Drug loaded contrast agents: combining diagnosis and therapy

摘要

This invention provides an improvement to methods of drug loading of ultrasound contrast agents. Echogenic drug-loaded polymer microcapsules, nanocapsules, or mixtures thereof produced by the method of the invention wherein the echogenic drug-loaded polymer microcapsules, nanocapsules, or mixtures thereof contain at least 10% more of a drug as compared to (1) echogenic drug-loaded polymer microcapsules, nanocapsules, or mixtures thereof prepared by adding drug prior to emulsifying or (2) echogenic drug-loaded polymer microcapsules, nanocapsules, or mixtures thereof prepared by adding drug to lyophilized polymer microcapsules, nanocapsules, or mixtures thereof.

主权项

1. A hardening stage adsorption method for producing echogenic doxorubicin-loaded polymer microcapsules, nanocapsules, or mixtures thereof, the method comprising:
(a) forming a first mixture comprising a solution of poly (D,L-lactic acid) (PLA) in at least one volatile non-polar solvent and optionally at least one non-water soluble sublimable substance; (b) forming a second mixture comprising a solution of at least one water soluble sublimable substance in at least one polar solvent; (c) adding said first mixture to said second mixture to form a third mixture; (d) emulsifying the third mixture to produce a first population of polymer microcapsules, nanocapsules, or mixtures thereof comprising PLA, said at least one water-soluble sublimable substance, and optionally, said at least one non-water sublimable soluble substance; (e) mixing said first population of polymer microcapsules, nanocapsules, or mixtures thereof with a surfactant solution and homogenizing to break apart said first population of microcapsules or nanocapsules to form a second population of polymer microcapsules, nanocapsules, or mixtures thereof that are smaller in size than said first population; (f) hardening said second population of polymer microcapsules, nanocapsules, or mixtures thereof by contacting with at least one hardening solvent comprising doxorubicin dissolved or dispersed in said at least one hardening solvent to form a first population of doxorubicin-loaded polymer microcapsules, nanocapsules, or mixtures thereof in which at least 95% of the non-polar solvent is removed; (g) optionally removing traces of said at least one hardening solvent and thereby further hardening said first population of doxorubicin-loaded polymer microcapsules, nanocapsules, or mixtures thereof; and (h) removing said water soluble sublimable substance and said non-water soluble sublimable substance if present from doxorubicin-loaded population of polymer microcapsules, nanocapsules, or mixtures thereof to form echogenic doxorubicin-loaded polymer microcapsules, nanocapsules, or mixtures thereof which comprise at least 119% more of doxorubicin as compared to (1) echogenic doxorubicin-loaded polymer microcapsules, nanocapsules, or mixtures thereof prepared by adding doxorubicin prior to said emulsifying or (2) echogenic doxorubicin-loaded polymer microcapsules, nanocapsules, or mixtures thereof prepared by adding doxorubicin to lyophilized polymer microcapsules, nanocapsules, or mixtures thereof.