JPS60178816A - Carcinostatic agent - Google Patents

Abstract

PURPOSE:A carcinostatic agent showing extremely low toxicity and improved carcinostatic activity, comprising a surface active agent as an active ingredient. CONSTITUTION:Various kinds of surface active agents were newly found to have differentiation and introduction activity against animal tumor cells. An amount of a surface active agent in a pharmaceutical preparation is preferably 0.3-15wt%, a daily dose is 0.01-100mg/kg weight of adult, the upper limit is 50mg/kg weight, especially 10mg/kg weight. A sodium salt of higher fatty acid, a sodium alkylbenzenesulfonate(cationic), trimethylammonium salt, alkylpyridinium salt(anionic), betaine derivative(ampholyltic), polyoxyalkylene fatty acid ester, oxyalkylamine(nonionic), etc. may be cited as the surface active agents used.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel anticancer agent characterized by containing a surfactant as an active ingredient.

Conventionally, as cancer chemotherapy agents, alkylating agents (nitrogen mustards, ethyleneimines, sulfonic acid esters) 1 antimetabolite) ft (9-acid antagonist, purine antagonist, pyrimidine antagonist), plant Fission poisons (colcemid, vingrastine, etc.), antibiotics (sarcomycin, carcinophilin).

mitomycin, etc.)% hormones (adrenal steroids, male hormones, female hormones), porphyrin lead acid (marphyrin%copp), etc. are used. However, most of these are Fi, cytotoxic substances and exhibit serious side effects, so there is a strong desire to develop anticancer agents with low toxicity and excellent anticancer activity.

Therefore, in view of the above-mentioned purpose, the present inventors searched for substances with low toxicity and anticancer activity, and as a result of intensive research, they found that substances with surfactant effects bring about changes in membranes and induce cell differentiation. Based on the prediction that this might occur, we investigated the differentiation-inducing activity of various surfactants. As a result, it was newly discovered that these substances have differentiation-inducing activity against animal tumor cells, and new knowledge was obtained that the substances have extremely low toxicity and excellent anticancer activity, and the present invention This led to the completion of an anticancer drug. The active ingredient of the anticancer agent of the present invention can serve as an excellent cancer chemotherapeutic agent for humans, livestock, warm-blooded animals such as dogs and cats.

Examples of various surfactants that are active ingredients of the present invention include the following.

As a cationic surfactant, higher fat a-7um salt, aliphatic hydrocarbon sulfate ether salt, alkylbenzenesulfonic acid sodium salt, as an anionic surfactant.

Trimethylammonium salt, alkylpyridinium salt.

As a zwitterionic surfactant, betaine derivatives As a nonionic surfactant.

Polyoxyalkylene 11 fatty acid ester, alkylaryl polyether alcohol, oxyalkylamine,
Examples include various surfactants such as holoxyethylene alkylphenyl ether, polyoxyethylene adducts of higher alcohols, polyoxyethylene adducts of higher fatty acids, and sorbitan fatty acid esters.

Examples of these compounds include primary compounds. All of these are known surfactants.

The anticancer agent of the present invention can be administered either orally or parenterally, and when administered orally, it is administered as a soft/hard capsule, tablet, granule, or powder; when administered parenterally, It can be administered in the form of a herbal medicine, such as an aqueous suspension, an oily preparation, subcutaneous or intravenous injection, one drop, and a solid or suspended viscous liquid to maintain sustained mucosal absorption. .

Formulation of the active ingredient of the present invention, excipients, lubricants, adjuvants,
and pharmaceutically acceptable film-forming substances for enteric-coated preparations in accordance with Committee 8.1. 3 using coating aids etc.
B'B can be performed, and the following are specific examples. Note that since the active ingredient of the present invention itself exhibits surface activity, it can improve the disintegration and dissolution of the composition of the present invention.

As excipients, for example sucrose, lactose, starch.

Crystalline cellulose, mannitol, light horn hydrothermal silicic acid, magnesium aluminate, magnesium metasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium hydrogen carbonate, calcium hydrogen phosphate.

1 or 2 pieces of carboxymethylcellulose calcium, etc.
A combination of more than one species can be added.

