Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1998-08-14
2003-10-14
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S486000, C424S487000
Reexamination Certificate
active
06632457
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions and methods for providing controlled release of therapeutic species using hydrogels.
BACKGROUND OF THE INVENTION
For a drug to be effective, a certain concentration level (called the therapeutic index) must be maintained for a certain period of time, at specific location(s). Systemically administered drugs accomplish the first two objectives, but in an inefficient fashion and with the potential for toxic side effects at high doses. Systemic administration of controlled release formulations accomplish these two objectives with a more efficient utilization of the drug and may reduce side effects. Local implantation of drug delivery systems may further improve the efficiency of drug utilization.
Hydrogels are materials that absorb solvents (such as water), undergo rapid swelling without discernible dissolution, and maintain three-dimensional networks capable of reversible deformation. Hydrogels may be uncrosslinked or crosslinked. Uncrosslinked hydrogels are able to absorb water but do not dissolve due to the presence of hydrophobic and hydrophilic regions. Covalently crosslinked networks of hydrophilic polymers, including water soluble polymers, are traditionally denoted as hydrogels in the hydrated state. A number of aqueous hydrogels have been used in various biomedical applications, such as, for example, soft contact lenses, wound management, and drug delivery.
Hydrogels can be formed from natural polymers such as glycosaminoglycans and polysaccharides, proteins, etc., where the term “glycosaminoglycan” encompasses complex polysaccharides that are not biologically active (i.e., not compounds such as ligands or proteins) and have repeating units of either the same saccharide subunit or two different saccharide subunits. Some examples of glycosaminoglycans include dermatan sulfate, hyaluronic acid, the chondroitin sulfates, chitin, heparin, keratin sulfate, keratosulfate, and derivatives thereof.
Glycosaminoglycans may be extracted from a natural source, purified and derivatized, or synthetically produced or synthesized by modified microorganisms such as bacteria. These materials may also be modified synthetically from a naturally soluble state to a partially soluble or water swellable or hydrogel state. This can be done, for example, by conjugation or replacement of ionizable or hydrogen bondable functional groups such as carboxyl and/or hydroxyl or amine groups with other more hydrophobic groups.
Hydrophilic polymeric materials suitable for use in forming hydrogels include poly(hydroxyalkyl methacrylate), poly(electrolyte complexes), poly(vinylacetate) cross-linked with hydrolyzable bonds, water-swellable N-vinyl lactams polysaccharides, natural gum, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya, gum tragacanth, locust beam gum, arabinogalactan, pectin, amylopectin, gelatin, hydrophilic colloids such as carboxymethyl cellulose gum or alginate gum cross-linked with a polyol such as propylene glycol, and the like. Several formulations of previously known hydrogels are described in U.S. Pat. Nos. 3,640,741 to Etes, 3,865,108 to Hartop, 3,992,562 to Denzinger et al., 4,002,173 to Manning et al., 4,014,335 to Arnold, 4,207,893 to Michaels, and in
Handbook of Common Polymers
, (Scott and Roff, Eds.) Chemical Rubber Company, Cleveland, Ohio.
Synthesis and biomedical and pharmaceutical applications of absorbable or biodegradable hydrogels based on covalently crosslinked networks, comprising polypeptide or polyester components as the enzymatically or hydrolytically labile components, respectively, have been described by a number of researchers. See, e.g., Jarrett, et al., “Bioabsorbable Hydrogel Tissue Barrier: In Situ Gelation Kinetics”,
Trans. Soc. Biomater
., Vol. XVIII, 182, 1995 and Park, “Enzyme-digestible Swelling Hydrogels as Platforms for Long-term Oral Drug Delivery: Synthesis and Characterization”,
Biomaterials
, 9:435 (1988).
The hydrogels most often cited in the literature are those made of water soluble polymers, such as polyvinyl pyrrolidone, which have been crosslinked with naturally derived biodegradable components such as those based on albumin. Totally synthetic hydrogels that have been studied for controlled drug release, and as membranes for the treatment of post-surgical adhesion, are based on covalent networks formed by the addition polymerization of acrylic-terminated, water soluble chains of polyether dipolylactide block copolymers.
Bioabsorbable hydrogels are well suited for local implantation, but relatively low molecular weight molecules are rapidly released from hydrogels due to the relatively open networks of previously known hydrogels. Relatively low molecular weight compounds, however, constitute a vast majority of therapeutic molecules and drugs. Controlled drug delivery from implantable and bioabsorbable devices has been the subject of extensive exploration, but no suitable absorbable systems are known that are capable of delivering both water soluble and water insoluble relatively low molecular weight drugs.
The development of compositions and methods to provide controlled release delivery of relatively low molecule weight drugs presents the following challenges: the delivery matrix needs to be safe and absorbable; drug release should be controlled and sustained, while being free from “burst effects”; and the devices should be simple to fabricate so as to prevent denaturation of sensitive entrapped drugs.
Previously known methods and compositions for providing sustained controlled release of therapeutic species, and applications suitable for use of such compositions and methods, are discussed hereinbelow, and include: (a) microencapsulation and (b) targeted microspheres.
a. Microencapsulation
Several previously known delivery systems employ biodegradable microspheres and/or microcapsules that include biodegradable polymers, such as poly d,l-lactic acid (PLA) and copolymers of lactic acid and glycolic acid (PLGA). These polymers are most widely used in sustained release devices, and may be obtained by polycondensation of lactic acid or glycolic acid in the presence or absence of a catalyst or other activator. Microcapsules prepared from such materials may be administered intramuscularly or by other parenteral routes.
The water solubility of a number of biologically active molecular compounds, however, has proven to be a limiting factor in optimizing molecular compound loading efficiency in biodegradable microspheres and/or microcapsules. Specifically, it has been observed that the loading efficiency of water soluble drugs into, for example, PLA or PLGA-polymeric microspheres, is relatively low when conventional oil/water systems are used in a solvent evaporation process. This has been attributed to the observation that such drugs readily diffuse into the aqueous outer phase of the emulsion system.
Most of the microspheres described in the literature belong to the class of “matrix-type” drug delivery capsules, in which the “foreign” (i.e. drug) particles are dispersed homogeneously in direct contact with the polymer. The process of manufacturing such capsules also frequently involves direct contact between the drug and a polymer solvent, such as acetonitrile or methylene chloride. Such contact between the biologically active molecule and the polymer, polymer solvent or enzymes in the biological system may promote degradation of the intended pharmaceutical.
Specifically, the monomer and dimer residues in the polymer may degrade the protein, and direct contact between the polymer and proteins and enzymes may result in polymeric degradation over time. Previously known techniques to encapsulate peptides in biodegradable polymers typically utilize a solvent-nonsolvent system. Such systems often produce high solvent residuals, poor content uniformity of the peptide in the microspheres, and instability due to the contact of the biological agent with the polymer, organic solvent (e.g. methylene chloride,
Incept LLC
Patterson Thuente Skaar & Christensen P.A.
Webman Edward J.
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