of claim 17 whereby 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 metbacrylic acid esters with quaternary ammonium groups.

19. The method of claim 18 whereby 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.

20. The method of claim 17 whereby the first and second water insoluble polymers are ethylcellulose and the enteric polymer is a pH sensitive methacrylic acid-methamethacrylate copolymer.

21. A method of propranolol therapy which comprises administering orally to a human in need thereof about 120 mg of propranolol or a pharmaceutically acceptable salt thereof in a timed sustained release (TSR) formulation including one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 2270 ng·

hr/mL.

22. A method of propranolol therapy which comprises administering orally to a human in need thereof a timed sustained release (TSR) formulation, said dosage form comprising beads, each of which comprises:

(a) a core particle comprising about 120 mg propranolol or a pharmaceutically acceptable salt thereof;

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

(c) a second, outer membrane comprising a mixture of a second water insoluble polymer and an enteric polymer, wherein the first and second water insoluble polymers are the same or different;

whereby following a lag time in propranolol blood concentration of about 2 to about 6 hours a maximum blood plasma concentration (C_max) within the range of 80% to 125% of about 130 ng/mL propranolol is reached between about 10 and about 14 hours after administration and the AUC_0-T is within the range of 80% to 125% of about 2270 ng·

hr/mL.

23. The method of claim 22 whereby the first and second water insoluble polymers are 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.

24. The method of claim 23 whereby 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.

25. The method of claim 22 whereby the first and second water insoluble polymers are ethylcellulose and the enteric polymer is a pH sensitive methacrylic acid-methamethacrylate copolymer.

26. A method of propranolol therapy which comprises administering orally to a human in need thereof about 80 mg of propranolol or a pharmaceutically acceptable salt thereof in a timed sustained release (TSR) formulation including one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 1443 ng·

hr/mL.

27. A method of propranolol therapy which comprises administering orally to a human in need thereof a timed sustained release (TSR) formulation, said dosage form comprising beads, each of which comprises:

(a) a core particle comprising about 80 mg propranolol or a pharmaceutically acceptable salt thereof;

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

(c) a second, outer membrane comprising a mixture of a second water insoluble polymer and an enteric polymer, wherein the first and second water insoluble polymers are the same or different;

whereby following a lag time in propranolol blood concentration of about 2 to about 6 hours a maximum blood plasma concentration (C_max) within the range of 80% to 125% of about 81 ng/mL propranolol is reached between about 10 and about 14 hours after administration and the AUC_0-T is within the range of 80% to 125% of about 1443 ng·

hr/mL.

28. The method of claim 27 whereby 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.

29. The method of claim 28 whereby 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.

30. The method of claim 27 whereby the first and second water insoluble polymers are ethylcellulose and the enteric polymer is a pH sensitive methacrylic acid-methamethacrylate copolymer.

31-33. -33. (canceled)

34. A method of decreasing blood pressure during the early waking hours comprising administering once daily before bedtime to a patient in need thereof a timed, sustained-release (TSR) pharmaceutical formulation comprising about 160 mg of propranolol or a pharmaceutically acceptable salt thereof and one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 3417 ng·

hr/mL.

35. A method of decreasing blood pressure during the early waking hours comprising administering once daily before bedtime to a patient in need thereof a timed, sustained-release (TSR) pharmaceutical formulation comprising about 120 mg of propranolol or a pharmaceutically acceptable salt thereof and one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 2270 ng·

hr/mL.

36. A method of decreasing blood pressure during the early waking hours comprising administering once daily before bedtime to a patient in need thereof a timed, sustained-release (TSR) pharmaceutical formulation comprising about 80 mg of propranolol or a pharmaceutically acceptable salt thereof and one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 1443 ng·

hr/mL.

37. A method for the prevention of angina during the early waking hours comprising administering once daily before bedtime to a patient in need thereof a timed, sustained-release (TSR) pharmaceutical formulation comprising about 160 mg of propranolol or a pharmaceutically acceptable salt thereof and one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 3417 ng·

hr/mL.

38. A method for the prevention of angina during the early waking hours comprising administering once daily before bedtime to a patient in need thereof a timed, sustained-release (TSR) pharmaceutical formulation comprising about 120 mg of propranolol or a pharmaceutically acceptable salt thereof and one or more polymers that delay release of the propranolol to provide that provides a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 2270 ng·

hr/mL.

39. A method for the prevention of angina during the early waking hours comprising administering once daily before bedtime to a patient in need thereof a timed, sustained-release (TSR) pharmaceutical formulation comprising about 80 mg of propranolol or a pharmaceutically acceptable salt thereof and one or more polymers that delay release of the propranolol to provide a lag time in propranolol blood plasma concentration of about 2 to about 6 hours and 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, whereby the AUC_0-T is within the range of 80% to 125% of about 1443 ng·

hr/mL.