DRUG DELIVERY MEDICAL DEVICE

• US 20150250926A1
• Filed: 10/18/2013
• Published: 09/10/2015
• Est. Priority Date: 10/18/2011
• Status: Active Grant

• Current Assignee: Micell Medtech Incorporated
• Original Assignee: Micell Technologies Inc.
• Inventors: McClain, James B., Taylor, Charles Douglas, Fagan, Meagan M.
• Granted Patent: US 10,188,772 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/622 Microcapsules
• CPC Class Codes: A61L 2300/624 Nanocapsules
• CPC Class Codes: A61L 2300/63 Crystals
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61M 2025/105 having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
• CPC Class Codes: C08L 29/04 Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

A medical device that releases a pharmaceutical agent to a target site is disclosed. The medical device includes a balloon, and a coating on at least a portion of the balloon. The coating includes particles of a pharmaceutical agent. Each particle of the particles of the pharmaceutical agent is at least partially encapsulated in a polymer material. A method of releasing a pharmaceutical agent at a target site is also disclosed. The method includes the steps of providing a device including a balloon, and a coating on at least a portion of the balloon, the coating including particles of a pharmaceutical agent, and each particle of the pharmaceutical agent is at least partially encapsulated in a polymer material; positioning the device to allow the balloon to reach the target site; and inflating the balloon of the device.

Claims

1. A medical device comprising:

a balloon; and

a coating on at least a portion of the balloon,

wherein the coating comprises particles of a pharmaceutical agent, and

wherein each particle of the pharmaceutical agent is at least partially encapsulated in a polymer material.

2. The medical device of claim 1, wherein at least 50% of the surface area of the pharmaceutical agent is encapsulated in the polymer material.

3. The medical device of claim 1, wherein at least 75% of the surface area of the pharmaceutical agent is encapsulated in the polymer material.

4. The medical device of claim 1, wherein at least 90% of the surface area of the pharmaceutical agent is encapsulated in the polymer material.

5. The medical device of claim 1, wherein at least 95% of the surface area of the pharmaceutical agent is encapsulated in the polymer material.

6. The medical device of claim 1, wherein the polymer layer has an average thickness of from 2 microns to 20 microns.

7. The medical device of claim 6, wherein the polymer layer has an average thickness of from 5 microns to 15 microns.

8. The medical device of claim 7, wherein the polymer layer has an average thickness of about 10 microns.

9. The medical device of claim 1, wherein the pharmaceutical agent has a crystallinity of at least 5%.

10. The medical device of claim 1, wherein the pharmaceutical agent has a crystallinity of at least 20%.

11. The medical device of claim 1, wherein the pharmaceutical agent has a crystallinity of from 25% to 95%.

12. The medical device of claim 1, wherein an average particle size of the encapsulated pharmaceutical agent is from 5 nm to 150 nm.

13. The medical device of claim 12, wherein an average particle size of the encapsulated pharmaceutical agent is from 10 nm to 100 nm.

14. The medical device of claim 1, wherein an average particle size of the encapsulated pharmaceutical agent is from 1 micron to 50 micron.

15. The medical device of claim 14, wherein an average particle size of the encapsulated pharmaceutical agent is from 1 micron to 10 micron.

16. The medical device of claim 1, wherein a weight ratio between the pharmaceutical agent and the polymer material is from 1:

99 to 70;

30.

17. The medical device of claim 1, wherein a weight ratio between the pharmaceutical agent and the polymer material is from 25:

75 to 40;

60.

18. The medical device of claim 1, wherein a weight ratio of the pharmaceutical agent and the polymer material is from 40:

60 to 60;

40.

19. The medical device of claim 1, wherein the pharmaceutical agent is at least partially encapsulated in the polymer material by spray-drying a mixture of the pharmaceutical agent, the polymer material, and a solvent.

20. The medical device of claim 19, wherein the mixture is a solution and the solvent is a polar aprotic solvent.

21. The medical device of claim 20, wherein the polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, and mixtures thereof.

22. The medical device of claim 19, wherein the mixture is a slurry and the solvent is water.

23. The medical device of claim 1, wherein the pharmaceutical agent is at least partially encapsulated in the polymer material by spraying and drying a solution of the polymer material on the particles of the pharmaceutical agent.

24. The medical device of claim 23, wherein the solution comprises the polymer material and a polar aprotic solvent.

25. The medical device of claim 24, wherein the polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, and mixtures thereof.

