Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From carboxylic acid or derivative thereof
Reexamination Certificate
2000-08-28
2002-12-31
Low, Christopher S. F. (Department: 1653)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From carboxylic acid or derivative thereof
C528S310000, C528S486000, C525S419000, C525S420000, C530S322000, C530S345000, C514S008100
Reexamination Certificate
active
06500916
ABSTRACT:
THE FIELD OF THE ART
The present invention relates to saccharide-modified polymers which are useful as carriers capable of migrating into target organs (cells), drug-containing polymers using them and the process for the preparation thereof.
BACKGROUND
The drug delivery systems into the target organs comprising low-molecular drugs bonded to high-molecular compounds as carriers capable of migrating into target organs have been studied in order to obtain the aimed pharmaceutical effect of the drugs on the target organs and to reduce the side effects of the drugs on the other organs.
For example, it is disclosed that drug delivery systems into liver comprising of drugs modified with the compounds obtained by combination of galactose and proteins or high-molecule compounds based on the fact that the receptors specific for galactose exist in liver parenchymal cell in High-Molecule Vol. 46, No. 11, 843-848 (1997).
In addition, it is disclosed that poly-L-glutamic acid derivatives wherein a part of or all of the consisting peptide bonds in the poly-L-glutamic acid of the formula
(wherein, Xa is degree of polymerization of 20~540, R
a
is hydrogen, lower alkyl or benzyl.) are replaced with a group of the formula
is useful as a carrier of drugs capable of migrating into liver in the Japanese Patent Application Kokai Hei 7-228688. The drugs have been conjugated to carboxyl group in the said glutamic acid via amide bond, ester bond or ion bond etc. directly. Vitamin K5 is described as an example of drugs in this publication.
Further, it is disclosed that polymers of PGE
1
-containing L-glutamic acid derivative (abbreviated as polymer PA) of the formula
is as high-molecule prodrug of PGE
1
capable of migrating into liver in International. J. Pharmaceutics, 155, 65-74 (1997). The drug (PGE
1
) is conjugated to L-glutamic acid via amide bond through ethylenediamine (—NH—CH
2
CH
2
—NH—) as a spacer.
In the process for the preparation of the said polymer PA, which comprises amidation by condensation between PGE
1
and ethylenediamine as a spacer (reacting the activated ester of PGE
1
with ethylenediamine using carbodiimide (CDI) etc.), the reaction was carried out in an alkaline condition. Therefore, there is a problem that the drug which is unstable in an alkaline condition (e.g. PGE
1
) would be decomposed and that the introducing rate of drugs into poly-L-glutamic acid does not increase. In this publication, quantity of drugs (PGE
1
) introduced into one molecule of polymer (degree of polymerization of L-glutamic acid=101) is 1.6 molecule.
The present inventors have dissolved such a problem by using hydrazine (—NH—NH—) instead of ethylenediamine (—NH—CH
2
CH
2
—NH—) as a spacer in the reaction of drugs (e.g. PGE
1
) and L-glutamic acid. That is to say, the reaction to introduce the drugs (PGE
1
) is carried out in a weak acidic condition, so it is possible to introduce the drugs constantly, even if it is unstable in an alkaline condition. Based on this reaction, they have improved the introducing rate of drugs (e.g. PGE
1
) into poly-L-glutamic acid, and then succeeded in synthesis of drugs-containing polymers showing the superior effect. In addition, it has proved that any compounds can be introduced into the polymer constantly by using this reaction. For example, quantity of drugs (PGE
1
) introduced into one molecule polymer of the present invention (degree of polymerization of L-glutamic acid=97) is 5 molecule, which means the polymer of the present invention has 3-folds superiority in introducing rate of drug to compare with the polymer of the said publication.
In addition, the polymer using hydrazine of the present invention shows superiority in both accumulation of drugs into liver after administration and effects of drugs (cytoprotective activity of PGE
1
) to the polymers using ethylelendiamine.
