Method of forming microparticles that include a bisphosphonate and a polymer

• US 20050260272A1
• Filed: 05/05/2005
• Published: 11/24/2005
• Est. Priority Date: 05/05/2004
• Status: Abandoned Application

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Prinn, Kristin, Yeoh, Thean Y., Figueiredo, Maria C., Maloney, Maura J., Kumar, Rajesh, Zale, Stephen E., Troiano, Gregory C., Scher, David S.
• Application Number:
  US11/122,796
• Publication Number:
  US 20050260272A1
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• 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 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: C08L 2205/02 containing two or more polymers of the same C08L -group
• CPC Class Codes: C08L 23/08 Copolymers of ethene C08L23/16 takes precedence
• CPC Class Codes: C08L 23/0815 Copolymers of ethene with aliphatic 1-olefins
• CPC Class Codes: C08L 2666/06 Homopolymers or copolymers of unsaturated hydrocarbons; Derivatives thereof

Abstract

Microparticles that include a bisphosphonate and a polymer are produced by a method that includes forming a water-in-oil emulsion by mixing an aqueous solution of the bisphosphonate with a combination of a biocompatible polymer and a polymer solvent. At least one aqueous liquid can be mixed with the water-in-oil emulsion to form a water-in-oil-in-water emulsion and to extract the polymer solvent from the polymer, thereby forming the microparticles. Methods of treating a patient in need of therapy include administering the microparticles described to the patient. In one embodiment, the microparticles are formulated for the sustained release of the bisphosphonate.

Claims

1. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:

a) forming a water-in-oil emulsion by mixing an aqueous solution of the bisphosphonate with a combination of a poly(lactide) or a poly(lactide-co-glycolide) polymer and a polymer solvent, wherein the molar ratio of the lactide component to the glycolide component in the polymer is at least about 65;

35; and

b) mixing at least one aqueous liquid with the water-in-oil emulsion to form a water-in-oil-in-water emulsion and to extract the polymer solvent from the polymer, thereby forming the microparticles.

2. The method of claim 1 wherein the molar ratio of the lactide component to the glycolide component of the polymer is about 65:

35 to about 85;

15.

3. The method of claim 1 wherein the inherent viscosity of the polymer measured in chloroform at 25°

C. is no more than about 0.65 deciliters/gram (dL/g).

4. The method of claim 1 wherein the inherent viscosity of the polymer measured in chloroform at 25°

C. is about 0.8 to about 0.85 deciliters/gram (dL/g).

5. The method of claim 1 wherein the poly(lactide) or the poly(lactide-co-glycolide) polymer includes an ester end group.

6. The method of claim 5 wherein the ester end group is selected from the group consisting of a methyl ester and a lauryl ester.

7. The method of claim 1 wherein the poly(lactide) or the poly(lactide-co-glycolide) polymer includes an acid end group.

8. The method of claim 7 wherein the acid end group is a free carboxyl end group.

9. The method of claim 1 wherein the bisphosphonate is a compound represented by the following chemical structure:

wherein,

R₁ is, independently, H, alkyl, aryl or heteroaryl;

X is H, —

OR, or halogen;

R₂ is H, O, S, N, (CH₂)_n, branched alkylene, branched or straight alkenylene or alkynylene;

n is an integer from about 0 to about 18;

Y is H, R₁, halogen, amino, cyano or amido group;

or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 wherein the bisphosphonate is selected from the group consisting of alendronate, risedronate, pamidronate, etidronate, tiludronate, ibandronate, pharmaceutically acceptable salts thereof and combinations thereof.

11. The method of claim 9 wherein the bisphosphonate is a compound represented by the following chemical structure:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 11 wherein the bisphosphonate is (1-hydroxy-2-(-3-pyridinyl)ethylidene)bis(phosphonic acid) monosodium salt.

13. The method of claim 1 wherein forming the water-in-oil emulsion includes mixing the aqueous solution with the combination of the polymer and the polymer solvent using rotor-stator mixing.

14. The method of claim 1 wherein forming the water-in-oil emulsion includes mixing the aqueous solution with the combination of the polymer and the polymer solvent using sonication.