26. The medical device of claim 1, wherein the pharmaceutical agent is at least partially encapsulated in the polymer material by adding particles of the polymer material to the pharmaceutical agent in a tumbling vessel.

27. The medical device of claim 26, wherein the particles of the polymer material have an average particle size of from 10 microns to 100 microns.

28. The medical device of claim 26, wherein the particles of the polymer material are added at a rate of from 100 μ

g to 1000 μ

g per minute.

29. The medical device of claim 28, wherein the particles of the polymer material are added at a rate of from 300 μ

g to 500 μ

g per minute.

30. The medical device of claim 1 wherein the pharmaceutical agent is at least partially encapsulated in the polymer material by forming an emulsion-based mixture comprising the pharmaceutical agent and the polymer material, and separating the polymer-encapsulated pharmaceutical agent from the emulsion-based mixture.

31. The medical device of claim 30, wherein the polymer material is a mixture of PVA and PLGA.

32. The medical device of claim 31, wherein the PVA has an average molecular weight of from about 20,000 to about 30,000.

33. The medical device of claim 31, wherein the PLGA has a weight ratio from about 40:

60 to about 60;

40 lactic acid;

glycolic acid.

34. The medical device of claim 30, wherein the pharmaceutical agent is amorphous.

35. The medical device of claim 34, wherein the pharmaceutical agent is at least partially encapsulated in the polymer material by forming the emulsion-based mixture comprising the pharmaceutical agent and the polymer material, evaporating a portion of the emulsion-based mixture, and filtering the remaining emulsion-based mixture.

36. The medical device of claim 35, wherein the encapsulated pharmaceutical agent is resuspended and lyophilized.

37. The medical device of claim 35, wherein the emulsion-based mixture is formed by combining a first polymer solution, a second polymer solution, a third polymer solution, and a pharmaceutical agent solution.

38. The medical device of claim 37, wherein the first and third polymer solutions comprise a first polymer and water.

39. The medical device of claim 38, wherein the first polymer is PVA.

40. The medical device of claim 38, wherein the first polymer solution has a polymer concentration of from about 1% to about 5%.

41. The medical device of claim 38, wherein the third polymer solution has a polymer concentration of from about 0.5% to about 2%.

42. The medical device of claim 37, wherein the second polymer solution comprises a second polymer and an organic solvent.

43. The medical device of claim 42, wherein the second polymer is PLGA.

44. The medical device of claim 42, wherein the organic solvent is dichloromethane.

45. The medical device of claim 37, wherein the pharmaceutical agent solution comprises the pharmaceutical agent and a polar aprotic solvent.

46. The medical device of claim 45, wherein the polar aprotic solvent is dimethylsulfoxide.

47. The medical device of claim 37, wherein the emulsion-based mixture is formed by mixing the pharmaceutical agent solution and the second polymer solution, adding the first polymer solution to the mixture, homogenizing the mixture, and adding the third polymer solution.

48. The medical device of claim 30, wherein the pharmaceutical agent is crystalline.

49. The medical device of claim 48, wherein the pharmaceutical agent is at least partially encapsulated in the polymer layer by forming the emulsion-based mixture comprising the pharmaceutical agent and the polymer material, evaporating a portion of the emulsion-based mixture, and filtering the remaining emulsion-based mixture.

50. The medical device of claim 48, wherein the encapsulated pharmaceutical agent is resuspended and lyophilized.

51. The medical device of claim 50, wherein the emulsion-based mixture is formed by combining a first polymer solution, a second polymer solution, a third polymer solution, and the pharmaceutical agent.

52. The medical device of claim 51, wherein the first polymer solution comprises a first polymer and an organic solvent.

53. The medical device of claim 52, wherein the first polymer solution is combined with the second polymer solution and the organic solvent is allowed to evaporate.

54. The medical device of claim 52, wherein the first polymer is PLGA.

55. The medical device of claim 52, wherein the organic solvent is dichloromethane.

56. The medical device of claim 51, wherein the second and third polymer solutions comprise a second polymer and water.

57. The medical device of claim 56, wherein the second polymer is PVA.

58. The medical device of claim 56, wherein second polymer solution has a polymer concentration of from about 0.5% to about 2%.

59. The medical device of claim 56, wherein the third polymer solution has a polymer concentration of from about 1% to about 5%.

