Chemistry of inorganic compounds – Nitrogen or compound thereof – Hydrogen containing
Reexamination Certificate
1999-06-10
2001-06-26
Langel, Wayne (Department: 1754)
Chemistry of inorganic compounds
Nitrogen or compound thereof
Hydrogen containing
C424S649000
Reexamination Certificate
active
06251355
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a fine cisplatin powder which can be used in cancer therapy particularly by hepatic intra-arterial injection etc.
BACKGROUND ART
Cisplatin whose antitumor effect was reported in 1969 by Rosenberg (Nature, 222, 385 (1969)) is a typical drug of an antitumor platinum complex developed as an anticancer agent and has an effect on a wide range of cancers such as bladder cancer, testicular tumor, esophageal carcinoma, ovarian cancer, lung cancer etc. Cisplatin is a yellow, odorless crystalline powder and is manufactured into a pharmaceutical preparation in the dosage form of solution mainly as an injection for intravenous infusion.
As cancer therapy is developed, the method of using an anticancer agent becomes diversified. It is said that hepatic carcinoma is a hardly remediable cancer, and that hepatic arterial embolization therapy, chemotherapy such as hepatic intra-arterial injection chemotherapy, general administration chemotherapy etc. plays a certain role for multidisciplinary treatment. In particular, hepatic intra-arterial injection chemotherapy which permits a drug to reach cancer tissues at high concentration is effective. Cisplatin is recognized as a highly effective anticancer agent, and is also expected to use for treatment of hepatic carcinoma. However, the solubility of cisplatin in water is as extremely low as about 1 mg/ml at room temperature, so a commercial injection thereof (0.5 mg/ml) is a dilute solution, thus disadvantageously requiring a too much volume for hepatic intra-arterial injection. Hence, a highly convenient powdered preparation capable of forming a solution at high concentration and usable in hepatic intra-arterial injection chemotherapy has been desired.
Methods for obtaining a fine cisplatin powder are known as disclosed in Japanese Patent Publication Nos. 10930/1987 and 13174/1991 in which cisplatin is dissolved in a tertiary amide or dialkylsulfoxide in which cisplatin can be dissolved, and this solution is mixed with a solvent such as water, alcohol etc. in which cisplatin is insoluble or sparingly soluble, to precipitate fine crystalline cisplatin which is then recovered by filtration.
In the fine cisplatin powder obtained by these methods, however, there remains a tertiary amide etc. used as the solvent at levels as relatively high as 70 ppm or more even in experimental scale, and the residual solvent at levels of 100 ppm or more is inevitable in industrial scale. Accordingly, the contamination of a product with the solvent is inevitable if these methods are used as such. In intra-arterial injection therapy, because a solution containing a medicine at high concentration is directly introduced into a topical affected part, so the effect of impurities should be taken into consideration more than in a conventional pharmaceutical preparation for intravenous injection. The adverse effect of the tertiary amide etc. on the human body is conceivable, and it is desired to remove these impurities at the maximum degree.
Further, the powder according to the conventional methods is a massive material after dried, and the step of disintegrating the massive material by grinding or screening is necessary. Because the bulk material contains 80% or more fine powder with a size of less than 5 &mgr;m, substantially 90% or more, the fine powder will be scattered in the handling thereof in the step of disintegrating the bulk material and in the later step of pharmaceutical manufacturing, so the pollution of the working environment is a problem. In particular, mutagenic anticancer agents such as cisplatin should carefully be handled, and from the problem of powder scattering, the operation in a dry process or in an open system should be avoided. Further, the conventional fine powder is highly agglomerable due to its small size, and thus powder particles are aggregated to form a powder with low fluidity and easily adhere to instruments etc., and the powder is not removed even by movement, thus making its handling difficult in the operation of pharmaceutical manufacturing. These secondarily agglomerated particles have been agglomerated via relatively strong bonding and are hardly dispersible in preparing a solution, thus preventing rapid dissolution.
As another method of pulverization, there is also known a method in which a cisplatin injection is lyophilized to give a powdered medicine. This method is easy in the sterilization process, and the resulting cisplatin powder has the advantage of rapid dissolution. However, a solution of cisplatin in the production step is a dilute solution as described in Japanese Patent Publication No. 13174/1991. Hence, to obtain a cisplatin powder in an amount suitable for use, a large amount of water should be removed, so the process is costly, time-consuming and thus impractical. Further, hydrogen chloride removed simultaneously during lyophilization causes the problem of corrosion of the system of the lyophilization unit. Further, from the problem of stability of the lyophilized product, its glass vessel should be stored at a refrigeration temperature (N.C.I. pharmaceutical data sheet).
Accordingly, the object of the present invention is to produce a bulk of fine cisplatin powder having a low content of a solvent for crystallization, not forming secondarily agglomerated particles preventing dissolution and the operation of pharmaceutical manufacturing, and having higher fluidity as a powder, as well as to provide a pharmaceutical preparation thereof excellent in stability.
DISCLOSURE OF THE INVENTION
The present inventors found that a fine cisplatin powder satisfying said object having high fluidity and hardly causing adhesion and agglomeration can be obtained by dissolving a raw medicine of cisplatin in a solvent such as dimethylformamide etc. containing hydrogen chloride and water, and according to the method of the invention, by precipitating cisplatin crystals. Further, the present inventors found that the resulting fine cisplatin powder is stirred for a predetermined time in a solvent such as dilute hydrochloric acid in which cisplatin is sparingly soluble and the residual solvent is eluted whereby the solvent such as DMF can be sufficiently removed, and also that even after this step of removing the residual solvent, the properties of the fine cisplatin powder obtained in the present invention are maintained so that it remains highly fluidic and hardly causes adhesion and agglomeration, and the present invention is thereby completed.
Further, the amount of the residual solvent in the fine cisplatin powder according to the present invention is considerably lower than those obtained by the prior art methods, and if DMF was used, its content was 60 ppm or less in analysis by gas chromatography. Further, the fine cisplatin powder of the invention is easily dispersed in water or physiological saline to be rapidly dissolved therein by slight shaking at 2 to 3 r.p.s. at room temperature. The raw medicine obtained after drying is highly fluidic powder which does not form secondarily agglomerated particles, thus eliminating procedures such as grinding, and there is no problem with powder scattering and adhesion, so the powder can be easily handled in the operation of pharmaceutical manufacturing. Further, aseptic techniques can be used for production of a sterile raw medicine, and it can be transferred as such to the operation of pharmaceutical manufacturing, thus enabling actual industrial application. The pharmaceutical preparation produced aseptically in this manner can be used as an anticancer agent for intra-arterial injection therapy.
Further, the pharmaceutical preparation of the fine powder of the invention possesses excellent stability and is suspended in distilled water for injection, physiological saline etc. so that it can be used as a pharmaceutical preparation for hepatic arterial embolization therapy.
That is, the present invention relates to the following 1 to 6:
1. A fine cisplatin powder consisting substantially of a fine cisplatin powder passing through a 40-mesh scre
Ishikawa Keizou
Iwata Kenji
Kogawa Osamu
Murata Toshitaka
Langel Wayne
Nields & Lemack
Nippon Kayaku Kabushiki Kaisha
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