Process for producing drug complexes

Details Process for producing drug complexes Process for producing drug complexes

1999-03-22

2001-09-18

Borin, Michael (Department: 1631)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S020000, C536S021000, C536S112000, C536S115000, C536S119000, C536S123120, C530S300000, C530S322000

Reexamination Certificate

active

06291671

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for preparing a drug complex in which a polysaccharide derivative and a drug compound such as antineoplastic agents are bound to each other.
2. Discussion of Background Information
Antineoplastic agents, used for treatment of solid cancers such as lung cancer or digestive organ carcinomas and blood cancers such as leukemia, are systemically administered through routes of administration such as intravenous or oral administration, and then, are distributed to specific tumorous sites and inhibit or suppress the proliferation of cancer cells to exhibit their therapeutic efficacy. However, the systemically-administered antineoplastic agents are rapidly taken into livers and reticuloendothelial organs from blood, or rapidly excreted into urine, and accordingly, their blood concentrations may sometimes be lowered to allow the distribution into tumorous sites to be insufficient. In addition, common antineoplastic agents themselves have poor distribution-selectivity to tumorous sites (tumor selectivity), and therefore, the antineoplastic agents are uniformly distributed over various tissues and cells of the whole body and act as cytotoxins also against normal cells and tissues, which results in problems of the appearance of adverse effects, e.g., emesis, pyrexia, or alopecia at an extremely high rate. Therefore, it has been desired to develop a means of efficiently and selectively distributing antineoplastic agents to tumorous sites.
As one of such means, a process was proposed in which a polysaccharide derivative having carboxyl groups is used as a drug delivery carrier, and an antineoplastic agent is bound to the polysaccharide derivative to delay the disappearance of the antineoplastic agent from blood and to enhance selectivity to tumor tissues. For example, International Publication WO94/19376 discloses a drug complex in which a peptide chain (the number of amino acid residues: 1 to 8) is bound to a carboxyl group of a polysaccharide having carboxyl groups, and doxorubicin, daunorubicin, mitomycin C, bleomycin or the like is further bound by means of the peptide chain. In addition, Japanese Patent Publication (KOKOKU) No. (Hei) 7-84481/1995 discloses a drug complex in which the aforementioned antineoplastic agent is introduced into a carboxymethylated mannoglucan derivative by means of a Schiff base or an acid amide bond. These drug complexes are characterized in that they have more excellent antitumor activity compared to the antitumor agent, per se, that is not bound to a drug delivery carrier, and reduced toxicity and adverse effects.
As for technologies relating to drug complexes utilizing polyalcoholized polysaccharide derivatives as drug delivery carriers, some reports are available, for example, “Researches on polysaccharide-peptide-doxorubicin complexes-Correlations between stabilities of polysaccharide carriers in blood and their anti-neoplastic activities” (Abstracts of 10th Meeting of the Japan Society of Drug Delivery System, 279, 1994); “Researches on polysaccharide-peptide-doxorubicin complexes—Pharmacokinetics and anti-neoplastic activity” (Abstracts of 9th Annual Meeting of Japanese Society for the study of xenobiotics, 292, 1994); Abstracts of 19th Seminar of Trends in Research and Development (held by
The Organization for Drug A D R Relief. R&D Promotion and Product Review
), D-9, 1995; and “Researches on drug delivery to a tumor tissue by polysaccharide carriers” (Abstracts of 12th Colloid and Interface Technology Symposium, The Chemical Society of Japan, 51, 1995).
These drug complexes have conventionally been manufactured by preparing sodium salt of a polysaccharide derivative having carboxyl groups, e.g., carboxymethylpullulan or carboxymethylmannoglucan, and then binding a carboxyl group of the polysaccharide derivative to an amino group of an antitumor agent (or a N-terminal amino group of a peptide chain binding to the antitumor agent) by means of an acid-amide bond. Sodium salt of polysaccharide derivatives is totally insoluble in organic solvents in the least, and accordingly, when carrying out the above reaction, the process has been adopted which comprises preparing sodium salt of a polysaccharide derivative as a solution in water or an aqueous organic solvent containing water, and then dissolving a condensing agent and an antitumor agent (or an antitumor agent having a peptide chain) in the form of hydrochloride or the like in the solution.
However, in the reaction, dehydration condensation is performed in a solvent containing water, and accordingly, it was impossible to obtain a desired product in high yields. Antitumor agents used as reaction materials are generally expensive, and it has been desired to develop a method for efficiently producing the aforementioned drug complexes from a viewpoint of the manufacturing cost. In addition, the compounds described in the Japanese Patent tjnexamined Publication (KOKAI) No. (Hei) 6-87746/1994, which are useful as antitumor agents, have a lactone ring in their molecules, and there are problems that, when these compounds each bound to a peptide chain are subjected to the aforementioned reaction, the lactone ring is opened in the presence of a base and water, and the resulting carboxyl group may react with the N-terminal amino group of the peptide chain bound to the antitumor agent to significantly reduce the yield of the desired product and fail to give the desired uniform drug complex. Therefore, it has been desired to develop a reaction method which can avoid the generation of compounds whose lactone ring is opened.
SUMMARY OF THE INVENTION
The present invention is to provide a method for efficiently producing drug complexes which are capable of site-selectively delivering an active ingredient such as antitumor agents or anti-inflammatory agents to tumorous sites or the like. More specifically, the present invention is to provides a method capable of producing the drug complexes in a large scale and at low cost by efficiently reacting a polysaccharide derivative having carboxyl groups with a drug compound such as antitumor agents or with a spacer comprising an oligopeptide or the like that is bound to a drug compound.
The present inventors conducted intensive researches, and a result, they found that, when a polysaccharide derivative having carboxyl groups is reacted with a drug compound or a spacer bound to a drug compound by using organic amine salt of the polysaccharide derivative instead of the sodium salt used conventionally, the salt of the polysaccharide derivative can be dissolved at a high concentration in an organic solvent substantially free from water so that the reaction of the polysaccharide derivatives with the drug compound or the spacer bound to the drug compound can be performed in extremely high yields, and that by-products or the like can be reduced. The present invention was achieved on the basis of these findings.
The present invention thus provides a method for preparing a drug complex in which a polysaccharide derivative having carboxyl groups and a residue of a drug compound are bound to each other by means of a spacer comprising an amino acid or a spacer comprising peptide-bonded 2 to 8 amino acids, or a drug complex in which a polysaccharide derivative having carboxyl groups and a residue of a drug compound are bound to each other without the spacer, characterized in that an organic amine salt of the polysaccharide derivative having carboxyl groups is reacted with the drug compound or the drug compound bound to the spacer in a non-aqueous system; and a method for preparing the aforementioned drug complex, which comprises the steps of (1) converting an alkali metal salt of the polysaccharide derivative having carboxyl groups into an organic amine salt thereof, and (2) reacting the organic amine salt with the drug compound or the drug compound bound to the spacer in a non-aqueous system.
According to preferred embodiments of the present invention, there are provided the above method whe

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