Method of producing submicron particles of a labile agent and use thereof

• US 6,444,223 B1
• Filed: 05/28/1999
• Issued: 09/03/2002
• Est. Priority Date: 05/28/1999
• Status: Expired due to Fees

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Jaworowicz, Warren E., Ward, Kevin L., Tracy, Mark A.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US09/321,091
• Time in Patent Office: 1,194 Days
• Field of Search: 424/486, 424/487, 424/497, 424/489, 514/951-952, 264/140, 451/28, 451/36
• US Class Current: 424/486
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin

Abstract

The present invention relates to a sustained release composition comprising micron particles of labile agent and a method of preparing and using the sustained release composition. The invention further relates to micron particles of a labile agent and a method of preparing the micron particles. The method of the invention for preparing a composition for the sustained release of a labile agent, comprises forming a suspension comprising the labile agent dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent. The suspension is then wet milled to achieve micron particles of the labile agent. The polymer solvent is then removed resulting in a solid polymer/labile agent matrix. The method for preparing micron particles of a labile agent comprises forming a suspension comprising the labile agent, dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent, and wet milling of the suspension.

Claims

1. A method for preparing a composition for the sustained release of a labile agent, comprising the steps of:

a) forming a suspension comprising human growth hormone complexed to a stabilizing metal cation and dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent;

b) wet milling the suspension to achieve submicron particles of the labile agent; and

c) removing the polymer solvent thereby forming a solid polymer matrix having the labile agent dispersed therein.

2. The method of claim 1 wherein the human growth hormone is complexed to Zn⁺².

11. The method of claim 1 wherein the submicron particles have a volume median particle size of less than 1 micron, measured by laser diffraction.

12. The method of claim 1 wherein step (b) is conducted at a temperature of less than about 30°

C.

13. The method of claim 12 wherein the temperature is less than about 10°

C.

14. The method of claim 12 wherein the temperature is less than about 4°

C.

15. The method of claim 1 wherein the labile agent is present in the suspension at a concentration of from about 0.01 to about 50% w/w of the combined weight of polymer and labile agent.

16. The method of claim 15 wherein the labile agent is present at a concentration of about 0.01 to 30% w/w of the combined weight of the polymer and labile agent.

17. The method of claim 1 wherein the biocompatible polymer is biodegradable.

18. The method of claim 17 wherein the biodegradable polymer is selected form the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-coglycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(caprolactone), polycarbonates, polyesteramides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polycyanoacrylates, polyamides, polyacetals, poly(ether ester)s, copolymers of poly(ethylene glycol) and poly(ortho ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, biodegradable polyurethanes, blends and copolymers thereof.

19. The method of claim 1 wherein wet milling comprises the steps of:

a) adding a grinding media to the suspension; and

b) applying a mechanical means.

20. The method of claim 19 wherein the mechanical means is a dispersion mill or rotary blender.

21. The method of claim 20 wherein the dispersion mill is selected from the group consisting of:

a rotary mill, a ball mill, an attrition mill, a vibratory mill, a planetary mill, a media mill or a bead mill.

22. The method of claim 1 wherein the polymer solvent is selected from the group consisting of:

methylene chloride, acetone, ethyl acetate, methyl acetate, chloroform, dimethylsulfoxide, hexafluoroisopropanol or a combination thereof.

3. A method for preparing a composition for the sustained release of a labile agent, comprising the steps of:

a) forming a suspension comprising the labile agent wherein the labile agent is a protein, polypeptide or oligonucleotide dispersed in a polymer solution comprising a poly(lactide-co-glycolide) polymer and at least one polymer solvent;

b) wet milling the suspension to achieve submicron particles of the labile agent; and

c) removing the polymer solvent thereby forming a solid polymer matrix having the labile agent dispersed therein.

23. The method of claim 3 wherein the submicron particles have a volume median particle size of less than 1 micron, measured by laser diffraction.

24. The method of claim 3 wherein step (b) is conducted at a temperature of less than about 30°

C.

25. The method of claim 24 wherein the temperature is less than about 10°

C.

26. The method of claim 24 wherein the temperature is less than about 4°

C.

27. The method of claim 3 wherein the labile agent is present in the suspension at a concentration of from about 0.01 to about 50% w/w of the combined weight of polymer and labile agent.

