JPH0725760A - Agent for prevention and treatment of alzheimer's disease - Google Patents

Abstract

PURPOSE:To obtain the agent composed mainly of a specific fatty acid and useful for the improvement of the symptom of the patient of Alzheimer's disease showing the decrease of acetylcholine in the brain or the prevention of Alzheimer's disease owing to its activity to produce acetylcholine in the cerebral cells. CONSTITUTION:This agent contains preferably 5-15wt.% of a compound selected from 6-10C fatty acid (preferably caprylic acid), its salt and its ester (excluding triglyceride). The standard administration rate of the agent for adult is 100-300g per day for oral administration in several divided doses. In the case of parenteral administration, the agent is used as a solution having a concentration of 10-30%w/v and administered by injecting into the stomach, duodenum or jejunum or injecting into the vein at a rate of 100-150ml/hr.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a prophylactic / therapeutic agent for Alzheimer's disease, and more particularly to a pharmaceutical agent for preventing and / or treating Alzheimer's disease caused by a decrease in acetylcholine content in the brain.

[0002]

2. Description of the Related Art It is generally known that in patients with Alzheimer's disease, which is one of senile dementia, a decrease in brain acetylcholine content is recognized, and it is an important index for drug development against this disease. There is.

Drugs currently in use or under development are acetylcholine synthesizing enzymes such as an enzyme that synthesizes acetylcholine, an enzyme that suppresses the degradation of acetylcholine, or choline, which is a precursor of acetylcholine, is supplied to the brain. Either by stimulation or by stimulating the receptor with an agonist of the muscarinic acetylcholine receptor.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a preventive and / or therapeutic agent for Alzheimer's disease which has a mechanism of action which is fundamentally different from that of conventional agents.

[0005]

Means for Solving the Problems As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that the carbon number is 6-10.
Fatty acid, its salt and its ester (excluding triglyceride) are transferred to the cerebrospinal fluid through the blood-brain barrier and are metabolized to acetyl-CoA in the brain cells. The inventors have found that acetylcholine is produced and completed the present invention.

The present invention has been completed based on this new finding, and contains at least one selected from fatty acids having 6 to 10 carbon atoms, salts thereof and esters thereof (excluding triglyceride) as a main component. It is a prophylactic / therapeutic agent for Alzheimer's disease.

The fatty acid having 6 to 10 carbon atoms in the present invention means saturated fatty acids such as caproic acid, enanthic acid, caprylic acid, pelargonic acid and capric acid, and particularly caprylic acid (octanoic acid) is preferable.

The salt of the above fatty acid is preferably an alkali metal or alkaline earth metal salt such as sodium salt, potassium salt or calcium salt, or a salt with a base such as ammonia.

The fatty acid ester includes monoglyceride and diglyceride.
Triglycerides are excluded. Preferable examples thereof include alkyl esters, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl and octyl having 1 to 8 carbon atoms.
And straight chain or branched alkyl.

The ester of the above fatty acid is produced by a method known per se, and can be obtained by an appropriate means such as synthesis from glycerol, partial esterification, transesterification with an enzyme, or fractionation of a high fat content. For example, it can be obtained by hydrolysis of cocoa butter or palm fat, fractionation of fatty acids by distillation and reselling with glycerol.

The preventive / therapeutic agent for Alzheimer's disease of the present invention is
1 to 50% by weight of the above-mentioned fatty acid (main component),
It is preferably contained in an amount of 5 to 15% by weight, and is mixed with itself or a pharmacologically acceptable carrier, excipient, diluent, etc., and is in a known solid form (tablet, capsule, granule, powder, etc.). ), Solution form (aqueous solution, etc.), suspension form,
It is provided in the present invention after being formulated into an emulsion form (emulsion, fat emulsion, etc.). That is, it can be administered orally or parenterally such as injection (eg, intravenous administration, tube administration to stomach, duodenum, jejunum, etc.).

As one dosage form of the preventive / therapeutic agent for Alzheimer's disease of the present invention, a fat emulsion can be mentioned. Such a fat emulsion is prepared from the above-mentioned main components (particularly fatty acids and esters thereof), an emulsifier, water, and appropriate added components by a conventional method.

Examples of the emulsifier include phospholipids (egg yolk phospholipids, soybean phospholipids), nonionic surfactants, etc., which may be those purified for medical use.

As the phospholipid, a purified phospholipid such as egg yolk lecithin or soybean lecithin is suitable, and it can be prepared by a conventional fractionation method using an organic solvent. It is mainly composed of phosphatidylcholine and phosphatidylethanolamine, and also contains phosphatidylinositol, phosphatidylserine, sphingomyelin and the like as other phospholipids.

