JPH0480885B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an anticancer agent containing bleomycin or adriamycin. Bleomycin (sometimes abbreviated as "BLM") is known to be highly effective against squamous cell carcinoma and malignant lymphoma. In addition, there is less bone marrow damage associated with many anticancer drugs,
It is unique among anticancer drugs. However, one of the side effects is pulmonary fibrosis, which is an irreversible change and is considered extremely serious. Additionally, adriamycin (sometimes abbreviated as "ADM") is characterized by its broad anticancer spectrum, and its antitumor effects have been established for breast cancer, bladder cancer, lung cancer, testicular tumors, malignant lymphoma, and acute leukemia. . However, in addition to bone marrow suppression and gastrointestinal disorders as side effects of conventional cancer drugs,
Cardiomyopathy, which is cardiotoxicity caused by ADM, has become a problem as a side effect. Therefore, to reduce the side effects of these bleomycin and adriamycin, other less toxic compounds such as coenzymes are also used.
It is being considered for use in conjunction with Q ₁₀ . The present inventors have conducted extensive research with the aim of further enhancing the efficacy of currently commercially available bleomycin or adriamycin through pharmaceutical innovation, and have discovered that it is sufficient to combine it with a polyisoprenyl compound. completed. That is, examples of the polyisoprenyl compound used in the present invention include compounds represented by the following formula. Pharmaceutically acceptable salts such as acid addition salts of the polyisoprenyl compounds can also be used. The mixing ratio of bleomycin or adriamycin and the polyisoprenyl compound is, for example, for adults, the dosage of the polyisoprenyl compound is 10 mg to 2 g/day for oral administration, and for injections, The dosage may be adjusted to be in the range of 4 mg to 1 g/day. Next, specific formulation examples of the present invention will be given, but the present invention is not limited to the following formulation examples. When the active ingredient of the present invention is orally administered, it may be administered in the form of tablets, granules, or powders, and in particular, the granules and powders can be made into unit dosage forms in the form of capsules, if necessary. These solid preparations for oral administration include commonly used excipients such as silicic anhydride, metasilicic acid, magnesium aluminate, synthetic aluminum silicate, lactose, sugar, corn starch, microcrystalline cellulose, hydroxypropyl starch, or glycine, and a binder. For example gum arabic, gelatin, tragacanth, hydroxypropylcellulose or polyvinylpyrrolidone, lubricants such as magnesium stearate, talc or silica, disintegrants such as potato starch, calcium carboxymethyl cellulose or lubricants such as polyethylene glycol, sorbitan monooleate, polyoxyethylene It may also contain hydrogenated castor oil, sodium lauryl sulfate, etc. The tablets may be coated according to conventional methods. Oral liquid preparations are aqueous or oily emulsion solutions,
It may be made into a syrup or the like, or it may be a dry product which can be redissolved in a suitable vehicle before use. Such liquid preparations may contain commonly used additives such as emulsifying aids such as sorbitol syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, etc., and emulsifying agents such as lecithin sorbitan monooleate, polyoxyethylene hydrogenated castor oil, non-aqueous vehicles such as Fractionated coconut oil, almond oil, peanut oil, preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate or sorbic acid may be added. Furthermore, these preparations for oral administration may contain preservatives, stabilizers, etc., if necessary. Next, when this compound is used as an injection, it may be in the form of an oil solution, emulsion, or aqueous solution.
These solvents may contain commonly used emulsifiers, stabilizers, etc. Depending on the method of administration, these compositions can contain 1% or more of the active ingredient combination, preferably 5 to 50%. The acute toxicity of the active ingredient of the present invention is shown in mice (ddY,
LD ₅₀ values when administered intravenously and intraperitoneally to males) [J.Pharmacol.Exp.Ther., Vol. 96, No. 99
- p. 113 (1949)].

[Table] Caprenylamine hydrochloride
Decaprenylamine hydrochloride 38.5 1294

[Table] In order to confirm the synergistic effect of the anticancer agent of the present invention, 300 Chinese hamster V79 cells were cultured in Eagle's medium for 18 hours, and then bleomycin or adriamycin alone or in combination with a polyisoprenyl compound was used. Cultured for another 7 days,
Calculate the number of cell colonies formed. From that number, calculate the _D10 value (concentration of the compound that suppresses cell colony by 90%), and check the combined effect using the formula below. In addition, in the investigation of the effect of combined use on cell colony formation using Chinese hamster V79 cells, the polyisoprenyl compound was dissolved in ethyl alcohol and added to the culture medium. D ₁₀ (bleomycin or adriamycin) / D ₁₀ (bleomycin or adriamycin +
Polyisoprenyl compound) In addition, 1 × 10 ⁶ Sarcoma180 tumor cells were intraperitoneally implanted into two groups of ICR male mice weighing approximately 20 g, and then bleomycin or adriamycin was intraperitoneally administered to the first group of mice every day for 10 days. The other group of mice was intraperitoneally administered with bleomycin or adriamycin for 10 consecutive days, and a polyisoprenyl compound was administered five times at one-day intervals starting the day after transplantation. The ratio of the survival rate (T/C) of the latter combined administration group to the survival rate (T/C) of the former single administration group is shown in Table 3. The polyisoprenyl compound was prepared as a suspension with Tween 80, and bleomycin or adriamycin was administered as an aqueous solution. The dosage was 0.2 μg/mouse/day for polyisoprenyl compound, 0.5 μg/mouse/day for bleomycin, and 0.5 μg/mouse/day for adriamycin.
2.0 μg/mouse/day. Next, the test results are shown in Tables 1 to 3.

