Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2002-09-20
2004-09-21
Leary, Louise N. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S009100, C514S011400
Reexamination Certificate
active
06794364
ABSTRACT:
BACKGROUND OF THE INVENTION
Polymer drug delivery systems have been developed for the controlled release of pharmaceutical polypeptides. For example, synthetic polyesters such as poly(DL-lactic acid), poly(glycolic acid), poly(lactic-glycolic acid), and poly(∈-caprolactone) have been used in the form of microcapsules, films, or rods to release biologically active polypeptides. See e.g., U.S. Pat. Nos. 4,767,628 and 4,675,189 and PCT Application No. WO 94/00148.
In addition to the synthetic polymeric chains, natural polymers and their derivatives have been used as components in similar sustained release compositions that dissociate by enzymatic degradation. One example of such natural polymers are those based on chitin, a poly(N-acetylglucosamine). However, since chitin is water insoluble, others have examined solubilizable derivatives which are based primarily on a partially deacetylated chitin, e.g., chitosan. See e.g., Sanford, P. A. et al., Eds., Advances in Chitin & Chitosan (1992). Although chitosan can be found in some fungi, the production of biodegradable chitosan is generally performed synthetically. See Mima, et. al., J. Appl. Polym. Sci. 28 1909-1917 (1983). Synthetic derivatives of chitosan have also been prepared to alter the polymer's in vivo biological characteristics. See Muzzarelli, et al., Carbohydrate Res. 207:199-214 (1980).
The use of chitin, as well as chitin derivatives, has been proposed in a number of drug delivery systems. See, e.g., European Patent Application Nos. 486,959, 482,649, 525,813 A1, and 544,000 A1; and U.S. Pat. No. 5,271,945.
SUMMARY OF THE INVENTION
In one aspect, the present invention features a copolymer including an N-acylated derivative of poly(2-amino-2-deoxy-D-glucose), wherein between 1 and 50 percent of the free amines of the poly(2-amino-2-deoxy-D-glucose) are acylated with a first acyl group, the first acyl group is COE
1
where E
1
is selected from the group consisting of C
3-33
carboxyalkyl, C
3-33
carboxyalkenyl, C
7-39
carboxyarylalkyl, and C
9-39
carboxyarylalkenyl, and between 50 and 99 percent of the free amines of the poly(2-amino-2-deoxy-D-glucose) are acylated with a second acyl group, the second acyl group is COE
2
where E
2
is selected from the group consisting of C
1-30
alkyl, C
2-30
alkenyl, C
6-37
arylalkyl, and C
8-37
arylalkenyl, provided at least one of the free amines of the derivative is acylated with the first acyl group.
The copolymer preferably has a molecular weight of about 3,000 to 90,000 daltons. In other preferred embodiments, over 90 percent of the free amines of the poly(2-amino-2-deoxy-D-glucose) are acylated with either the first acyl group or the second acyl group. Preferably, between 10 and 30 percent of the free amine of the poly(2-amino-2-deoxy-D-glucose) are acylated with the first acyl group. Some of the free hydroxy groups (e.g., between 1 and 30 percent) of the derivative may be acylated with either the first acyl group or the second acyl group.
In a preferred embodiment, the copolymer is of the formula:
wherein:
R
1
, for each individual repeat unit, is selected from the group consisting of first acyl group, second acyl group, and H;
R
2
, for each individual repeat unit, is selected from the group consisting of first acyl group, second acyl group, and H;
R
3
, for each individual repeat unit, is selected from the group consisting of first acyl group, second acyl group, and H;
R
4
is selected from the group consisting of first acyl group, second acyl group, and H;
R
5
is selected from the group consisting of first acyl group, second acyl group, and H;
R
6
is selected from the group consisting of first acyl group, second acyl group, and H;
R
7
is selected from the group consisting of COH and CH
2
OR
8
;
R
8
is selected from the group consisting of first acyl group, second acyl group, and H;
n is between 2 and 200; and
for between 1 and 50 percent of the repeat units, R
1
is first acyl group, and for between 50 and 99 percent of the repeat units, R
1
is second acyl group, provided that for at least one of the repeat units, R
1
is first acyl group.
