Intraluminal Prostheses Having Polymeric Material with Selectively Modified Crystallinity and Methods of Making Same

• US 20110169198A1
• Filed: 03/30/2011
• Published: 07/14/2011
• Est. Priority Date: 03/10/2003
• Status: Active Grant

• Current Assignee: Joseph M. DeSimone, Michael S. Williams
• Original Assignee: Joseph M. DeSimone, Michael S. Williams
• Inventors: Williams, Michael S., DeSimone, Joseph M.
• Granted Patent: US 8,906,286 B2
• Time in Patent Office: Days
• US Class Current: 264/482
• CPC Class Codes: A61F 2/07 Stent-grafts
• CPC Class Codes: A61L 2300/20 containing or releasing organic materials
• CPC Class Codes: A61L 27/44 having a macromolecular matrix
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/04 Macromolecular materials
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: Y10T 428/1352 Polymer or resin containing [i.e., natural or synthetic]
• CPC Class Codes: Y10T 428/139 Open-ended, self-supporting conduit, cylinder, or tube-type article

Abstract

Methods of manufacturing polymeric intraluminal prostheses include annealing the polymeric material to selectively modify the crystallinity thereof. Annealing may be utilized to selectively modify various properties of the polymeric material of an intraluminal prosthesis, including: selectively increasing the modulus of the polymeric material; selectively increasing the hoop strength of the intraluminal prosthesis; selectively modifying the elution rate (increase or decrease) of a pharmacological agent subsequently disposed on or within the annealed polymeric material; selectively increasing/decreasing stress in the intraluminal prosthesis; and selectively modifying the polymeric material such that it erodes at a different rate.

Claims

1-77. -77. (canceled)

78. A method of manufacturing an intraluminal prosthesis having an outer surface of polymeric material, wherein the intraluminal prosthesis is expandable from a contracted configuration when deployed within a lumen of a subject body, the method comprising annealing a selected portion of the polymeric material for a time prior to deployment and at a temperature sufficient to selectively modify the crystallinity thereof, wherein annealing comprises heating the selected portion of the polymeric material via a light source to a first temperature greater than or equal to the glass transition temperature of the polymeric material for a first period of time and then quenching the selected portion of the polymeric material to a second temperature lower than the glass transition temperature for a second period of time sufficient to selectively control the crystallinity of the selected portion of the polymeric material.

79. The method of claim 78, wherein the light source is a laser.

80. The method of claim 78, wherein the selected portion of the polymeric material comprises a plurality of selected portions of the polymeric material.

81. The method of claim 78, wherein annealing selectively increases the crystallinity of the selected portion of the polymeric material.

82. The method of claim 78, wherein the first temperature is higher than the melting temperature of the polymeric material.

83. The method of claim 78, wherein annealing selectively increases or decreases the modulus of the selected portion of the polymeric material.

84. The method of claim 78, wherein annealing selectively increases or decreases the hoop strength of the intraluminal prosthesis.

85. The method of claim 78, wherein annealing selectively modifies an elution rate of a pharmacological agent subsequently elutably trapped within the selected portion of the polymeric material.

86. The method of claim 78, wherein annealing selectively affects heat sensitive agents within the selected portion of the polymeric material.

87. The method of claim 85, wherein the elution rate is increased.

88. The method of claim 85, wherein the elution rate is decreased.

89. The method of claim 78, wherein annealing selectively decreases stress in the intraluminal prosthesis.

90. The method of claim 78, wherein annealing selectively increases stress in the intraluminal prosthesis.

91. The method of claim 78, wherein the polymeric material is configured to erode at a first rate when deployed within a lumen of a subject body, and wherein annealing selectively modifies the selected portion of the polymeric material such that it erodes at a second rate that is greater than the first rate when deployed within a lumen of a subject body.

92. The method of claim 78, wherein the polymeric material is configured to erode at a first rate when deployed within a lumen of a subject body, and wherein annealing selectively modifies the selected portion of the polymeric material such that it erodes at a third rate that is less than the first rate when deployed within a lumen of a subject body.

