Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active...
Reexamination Certificate
2000-03-07
2001-11-20
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
C424S422000, C424S423000, C424S426000, C525S432000, C528S176000
Reexamination Certificate
active
06319492
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to copolymers of tyrosine-based polycarbonates and poly(alkylene oxide) and to methods of synthesizing such polymers.
Linear aromatic polycarbonates derived from diphenols such as bisphenol-A represent an important class of condensation polymers. Such polycarbonates are strong, tough, high melting materials. They are well-known in the literature and are commercially produced in large quantities.
The early investigations on block copolymers of poly(bisphenol-A carbonate) and poly(alkylene oxide) started in 1961 and were conducted by the groups of Merrill and Goldberg. Merrill,
J. Polym. Sci.,
55 343-52 (1961) for the first time introduced poly(alkylene oxide) blocks into poly(bisphenol-A carbonate). Merrill described the interfacial copolymerization of poly(bisphenol-A carbonate) (dissolved in methylene chloride) and poly(alkylene oxide) bischloroformate (dissolved in aqueous sodium hydroxide). The presence of flexible blocks of poly(alkylene oxide) promoted the crystallization of the polycarbonate, which resulted in flexible polymers with high melting points. Later on, Goldberg,
J. Polym. Sci., Part C,
4, 707-30 (1964) reported more work on block copolymers of poly(bisphenol-A carbonate) and poly(ethylene oxide). The incorporation of flexible, polar, water soluble block segments into the rigid, linear, aromatic polycarbonate chains produced elastomers with unusual thermal and plastic properties. In particular Goldberg described the use of poly(ethylene oxide) as a comonomer with bisphenol-A. The synthesis was based on the reaction of phosgene with the mixture of monomers in pyridine followed by purification of the copolymer by precipitation in isopropanol. Copolymers were studied for structure-property correlations as a function of poly(ethylene oxide) molecular weight and copolymer composition. Remarkable strength and snappy elasticity were observed at poly(ethylene oxide) block concentration greater than 3 mole-%. These thermoplastic elastomers also exhibited high softening temperatures (>180° C.) and tensile elongations up to about 700%. Both glass transition temperature and softening temperature varied linearly with the molar ratio of poly(ethylene oxide). The early studies established that these copolymers are good elastomers, but no medical applications were considered.
Later on, Tanisugi et al.,
Polym. J.,
17(3), 499-508 (1985); Tanisugi et al.,
Polym. J.,
16(8), 633-40 (1984); Tanisugi et al.,
Polym. J.,
17(8), 909-18(1984); Suzuki et al.,
Polym. J.,
16(2), 129-38 (1983); and Suzuki et al.,
Polym. J.,
15(1), 15-23 (1982) reported detailed studies of mechanical relaxation, morphology, water sorption, swelling, and the diffusion of water and ethanol vapors through membranes made from the copolymers.
Mandenius et al.,
Biomaterials,
12(4), 369-73 (1991) reported plasma protein absorption of the copolymer, compared to polysulphone, polyamide and polyacrylonitrile as membranes for blood purification. Adhesion of platelets onto Langmuir and solvent cast films of the copolymers was also reported by Cho et al.,
J. Biomed. Mat Res.,
27, 199-206 (1993). The use of copolymers of poly(bisphenol-A carbonate) and poly(alkylene oxide) as hemodialysis membrane or plasma separator was disclosed in U.S. Pat. Nos. 4,308,145 and 5,084,173 and in EP 46,817; DE 2,713,283; DE 2,932,737 and DE 2,932,761.
Heretofore, block copolymers of polycarbonates and poly(alkylene oxide) have not been studied as medical implantation materials. Although an extensive search of the literature revealed no studies of in vitro or in vivo degradation, one of ordinary skill in the art would not expect that the currently known block copolymers of poly(bisphenol-A carbonate) and poly(alkylene oxide) would degrade under physiological conditions at rates suitable for the formulation of degradable implants.