60. The medical device of claim 51, wherein the emulsion-based mixture is formed by mixing the first polymer solution and the second polymer solution to form an emulsion, mixing the pharmaceutical agent and the third polymer solution to form a suspension, and combining the emulsion and suspension.

61. The medical device of claim 1, wherein the pharmaceutical agent is a macrolide immunosuppressant.

62. The medical device of claim 61, wherein the macrolide immunosuppressant is rapamycin or a derivative, a prodrug, a hydrate, an ester, a salt, a polymorph, a derivative or an analog thereof.

63. The medical device of claim 61, wherein the macrolide immunosuppressant is selected from the group consisting of rapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4′

-Hydroxymethyl)benzyl-rapamycin, 40-O-[4′

-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin, 40-O-[3′

-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′

-en-1′

-yl]-rapamycin, (2′

;

E,4′

S)-40-O-(4′

,5′

-Dihydroxypent-2′

-en-1′

-yl)-rapamycin 40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin, 40-O-(3-Hydroxyl)propyl-rapamycin 40-O-(6-Hydroxyl)hexyl-rapamycin 40-O-[2-(2-Hydroxyl)ethoxy]ethyl-rapamycin 40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-Methyl-N′

-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxyl)ethyl-rapamycin, 28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin 40-O-(2-Nicotinamidoethyl)-rapamycin, 40-O-(2-(N-Methyl-imidazo-2′

-ylcarbethoxamido)ethyl)-rapamycin, 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, 40-O-[2-(4′

,5′

-Dicarboethoxy-1′

,2′

,3′

-triazol-1′

-yl)-ethyl]-rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), and 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin

64. The medical device of claim 1, wherein the pharmaceutical agent is rapamycin.

65. The medical device of claim 1, wherein the polymer material comprises a bioabsorbable polymer.

66. The medical device of claim 65, wherein the bioabsorbable polymer is selected from the group consisting of polylactides (PLA);

poly(lactide-co-glycolide) (PLGA);

polyanhydrides;

polyorthoesters;

poly(N-(2-hydroxypropyl) methacrylamide);

poly(dl-lactide) (DLPLA);

poly(l-lactide) (LPLA);

polyglycolide (PGA);

poly(dioxanone) (PDO);

poly(glycolide-co-trimethylene carbonate) (PGA-TMC);

poly(l-lactide-co-glycolide) (PGA-LPLA);

poly(dl-lactide-co-glycolide) (PGA-DLPLA);

poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);

poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC), polyvinyl alcohol (PVA), polyarginine, and mixtures or co-polymers thereof.

67. The medical device of claim 66, wherein the biodegradable polymer is selected from the group consisting of PLGA, PVA, polyarginine, and mixtures thereof.

68. The medical device of claim 1, wherein the polymer material comprises PLGA and PVA.

69. The medical device of claim 1, wherein the polymer material comprises PLGA.

70. The medical device of claim 69 wherein the PLGA comprises about 50:

50 lactic acid;

glycolic acid.

71. The medical device of claim 1, wherein the polymer material comprises a durable polymer.

72. The medical device of claim 1, further comprising a binding agent deposited on an exterior surface of the encapsulated particles of the pharmaceutical agent.

73. The medical device of claim 72, wherein a weight ratio between the binding agent and the polymer is from 1:

99 to 25;

75.

74. The medical device of claim 72, wherein a weight ratio between the binding agent and the polymer is from 1:

99 to 10;

90.

75. The medical device of claim 72, wherein the binding agent is deposited by spraying and drying a solution of the binging agent on the encapsulated particles of the pharmaceutical agent.

76. The medical device of claim 75, wherein the solution comprises the binding agent and water.

77. The medical device of claim 72, wherein the binding agent comprises at least one of:

polyarginine, polyarginine 9-L-pArg, DEAE-Dextran (Diethylaminoethyl cellulose-Dextran), DMAB (Didodecyldimethylammonium bromide), PEI (Polyethyleneimine), TAB (Tetradodecylammonium bromide), and DMTAB (Dimethylditetradecylammonium bromide).

78. The medical device of claim 72, wherein the binding agent is polyarginine.

79. The medical device of claim 78, wherein the polyarginine has an average molecular weight of about 70 kDa.

80. The medical device of claim 78, wherein the polyarginine has an average molecular weight of 5-15 kDa.

81. The medical device of claim 1 wherein the encapsulated particles of the pharmaceutical agent are deposited on the balloon using an eSTAT coating process.