93. The method of claim 78, wherein annealing is performed in the presence of carbon dioxide.

94. The method of claim 78, wherein annealing is preceded by immersing the polymeric material in carbon dioxide.

95. The method of claim 78, wherein annealing is performed in the presence of a nucleating agent disposed on or within the polymeric material.

96. The method of claim 78, further comprising modifying molecular crosslinking of the polymeric material by subjecting the polymeric material to chemical treatment.

97. The method of claim 96, wherein subjecting the polymeric material to chemical treatment comprises subjecting the polymeric material to one or more multifunctional cross-linking agents.

98. The method of claim 97, wherein the one or more multifunctional cross-linking agents are selected from the group consisting of formaldehyde, difunctional dialdehyde, and diisocyantes.

99. The method of claim 98, wherein subjecting the polymeric material to chemical treatment comprises subjecting the polymeric material to one or more enzymatic cross-linking agents.

100. The method of claim 99, wherein the one or more enzymatic crosslinking agents are selected from the group consisting of polyethylene glycols (PEG) functionalized with a glutaminamide and a lysine-containing polypeptide using a natural tissue enzyme, and transglutaminase.

101. The method of claim 96, wherein the polymeric material is subjected to chemical treatment during annealing.

102. The method of claim 96, wherein the polymeric material is subjected to chemical treatment after annealing.

103. The method of claim 78, further comprising modifying molecular crosslinking of the polymeric material by subjecting the polymeric material to irradiation.

104. The method of claim 78, further comprising sterilizing the polymeric material by subjecting the polymeric material to irradiation.

105. The method of claim 103, wherein radiation utilized to modify molecular crosslinking is selected from the group consisting of ionizing radiation and UV/visible radiation.

106. The method of claim 104, wherein ionizing irradiation comprises e-beam irradiation or gamma irradiation.

107. The method of claim 103, wherein radiation utilized to modify molecular crosslinking comprises UV/visible radiation in the presence of a photoacid generator.

108. The method of claim 107, wherein the photoacid generator is selected from the group consisting of dinitrobenzyltosylates, sulfonium salts, iodonium salts, diazodisulfone derivatives and sulfonates.

109. The method of claim 103, wherein the polymeric material is subjected to irradiation during annealing.

110. The method of claim 103, wherein the polymeric material is subjected to irradiation after annealing.

111. The method of claim 78, wherein the intraluminal prosthesis is a stent.

112. The method of claim 78, wherein the polymeric material is erodible.

113. The method of claim 78, wherein the polymeric material is non-erodible.

114. The method of claim 78, wherein the polymeric material is a coating on the intraluminal prosthesis.

115. The method of claim 112, wherein the erodible polymeric material is selected from the group consisting of, surgical gut, silk, cotton, poly(hydroxybutyrate), polycarbonate, polyacrylate, polyanhydride, poly(ortho esters), poly(phosphoesters), polyesters, polyamides, polyphosphazenes, poly(p-dioxane), poly(amino acid), polyglactin, erodable hydrogels, collagen, chitosan, poly(lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(ε

-caprolactone), poly(valerolactone), poly(hydroxy butyrate), poly(hydrovalerate), polydioxanone, poly(propylene fumarate), poly(ethyleneoxide)-poly(butylenetetraphthalate), poly(lactic acid-co-lysine), poly(lactic acid-co-trimethylene carbonate), poly(L-lactic acid) and poly(ε

-caprolactone) copolymers.

116. The method of claim 112, wherein the erodible polymeric material comprises a blend of polymeric material selected from the group consisting of, surgical gut, silk, cotton, poly(hydroxybutyrate), polycarbonate, polyacrylate, polyanhydride, poly(ortho esters), poly(,phosphoesters), polyesters, polyamides, polyphosphazenes, poly(p-dioxane), poly(amino acid), polyglactin, erodable hydrogels, collagen, chitosan, poly(lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(ε

-caprolactone), poly(valerolactone), poly(hydroxy butyrate), poly(hydrovalerate), polydioxanone, poly(propylene fumarate), poly(ethyleneoxide)-poly(butylenetetraphthalate), poly(lactic acid-co-lysine), poly(lactic acid-co-trimethylene carbonate), poly(L-lactic acid) and poly(ε

-caprolactone) copolymers.

