Bioresorbable polymers synthesized from monomer analogs of natural metabolites

Abstract

New bioresorbable polymers are synthesized from monomer analogs of natural metabolites In particular, polymers are polymerized from analogs of amino acids that contribute advantageous synthesis, processing and material properties to the polymers prepared therefrom, including particularly advantageous degradation profiles

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]The present application claims priority benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No. 61 / 097,494 filed Sep. 16, 2008, the disclosure of which is incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]The present invention relates to new bioresorbable polymers synthesized from monomer analogs of natural metabolites. In particular, the present invention relates to polymers polymerized from analogs of amino acids that contribute advantageous synthesis, processing and material properties to the polymers prepared therefrom, including particularly advantageous degradation profiles.[0003]U.S. Pat. No. 5,099,060 discloses diphenolic monomers based on 3-(4-hydroxy-phenyl) propionic acid and L-tyrosine alkyl esters (desaminotyrosyl-tyrosine alkyl esters). Subsequent related patents involve variations of this basic monomer structure, including halogenated radiopaque diphenolic monomers, such as the 3,5-di-...

AI Technical Summary

Benefits of technology

[0038]The advantageous physical properties in no particular order of importance include DAT's lack of a chiral center, so that DAT, unlike amino acids, does not give rise to diastereomers when coupled with amino acids. Also, because the COOH on DAT is not linked to a chiral carbon, there is no racemization during coupling to make the monomer. Furthermore, DAT is easier to iodinate than an aromatic amino acid such as tyrosine when a radio-opaque polymer is desired. In addition, despite not being a nutrient, DAT is naturally found in the body as an end-stage metabolite and is excreted in urine. As a natural constituent of human metabolism, DAT has low toxicity, attributable in part to being a closely-related analog of the essential amino acid L-tyrosine. More significantly, DAT is an end stage metabolite; there is no cause for concern that DAT may be further converted to other metabolites. In addition to being non-toxic, DAT's aromatic ring imparts good mechanical properties to polymers, and removal of the tyrosine amino group gives better polymer processing properties compared to amino acids.

[0045]Thus, a highly bromine or iodine ring-substituted version of a polymer according to the present invention may fall within the first or second polymer embodiment, while a less substituted counterpart may fall within the third or fourth polymer embodiment. Stated another way, one of ordinary skill in the art can design or modify some polymers to fall within the first or second embodiment rather than the third or fourth embodiment by increasing the level of bromine or iodine ring substitution. While not every polymer according to the present invention can be moved between the first and fourth polymer embodiments or the second and third poly-mer embodiments by adjusting or selecting the degree of iodine or bromine ring-substitution, one of ordinary skill in the art will readily recognize the polymers that can be modified or designed in this manner. Furthermore it is important to note that the level of bromine or iodine substitution may not be subject to modification if it is necessary for the polymer to be radio-opaque or radio-transparent.

[0054]Thus, a poly(alkylene oxide) block copolymer may fall within the third or fourth polymer embodiment, while a counterpart polymer with a lesser degree of block copolymerization, or one that is free of poly(alkylene oxide) blocks may fall within the first or second polymer embodiment, while a less substituted counterpart may fall within the third or fourth polymer embodiment. Stated another way, one of ordinary skill in the art can design or modify some polymers to fall within the first or second embodiment rather than the third or fourth embodiment by decreasing or eliminating poly(alkylene oxide) block copolymerization.

[0057]Thus, a highly N-substituted version of a polymer according to the present invention may fall within the third or fourth polymer embodiment, while a less substituted counter-part with may fall within the first or second polymer embodiment. Stated another way, one of ordinary skill in the art can design or modify some polymers to fall within the first or second embodiment rather than the third or fourth embodiment by decreasing the level of N-substitution. This can be done in combination with increasing the level of bromine or iodine ring substitution. While not every polymer according to the present invention can be moved between the first and fourth polymer embodiments or the second and third polymer embodiments by adjusting or selecting the degree of N-substitution, alone or in combination with adjusting or selecting the level of iodine or bromine ring-substitution and degree of poly(alkylene oxide) block copolymerization, one of ordinary skill in the art will readily recognize the polymers that can be modified or designed in this manner.

[0070]Load-bearing medical devices formed from the first and second polymer embodiments of the present invention include stents for the treatment of a body lumen including, but not limited to, any blood vessels, the esophagus, urinary tract, bile tract, and the ventricles of the central nervous system (brain and spinal cord). Preferred stents are formed from or coated with radio-opaque polymers according to the first and second polymer embodiments of the present invention, so that fluoroscopic imaging can be used to guide positioning of the device. One radio-opaque, bioresorbable stent provided by the present invention is formed from a bioresorbable polymer with sufficient halogen atoms to render the stent inherently visible by X-ray fluoroscopy during stent placement.

[0076]The poly(alkylene oxide) segments decrease the surface adhesion of the polymers provided by the present invention. As the molar fraction of poly(alkylene oxide) increases, the surface adhesion decreases. Coatings containing polymers with poly(alkylene oxide) segments provided by the present invention may thus be prepared that are resistant to cell attachment and are useful as non-thrombogenic coatings on surfaces in contact with blood. Such polymers also resist bacterial adhesion in this and in other medical applications as well. The present invention therefore also provides blood contacting devices and medical implants having surfaces coated with the poly(alkylene oxide) block copolymers provided by the present invention.

Problems solved by technology

These monomers, although useful in many applications, have several limitations:

Use of monomers having two phenolic hydroxyl groups, as disclosed in the above mentioned patent applications, tend to limit the resulting homopolymers to fully aromatic backbone structures.

Such polymers have generally good mechanical properties—but slow degradation rates.

Hence, such polymers will tend to have some use limitations as medical implant materials when the processes of degradation and resorption need to occur concomitantly.

As a result, implantable medical devices and drug delivery implants prepared from the previously described homopolymers that are intended to be resorbed are still substantially undissolved at the end of their useful life as measured by reduction in polymer molecular weight or mechanical strength.

This is particularly a problem for drug delivery implants and implantable medical devices that are intended to be replaced as part of a long-term treatment regimen.

However, implants formed with many of the previously described homopolymers will not only be substantially undissolved when a replacement device must be implanted, significant mass will remain when the next replacement device is due for implantation.

This creates the untenable situation where patient would be expected to endure having several depleted polymeric drug delivery implants in their body at various stages of resorption while replacement devices continue to be implanted at a periodic rate.

However, despite their apparent potential as biomaterials, such poly(amino acids) have actually found few practical applications.

A major problem is that most of the poly(amino acids) are highly intractable (e.g., non-processable by conventional thermal or solvent fabrication methods), which limits their utility.

It is hard to control the composition and hard to predict the polymer properties.

There are very few degradable polymers for medical uses that have been successfully commercialized.

However, these polymers degrade to form tissue-irritating acids.

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