High viscosity liquid controlled delivery system and medical or surgical device

• US 20040101557A1
• Filed: 12/10/2002
• Published: 05/27/2004
• Est. Priority Date: 06/07/1995
• Status: Active Grant

• Current Assignee: DURECT Corporation
• Original Assignee: DURECT Corporation
• Inventors: Gibson, John W., Miller, Stacey S., Middleton, John C., Tipton, Arthur J.
• Granted Patent: US 7,833,543 B2
• Time in Patent Office: Days
• US Class Current: 424/484
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• 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 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/7015 Drug-containing film-forming compositions, e.g. spray-on
• CPC Class Codes: A61L 15/20 containing organic materials
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/402 Anaestetics, analgesics, e.g. lidocaine
• CPC Class Codes: A61L 2300/43 Hormones, e.g. dexamethasone
• 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 24/0026 Sprayable compositions
• 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 5/006 : Antidandruff preparations

Abstract

The present invention relates to novel nonpolymeric compounds and compositions that form liquid, high viscosity materials suitable for the delivery of biologically active substances in a controlled fashion, and for use as medical or surgical devices. The materials can optionally be diluted with a solvent to form a material of lower viscosity, rendering the material easy to administer. This solvent may be water insoluble or water soluble, where the water soluble solvent rapidly diffuses or migrates away from the material in vivo, leaving a higher viscosity liquid material.

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 is present in an amount from about 99.5 percent to about 1 percent by weight, relative to the total weight of the composition; and

(b) a biologically active substance.

2. The composition of claim 1, wherein the non-polymeric non-water soluble liquid carrier material is present in an amount from about 95 percent to about 10 percent by weight, relative to the total weight of the composition.

3. The composition of claim 2, wherein the non-polymeric non-water soluble high viscosity liquid carrier material is present in an amount from about 85 percent to about 25 percent by weight, relative to the total weight of the composition.

116. An fluid-imbibing active agent delivery system comprising:

an impermeable reservoir; and

a piston that divides the reservoir into an active agent containing chamber and a water-swellable agent containing chamber;

wherein the active agent containing chamber is provided with a back-diffusion regulating outlet and the water-swellable agent containing chamber is provided with a semipermeable plug;

wherein the plug is releasable from the reservoir at an internal pressure that is lower than the maximum osmotic pressure generated by the water-swellable agent;

and wherein the active agent containing chamber contains the formulation of claim 1.

117. The delivery system of claim 116, wherein the system is implantable into the patient'"'"'s tissue.

118. The delivery system of claim 116, wherein the system is orally administrable.

4. 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;

(b) a biologically active substance; and

(c) a solvent in which the non-polymeric non-water insoluble liquid carrier material is soluble.

5. The composition of claim 4, wherein the solvent is selected from the group consisting of ethanol, dimethylsulfoxide, benzyl benzoate, benzyl alcohol, polyethylene glycol, glycerol triacetin, triethyl citrate, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, 2-pyrrolidone, N-methylpyrrolidone, propylene carbonate, and glycofurol.

6. The composition of claim 4, further comprising (d) an additive

7. The composition of claim 6, wherein the additive is selected from the group consisting of biodegradable polymers, non-biodegradable polymers, natural oils, synthetic oils, carbohydrates, inorganic salts, and inert organic compounds.

8. The composition of claim 4, wherein the solvent is present in an amount from about 10 to about 50 percent by weight, relative to the weight of the composition.

9. A liquid emulsion 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;

(b) a biologically active substance; and

(c) a solvent in which the non-polymeric non-water soluble liquid carrier material is insoluble or sparingly soluble.

10. The liquid emulsion of claim 9, wherein the high viscosity liquid carrier material is in the dispersed phase.

11. The liquid emulsion of claim 10, wherein the dispersed phase comprises a mixture of sucrose acetate isobutyrate and a solvent therefore, and the continuous phase comprises water, glycerol, or a combination thereof.

12. The liquid emulsion of claim 9, wherein the high viscosity liquid carrier material is in the continuous phase.

13. 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;

(b) a biologically active substance; and

(c) an additive.

14. The composition of claim 13, wherein the additive is selected from the group consisting of biodegradable polymers, non-biodegradable polymers, natural oils, synthetic oils, carbohydrates, inorganic salts, and inert organic compounds.