15. The method of claim 1 wherein forming the water-in-oil emulsion includes mixing the aqueous solution with the combination of the polymer and the solvent using a high pressure homogenizer.

16. The method of claim 1 wherein the step of mixing at least one aqueous liquid with the water-in-oil emulsion to form a water-in-oil-in-water emulsion includes mixing the water-in-oil emulsion with an aqueous liquid in a static mixer.

17. The method of claim 16 wherein the water-in-oil emulsion is mixed in the static mixer at a water-in-oil emulsion flow rate of about 20 mL/min to about 1500 mL/min.

18. The method of claim 1 wherein the step of mixing at least one aqueous liquid with the water-in-oil emulsion to form a water-in-oil-in-water emulsion includes mixing the water-in-oil emulsion with an aqueous liquid that includes a surfactant.

19. The method of claim 18 wherein the surfactant is selected from the group consisting of polyvinyl alcohol, poloxamers, and polysorbates.

20. The method of claim 1 wherein the step of mixing at least one aqueous liquid with the water-in-oil emulsion includes mixing an aqueous liquid with the water-in-oil emulsion to form a water-in-oil-in-water emulsion and then mixing the water-in-oil-in-water emulsion with an aqueous liquid extraction medium.

21. The method of claim 20 wherein the aqueous liquid extraction medium is water.

22. The method of claim 1 further comprising the step of isolating the microparticles.

23. The method of claim 22 wherein isolating the microparticles includes filtering the microparticles from the at least one aqueous liquid.

24. The method of claim 22 wherein isolating the microparticles includes lyophilizing the microparticles.

25. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:

a) forming a water-in-oil emulsion by mixing an aqueous solution of the bisphosphonate with a combination of a biocompatible polymer and a polymer solvent, wherein the concentration of the bisphosphonate in the aqueous solution is greater than the room temperature solubility limit of the bisphosphonate; and

b) mixing at least one aqueous liquid with the water-in-oil emulsion to form a water-in-oil-in-water emulsion and to extract the polymer solvent from the polymer, thereby forming the microparticles.

26. The method of claim 25 wherein the concentration of the bisphosphonate in the aqueous solution is at least about 75 mg/mL.

27. The method of claim 26 wherein the concentration of the bisphosphonate in the aqueous solution is at least about 100 mg/mL.

28. The method of claim 25 wherein the concentration of the bisphosphonate in the aqueous solution is at least about twice the room temperature solubility limit of the bisphosphonate.

29. The method of claim 26 wherein the aqueous solution of the bisphosphonate is prepared by heating a mixture of the bisphosphonate and water.

30. The method of claim 26 wherein the temperature of the aqueous solution is higher than room temperature.

31. The method of claim 30 wherein the temperature of the aqueous solution is at least about 50°

C.

32. The method of claim 31 wherein the temperature of the aqueous solution is at least about 75°

C.

33. The method of claim 30 wherein the temperature of the aqueous solution is about 75°

C. to about 85°

C.

34. The method of claim 30 wherein the concentration of the bisphosphonate in the aqueous solution is less than the solubility limit of the bisphosphonate at the temperature of the aqueous solution.

35. The method of claim 25 wherein the aqueous solution is a supersaturated solution of the bisphosphonate.

36. The method of claim 25 wherein the temperature of the aqueous solution is higher than the temperature of the combination of polymer and polymer solvent.

37. The method of claim 25 wherein the temperature of the combination of polymer and polymer solvent is about room temperature.

38. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:

a) preparing an aqueous mixture of the bisphosphonate and a surfactant;

b) forming a water-in-oil emulsion by mixing the aqueous mixture with a combination of a biocompatible polymer and a polymer solvent;

c) forming a water-in-oil-in-water emulsion by mixing the water-in-oil emulsion with an aqueous liquid; and

d) removing the polymer solvent from the polymer, thereby forming the microparticles.

39. The method of claim 38 wherein the surfactant is selected from the group consisting of polyvinyl alcohol, poloxamers and polysorbates.