117. The method of claim 78, further comprising the step of impregnating the polymeric material with a predetermined amount of a pharmacological agent after annealing.

118. The method of claim 117, wherein impregnating the polymeric material with a predetermined amount of a pharmacological agent comprises:

immersing the intraluminal prosthesis in a mixture of a carrier fluid and a pharmacological agent;

pressurizing the mixture for a time sufficient to cause the polymeric material to swell such that the carrier fluid and pharmacological agent at least partially penetrate the swollen polymeric material; and

removing the pressure such that the carrier fluid diffuses out of the swollen polymeric material and such that a predetermined amount of the pharmacological agent remains elutably trapped within the polymeric material.

119. The method of claim 118, wherein the carrier fluid is carbon dioxide, and wherein the pharmacological agent is hydrophobic.

120. The method of claim 119, wherein the pharmacological agent is selected from the group consisting of antineoplastics, antimitotics, antiinflammatories, antiplatelets, anticoagulants, antifibrins, antithrombins, antiproliferatives, antibiotics, antioxidants, immunosuppressives, antiallergic substances, and combinations thereof.

121. The method of claim 118, wherein the carrier fluid is water, and wherein the pharmacological agent is hydrophilic.

122. The method of claim 121, wherein pressurizing the mixture of carrier fluid and pharmacological agent comprises subjecting the mixture of carrier fluid and pharmacological agent to pressurized carbon dioxide.

123. The method of claim 119, wherein the carbon dioxide is present in a supercritical state.

124. The method of claim 123, wherein the carbon dioxide contains a co-solvent.

125. The method of claim 124, wherein the co-solvent is selected from the group consisting of ethanol and methanol.

126. A method of manufacturing an intraluminal prosthesis having an outer surface of polymeric material, wherein the intraluminal prosthesis is expandable from a contracted configuration when deployed within a lumen of a subject body, the method comprising annealing a selected portion of the polymeric material for a time prior to deployment and at a temperature sufficient to selectively modify the crystallinity thereof, wherein annealing comprises heating the selected portion of the polymeric material via a light source to a first temperature greater than or equal to the melting temperature of the polymeric material for a first period of time and then quenching the selected portion of the polymeric material to a second temperature lower than the melting temperature for a second period of time sufficient to selectively control the crystallinity of the selected portion of the polymeric material.

127. A method of manufacturing an intraluminal prosthesis having an outer surface of polymeric material, wherein the intraluminal prosthesis is expandable from a contracted configuration when deployed within a lumen of a subject body, the method comprising:

annealing a selected portion of the polymeric material via a light source for a time prior to deployment and at a temperature sufficient to selectively modify the crystallinity thereof; and

modifying molecular crosslinking of the selected portion of the polymeric material by subjecting the polymeric material to irradiation, wherein the selected portion of the polymeric material is subjected to irradiation during annealing.

128. The method of claim 127, wherein the light source is a laser.

129. The method of claim 127, wherein the selected portion of the polymeric material comprises a plurality of selected portions of the polymeric material.

130. The method of claim 127, wherein annealing comprises heating the selected portion of the polymeric material to a temperature between the glass transition temperature and the melting temperature of the polymeric material for a period of time sufficient to selectively increase or decrease one or more of the following:

the crystallinity of the selected portion of the polymeric material, the modulus of the selected portion of the polymeric material, the hoop strength of the intraluminal prosthesis, the elution rate of a pharmacological agent subsequently elutably trapped within the selected portion of the polymeric material, stress in the intraluminal prosthesis.

131. The method of claim 127, wherein annealing comprises heating the selected portion of the polymeric material to a temperature between the glass transition temperature and the melting temperature of the polymeric material for a period of time sufficient to selectively affect heat sensitive agents within the polymeric material.