15. The composition of claim 13, 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.

16. The composition of claim 13, wherein the additive is cellulose, a cellulose ester, or a cellulose ether.

17. The composition of claim 16, wherein the additive is cellulose acetate butyrate.

18. The composition of claim 16, wherein the additive is cellulose acetate propionate.

19. The composition of claim 13, wherein the additive comprises a poly(lactide).

20. The composition claim 13, wherein the additive is poly(caprolactone).

21. The composition of claim 13, wherein the additive is poly(D,L-lactic acid).

22. The composition of claim 13, wherein the additive comprises a poly(lactide-co-glycolide).

23. The composition of claim 13, wherein the additive is a poly(glycolide).

24. The composition of claim 13, wherein the additive is oxidized cellulose.

25. The composition of claim 13, wherein the additive is a nonbiodegradable polymer.

26. The composition of claim 13, wherein the additive is a biodegradable polymer.

27. The composition of claim 13, wherein the additive is polyvinyl pyrrolidone.

28. The composition of claim 13, wherein the additive is polyethylene glycol.

29. The composition of claim 13, wherein the additive is sesame oil.

30. The composition of claim 13, wherein the additive is a carbohydrate.

31. The composition of claim 30, wherein the additive is sucrose.

107. The composition of claim 13, wherein the additive comprises a multivalent metal.

108. The composition of claim 107, wherein the multivalent metal comprises zinc ion.

32. A liquid composition for the delivery of biologically active substances and suitable for topical, systemic, parenteral, rectal, vaginal, nasal, pericardial, or oral administration, or a combination thereof, 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.

33. The composition of claim 32 suitable for topical administration.

34. The composition of claim 32 suitable for systemic administration.

35. The composition of claim 32 suitable for parenteral administration.

36. The composition of claim 32, suitable for rectal administration.

37. The composition of claim 32, suitable for vaginal administration.

38. The composition of claim 32, suitable for nasal administration.

39. The composition of claim 32, suitable for oral administration.

110. The composition of claim 32, further comprising a polymeric excipient.

111. The composition of claim 110, comprising one or more particles comprising the biologically active substance and the polymeric excipient.

112. The composition of claim 110, wherein the composition is in the form of a microsphere.

113. The composition of claim 110, wherein the composition is orally administrable.

114. The composition of claim 32, wherein the biologically active substance forms a particle with an optional solid additive.

115. The composition of claim 114, wherein the solid additive comprises calcium phosphate.

40. 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;

(b) a biologically active substance; and

(c) a lower viscosity liquid carrier material.

41. The composition of claim 40, wherein the lower viscosity liquid carrier material has a viscosity of less than 1000 cp.

42. The composition of claim 40, wherein the lower viscosity liquid carrier material comprises a mixture of a high viscosity liquid carrier material and a solvent therefore.

43. 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 useful for agricultural, human therapy, veterinary, or pesticidal purposes, or a combination thereof.

44. The composition of claim 43, wherein the biologically active substance is useful for agricultural purposes.

45. The composition of claim 43, wherein the biologically active substance is useful for human therapy purposes.

46. The composition of claim 43, wherein the biologically active substance is useful for veterinary purposes.

47. The composition of claim 43, wherein the composition is useful for the control of pests.

48. The composition of claim 47, wherein the active agent is useful for the control of weeds.

49. The composition of claim 47, wherein the active agent is useful for the control of insects.

50. 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 wherein the biologically active substance is a drug.

51. The composition of claim 50, wherein the biologically active agent is theophylline.

52. The composition of claim 50, wherein the biologically active agent is flurbiprofen.

53. The composition of claim 50, wherein the biologically active agent is naproxen.

54. The composition of claim 50, wherein the biologically active agent is chlorhexidine.

55. The composition of claim 50, wherein the biologically active agent is diclofenac.

56. The composition of claim 50, wherein the biologically active substance is an anesthetic.

57. The composition of claim 56, wherein the anesthetic is selected from the group consisting of benzocaine, bupivacaine, chloroprocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, ropivacaine, and tetracaine.

58. The composition of claim 57, wherein the anesthetic is bupivacaine.

59. The composition of claim 55, further comprising an augmenting agent.

60. The composition of claim 59, wherein the augmenting agent is selected from the group consisting of dexamethasone, epinephrine, and combinations thereof.

