High viscosity liquid controlled delivery system

• US 5,747,058 A
• Filed: 06/07/1995
• Issued: 05/05/1998
• Est. Priority Date: 06/07/1995
• Status: Expired due to Term

• Current Assignee: DURECT Corporation
• Original Assignee: Southern Biosystems, Inc. (DURECT Corporation)
• Inventors: Holl, Richard J., Tipton, Arthur J.
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US08/474,337
• Time in Patent Office: 1,063 Days
• Field of Search: 424/45, 424/423, 424/430, 424/435, 424/436, 424/443, 424/451, 424/464
• US Class Current: 424/423
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 8/60 Sugars; Derivatives thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 26/0066 Medicaments; Biocides
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61Q 11/00 Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• CPC Class Codes: A61Q 5/006 Antidandruff preparations

Abstract

A composition for the controlled release of substances is provided that includes: (i) a non-polymeric, non-water soluble liquid carrier material (HVLCM) of viscosity of at least 5,000 cP at 37° C. that does not crystallize neat under ambient or physiological conditions; and (ii) a substance to be delivered.

Claims

1. A liquid composition for the delivery of biologically active substances comprising:

(a) a non-polymeric, non-water soluble high viscosity liquid carrier material having a viscosity of at least 5,000 cP at 37°

C. that does not crystallize neat under ambient or physiological conditions; and

(b) a biologically active substance.

2. The composition of claim 1, wherein the non-polymeric non-water soluble liquid carrier material is sucrose acetate isobutyrate.

3. The composition of claim 2, wherein the non-polymeric non-water soluble liquid carrier material is present in an amount from about 99.5 percent to about 10 percent by weight, relative to the total weight of the composition.

4. The composition of claim 3, wherein the non-polymeric non-water soluble liquid carrier material is present in an amount from about 95 percent to about 25 percent by weight, relative to the total weight of the composition.

5. The composition of claim 2, wherein the composition further comprises a solvent in which the non-polymeric non-water insoluble liquid carrier material is soluble.

6. The composition of claim 5, wherein the solvent is selected from the group consisting of ethanol, dimethylsulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, 2-pyrrolidone, N-methylpyrrolidone, propylene carbonate, and glycofurol.

7. The composition of claim 5, wherein the solvent is present in an amount from about 10 to about 50 percent by weight, relative to the weight of the composition.

8. The composition of claim 2, wherein the composition further comprises an additive.

9. The composition of claim 8, wherein the additive is selected from biodegradable polymers, non-biodegradable polymers, natural oils, synthetic oils, carbohydrates, inorganic salts, and inert organic compounds.

10. The composition of claim 8, wherein the additive is present in an amount in the range from about 1 to about 20 percent by weight, relative to the total weight of the composition.

11. The composition of claim 2, wherein the biologically active substance is selected from the group consisting of peptides, proteins, nucleoproteins, mucoproteins, lipoproteins, and synthetic polypeptides.

12. The composition of claim 3, wherein the non-polymeric non-water soluble high viscosity liquid carrier material is present in an amount from about 85 percent to about 45 percent by weight, relative to the total weight of the composition.

13. The composition of claim 2 suitable for topical administration.

14. The composition of claim 2 suitable for systemic administration.

15. The composition of claim 2 suitable for parenteral administration.

16. The composition of claim 5, wherein the solvent is selected from the group consisting of 2-pyrrolidone, N-methylpyrrolidone and ethanol.

17. The composition of claim 2, further comprising a lower viscosity liquid carrier material.

18. The composition of claim 17, wherein the lower viscosity liquid carrier material has a viscosity of less than 1000 cp.