132. The method of claim 127, wherein the polymeric material is configured to erode at a first rate when deployed within a lumen of a subject body, and wherein annealing comprises heating the selected portion of the polymeric material to a temperature between the glass transition temperature and the melting temperature of the polymeric material for a period of time sufficient to selectively modify the selected portion of the polymeric material such that it erodes at a second rate that is greater than the first rate when deployed within a lumen of a subject body.

133. The method of claim 127, wherein the polymeric material is configured to erode at a first rate when deployed within a lumen of a subject body, and wherein annealing comprises heating the selected portion of the polymeric material to a temperature between the glass transition temperature and the melting temperature of the polymeric material for a period of time sufficient to selectively modify the selected portion of the polymeric material such that it erodes at a third rate that is less than the first rate when deployed within a lumen of a subject body.

134. The method of claim 127, wherein annealing is performed in the presence of carbon dioxide.

135. The method of claim 127, wherein annealing is preceded by immersing the polymeric material in carbon dioxide.

136. The method of claim 127, wherein annealing is performed in the presence of a nucleating agent disposed on or within the polymeric material.

137. The method of claim 127, further comprising sterilizing the polymeric material by subjecting the polymeric material to irradiation.

138. The method of claim 127, wherein radiation utilized to modify molecular crosslinking is selected from the group consisting of ionizing radiation and UV/visible radiation.

139. The method of claim 138, wherein ionizing irradiation comprises e-beam irradiation or gamma irradiation.

140. The method of claim 127, wherein radiation utilized to modify molecular crosslinking comprises UV/visible radiation in the presence of a photoacid generator.

141. The method of claim 140, wherein the photoacid generator is selected from the group consisting of dinitrobenzyltosylates, sulfonium salts, iodonium salts, diazodisulfone derivatives and sulfonates.

142. The method of claim 127, wherein the intraluminal prosthesis is a stent.

143. The method of claim 127, wherein the polymeric material is erodible.

144. The method of claim 127, wherein the polymeric material is non-erodible.

145. The method of claim 127, wherein the polymeric material is a coating on the intraluminal prosthesis.

146. The method of claim 143, wherein the erodible polymeric material is selected from the group consisting of, surgical gut, silk, cotton, poly(hydroxybutyrate), polycarbonate, polyacrylate, polyanhydride, poly(ortho esters), poly(phosphoesters), polyesters, polyamides, polyphosphazenes, poly(p-dioxane), poly(amino acid), polyglactin, erodable hydrogels, collagen, chitosan, poly(lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(ε

-caprolactone), poly(valerolactone), poly(hydroxy butyrate), poly(hydrovalerate), polydioxanone, poly(propylene fumarate), poly(ethyleneoxide)-poly(butylenetetraphthalate), poly(lactic acid-co-lysine), poly(lactic acid-co-trimethylene carbonate), poly(L-lactic acid) and poly(ε

-caprolactone) copolymers.

147. The method of claim 143, wherein the erodible polymeric material comprises a blend of polymeric material selected from the group consisting of, surgical gut, silk, cotton, poly(hydroxybutyrate), polycarbonate, polyacrylate, polyanhydride, poly(ortho esters), poly(phosphoesters), polyesters, polyamides, polyphosphazenes, poly(p-dioxane), poly(amino acid), polyglactin, erodable hydrogels, collagen, chitosan, poly(lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(ε

-caprolactone), poly(valerolactone), poly(hydroxy butyrate), poly(hydrovalerate), polydioxanone, poly(propylene fumarate), poly(ethyleneoxide)-poly(butylenetetraphthalate), poly(lactic acid-co-lysine), poly(lactic acid-co-trimethylene carbonate), poly(L-lactic acid) and poly(ε

-caprolactone) copolymers.

148. The method of claim 127, further comprising the step of impregnating the polymeric material with a predetermined amount of a pharmacological agent after annealing.

149. The method of claim 148, wherein impregnating the polymeric material with a predetermined amount of a pharmacological agent comprises:

immersing the intraluminal prosthesis in a mixture of a carrier fluid and a pharmacological agent;

pressurizing the mixture for a time sufficient to cause the polymeric material to swell such that the carrier fluid and pharmacological agent at least partially penetrate the swollen polymeric material; and

removing the pressure such that the carrier fluid diffuses out of the swollen polymeric material and such that a predetermined amount of the pharmacological agent remains elutably trapped within the polymeric material.