Lubricants and U7 include 1, e.g. stearinic magnesium,
One or more types of talc, hydrogenated oil, etc. can be added, and salt, saccharin,
Sweeteners such as sugar, mannitol, orange oil licorice extract, citric acid, glucose, menthol, eucalyptus oil, and malic acid, fragrances, colorants, preservatives, and the like may be included.

Adjuvants such as clouding agents and wetting agents include coconut oil, olive oil, sesame oil, peanut oil, calcium lactate,
Safflower oil, soybean phospholipids, etc. can be contained.

In addition, film-forming substances include cellulose, cellulose acetate phthalate (CAP) as a carbohydrate derivative such as sugar, etc.
Also, as polyvinyl derivatives such as acrylic acid copolymers and dibasic acid monoesters, methyl acrylate/methacrylic acid copolymers and methyl methacrylate/methacrylic acid copolymers are praised.

In addition, when coating the above-mentioned film-forming substance, in addition to commonly used coating aids 1 such as plasticizers, various additives to prevent mutual adhesion of chemicals during coating operations can be added to improve the properties of the film-forming agent. This can improve the coating process and make coating operations easier. Note that a dosage form may be prepared in which the active ingredient is microencapsulated using a film-forming substance and then mixed with excipients and the like.

In particular, the blending ratio in typical dosage forms is as follows.

Particularly preferred range of active ingredients: o, i - 90 weight ratio 0.3 - 15 weight ratio Excipients 10 - 99-8'85 - 99.41 smoothness 0 -
501O-201 Film-forming substance 0.1-501 G, 5-20 #Particularly preferred excipients are lactose and crystalline cellulose.

Carboxymethyl cellulose calcium is also available.

The dosage is sufficient to effectively treat the target tumor, and depends on the symptoms of the tumor, route of administration, dosage form, etc., but in general, when administered orally, the daily dose for adults is approximately 0.
．． 9 weight for 01-100m97 (Fi, 0 for dwarfs)
01-60-97kP body weight) CD range, the upper limit of which is preferably about 50 mp/4 body weight, more preferably about 10
In the case of parenteral administration, the upper limit is about 10 m9/kg body weight, preferably about 5 to 97 kg body weight, preferably 7 (#'12 me /
ky body M ka J to T al.

Next, an anticancer test in which the anticancer activity of the compound of the present invention was confirmed will be described.

[1] Friend leukemia cells (mouse erythr
oldleukemia cot I, B8 cells) K vs. Sur test & QGIBCO HAM F-12
The medium was supplemented with 15% fetal bovine serum and 60 mg/t kanamycin (DK, 25 x 104 c).
88 cells are inoculated at a density of o/mε, and a predetermined amount of the test compound is added thereto (final volume: 5 ml).

7.5 Coz cultured at 57°C for 7 days and stained with Orkin's benzidine staining method, and the number of stained cells, that is, cells that began to produce hemoglobin by differentiation into red spheres. Measure the number and calculate the differentiation induction rate.

[2] Mouse myeloid leukemia cells
loidLeukemia cell, M1)
11 Test GIBCOJIIJ-glu MEM medium supplemented with 10'l of horse serum and bamq/l of kanamycin, 5, OX 104 cells/m
/2M/cells are inoculated, and a predetermined amount of the test compound is added thereto (lθ final volume: 5 ml).

After culturing in 7.5 coz at 57°C for 7 days,
ll! ',b or examine lysozyme activity induced by differentiation into granulocytes. In addition, 1 of lysozyme activity
Unit (unii)? i, Mlcrococcus 1ysod
lysozyme was applied to a suspension of the image (elkNcus) as a substrate, measured at pH 6.24, m degrees and 25°C, and
The absorbance at a wavelength of 50 mzi total per minute is y[-, which is the sum of y[-] of lysozyme.

[5] Mouse teratoma cells
(Arclnomacells) Biteratoma cells were transplanted from the peritoneal cavity of a mouse to the peritoneal cavity, and 1 month had elapsed since then. Teratoma cells exist in the peritoneal cavity as a cell mass called an embryoid body, which resembles an initial pressure, and were inserted without trypsin treatment. Embryoid bodies collected by natural settling in 11 volumes of ascites were washed three times with Dulbecault's modified medium or Hank's solution, and then inoculated into a medium containing 10 volumes of tallow serum, and a predetermined amount of the test compound was added. and CO2 at 57℃.
7. Saturate water vapor containing fractions 5 to 8 and culture in air for one week. Centrifugation (z O00r, p, m, 1 (
After washing the embryoid bodies obtained with 0.86 Naα solution, naphthol AS-MX phosphate and diazo reagent (
Fast Violet 85alt) was added and left at room temperature for 1 hour. This is before the whole centrifugation (2000r, p,
10 minutes), the whole embryoid body is separated, ethanol is added, and the embryoid bodies are left at room temperature for 1 hour.