61. The composition of claim 50, wherein the biologically active agent is a hormone.

62. The composition of claim 50, wherein the biologically active material is a steroid.

63. The composition of claim 62, wherein the biologically active compound is an estrogen.

64. The composition of claim 62, wherein the biologically active agent is a progesterone.

65. The composition of claim 62, wherein the biologically active agent is 17-β

-estradiol.

66. The composition of claim 62, wherein the biologically active agent is a progesterone and estradiol in combination.

67. The composition of claim 50, wherein the biologically active agent is dexamethasone.

68. The composition of claim 50, wherein the biologically active agent is an antipsychotic.

69. The composition of claim 50, wherein the biologically active agent is an antibiotic.

70. The composition of claim 69, wherein the biologically active agent is tetracycline.

71. The composition of claim 69, wherein the biologically active agent is azithromycin.

72. The composition of claim 69, wherein the biologically active material is doxycycline.

73. The composition of claim 50, wherein the biologically active agent is a growth factor.

74. The composition of claim 73, wherein the biologically material is transforming growth factor-beta.

75. The composition of claim 50, wherein the biologically active substance is a chemotherapeutic agent.

76. The composition of claim 50, wherein the biologically active molecule is heparin.

96. The composition of claim 68, wherein the antipsychotic comprises olanzapine, risperidone, or a combination thereof.

97. The composition of claim 50, wherein the drug comprises a statin.

98. The composition of claim 97, wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.

99. The composition of claim 50, wherein the drug comprises an antiasthmatic.

100. The composition of claim 99, wherein the antiasthmatic comprises a cromolyn.

101. The composition of claim 50, wherein the drug comprises a narcotic antagonist.

102. The composition of claim 50, wherein the drug comprises a bone resorption prevention agent.

103. The composition of claim 102, wherein the bone resorption prevention agent is selected from the group consisting of alendronate, risendronate, zolendronate, pamidronate, and ibandronate.

104. The composition of claim 61, wherein the hormone comprises a calcium regulating hormone.

105. The composition of claim 50, wherein the drug comprises a cardiac agent.

106. The composition of claim 105, wherein the cardiac agent comprises an antiarrhythmic agent, an antiangina agent, or an antihypertensive agent.

77. 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 selected from the group consisting of peptides, proteins, nucleoproteins, mucoproteins, lipoproteins, and synthetic polypeptides.

78. The composition of claim 77, wherein the biologically active compound is a peptide.

79. The composition of claim 77, wherein the biologically active compound is a protein.

80. The composition of claim 79, wherein the protein is selected from the group consisting of α

-interferon and β

-interferon.

81. 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 selected from the group consisting of a nucleic acid, a nucleotide, nucleoside, or oligonucleotide.

82. The composition of claim 81, wherein the biologically active agent is a nucleoside or nucleotide.

83. 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 which is a gene.

84. 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 selected from the group consisting of a vaccine, a lipid, and a vitamin.

85. The composition of claim 84, wherein the biologically active agent is a vaccine.

86. The composition of claim 84, wherein the biologically active material is a lipid.

87. The composition of claim 84, wherein the biologically active material is a vitamin.

88. 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;

wherein the composition is useful to control lice, to control dandruff, as a tissue adhesive, or in wound healing.

89. The composition of claim 88, wherein the composition is useful to control lice.

90. The composition of claim 88, wherein the composition is useful to control dandruff.

91. The composition of claim 88 useful as a tissue adhesive.

92. The composition of claim 88 useful in wound healing.

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

(a) a non-polymeric, non-water soluble high viscosity liquid carrier material;

(b) a non-water soluble solvent in which the non-polymeric non-water insoluble liquid carrier material is soluble.

94. The liquid composition of claim 93, wherein the solvent is selected from the group consisting of benzyl benzoate, caprylic/capric triglycerides, benzyl alcohol, and triethylcitrate.

95. The liquid composition of claim 94, wherein the solvent is benzyl alcohol.

109. A multi-part, storage-stable composition for administration to a patient, comprising:

(a) a non-polymeric, non-water soluble high viscosity liquid carrier material;

(b) a biologically active substance;

wherein the carrier material and biologically active substance are maintained in separate containers, and are capable of forming a homogeneous solution on mixing.