JPS61200913A - Carcinostatic agent - Google Patents

Abstract

PURPOSE:To provide a carcinostatic agent containing adriamycin and a specific compound as active components, having excellent carcino-static activity and exhibiting high drug action against the cancer cell having drug resistance. CONSTITUTION:The objective agent contains adriamycin and N-solanesyl-N,N'- bis(3,4-dimethoxybenzyl)ethylenediamine of formula as active components. Preferable daily dose is about 4mg-2g/kg for the compound of formula or its salt, and is about 10mg-2g/kg by oral administration and about 4mg-1g/kg for parenteral administration. The content of the active drug component depends upon the method of administration, and is >=1wt%, preferably 5-50wt%.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to anticancer agents.

[Problems to be solved by conventional techniques and inventions] Recently, leukemia, malignant phosphorus, ? A variety of anticancer drugs have been developed. However, no drug can completely cure or prevent it.

For example, adriamycin is characterized by its broad anticancer effect9, and is known to have antitumor effects against breast cancer, bladder cancer, lung cancer, canker tumor, malignant lymphoma, and acute leukemia. However, the effectiveness of these drugs is limited, and the problem of drug resistance also arises.

The purpose of the present invention is to enhance the efficacy of adriamycin, particularly against cancer cells that have developed drug resistance, by using a combination agent of adriamycin.

[Rounding method to solve the problem]

The present invention relates to an anticancer agent containing adriamycin and a compound of the formula or a pharmaceutically acceptable salt thereof as active ingredients.

Adriamycin used in the present invention is a conventionally used anticancer drug and has a wide anticancer R spectrum, and is used for the treatment of breast cancer, bladder cancer, lung cancer, testicular abscess, malignant phosphorus/mass, acute leukemia, etc. It is used in

Also, the compound of formula (I) used with adriamycin in the present invention [i.e., N-solanesyl-N,N'-
Bis(3,4-dimethoxybenzyl)ethylenediamine] itself and its pharmaceutically acceptable salts such as hydrochloride, hydrobromide, sulfate, fumarate, citrate, and the like.

The compound of formula (1) itself is a known compound.

In the present invention, adriamycin and a compound of formula (1) or a salt thereof are used in combination; in this case, the daily dose of adriamycin is the usual dose, and the compound of formula (1) or a salt thereof is about 4w9 to 211/Kg. is suitable, and preferably about 1011P to 217147 days for oral administration, and about 4v to 111/1'47 days for parenteral administration.

When the active ingredient of the present invention is orally administered, there are various forms, such as tablets, granules, fine granules, powders, syrups, and elixirs. In particular, granules and powders may be encapsulated in capsules as necessary. It can be made into a unit dosage form.

These medium solid preparations for oral administration contain commonly used excipients such as silicic anhydride, metasilicic acid, magnesium aluminate, synthetic aluminum silicate, lactose, sugar, corn starch,
Fine quality cellulose, hydroxypropyl starch or glycine, binders such as gum arabic, gelatin, tragacanth, hydroxypropyl cellulose, polyvinylpyrrolidone, lubricants such as magnesium stearate, talc or silica, disintegrants such as potato starch, It may also contain carboxymethylcellulose calcium or wetting agents such as polyethylene glycol, sorbitan monooleate, polyoxyethylene hydrogenated castor oil, sodium diuryl sulfate, and the like. Tablets may also be coated using conventional methods.

Solutions for oral administration may be aqueous or oily emulsions, syrups, etc., or they may be dry products that can be redissolved in a suitable vehicle before use. Such liquid preparations contain commonly used additives such as emulsification aids such as sorbitol syrup, methylcellulose, gelatin,
Hydroxyethylcellulose, etc., also emulsifiers such as ebalecitin 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 oral preparations may contain preservatives, if necessary.
It may also contain a stabilizer or the like.

In addition, when the active ingredient of the present invention is made into an injection, an oil solution,
It may be in the form of an emulsion or an aqueous solution, and these liquids may contain commonly used emulsifiers, stabilizers, and the like. These drugs contain only one active ingredient depending on the administration method.
It can be contained in an amount of t% or more, preferably 5 to 50% by weight. Furthermore, the active ingredient of the present invention can be made into a raw material by a conventional method.

The following table shows the acute toxicity of the active ingredients of the present invention in mice (dd
7, male) LD5Q values when K was administered intravenously and intraperitoneally (r J, Pharmacol, Exp.

Ther, J Vol. 96, pp. 99-113 (1949)].

LD50 (qA) Adriamycin 9.8 13.7 Compound of formula (1) 268 350 Examples are shown below.

