Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From carboxylic acid or derivative thereof
Reexamination Certificate
2000-01-19
2001-11-13
Acquah, Samuel A. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From carboxylic acid or derivative thereof
C528S272000, C528S335000, C524S186000, C524S195000, C524S221000, C524S233000
Reexamination Certificate
active
06316585
ABSTRACT:
FIELD
This invention relates to a process of preparation of enzymatically degradable polymers. This invention particularly relates to a process for preparation of poly (ester) prodrugs by polycondensation of dicarboxylic acids with diesters of poly (oxyalkylene glycol) and trifunctional amino acid hydrochloride, in the presence of a condensing agent. More particularly, it relates to a process for the preparation of enzymatically degradable polymeric pro-drugs having repeating structural unit according to
FIG. 1
as shown in the drawing accompanying this specification, wherein, X is selected from phenolic —OH of tyrosine, —OH of serine and threonine, and —SH of cysteine, Y is pendant group selected from drug molecules containing carboxyl groups, R is hydrogen, methyl or mixture of hydrogen and methyl on the individual molecule, n is an integer from 0 to about 100 and m is an integer from 0 to 10.
BACKGROUND
Water soluble polymeric prodrugs have been extensively investigated as they can provide site specific drug delivery, longevity in blood circulation, lower drug dosage levels, bicompatibility and biodegradability (R. Duncan, J. Kopecek,
Adv. Polym. Sci
. 57, 51 (1984), P. Sinko and J. Kohn, “
Polymeric Drug Delivery Systems
” In: Polymeric Delivery Systems, M. A. El-Nokaly, D. M. Piatt, B. A. Charpentier, Eds. ACS Symposium series 520, American Chemical Society, Washington, D.C., P.18-42 (1993)). Due to immunogenic nature of poly(&agr; amino acid)s researchers have developed various synthetic polymeric prodrugs as alternatives. These can broadly be classified into two types, 1) bidcompatible prodrugs and 2) biodegradable prodrugs.
Some of the biocompatible polymeric prodrug systems developed are poly (methacrylic acid—co—2(methyl sulfinyl) ethyl methacrylate) (P. Moltz, Int.
J Biol. Macromol
. 2, 245 (1980)), poly (methacrylic acid—co—N-2 (hydroxypropyl) methacrylamide) and poly (N-vinyl pyrrolidone—co—vinyl amine) (V. Hoffman, H. Ringsdorf, A. Seganova,
Macromol. Chem
. 180, 837 (1979), R. Duncan, J. Kopecek, P. Rajmanova, J. B. Lloyed,
Biochem, Biophys. Acta
755, 518 (1983)). Various drug molecules such as chlorambucil, daunomycin, bis (2 chloroethyl) amine etc. were chemically linked to these polymers and prodrugs so synthesized were evaluated.
Prodrugs based on high molecular weight poly (ethylene glycol)s and poly (oxyethylene dicarboxylic acid)s have also been developed (T. Ouchi, Y. Hagihara, K. Takahashi, Y. Takano, I. Igarashi,
Drug Design and Disceovery
9, 93 (1992), R. B. Greenwald, C. W. Gilbert, A. Pendri, C. D. Conover, J. Xia, A. Martinez,
J. Med. Chem
. 39,424 (1996)).
Although these polymers are biocompatible, they are not biodegradable. Thus, they tend to accumulate in body after the delivery of attached drug molecule (R. Duncan, J. Kopecek
Adv. Polym. Sci
. 57, 51 (1984). Therefore, biodegradable prodrugs are preferred over biocompatible ones.
