Sequential drug delivery systems

• US 20050031677A1
• Filed: 09/08/2004
• Published: 02/10/2005
• Est. Priority Date: 07/10/2001
• Status: Active Grant

• Current Assignee: Cima Labs Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Cima Labs Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Hontz, John, Siebert, John M., Pather, S. Indiran
• Granted Patent: US 7,670,617 B2
• Time in Patent Office: Days
• US Class Current: 424/448
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/025 characterised by shape or structure, e.g. hollow layered, coated
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50

Abstract

The invention relates to methods and composition for improving absorption and dissolution of active ingredients of drugs. The invention provides a method of administration of an active ingredient to a mammal through a transmucosal route that includes delivering the active ingredient to a desired site in a body of the mammal, and, sequentially, at the desired site, promoting dissolution and absorption of the active ingredient. In a preferred embodiment, the pH of the localized environment of the active ingredient is sequentially modified to promote dissolution and absorption.

Claims

1. A method of administration of an active ingredient to a mammal through a transmucosal route, said method comprising:

a. delivering said active ingredient to a desired site in a body of said mammal; and

, sequentially, at said desired site,

i. adjusting a localized environment of said active ingredient to promote dissolution of said active ingredient,

ii. adjusting said localized environment to promote absorption of said active ingredient.

2. The method of claim 1, wherein said active ingredient is delivered in a dosage form having a first portion and a second portion;

said step of adjusting said localized environment to promote said dissolution comprising releasing said first portion of said dosage form;

said step of adjusting said localized environment to promote said absorption comprising releasing said second portion of said dosage form.

3. The method of claim 2, wherein said desired site is selected from the group consisting of a site of administration and a site of absorption.

4. The method of claim 2, wherein said first portion includes one or more first substances that promote said dissolution of said active ingredient, said one or more first substances selected from the group consisting of pH-adjusting substances, surface-active compounds, pharmaceutically-acceptable solvents and enveloping additives;

said second portion including one or more second substances that promote absorption, said one or more second substances selected from the group consisting of pH-adjusting substances, effervescent penetration enhancers, non-effervescent penetration enhancers and bioadhesives.

5. The method of claim 2, wherein said first portion of said dosage form includes a first pH-adjusting substance thereby said active ingredient attains a first state of dissociation that promotes dissolution;

said second portion of said dosage form including a second pH-adjusting substance thereby said active ingredient attains a second state of dissociation that promotes absorption.

6. The method of claim 5, wherein said first and said second pH-adjusting substances are respectively an acid and a base.

7. The method of claim 5, wherein said first and said second pH-adjusting substances are respectively a base and an acid.

8. The method of claim 5, wherein said first and said second pH-adjusting substance are respectively a base and a base.

9. The method of claim 5, wherein said first and said second pH-adjusting substances are respectively an acid and an acid.

10. The method of claim 1, wherein said transmucosal route is selected from the group consisting of buccal, sublingual, gingival, gastrointestinal, rectal, vaginal, and nasal routes.

11. The method of claim 1, wherein said active ingredient is selected from the group consisting of analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics, antiflatuents, antimigraine agents, antispasmodics, sedatives, antihyperactives, antihypertensives, tranquilizers, decongestants, beta blockers, peptides, proteins, and oligonucleotides.

12. The method of claim 5, wherein said dosage form includes means for said sequential release of said first portion and said second portion, said means for sequential release selected from the group consisting of coatings, membranes, matrix materials, pre-cursors of active ingredients and pre-cursors of pH-adjusting substances.

13. The method of claim 5, wherein said second portion of said dosage form comprises said second pH-adjusting substance dispersed in a controlled release matrix material.

14. The method of claim 5, wherein said first portion of said dosage form includes said active ingredient.

15. The method of claim 5, wherein said second portion of said dosage form comprises said second pH-adjusting substance surrounded by a coating, whereby said first pH-adjusting substance is peripheral to said coating in said dosage form.