As the phospholipid, those not containing phosphatidylethanolamine may be used. This product can be obtained by subjecting commonly available phospholipids such as egg yolk and soybeans to organic solvent fractionation by a conventional method and then purifying with an inorganic absorbent such as silica gel or alumina. The phospholipid thus obtained is mainly composed of phosphatidylcholine, and may contain phosphatidylinositol, phosphatidylserine, and sphingomyelin as other phospholipids. Furthermore, phosphatidylcholine itself may be used.

The water to be used varies depending on the administration form, and water suitable for intravenous injection (for example, distilled water for injection, purified water for injection, etc.) or water suitable for oral administration (for example, purified water) is used.

The content of each component of the fat emulsion is, for example, 1 to 50% (w / v) of the oil component (main component), preferably 5 to 15% (w / v). For example, one consisting of 1 to 500 parts (preferably 10 to 50 parts) of an emulsifier and a suitable amount of water is used per part.

In addition, if necessary, an emulsification aid [for example, a fatty acid having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms in an amount up to 0.3% (w / v) or a pharmacologically acceptable salt thereof. Salt, etc.], stabilizer [eg 0.5% (w / v)
Below, preferably 0.1% (w / v) or less cholesterol, or 5% (w / v) or less, preferably 1%
(W / v) or less amount of phosphatidic acid, etc.], polymeric substance (for example, 0.1 to 5% (w / v), preferably 0.1.
5 to 1% (w / v) albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, hydroxyethyl starch, etc.], tonicity agent (eg, glycerin,
Glucose, etc.), fragrance, etc. can also be added.

Any fatty acid having 6 to 22 carbon atoms as an emulsification aid can be used as long as it can be added to a pharmaceutical product. This fatty acid may be linear or branched,
It is preferable to use linear stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid and the like. These salts include physiologically acceptable salts such as alkali metal salts (for example, sodium salt,
Potassium salt etc.), alkaline earth metal salt (eg calcium salt, magnesium salt etc.) and the like can be used.

Further, an aliphatic amine may be used as an emulsification aid. Specifically, those having 2 to 22 carbon atoms are exemplified. Any of these aliphatic amines can be used as long as they can be added to pharmaceutical products. This aliphatic amine is linear,
It may be branched, but it is preferable to use linear ethylamine, propylamine, octylamine, stearylamine, oleylamine or the like. The amount added is, for example, about 0.0001 to 0.01% (w / v). If the emulsification is insufficient, various known emulsification aids may be used.

Cholesterol, phosphatidic acid and the like as stabilizers are not particularly limited as long as they can be used for medicinal purposes. In addition, albumin is preferably of human origin because of the problem of antigenicity, and examples of vinyl polymers include polyvinylpyrrolidone and polyvinyl alcohol. As the nonionic surfactant, polyalkylene glycol (e.g., polyethylene glycol having an average molecular weight of 1,000 to 10,000, preferably 4,000 to 6,000) and polyoxyalkylene copolymer (e.g., average molecular weight of 1,000 to 20,000, preferably 6, 00
0-10,000 polyoxyethylene-polyoxypropylene copolymer), hydrogenated castor oil polyoxyalkylene derivative (for example, hydrogenated castor oil polyoxyethylene- (20)-
Ether, same- (40) -ether, same- (100) -ether and the like], castor oil polyoxyalkylene derivative (for example, castor oil polyoxyethylene- (20) -ether, same- (40) -ether, same) -(100) -ether and the like] can be used.

The fat emulsion in the present invention is produced, for example, by the following method. That is, a predetermined amount of an oil component (main component), an emulsifier (preferably phospholipid) and the other additives described above are mixed and heated to form a solution, and a conventional homogenizer (for example, a high-pressure jet homogenizer or an ultrasonic homogenizer) is used. Etc.) to make a water-in-oil dispersion, and then add water containing necessary amount of tonicity agent, stabilizer, etc., and homogenize again with the homogenizer. It can be produced by converting to an oil-in-water emulsion. Depending on the production convenience, additives such as a stabilizer and a tonicity agent may be added after the formation of the fat emulsion (see JP-A-58-222014).

The fat emulsion thus produced is extremely fine, and the average particle size of fat particles is about 0.05 to 0.5 μm.
And its storage stability is extremely good.

