Title:  Method for fabricating polymer-based controlled-release devices

United States Patent:  6,183,781

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

Filed:  January 7, 1997

The present invention includes a method for producing an implantable polymer/drug matrix mass, comprising the steps of (1) forming a polymer solution/drug mixture comprising a polymer dissolved in an organic solvent and a suspended labile drug; (2) removing the solvent from the polymer solution/drug mixture, thereby forming a solid polymer/drug matrix; and (3) mechanically compressing the polymer/drug matrix, thereby forming an implantable polymer/drug matrix mass.

SUMMARY OF THE INVENTION

The present invention relates to a method for forming polymer-encapsulated drug microparticles (hereinafter referred to as "polymer/drug matrix microparticles"). The method comprises (1) forming a polymer solution/drug mixture comprising a polymer-dissolved in an organic solvent and a co-dissolved or suspended drug; (2) removing the solvent from the polymer solution/drug mixture, thereby forming a solid polymer/drug matrix; and (3) fragmenting the polymer/drug matrix at a temperature below the glass transition temperature of the polymer/drug matrix, thereby forming polymer/drug matrix microparticles. The polymer/drug matrix can be fragmented by, for example, grinding or milling. In one embodiment, the polymer/drug matrix is formed by removing the solvent from a polymer solution/drug mixture, for example, by freezing the polymer solution/drug mixture and extracting the solvent from the resulting solid polymer solution/drug matrix.

In one embodiment, the polymer solution/drug mixture is frozen by, for example, pouring, dripping, atomizing or extruding the mixture into a liquid nonsolvent which is at a temperature below the freezing point of the polymer solution/drug mixture. The polymer can be any biocompatible polymer, such as poly(lactic acid) or a poly(lactic acid-co-glycolic acid) copolymer. The drug can be a therapeutic, prophylactic or diagnostic agent, such as a protein, nucleic acid or small organic molecule.

Another embodiment of the present invention includes the polymer/drug matrix particles that are formed by the method outlined above. Preferably, these particles are microparticles. These comprise a biocompatible polymer, such as poly(lactic acid) or a poly(lactic acid-co-glycolic acid) copolymer, a drug, such as a therapeutic, prophylactic or diagnostic agent, and, optionally, one or more excipients or release modifiers, such as a metal-containing salt.

A further embodiment of the present invention is a method for forming an implantable polymer/drug matrix mass. The method comprises the steps of (1) forming a polymer solution/drug mixture comprising a polymer dissolved in an organic solvent and a co-dissolved or suspended drug; (2) removing the solvent from the polymer solution/drug mixture, thereby forming a solid polymer/drug matrix; and (3) mechanically compressing the polymer/drug matrix, thereby forming an implantable polymer/drug matrix mass. The invention also includes a implantable drug/polymer matrix mass produced by this method. The method, thus, produces a substantial dispersion of the drug substance throughout the polymer matrix without using heat extrusion.

The method described herein offers the advantage of uncoupling the polymer/drug matrix fabrication step from the fragmentation or compression step, which determines the polymer/drug matrix device size and morphology. The method allows the use of fabrication methods employing mild conditions, for example, low temperature. Thus, the method is particularly well-suited for thermally labile drugs, such as many proteins, polypeptides and polynucleotides. The method also enables the formation of the polymer/drug matrix without dissolving the drug in an organic solvent, or bringing an aqueous solution of the drug into contact with an organic solvent. Certain drugs, such as many proteins and oligonucleotides, are soluble in few organic solvents suitable for forming polymer solutions, and are denatured at an aqueous/organic interface, a problem which is eliminated by the present invention. The method, thus, allows the formation of polymer/drug matrix microparticles and implantable devices maintaining a high degree (greater than about 90%) of the drug, for example, protein, activity present prior to processing.

The method also reduces process variables in the determination of particle size and allows for storage of the solid polymer/drug matrix prior to fragmentation or compression. These features provide considerably more flexibility and simplicity in the manufacture of polymer/drug matrix microparticles and implantable devices than provided by previously described methods and permit the facile scale-up of the method.

Claim 1 of 11 Claims

What is claimed is:

1. A method for preparing a polymer/drug matrix mass, wherein the drug is a labile drug, consisting essentially of the steps of:

(a) forming a polymer solution/drug mixture comprising a polymer dissolved in an organic solvent and a drug suspended in said solvent;

(b) removing the solvent from the polymer solution/drug mixture, thereby forming a solid polymer/drug matrix;

(c) fragmenting the solid polymer/drug matrix at a temperature below the glass transition temperature of the solid polymer/drug matrix, thereby forming polymer/drug matrix microparticles; and

(d) compressing the polymer/drug matrix microparticles to produce a polymer/drug matrix mass.

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