〔Example〕

Example 1 Hard capsule for oral use Compound 25J9 of formula (1). Adriamycin 59 and polyoxyethylene castor oil Zsl were dissolved in methanol and then silicic anhydride 25.9 was mixed. After evaporating the methanol, further added carboxymethylcellulose calcium 5Ii, corn starch 5I, hydroxypropylcellulose 7,511 and microcrystalline cellulose 20I.
50 yd of water was added, kneaded and granulated. The granules were granulated using a granulator equipped with a T-muku 4 mesh (B, S, λ screen). The granules were dried to a moisture content of less than 5% and processed through an A16 mesh (B, S,) sieve. Then, fill each capsule with 200+19 particles using a capsule filling machine.

Example 2 Soft capsule for oral use Compound 3011 of formula (1) Adriamycin Z5I and polyethylene glycol (Macrogol 400) 11
50 jl were mixed to make a homogeneous solution. Separately gelatin 9
3I, 19I% glycerin, 10g of D-sorbitol, 0.1+ ethyl hydroxybenzoate, 0.2I propyl hydroxybenzoate, and titanium oxide α4J' were prepared. Soft capsules containing 190q of contents were manufactured by a flat plate punching method.

Example 3 Soft capsules for daily use Compound 40I of formula (1), Adriamycin 4II$J
:Hyd(IJ ethylene glycol (macrogol 400)
) 121 were mixed to form a homogeneous solution. Separately gelatin 9
0Ii, glycerin 16N, D-sorbitol 81. A gelatin solution consisting of 35 g of ethyl oxybenzoate, 0.2.9 g of propyl oxybenzoate, and 0.3 y of titanium oxide was prepared, and this was used as a capsule coating agent by manual plate punching. Contents 1801! l
Soft capsules containing i were produced.

Example 4 Injection Hydrochloride of compound of formula (I) 5y, Adriamycin 51
1. An appropriate amount of peanut oil and benzyl alcohol 11 were mixed, and the total amount was adjusted to 1 oocc using peanut oil. This solution was dispensed into ampoules KICc by aseptic operation and melted and sealed.

Example 5 Injection Hydrochloride of compound of formula (1) sfI, Adriamycin 5
11. An appropriate amount of peanut oil and benzyl alcohol 11 were mixed, and further peanut oil was used to make the total amount 100 cc. Dispense 1 cc of this solution into an ampoule using aseptic technique and melt and close.

Example 6 Injection Hydrochloride of compound of formula (1)? Ii, adriamycin 4
II, hydrogenated castor oil polyoxyethylene (60 mol) ether [Niracol HCO60) s, o II,
20 g of propylene glycol, 10.9 g of glycerin, and 1.0 g of ethyl alcohol were mixed, and 100 g of distilled water was added and stirred.

Dispense this solution into ampoules 2.0 and 2.0 by aseptic technique and melt and close.

Example 7 Injection Hydrochloride of compound of formula (I) 5Ii, Adriamycin 5
1. Hydrogenated castor oil polyoxyethylene (607 l)
Ether 5. Ofi, -10 pyrene glycol 20g,
Glycerin 1011 and ethyl alcohol s, a
II was mixed, 100 ml of distilled water was added thereto, and the mixture was stirred. This solution was dispensed into ampules 2.0- and fused and closed using aseptic techniques.

〔effect〕

Next, the effects of the anticancer agent of the present invention will be explained.

After culturing 600 cells of human nasal epidermis-derived tumor cells (xB-3-1) or its drug-resistant strain (KB-ChR-24) in Eagle's medium for 18 hours, adriamycin or the compound of formula (1) alone or together with adriamycin or the compound of formula (1) was added. The combination with the compound of formula (I) is administered and cultured for an additional 9 days, and the number of cell colony formation is calculated. The D10 value (concentration of the compound that suppresses 9C1 cell colony) is calculated from the number, and the combination effect is determined using the following formula.

Note that the compound of formula (1) was dissolved in ethyl alcohol and added to the culture solution.

Dlo (Adriamycin) Dlo (Adriamycin compound of formula (1)) Next,
D10 values obtained using adriamycin, a compound of formula ([), or both are shown.

Compound of Formula (1) 160 140 Adriamycin 48 880 As is clear from the above table, the anticancer effect of Adriamycin is enhanced by the combination of Adriamycin, which is the active ingredient of the present invention, and the compound of Formula (1). Cellular sensitivity to adriamycin is largely restored.

Claims (1)

[Claims] An anticancer agent containing adriamycin and a compound of the formula ▲ (numerical formula, chemical formula, table, etc.) (I) or a pharmaceutically acceptable salt thereof as active ingredients.