Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Implantable prosthesis – Bone
Reexamination Certificate
1998-10-02
2002-07-16
Isabella, David J. (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Implantable prosthesis
Bone
C623S023590, C528S340000, C528S272000, C528S287000, C528S398000
Reexamination Certificate
active
06419709
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to biodegradable homopolymer and block copolymer compositions, in particular those containing both phosphite and terephthalate ester linkages in the polymer backbone, which degrade in vivo into non-toxic residues. The copolymers of the invention are particularly useful as essentially non-osteoconductive, non-porous implantable medical devices and drug delivery systems.
2. Description of the Prior Art
Biocompatible polymeric materials have been used extensively in therapeutic drug delivery and medical implant device applications. Sometimes, it is also desirable for such polymers to be, not only biocompatible, but also biodegradable to obviate the need for removing the polymer once its therapeutic value has been exhausted.
Conventional methods of drug delivery, such as frequent periodic dosing, are not ideal in many cases. For example, with highly toxic drugs, frequent conventional dosing can result in high initial drug levels at the time of dosing, often at near-toxic levels, followed by low drug levels between doses that can be below the level of their therapeutic value. However, with controlled drug delivery, drug levels can be more easily maintained at therapeutic, but non-toxic, levels by controlled release in a predictable manner over a longer term.
If a biodegradable medical device is intended for use as a drug delivery or other controlled-release system, using a polymeric carrier is one effective means to deliver the therapeutic agent locally and in a controlled fashion, see Langer et al., “Chemical and Physical Structures of Polymers as Carriers for Controlled Release of Bioactive Agents”,
J. Macro. Science, Rev. Macro. Chem. Phys.
, C23:1, 61-126 (1983). As a result, less total drug is required, and toxic side effects can be minimized. Polymers have been used as carriers of therapeutic agents to effect a localized and sustained release. See Leong et al., “Polymeric Controlled Drug Delivery”,
Advanced Drug Delivery Reviews,
1:199-233 (1987) and Langer, “New Methods of Drug Delivery”, Science, 249:1527-33 (1990); and Chien et al.,
Novel Drug Delivery Systems
(1982). Such delivery systems offer the potential of enhanced therapeutic efficacy and reduced overall toxicity.
For a non-biodegradable matrix, the steps leading to release of the therapeutic agent are water diffusion into the matrix, dissolution of the therapeutic agent, and diffusion of the therapeutic agent out through the channels of the matrix. As a consequence, the mean residence time of the therapeutic agent existing in the soluble state is longer for a non-biodegradable matrix than for a biodegradable matrix, for which passage through the channels of the matrix, while it may occur, is no longer required. Since many pharmaceuticals have short half-lives, therapeutic agents can decompose or become inactivated within the non-biodegradable matrix before they are released.
This issue is particularly significant for many bio-macromolecules and smaller polypeptides, since these molecules are generally hydrolytically unstable and have low permeability through a polymer matrix. In fact, in a non-biodegradable matrix, many bio-macromolecules aggregate and precipitate, blocking the channels necessary for diffusion out of the carrier matrix.
These problems are alleviated by using a biodegradable matrix that, in addition to some diffusion release, also allows controlled release of the therapeutic agent by degradation of the polymer matrix. Use of a biodegradable polymer matrix also obviates the need for the polymer to form a highly porous material since the release of the therapeutic agent is no longer soley conditioned upon diffusion through the pores of the polymeric matrix. Examples of classes of synthetic polymers that have been studied as possible biodegradable materials include polyesters (Pitt et al., “Biodegradable Drug Delivery Systems Based on Alipathic Polyesters: Application to Contraceptives and Narcotic Antago-nists”,
Controlled Release of Bicactive Materials,
19-44 (Richard Baker ed., 1980); poly(amino acids) and pseudo-poly(amino acids) (Pulapura et al., “Trends in the Development of Bioresorbable Polymers for Medical Applications,”
J. of Biomaterials Appl.,
6:1, 216-50 (1992); polyurethanes (Bruin et al., “Biodegradable Lysine Diisocyanate-based Poly-(Glycolide-co-&egr; Caprolactone)-Urethane Network in Artificial Skin”,
Biomaterials,
11:4, 291-95 (1990); polyorthoesters (Heller et al., “Release of Norethin-drone from Poly(Ortho Esters)”,
Polymer Engineering Sci.,
21:11, 727-31 (1981); and polyanhydrides (Leong et al., “Polyanhydrides for Controlled Release of Bioactive Agents”,
Biomaterials,
7:5, 364-71 (1986).
Specific examples of biodegradable materials that are used as medical implant materials are polylactide, polyglycolide, polydioxanone, poly(lactide-co-glycolide), poly(glycolide-co-polydioxanone), polyanhydrides, poly(glycolide-co-trimethylene carbonate), and poly(glycolide-co-caprolactone). Injectable polyphosphazenes have also been described as useful for forming solid biodegradable implants in situ. See, Dunn et al., in U.S. Pat. Nos. 5,340,849; 5,324,519; 5,278,202; and 5,278,201.
Polymers having phosphoester linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. See Penczek et al.,
Handbook of Polymer Synthesis
, Chapter 17: “Phosphorus-Containing Polymers”, 1077-1132 (Hans R. Kricheldorf ed., 1992). The respective structures of each of these three classes of compounds, each having a different side chain connected to the phosphorus atom, is as follows:
The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding can involve the 3p orbitals or various 3s-3p hybrids; spd hybrids are also possible because of the accessible d orbitals. Thus, the physico-chemical properties of the poly(phosphoesters) can be readily changed by varying either the R or R′ group. The biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the side chain, a wide range of biodegradation rates are attainable. Kadiyala et al.,
Biomedical Applications of Synthetic Biodegradable Polymers
, Chapter 3: “Poly(phosphoesters): Synthesis, Physicochemical Characterization and Biological Response”, 33-57, 34-5 (Jeffrey O. Hollinger ed., 1995). See also copending U.S. patent application Ser. No. 09/053,648 for a discussion of terephthalate poly(phosphate) polymers useful as biodegradable materials.
An additional feature of poly(phosphates) and poly(phosphonates) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically linked to the polymer, as well as physically dissolved in the polymer, prior to shaping the polymer into its final form. For example, drugs with —O-carboxy groups may be coupled to the phosphorus via an ester bond, which is hydrolyzable. The P—O—C group in the polymer backbone also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing. Kadiyala et al. at page 35.
Poly(phosphite) esters have been known for some time. Specifically, Coover et al., U.S. Pat. No. 3,271,329, discloses the production of polymers from dialkyl or diaryl hydrogen phophites and certain glycols or dihydroxy aromatic hydrocarbons. The resulting high molecular weight polymers were found to be highly flame resistent.
Similarly, Friedman, U.S. Pat. No. 3,422,982, discloses polyphosphites of 2,2-dimethyl-3-hydroxypropyl-2-dimethyl-3-hydroxypropionate. The resulting compounds were found to be remarkably stable toward hydrolysis, heat and light, and were therefore taught to be useful as stabilizers for other polymers.
Kadiyala et al. discloses loading a biodegradable porous material with bone morphogenetic
Dang Wensin
English James P.
Leong Kam W.
Mao Hai-quan
Nowotnik David P.
Foley Hoag & Eliot LLP
Guilford Pharmaceuticals Inc.
Isabella David J.
LandOfFree
Biodegradable terephthalate polyester-poly(Phosphite)... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Biodegradable terephthalate polyester-poly(Phosphite)..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Biodegradable terephthalate polyester-poly(Phosphite)... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2902505