U.S. Pat. Nos. 5,198,507 and 5,216,115 disclosed tyrosine-derived diphenolic monomers, the chemical structure of which was designed to be particularly useful in the polymerization of polycarbonates, polyiminocarbonates and polyarylates. The resulting polymers are useful as degradable polymers in general, and as tissue compatible bioerodible materials for biomedical uses in particular. The suitability of these polymers for this end-use application is the result of their derivation from naturally occurring metabolites, in particular, the amino acid L-tyrosine.
Tyrosine-based polycarbonates are strong, tough, hydrophobic materials that degrade slowly under physiological conditions. For many medical applications such as drug delivery, non-thrombogenic coatings, vascular grafts, wound treatment, artificial skin, relatively soft materials are needed that are more hydrophilic and degrade faster than the available tyrosine-based polycarbonates.
SUMMARY OF THE INVENTION
In this invention, the introduction of poly(alkylene oxide) segments into the backbone of tyrosine-based polycarbonates was found to lead to softer, more hydrophilic polymers that exhibited significantly increased rates of degradation. Since the previously known block copolymers of poly(bisphenol-A carbonate) and poly(alkylene oxide) apparently do not degrade appreciably under physiological conditions, the finding was unexpected that the incorporation of poly(alkylene oxide) into tyrosine-based polycarbonate significantly increased the rate of degradation. Furthermore, the disclosed copolymers of tyrosine-based polycarbonate and poly(ethylene oxide) have an alkyl ester pendent chain at each monomeric repeat unit. This pendent chain is an unprecedented structural feature among the currently known block copolymers of poly(bisphenol A carbonate) and poly(alkylene oxide). As shown in more detail below, variation in the length of the pendent chain can be used to fine-tune the polymer properties. Studies of this kind are known in the literature for other polymer systems, but have not been performed for block copolymers of poly(bisphenol A carbonate) and poly(alkylene oxide). In addition, the presence of a carboxylic acid containing pendent chain can facilitate the attachment of biologically or pharmaceutically active moieties to the polymer backbone. This, too, is an unprecedented feature among the previously known copolymers of bisphenol-A and poly(alkylene oxide).
Therefore, according to one aspect of the present invention, a random block copolymer of a tyrosine-derived diphenol monomer and a poly(alkylene oxide) is provided having the structure of Formula I:
wherein
R
1
is —CH═CH— or (—CH
2
—)
j
, in which j is zero or an integer from one to eight;
R
2
is selected from straight and branched alkyl and alkylaryl groups containing up to 18 carbon atoms and optionally containing at least one ether linkage and derivatives of biologically and pharmaceutically active compounds covalently bonded to the copolymer;
each R
3
is independently selected from alkylene groups containing from 1 up to 4 carbon atoms;
y is between about 5 and about 3000; and
f is the percent molar fraction of alkylene oxide in the copolymer, and ranges between about 1 and about 99 mole percent.
Another important phenomena that was observed for the copolymers is the temperature dependent inverse phase transition of the polymer gel or the polymer solution in aqueous solvents. Inverse temperature transitions have been observed for several natural and synthetic polymer systems such as proteins and protein-based polymers as described by Urry,
Tissue Engineering: Current Perspectives
(Boston Birkhauser, New York), 199-206, poly(acrylic acid) derived copolymers as described by Annaka et al.,
Nature,
355, 430-32(1992); Tanaka et al.,
Phys. Rev. Lett.,
45(20), 1636-39(1980) and Hirokawa et al.,
J. Chem. Phys.,
81(12), 6379-80(1984), and poly(ethylene glycol)-poly(propylene glycol) copolymers as described by Armstrong et al.,
Macromol. Reports
, A31(suppl. 6&7), 1299-306(1994). Polymer gels and solutions of these polymers are known to undergo continuous or discontinous volume change upon changes in temperature,
Kohn Joachim B.
Yu Chun
Di Nola-Baron Liliana
Page Thurman K.
Rutgers The State University
Synnestvedt & Lechner LLP
LandOfFree
Copolymers of tyrosine-based polyarylates and poly(alkylene... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Copolymers of tyrosine-based polyarylates and poly(alkylene..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Copolymers of tyrosine-based polyarylates and poly(alkylene... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2573045