The terms COE
1
and COE
2
stand for —C═O·E
1
and —C═O·E
2
, respectively. The substituents carboxyalkyl, carboxyalkenyl, carboxyarylalkyl, and carboxyarylalkenyl may contain 1-4 carboxylic acid functionalities. Examples of the first acyl group include, but are not limited to, succinyl, 2-(C
1-30
alkyl)succinyl, 2-(C
2-30
alkenyl)succinyl, maleyl, phthalyl, glutaryl, and itaconyl. Examples of the second acyl group include but are not limited to, acetyl, benzoyl, propionyl, and phenylacetyl.
The present invention also features a composition including the above copolymer and a polypeptide, the polypeptide comprising at least one effective ionogenic amine, wherein at least 50 percent, by weight, of the polypeptide present in the composition is ionically bound to the polymer. Preferably, the composition comprises between 5 and 50 percent, by weight, of the polypeptide.
Preferred embodiments of the present invention include a copolymer wherein the first acyl group is succinyl and the second acyl group is acetyl and R
7
is COH or CH
2
OH; a composition comprising said copolymer of claim
1
and H-&bgr;-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH
2
or a pharmaceutically acceptable salt thereof, wherein the two Cys are bonded by a disulfide bond, where at least 50 percent, by weight, of H-&bgr;-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH
2
or a pharmaceutically acceptable salt thereof, present in said composition is ionically bound to said copolymer; a composition comprising the foregoing copolymer and a peptide selected from the group consisting of
or a pharmaceutically acceptable salt thereof, where at least 50 percent, by weight, of said peptide or a pharmaceutically acceptable salt thereof present in said composition is ionically bound to said copolymer; a composition comprising the foregoing copolymer and a peptide selected from the group consisting of (p-Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH
2
), ([D-Ser(t-Bu)
6
, des-Gly-NH
2
10
]-LHRH(1-9)NHEt), ([D-Trp
6
, des-Gly-NH
2
10
]-LHRH(1-9)NHEt, ([des-Gly-NH
2
10
]-LHRH(1-9)NHEt), ([D-Ser(t-Bu)
6
, Azgly
10
]-LHRH), ([D-His(Bzl)
6
, des-Gly-NH
2
10
]-LHRH(1-9)NHEt), ([D-Leu
6
, des-Gly-NH
2
10
]-LHRH(1-9)NHEt), ([D-Trp
6
, MeLeu
7
, des-Gly-NH
2
10
]-LHRH(1-9)NHEt), and ([D-Nal
6
]-LHRH, or a pharmaceutically acceptable salt thereof, where at least 50 percent, by weight, of said peptide or a pharmaceutically acceptable salt thereof, present in said composition is ionically bound to said copolymer; a composition comprising the foregoing copolymer and parathyroid hormone, an analogue thereof or a pharmaceutically acceptable salt thereof, where at least 50 percent, by weight, of parathyroid hormone, an analogue thereof or a pharmaceutically acceptable salt thereof, present in said composition is ionically bound to said copolymer.
Further preferred embodiments of the present invention include a copolymer wherein the first acyl group is glutaryl and the second acyl group is propionyl and R
7
is COH or CH
2
OH; a composition comprising the foregoing copolymer and H-&bgr;-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH
2
, wherein the two Cys are bonded by a disulfide bond, where at least 50 percent, by weight, of H-&bgr;-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH
2
, present in said composition is ionically bound to said copolymer; a composition comprising the foregoing copolymer and a peptide selected from the group consisting of
or a pharmaceutically acceptable salt thereof, where at least 50 percent, by weight, of said peptide or a pharmaceutically acceptable salt thereof present in said composition is ionically bound to said copolymer; a composition comprising the foregoing copolymer and a peptide selected from the group consisting of (p-Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH
2
), ([D-Ser(t-Bu)
6
, des-Gly-NH
2
10
]-LHRH(1-9)NHEt), ([D-Trp
6
, des-Gly-NH
2
10
]-LHR
Ignatious Francis X.
Jackson Steven A.
Moreau Jacques-Pierre
Russell Ruth M.
Shalaby Shalaby W.
Audet Maury
Feeney Alan F.
Fish & Richardson
Kinerton Limited
Leary Louise N.
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