28. The method of claim 27 wherein the labile agent is present at a concentration of about 0.01 to 30% w/w of the combined weight of the polymer and labile agent.

29. The method of claim 3 wherein the labile agent is a protein.

30. The method of claim 29 wherein the protein is complexed to a stabilizing metal cation.

31. The method of claim 30 wherein said stabilizing metal cation is selected from the group consisting of Zn⁺², Ca⁺², Cu+², Mg+², K⁺and any combination thereof.

32. The method of claim 31 wherein said stabilizing metal cation is Zn⁺².

33. The method of claim 3 wherein wet milling comprises the steps of:

a) adding a grinding media to the suspension; and

b) applying a mechanical means.

34. The method of claim 33 wherein the mechanical means is a dispersion mill or rotary blender.

35. The method of claim 34 wherein the dispersion mill is selected from the group consisting of:

a rotary mill, a ball mill, an attrition mill, a vibratory mill, a planetary mill, a media mill or a bead mill.

36. The method of claim 3 wherein the polymer solvent is selected from the group consisting of:

methylene chloride, acetone, ethyl acetate, methyl acetate, chloroform, dimethylsulfoxide, hexafluoroisopropanol or a combination thereof.

4. A method for preparing a composition for the sustained release of a labile agent, comprising the steps of:

a) forming a suspension comprising the labile agent wherein the labile agent is a protein, polypeptide or oligonucleotide dispersed in a polymer solution comprising at least one biocompatible polymer and a polymer solvent selected from the group consisting of methylene chloride, chloroform, acetone, ethyl acetate, methyl acetate, dimethylsulfoxide, hexafluoroisopropanol and any combinations thereof;

b) wet milling the suspension to achieve submicron particles of the labile agent; and

c) removing the polymer solvent thereby forming a solid polymer matrix having the labile agent dispersed therein.

6. The method of claim 4, wherein the metal component is selected from the group consisting of Mg(OH)₂, MgCO₃, CaCO₃, ZnCO₃, Mg(OAc)₂, Zn(OAc)₂, ZnSO₄, MgCl₂, ZnCl₂, MgSO₄, zinc citrate and magnesium citrate.

37. The method of claim 4 wherein the submicron particles have a volume median particle size of less than 1 micron, measured by laser diffraction.

38. The method of claim 4 wherein step (b) is conducted at a temperature of less than about 30°

C.

39. The method of claim 38 wherein the temperature is less than about 10°

C.

40. The method of claim 38 wherein the temperature is less than about 4°

C.

41. The method of claim 4 wherein the labile agent is present in the suspension at a concentration of from about 0.01 to about 50% w/w of the combined weight of polymer and labile agent.

42. The method of claim 41 wherein the labile agent is present at a concentration of about 0.01 to 30% w/w of the combined weight of the polymer and labile agent.

43. The method of claim 4 wherein the labile agent is a protein.

44. The method of claim 43 wherein the protein is complexed to a stabilizing metal cation.

45. The method of claim 44 wherein said stabilizing metal cation is selected from the group consisting of Zn⁺², Ca⁺², Cu⁺², Mg⁺², K⁺and any combination thereof.

46. The method of claim 45 wherein said stabilizing metal cation is Zn⁺².

47. The method of claim 4 wherein the biocompatible polymer is biodegradable.

48. The method of claim 47 wherein the biodegradable polymer is selected form the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-coglycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(caprolactone), polycarbonates, polyesteramides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polycyanoacrylates, polyamides, polyacetals, poly(ether ester)s, copolymers of poly(ethylene glycol) and poly(ortho ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, biodegradable polyurethanes, blends and copolymers thereof.

49. The method of claim 4 wherein wet milling comprises the steps of:

a) adding a grinding media to the suspension; and

b) applying a mechanical means.

50. The method of claim 49 wherein the mechanical means is a dispersion mill or rotary blender.

51. The method of claim 50 wherein the dispersion mill is selected from the group consisting of:

a rotary mill, a ball mill, an attrition mill, a vibratory mill, a planetary mill, a media mill or a bead mill.

5. A method for preparing a composition for the sustained release of a labile agent, comprising the steps of:

a) forming a suspension comprising the labile agent wherein the labile agent is a protein, polypeptide or oligonucleotide dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent;

b) wet milling the suspension to achieve submicron particles of the labile agent;

c) adding a metal cation component to the suspension which modulates the release of the labile agent; and

d) removing the polymer solvent thereby forming a solid polymer matrix having the labile agent dispersed therein.