【table】

【table】

【table】

【table】

[Table] Tables 1 and 2 show D ₁₀ values when polyisoprenyl compounds and anticancer drugs are used alone. On the other hand, as shown in Table 3, a remarkable synergistic effect was observed when a polyisoprenyl compound was used in combination with adriamycin or bleomycin. In addition, in animal experiments using Sarcoma180 tumor cells, the combined use of decaprenylamine or N-para-methylbenzyldecaprenylamine and bleomycin increased the survival rate by approximately 2 times compared to using either alone.
It can extend your lifespan by double. The dose of the polyisoprenyl compound administered to the animals was 0.2 μg/mouse, which was an extremely low dose that showed almost no toxicity. Formulation Example 1 Hard capsule for oral use Decaprenyl methyl ether 25g, bleomycin 5g and polyoxyethylene castor oil 7.5g
g in methanol and then mixed with 25 g of silicic anhydride. After evaporating the methanol, add 5 g of carboxymethyl cellulose calcium, 5 g of corn starch, and hydroxypropyl cellulose.
Mix 7.5g and 20g of microcrystalline cellulose,
Add ml of water, mix and granulate. this
The pellets were granulated using a No. 24 mesh (BS) granulator equipped with a screen (Eck pelleter, manufactured by Fuji Paudal Co., Ltd.). The granules are dried to a moisture content of less than 5% and No.
It was processed through a 16 mesh (BS) sieve. Next, the particles are packed in a capsule filling machine to produce 200 mg per capsule.
was filled. Formulation example 2 Soft capsule for oral use Decaprenic acid 30g, bleomycin 7.5g and polyethylene glycol (Macrogol 400)
Mix 130g to make a homogeneous solution. Separately 93g gelatin, 19g glycerin, 10g D-sorbitol
g, ethyl paraoxybenzoate 0.4g, propyl paraoxybenzoate 0.2g and titanium oxide 0.4g
A gelatin solution having the composition was prepared, and this was used as a capsule coating agent to produce soft capsules containing 190 mg of content by manual plate punching. Formulation Example 3 Oral Soft Capsules 40 g of ethyl decaprenoate, 4 g of adriamycin, and 120 g of polyethylene glycol (Macrogol 400) are mixed to form a uniform solution. Separately, prepare a gelatin solution consisting of 90 g of gelatin, 16 g of glycerin, 8 g of D-sorbitol, 0.35 g of ethyl paraoxybenzoate, 0.2 g of propyl paraoxybenzoate, and 0.3 g of titanium oxide,
This was used as a capsule coating agent to produce soft capsules containing 180 mg of content by manual plate punching. Formulation Example 4 Injection Mix 5 g of decaprenylamine hydrochloride, 5 g of pleomycin, an appropriate amount of peanut oil, and 1 g of benzyl alcohol, and add peanut oil to the total amount.
100c.c. Dispense 1 c.c. of this solution into ampoules using aseptic techniques and melt and seal. Formulation Example 5 Injection 5 g of N-paramethylbenzyldecaprenylamine hydrochloride, 5 g of adriamycin, an appropriate amount of peanut oil and 1 g of benzyl alcohol are mixed, and the total amount is made up to 100 c.c. using peanut oil. Dispense 1 c.c. of this solution into ampoules using aseptic techniques and melt and seal. Formulation Example 6 Injection Mix 4 g of solanesylamine hydrochloride, 4 g of bleomycin, 5.0 g of Nitsukol HCO60 [hydrogenated castor oil polyoxyethylene (60 mol) ether], 20 g of propylene glycol, 10 g of glycerol, and 5.0 g of ethyl alcohol, and add distilled water to the mixture. Add 100ml and stir. Dispense this solution into 2.0 ml ampoules using aseptic technique and melt and seal. Formulation Example 7 Injection Mix 5 g of α-saturated solanesylamine hydrochloride, 5 g of Adriamycin, 5.0 g of Nitukol HCO, 20 g of propylene glycol, 10 g of glycerol, and 5.0 g of ethyl alcohol, and add 100 g of distilled water to this mixture.
ml and stir. Dispense this solution into 2.0 ml ampoules using aseptic technique and melt and seal.

Claims (1)

[Claims] 1. Bleomycin or adriamycin;
An anticancer agent characterized by containing a polyisoprenyl compound as an active ingredient. 2 The polyisoprenyl compound has the following structural formula The anticancer agent according to claim 1, which is selected from compounds and pharmaceutically acceptable salts thereof.