Formulations and methods for the controlled release of active drug substances

• US 9,023,394 B2
• Filed: 06/26/2013
• Issued: 05/05/2015
• Est. Priority Date: 06/24/2009
• Status: Active Grant

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Andersen, Christine, Lindhardt, Karsten, Oevergaard, Jan Martin, Lyhne-Iversen, Louise Inoka, Olsen, Martin Rex, Haahr, Anne-Mette, Hoeyrup Hemmingsen, Pernille Kristine
• Primary Examiner(s): Singh, Anoop
• Assistant Examiner(s): FALKOWITZ, ANNA R
• Application Number:
  US13/928,135
• Publication Number:
  US 20130287849A1
• Time in Patent Office: 678 Days
• Field of Search: 424/486, 424/468, 514/282, 514/411
• US Class Current: 424/486
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

Controlled release formulations and methods for preparing controlled release formulations for delivery of active drug substances are described herein. The formulations described herein may be employed to produce pharmaceutical compositions, such as controlled release dosage forms, adjusted to a specific administration scheme.

Claims

1. A tablet for oral delivery of hydrocodone, the tablet comprising:

a) a matrix composition having a cylindrical shape with two ends, wherein each of the two ends is optionally tapered, the length of the matrix is in the range of 8.0 to 15 mm, the matrix composition comprises (i) hydrocodone and (ii) at least one polyglycol, and the matrix composition exhibits a release rate of the hydrocodone from the matrix in ethanol that is equal to or lower than the release rate of the hydrocodone from the matrix in water; and

b) a coating substantially surrounding the matrix composition and having one or two openings exposing at least one surface of the matrix composition, the coating being substantially impermeable to an aqueous medium,

wherein the tablet provides controlled release of the hydrocodone over an interval of 24 hours,

wherein the tablet provides a C_min of hydrocodone reached no earlier than 18 hours after last administration, and

wherein the tablet is resistant to isolation of the hydrocodone by any of crushing of the tablet, melting of the tablet, and ethanol extraction.

2. The tablet according to claim 1, wherein the matrix has a cross section with an area in the range of 1 to 75 mm².

3. The tablet according to claim 1, wherein the matrix has a cross section with an area of at least 20 mm².

4. The tablet according to claim 1, wherein the matrix has a length of 8 to 10 mm.

5. The tablet according to claim 1, wherein the matrix has a length of 8.5 to 9.5 mm.

6. The tablet according to claim 1, wherein the coating comprises two openings each exposing one end of the matrix.

7. The tablet according to claim 1, wherein a therapeutically effective response is achieved over the entire interval between once daily administrations.

8. The tablet according to claim 1, wherein the tablet provides a steady state trough of hydrocodone that is at least 20% of steady state C_max.

9. The tablet according to claim 1, wherein the tablet provides a steady state trough of hydrocodone that is in a range of 30 to 80% of steady state C_max.

10. The tablet according to claim 1, wherein a 1^st point where a plasma concentration of hydrocodone of 50% of steady state C_max is reached occurs 0.5 to 2.5 hours after last administration.

11. The tablet according to claim 10, wherein the tablet provides controlled release of hydrocodone such that a 2^nd point where a plasma concentration of hydrocodone of 50% of steady state C_max is reached occurs no earlier than 12 hours after last administration.

12. The tablet according to claim 1, wherein the tablet provides controlled release of hydrocodone in a manner that results in a mean residence time (MRT) of at least 11 hours.

13. The tablet according to claim 1, wherein the tablet provides controlled release of hydrocodone in a manner that results in a T_max of 3 to 6 hours after last administration to a steady state individual.

14. The tablet according to claim 1, wherein the tablet provides a hydrocodone protraction index of at least 0.40.

15. The tablet according to claim 1, wherein the tablet delivers sufficient hydrocodone in a controlled manner over a 24-hour period to achieve pain relief over a 24-hour period.

16. The tablet according to claim 1, containing a dosage of hydrocodone in the range of 10 to 500 mg.

17. The tablet according to claim 1, wherein the polyglycol is a water soluble crystalline or semi-crystalline polymer.

18. The tablet according to claim 1, wherein the matrix comprises at least one polyglycol that is a homopolymer.

19. The tablet according to claim 1, wherein the matrix comprises at least one polyglycol that is a copolymer.

20. The tablet according to claim 1, wherein the total concentration of the at least one polyglycol included in the matrix composition is from 5 to 99% w/w.

21. The tablet according to claim 18, wherein the at least one polyglycol is a polyethylene glycol and/or a polyethylene oxide.

22. The tablet according to claim 21, wherein the polyethylene glycol and/or polyethylene oxide has a molecular weight from 20,000 to 700,000 daltons.

23. The tablet according to claim 1, wherein the matrix comprises at least two different polyglycols, wherein the different polyglycols are selected from the group consisting of polyethylene oxides.

24. The tablet according to claim 23, wherein one polyethylene oxide has an average molecular weight in the range of 150,000 to 250,000 daltons and the other polyethylene oxide has an average molecular weight in the range of 250,000 to 350,000 daltons.

25. The tablet according to claim 18, wherein the concentration of homopolymer in the matrix composition is from 5 to 90% w/w.

26. The tablet according to claim 19, wherein the copolymer is a poloxamer that has an average molecular weight selected from the group consisting of 2,000 to 30,000 daltons.

27. The tablet according to claim 19, wherein the matrix comprises one or more poloxamers.

28. The tablet according to claim 27, wherein the matrix comprises only one poloxamer and has a length of 8.0 to 10 mm.

29. The tablet according to claim 19, wherein the concentration of copolymer in the matrix composition is from 1 to 20% w/w.

30. The tablet according to claim 1, wherein the coating is insoluble in an aqueous medium.

31. The tablet according to claim 1, wherein the coating comprises one or more polymers selected from the group consisting of starch based polymers, cellulose based polymers, synthetic polymers, and biodegradable polymers.

32. The tablet according to claim 1, wherein the coating comprises one or more polymers selected from the group consisting of ethyl cellulose grade 20, ethyl cellulose grade 100, polylactic acid (PLA), Cornpack 200, polycaprolactone, PEO 7000000, and polyhydroxybuturate.

33. The tablet according to claim 1, wherein the coating comprises an ethyl cellulose selected from an ethyl cellulose of grade 20 and an ethyl cellulose of grade 100.

34. The tablet according to claim 1, wherein the coating comprises one or more biodegradable polymers, selected from the group consisting of polylactic acid and polycaprolactone.

35. The tablet according to claim 1, wherein the coating comprises at least 85% w/w polymers, wherein the polymers are selected from the group consisting of biodegradable polymers and cellulose based polymers.

36. The tablet according to claim 1, wherein the coating comprises one or more plasticizers.

37. The tablet according to claim 1, wherein the tablet is formed by injection molding.

38. The tablet according to claim 1, wherein the tablet is formed by extrusion.