40. The method of claim 39 wherein the surfactant is poloxamer 188.

41. The method of claim 39 wherein the surfactant is polysorbate 20.

42. The method of claim 38 wherein the concentration of the bisphosphonate in the aqueous mixture is greater than the room temperature solubility limit of the bisphosphonate.

43. The method of claim 38 wherein the temperature of the aqueous mixture is higher than room temperature.

44. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:

a) forming a water-in-oil emulsion by mixing an aqueous solution consisting essentially of water and the bisphosphonate with a combination of a biocompatible polymer and a polymer solvent; and

b) mixing at least one aqueous liquid with the water-in-oil emulsion to form a water-in-oil-in-water emulsion and to extract the polymer solvent from the polymer, thereby forming the microparticles.

45. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:

a) forming a bisphosphonate suspension in a combination consisting essentially of a biocompatible polymer and a polymer solvent; and

b) mixing at least one aqueous liquid with the bisphosphonate suspension to form a solid-in-oil-in-water emulsion and to extract the polymer solvent from the polymer, thereby forming the microparticles.

46. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:

a) forming a water-in-oil emulsion by mixing an aqueous solution of the bisphosphonate with a combination of a biocompatible polymer and a polymer solvent; and

b) mixing at least one aqueous liquid with the water-in-oil emulsion to form a water-in-oil-in-water emulsion and to extract the polymer solvent from the polymer, thereby forming the microparticles.

47. The method of claim 46 wherein the step of mixing at least one aqueous liquid with the water-in-oil emulsion includes mixing the water-in-oil emulsion with an aqueous liquid in a static mixer.

48. The method of claim 47 wherein the water-in-oil emulsion is mixed in the static mixer at a water-in-oil emulsion flow rate of about 20 mL/min to about 1500 mL/min.

49. The method of claim 46 wherein the step of mixing at least one aqueous liquid with the water-in-oil emulsion includes mixing the water-in-oil emulsion with an aqueous liquid that includes a surfactant.

50. The method of claim 49 wherein the surfactant includes polyvinyl alcohol.

51. The method of claim 46 wherein the step of mixing at least one aqueous liquid with the water-in-oil emulsion includes mixing an aqueous liquid extraction medium with the water-in-oil-in-water emulsion.

52. The method of claim 51 wherein the aqueous liquid extraction medium is water.

53. The method of claim 51 wherein the aqueous liquid extraction medium has a room temperature capacity for the polymer solvent of at least about 5 weight percent.

54. The method of claim 53 wherein the aqueous liquid extraction medium has a room temperature capacity for the polymer solvent of at least about 7 weight percent.

55. The method of claim 46 wherein the polymer solvent is represented by the chemical structure, R₃COOR₄, wherein R₃ and R₄ are, independently, alkyl groups having from about 1 to about 4 carbon atoms.

56. The method of claim 55 wherein the polymer solvent is ethyl acetate.

57. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:

a) forming a water-in-oil emulsion by mixing an aqueous solution of the bisphosphonate with a combination of a biocompatible polymer and a polymer solvent, wherein the concentration of the bisphosphonate in the aqueous solution is greater than the room temperature solubility limit of the bisphosphonate;

b) forming a water-in-oil-in-water emulsion by mixing a first aqueous liquid with the water-in-oil emulsion; and

c) extracting the polymer solvent from the polymer into a second aqueous liquid, thereby forming the microparticles.

58. The method of claim 57 wherein the bisphosphonate is (1-hydroxy-2-(-3-pyridinyl)ethylidene)bis(phosphonic acid) monosodium salt.

59. The method of claim 57 wherein the concentration of the bisphosphonate in the aqueous solution is at least about 100 mg/mL.

60. The method of claim 57 wherein the temperature of the aqueous solution is about 75°

C. to about 85°

C.

61. The method of claim 57 wherein the temperature of the combination of the biocompatible polymer and the polymer solvent is about room temperature.

62. The method of claim 57 wherein the biocompatible polymer is a poly(lactide) or a poly(lactide-co-glycolide).

63. The method of claim 62 wherein the molar ratio of the lactide component to the glycolide component in the biocompatible polymer is about 65:

35 to about 100;

0.

