CONTROLLED RELEASE FORMULATIONS WITH CONTINUOUS EFFICACY

• US 20100203129A1
• Filed: 01/26/2010
• Published: 08/12/2010
• Est. Priority Date: 01/26/2009
• Status: Abandoned Application

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Jespersen, Lillian, Hoeilund-Jensen, Jacob Aas, Christensen, Lars Hedevang, Lindhardt, Karsten, Lyhne-Iversen, Louise Inoka, Andersen, Christine, Olsen, Martin Rex, Oevergaard, Jan Martin
• Application Number:
  US12/694,197
• Publication Number:
  US 20100203129A1
• Time in Patent Office: Days
• US Class Current: 424/474
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2853 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention relates to pharmaceutical compositions, which provide controlled release of a drug. The compositions are suitable for continuous administration as they remain effective throughout the treatment regimen. The present invention also relates to the use of the compositions for preparation of a medicament for continuous treatment of an individual.

Claims

1. A pharmaceutical composition comprising:

a) a matrix composition having a cylindrical shape and, optionally, one or more tapered end, the matrix composition comprising;

i) an active drug substance which is an analgesic; and

ii) at least one polyglycol; and

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

wherein the pharmaceutical composition provides a steady state C24 of the active drug substance that is at least 20% of steady state Cmax of the active drug substance.

3. The composition according to claim 1, wherein the composition is prepared for administration once daily for a period selected from at least 3 days, at least 7 days, and at least 14 days.

4. The composition according to claim 1, wherein the daily dosage of the active drug substance delivered from the composition is in the range of 15 to 500 mg.

5. The composition according to claim 1, wherein steady state C24 of the active drug substance provided by the composition is selected from at least 25%, at least 30%, at least 40%, and at least 50% of steady state Cmax of the active drug substance.

6. The composition according to claim 1, wherein steady state C24 of the active drug substance is selected from a range of 30 to 80% and a range of 30 to 60% of the steady state Cmax of the active drug substance.

7. The composition according to claim 1, wherein the 2^nd point where a concentration of 50% of steady state Cmax of the active drug substances is reached is in the range of 4 to 13.5 hours after last administration of the composition to a steady state individual.

8. The composition according to claim 1, wherein the 1^st point where a concentration of 50% of steady state Cmax of the active drug substance is reached is at a time selected from no earlier than 0.25 hours, a range of 0.25 to 2.5 hours, and a range of 0.25 to 3 hours after last administration of the composition to a steady state individual.

9. The composition according to claim 1, wherein administration of the composition to an individual results in occurrence of T_max of the active drug substance in the range of 3 to 4 hours after last administration of the composition to a steady state individual.

10. The composition according to claim 1, wherein Cmin of the active drug substance is reached no earlier than 12 hours after last administration of the composition to a steady state individual.

11. The composition according to claim 1, wherein the composition provides a Protraction index is selected from at least 0.20 and at least 0.30.

12. The composition according to claim 1, wherein administration of the composition to an individual in need thereof results in an average number of daily Break Through Pain episodes, as determined in at least 30 steady state individuals, selected format the most 2 and at the most 1.

13. The composition according to claim 1, wherein administration of the composition to an individual in need thereof results in an average pain intensity, as determined in at least 30 steady state individuals 23.5 to 24 hours after last administration of the composition, selected from at the most 4 and at the most 3 on a scale from 0 to 10, where 0 is equivalent to no pain and 10 is equivalent to pain as bad as you can imagine.

14. The composition according to claim 1, wherein administration of the composition to an individual in need thereof results in an average pain intensity, as determined in at least 30 steady state individuals from 11.5-12 hours to 23.5-24 hours after last administration of the composition, selected from at most 4 and at the most 3, on a scale from 0 to 10, where 0 is equivalent to no pain and 10 is equivalent to pain as bad as you can imagine.

15. The composition according to claim 1, wherein the analgesic is an opioid.

16. The composition according to claim 1, wherein the analgesic is morphine or a pharmaceutically acceptable salt thereof.

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

18. The composition according to claim 1, wherein at least one polyglycol is a homopolymer.

19. The composition according to claim 1, wherein at least one polyglycol is a copolymer.

20. The composition according to claim 1, wherein the total concentration of polyglycols in the matrix composition is from 5 to 99% w/w such as from 15 to 95% w/w, for example from 30 to 90% w/w, such as from 30 to 85% w/w, for example from 30 to 80% w/w, such as from 40 to 80% w/w, for example from 45 to 75% w/w, such as from 40 to 50% w/w, for example from 45 to 50% w/w, such as from 60 to 85% w/w, for example from 70 to 80% w/w, for example from 70 to 75% w/w.

21. The composition according to claim 1, wherein at least one polyglycol is a polyethylene glycol and/or a polyethylene oxide.

22. The composition according to claim 21, wherein the polyethylene glycol and/or polyethylene oxide has a molecular weight of in the range of 20,000 to 700,000 daltons, such as in the range of 20,000 to 600,000 daltons, for example in the range of 35,000 to 500,000 daltons, such as in the range of 35,000 to 400,000 daltons, for example in the range off 35,000 to 300,000 daltons, such as in the range of 50,000 to 300,000 daltons, for example about 200,000 daltons, such as about 300,000 daltons.