16. The method of claim 15, wherein said active ingredient is peripheral to said coating in said dosage form.

17. The method of claim 5, wherein said second portion of said dosage form includes said second pH-adjusting substance surrounded by a membrane, said first pH-adjusting substance being peripheral to said membrane.

18. The method of claim 17, wherein said active ingredient is peripheral to said membrane in said dosage form.

19. A method for administering an active ingredient via a transmucosal route in a mammal, comprising administering said active ingredient in a dosage form with a first pH-adjusting substance and a second pH-adjusting substance thereby the localized environment of the active ingredient attains a first pH and then a second pH, said first pH promoting dissolution of said active ingredient and said second pH promoting absorption of said active ingredient.

20. The method of claim 47, wherein said first and said second pH-adjusting substances are respectively an acid and a base.

21. The method of claim 47, wherein said first and said second pH-adjusting substances are respectively a base and an acid.

22. The method of claim 47, wherein said first and said second pH-adjusting substance are respectively a base and a base.

23. The method of claim 47, wherein said first and said second pH-adjusting substances are respectively an acid and an acid.

24. The method of claim 47, wherein said transmucosal route is selected from the group consisting of buccal, sublingual, gingival, gastrointestinal, rectal, vaginal, and nasal.

25. The method of claim 47, wherein said active ingredient is selected from the group consisting of analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics, antiflatuents, antimigraine agents, antispasmodics, sedatives, antihyperactives, antihypertensives, tranquilizers, decongestants, beta blockers, peptides, proteins, and oligonucleotides.

26. The method of claim 47, wherein said administering step includes providing said second pH-adjusting substance dispersed in a controlled release matrix material in said dosage form.

27. The method of claim 26, wherein said active ingredient is peripheral to said controlled release matrix material in said dosage form.

28. The method of claim 47, wherein said administering step includes providing said second pH-adjusting substance surrounded by a coating, wherein said first pH-adjusting substance is peripheral to said coating in said dosage form.

29. The method of claim 28, wherein said active ingredient is peripheral to said coating in said dosage form.

30. The method of claim 47, wherein said administering step includes providing said second pH-adjusting substance surrounded by a membrane, wherein said first pH-adjusting substance is peripheral to said membrane in said dosage form.

31. The method of claim 30, wherein said active ingredient is peripheral to said membrane in said dosage form.

47. The method of claim 19, wherein said first pH-adjusting substance attains peak activity in the localized environment of the active ingredient before said second pH-adjusting substance attains peak activity in the localized environment of the active ingredient.

32. A pharmaceutical composition comprising an active ingredient in a dosage form comprising a first portion, a second portion and means for sequential release of said first portion and said second portion at a desired site;

said first portion including one or more first substances that adjust a localized environment of said active ingredient at said desired site to promote dissolution of said active ingredient;

said second portion including one or more second substances that adjust said localized environment of said active ingredient at said desired site to promote absorption of said active ingredient.

33. The composition of claim 32, wherein said first substance comprises a first pH-adjusting substance, said second substance comprises a second pH-adjusting substance, and said means for sequential release are means for sequentially controlling the activity of said pH-adjusting substances so that said first pH-adjusting substance attains peak activity in the localized environment of the active ingredient before said second pH-adjusting substance attains peak activity in the localized environment;

whereby the localized environment of the active ingredient attains a first pH and then a second pH, said first pH promoting dissolution of said active ingredient and said second pH promoting absorption of said active ingredient.

34. The pharmaceutical composition of claim 33, wherein said first and second pH-adjusting substances are respectively an acid and a base.

35. The pharmaceutical composition of claim 33, wherein said first and said second pH-adjusting substances are respectively a base and an acid.

36. The pharmaceutical composition of claim 33, wherein said first and said second pH-adjusting substance are respectively a base and a base.

37. The pharmaceutical composition of claim 33, wherein said first and second pH-adjusting substances are respectively an acid and an acid.

