Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-04-13
2003-11-25
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S034000
Reexamination Certificate
active
06653455
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a crystallizing method of doxorubicin hydrochloride and a crystalline aggregate of doxorubicin hydrochloride having a fixed characteristic.
BACKGROUND
Doxorubicin (or called adriamycin) is an antibiotic represented by the following formula:
and produced from
streptomyces peuceticus var caestius
. Also, doxorubicin is provided as well by chemical conversion of daunorbicin (or called daunomycin). This hydrochloride (that is, doxorubicin hydrochloride) has a broad anti-cancer spectrum and has an excellent efficacy in chemical therapy of malignant lymphoma, pulmonary cancer, digestive cancer and mammary cancer. As a matter of fact, a liquid preparation of doxorubicin hydrochloride (a preparation for injection and a solution of saline) is widely used for clinical therapy of the various cancers described above.
Powdery or crystalline doxorubicin hydrochloride is provided as a raw material for such liquid preparations, but those which can be available at present are not necessarily satisfactory in terms of solubility in water. In particular, when a liquid preparation is prepared at a therapy site immediately before use, solid doxorubicin hydrochloride which is more quickly dissolved in water shall be desired to be provided.
On the other hand, powdery or crystalline doxorubicin hydrochloride is obtained usually by precipitation or crystallization from an organic solvent system or a water-based solvent system containing an organic solvent, but it is difficult to reduce or remove the residual solvent or the intended crystals have a low yield in many cases.
Solid doxorubicin hydrochloride which is commercially available for medical use at present contains less amount of residual solvents than allowed for a use purpose thereof, but some of them requires about 10 minutes until they are dissolved by stirring treatment in water at, an ambient temperature (25° C.). In addition thereto, the small undissolved remainder is observed in a certain case even after a large part thereof is dissolved in water. A standard product of USP (available from Japan Koteisho Association; 2-12-5, Shibuya, Shibuya-ku, Tokyo) is especially excellent in a solubility in water. In this case, however, the small undissolved remainder is observed so often after dissolving treatment.
DISCLOSURE OF THE INVENTION
Accordingly, an object of the present invention is to provide a crystallizing method which is excellent in reducing a residual solvent as well as raising the yield in crystallization and can produce a finished doxorubicin hydrochloride product having a high solubility in water, and a doxorubicin hydrochloride crystalline aggregate having such characteristic as described above.
A crystallizing method of doxorubicin hydrochloride has been investigated by the present inventors, and it has been found by them that the object described above can be achieved by carrying out crystallization in a specific solvent system at some fixed temperature or higher, which is different from a usual common sense (refer to, for example, Japanese Patent Application Laid-Open No. 118797/1984 or U.S. Pat. No. 4,861,870).
Accordingly, the present invention relates to a crystallizing method of doxorubicin hydrochloride from a doxorubicin hydrochloride-containing solution, wherein the doxorubicin hydrochloride-containing solution is a water-based solution containing doxorubicin and a poor solvent to doxorubicin, and the crystallization is carried out at a temperature of 40° C. or higher.
Further, the present invention relates to a crystalline aggregate of doxorubicin hydrochloride having characteristics that:
(A) moisture content accounts for 2% by weight or less and the other total residual solvents account for 1.5% or less,
(B) the average particle diameter is 15 &mgr;m or more in terms of a circle-corresponding diameter determined by image projection, and
(C) the aggregate has such a solubility that it is substantially completely dissolved in water in about 2 minutes or shorter under a stirring condition at 25° C.
BEST MODE FOR CARRYING OUT THE INVENTION
Doxorubicin hydrochloride (hereinafter referred to as DOX.HCl) which can be used for the crystallizing method according to the present invention may be any one regardless of a production process and a refining step thereof as long as it has a fixed or higher purity. That is, the crystallizing method of the present invention can be used in a preliminary refining step for obtaining roughly refined DOX.HCl and a final refining step for obtaining a finished product. However, the crystallizing method according to the present invention is used suitably in a final refining step of DOX.HCl considering actions and effects such as easiness of a reduction in the residual solvent and obtainability of the crystals having a high solubility in water. Accordingly, the present invention shall be explained below taking primarily use in the final refining step into consideration, but it should be understood that the present invention shall not be restricted thereto.
A DOX.HCl-containing solution used for the crystallizing method according to the present invention is a water-based solution containing doxorubicin (hereinafter referred to as DOX) and a poor solvent to DOX.HCl. In preparing such water-based solution, DOX.HCl is first dissolved in water or DOX is dissolved in a diluted hydrochloric acid aqueous solution (for example, 0.001N HCl), and in some cases, water-miscible organic solvents including a poor solvent which shall be described later may be contained in the aqueous solution described above. Next, the DOX.HCl-containing aqueous solution (hereinafter referred to as a dissolved solution) thus prepared is usually mixed with a poor solvent to DOX.HCl. This mixing may be carried out either by mixing the DOX.HCl-containing aqueous solution with the poor solvent in one lot or adding the former little by little to the latter or in contrast with this, adding the latter little by little to the former.
The poor solvent may be any ones as long as they meet the, object of the present invention, and capable of being usually given are methanol, ethanol isopropanol, acetonitrile, acetone and mixed solvents of two or more kinds thereof. Among them, ethanol, acetone and a mixed solvent of ethanol and acetone are preferred, and out of them, ethanol and a mixed solvent of ethanol and acetone are particularly preferred. Preferred is the mixed solvent of ethanol and acetone in which they are mixed in a proportion ethanol to acetone of 4:1 to 1:1, particularly 2.5:1.
On the other hand, the organic solvent contained in the dissolved solution described above may be any of the poor solvents described above. However, water (acid water) mixed with ethanol is preferred, and in this case, water mixed with ethanol in a proportion water to ethanol of 7.5:5 to 7.5:15 is particularly preferred.
Among such solvent systems, particularly preferred is a combination of the solvent systems in which the solvent contained in the dissolved solution described above comprises water and ethanol in the preferred proportion and the poor solvent comprises ethanol and acetone in the preferred proportion.
Such combination of the dissolved solution and the poor solvent can be varied according to the content of DOX.HCl. In general, the dissolved solution to the poor solvent stays in a proportion of 1:2 to 1:10, preferably about 1:5.
The DOX.HCl-containing solution comprising such solvent system may stay in a state in which DOX.HCl is dissolved before the crystallization, and a concentration of DOX.HCl shall not be restricted. In general, however, a concentration of 8 to 4.5 (weight/volume) % up to 10 (weight/volume) % of DOX.HCl is preferred.
According to the present invention, a temperature for carrying out the crystallization has to be set to 40° C. or higher. When the DOX.HCl-containing solution is prepared at 40° C. or higher, this temperature may be maintained as it is or reduced a little. Usually, the DOX.HCl-containing solution is prepared at 5 to 35° C., and the temperature is elevated fr
Johdo Osamu
Nakao Takuma
Yoshioka Takeo
Mercian Corporation
Owens. Jr. Howard V.
Wenderoth, Lind & Ponack, Ltd.
Wilson James O.
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