Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1998-08-17
2001-12-04
Page, Thurman K. (Department: 1615)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C530S350000, C528S310000, C528S328000, C514S772200
Reexamination Certificate
active
06326511
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to alkyl and/or alkylene esters of poly-&ggr;-glutamic acid (PGA) that are prepared by esterifying PGA with a labile alkyl or alkylene group, methods for the preparation of such esters, and of their cross-linking upon exposure to light of predetermined, specified wavelength to form hydrophilic gels.
DESCRIPTION OF PRIOR PUBLICATIONS RELATING TO GLUTAMIC ACID
British Patent 1,099,227 discloses plasticized polymeric compositions comprising a major proportion of a normally solid polymer of (A) vinyl chloride or vinyl acetate or a mixture of the two, and (B) a polymer prepared by reacting glutamic acid with an alcohol of formula RCH
2
OH wherein R is phenyl or a C
5-21
alkyl radical.
U.S. Pat. No. 3,933,492 discloses photoconductive substances of the formula
wherein R is a polynuclear or a heterocyclic nitrogen group, each containing up to 16 carbon atoms, and n is 1 or 2.
U.S. Pat. No. 4,450,150 discloses an implantable drug delivery depot comprising a copolymer of glutamic acid and glutamic acid ethyl ester having one or more drug or diagnostic agents physically contained therein.
DETAILED DESCRIPTION
The starting material of the present invention is poly-&ggr;-glutamic acid which is most conveniently prepared by fermentation of a suitable microrganism capable of producing poly-&ggr;-glutamic acid in a suitable fermentation medium for times and under conditions and time appropriate for the organism used. Agar containing yeast extract (typically 0.5%) is a suitable nutrient substrate. Culture plates (nutrient agar with about 0.5% yeast extract) are inoculated with an organism capable of producing poly-&ggr;-glutamic acid, preferably with a spore suspension of the microorganism, and incubated at a suitable temperature. A preferred organism is
Bacillus licheniformis
(ATCC 9945a). Colonies are selected and used to inoculate the fementation medium which is incubated at suitable conditions of temperature, agitation and time, typically, about 37° C. on an orbit shaker (about 100-200 rpm) for 24-72 hours. Medium E is a suitable fermentation medium. The resulting suspension is used as a seed to inoculate a 2-liter flask which is incubated on the shaker for an appropriate time, generally from about 2 to about 10 days.
The resulting culture medium is treated, e.g. by centrifugation, filtration, or other suitable means, to separate the cells from the poly-&ggr;-glutamic acid and the resulting cell-free liquid is treated to yield the desired poly-&ggr;-glutamic acid in purified form as the free acid, e.g. by addition of an alkanol of from 1 to 4 carbons, preferably, ethanol or methanol. The molecular weight (M
w
) of the PGA free acid product is from about 0.5×10
6
to about 1.5×10
6
.
The free acid product is then partially esterified by reaction with a C
2-20
alkenyl halide, or acetate, preferably a C
2
-C
6
alkenyl halide or acetate, and most preferably with vinyl bromide or vinyl acetate. This reaction takes place in a polar solvent, e.g. dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), dimethyl acetamide (DMA), or their equivalents, in the presence of a base such as NAHCO
3
, Na
2
CO
3
, KHCO
3
, K
2
CO
3
, or their equivalents, and mixtures thereof, preferably using a molar excess of the base. The degree of esterification is monitored by NMR measurements, using 200 MHz for
1
H and the reaction is terminated when up to about 30%, preferably from about 20% to about 30%, of the carboxyl groups of the PGA have been esterified.
This partial ester product then can then be further esterified by repeating the foregoing treatment with the alkyl or alkenyl compound whereby the extent of esterification is increased to up to about 60%, preferably from about 50% to about 60%.
The second esterification product can itself be further esterified by repeating the foregoing treatment with the alkyl and/or alkenyl halide whereby the extent of esterification is increased to about 99%, preferably from about 90% to about 98%. Any of the three esterification products can be cross-linked by addition of an initiator such as, for example, benzoin methyl ether, or another light initiator as a catalyst, and exposure to light having a wavelength of from about 226 nm to about 460 nm. More preferably, the light is (1) ultra-violet (UV) light having a wave length of from about 246 to about 266 nm, most preferably about 256 nm, or (2) low energy UV light having a wave length of from about 350 nm to about 370 nm, most preferably about 360 nm, or (3) blue visible light having a wave length of from about 410 nm to about 430 nm, most preferably about 420 nm.
The final products of the present invention are useful in local drug delivery in depot form, for guided tissue regeneration, and for inhibition of post-surgical adhesion. For these applications, they are used similarly to agents known to be effective for such applications.
REFERENCES:
patent: 3719520 (1973-03-01), Fujimoto et al.
patent: 5118784 (1992-06-01), Kubota et al.
patent: 5378807 (1995-01-01), Gross et al.
patent: 5461085 (1995-10-01), Nagamoto et al.
Lajos Kossuth University
Page Thurman K.
Perrella Donald J.
Pulliam Amy E
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