38. The pharmaceutical composition of claim 32, wherein said means for sequential release are selected from the group consisting of coatings, membranes, matrix materials, active ingredients pre-cursors and precursors of pH-adjusting substances.

39. The pharmaceutical composition of claim 33, wherein said means for sequentially controlling the activity of said pH-adjusting substances comprises at least one coating that surrounds said second pH-adjusting substance, said first pH-adjusting substance being peripheral to said coating in said dosage form.

40. The pharmaceutical composition of claim 39, wherein said active ingredient is peripheral to said coating in said dosage form.

41. The pharmaceutical composition of claim 33, wherein said means for sequentially controlling the activity of said pH-adjusting substances comprises a controlled release matrix material in said dosage form, said second pH-adjusting substance being dispersed in said controlled release matrix material, and said first pH-adjusting substance being peripheral to said controlled release matrix material in said dosage form.

42. The pharmaceutical composition of claim 41, wherein said active ingredient is peripheral to said matrix material in said dosage form.

43. The pharmaceutical composition of claim 33, wherein said means for sequentially controlling the peak activities of said pH-adjusting substances comprises at least one membrane in said dosage form that surrounds said second pH-adjusting substance, said first pH-adjusting substance being peripheral to said membrane in said dosage form.

44. The pharmaceutical composition of claim 43, wherein said active ingredient is peripheral to said membrane in said dosage form.

45. The pharmaceutical composition of claim 32, wherein said active ingredient is selected from the group consisting of analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics, antiflatuents, antimigraine agents, antispasmodics, sedatives, antihyperactives, antihypertensives, tranquilizers, decongestants, beta blockers, peptides, proteins, and oligonucleotides.

46. The pharmaceutical composition of claim 32, wherein said one or more first substances are selected from the group consisting of pH-adjusting substances, surface-active compounds, pharmaceutically-acceptable solvents and enveloping additives, said one or more second substances are selected from the group consisting of pH-adjusting substances, effervescent penetration enhancers and non-effervescent penetration enhancers.

48. A pharmaceutical composition that dissolves and is absorbed sequentially at a desired site in a mammal, comprising:

a first portion for promoting dissolution of said pharmaceutical composition;

a second portion for promoting absorption of said pharmaceutical composition; and

an active ingredient.

49. The pharmaceutical composition as claimed in claim 48, wherein said active ingredient is a vitamin, mineral, dietary supplement, or a non-systemically distributable drug.

50. The pharmaceutical composition as claimed in claim 48, wherein said second portion for promoting absorption is achieved by a mechanism chosen from the group consisting of reduction in the thickness of the mucus layer, reduction in the viscosity of the mucus layer, changes in the structure of the cell membrane, increases in the hydrophobicity within the cellular membranes, alteration of tight junctions, ion pairing and complexation, enhancement of active transport mechanisms, modification of the cellular efflux mechanisms, and changes in the stability of active ingredients toward enzymes.

51. The pharmaceutical composition as claimed in claim 48, wherein said first portion for promoting dissolution is achieved by a first pH change, and said second portion for promoting absorption is achieved by a second pH change, said first pH change and said second pH change have a time difference of about 30 seconds to about 60 minutes.

52. The pharmaceutical composition as claimed in claim 48, wherein said first portion for promoting dissolution is achieved by a first pH change, and said second portion for promoting absorption is achieved by a second pH change, said first pH change and said second pH change have a time difference of about 3 minutes to about 15 minutes.

53. The pharmaceutical composition as claimed in claim 48, further comprising an organic solvent.

54. The pharmaceutical composition as claimed in claim 48, wherein said first portion for promoting dissolution is achieved by a first pH change, and said second portion for promoting absorption is achieved by a second pH change, said first pH change changes the pH about 1 pH unit, and said second pH change changes the pH about 1 pH unit.

55. The pharmaceutical composition as claimed in claim 54, wherein said active ingredient is selected such that the pKa of said active ingredient is selected at about the center of the pH of said first pH change and the pH of said second pH change.

