Title:  Method of producing sub-micron particles of biologically active agents and uses thereof

United States Patent:  6,428,815

Issued:  August 6, 2002

Inventors:  Costantino; Henry R. (Grantham, NH); Jaworowicz; Warren E. (Boxboro, MA); Tracy; Mark A. (Arlington, MA); Beganski; Christopher P. (Littleton, MA)

Assignee:  Alkermes Controlled Therapeutics, Inc. (Cambridge, MA)

Appl. No.:  898524

Filed:  July 3, 2001

Submicron particles of a biologically active agent are prepared by atomizing using multifluid atomization a dispersed system comprising at least one biologically active agent and at least one solvent to produce droplets, freezing the droplets to produce frozen droplets, lyophilizing the frozen droplets to obtain microstructures capable of being further fragmented into submicron particles by techniques such as probe sonication. The submicron particles can be incorporated into sustained release compositions having a reduced initial release of biologically active agent. The sustained release compositions can be administered to a human or animal.

SUMMARY OF THE INVENTION

The present invention relates to submicron particles of a biologically active agent and a method of preparing the submicron particles. The invention further relates to sustained release compositions comprising the submicron particles of biologically active agent described herein and to a method of preparing and administering the sustained release composition.

The method for preparing submicron particles of a biologically active agent comprises the steps of atomizing using multifluid atomization a dispersed system comprising at least one biologically active agent and at least one solvent at a mass flow ratio of about 0.30 or greater to produce droplets, freezing the droplets to produce frozen droplets, removing the solvent from the frozen droplets to produce friable microstructures, forming a dispersion of the friable microstructures in at least one non-solvent for the biologically active agent and fragmenting the dispersed friable microstructures to produce submicron particles of the biologically active agent.

The submicron particles of a biologically active agent, as described herein, are prepared according to the method of the invention. The submicron particles of a biologically active agent are prepared by atomizing using multifluid atomization a dispersed system comprising at least one biologically active agent and at least one solvent at a mass flow ratio of about 0.30 or greater to produce droplets, freezing the droplets to produce frozen droplets, removing the solvent from the frozen droplets to produce friable microstructures, forming a dispersion of the friable microstructures in at least one non-solvent for the biologically active agent and fragmenting the dispersed friable microstructures to produce submicron particles of the biologically active agent.

The method of the invention for producing a composition for the sustained release of a biologically active agent comprises the steps of atomizing using multifluid atomization a dispersed system comprising at least one biologically active agent and at least one solvent at a mass flow ratio of about 0.30 or greater to produce droplets, freezing the droplets to produce frozen droplets, removing the solvent from the frozen droplets to produce friable microstructures, forming a dispersion of the friable microstructures in at least one non-solvent for the biologically active agent, fragmenting the dispersed friable microstructures to produce submicron particles of the biologically active agent, providing a suspension comprising the submicron particles of the biologically active agent, at least one biocompatible polymer and at least one polymer solvent and removing the polymer solvent to form a solid polymer/active agent matrix.

The composition for sustained release of a biologically active agent is likewise prepared according to the method of the invention. In other words, the composition for the sustained release of a biologically active agent as described herein is a composition prepared by the method comprising the steps of atomizing using multifluid atomization a dispersed system comprising at least one biologically active agent and at least one solvent at a mass flow ratio of about 0.30 or greater to produce droplets, freezing the droplets to produce frozen droplets, removing the solvent from the frozen droplets to produce friable microstructures, forming a dispersion of the friable microstructures in at least one non-solvent for the biologically active agent, fragmenting the dispersed friable microstructures to form submicron particles of the biologically active agent, providing a suspension comprising the submicron particles of biologically active agent, at least one biocompatible polymer, and at least one polymer solvent, and removing the polymer solvent to form a solid polymer/active agent matrix.

The sustained release composition of the present invention can be used in a method for providing a therapeutically, prophylactically, or diagnostically effective amount of a biologically active agent to a subject for a sustained period. The invention therefore also relates to a method for providing a therapeutically, prophylactically or diagnostically effective amount of a biologically active agent to a subject for a sustained period, comprising administering a dose of the sustained release composition prepared as described herein to a subject over a therapeutically useful period of time.

The invention has numerous advantages. For example, the submicron particles retain biological activity and are prepared with minimal agglomeration or aggregation. In addition, the submicron particles of biologically active agent, once formed, can, without isolation or additional comminution steps, be processed to form a composition for sustained release of the biologically active agent. The sustained release compositions, which are prepared according to the claimed method, exhibit a more favorable release profile than that observed with compositions having larger particles of biologically active agent incorporated therein. For example, the sustained release compositions having submicron particles show a decrease in the release of agent over the first twenty-four hours, and/or show an increase in the duration of sustained release, thereby possibly providing increased therapeutic benefits.

Claim 1 of 20 Claims

What is claimed is:

1. A method for preparing a composition for the sustained release of biologically active protein comprising the steps of:

a) atomizing using multifluid atomization a dispersed system comprising at least one biologically active protein and at least one solvent at a mass flow ratio of about 0.30 or greater to produce droplets;

b) freezing the droplets to produce frozen droplets;

c) removing the solvent from the frozen droplets to produce friable microstructures;

d) dispersing the friable microstructures in at least one non-solvent for the biologically active protein;

e) fragmenting the dispersed friable microstructures to produce submicron particles of the biologically active protein;

f) providing a suspension comprising the submicron particles of the biologically active protein, at least one biocompatible polymer and at least one polymer solvent; and

g) removing the polymer solvent to form a solid polymer/protein matrix.
 

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