JPH01233219A - Carcinostatic agent composition - Google Patents

Abstract

PURPOSE:To provide a carcinostatic agent composition containing a liposome including a fatty acid and its derivative as an active component, having low toxicity and excellent carcinostatic action and giving little side effect even in the case of applying to the center of the deep part of body, e.g., liver cancer or pulmonary cancer. CONSTITUTION:A liposome containing a fatty acid or its derivative (e.g., caproic acid, caprylic acid or lauric acid) is used as an active component. The amount of the fatty acid and its derivative included in liposome depends upon the kind of the cancer to be treated, however, it is preferably 1-20wt.% based on the lipid. It is administered at a dose of 5-400mg/kg daily. The inclusion of the active component in liposome enables the accurate chemotherapeuric treatment of the objective cancer in the living body.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a pharmaceutical composition, particularly an anticancer composition used as a chemotherapeutic agent for cancer.

[Conventional technology]

To date, alkylating agents, antimetabolites, antibiotics, and plant alkaloids have been formulated as chemotherapeutic agents for cancer. In addition, it has recently been discovered that certain plant extracts have immunostimulatory effects and are being put into practical use as anticancer agents, and fatty acids or their esters have also been found to have anticancer effects. .

[Problem to be solved by the invention]

As mentioned above, many formulations of anticancer drugs are known.
In addition, various other proposals have been made, but none of the anticancer drugs and proposals have a strong anticancer effect, but have strong side effects and have many restrictions in actual use. The development of active anticancer agents is strongly desired.

Therefore, the present inventors focused on fatty acids that exist in large quantities in the form of glycide or phospholipids in nature, especially in living organisms, and after intensive study, they completed a method for using free fatty acids as anticancer agents (particularly Kaisho 62-12716
issue). This method involves emulsifying the fatty acid itself and administering it directly to the cancer site, and has demonstrated excellent anticancer effects. However, this method has not been very effective against cancers inside the body, such as liver cancer, lung cancer, and stomach cancer.

An object of the present invention is to provide an anticancer agent that can exert an excellent therapeutic effect even on cancers deep within the human body, focusing on the anticancer properties of fatty acids with low toxicity.

[Means to solve the problem]

The anticancer composition of the present invention contains a ribosome containing a fatty acid or a derivative thereof as an active ingredient.

The ribosomes of the present invention are formed when naturally derived phospholipids are redispersed in water. Specific examples of naturally occurring phospholipids include phosphatidylcholine, phosphatidino C ethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, and sphingoemylin.

Furthermore, in order to improve the stability in vivo, the outer surface of the ribosome was coated with a naturally occurring polysaccharide derivative through non-covalent interaction (Japanese Patent Application No. 56-147).
No. 587 and Japanese Patent Application No. 59-189746) are preferred.

There is no particular problem with the structure of the ribosome, whether it is a single layer structure or a multilayer structure, but the particle size is preferably 0.1 to 0.2p.

In the present invention, the surface of the ribosome can be further coated with a multi-tin coating. The polysaccharide used for coating is
Examples include pullulan, amylopectin, amylose, dextran, mannan, etc., and 4.0 per 100 monosaccharides.
~5.0 primary alcohol groups are substituted with aminoethylaminocarbonyl groups, and 10 to 50 residues of the aminoethylcarbonylmethyl groups are substituted with cholesteryloxycarbonyl groups!
Ribosomes coated with 50 to 100% of the derivative based on the weight of lipids are preferred.

The fatty acids or derivatives thereof used in the present invention may be naturally occurring fatty acids or derivatives thereof, and specifically include caproic acid, caprylic acid, capric acid, lauric acid, tridecanoic acid, myristic acid, and pentadecanoic acid. , palmitic acid, stearic acid, behenic acid, etc. with 5 or more carbon atoms
22 saturated fatty acids, unsaturated fatty acids such as myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, lylunic acid, highly unsaturated fatty acids such as arachidonic acid, eicosapencitric acid, docosahexaenoic acid, and branched fatty acids , furanoid fatty acids, fatty acids having a hydroxyl group, or derivatives thereof such as ethyl esters and glycerin esters.

The amount of fatty acids or their derivatives contained in ribosomes varies depending on the type of cancer, symptoms, and administration method, but is preferably in the range of 1 to 20% based on the weight of lipids. In addition, the dosage is 5-4% of fatty acids or derivatives thereof.
It is preferable to use it so that it can be administered in the range of 00 mg/kg/day.