Further, there is a merit that such a reaction between hydrazine and the drug (PGE
1
) has been carried out by a simple procedure comprising of only stirring them at room temperature.
DISCLOSURE OF THE INVENTION
The present invention relates to
(1) the polymer (abbreviated as Polymer P1.) wherein a part of or all of the consisting peptide bonds in the poly-L-glutamic acid of the formula (A)
(wherein, degree of polymerization d is 20~500, R is hydrogen, C1~6 alkyl or benzyl, with the proviso that each multiple R may be same or different.)
are replaced with a group of the formula
wherein
(wherein, G is a modified saccharide capable of conjugating to hydrazine))
as essential substituents with the proviso that when the number of replacement groups of the formula (C) is 2 or more, all of said groups are the same,
(2) the polymer (abbreviated as Polymer P2) wherein a part of or all of the peptide bonds in the poly-L-glutamic acid of the formula (A)
(wherein, all the symbols are defined as hereinbefore)
(wherein,
is defined as hereinbefore,
(wherein, D is a drug))
with the proviso that (1) groups of both the formula (C) and (D) are essential substituents, (2) when the number of replacement groups of the formula (C) or (D) is 2 or more, all of said groups of the formula (C) or (D) are the same and (3) the number of replacement groups of the formula (B) may be 0), and (3) the process for the preparation thereof.
DETAILED DESCRIPTION OF THE INVENTION
Polymer P1 is a carrier polymer capable of migrating into target organs (cells) and Polymer P2 is a drug-containing polymer, which is obtained by utilizing the said carrier polymer, capable of migrating into target organs (cells).
The delivery of the polymer of the present invention into target organs (cells) depends upon the saccharide (represented by G) conjugated to glutamic acid. It is known that various kinds of receptors for saccharides exist in organs (cells) and, new receptors may be found in the future study. It is possible to obtain the drug delivery system into target organs (cells) by choice of saccharide (G) capable of conjugating to the aimed organs (cells) including such known or new receptors.
For example, in case of monosaccharide, galactose receptor, mannose receptor and fucose receptor exist in liver parenchymal cells, liver nonparenchymal cells (endotherial cells and Kupffer cells) and Kupffer cells, respectively, so it is possible to obtain drug delivery system into liver (the said liver cells) by conjugate of galactose, mannose or fucose derivative (corresponds to Polymer P1 and P2 of the present invention in which
is a group of the formula of (G
1
), (G
2
) and (G
3
) described hereinafter.). For example, in case of oligosacchardies such as di, tri or tetrasaccharides etc. or multi-saccharides, the delivery of the polymer of the present invention into target organs (cells) depends upon the terminal saccharide. For example, the terminal saccharide of lactose which is one of disaccharide (corresponds to Polymer P1 and P2 of the present invention in which
is a group of the formula (G
4a
) and (G
5a
).) is galactose, so such a polymer migrates into liver parenchymal cell mainly. As for the aimed saccharide, natural ones or artificial ones which are synthesized may be used.
The symbols and degree of polymerization etc. of Polymer P1 and P2 of the present invention are explained in detail as follows:
The symbol d in the formula (A) in Polymer P1 and P2 of the present invention means the degree of polymerization of L-glutamic acid which is a unit of the polymer of the present invention and it is an integer of 20~500, preferably 40~300 and more preferably 50~150.
The number of replacement of group of the formula (B) in Polymer P1 (corresponds to y
2
described hereinafter.) is 5~250 and preferably 5~50.
The number of replacement of group of the formula (C) (corresponds to z
2
described hereinafter.) is 10~100, and preferably 20~60.
The number of replacement of group of the formula (B) in Polymer P2 (corresponds to y
3
described hereinafter.) is 0~250, and preferably 0~50.
The number of replacement of group of the formula (C) (corresponds to Z
3
described hereinafter.) is 10~100
Akamatsu Ken
Hashida Mitsuru
Low Christopher S. F.
Lukton David
Ono Pharmaceutical Co. Ltd.
Sughrue & Mion, PLLC
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