Pharmaceutical compositions containing DDS compounds

Details Pharmaceutical compositions containing DDS compounds Pharmaceutical compositions containing DDS compounds

2003-01-13

2004-11-09

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S054000, C514S053000, C514S008100, C536S112000, C536S123100, C536S123120, C530S322000, C530S330000

Reexamination Certificate

active

06815435

ABSTRACT:

TECHNICAL FIELD
This invention relates to a freeze-dried preparation of a pharmaceutical composition containing a drug delivery system (DDS) compound wherein a polysaccharide derivative having a carboxyl group is bonded to a camptothecin derivative via a peptide chain (a spacer) or without mediated by any spacer.
BACKGROUND ART
When administered to the whole body, many anti-tumor agents are distributed into various cells and tissues in the whole body and act as cytotoxins on normal cells and tissues too. As a result, there arises a serious problem of side effects causing, for example, diarrhea, fever, vomiting and hair removal at an extremely high frequency. To overcome this problem, it has been required to develop means of delivering an anti-tumor agent efficiently and selectively to a tumor site.
As an example of such means, there is reported a DDS technique wherein a polysaccharide derivative, which is used as a drug carrier, is bonded to an anti-tumor agent to thereby delay the disappearance of the anti-tumor agent in the blood and enhance the directivity toward the cancer tissue (WO 094/19376, WO 094/19376, JP-B-7-84481; the term “JP-B” as used herein means an “examined Japanese patent publication”).
Among DDS compounds with the use of polysaccharide derivatives as drug carriers, a DDS compound wherein a polysaccharide derivative obtained by polyalcoholizing carboxymethyldextran is used as a drug carrier and bonded to a camptothecin derivative (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13 (9H,15H)-dione (hereinafter sometimes referred to as the compound A) via a peptide chain has an extremely excellent tumor selectivity and anti-tumor activity. Thus, attempts are now underway to clinically test this compound.
However, preparations obtained by freeze-drying the above-described DDS compounds suffer from a problem of having very poor preservation stability, since the molecular weight thereof is increased during preservation, thereby causing changes in the form of the preparations and worsening the re-dissolution properties thereof.
The present invention provides pharmaceutical compositions containing a drug delivery system (DDS) compound wherein a polysaccharide derivative having a carboxyl group is bonded to a camptothecin derivative via a peptide chain (a spacer) or without mediated by any spacer to thereby ensure high preservative stability of the compound.
DISCLOSURE OF INVENTION
As the results of intensive studies, the inventors have found out that an increase in the molecular weight of the above-described compound can be inhibited by adding to the compound a sugar or a sugar alcohol together with, if needed, a pH-adjusting substance and then freeze-drying.
Accordingly, the present invention relates to a pharmaceutical composition containing a drug delivery system (DDS) compound, wherein a polysaccharide derivative having a carboxyl group is bonded to a camptothecin derivative via a peptide chain (a spacer) or without mediated by any spacer, and a sugar or a sugar alcohol.
More particularly, the present invention relates to a pharmaceutical composition containing a compound wherein a polysaccharide derivative having a carboxyl group is bonded to (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione via a spacer consisting of one amino acid or a spacer consisting of 2 to 8 amino acids bonded to each other via peptide bonds, or a compound wherein a polysaccharide derivative having a carboxyl group is bonded to (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione without mediated by any spacer and one or more sugars or sugar alcohols selected from the group consisting of maltose, glucose, lactose, trehalose, saccharose, mannitol, inositol, galactose, ribose, xylose, mannose, sucrose, cellobiose, raffinose and maltotriose.
The present invention further relates to the above-described pharmaceutical composition containing a compound wherein a polysaccharide derivative having a carboxyl group is bonded to (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[2-b]quinoline-10,13(9H,15H)-dione via a spacer consisting of one amino acid or a spacer consisting of 2 to 8 amino acids bonded to each other via peptide bonds, or a compound wherein a polysaccharide derivative having a carboxyl group is bonded to (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione without mediated by any spacer, one or more sugars or sugar alcohols selected from the group consisting of maltose, glucose, lactose, trehalose, saccharose, mannitol, inositol, galactose, ribose, xylose, mannose, sucrose, cellobiose, raffinose and maltotriose, and a pH-adjusting substance.
Further, it relates to the above-described pharmaceutical composition wherein the polysaccharide derivative having a carboxyl group is a carboxy(C
1-4
alkyl)dextran polyalcohol.
Moreover, it relates to the above-described pharmaceutical composition wherein the polysaccharide derivative having a carboxyl group is carboxymethyldextran polyalcohol.
Further, it relates to the above-described pharmaceutical composition wherein the weight-average molecular weight of the carboxymethyldextran polyalcohol ranges from 50,000 to 500,000.
Moreover, it relates to the above-described pharmaceutical composition wherein the carboxymethyldextran polyalcohol has a degree of carboxymethylation of from 0.2 to 0.5.
Further, it relates to the above-described pharmaceutical composition wherein the spacer consists of amino acids represented by the amino acid sequence (N end)-Gly-Gly-Phe-Gly-(C end).
Moreover, it relates to the above-described pharmaceutical composition wherein (1S,9S) -1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione is introduced in an amount of 2 to 10% by weight based on the weight of a compound wherein a polysaccharide derivative having a carboxyl group is bonded to (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione via a spacer consisting of one amino acid or a spacer consisting of 2 to 8 amino acids bonded to each other via peptide bonds, or a compound wherein a polysaccharide derivative having a carboxyl group is bonded to (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione without mediated by any spacer.
Further, it relates to the above-described pharmaceutical composition wherein the sugar or sugar alcohol is maltose.
Moreover, it relates to the above-described pharmaceutical composition wherein the content of maltose, in terms of the weight as maltose monohydrate, is thrice or more as much as the weight of the compound wherein a polysaccharide derivative having a carboxyl group is bonded to (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione via a spacer consisting of one amino acid or a spacer consisting of 2 to 8 amino acids bonded to each other via peptide bonds, or a compound wherein a polysaccharide derivative having a carboxyl group is bonded to (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]qui

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