52. The method of claim 5 wherein the submicron particles have a volume median particle size of less than 1 micron, measured by laser diffraction.

53. The method of claim 5 wherein step (b) is conducted at a temperature of less than about 30°

C.

54. The method of claim 53 wherein the temperature is less than about 10°

C.

55. The method of claim 53 wherein the temperature is less than about 4°

C.

56. The method of claim 5 wherein the labile agent is present in the suspension at a concentration of from about 0.01 to about 50% w/w of the combined weight of polymer and labile agent.

57. The method of claim 56 wherein the labile agent is present at a concentration of about 0.01 to 30% w/w of the combined weight of the polymer and labile agent.

58. The method of claim 5 wherein the labile agent is a protein.

59. The method of claim 58 wherein the protein is complexed to a stabilizing metal cation.

60. The method of claim 59 wherein said stabilizing metal cation is selected from the group consisting of Zn⁺², Ca⁺², Cu⁺², Mg⁺², K⁺and any combination thereof.

61. The method of claim 60 wherein said stabilizing metal cation is Zn⁺².

62. The method of claim 5 wherein the biocompatible polymer is biodegradable.

63. The method of claim 62 wherein the biodegradable polymer is selected form the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-coglycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(caprolactone), polycarbonates, polyesteramides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polycyanoacrylates, polyamides, polyacetals, poly(ether ester)s, copolymers of poly(ethylene glycol) and poly(ortho ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, biodegradable polyurethanes, blends and copolymers thereof.

64. The method of claim 5 wherein wet milling comprises the steps of:

a) adding a grinding media to the suspension; and

b) applying a mechanical means.

65. The method of claim 64 wherein the mechanical means is a dispersion mill or rotary blender.

66. The method of claim 65 wherein the dispersion mill is selected from the group consisting of:

a rotary mill, a ball mill, an attrition mill, a vibratory mill, a planetary mill, a media mill or a bead mill.

67. The method of claim 5 wherein the polymer solvent is selected from the group consisting of:

methylene chloride, acetone, ethyl acetate, methyl acetate, chloroform, dimethylsulfoxide, hexafluoroisopropanol or a combination thereof.

7. A method for preparing submicron particles of a labile agent, wherein said method comprises the steps of:

a) forming a suspension comprising the labile agent wherein the labile agent is a protein, polypeptide or oligonucleotide dispersed in a polymer solution comprising a poly(lactide-co-glycolide) polymer and at least one polymer solvent; and

b) wet milling the suspension.

68. The method of claim 7 wherein the submicron particles have a volume median particle size of less than 1 micron, measured by laser diffraction.

69. The method of claim 7 wherein step (b) is conducted at a temperature of less than about 30°

C.

70. The method of claim 69 wherein the temperature is less than about 10°

C.

71. The method of claim 69 wherein the temperature is less than about 4°

C.

72. The method of claim 7 wherein the labile agent is present in the suspension at a concentration of from about 0.01 to about 50% w/w of the combined weight of polymer and labile agent.

73. The method of claim 72 wherein the labile agent is present at a concentration of about 0.01 to 30% w/w of the combined weight of the polymer and labile agent.

74. The method of claim 7 wherein the labile agent is a protein.

75. The method of claim 74 wherein the protein is complexed to a stabilizing metal cation.

76. The method of claim 75 wherein said stabilizing metal cation is selected from the group consisting of Zn⁺², Ca⁺², Cu⁺², Mg⁺², K⁺and any combination thereof.

77. The method of claim 76 wherein said stabilizing metal cation is Zn⁺².

78. The method of claim 7 herein wet milling comprises the steps of:

a) adding a grinding media to the suspension; and

b) applying a mechanical means.

79. The method of claim 78 wherein the mechanical means is a dispersion mill or rotary blender.

80. The method of claim 79 wherein the dispersion mill is selected from the group consisting of:

a rotary mill, a ball mill, an attrition mill, a vibratory mill, a planetary mill, a media mill or a bead mill.

81. The method of claim 7 wherein the polymer solvent is selected from the group consisting of:

methylene chloride, acetone, ethyl acetate, methyl acetate, chloroform, dimethylsulfoxide, hexafluoroisopropanol or a combination thereof.