The anticancer drug composition of the present invention can be administered by intravenous injection, dynamic administration, intralymphatic administration, direct administration to cancer sites, etc. It is possible to exhibit excellent anticancer effects with few side effects even for cancers deep within the body.

〔Effect of the invention〕

The anticancer drug composition of the present invention has low toxicity despite the excellent anticancer activity of fatty acids, and since it is formed into ribosomes, it is possible to accurately administer chemotherapy to the target cancer site in the body.

〔Example〕

Hereinafter, the present invention will be explained in detail with reference to examples.

Example 1 All ribosome preparation experiments were conducted under sterile conditions. Egg yolk lecithin (60m
After solubilizing g) and α-9217M (11 mg) in chloroform, the solvent was removed under reduced pressure. Physiological saline was added to this, and a ribosome suspension was obtained using portex. Furthermore, polysaccharide cholesterol derivative (CHP-50-1
, 8) (6 mg) was added to prepare polysaccharide-coated ribosomes. Polysaccharide cholesterol derivative (CHP-
50-1,8) is a cholesterol derivative of pullulan with a molecular weight of 50,000 and a degree of cholesterol substitution per 100 monosaccharides of 1.8.

The anticancer activity and cytotoxicity of α-lylunic acid-containing ribosomes were investigated using normal cells (mouse fibroblast L-cells) and human colon cancer cells (RP MI #4788).

24 each cell 1 mff1 (3X10' cells)
The anticancer drug-containing ribosomes or ribosomes alone were added to the plate and incubated at 37°C in an incubator in an atmosphere of 5% CO□.
The cells were cultured for 5 days, and the number of cells was measured during that time. The results are shown in FIGS. 1 and 2.

When compared under the same conditions, α-lylunic acid-containing lysusomes were found to have an excellent anticancer effect on human colorectal cancer cells, although they show almost no toxicity to normal cells. did.

Example 2 The amount of superoxide (OX-) produced from neutrophils was measured according to the method described below. The amount of 02- produced is an indicator of the anticancer activity of the cells.

Neutrophils were isolated from the blood of healthy human adults using 5% dextran and the Ficoll-Conray method.

CHA I)-112-2,1 (molecular weight 11
．． 20,000 and a cholesterol derivative of amylopectin with a degree of cholesterol substitution of 2.1) (egg yolk lecithin 0.71 mg, α-lylunic acid 0.13 m
g) was added and cultured with shaking at 37°C for 1 to 4 hours.

After a certain period of time, neutrophils were separated by centrifugation (400 G, 10 minutes), resuspended in Taleb's Ringer buffer, and the number of cells was adjusted to 1×10 6 cells/3 ml. This 0698m1
was placed in a cuvette, glucose, cytochrome C, and PMA (phorbol-12-myristate-13~acetate) as a stimulant were added in this order to 540 ml.
The change in absorbance at 550 nm versus nm was measured. C
Only ribosomes coated with HAp and only α-lylunic acid were measured in the same manner.

α-lylunic acid-containing CHAp determined from these results
Only ribosomes coated with CHAp,
FIG. 2 shows the relationship between the 0□-production rate (%) and the culture time (hours) for α-lylunic acid alone.

From this, α-lylunic acid-containing CHAp-coated lysomes (
・) can increase the amount of 02- produced at the early stage of neutrophil culture to the same level as α-lylunic acid alone (△) than CHAp-coated ribosomes alone (○). Therefore, in the method according to the present invention, anticancer activity is also expected due to the immunostimulatory effect expressed by fatty acids.

[Brief explanation of the drawing]

Figure 1 is a graph showing the relationship between proliferation rate (%) and culture time (days) in normal cells when the content of α-lylunic acid is varied. Figure 2 is the same relationship in human colon cancer cells. The graph shown in FIG.
), 02-production rate (%) in CHAp-coated ribosomes only (O), and α-lylunic acid only (△)
) and culture time (hours).

Claims (2)

[Claims] (1) An anticancer drug composition containing a ribosome containing a fatty acid or a derivative thereof as an active ingredient. (2) The anticancer drug composition according to claim 1, wherein the surface of the ribosome is coated with a polysaccharide derivative.