JPH01279830A - Cholinergic drug - Google Patents

Abstract

PURPOSE:To improve Alzheimer type senile dementia, etc., without side effects by using lipid microspheres containing a lipid containing eicosapentaenoic acid and/or docosahexaenoic acid, physostigmine and phosphatidyl choline as active ingredient. CONSTITUTION:Lipid microspheres containing a lipid containing eicosapentaenoic acid and/or docosahexaenoic acid, physostigmine and phosphatidyl choline as active ingredients. Physostigmine or physostigmine salicylate, etc., are used as the physostigmine and the amount thereof used is 10-2,000ppm based on the lipid. The lipid preferably contains >=50% eicosapentaenoic or docosahexaenoic acid. Phosphatidyl choline in >=95% purity purified from raw material soybeans or egg yolk lecithin is preferred as the phosphatidyl choline.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a cholinergic drug using lipid microspheres.

(Conventional technology) In recent years, research on the quality of neurotransmission has progressed, and the levels of neurotransmitter synthase and decomposition enzymes have been measured in the brains of people with Alzheimer's disease. It was found that there was a selective decrease. On the other hand, it has been shown that anticholinergic drugs such as scopolamine cause cognitive and memory impairment in normal people, and that this impairment can be improved by physostigmine, an inhibitor of acetylcholine degrading enzyme. Selective impairment of cholinergic system neurons has been highlighted as a major aspect of the pathology, since the early symptoms of Alzheimer's type senile dementia are impairments in recent memory, and the decrease in choline acetyltransferase correlates with the degree of dementia. . Therefore, an attempt was made to administer cholinergic drugs to patients with Alzheimer's type senile dementia to promote central cholinergic light transmission.

In order to improve the impairment of cholinergic system neurons in Alzheimer's type senile dementia, large amounts of precursors are administered to replenish the neurotransmitter acetylcholine. Additionally, attempts are being considered to increase acetylcholine in the brain by suppressing the degrading enzyme by administering an inhibitor of cholinesterase, which degrades acetylcholine. the current,
As the anticholinesterase, physostigmine is administered by injection at 0.2 to 1.0 μl/time and orally at 1 to 5 mg.

(Problems to be Solved by the Invention) Choline, lecithin, and dianol have been used as the above-mentioned choline agents, but the drugs other than lecithin have serious side effects. Furthermore, because current lecithin has a low phosphatidylcholine content, it is administered at a dose of 20 to 100 g/day, but it poses a problem of inducing gastrointestinal symptoms and convulsions.

Furthermore, the efficacy of oral administration of physostigmine is unclear, and injection causes peripheral side effects including gastrointestinal symptoms such as nausea and vomiting. These results are thought to be due to the fact that physostigmine not only inhibits cholinesterase in the brain, but also inhibits cholinesterase in the periphery. Furthermore, the duration of action of physostigmine is extremely short even when injected as a single shot or continuously administered using an intravenous catheter, making it difficult to use for treatment.

Conventionally, even when physostigmine is administered orally or by injection, some of it passes through the blood-brain barrier and exhibits anticholinergic effects;
At this time, it is known that most of the drug is transported outside the brain, causing various side effects, and that the administered drug is rapidly degraded and has an extremely short action time. The reason for this is that drugs are administered in a water-soluble state, so they are transported throughout the body and are rapidly degraded by degrading enzymes, resulting in less delivery to the target brain and causing side effects in the periphery.

For the above reasons, a drug delivery system suitable for combining lecithin and physostigmine to achieve clinical efficacy is desired.

The present invention is a cholinergic drug that selectively transports physostigmine, a cholinesterase inhibitor, and phosphatidylcholine, a choline precursor, into the brain, increases the amount of acetylcholine, a neurotransmitter in the brain, and enhances the activation effect of the brain. is intended to provide.

