Phosphate based biodegradable polymers

Details Phosphate based biodegradable polymers Phosphate based biodegradable polymers

2001-03-10

2004-10-19

Azpuru, Carlos A. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C514S772300, C523S111000, C523S113000, C528S398000

Reexamination Certificate

active

06805876

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to biodegradable and biocompatible polymer compositions and more particularly to biodegradable copolymers and terpolymers; methods used for preparation of the recited polymers; articles useful for implantation or injection into the human body that are fabricated from said compositions; and, methods for the controlled release of biologically active substances.
2. Background
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 nearly 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., Rev. Macro. Chem. Phys., C23(1), 61 (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 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 diffusional release, also allows controlled release of the therapeutic agent by degradation of the polymer matrix. Examples of classes of synthetic polymers that have been studied as possible biodegradable materials include polyesters (Pitt et al., Controlled Release of Bioactive Materials, (Baker, ed. 1980); polyamides; polyurethanes; polyorthoesters (Heller et al., Polymer Engineering Sci., 21:727 (1981); and polyanhydrides (Leong et al., Biomaterials 7:364 (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).
Polymers having phosphate linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. The respective structures of these three classes of compounds, each having a different sidechain connected to the phosphorus atom, are 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 sidechain, a wide range of biodegradation rates are attainable.
An additional feature of poly(phosphoesters) 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 shown by Leong, U.S. Pat. Nos. 5,194,581 and 5,256,765. 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 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.
Polylactide, referred to herein as PLA, and poly(lactide-co-glycolide), referred to herein as PLGA, are among the most popular and well characterized biodegradable polymeric materials used today for drug delivery and tissue engineering. Further, the present invention provides the ability to incorporate side chain modifications into both PLA and PLGA.
The growing needs in biomedical practice have continued to stimulate the studies for developing new biodegradable materials. Although several classes of synthetic polymers, including polyesters, poly(amino acid)s/polyamides, polyurethanes, poly(orthoester)s, poly(anhydride)s, polycarbonates, poly(imidocarbonate)s, and poly(phosphazene)s, have been studied for controlled drug delivery and tissue engineering, polylactide (PLA) and poly(lactide-co-glycolide) (PLGA) still remain the most popular and well characterized bio degradable polymeric biomaterials. Their regulatory approval and extensive database of human use render them obvious choice in contemplating a medical application that ranges from controlled drug delivery to tissue engineering.
The widening scope of applications in controlled delivery and tissue engineering require the biomaterials to assume different configurations to serve different functions. Applying the controlled release device as more than just a monolithic matrix, for example, as coating materials for a drug-eluting stent, may obligate the polymer to have elastomeric properties. In the new and exciting field of tissue engineering where local and sustained delivery of growth factors may influence the course of tissue development, the polymeric drug-carriers may also need to provide structural support or scaffolding functions. With such a broad utility for these biodegradable materials, PLA and PLGA cannot be expected to satisfy all requirements of different applications.
Besides physical blending, one of the most plausible ways to adjust the physico-chemical properties of PLA and PLGA is through copolymerization. Lactide copolymers with different constituent monomers can offer a broad range of physico-chemical properties and degradation rates. Poly(lactide-co-ester)s [e.g. (lactide-co-caprolactone)], poly(lactide-co-ether)s [e.g. poly(dioxanone), poly(ethylene glycol-b-lactide)], poly(lactide-co-carbonate) [e.g. poly(lactide-co-1,3-dioxan-2-one)], and poly(lactide-co-amide)s [poly(lactide-co-L-lysine)] are a few of the examples that have been evaluated so far.
Mao et al. (Mao, H.-Q., Z. Zhao, J. P. English and K. W. Leong (1997), Biodegradable polymers chain-extended byphosphoesters, compositions, articles and methods for making and using the same. U.S. Pat. No. 6,166,173) synthesized oligomeric lac

Affiliated with

Also associated with

Rating

Phosphate based biodegradable polymers does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Phosphate based biodegradable polymers, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Phosphate based biodegradable polymers will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3295891