Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From phenol – phenol ether – or inorganic phenolate
Reexamination Certificate
1999-12-10
2001-09-04
Boykin, Terressa M. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From phenol, phenol ether, or inorganic phenolate
Reexamination Certificate
active
06284862
ABSTRACT:
TECHNICAL FIELD
The present invention relates to monomers prepared from &agr;-, &bgr;-, and &ggr;-hydroxy acids and derivatives of the natural amino acid L-tyrosine. The present invention further relates to poly(amide carbonates) and aliphatic-aromatic poly(amide esters) prepared from the monomers of the present invention.
BACKGROUND ART
U.S. Pat. No. 5,099,060 discloses diphenolic monomers based on 3-(4-hydroxyphenyl) propionic acid and L-tyrosine alkyl esters (desaminotyrosyl-tyrosine alkyl esters). Subsequent related patents involve variations of this basic monomer structure. These monomers, although useful in many applications, have several limitations:
The monomers are insoluble in water and therefore the polymers made from them are not readily resorbable. In other words, the previously described polymers prepared from the previously described water-insoluble monomers will not have any weight loss while the degradation of the polymer backbone results in the loss of mechanical strength and reduction in the polymer molecular weight.
The monomers provide two phenolic hydroxyl groups, limiting the resulting polymers to be fully aromatic backbone structures, which may lead to good mechanical strength but slow degradation rate.
Poly(hydroxy acids), such as poly(glycolic acid) (PGA), poly(lactic acid) (PLA) and their copolymers are certainly the most widely investigated synthetic, degradable polymers due to their established record of safety and FDA approval. Poly(amino acids) derived from naturally occurring &agr;-L-amino acids form another major group of degradable polymers. Despite their apparent potential as biomaterials, 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-processible, which limits their utility).
Although several copolymers of hydroxy acids and amino acids have been prepared and evaluated from a biological perspective, their investigation as biomaterials has been rather limited. Helder et al.,
J.Biomed. Mater. Res.,
(24), 1005-1020 (1990) discloses the synthesis of glycine and DL-lactic acid copolymers and the resulting in vitro and in vivo degradation. The elegant synthesis of a copolymer derived from lactic acid and lysine was reported by Barrera et al.,
Macromolecules, (
28), 425-432 (1995). The lysine residue was utilized to chemically attach a cell-adhesion promoting peptide to the copolymer. Other polymers of amino acids and hydroxy acids are disclosed by U.S. Pat. No. 3,773,737.
The three types of copolymers mentioned above were random copolymers prepared from cyclic monomers by ring-opening polymerization. The composition of the copolymers is highly dependent on the relative reactivity of the two types of cyclic monomers and on the exact polymerization conditions used. It is hard to control the composition and hard to predict the polymer properties. Also, there may be large batch-to-batch variations in the polymer microstructure and sequence. Furthermore, most previous reports described polymers of low molecular weight (M
w
<10,000) only.
There are only very few degradable polymers for medical uses that have been successfully commercialized. Poly(glycolic acid) (PGA), poly(lactic acid) (PLA) and their copolymers are representative examples. There still remains a need for biodegradable, especially bioresorbable polymers suitable for use as tissue-compatible materials. For example, many investigators in the emerging field of tissue engineering have proposed to engineer new tissues by transplanting isolated cell populations on biomaterial scaffolds to create functional new tissues in vivo. Bioresorbable materials whose degradation and resorption rates can be tailored to correspond to the rate of tissue growth are needed. This will require that libraries of many different materials are available so that the specific polymer properties can be optimally matched with the requirements of the specific application under development.
SUMMARY OF THE INVENTION
This need is met by the present invention. The present invention provides a novel class of non-toxic, aliphatic-aromatic dihydroxy monomers and bioresorbable polymers derived therefrom. The monomers are prepared from &agr;-, &bgr;-, and &ggr;-hydroxy acids and derivatives of the natural amino acid L-tyrosine.
Therefore, according to one aspect of the present invention, monomers are provided having a structure according to Formula I:
wherein R
1
and R
2
are each independently selected from H or straight or branched alkyl groups having up to 18 carbon atoms; R
3
is selected from the group consisting of —CH═CH— and (—CH
2
—)
k
, wherein k is between 0 and 6, inclusive; each Z is an iodine or bromine atom; d and n are independently 0, 1 or 2; and X is hydrogen or a pendant group having the structure according to Formula II:
wherein Y is selected from straight or branched alkyl and alkylaryl groups having up to 18 carbon atoms.
In terms of the prior art, the new monomers are similar to the desaminotyrosyl-tyrosine alkyl esters disclosed in U.S. Pat. No. 5,099,060 with the important difference that the desaminotyrosyl unit has been replaced by aliphatic hydroxy acids. In particular, the new dihydroxy monomers are water-soluble. This feature could not have been predicted and represents an important difference to the sparingly soluble desaminotyrosyl-tyrosine alkyl esters disclosed before.
The monomers may be polymerized to form polymers that display excellent physical, chemical and biological properties, which make them useful as shaped structures such as films, fibers, rods, and in particular polymeric scaffolds for tissue reconstruction or tissue engineering. In addition to being non-toxic in polymer form, the polymers of the present invention are expected to form non-toxic degradation products by hydrolytic chain cleavage under physiological conditions. The most significant improvement of the new polymers disclosed here is their increased rate of degradation and bioresorption.
The aliphatic-aromatic dihydroxy monomers can be used in the same fashion as the desaminotyrosyl-tyrosine alkyl esters disclosed before. In particular, the monomers can be used to prepare polycarbonates, polyiminocarbonates, polyurethanes, poly(ester amides), and polyethers. Of these many different polymers, aliphatic-aromatic poly(amide carbonates), and aliphatic-aromatic poly(amide esters) are preferred embodiments.
The present invention therefore also includes aliphatic-aromatic poly(amide carbonates) prepared from the monomers of the present invention. The poly(amide carbonates) are prepared by the process disclosed by U.S. Pat. No. 5,198,507, the disclosure of which is incorporated herein by reference. The present invention further includes aliphatic-aromatic poly(amide esters) prepared from the monomers of the present invention. The poly(amide esters) are prepared by the process disclosed by U.S. Pat. No. 5,216,115, the disclosure of which is also incorporated herein by reference.
Aliphatic-aromatic poly(amide carbonates) according to the present invention have the repeating structural units of Formula III:
Aliphatic-aromatic poly(amide esters) according to the present invention have the repeating structural units of Formula IV:
In Formulas III and IV, R
1
, R
2
, R
3
, X, Z, d and n are defined exactly as in Formulas I and II. In addition, Y of X may also be hydrogen. R is selected from saturated and unsaturated, substituted and unsubstituted alkyl, aryl and alkylaryl groups containing up to 24 carbon atoms; and m is the number of repeat units in the average polymer chain and can range from 2 to 1,000.
The poly(amide carbonates) and poly(amide esters) of the present invention will degrade faster and will bioresorb faster than prior art polycarbonates and polyarylates polymerized from desaminotyrosyltyrosine alkyl esters. The polymers of the present invention thus can be used as biomaterials in all those situations that require a faster degradation and resorption rate than the previously disclosed polymers. Speci
Kohn Joachim B.
Qui Bo
Boykin Terressa M.
Rutgers The State University
Synnestvedt & Lechner LLP
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