(Means for Solving the Problems) The present invention is a cholinergic drug using lipid microspheres containing a lipid containing eicosapene citric acid and/or docosahexaenoic acid, physostigmine, and phosphatidylcholine as active ingredients. It is characterized by

As the physostigmine used in the present invention, physostigmine, physostigmine salicylate, physostigmine sulfate, etc. can be used.
It is used by adding 000 ppm.

Physostigmine is an anticholinesterase drug that can pass through the blood-brain barrier, but in order to further increase the amount delivered to the brain, we investigated a method of dissolving physostigmine in lipids to escape degradation by systemic enzymes.

As a result, they found that when eicosapencitric acid and docosahexaenoic acid, which are part of the fatty acids that make up brain lipids, are used as lipids, they can cross the blood-brain barrier at a high rate.

The lipid used in the present invention preferably contains 50% or more of eicosapentaenoic acid or docosahexaenoic acid, and is industrially obtained by concentration separation from fish oil.

As the concentration separation method, there are known methods such as urea addition method, molecular distillation, and column fractionation.

Eicosapentaenoic acid and docosahexaenoic acid contained in the lipids used in the present invention can be used in the form of fatty acids, fatty acid methyl esters, ethyl esters, glycerides, and the like. These highly unsaturated fatty acids exist in fish oil as an industrial raw material, but their individual content in general fish oil is 1.
It is low at 0 to 15%, which is not desirable for the purpose of delivery of the main rule,
However, those whose content is adjusted to 50% or more are suitable for liquid microspheres that can be dissolved and uniformly dispersed in water.

As the phosphatidylcholine used in the present invention, phosphatidylcholine with a purity of 95% or more purified from the raw material soybean lecithin or egg yolk lecithin is preferable.

Furthermore, phosphatidylcholine as a choline agent of the acetylcholine precursor is used in a 0/-
The surfactant ability to prepare type emulsions is also very good and suitable for obtaining lipid microspheres.

The composition of the present invention is administered orally or by injection in the form of lipid microspheres, which are 0/- type emulsions. For delivery, the particle size of oil droplets should be 1.0-0.
．． 1- is preferred.

When preparing the drug of the present invention, physostigmine is dissolved in a lipid containing eicosapentaenoic acid and/or docosahexaenoic acid, and highly purified phosphatidylcholine is further added thereto in an amount of 5 to 20% by weight based on the lipid. preferred from the viewpoint of stability.

When dispersing lipids in which physostigmine and phosphatidylcholine are dissolved into fine particles in purified water for injection, the amount of lipids to be mixed with water is 10 to 20% depending on the viscosity and stability of the emulsion.
% is preferable.

The glued microspheres of the present invention are produced by pre-emulsifying with a homomixer, ultrasonic homogenizer, etc., and then performing emulsification treatment with a pressurized injection type homogenizer or Manton-Bowlin homogenizer.

The composition of the present invention can be administered as is as an oral emulsion or injection.

Isotonic agents for administration by injection include physiological saline, glycerin, and glucose, but glycerin was particularly excellent in terms of emulsion stability.

The appropriate daily dose for an adult of the drug of the present invention is such that the dose of physostigmine is 2000 to 20 m/day, calculated from 10 to 0.01 m/day.

(Effects of the Invention) According to the cholinergic drug of the present invention, it is possible to simultaneously administer phosphatidylcholine and physostigmine, which can increase the amount of acetylcholine in the brain, and to promote the transfer of physostigmine into the brain. Therefore, it is not only effective in treating Alzheimer's type senile dementia, etc.
It is effective in extending the action time and reducing side effects. Also,
An anticholinesterase agent other than physostigmine, a brain tumor treatment agent, a neuropsychiatric agent, a cerebral vasodilator, a brain metabolism activator, etc. are dissolved in the oil of this composition to promote passage through the blood-brain barrier and enhance efficacy. becomes possible.

(Example) Hereinafter, the present invention will be specifically explained based on Examples.