150. The method of claim 149, wherein the carrier fluid is carbon dioxide, and wherein the pharmacological agent is hydrophobic.

151. The method of claim 150, wherein the pharmacological agent is selected from the group consisting of antineoplastics, antimitotics, antiinflammatories, antiplatelets, anticoagulants, antifibrins, antithrombins, antiproliferatives, antibiotics, antioxidants, immunosuppressives, antiallergic substances, and combinations thereof.

152. The method of claim 148, wherein the carrier fluid is water, and wherein the pharmacological agent is hydrophilic.

153. The method of claim 152, wherein pressurizing the mixture of carrier fluid and pharmacological agent comprises subjecting the mixture of carrier fluid and pharmacological agent to pressurized carbon dioxide.

154. The method of claim 150, wherein the carbon dioxide is present in a supercritical state.

155. The method of claim 154, wherein the carbon dioxide contains a co-solvent.

156. The method of claim 155, wherein the co-solvent is selected from the group consisting of ethanol and methanol.

157. A method of manufacturing an intraluminal prosthesis having an outer surface of polymeric material, wherein the intraluminal prosthesis is expandable from a contracted configuration when deployed within a lumen of a subject body, the method comprising:

annealing a selected portion of the polymeric material via a light source for a time prior to deployment and at a temperature sufficient to selectively modify the crystallinity thereof; and

modifying molecular crosslinking of the polymeric material by subjecting the selected portion of the polymeric material to irradiation, wherein the selected portion of the polymeric material is subjected to irradiation after annealing.

158. The method of claim 157, wherein the light source is a laser.

159. The method of claim 157, wherein the selected portion of the polymeric material comprises a plurality of selected portions of the polymeric material.

160. The method of claim 157, wherein annealing comprises heating the selected portion of the polymeric material to a temperature between the glass transition temperature and the melting temperature of the polymeric material for a period of time sufficient to selectively increase or decrease one or more of the following:

the crystallinity of the selected portion of the polymeric material, the modulus of the selected portion of the polymeric material, the hoop strength of the intraluminal prosthesis, the elution rate of a pharmacological agent subsequently elutably trapped within the selected portion of the polymeric material, stress in the intraluminal prosthesis.

161. The method of claim 157, wherein annealing comprises heating the selected portion of the polymeric material to a temperature between the glass transition temperature and the melting temperature of the polymeric material for a period of time sufficient to selectively affect heat sensitive agents within the polymeric material.

162. The method of claim 157, wherein the polymeric material is configured to erode at a first rate when deployed within a lumen of a subject body, and wherein annealing comprises heating the selected portion of the polymeric material to a temperature between the glass transition temperature and the melting temperature of the polymeric material for a period of time sufficient to selectively modify the selected portion of the polymeric material such that it erodes at a second rate that is greater than the first rate when deployed within a lumen of a subject body.

163. The method of claim 157, wherein the polymeric material is configured to erode at a first rate when deployed within a lumen of a subject body, and wherein annealing comprises heating the selected portion of the polymeric material to a temperature between the glass transition temperature and the melting temperature of the polymeric material for a period of time sufficient to selectively modify the selected portion of the polymeric material such that it erodes at a third rate that is less than the first rate when deployed within a lumen of a subject body.

164. The method of claim 157, wherein annealing is performed in the presence of carbon dioxide.

165. The method of claim 157, wherein annealing is preceded by immersing the polymeric material in carbon dioxide.

166. The method of claim 157, wherein annealing is performed in the presence of a nucleating agent disposed on or within the polymeric material.

167. The method of claim 157, further comprising sterilizing the polymeric material by subjecting the polymeric material to irradiation.

168. The method of claim 157, wherein radiation utilized to modify molecular crosslinking is selected from the group consisting of ionizing radiation and UV/visible radiation.