82. The medical device of claim 1, wherein the device releases at least 3% of the pharmaceutical agent upon inflation of the balloon.

83. The medical device of claim 1 wherein the device releases at least 5% or at least 10% of the pharmaceutical agent upon inflation of the balloon.

84. The medical device of claim 1 wherein the device releases at least about 2 ng/mg, at least about 3 ng/mg, at least about 5 ng/mg, at least about 10 ng/mg, at least about 20 ng/mg, at least about 30 ng/mg, or at least about 40 ng/mg of the pharmaceutical agent 76 hours after inflation of the balloon.

85. The medical device of claim 1, wherein the balloon is an invertable balloon having an abluminal side;

wherein the coating is provided on the abluminal side of the invertable balloon.

86. The medical device of claim 85, wherein the balloon is inverted within a catheter.

87. The medical device of claim 86, wherein the balloon is capable of being pushed out of the catheter using balloon inflation pressure or by moving the distal end of the balloon distally through the balloon, or a combination thereof.

88. The medical device of claim 85, wherein the invertible balloon is inverted on an outside of a catheter.

89. The medical device of claim 88, wherein a treatment length of the invertible balloon is controlled by partially un-inverting the invertible balloon on the outside of the catheter.

90. The medical device of claim 88, further comprising a sheath provided over the invertible balloon.

91. The medical device of claim 90, wherein the sheath is retractable once the coated balloon reaches the treatment site, is positioned near the treatment site, is positioned at the treatment site, is proximal to the treatment site, is distal to the treatment site, or is within the treatment site.

92. The medical device of claim 1, further comprising an occluder configured to block the flow of bodily fluids toward the balloon before the balloon is inflated.

93. The medical device of claim 92, wherein the occluder comprises a second balloon.

94. The medical device of claim 92, wherein the balloon comprises first and second sections, the first section comprising the occluder and the second section comprising the coating.

95. The medical device of claim 92, wherein the balloon comprises a distal node and a proximal node wherein the distal node comprises the coating and wherein the proximal node comprises the occluder, or wherein the proximal node comprises the coating and wherein the distal node comprises the occluder.

96. The medical device of claim 92, wherein a distal portion of the balloon is coated and wherein a proximal portion of the balloon is not coated, and wherein the proximal portion of the balloon is the occlude, or wherein a proximal portion of the balloon is coated and wherein a distal portion of the balloon is not coated, and wherein the distal portion of the balloon is the occluder.

97. A method of releasing a pharmaceutical agent at a target site, comprising

providing a device comprising a balloon, and a coating on at least a portion of the balloon, wherein the coating comprises particles of a pharmaceutical agent, and wherein each particle of the pharmaceutical agent is at least partially encapsulated in a polymer material;

positioning the device to allow the balloon to reach the target site; and

inflating the balloon of the device,

wherein at least some of the pharmaceutical agent is released to the target site upon inflating the balloon.

98. The method of claim 97, wherein the target site is a blood vessel.

99. The method of claim 97, wherein at least 3% of the pharmaceutical agent is released to the blood vessel upon inflation of the balloon.

100. The method of claim 97, wherein at least 5% of the pharmaceutical agent is released to the blood vessel upon inflation of the balloon.

101. The method of claim 97, wherein at least 10% of the pharmaceutical agent is released to the blood vessel upon inflation of the balloon.

102. The method of claim 97, wherein the pharmaceutical agent is a macrolide immunosuppressant.

103. The method of claim 102, wherein the macrolide immunosuppressant is rapamycin or a derivative, a prodrug, a hydrate, an ester, a salt, a polymorph, a derivative or an analog thereof.

