Gastric release pulse system for drug delivery

Abstract

Disclosed are pharmaceutical products for providing pulses of at least one pharmaceutically active ingredient from a patient's stomach, or from a subsequent gastrointestinal site proximal thereto, for absorption thereof at a site(s) more distal in the gastrointestinal tract than the patient's stomach, or than the subsequent gastrointestinal site proximal thereto. The product comprises first, second, and third pharmaceutical dosage forms, each of which comprises at least one pharmaceutically active agent and a pharmaceutically acceptable carrier. The product is formulated such that at least two of the first, second, and third pharmaceutical dosage forms further comprise means for providing temporary gastric-retention of the at least two of the first, second, and third pharmaceutical dosage forms within the patient's stomach, or at the subsequent gastrointestinal site proximal thereto.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a graphical illustration of the pulse collapse effect. FIG. 1(A) shows the hypothetical number distribution of pH-dependant pellets passing their respective early middle and late trigger points. As the pH trigger point becomes higher and thus later in GI transit time the pellet population is subject to more spread, resulting in fewer pellets passing the trigger point per unit time thus prolonging the in vivo release rate as illustrated in FIG. 1(B).

FIG. 2 represents the pharmacokinetic profile of two formulations, A and B, with trigger points of pH 7.5 and 6.8, respectively. The formulations were administered in the fed and fasted state. In both conditions the phenomenon of pellet spreading is evidenced by the reduced absorption rate of the higher trigger point formulation.

FIG. 3 is a graphical representation of actual pharmacokinetic performance of a prior art pH-dependent formulation with a pH trigger point of 7.5 versus a simulated pharmacokinetic profile of the current invention. Suggested from this graphic is the significantly improved lag time in the greatly increased bioavailability offered by the current invention.

FIG. 4 graphically depicts the type of improvement possible from a composite three-pulse formulation. The prior art profile is actual pharmacokinetic data from a three-pulse product manufactured utilizing prior art technologies. The current invention profile is actual pharmacokinetic data generated by administering three equivalent immediate release doses at time zero, 1.5 hours and three hours; this type of dosing scheme represents the type of pharmacokinetic profile that can be made possible from a single dose of the current invention.

FIG. 5 is a cross section of a three-pulse composite tablet product of the current invention designated generally by the reference numeral 20. The three pulse composite tablet product includes an outer aesthetic/moisture barrier layer 1, that is non release rate modifying; an outermost drug layer 2, containing P1; a first pH independent layer 3 (providing a first delayed release); a drug layer 4 containing P2L1, which may be the same drug as in P1 or alternately may be a different drug, this drug layer may optionally contain a disintegrating agent to assist in the removal of the first pH independent layer 3; a second pH independent layer 5 (providing a second delayed release); an inner core tablet 6 containing drug for P2L2, which core tablet optionally contains any or each of: a disintegration agent 7 to assist with removal of coating, a hydrophilic bioadhesive agent 8a, or a hydrophobic bioadhesive agent 8b.

FIG. 6 is a cross section of a three-pulse composite pouch product of the current invention designated generally by the reference numeral 30 The three-pulse composite pouch product includes pellets 9, formulated for immediate release (P1); pellets 10, formulated for a first delayed release (P2L1); pellets 11, formulated for a delayed sustained release (P3L2); and a pouch or wall 12 to contain the pellets until administration as a sprinkle.

FIGS. 7(A) and 7(B) are illustrative cross sections of dosage forms designated generally by the reference numerals 40 and 50, respectively. Each shows the preferred methods of incorporation of the bioadhesive entities into the dosage form of the product of the instant invention. FIG. 7(A) shows a core 40, containing a hydrophilic bioadhesive agent 13, and/or a hydrophobic bioadhesive agent 14, dispersed with drug in a matrix. FIG. 7(B) shows a core 50, containing drug and a hydrophilic bioadhesive agent 16 in a matrix coated with a hydrophobic bioadhesive agent 15.

FIG. 8 illustrates some of the contemplated release profiles of the current invention.

Claims

1. A pharmaceutical product for providing pulses of at least one pharmaceutically active ingredient from a patient's stomach, or from a subsequent gastrointestinal site proximal thereto, for absorption thereof at a site(s) more distal in the gastrointestinal tract than said patient's stomach, or than said subsequent gastrointestinal site proximal thereto, said product comprising: first, second, and third pharmaceutical dosage forms; each of said pharmaceutical dosage forms comprising at least one pharmaceutically active agent and a pharmaceutically acceptable carrier, and wherein at least two of said first, second, and third pharmaceutical dosage forms further comprise means for providing temporary gastric-retention of said at least two of said first, second, and third pharmaceutical dosage forms within said patient's stomach, or at said subsequent gastrointestinal site proximal thereto.

2. The pharmaceutical product of claim 1, wherein said site(s) more distal in the gastrointestinal tract than said patient's stomach, or than said subsequent gastrointestinal site proximal thereto, is the duodenum.

3. The pharmaceutical product of claim 1, wherein said site(s) more distal in the gastrointestinal tract than said patient's stomach, or than said subsequent gastrointestinal site proximal thereto, are the duodenum and the jejunum.

4. The pharmaceutical product of claim 1, wherein said site(s) more distal in the gastrointestinal tract than said patient's stomach, or than said subsequent gastrointestinal site proximal thereto, is the small intestine.

