Elastomeric functional biodegradable copolyester amides and...

Details Elastomeric functional biodegradable copolyester amides and... Elastomeric functional biodegradable copolyester amides and...

2000-08-30

2003-01-07

Acquah, Samuel A. (Department: 1711)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C528S176000, C528S179000, C528S182000, C528S184000, C528S189000, C528S332000, C528S335000, C528S336000, C528S339000, C524S086000, C524S233000, C424S426000, C424S451000, C424S457000, C424S489000, C424S490000

Reexamination Certificate

active

06503538

ABSTRACT:

BACKGROUND OF THE INVENTION
While they potentially offer many advantages due to their “organic nature,” conventional poly(&agr;-amino acids) possess many undesirable physical, chemical and biodegradation properties. For example, the biological and material properties of conventional poly(&agr;-amino acids) cannot be varied over a wide range. In addition, the synthesis of many conventional poly(&agr;-amino acids) is difficult and expensive.
A considerable amount of attention has therefore been focussed on replacing the amide (peptide) linkage in the conventional poly(&agr;-amino acids) with a variety of non-amide bond to provide novel polymeric systems that are based on &agr;-amino acids. One class of &agr;-amino acid derived polymers are polyisopeptides (alternatively known as pseudo-poly(amino acids)), which belong to the XY-type heterochain polymers. Polyisopeptides are usually foamed by linking trifunctional &agr;-amino acids in the backbone chains. However, relatively few attempts have been made to synthesize polyisopeptides. For example, Sekiguchi et al. obtained poly-&bgr;-(&agr;-alkyl-L-aspartate) by the ring-opening polymerization of &bgr;-lactams. See, Rodriguez-Galan, A. et al.,
Makromol. Chem., Makromol. Symp
., 6, 277 (1986) and Vives, J. et al.,
Makromol. Chem., Rapid Commun
., 10(1):13 (1989). One major limiting feature of polyisopeptides is that structural modifications are limited solely to chemical variations at the N-acyl residue of the polyisopeptide. This narrow range of chemical modification has resulted in an undesirably narrow range of material properties of these polymers.
Another class of &agr;-amino acid derived polymers are amino acid based bioanalagous polymers (AABBPs), which belong to the XX-YY heterochain polymers. AABBPs are mainly obtained by the polycondensation of XX (one type of monomer having two X functional groups) and YY (another type of monomer having two Y functional groups). AABBPs are not pure polyamino acids or pseudo-polyamino acids because they include residues of other types of monomers (e.g., dicarboxylic acids and diols).
One class of AABBPs are poly(ester ureas) (PEUs), which are prepared from bis-&agr;-aminoacyl diol monomers. The first attempt to use bis-&agr;-aminoacyl(phenylalanyl) diol for preparing bioabsorbable, semi-physiological polymers similar to poly(ester urea) was by Huang et al. Huang S. J., et al.,
J. Appl. Polym. Sci
., 23(2): 429 (1979). Only low-molecular-weight PEUs, having limited material properties, could be prepared by this route.
Lipatova et al. have also synthesized semi-physiological poly(ester urethane ureas) from bis-L-phenylalanyl diols, diols, and diisocyanates. Lipatova T. E., et al.,
Dokl. Akad. Nauk SSSR
, 251(2): 368 (1980) and Gladyr I. I., et al.
Vysokomol. Soed
., 31B(3): 196 (1989). However, no information on the synthesis of the starting material (e.g., &agr;-diamino diesters) was given.
Yoneyama et al. reported on the synthesis of high-molecular-weight semi-physiological PEUs by the interaction of free &agr;-diamino-diesters with non-physiological diisocyanates. Yoneyama M., et al.,
Polym. Prepr. Jpn
., 43(1): 177 (1994). Contrary to Huang et al. (Huang S. J., et al.,
J. Appl. Polym. Sci
., 23(2): 429 (1979)), high-molecular-weight PEUs were obtained in some cases. In view of this preliminary data, there remains an ongoing need for novel polymers based on &agr;-amino acids that possess a wide range of physical, chemical and biodegradation properties.
SUMMARY OF THE INVENTION
