JPS6183115A - Insecticides and their manufacturing methods - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] [Industrial Field of Application] The present invention is directed to insecticides, particularly insecticides for insecticides (hydatids, echinocysts, etc.).
coacosis) and alveococcosis (alve
ococcosis), preparations for use in human and veterinary medicine.

[Conventional technology]

Already, mependazole (methyl-5-benzoyl-2-
It is known to use benzimidazole carbamates) as a drug in the form of tablets to treat cysticerci and alveococcosis. (References, 1. Zahari
sva E, et al.

Drugs re fer enc e boo
k + So fia 1982 r p , 826
).

The disadvantages of mebendazole as an insecticide are 1-5.
These include low efficacy in humans and animals even when administered daily throughout the year, toxicity to the recipient organism, and harm to the preparation when administered at the end of pregnancy.

Known methods for preparing ribosomes containing biologically active substances include dissolving phospholipids at a given concentration in an organic solvent, evaporating, adding water or a buffer, and then using ultrasound, detergents, ethanol, etc.・Includes processing of ether, etc. (References, 2Franc IS 5zoka ltTr
-*D@me tr1013 Papahadj
opoulos 1Ann, Rev, Biophys,
Bioeng, 1980, 9. p, 467-508
3. Liposomes in biologicala
l S7S75te, TranSla-1i On
r C) −() r e Or i a d i 8
r A # A 1) S On 1M OS CO
W +"Medizina"1)9s31p,384)
[Problems to be Solved by the Invention] The ribosomes obtained by the methods of the prior art mainly have a monolayer structure, and therefore, in the case of mependazole, the efficiency in incorporating an appropriate amount of a hydrophobic drug substance is low.

[Means for solving problems]

The object of this invention is to create an insecticide, in particular for treating alveolar coccyx and alveococcosis, based on mebendazole, and which allows intravenous administration, has high efficiency against parasites and against the host. Concerning less toxic manufacturing methods.

For this purpose, mebenguzole (methyl-5-benzoyl-2-benzimidazole carbamate 0.5 to z
This is achieved by providing an insecticide exhibiting ribosomal morphology containing 0.2 to 0.6 p of total lipids from egg yolk, 20 to 80 p of a 0.9% aqueous solution of sodium chloride.

The bones produced in this way are homogeneous in terms of average diameter, which is on average 0.4 microns as determined by electron microscopy, and ribosomes with diameters of 0.3 and 0.5 are also observed. This ribosome is multilayered and is formed of several bilayers.

The method for producing an insecticide according to the present invention consists of the following steps.

That is, methyl-5-benzoyl-2-benzimidazole carbamate is added to a chloroform/methanol bath solution of whole egg yolk lipids.

The contents are stirred and evaporated to dryness at a temperature of 20-40°C. A 0.9% aqueous solution of sodium chloride is then added at ambient temperature with constant stirring to hydrate the lipids.

The latter is subjected to 1-12 freeze-thaw cycles at temperatures of -196°C and +35°C.

The ratio of aqueous phase: mependazole: finger material is 15:0.6
:0.1 to 25:0.5:0.2. The result was a ribosomal form of the insecticide that could be administered intravenously.

〔effect〕

The advantages of the inclusion and treatment insecticide for alveococcosis according to the invention include high efficiency, short processing time and non-toxicity. This made it possible to reduce the frequency of administration and reduce the total number of active devices, resulting in the effect of prolonging the activity. This insecticide is biologically degradable.

Advantages of the method of the invention include that it does not require special equipment and raw materials, is fast and easy to carry out,
This may ensure that stable ribosomes are obtained.

〔Example〕

The invention will be explained in more detail with the following examples.

Example 1゜ The insecticide according to the invention has the following content:

Aqueous phase (0.9% aqueous solution of sodium chloride) 40M1)
Mebenguzole (substance) IP, lipids (all ingredients from egg yolk) 0.4%.

Electron microscopy reveals more detailed characteristics of ribosomes. The ribosome thus obtained is a vesicular, multilayered structure exhibiting a two-layered lipid structure (Fig. 1). Many distinct layers forming ribosomes are observed. Each layer is about 5
It is a bimolecular lipid layer with a thickness of OA, which corresponds to the thickness of natural biological membranes.

Example 2 The insecticide according to the present invention is produced by the following method.

In a round bottom flask, under sterile conditions, dissolve 3.2 parts of total egg yolk lipids in distilled chloroform and methanol (
1%) with a pipette.

The initial concentration of the fat g solution was 129rn9/g.