Example 1 24 g of physostigmine salicylate and 12 g of soybean-derived phosphatidylcholine were dissolved in 100 g of triglyceride containing 55% docosahexaenoic acid and 17% eicosapentaenoic acid under a nitrogen stream.

On the other hand, 25 g of attribute glycerin was dissolved in 863 g of distilled water for injection, and using an autohomogen mixer (Tokushu Kika Kogyo),
Rotation speed 10. Mechanical emulsification was performed at OOOrpm at 90° C. for 30 minutes under a nitrogen stream.

After that, Manton Bowlin homogenizer (Doei Shoji)
A fat emulsion was prepared by emulsifying the mixture under a nitrogen stream. The particle size of the emulsion particles was 0.1-0.4-.

Wistar rats - group of 8 (sex A, 4 weeks old, weight approx. 30
The above emulsion 19- was injected into the tail vein of 0g), and 9 to 10 hours later, microwave irradiation (Japan Radio, 10Kw,
1.19 sec). Immediately after irradiation, the head was cooled for 10 seconds with dry ice acetone, and after speaking, the whole brain was removed on ice, frozen on dry ice, and stored at -80°C.

Prepare a section of the target area using a cryostat, then -
In a freezing box at 15° C., six sites, including the frontal cortex, striatum, hippocampus, hypothalamus, interpeduncular nucleus, and septal nucleus, were cut out freehand and used as measurement samples. The amount of acetylcholine was measured by HPLC equipped with an electric detector using ethyl homocholine as an internal standard substance.

Physostigmine was not used at the same time, otherwise Example 1
Control Example 1, which was prepared in exactly the same manner as in the previous example, Control Example 2, in which only the same amount of physostigmine as in the previous example was intraperitoneally administered 20 minutes before slaughter.
A similar test was conducted using a non-treated group as a control example 3.

Protein measurement was carried out by the method of Lowry.

The amount of acetylcholine was calculated per square unit of the target section of the brain, and the comparison results for the sections of Example 1, Control Examples 1, 2, and 3 are shown in Table 1.

Table 1 This table shows that the intracholinergic neuron concentration of acetylcholine in Example 1 using the present composition was increased compared to Control Examples 1.2 and 3. It should be noted that no side effects caused by this composition were observed within this test period.

Example 2 Eicosapentaenoic acid ethyl ester (93%) 200
48 g of physostigmine salicylate and 24 g of egg yolk-derived phosphatidylcholine were dissolved in 1 g of physostigmine salicylate. On the other hand, a fat emulsion was prepared in accordance with Example 1 except that 50 g of glycerin was dissolved in 726 g of distilled water for injection.

As in Example 1, the above emulsion 9.5- was injected into the tail vein of Wistarsat. After a 3-week acclimatization period, the rafts used in Example 2 were fed a low-choline diet (choline 1/g) for 2 weeks.
) was ingested. This untreated group was designated as Control Example 4. Table 2 shows the results of comparison between Example 2 and Control Example 4.

Table 2 From this table, it can be seen that the same results as in Example 1 were obtained in Example 2.

Example 3 Tridocosahexaenoic acid glyceride (94%) 100g
48 g of physostigmine salicylate and 12 g of phosphatidylcholine cytocosahexaenoate (94%) were dissolved in the solution. On the other hand, 863g of distilled water for injection contains 2 attributes of glycine + phosphorus.
5 g was dissolved and treated in the same manner as in Example 1 to obtain a similar fat emulsion. The test was conducted in the same manner as in Example 2. Control example 5 was the untreated group. Table 3 shows the results of comparison between Example 3 and Control Example 5.

From this table, it can be seen that the same results as in Example 1 were obtained in Example 3 as well.

Claims (1)

[Claims] A cholinergic drug using lipid microspheres containing a lipid containing eicosapentaenoic acid and/or docosahexaenoic acid, physostigmine, and phosphatidylcholine as active ingredients.