Method for stabilizing duocarmycin derivatives

Details Method for stabilizing duocarmycin derivatives Method for stabilizing duocarmycin derivatives

1996-10-30

1997-12-30

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544373, A61K 31495, C07D24104

Patent

active

057030804

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP/95/00962 filed May 19, 1995.


TECHNICAL FIELD

The present invention relates to a method for the stabilization of duocarmycin derivatives and to preparations containing such stabilized derivatives.


BACKGROUND ART

Duocarmycin derivatives such as Compound A represented by the formula shown below are known to have anti-tumor activity (see U.S. Pat. No. 5,070,092). In addition, Compound A is known to be stabilized in its hydrobromide form (see European Patent No. A.degree. 537575). ##STR2##
However, duocarmycin derivatives including Compound A in its hydrobromide form easily decompose in an aqueous solution. Thus, the instability of these compounds is a major problem in medications intended for long-term storage. Accordingly, a need exists for stable pharmaceutical preparations containing duocarmycin derivatives, which can be stored for a long period of time.


DISCLOSURE OF THE INVENTION

The present invention provides a method for stabilizing duocarmycin derivatives represented by general formula (I): ##STR3## wherein R represents a lower alkyl group, an allyl group or a benzyl group, and X represents a chlorine atom or a bromine atom, which method is characterized in that at least one member selected from the group consisting of a saccharide, an electrolyte, a water-soluble polymer, a polyhydric alcohol and a surfactant is present in a solution containing said duocarmycin derivatives. Preferably, in the method for the stabilization, a solution containing said duocarmycin derivative represented by formula (I) and a saccharide is freeze-dried. More preferably, a solution further containing at least one member selected from the group consisting of an electrolyte, a water-soluble polymer, a polyhydric alcohol and a surfactant is freeze-dried. The present invention provides freeze-dried pharmaceutical preparations containing duocarmycin derivatives, which have been stabilized by the above-mentioned method.
In the definition of formula (I), the lower alkyl group means a straight chain or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group.
Duocarmycin derivatives represented by formula (I) can be produced by the method described in U.S. Pat. No. 5,070,092.
Specific examples of duocarmycin derivatives for use in the present invention are shown in Table 1.


TABLE 1 __________________________________________________________________________ ##STR4## Compound No. X IR (KBr), .nu. (cm.sup.-1) __________________________________________________________________________ 1 (Compound A) Br 3475, 3232, 2944, 1698, 1491, 1410, 1313, 1217, 1110 1 (Compound A)* Br 1717, 1692, 1608, 1525, 1490, 1409, 1310, 1218, 1167, 1108 2 Cl 2940, 1698, 1637, 1491, 1410, 1314, 1218, 1154, __________________________________________________________________________ 1109 *Hydrobromide monohydrate
In accordance with the present invention, a duocarmycin derivative represented by formula (I) and at least one member selected from the group consisting of a saccharide, an electrolyte, a water-soluble polymer, a polyhydric alcohol and a surfactant are dissolved in a solution, preferably an acidic solution, more preferably an acidic solution that has been adjusted to pH 5 or less. The resulting solution is filtered through a membrane filter under germ-free conditions and freeze-dried.
As the saccharide, lactose, sucrose, raffinose, dextran, etc. may be used. Preferred is lactose. The concentration of the saccharide in the solution is from 0.005 to 1000 mg/ml, preferably from 1 to 500 mg/ml. Any electrolyte which is pharmaceutically acceptable and which can increase the ionic strength of the solution can be employed. For instance, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, carbonic acid, silicic acid, phosphoric acid, and boric acid; organic acids such as citric acid, and acetic ac

REFERENCES:
patent: 5070092 (1991-12-01), Kanda et al.
patent: 5326753 (1994-07-01), Ohtsuki et al.

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