JPH0623095B2 - Emulsion formulation containing anti-cancer agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to emulsion formulations containing substances with anti-cancer agents.

Many anti-cancer agents are soluble in water and therefore used as injections, but when administered intravenously, they are rapidly excreted in urine and bound to serum proteins with a rapid rise in blood concentration. , Or due to nonspecific systemic distribution, there is a rapid decrease in effective blood levels. Therefore, in order to increase the drug concentration effective for cancer cells, the clinical dose is defined as an amount larger than the effective dose converted from the effective concentration in vitro.
Therefore, side effects of anticancer drugs are likely to occur clinically.
On the other hand, there are cases where the mechanism of action of the anticancer drug causes side effects. In order to reduce the side effects of anticancer agents and to improve their clinical distribution and specific distribution to cancer cells, pharmaceutical studies are required for their more effective clinical application. Emulsion preparations are considered as preparations that change the blood concentration and distribution in the body, but most of the anticancer agents are water-soluble and consist of an aqueous phase (internal water phase) encased in oil when the water-soluble substance is made into an emulsion. W / O / W type emulsions are considered as improved formulations. The properties that a W / O / W emulsion formulation should have are:
It is necessary to improve the uptake rate of cancer-producing agents, stability, and formulation materials with low toxicity.

For example, adriamycin is an excellent antitumor agent and is effective against malignant lymphoma, malignant solid tumor and leukemia, but has strong side effects such as hair loss, bone marrow suppression, myocardial injury, etc., and clinically it is unavoidable to discontinue. According to a general W / O / W type emulsion production method (Oil Chemistry Vol. 26, No. 10, P655, 1977), adriamycin solution was used liquid paraffin as oily substance, span 80 as primary emulsifier, and twin 20 as secondary emulsifier. Created. The uptake rate of adriamycin into this formulation was 70%, and after 4 days 3
It had dropped to 2%. In addition, in terms of reducing side effects, the survival rate of mice was slightly improved (Proceedings of the 102nd Annual Meeting of the Pharmaceutical Society of Japan, P70
4,1982), but due to its stability and toxicity such as hemolytic properties of these materials, it cannot be applied in clinical practice.

The present inventors have studied a material having a high uptake rate, stable, and less toxic, and as a result, in the method for producing the W / O / W type emulsion preparation, as an oily substance, a middle to higher fatty acid ester, a middle to higher triglyceride And at least one selected from vegetable oils, at least one selected from tocopherols, a carcinostatic agent and water mixture, at least one selected from polyoxyethylene hydrogenated castor oil derivatives, soybean phospholipids and egg yolk phospholipids. At least one selected from the group consisting of polyoxyethylene hydrogenated castor oil derivatives, soybean phospholipids, egg yolk phospholipids, and pluronic nonionic surfactants by first emulsifying using seeds and further adding an isotonicity agent and water. When one type is used for secondary emulsification, the anticancer agent uptake rate is high, the stability is good, and the remarkable side effect reducing effect is brought about. Been found that the formulation is obtained. In addition, the selected material has already been used as an injectable preparation material, and the present invention could be completed without toxicity such as hemolysis.

That is, the present invention, as an anticancer agent, including one or more selected from adriamycin, daunomycin, mitomycin C, bleomycin and 5-fluorouracil, as the oily substance, soybean oil, sesame oil, vegetable oils such as safflower oil and cottonseed oil, It contains at least one selected from middle to higher fatty acid esters or middle to higher triglycerides, contains at least one selected from α, β, γ and δ-tocopherols as tocopherols, and uses polyoxyethylene cured castor as an emulsifier. An emulsion preparation containing a carcinostatic agent, which comprises at least one selected from oil derivatives, soybean phospholipids, egg yolk phospholipids and pluronic nonionic surfactants, and sugar alcohols as isotonic agents, Contains monosaccharides, disaccharides, etc. .

