Process for making absorbable microparticles

Details Process for making absorbable microparticles Process for making absorbable microparticles

2000-07-26

2003-04-29

Beck, Shrive P. (Department: 1762)

Coating processes

Medical or dental purpose product; parts; subcombinations;...

Particulate or unit-dosage-article base

C427S002210, C427S212000, C427S213300, C427S213310, C427S421100

Reexamination Certificate

active

06555156

ABSTRACT:

TECHNICAL FIELD
This invention pertains to a process for making an encased bound microparticle which is a sustained release complex of one or more peptide, one or more protein or a combination thereof immobilized on an absorbable polymer microparticle having an absorbable encasing polymer. The microparticle complex made by a process of this invention comprises a peptide(s) and/or protein(s) which have at least one amino group and/or at least one carboxyl group per molecule, a solid absorbable polyester micropartide having surface and subsurface carboxylic groups or amino groups in sufficient amounts to bind the peptide(s) and/or protein(s) so that the immobilized peptide(s) or protein(s) represent 0.1% to 30% of the total mass of the microparticle complex which is encased individually or in groups with an absorbable encasing polymer to control the release of the immobilized peptide(s) and/or protein(s).
BACKGROUND ART
Many drug delivery systems have been developed, tested and utilized for the controlled in vivo release of pharmaceutical compositions. For example, polyesters such as poly(DL-lactic acid), poly(glycolic acid), poly(&egr;-caprolactone) and various other copolymers have been used to release biologically active molecules such as progesterone; these have been in the form of microcapsules, films or rods (M. Chasin and R. Langer, editors, Biodegradable Polymers as Drug Delivery Systems, Dekker, N.Y. 1990). Upon implantation of the polymer/therapeutic agent composition, for example, subcutaneously or intramuscularly, the therapeutic agent is released over a specific period of time. Such bio-compatible biodegradable polymeric systems are designed to permit the entrapped therapeutic agent to diffuse from the polymer matrix. Upon release of the therapeutic agent, the poller is degraded in vivo, obviating surgical removal of the implant. Although the factors that contribute to poller degradation are not well understood, it is believed that such degradation for polyesters may be regulated by the accessibility of ester linkages to non-enzymatic autocatalytic hydrolysis of the polymeric components.
For example, Deluca (EPO Publication 0 467 389 A2) describes a physical interaction between a hydrophobic biodegradable polymer and a protein or polypeptide. The composition formed was a mixture of a therapeutic agent and a hydrophobic polymer that sustained its diffusional release from the matrix after introduction into a subject.
Hutchinson (U.S. Pat. No. 4,767,628) controlled the release of a therapeutic agent by uniform dispersion in a polymeric device. It is disclosed that this formulation provides for controlled continuous release by the overlap of two phases: first, a diffusion-dependent leaching of the drug from the surface of the formulation; and second, releasing by aqueous channels induced by degradation of the polymer.
Other in-situ forming biodegradable implants and methods of forming them are described in U.S. Pat. Nos. 5,278,201 ('201 Patent) and U.S. Pat. No. 5,077,049 ('049 Patent), to Dunn et al. The Dunn et al. patents disclose methods for assisting the restoration of periodontal tissue in a periodontal pocket and for retarding a migration of epithelial cells along the root surface of a tooth. The '049 Patent discloses methods which involve placement of an in-situ forming biodegradable barrier adjacent to the surface of the tooth. The barrier is microporous and includes pores of defined size and can include biologically active agents. The barrier formation is achieved by placing a liquid solution of a biodegradable polymer, such as poly(dl-lactide co-glycolide) water-coagulatable, thermoplastic in a water miscible, non-toxic organic solvent such as N-methyl pyrrolidone (i.e., to achieve a typical polymer concentration of about 50%) into the periodontal pocket The organic solvent dissipates into the periodontal fluids and the biodegradable, water coagulatable polymer forms an in-situ solid biodegradable implant The dissipation of solvent creates pores within the solid biodegradable implant to promote cell in growth. The '859 Patent likewise discloses methods for the same indications involving the formation of the biodegradable barrier from a liquid mixture of a biodegradable, curable thermosetting prepolymer, curing agent and water-soluble material such as salt, sugar, and water-soluble polymer. The curable thermosetting prepolymer is described as an acrylic-ester terminated absorbable polymer.
In addition, a number of systems for the controlled delivery of biologically active compounds to a variety of sites are disclosed in the literature. For example, U.S. Pat. No. 5,011,692, to Fujioka et al., discloses a sustained pulsewise release pharmaceutical preparation which comprises drug-containing polymeric material layers. The polymeric material layers contain the drug only in a slight amount, or free of the drug. The entire surface extends in a direction perpendicular to the layer plane and is coated with a polymeric material which is insoluble in water. These types of pulsewise-release pharmaceutical dosages are suitable for embedding beneath the skin.
U.S. Pat. No. 5,366,756, to Chesterfield et al., describes a method of preparing porous bioabsorbable surgical implant materials. The method comprises providing a quantity of particles of bioabsorbable implant material, and coating particles of bioabsorbable implant material with at least one growth factor. The implant can also contain antimicrobial agents.
U.S. Pat. No. 5,385,738, to Yamhira et al., discloses a sustained-release injection system, comprising a suspension of a powder comprised of an active ingredient and a pharmaceutically acceptable biodegradable carrier (e.g., proteins, polysaccharides, and synthetic high molecular weight compounds, preferably collagen, atelo collagen, gelatin, and a mixture thereof) in a viscous solvent (e.g., vegetable oils, polyethylene glycol, propylene glycol, silicone oil, and medium-chain fatty acid triglycerides) for injection. The active ingredient in the pharmaceutical formulation is incorporated into the biodegradable carrier in the following state: (i) the active ingredient is chemically bound to the carrier matrix; (ii) the active ingredient is bound to the carrier matrix by intermolecular action; or (iii) the active ingredient is physically embraced within the carrier matrix.
Moreover, such systems as those previously described in the literature, for example, such as by Dunn, et al. (U.S. Pat. No. 4,938,763), teach in-situ formations of biodegradable, microporous, solid implants in a living body through coagulation of a solution of a polymer in an organic solvent such as N-methyl-2-pyrrolidine. However, the use of solvents, including those of low molecular organic ones, facilitates migration of the solution from the application site thereby causing damage to living tissue including cell dehydration and necrosis. Loss of the solvent mass can lead to shrinkage of the coagulum and separation from surrounding tissue.
U.S. Pat. No. 5,612,052 describes cation-exchanging microparticles made typically of carboxyl-bearing polyester chains onto which basic bioactive agents are immobilized to provide a control release system within an absorbable gel-forming liquid polyester. The contents of U.S. Pat. No. 5,612,052 is incorporated herein by reference. Conjugating carboxylic entities, tonically, with basic polypeptide has been noted in the prior art as described in U.S. Pat. No. 5,672,659 and U.S. Pat. No. 5,665,702. However, these complexes are soluble chemical entities formed by molecularly reacting the individual basic and carboxylic components in their respective solutions to form a well-defined ion-conjugate as a new chemical entity with physicochemical properties.
DISCLOSURE OF INVENTION
The present invention is directed to a process (process A) for making an encased bound micropartide or microparticles wherein the encased bound micropartide or microparticles comprise bound micropartide or microparticles and an absorbable encasing polymer where the bound m

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