64. The method of claim 57 wherein the polymer solvent is ethyl acetate.

65. The method of claim 57 wherein the aqueous liquid contains a surfactant.

66. The method of claim 65 wherein the surfactant is selected from the group consisting of polyvinyl alcohol, poloxamers and polysorbates.

67. The method of claim 66 wherein the surfactant is polyvinyl alcohol.

68. The method of claim 57 wherein forming the water-in-oil-in-water emulsion includes mixing the water-in-oil emulsion with the first aqueous liquid in a static mixer.

69. The method of claim 57 wherein the second aqueous liquid is water.

70. The method of claim 57 further comprising the step of isolating the microparticles.

71. The method of claim 70 wherein isolating the microparticles includes filtering the microparticles from the first and second aqueous liquids.

72. The method of claim 70 wherein isolating the microparticles includes lyophilizing the microparticles.

73. Microparticles prepared by the method of claim 57.

74. A pharmaceutical composition for the sustained release of a bisphosphonate, comprising the microparticles prepared by the method of claim 57.

75. A method for treating a patient in need of therapy, comprising the step of administering to the patient a therapeutically effective amount of the microparticles made by the method of claim 57.

76. The method of claim 75 wherein administering the microparticles to the patient includes intramuscular injection of the microparticles.

77. The method of claim 75 wherein administering the microparticles to the patient includes subcutaneous injection of the microparticles.

78. Microparticles consisting essentially of a biocompatible polymer and at least about 3 weight percent of risedronate or a salt thereof.

79. The microparticles of claim 78 wherein the biocompatible polymer is a poly(lactide) or a poly(lactide-co-glycolide).

80. The microparticles of claim 79 wherein the molar ratio of the lactide component to the glycolide component in the biocompatible polymer is about 65:

35 to about 100;

0.

81. The microparticles of claim 78 wherein the microparticles have been gamma-irradiated.

82. The microparticles of claim 81 wherein the microparticles have been gamma-irradiated with about 15 to about 45 kGy of gamma radiation.

83. The microparticles of claim 82 wherein the microparticles have been gamma-irradiated with about 16 kGy of gamma radiation.

84. The microparticles of claim 82 wherein the microparticles have been gamma-irradiated with about 26 kGy of gamma radiation.

85. The microparticles of claim 78 wherein the microparticles have an in vitro 24-hour cumulative risedronate release of less than about 10 weight percent from the microparticles.

86. The microparticles of claim 85 wherein the in vitro 24-hour cumulative risedronate release is in a phosphate buffered saline composition at 37°

C.

87. The microparticles of claim 78 wherein the microparticles, upon administration to a patient, have an in vivo duration of risedronate release from the microparticles of at least about 60 days.

88. Microparticles consisting essentially of a bisphosphonate and a biocompatible polymer wherein the microparticles have an in vitro 24-hour cumulative bisphosphonate release of less than about 15 weight percent.

89. The microparticles of claim 88 having an in vitro 24-hour cumulative bisphosphonate release of less than about 10 weight percent.

90. The microparticles of claim 89 having an in vitro 24-hour cumulative bisphosphonate release of less than about 5 weight percent.

91. The microparticles of claim 88 wherein the in vitro 24-hour bisphosphonate release is in a phosphate buffered saline composition at 37°

C. containing 0.02 weight percent polysorbate 20.

92. The microparticles of claim 88 wherein the bisphosphonate is selected from the group consisting of alendronate, risedronate, pamidronate, etidronate, tiludronate, ibandronate, pharmaceutically acceptable salts thereof and combinations thereof.

93. The microparticles of claim 88 wherein the bisphosphonate is (1-hydroxy-2-(-3-pyridinyl)ethylidene)bis(phosphonic acid) monosodium salt.

94. The microparticles of claim 88 wherein the biocompatible polymer is a poly(lactide) or a poly(lactide-co-glycolide).

95. The microparticles of claim 88 wherein the molar ratio of the lactide component to the glycolide component in the biocompatible polymer is about 65:

35 to about 100;

0.

96. The microparticles of claim 88 wherein the microparticles, upon administration to a patient, have an in vivo duration of bisphosphonate release from the microparticles of at least about 30 days.

