Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
1998-10-14
2002-10-01
Webman, Edward J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C424S078300, C514S449000, C514S059000, C514S017400, C514S018700, C514S002600, C514S169000
Reexamination Certificate
active
06458347
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a drug complex of a drug having a hydroxyl group, wherein the drug complex is capable of controlling the rate of the release of the drug therefrom in blood when administered to a living body. The present invention also relates to a novel polysaccharide-taxane complex which is capable of not only obviating the defect (poor water-solubility) of a drug, for example, a taxane compound which is useful as an antitumor drug, but also delaying the disappearance of the taxane compound from blood and also enhancing the transferability of the taxane compound to tumor tissues.
2. Prior Art
Paclitaxel (tradename: Taxol; manufactured and sold by Bristol-Myers Squibb, U.S.A.) is a naturally occurring product, which is extracted from the bark of a taxaceous tree,
Taxus brevifolia,
native to Pacific-rim countries, and has been confirmed to have excellent antitumor activities by assays using animal models. In recent studies, it has been reported that the antitumor activities of paclitaxel is due to a specific mechanism involving the induction of abnormal polymerization of tubulin and the inhibition of mitosis. Further, in recent years, promising results have been obtained in the studies with respect to the antitumor activities of paclitaxel against various types of tumors, such as oophoroma, mastocarcinoma, carcinoma of colon and rectum, and lung cancer. A semi-synthesized homologue of paclitaxel, called docetaxel (tradename: Taxotere; manufactured and sold by Rhône-Poulenc Rorer Pharmaceuticals Limited, U.S.A./France), has also been found to have good antitumor activities.
One of the defects of taxane compounds, a representative example of which is paclitaxel, is poor solubility in water. Therefore, paclitaxel needs to be formulated into a pharmaceutical composition by use of a non-aqueous adjuvant for dissolving medicines. One of the dissolving adjuvants, which are currently used, is Cremophor EL (manufactured and sold by Sigma, U.S.A.). However, Cremophor EL itself may cause undesirable adverse side effects, such as anaphylaxis in human. For that reason, a lot of researches have been made with respect to water-soluble derivatives of paclitaxel. For example, the technique of using phosphonooxymethyl ether derivatives of taxane compounds [Unexamined Japanese Patent Application Laid-Open Specification (Japanese Kokai) No. 7-149779] and the technique of using carbonate type and ester type pro-drugs of taxane compounds having a leaving moiety which can be removed under basic conditions [Nature, 365, 464-466 (1993)] are known. However, satisfactory techniques have not yet been developed with respect to prodrugs of taxane compounds.
In the techniques to improve various defects of a drug by chemically modifying the molecular structure of the drug, the effectiveness of the prodrug comprising a drug having bonded thereto a leaving moiety depends heavily on the selection of the mode of a bonding between the drug and the leaving moiety [see “Doraggu Deribarii Sisutemu” (Drug Delivery System), edited by Hitoshi Sezaki and published by Nankodo, Japan]. In general, when it is intended to restore a drug from a prodrug by utilizing an enzymatic reaction, the types of enzymes distributed broadly in a living body, such as an esterase, an amidase and a carbamidase, will be determining factors for selecting the appropriate bonding mode. Therefore, when the drug has a hydroxyl group, the bonding mode is frequently selected among a carboxylic ester bond, a phosphoric ester bond and an acyloxymethyl ether bond, and when the drug has a carboxyl group, the bonding mode is frequently selected between an ester and an amide bond.
On the other hand, in general, high molecular weight compounds exhibit various unique properties and functions and, therefore, interact with a living body in manners which are largely different from the manners in which low molecular weight compounds interact with a living body. Therefore, a large number of attempts have been made, in which a drug having a low molecular weight is bonded to a high molecular weight compound as a leaving moiety to thereby produce a prodrug and the prodrug is used so as to control the behavior of the drug in a living body and the interactions between the drug and cells. Also in this case, the selection of the mode of a bonding between the drug and the high molecular weight compound is an important factor of determining the effectiveness of the prodrug. Usually, in a prodrug comprising a drug having bonded thereto a leaving moiety, the functional group of the drug is directly bonded to the functional group of the leaving moiety. It is still rare that a prodrug is constructed such that the drug is bonded to the leaving moiety through a spacer.
With respect to examples of such prodrugs comprising a drug, a spacer and a leaving moiety, although the number of examples thereof is small, there can be mentioned an example in which a carboxymethylated dextran (carboxymethyldextran), which is a high molecular-weight polysaccharide, is used as a carrier. In this example of prodrug, doxorubicin having an amino group in the structure thereof is used as a drug, wherein a carboxymethyl dextran is introduced into the amino group of doxorubicin through the spacer (see, International Application Publication No. WO 94/19376). As mentioned above, doxorubicin has an amino group in the structure thereof. In this technique, a peptide is used as a spacer. Therefore, each of the mode of the bonding formed between the amino group of the spacer and the carboxyl group of the carboxymethyldextran and the mode of the bonding formed between the carboxyl group of the spacer and the amino group of the drug is an amide bond. However, an amide bond is extremely stable in blood and, therefore, the rate of the release of the drug from the drug complex (prodrug) is very low in blood. Further, it is noted that, in this WO publication, there is no description with respect to the release of a drug having a hydroxyl group.
As examples of prodrugs containing a synthetic polymer as a carrier, there can be mentioned prodrugs comprising doxorubicin as a drug, in which a high molecular weight compound (HPMA) (which is a product of copolymerization of a plurality of hydroxypropyl methacrylamide derivatives) is bonded to doxorubicin at the amino group thereof through a peptide as a spacer [see, J. Contr. Rel., 10, 51-63 (1989), J. Contr. Rel., 19, 331-346 (1992), Eur. J. Cancer, 31A (suppl 5), S193 (1995)]. In these examples also, each of the mode of each of the bonding between the drug and the spacer and the mode of the bonding between the spacer and the carrier is an amide bond. Further, as mentioned above, the carrier is a synthetic polymer. Therefore, it is predicted that the carrier would not be degraded (metabolized) at all in a living body. As a result, when a drug complex (prodrug) containing the above-mentioned synthetic polymer as a carrier is administered to a living body, there is a danger of the accumulation of the toxicity and antigenicity of the carrier because the carrier stays as a foreign substance in a living body for a long period of time. Therefore, the molecular weight of the carrier should be controlled to a level such that the carrier is not accumulated in a living body, but can be excreted rapidly.
As another example of a prodrug containing, as a carrier, a synthetic polymer produced in substantially the same manner as mentioned above, there can be mentioned a prodrug comprising paclitaxel (a drug having hydroxyl groups) as a drug, in which a high molecular weight compound (HPMA) (which is a product of copolymerization of a plurality of hydroxypropylmethacrylamide derivatives) is bonded to the paclitaxel at least at one of the hydroxyl groups thereof through a peptide as a spacer (see, U.S. Pat. No. 5,362,831). In this case also, since the carrier is a synthetic polymer, it is predicted that the carrier would not be degraded at all in a living body. As a result
Kajiki Masahiro
Kitaguchi Nobuya
Kuriyama Hiroshi
Sugawara Shuichi
Asahi Kasei Kabushiki Kaisha
Webman Edward J.
Young & Thompson
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