The present invention provides polymers that are based on &agr;-amino acids. In contrast to conventional poly(&agr;-amino acids), the polymers of the present invention (e.g., elastomeric functional copolyester amides and copolyester urethanes) possess advantageous physical, chemical and biodegradation properties. For example, the polymers of the present invention possess suitable biodegradation (weight loss percent) properties under varying conditions, (see, Table III). The hydrolysis of the polymers can be catalyzed by hydrolases (e.g., trypsin, &agr;-chymotrypsin, lipase, etc.). As such, the polymers can be used as carriers for covalent immobilization (attachment) of various drugs and other bioactive substances. In addition, the enzyme catalyzed biodegradation rates of the polymer of the present invention can be changed by varying the polymer composition (e.g., l/p ratio) and/or the nature of the functional groups (e.g., dicarboxylic acids, diols, or &agr;-amino acids).
The present invention provides a polymer of formula (VII):
wherein
m is about 0.1 to about 0.9;
p is about 0.9 to about 0.1;
n is about 50 to about 150;
each R
1
is independently (C
2
-C
20
)alkylene;
each R
2
is independently hydrogen, or (C
6
-C
10
)aryl(C
1
-C
6
)alkyl;
each R
3
is independently hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, or (C
6
-C
10
)aryl(C
1
-C
6
)alkyl; and
each R
4
is independently (C
2
-C
20
)alkylene; comprising one or more subunits of the formula (I):
 and one or more subunits of the formula (II):
 wherein
the combined number of subunits (I) and (II) is about 50 to about 150.
Specifically, each R
1
can independently be (CH
2
)
4
, (CH
2
)
8
, or (CH
2
)
12
; R
2
can independently be hydrogen or benzyl; each R
3
can independently be iso-butyl or benzyl; and R
4
can independently be (CH
2
)
4
, (CH
2
)
6
, (CH
2
)
8
, or (CH
2
)
12
.
The present invention also provides a polymer of formula (VII):
wherein
m is about 0.1 to about 0.9;
p is about 0.9 to about 0.1;
n is about 50 to about 150;
each R
1
is independently (C
2
-C
20
)alkylene;
each R
2
is independently hydrogen, or (C
6
-C
10
)aryl(C
1
-C
6
)alkyl;
each R
3
is independently hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, or (C
6
-C
10
)aryl(C
1
-C
6
)alkyl; and
each R
4
is independently (C
2
-C
20
)alkylene.
Specifically, each R
1
can independently be (CH
2
)
4
, (CH
2
)
8
, or (CH
2
)
12
; each R
2
can independently be hydrogen or benzyl; each R
3
can independently be iso-butyl or benzyl; each R
4
can independently be (CH
2
)
4
, (CH
2
)
6
, (CH
2
)
8
, or (CH
2
)
12
; p/(p+m) can be about 0.9 to about 0.1; and m/(p+m) can be about 0.1 to about 0.9.
The present invention also provides a polymer of formula (VII) formed from an amount of one or more compounds of formula (III):
wherein
each R
3
is independently hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, or (C
6
-C
10
)aryl(C
1
-C
6
)alkyl; and
R
4
is independently (C
2
-C
20
)alkylene; or a suitable salt thereof; and an amount of one or more compounds of formula (IV):
 wherein
R
2
is independently hydrogen, or (C
6
-C
10
)aryl(C
1
-C
6
)alkyl; or a suitable salt thereof; and
an amount of one or more compounds of formula (V):
wherein
R
1
is independently (C
2
-C
20
)alkylene; and
each R
5
is independently (C
6
-C
10
)aryl, optionally substituted with one or more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy.
Specifically, R
1
can independently be (CH
2
)
4
, (CH
2
)
8
, or (CH
2
)
12
; R
2
can independently be hydrogen or benzyl; each R
3
can independently be iso-butyl or benzyl; R
4
can independently be (CH
2
)
4
, (CH
2
)
6
, (CH
2
)
8
, or (CH
2
)
12
; each R
5
can independently be p-nitrophenyl; the compound of formula (III) can be the di-p-tolunesulfonic acid salt of a bis-(L-&agr;-amino acid)-&agr;,&ohgr;-alkylene diester; the compound of formula (IV) can be the di-p-tolunesulfonic acid salt of L-lysine benzyl ester; and the compound of formula (V) can be di-p-nitrophenyl adipate, di-p-nitrophenyl sebacinate, or di-p-nitrophenyl dodecyldicarboxylate.
The present invention also provides a method for preparing a polymer of formula (VII):
wherein
m is about 0.1 to about 0.9;
p is about 0.9 to about 0.1;
n is about 50 to about 150;
each R
1
is independently (C
2
-C
20
)alkylene;
each R
2
is independently hydrogen, or (C
6
-C
10
)aryl(C
1
-C
6
)alkyl;
each R
3
is independently hydrogen, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, or (C
6
-C
10
)aryl(C
1

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