23. The composition according to claim 18, wherein the concentration of the homopolymers in the matrix composition is in the range of 5 to 90% w/w, for example in the range of 20 to 75% w/w, such as in the range of 20 to 70% w/w, for example in the range of 20 to 40% w/w, such as in the range of 20 to 85% w/w, such as in the range of 30 to 85% w/w, for example in the range of about 30 to 75% w/w, such as in the range of 30 to 50% w/w, for example in the range of 30 to 40% w/w, such as in the range of 30 to 35% w/w, such as in the range of 31 to about 33% w/w, such as in the range of 50 to 85% w/w, from 60 to 80% w/w, for example in the range of 70 to 80% w/w, for example in the range of 70 to 75% w/w, such as in the range of 71 to about 73% w/w.

24. The composition according to claim 19, wherein the copolymer is a poloxamer that has an average molecular weight in the range of 2,000 to 30,000 dalton, such as in the range of 2,000 daltons to 20,000 daltons, for example in the range of 4,000 daltons to 18,000 daltons, such as in the range of 6,000 daltons to 10,000 daltons.

25. The composition according to claim 19, wherein the concentration of copolymer in the matrix composition is in the range of 0 to 30% w/w, such as in the range of 1 to 20% w/w, for example in the range of 2 to 10% w/w, such as in the range of 2 to 5% w/w, such as in the range of 5 to 30% w/w, for example in the range of 10 to 30% w/w, such as in the range of 10 to 20% w/w, for example in the range of 10 to 15% w/w.

26. The composition according to claim 1, wherein the matrix further comprises one or more gelling agent(s).

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

28. The composition according to claim 1, wherein the coating comprises a cellulose derivative.

29. The composition according to claim 28, wherein the cellulose derivative is ethyl cellulose.

30. The composition according to claim 27, wherein the coating comprises at least 80% w/w of said cellulose derivative.

31. The composition according to claim 27, wherein the coating further comprises at least one selected from the group consisting of

i) polymers which are soluble or dispersible in water,

ii) plasticizers, and

iii) one or more fillers.

32. The composition according to claim 1, wherein the coating comprises polylactic acid.

33. The composition according to claim 32, wherein the coating comprises at least 80% w/w of said polylactic acid.

34. The composition according to claim 1, wherein the composition comprises morphine sulphate as the active drug, a mixture of polyethylene oxide 200,000 and polyethylene oxide 300,000 as polyglycol, poloxamer as plasticizer, mannitol as stabilizer, a mixture of carrageenan and hydroxypropylmethylcellulose as gelling agent, butylated hydroxytoluene as antioxidant and a mixture of polactic acid and polyethyleneoxide as the coating.

35. The composition according to claim 1, wherein the composition comprises morphine sulphate as the active drug, polyethylene oxide 300,000 as polyglycol, poloxamer as plasticizer, a mixture of mannitol and butylated hydroxytoluene as stabilizer and a mixture of ethylcellulose, cetostearyl alcohol and titanium dioxide as the coating.

36. The composition according to claim 1, wherein the composition is designed for oral administration.

37. The composition according to claim 1, wherein the composition is in the form of tablets.

38. The composition according to claim 1, wherein the pharmaceutical composition is an injection moulded or extruded composition.

39. The composition according to claim 1, wherein the composition is compressed.

40. The composition according to claim 1, wherein the matrix composition has a solubility and/or release rate in ethanol that is equal to or lower than that in water.

41. The composition according to claim 1, wherein the composition is resistant to isolation of the active drug substance by crushing, melting and ethanol extraction.

42. The composition according to claim 1, wherein said pain is chronic pain.

43. The composition according to claim 1, wherein said pain is moderate to severe.

44. The composition according to claim 1, wherein the composition is administered to an individual suffering from cancer.

45. The composition according to claim 1, wherein the composition is administered to an individual suffering from a severe injury.

46. The composition according to claim 1, wherein the composition is administered to an individual that is a post-surgical individual.

2. A pharmaceutical composition for treatment of a clinical condition, wherein the medicament is prepared for administration once daily for at least 3 days, the pharmaceutical composition comprising:

a) a matrix composition having a cylindrical shape and, optionally, one or more tapered end, the matrix composition comprising;

i) an active drug substance; and

ii) at least one polyglycol; and

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

47. A method for continuously treating pain in an individual in need thereof, said method comprising continuously administering to said individual once daily, a pharmaceutical composition comprising:

a) a matrix composition having a cylindrical shape and optionally including one or more tapered end(s), the matrix composition comprising;

i) an active drug substance which is an analgesic; and

ii) at least one polyglycol; and

b) a coating substantially surrounding said matrix composition and having at least one opening exposing at least one surface of said matrix, said coating being impermeable to water;

wherein the composition provides a steady state C24 of the active drug substance that is at least 20% of steady state Cmax of the active drug substance.

48. Use of a composition of an active drug substance for the preparation of a medicament for continuous treatment of pain in an individual in need thereof, wherein the medicament is prepared for continuous administration once daily, and wherein steady state C24 of the active drug substance is at least 20% of steady state Cmax of the active drug substance and the composition comprises:

a) a matrix composition having a cylindrical shape and optionally including one or more tapered end(s), the matrix composition comprising;

i) an active drug substance which is an analgesic; and

ii) at least one polyglycol; and

b) a coating substantially surrounding said matrix composition and having at least one opening exposing at least one surface of said matrix, said coating being impermeable to water.