Next, add 10++ J of chloroform and warm the contents by shaking vigorously (vortex @). In lipids, mebendazole substance 1,09
- are added to each mass while stirring constantly. Evaporate for 5-6 minutes in a rotor evaporator at ambient temperature. Another 5 rpl of chloroform are added and the contents are evacuated on a rotor evaporator for 1.5 hours at a temperature of 35±2° C. (water bath). Remove traces of chloroform by bubbling nitrogen for 5 minutes. The material thus dried is added to sterile physiological serum (0.9% sodium chloride bath solution). Then, incubate for 1 hour at ambient temperature with full nitrogen purge for 5 minutes, with constant stirring (vortex@). after that,
Freezing with liquid nitrogen is performed for 2-3 minutes and then thawing in a water bath adjusted to 50°C for 2-3 minutes. Always shake vigorously when doing this. The temperature inside the flask is 40'C
Manage so as not to exceed.

Example 3゜This insecticide was used experimentally to treat cysticercosis (hydatldosig).
) was tested on infected animals. Animal (sheep) A
Treatment for patients and B began 20 months after infection. In order to follow the effectiveness of the treatment, blood tests were taken before each injection for the study of antibody dynamics by the RPH (passive hemagglutination) method. Figure 2゜The general condition of the animals was checked during treatment. Microscopic images, histopathology in parasites
istr.

gic) changes, ultrastructural changes in the internal organs of the host, parasites and infected organs. 20- was injected intravenously (jugular vein,
V, jugularis).

This dose is 10m97Kl for mepenguzole.
This is once a week. Dosing speeds of 4-5 minutes to 5-6 seconds do not affect the tolerability of the formulation. No harmful side effects were observed in any case during the two sessions of treatment. The course of treatment includes 6 injections. Treated animals were sacrificed 3 weeks after the last injection, but 1 hour prior to ribosome establishment in the organ.
Injections were performed for microscopic re-examination of item n). A control group of 14 animals infected with the same parasites but released without treatment was also subjected to histological and spermatoscopic examination. At the end of the experiment, the treated animals were in very good condition.
He became depressed and his weight increased. The titer of anti-K (Figure 2) is
After the second injection, it began to decrease gradually until the 6th treatment, then stabilized and remained constant for 9 weeks until the end of the study period. In the case of control animals, a characteristic microscopic pattern and a diameter of 1 mm with 1 ridge
0-20 parasite cysts were confirmed. The cyst of the treated animal had a diameter of Vii-5mrL, and histopathological findings revealed complete destruction of the germination layer and considerable changes in the epidermis (1) (Fig. 3). Calcium precipitates were observed locally in the walls, in the trenches, and in some cases in the follicles themselves. Treatment/2 The internal organs of animals are
・No change 2 was shown as a deviation from the 1 quasi.

Ultrastructurally, a well-conserved orientation was confirmed. Numerous secondary ribosomes with autophagosome characteristics and residual booklets were observed. Some of it was determined to be destroyed and phagocytized, or to be bonome residues. Germinated membranes show complete destruction, but vesicles, membrane formation, and osmiophyllics (osmi.

It was confirmed that the particles remained in the form of particles (Fig. 4). It was confirmed that the necrotic zone contains characteristics of ribosomes subjected to destruction.

[Brief explanation of drawings]

C1), FIG. 3, and FIG. 4 are photographs of animal tissues to demonstrate the effects of the insecticide of the present invention. FIG. 2 is a diagram showing changes in antibody titer due to insecticide treatment of the present invention. Appearing agent Patent attorney Takehiko Suzue Continuation of page 1b Author: Olga Todorova Po Sofialya Kowerkulesteva, Bulgariab Author: Ivan Vasileev Ei Sofiavanov, Bulgaria - Toubrok
25 Yoshi Akira Tofuik Husei Brigalia, Sofian ψno\tsan, Ef Kanits Street 32, Kok Pontyev Street, Bowl φTolbukhin 2A

Claims (2)

[Claims] (1) An insecticide based on methyl-5-benzoyl-2-benzimidazole carbamate, especially against alveolidia and alveococcosis, containing a 0.9% aqueous solution of total egg yolk lipids and sodium chloride, the proportion of which is methyl -5-benzoyl-2-benzimidazole carbamate 0.5 to 2.0 g Egg yolk total lipid 0.2 to 0.6 g 0.9% aqueous solution of NaCl 20 to 80 ml An insecticide characterized by exhibiting a ribosomal form. . (2) Add methyl-5-benzoyl-2-benzimidazole carbamate to a chloroform-methanol solution of total lipids from egg yolk, and stir this solution at 20° to 40°C.
evaporated to dryness at a temperature of -196°C and to this dry residue was added a 0.9% solution of sodium chloride with stirring and then evaporated to -196°C.
Methyl-5-benzoyl-, characterized by carrying out 1-12 freezing and thawing cycles at a temperature of +35°C.
Process for the preparation of insecticides based on 2-benzimidazole carbamates, especially against alveoli and alveococcoses.