19. The composition of claim 2, wherein the biologically active substance is useful for agricultural purposes.

20. The composition of claim 2, wherein the biologically active substance is useful for human therapy purposes.

21. The composition of claim 2, wherein the biologically active substance is useful for veterinary purposes.

22. The composition of claim 19, wherein the active agent is useful for the control of weeds.

23. The composition of claim 19, wherein the active agent is useful for the control of insects.

24. The composition of claim 19, wherein the composition is useful for the control of pests.

25. The composition of claim 20, wherein the biologically active agent is a steroid.

26. The composition of claim 2, wherein the biologically active agent is a vaccine.

27. The composition of claim 2, wherein the composition is useful to control lice.

28. The composition of claim 2, wherein the composition is useful to control dandruff.

29. The composition of claim 2, wherein the biologically active agent is theophylline.

30. The composition of claim 8, wherein the additive is cellulose acetate butyrate.

31. The composition of claim 2, wherein the biologically active agent is flurbiprofen.

32. The composition of claim 2, wherein the biologically active agent is naproxen.

33. The composition of claim 2, wherein the biologically active agent is chlorhexidine.

34. The composition of claim 2, wherein the biologically active agent is diclofenac.

35. The composition of claim 2, wherein the biologically active substance is a drug.

36. The composition of claim 2, wherein the biologically active substance is an anesthetic.

37. The composition of claim 2, wherein the biologically active compound is a peptide.

38. The composition of claim 2, wherein the biologically active compound is an estrogen.

39. The composition of claim 2, wherein the biologically active agent is a progesterone.

40. The composition of claim 2, wherein the biologically active agent is a hormone.

41. The composition of claim 2, wherein the biologically active agent is an antibiotic.

42. The composition of claim 2, wherein the biologically active agent is an antipsychotic.

43. The composition of claim 2, wherein the biologically active agent is tetracycline.

44. The composition of claim 2, wherein the biologically active agent is azithromycin.

45. The composition of claim 2, wherein the biologically active agent is a nucleoside or nucleotide.

46. The composition of claim 2, wherein the biologically active agent is dexamethasone.

47. The composition of claim 2, wherein the biologically active agent is 17-β

-estradiol.

48. The composition of claim 2, wherein the biologically active agent is a progesterone and estradiol in combination.

49. The composition of claim 2, wherein the biologically active agent is a growth factor.

50. The composition of claim 8, wherein the additive comprises a poly(lactide).

51. The composition of claim 8, wherein the additive comprises a poly(lactide-co-glycolide).

52. The composition of claim 8, wherein the additive is a poly(glycolide).

53. The composition claim 8, wherein the additive is poly(caprolactone).

54. The composition of claim 8, wherein the additive is oxidized cellulose.

55. The composition of claim 8, wherein the additive is poly(D,L-lactic acid).

56. The composition of claim 8, wherein the additive is a nonbiodegradable polymer.

57. The composition of claim 8, wherein the additive is a biodegradable polymer.

58. The composition of claim 8, wherein the additive is polyvinyl pyrrolidone.

59. The composition of claim 8, wherein the additive is polyethylene glycol.

60. The composition of claim 8, wherein the additive is cellulose acetate butyrate.

61. The composition of claim 8, wherein the additive is cellulose acetate propionate.

62. The composition of claim 8, wherein the additive is peanut oil.

63. The composition of claim 8, wherein the additive is sesame oil.

64. The composition of claim 8, wherein the additive is sucrose.

65. The composition of claim 8, wherein the biologically active material is doxycycline.

66. The composition of claim 2, suitable for rectal administration.

67. The composition of claim 2, suitable for vaginal administration.

68. The composition of claim 2, suitable for nasal administration.

69. The composition of claim 8, wherein the additive is a carbohydrate.

70. The composition of claim 2, suitable for oral administration.

71. The composition of claim 2, wherein the biologically material is transforming growth factor-beta.

72. The composition of claim 2, wherein the biologically active material is a steroid.

73. The composition of claim 2, wherein the biologically active substance is a chemotherapeutic agent.

74. A method for the administration of the controlled release composition of claim 1, comprising the steps of

(a) providing an amount of the controlled release composition;

and

(b) administering the composition to the host in a emulsion or in a solution.

75. A method for the administration of the controlled release composition of claim 1, comprising the step of administering the composition to the host via injection.

76. The composition of claim 1, wherein the biologically active material is an antiviral.

77. The composition of claim 1 useful to block surgical adhesions.

78. The composition of claim 1 useful in scaffolding, void filling, or tissue regeneration.

79. The composition of claim 1 for use to block the arterial supply of a tumor.

80. The composition of claim 2 useful as a tissue adhesive.

81. The composition of claim 2 useful in wound healing.

82. The composition of claim 2, wherein the biologically active molecule is heparin.

83. The composition of claim 1, wherein the carrier is disaccharide acetate butyrate.

84. The composition of claim 1, wherein the carrier is a disaccharide ester.

85. The composition of claim 1, wherein the biologically active substance is prepared by the steps comprising:

(a) encapsulating the biologically active substance within a microsphere, to give an encapsulated microsphere; and

(b) mixing the encapsulated microsphere with the carrier material;

(c) to give the desired composition.

86. The composition of claim 1, wherein the biologically active substance is complexed with a complexing agent such as cyclodextrin.

87. The composition of claim 1, wherein the biologically active substance is in the form of a prodrug.

88. The composition of claim 1, wherein the composition is placed within a gelatin capsule for oral administration.

89. The composition of claim 1, wherein the composition is encapsulated within a microsphere or microcapsule.

90. The composition of claim 40, wherein the microsphere is a biodegradable polymer.

91. The composition of claim 1, wherein the controlled release formulation is associated with inert pharmaceutical excipients, said excipients optionally processed into spheres or other shapes and incorporated into a dosage form.

92. The composition of claim 2, wherein the biologically active material is selected from the group consisting of a nucleic acid, a nucleotide, nucleoside, or oligonucleotide.

93. The composition of claim 2, wherein the biologically active material is a gene.

94. The composition of claim 2, wherein the biologically active material is a lipid.

95. The composition of claim 2, wherein the biologically active material is a vitamin.