C undifferentiated cells #'i, colored red).

The absorption at b555 nm is measured to determine alkaline phosphatase activity (degree of differentiation induction).

Hexamethylene bisacetamide (8M8A) 5mM'
(When HMBA i is added (no alkaline phosphatase activity is shown at all), it is marked as "++", and when HMBA i is not added (it shows very strong alkaline phosphatase activity).
is marked as "--", and the degree of differentiation induction is shown in the following steps.

++: Shows no alkaline phosphatase activity.

+: Does not show any alkaline phosphatase activity.

±: Slightly shows alkaline phosphatase activity.

m: O exhibiting strong alkaline phosphatase activity - Shows extremely strong di-alkaline phosphatase activity.

In addition, in the test examples described below, Et showed anticancer activity with 1 differentiation inducing effect.

The present invention will be specifically explained and explained below using formulation examples and test examples.

Formulation Example 1 (Injection/Drop) Compound + 1) Powdered glucose 5 to contain 10 ■
Aseptically dispense into vials, seal tightly, fill with inert gas such as nitrogen or helium, and store in a cool, dark place. Dissolve in ethanol and 0.851 saline 100# before use! 7! was added to make an intravenous injection, and 1F
Administer by intravenous injection or drip depending on the symptoms.

Formulation Example 2 (Injection/Drop) Compound (102m9') was prepared as an intravenous injection for mild symptoms by the same method as Formulation Example 1.% 1 day, 10-100%
Tn! , is administered by intravenous injection or drip depending on the symptoms.

Formulation Example 5 (Enteric Coated Capsules) Compound 52, 2.46 lactose and 0.04 t'r of hydroxyzorobyl cellulose were mixed together, then molded into granules according to a conventional method, and then thoroughly mixed. Granules suitable for bottles, heat seal packaging, etc. are manufactured by drying and sieving. Next, phthalate acetate 11f,? Cellulose 0.5 and Hydroxyglobil Methylcellulose Fukure) 0
．． 5F is dissolved to form a dressing, and the M granules are made to float and flow, and this base material is coated to form enteric-coated granules. Enteric-coated capsule preparation 10 by filling this composition into capsules.
0 pieces f: Manufacture.

Test Example Using the compounds in Table 1, the differentiation induction rate of Friend leukemia cells, lysozyme activity by differentiation induction of mouse myeloid leukemia cells, and mouse malformed lung cells were determined by the above test methods [1], (2), and [3]. When the differentiation-inducing activity of iL' was determined, significant differentiation-inducing activity was observed in the concentration range shown in Table 2. In addition, the criteria for Ioatsusei are as follows.

(Friend leukemia cells (εLC) 1.510M5O (+1 hemoglobin 45, I
Pr/cell (-) Hemoglobi7 12 , 8 P'
l/call (2) Mouse myeloid leukemia cells (MLC
) 10-5M Dexamethacin ←) Lysozyme 1 B −
9ttLJ/cell(-)lysozyme 5.5aU/
ce11f31 -f '7 Sumiform 11 [ftal cell (TER) 5mM hexamethylene bisacetamide (+
) Alkaline phosphatamine 0-2081 U/mlJ nutrient solution (-) Alkaline phosphater vo, 5491U/
Jf nutrient solution As is clear from the results of the above test examples, the various surfactants Vi, which are the active ingredients of the present invention, exhibit an effect of inducing differentiation of cancer cells into normal cells. It has been demonstrated that it exhibits anticancer activity.

Patent applicant: RIKEN 1, case indication: 1982 Patent Application No. 33755 2,
Title of the invention System cancer drug 3, relationship with the case of the person making the amendment Applicant name (679) RIKEN 4, agent

Claims (1)

[Scope of Claims] (Li) An anticancer agent characterized by containing a surfactant as an active ingredient. (2) An anticancer agent according to claim 1 in a parenteral administration form. (3) Oral administration form vB The anticancer agent according to claim 1.