56. The pharmaceutical composition as claimed in claim 48, wherein said first pH change and said second pH change are achieved by a pH-adjusting substance, said pH-adjusting substance selected from the group consisting of citric acid, tartaric acid, amalic acid, fumeric acid, adipic acid, succinic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and magnesium carbonate.

57. The pharmaceutical composition as claimed in claim 48, wherein said first portion for promoting dissolution contains said active ingredient, and said second portion for promoting absorption is contained in a coating.

58. The pharmaceutical composition as claimed in claim 48, wherein said first portion for promoting dissolution contains said active ingredient, said first portion for promoting dissolution and said active ingredient is contained in a coating, and said second portion for promoting absorption is contained in a coating.

59. The pharmaceutical composition of claim 57, wherein said coating is selected from the group consisting of an enteric coating, a coating responsive to pH changes, a coating which is metabolized by enzymes present specifically in the localized environment of the target site of absorption, a coating which is metabolized by enzymes predominantly in the localized environment of the target site of absorption, a coating which dissolves after a certain period of time, and a coating which dissolves after exposure to a certain volume of liquid.

60. The pharmaceutical composition of claim 58, wherein said coating is selected from the group consisting of an enteric coating, a coating responsive to pH changes, a coating which is metabolized by enzymes present specifically in the localized environment of the target site of absorption, a coating which is metabolized by enzymes predominantly in the localized environment of the target site of absorption, a coating which dissolves after a certain period of time, and a coating which dissolves after exposure to a certain volume of liquid.

61. The pharmaceutical composition as claimed in claim 48, wherein said first portion for promoting dissolution is achieved by containing said first portion in a coating and a matrix.

62. The pharmaceutical composition as claimed in claim 48, wherein said first portion for promoting dissolution is achieved by containing said first portion in a coating and a membrane.

63. The pharmaceutical composition as claimed in claim 48, wherein said first portion for promoting dissolution is achieved by containing said first portion in a membrane and a matrix.

64. The pharmaceutical composition as claimed in claim 48, wherein said second portion for promoting absorption is achieved by containing said first portion in a coating and a matrix.

65. The pharmaceutical composition as claimed in claim 48, wherein said second portion for promoting absorption is achieved by containing said first portion in a coating and a membrane.

66. The pharmaceutical composition as claimed in claim 48, wherein said second portion for promoting absorption is achieved by containing said first portion in a membrane and a matrix.

67. The pharmaceutical composition as claimed in claim 48, wherein said active ingredient is a drug that displays poor pharmacokinetic characteristics.

68. The pharmaceutical composition as claimed in claim 48, wherein said active ingredient has poor bioavailability.

69. The pharmaceutical composition as claimed in claim 48, wherein said active ingredient has a pK_a within the pH range of the desired target body cavity.

70. The pharmaceutical composition as claimed in claim 48, wherein said pharmaceutical composition is administered in a suitable dosage form, said suitable dosage form selected from the group consisting of tablets, granules, pellets, multiparticulates, capsules, minitablets, beads, powders, suppositories, gels, solutions, liquid drugs, emulsions, and microemulsions.

71. The pharmaceutical composition as claimed in claim 48, further consisting of a bioadhesive.

72. The pharmaceutical composition as claimed in claim 48, further consisting of a glidant.

73. The pharmaceutical composition as claimed in claim 48, further consisting of a lubricant.

74. The pharmaceutical composition as claimed in claim 48, further consisting of a binder.

75. The pharmaceutical composition as claimed in claim 48, wherein said binder is selected from the group consisting of povidone, acacia, tragacanth, gelatin, starch, methyl cellulose, sodium carboxy methyl cellulose, alginic acid, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acid, bentonite, sugar, and invert sugar.

76. The pharmaceutical composition as claimed in claim 48, further consisting of an excipient.

77. The pharmaceutical composition as claimed in claim 48, further consisting of a flavoring.