Method of forming microparticles that include a bisphosphonate and a polymer
First Claim
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.
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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.
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Citations
119 Claims
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1. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:
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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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
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25. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:
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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. - View Dependent Claims (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)
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38. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:
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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. - View Dependent Claims (39, 40, 41, 42, 43)
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44. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:
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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.
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45. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:
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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.
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46. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:
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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. - View Dependent Claims (47, 48, 49, 50, 51, 52, 53, 54, 55, 56)
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57. A method of forming microparticles that include a bisphosphonate and a polymer, comprising the steps of:
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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. - View Dependent Claims (58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77)
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- 78. Microparticles consisting essentially of a biocompatible polymer and at least about 3 weight percent of risedronate or a salt thereof.
- 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.
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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.
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102. Microparticles comprising:
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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. - View Dependent Claims (103, 104, 105, 106, 107)
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108. Microparticles comprising:
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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. - View Dependent Claims (109, 110, 111)
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112. Microparticles comprising:
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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. - View Dependent Claims (113, 114, 115)
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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.- View Dependent Claims (117, 118)
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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.
Specification