97. The microparticles of claim 96 wherein the microparticles, upon administration to a patient, have an in vivo duration of bisphosphonate release from the microparticles of at least about 60 days.

98. Microparticles consisting essentially of a bisphosphonate and a biocompatible polymer wherein the microparticles cause a local site reaction in vivo upon parenteral administration to a patient that is substantially similar to a local site reaction caused by placebo microparticles that include the biocompatible polymer.

99. Microparticles consisting essentially of a bisphosphonate and a biocompatible polymer wherein the microparticles have clinically acceptable local tolerability in vivo upon administration to a patient.

100. The microparticles of claim 99 wherein the microparticles cause a local site reaction in vivo upon parenteral administration to a patient that is substantially similar to a local site reaction caused by placebo microparticles that include the biocompatible polymer.

101. The microparticles of claim 99 wherein the microparticles cause a local site reaction in vivo upon parenteral administration to a patient that is substantially reduced as compared to a local site reaction caused by a parenteral administration to the patient of a bisphosphonate not formed into microparticles with a biocompatible polymer.

102. Microparticles comprising:

a) a poly(d,l-lactide-co-gylcolide) polymer having about 75 mol % d,l-lactide, about 25 mol % glycolide, and a lauryl ester end group; and

b) risedronate or a salt thereof;

wherein the volume median diameter of the microparticles is about 20 to about 60 microns.

103. The microparticles of claim 102 wherein the volume median diameter of the microparticles is about 45 to about 55 microns

104. The microparticles of claim 102 wherein the volume median diameter of the microparticles is about 35 to about 45 microns.

105. The microparticles of claim 102 wherein the volume median diameter of the microparticles is about 25 to about 35 microns.

106. The microparticles of claim 102 wherein the polymer has an inherent viscosity measured in chloroform at 25°

C. of about 0.8 to about 0.9 dL/g.

107. The microparticles of claim 102 wherein the risedronate or the salt thereof is present in the microparticles at a concentration of about 3 to about 6 percent by weight.

108. Microparticles comprising:

a) a poly(d,l-lactide-co-gylcolide) polymer having about 65 mol % d,l-lactide, about 35 mol % glycolide, and a lauryl ester end group; and

b) risedronate or a salt thereof;

wherein the volume median diameter of the microparticles is about 40 to about 60 microns.

109. The microparticles of claim 108 wherein the volume median diameter of the microparticles is about 45 to about 55 microns.

110. The microparticles of claim 108 wherein the polymer has an inherent viscosity measured in chloroform at 25°

C. of about 0.5 to about 0.65 dL/g.

111. The microparticles of claim 108 wherein the risedronate or the salt thereof is present in the microparticles at a concentration of about 3 to about 6 percent by weight.

112. Microparticles comprising:

a) a poly(d,l-lactide) polymer having a methyl ester end group; and

b) risedronate or a salt thereof;

wherein the volume median diameter of the microparticles is about 40 to about 60 microns.

113. The microparticles of claim 112 wherein the volume median diameter of the microparticles is about 45 to about 55 microns.

114. The microparticles of claim 112 wherein the polymer has an inherent viscosity measured in chloroform at 25°

C. of about 0.48 dL/g.

115. The microparticles of claim 112 wherein the risedronate or the salt thereof is present in the microparticles at a concentration of about 3 to about 6 percent by weight.

116. A method for treating a patient in need of therapy, comprising:

administering to the patient a therapeutically effective amount of microparticles consisting essentially of a biocompatible polymer and risedronate or a salt thereof;

wherein the microparticles have an in vitro 24-hour cumulative risedronate release from the microparticles of less than about 15 weight percent.

117. The method of claim 116 wherein the in vitro 24-hour cumulative risedronate release from the microparticles is less than about 10 weight percent.

118. The method of claim 116 wherein the in vitro 24-hour cumulative risedronate release is in a phosphate buffered saline composition at 37°

C.

119. A method for treating a patient in need of therapy, comprising:

administering to the patient a therapeutically effective amount of microparticles consisting essentially of a biocompatible polymer and risedronate or a salt thereof;

wherein the microparticles have an in vivo duration of risedronate release from the microparticles of at least about 60 days.