Polymers based on low molecular weight poly (ethylene glycol) and various trifunctional amino acids are being investigated as biodegradable prodrugs because the pendant functional groups in such polymers can be used for chemical linkage of drug molecules. Kohn et al (1992) reported water-soluble poly (ether-urethane) based on L-lysine and poly (ethylene glycol). The polymer was synthesize by the reaction of L-lysine ethyl ester with bis (succinimidyl) carbonate derivative poly (ethylene glycol). The polymer so synthesized was treated with sodium hydroxide in order to de-block the side chain carboxyl groups of L-lysine and make them available for drug linkage. (A. Nathan, D. Bolika, N. Vyavahare, S. Zalipsky, J. Kohn,
Macromolecules
25, 4476 (1992)). Ulbrich et al (1997) reported a prodrug system based on poly (oxyethylene glycol) and L-glutanic acid. This polymer was synthesized by connecting two blocks of monomethoxy poly (oxyethylene) carboxylic acid via biodegradable oligopeptide-1,4 bis (&ggr;-para-nitroanilido glutamido) ethylene diamide (M. Pechar, J. Strohalm, K. Ulbrich,
Macromol. Chem
. 198, 1009 (1997)). The oligopeptide was synthesized following standard procedures of blocking and de-blocking of —NH
2
and —COOH groups of amino acid. Won et al (1998) reported a polymer based on poly (ethylene glycol) and L-aspartic acid. In this, N-benzyloxylcarbonyl L-aspartic acid (N-cbz-L-aspartic acid) was converted into N-cbz-aspartic anhydride by the reaction of thionyl chloride. Subsequently, N-cbz-aspartic anhydride was reacted with poly (ethylene glycol) to obtain a polymer with blocked —NH
2
groups. This polymer was treated with 1,4 cyclohexadiene and Palladium/activated charcoal in order to de-block —NH
2
groups and make them available for drug linkage (C-Y Won, C-C chu J. D. Lee,
J. Polym. Sci. Chem. Ed
. 36, 2949 (1998).
Thus, due to such tedious blocking and de-blocking procedures of —NH
2
and —COOH groups, a very few examples (mentioned herein above) of prodrugs based on trifunctional amino acids and poly (ethylene glycol) are reported so far.
OBJECTS
It is, therefore, an object of the present invention to provide a simpler process for the preparation of novel water soluble polymeric prodrug systems based on poly (oxyalkylene glycol) and trifunctional amino acids, which will eliminate the conventional blocking and de-blocking chemistry of —NH
2
group.
It is also an object to provide a process applicable to various trifunctional amino acids.
Another object is to provide enzymatically degradable polymers, which polymers are stable and degrade only in the presence of certain enzymes, depending upon the amino acid present in the polymer, thus providing means of developing site specific drug delivery systems. Polymers based on poly (oxyalkylene glycol) and amino acids are suitable for this purpose.
DETAILED DESCRIPTION
Accordingly, the present invention provides a novel process for the preparation of condensation polymers based on dicarboxylic acids and diesters of poly (oxyalkylene glycol) and amino acid hydrochlorides. The main advantage of this novel process over the conventional processes is that it eliminates the use of —NH
2
blocking groups namely N-benzyloxycarbonyl (N-cbz) and N-tertiarybutyloxycarbonyl (N-tboc) and the subsequent tedious procedures of de-blocking viz. hydrogenation or reaction with 1,4 cyclohexadiene/Palladium/Charcoal and the acid hydrolysis respectively. The drug linkage to the polymers synthesized by the process of the invention is much simpler as this involves only neutralization of hydrochloride salts by the treatment of commonly used bases.
Also, the polymers synthesized by following the process of the present invention are novel.
Accordingly, the present invention provides a process for the preparation of enzymatically degradable polymers, having repeating structural unit in the formula hereinbelow:
wherein, X is selected from phenolic —OH of tyrosine, —OH of serine aid threonine and —SH of cysteine, Y is the pendant group selected from drug molecules containing carboxyl groups, R is hydrogen, methyl or mixture of hydrogen and methyl on the individual molecule, n is an integer from 0 to about 100 and m is an integer from 0 to 10, which process comprises the steps of:
(i) reacting diester of poly (oxyalkylene glycol) and hydrochloride of trifunctional amino acid with a dicarboxylic acid in the presence of a condensing agent in a solvent at a temperature in the range of 0° C. to room temperature for a period ranging between 1 hr to 24 hrs,
(ii) neutralizing the hydrochloride salt using a base, and
(iii) reacting the free side chain amino groups of the polymer with drug molecule containing carboxyl groups to obtain the desired enzymatically degradable polymer.
In an embodiment, the diesters of poly (oxyalkylene glycol) is selected from the group comprising compounds of the formula HOCH
2
—CHR—(CH
2
—CHR—O—)
n
—CH
2
—CHR—OH wherein R is hydrogen, methyl or mixture of hydrogen and methyl on the individual molecule, n is an integer which represents the average number of oxyalkylene groups, preferably from 0 to 100.
In yet another embodiment, the glycol is selected fr
Kulkarni Mohan Gopalkrishna
Lele Bhalchandra Shripad
Padmaja Turumella
Acquah Samuel A.
Birch & Stewart Kolasch & Birch, LLP
Council of Scientific and Industrial Research
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