5. The pharmaceutical product of claim 1, wherein said site(s) more distal in the gastrointestinal tract than said patient's stomach, or than said subsequent gastrointestinal site proximal thereto, is the small intestine and colon.

6. The pharmaceutical product of claim 1, wherein said site(s) more distal in the gastrointestinal tract than said patient's stomach, or than said subsequent gastrointestinal site proximal thereto, is the jejunum.

7. The pharmaceutical product of claim 1, wherein said site(s) more distal in the gastrointestinal tract than said patient's stomach, or than said subsequent gastrointestinal site proximal thereto, is the ileum.

8. The pharmaceutical product of claim 1, wherein said site(s) more distal in the gastrointestinal tract than said patient's stomach, or than said subsequent gastrointestinal site proximal thereto, is the colon.

9. The pharmaceutical product of claim 1, wherein said subsequent gastrointestinal site proximal to said stomach, is the duodenum.

10. The pharmaceutical product of claim 1, wherein said subsequent gastrointestinal site proximal to said stomach is selected from the group consisting of the duodenum and the jejunum, and wherein said site(s) more distal in the gastrointestinal tract than said patient's stomach, or than said subsequent gastrointestinal site proximal thereto is selected from the group consisting of the ileum and the colon.

11. The pharmaceutical product of claim 1, wherein said means for providing gastric-retention of said at least two of said first, second, and third pharmaceutical dosage forms dosage forms within said patient's stomach, or at said subsequent gastrointestinal site proximal thereto, are independently selected from the group consisting of bioadhesion, size exclusion, density manipulation, and other means of modifying transit and release of the dosage form.

12. The pharmaceutical product of claim 1, wherein each of said first, second, and third pharmaceutical dosage forms initiates release of active pharmaceutical ingredient at different times.

13. The pharmaceutical product of claim 1, wherein each of said first, second, and third pharmaceutical dosage forms have different lag times.

14. The pharmaceutical product of claim 1, wherein each of said first, second, and third pharmaceutical dosage forms have different rates of release.

15. The pharmaceutical product of claim 1, wherein said product is in oral dosage form.

16. The pharmaceutical product of claim 15, wherein said oral dosage form is selected form the group consisting of tablets, capsules, sachets, sprinkles, ampules, and solutions.

17. The pharmaceutical product of claim 1, wherein said temporary gastric-retention of all three of said pharmaceutical dosage forms occurs in the stomach.

18. The pharmaceutical product of claim 1, wherein said temporary gastric-retention of one of said pharmaceutical dosage forms occurs in the stomach and wherein said temporary gastric-retention of two of said pharmaceutical dosage forms occurs independently at a group consisting of the upper small intestine and the proximal small intestine.

19. The pharmaceutical product of claim 1, wherein the release of said pulse of at least one pharmaceutically active agent from each of said pharmaceutical dosage forms is separated by about at least one hour.

20. The pharmaceutical product of claim 1, wherein said pulse of at least one pharmaceutically active agent from each of said pharmaceutical dosage forms is about at least 50% dissolved before release of said pulse of at least one pharmaceutically active agent is initiated from the subsequently releasing dosage form.

21. The pharmaceutical product of claim 1, wherein the release of said pulse of at least one pharmaceutically active agent from each of said pharmaceutical dosage forms is separated by about at least one hour and wherein said pulse of at least one pharmaceutically active agent from each of said pharmaceutical dosage forms is about at least 50% dissolved before release of said pulse of at least one pharmaceutically active agent is initiated from the subsequently releasing dosage form.

22. The pharmaceutical product of claim 1, wherein the pulses are released so that the corresponding Cmax of each of the at least three pulses is distinguishable in a pharmacokinetic plasma profile.

23. The pharmaceutical product of claim 1, wherein the pulses are released so that the corresponding Tmax of each of the at least three pulses is distinguishable in a pharmacokinetic plasma profile.

24. The pharmaceutical product of claim 1, wherein the corresponding Cmax and Tmax of each of the at least three pulses is distinguishable in a pharmacokinetic plasma profile.

25. The pharmaceutical product of claim 1, wherein each dosage form initiates release of said pulse of at least one pharmaceutically active ingredient at a different time and/or at a different rate.

26. The pharmaceutical product of claim 1, having a pharmacokinetic plasma profile characteristic of a controlled release or sustained release product.

27. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 1, in the fed or fasted state.

28. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 2, in the fed or fasted state.

29. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 3, in the fed or fasted state.

30. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 4, in the fed or fasted state.

31. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 5, in the fed or fasted state.

32. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 6, in the fed or fasted state.

33. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 7, in the fed or fasted state.

34. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 8, in the fed or fasted state.

35. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 9, in the fed or fasted state.

36. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 10, in the fed or fasted state.

37. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 11, in the fed or fasted state.

38. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 12, in the fed or fasted state

39. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 13, in the fed or fasted state.

40. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 14, in the fed or fasted state.

41. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 15, in the fed or fasted state.

42. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 16, in the fed or fasted state.

43. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 17, in the fed or fasted state.

44. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 18, in the fed or fasted state.

45. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 19, in the fed or fasted state.

46. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 20, in the fed or fasted state.

47. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 21, in the fed or fasted state.

48. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 22, in the fed or fasted state.

49. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 23, in the fed or fasted state.

50. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 24, in the fed or fasted state.

51. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 25, in the fed or fasted state.

52. A method of treating a patient with a pharmaceutically active ingredient comprising administering to said patient the pharmaceutical product of claim 26, in the fed or fasted state.