104. The method of claim 102, wherein the macrolide immunosuppressant is selected from the group consisting of rapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4′

-Hydroxymethyl)benzyl-rapamycin, 40-O-[4′

-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin, 40-O-[3′

-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′

-en-1′

-yl]-rapamycin, (2′

;

E,4′

S)-40-O-(4′

,5′

-Dihydroxypent-2′

-en-1′

-yl)-rapamycin 40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin, 40-O-(3-Hydroxyl)propyl-rapamycin 40-O-(6-Hydroxyl)hexyl-rapamycin 40-O-[2-(2-Hydroxyl)ethoxy]ethyl-rapamycin 40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 40-O-(2-Acetoxy)ethyl-rapamycin 40-O-(2-Nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-Methyl-N′

-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxyl)ethyl-rapamycin, 28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin 40-O-(2-Nicotinamidoethyl)-rapamycin, 40-O-(2-(N-Methyl-imidazo-2′

-ylcarbethoxamido)ethyl)-rapamycin, 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, 40-O-[2-(4′

,5′

-Dicarboethoxy-1′

,2′

,3′

-triazol-1′

-yl)-ethyl]-rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), and 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin

105. The method of claim 97, wherein the pharmaceutical agent is rapamycin.

106. The method of claim 97, wherein the polymer material comprises a biodegradable polymer.

107. The method of claim 106 wherein the bioabsorbable polymer is selected from the group consisting of polylactides (PLA);

poly(lactide-co-glycolide) (PLGA);

polyanhydrides;

polyorthoesters;

poly(N-(2-hydroxypropyl) methacrylamide);

poly(dl-lactide) (DLPLA);

poly(l-lactide) (LPLA);

polyglycolide (PGA);

poly(dioxanone) (PDO);

poly(glycolide-co-trimethylene carbonate) (PGA-TMC);

poly(l-lactide-co-glycolide) (PGA-LPLA);

poly(dl-lactide-co-glycolide) (PGA-DLPLA);

poly(l-lactide-co-dl-lactide) (LPLA-DLPLA);

poly(glycolide-co-trimethylene carbonate-co-dioxanone) (PDO-PGA-TMC), polyvinyl alcohol (PVA), and mixtures or co-polymers thereof.

108. The method of claim 107, wherein the biodegradable polymer is selected from the group consisting of PLGA, PVA, polyarginine, and mixtures thereof.

109. The method of claim 97, wherein the polymer material comprises PLGA and PVA.

110. The method of claim 97, wherein the polymer layer comprises PLGA.

111. The method of claim 110, wherein the PLGA comprises about 50:

50 lactic acid;

glycolic acid.

112. The method of claim 110, wherein the polymer layer comprises a durable polymer.

113. The method of claim 97, wherein the device further comprises a binding agent deposited on an exterior surface of the encapsulated particles of the pharmaceutical agent.

114. The method of claim 113, wherein the binding agents comprises at least one of:

polyarginine, polyarginine 9-L-pArg, DEAE-Dextran (Diethylaminoethyl cellulose-Dextran), DMAB (Didodecyldimethylammonium bromide), PEI (Polyethyleneimine), TAB (Tetradodecylammonium bromide), and DMTAB (Dimethylditetradecylammonium bromide).

115. The method of claim 113, wherein the binding agent is polyarginine.

116. The method of claim 97, wherein the encapsulated particles of the pharmaceutical agent are deposited on the balloon using an eSTAT coating process.

117. A method of forming polymer-encapsulated crystalline rapamycin, the method comprising:

forming the emulsion-based mixture comprising the pharmaceutical agent and the polymer material;

evaporating a portion of the emulsion-based mixture, and filtering the remaining emulsion-based mixture.

118. The method claim 117, further comprising resuspending and lyophilizing the encapsulated pharmaceutical agent.

119. The method of claim 117, wherein the emulsion-based mixture is formed by combining a first polymer solution, a second polymer solution, a third polymer solution, and the pharmaceutical agent.

120. The method of claim 119, wherein the first polymer solution comprises a first polymer and an organic solvent.

121. The method of claim 120, wherein the first polymer solution is combined with the second polymer solution and the organic solvent is allowed to evaporate.

122. The method of claim 121, wherein the first polymer is PLGA.

123. The method of claim 122, wherein the organic solvent is dichloromethane.

124. The method of claim 119, wherein the second and third polymer solutions comprise a second polymer and water.

125. The method of claim 124, wherein the second polymer is PVA.

126. The method of claim 125, wherein second polymer solution has a polymer concentration of from about 0.5% to about 2%.

127. The method of claim 125, wherein the third polymer solution has a polymer concentration of from about 1% to about 5%.

128. The method of claim 119, wherein the emulsion-based mixture is formed by mixing the first polymer solution and the second polymer solution to form an emulsion, mixing the pharmaceutical agent and the third polymer solution to form a suspension, and combining the emulsion and suspension.