88. The method of claim 7 wherein the labile agent is a protein.

89. The method of claim 88 wherein the protein is complexed to a stabilizing metal cation.

90. The method of claim 89 wherein said stabilizing metal cation is selected from the group consisting of Zn⁺², Ca⁺², Cu⁺², Mg⁺², K⁺and any combination thereof.

91. The method of claim 90 wherein said stabilizing metal cation is Zn⁺².

8. A method for preparing submicron particles of a labile agent, wherein said method comprises the steps of:

a) forming a suspension comprising the labile agent wherein the labile agent is a protein, polypeptide or oligonucleotide dispersed in a polymer solution comprising at least one biocompatible polymer and a polymer solvent selected from the group consisting of methylene chloride, acetone, ethyl acetate, methyl acetate, chloroform, dimethylsulfoxide, hexafluoroisopropanol and any combination thereof; and

b) wet milling the suspension.

82. The method of claim 8 wherein the submicron particles have a volume median particle size of less than 1 micron, measured by laser diffraction.

83. The method of claim 8 wherein step (b) is conducted at a temperature of less than about 30°

C.

84. The method of claim 83 wherein the temperature is less than about 10°

C.

85. The method of claim 83 wherein the temperature is less than about 4°

C.

86. The method of claim 83 wherein the labile agent is present in the suspension at a concentration of from about 0.01 to about 50% w/w of the combined weight of polymer and labile agent.

87. The method of claim 86 wherein the labile agent is present at a concentration of about 0.01 to 30% w/w of the combined weight of the polymer and labile agent.

92. The method of claim 8 wherein the biocompatible polymer is biodegradable.

93. The method of claim 92 wherein the biodegradable polymer is selected form the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-coglycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(caprolactone), polycarbonates, polyesteramides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polycyanoacrylates, polyamides, polyacetals, poly(ether ester)s, copolymers of poly(ethylene glycol) and poly(ortho ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, biodegradable polyurethanes, blends and copolymers thereof.

94. The method of claim 8 wherein wet milling comprises the steps of:

a) adding a grinding media to the suspension; and

b) applying a mechanical means.

95. The method of claim 94 wherein the mechanical means is a dispersion mill or rotary blender.

96. The method of claim 95 wherein the dispersion mill is selected from the group consisting of:

a rotary mill, a ball mill, an attrition mill, a vibratory mill, a planetary mill, a media mill or a bead mill.

9. A method for preparing submicron particles of a labile agent, wherein said method comprises the steps of:

a) forming a suspension comprising human growth hormone complexed to a stabilizing metal cation and dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent; and

b) wet milling the suspension.

10. The method of claim 9, wherein the human growth hormone is complexed to Zn⁺².

97. The method of claim 9 wherein the submicron particles have a volume median particle size of less than 1 micro , measured by laser diffraction.

98. The method of claim 9 wherein step (b) is conducted at a temperature of less than about 30°

C.

99. The method of claim 98 wherein the temperature is less than about 10°

C.

100. The method of claim 98 wherein the temperature is less than about 4°

C.

101. The method of claim 9 wherein the labile agent is present in the suspension at a concentration of from about 0.04 to about 50% w/w of the combined weight of polymer and labile agent.

102. The method of claim 101 wherein the labile agent is present at a concentration of about 0.01 to 30% w/w of the combined weight of the polymer and labile agent.

103. The method of claim 9 wherein the biocompatible polymer is biodegradable.

104. The method of claim 103 wherein the biodegradable polymer is selected form the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-coglycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(caprolactone), polycarbonates, polyesteramides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polycyanoacrylates, polyamides, polyacetals, poly(ether ester)s, copolymers of poly(ethylene glycol) and poly(ortho ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, biodegradable polyurethanes, blends and copolymers thereof.

105. The method of claim 9 wherein wet milling comprises the steps of:

a) adding a grinding media to the suspension; and

b) applying a mechanical means.

106. The method of claim 105 wherein the mechanical means is a dispersion mill or rotary blender.

107. The method of claim 106 wherein the dispersion mill is selected from the group consisting of:

a rotary mill, a ball mill, an attrition mill, a vibratory mill, a planetary mill, a media mill or a bead mill.

108. The method of claim 9 wherein the polymer solvent is methylene chloride, acetone, ethyl acetate, methyl acetate, chloroform, dimethylsulfoxide, hexafluoroisopropanol and a combination thereof.