Example 1 2 mg of adriamycin are dissolved in 0.8 m of water. Separately, as an oily substance, 400 mg of soybean oil and α-tocopherol 2
Soybean phospholipid (120 mg) was dissolved in 00 mg, and the above adriamycin aqueous solution was added dropwise little by little, and the mixture was emulsified with a Polytron homogenizer for 5 minutes to obtain a W / O emulsion. By emulsifying the above emulsion with a mixed solution of 1% Pluronic F68 and 2.5% glycerin for 5 minutes with the above homogenizer, adriamycin-containing W / O /
W type emulsion preparation 5m was obtained. The adriamycin uptake rate of this product was 94.2%.

Example 2 2 mg of adriamycin are dissolved in 0.8.m of water. Separately, 400 mg of soybean oil and α-tocopherol 4 as an oily substance
Egg yolk phospholipid 120 mg was dissolved in 00 mg, and the above adriamycin aqueous solution was added dropwise little by little, and the mixture was emulsified with a Polytron homogenizer for 5 minutes to obtain a W / O emulsion. By emulsifying the above emulsion with a mixed solution of 1% Pluronic F68 and 2.5% glycerin for 5 minutes with the above homogenizer, adriamycin-containing W / O /
W type emulsion preparation 5m was obtained. The adriamycin uptake rate of this product was 92.4%.

Example 3 2 mg of mitomycin C are dissolved in 0.8 m of water. Separately, as an oily substance, 400 mg of cottonseed oil and α-tocopherol 2
120 mg of soybean phospholipid was dissolved in 00 mg, and the above mitomycin C aqueous solution was added dropwise little by little to emulsify for 5 minutes with a Polytron homogenizer to obtain a W / O emulsion. The above emulsion was emulsified with a mixed solution of 1% soybean phospholipid and 5% glucose for 5 minutes by the above homogenizer to obtain 5m of mitomycin C-containing W / O / W emulsion preparation. The mitomycin C uptake rate of this product was 86.2%.

Example 4 10 mg of adriamycin are dissolved in 1 m of water. The same operation as in Example 1 was carried out to obtain 10 m of the adriamycin-containing W / O / W emulsion preparation. The uptake rate of adriamycin was 93.2%.

Pharmacological test Adriamycin (1.0 mg / m) containing α-tocopherol (5.0 mg / m) prepared in the same manner as in Example 1 above.
m) emulsion preparation (No. 1), α-tocopherol-free adriamycin (1.0 mg / m) emulsion preparation (No. 2), and adriamycin (1.0 mg / m) aqueous solution (No. 3) as a control, respectively. Regarding the survival rate for 28 days against the lethality rate due to the side effect of adriamycin in mice, the adriamycin emulsion preparation containing α-tocopherol shows a markedly good result. (Table 1) Table 1 Drugs Survival rate for 28 days (%) No.1 α-tocopherol-containing adriamycin emulsion preparation 85% No.2 Adriamycin emulsion preparation 45% No.3 Adriamycin aqueous solution 5% Emulsion according to the present invention The method of administration of the preparation is mainly intended for intravascular administration, but can also be applied to chemotherapy such as oral administration or intraperitoneal administration.

 ─────────────────────────────────────────────────── ─── Continuation of the front page Examiner Misao Takanashi (56) Reference JP-A-58-124714 (JP, A)

Claims (1)

[Claims] 1. At least one selected from the group consisting of intermediate to higher fatty acid esters, intermediate to higher triglycerides and vegetable oils, at least one tocopherol,
A mixture of at least one selected from polyoxyethylene hydrogenated castor oil derivative, soybean phospholipid and egg yolk phospholipid, a carcinostatic agent and water is first emulsified, and further polyoxyethylene hydrogenated castor oil derivative, soybean phospholipid, egg yolk Secondary emulsified by adding at least one selected from the group consisting of phospholipids and pluronic nonionic surfactants, at least one selected from the group consisting of sugar alcohols, monosaccharides and disaccharides, and water Emulsion formulation containing W / O / W type anticancer agent.