169. The method of claim 168, wherein ionizing irradiation comprises e-beam irradiation or gamma irradiation.

170. The method of claim 157, wherein radiation utilized to modify molecular crosslinking comprises UV/visible radiation in the presence of a photoacid generator.

171. The method of claim 170, wherein the photoacid generator is selected from the group consisting of dinitrobenzyltosylates, sulfonium salts, iodonium salts, diazodisulfone derivatives and sulfonates.

172. The method of claim 157, wherein the intraluminal prosthesis is a stent.

173. The method of claim 157, wherein the polymeric material is erodible.

174. The method of claim 157, wherein the polymeric material is non-erodible.

175. The method of claim 157, wherein the polymeric material is a coating on the intraluminal prosthesis.

176. The method of claim 173, wherein the erodible polymeric material is selected from the group consisting of, surgical gut, silk, cotton, poly(hydroxybutyrate), polycarbonate, polyacrylate, polyanhydride, poly(ortho esters), poly(phosphoesters), polyesters, polyamides, polyphosphazenes, poly(p-dioxane), poly(amino acid), polyglactin, erodable hydrogels, collagen, chitosan, poly(lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(ε

-caprolactone), poly(valerolactone), poly(hydroxy butyrate), poly(hydrovalerate), polydioxanone, poly(propylene fumarate), poly(ethyleneoxide)-poly(butylenetetraphthalate), poly(lactic acid-co-lysine), poly(lactic acid-co-trimethylene carbonate), poly(L-lactic acid) and poly(ε

-caprolactone) copolymers.

177. The method of claim 173, wherein the erodible polymeric material comprises a blend of polymeric material selected from the group consisting of, surgical gut, silk, cotton, poly(hydroxybutyrate);

polycarbonate, polyacrylate, polyanhydride, poly(ortho esters), poly(phosphoesters), polyesters, polyamides, polyphosphazenes, poly(p-dioxane), poly(amino acid), polyglactin, erodable hydrogels, collagen, chitosan, poly(lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(ε

-caprolactone), poly(valerolactone), poly(hydroxy butyrate), poly(hydrovalerate), polydioxanone, poly(propylene fumarate), poly(ethyleneoxide)-poly(butylenetetraphthalate), poly(lactic acid-co-lysine), poly(lactic acid-co-trimethylene carbonate), poly(L-lactic acid) and poly(ε

-caprolactone) copolymers.

178. The method of claim 157, further comprising the step of impregnating the polymeric material with a predetermined amount of a pharmacological agent after annealing.

179. The method of claim 178, wherein impregnating the polymeric material with a predetermined amount of a pharmacological agent comprises:

immersing the intraluminal prosthesis in a mixture of a carrier fluid and a pharmacological agent;

pressurizing the mixture for a time sufficient to cause the polymeric material to swell such that the carrier fluid and pharmacological agent at least partially penetrate the swollen polymeric material; and

removing the pressure such that the carrier fluid diffuses out of the swollen polymeric material and such that a predetermined amount of the pharmacological agent remains elutably trapped within the polymeric material.

180. The method of claim 179, wherein the carrier fluid is carbon dioxide, and wherein the pharmacological agent is hydrophobic.

181. The method of claim 180, wherein the pharmacological agent is selected from the group consisting of antineoplastics, antimitotics, antiinflammatories, antiplatelets, anticoagulants, antifibrins, antithrombins, antiproliferatives, antibiotics, antioxidants, immunosuppressives, antiallergic substances, and combinations thereof.

182. The method of claim 179, wherein the carrier fluid is water, and wherein the pharmacological agent is hydrophilic.

183. The method of claim 182, wherein pressurizing the mixture of carrier fluid and pharmacological agent comprises subjecting the mixture of carrier fluid and pharmacological agent to pressurized carbon dioxide.

184. The method of claim 180, wherein the carbon dioxide is present in a supercritical state.

185. The method of claim 184, wherein the carbon dioxide contains a co-solvent.

186. The method of claim 185, wherein the co-solvent is selected from the group consisting of ethanol and methanol.