The above-mentioned fat emulsion may contain a long-chain fatty acid triglyceride (hereinafter referred to as "LCT"), and a fatty acid triglyceride having a saturated or unsaturated fatty acid having 16 to 18 carbon atoms as a constituent fatty acid is preferable. It is illustrated as one. LCT contains the LCT as a main component, for example, vegetable oil containing 95% (weight) or more, preferably 99% or more of the LCT (eg, cottonseed oil, soybean oil, corn oil, peanut oil, safflower oil). Etc.) and the like. A preferred LCT is soybean oil. As the soybean oil, highly purified purified soybean oil is preferably used, and more preferably, the highly purified purified soybean oil obtained by further purifying the purified soybean oil by, for example, a steam distillation method (purity: containing 99.9% or more as triglyceride) Is used. Examples of the fatty acid that constitutes LCT include palmitic acid, stearic acid, linoleic acid, linolenic acid,
Examples thereof include oleic acid. When LCT is contained, the weight ratio of the main component to LCT is 4: 1 to 1: 1.
4, preferably 2: 1 to 1: 2, more preferably 1:
It is 1.

The above-mentioned main component contained in the Alzheimer's disease prophylactic / therapeutic agent of the present invention is generally, after administration, rapidly and easily absorbed from intestinal epithelial cells, transported to the liver via the portal vein, and oxidized in the liver to generate energy. Therefore, it is used as a nutritional supplement as a high-calorie energy source that can be easily absorbed. Therefore, the preventive / therapeutic agent for Alzheimer's disease of the present invention includes proteins, amino acids, peptides, plant lipids, sugars, minerals, vitamins and other known additives (e.g. You may mix | blend a (agent) etc. suitably.

Examples of the protein include vegetable protein, whey protein and low-lactose milk protein, and the amino acids include valine, leucine, isoleucine, threonine, lysine,
Examples of methionine, phenylalanine, tryptophan, as plant lipids, safflower oil, corn oil, soybean oil, cottonseed oil, sunflower oil, linoleic acid such as linseed oil, lipids containing linolenic acid are exemplified, as the sugar , Glucose, mannose, galactose, monosaccharides such as fructose, lactose, sucrose, disaccharides such as maltose, dextrin, polysaccharides such as pregelatinized starch, and the like, minerals include sodium, potassium, calcium, magnesium, Iron, zinc, chlorine, phosphorus, copper,
Examples of manganese, cobalt, molybdenum, chromium, selenium, and the like include vitamins A (A ₁ , A ₁ ,
A ₂ , retinene, provitamin A), vitamin B ₁ (thiamine, anoylin), vitamin B ₂ (riboflavin,
Lactoflavin), vitamin B ₆ (pyridoxine, pyridoxal, pyridoxamine, pyridoxal phosphate), pantothenic acid, nicotinic acid amide, biotin, folic acid, vitamin B ₁₂ , vitamin C, vitamin D (D ₂ , D)
₃ , provitamin D), vitamin E (tocopherol), vitamin K (K ₁ , K ₂ , K ₃ ) and the like.

The preventive / therapeutic agent for Alzheimer's disease of the present invention is
In the case of oral administration, the standard adult dose is 100 g to 300 g per day.
(For example, if it is a 10% w / v solution, 1,000 ml to 3,000 m
l) is given in several divided doses, and 10% if given parenterally
Dosage rate 100-150 as w / v-30% w / v solution
It is continuously administered to the stomach, duodenum, or jejunum at a rate of ml / hour, or divided into several times a day by instillation or intravenous administration. The dose, dose concentration, and dose rate may be appropriately increased or decreased according to age, symptoms, body weight, and the like.

[0028]

According to the preventive / therapeutic agent for Alzheimer's disease of the present invention, at least one selected from fatty acids having 6 to 10 carbon atoms, salts thereof and esters thereof (excluding triglyceride) is contained as a main component. Fatty acids such as caprylic acid pass through the blood-brain barrier and are transferred to cerebrospinal fluid, and are metabolized to acetyl CoA in brain cells, and excess acetyl CoA produces acetylcholine together with choline.

[0029]

EXAMPLES In order to explain the present invention in more detail, examples and experimental examples will be given below, but the present invention is not limited thereto.

Example 1 50 g of purified soybean oil (LCT), 50 g of caprylic acid, 22.1 g of glycerin in the Japanese Pharmacopoeia and an appropriate amount of distilled water for injection were taken,
12 g of egg yolk phospholipid was mixed as an emulsifier, the total amount was adjusted to 1 liter, and coarse emulsification was performed using a homomixer. Further, using a Manton-Gaulin homogenizer, a total pressure of 200
It was emulsified for 10 minutes under a pressure of ˜250 kg / cm ² . This gave a homogenized very fine emulsion (pH 6.3). The average grain size of this emulsion was 0.2 to 0.4 μm. This emulsion was placed in a glass bottle of appropriate quality, and then heat-sterilized by a conventional method to obtain a milk-like intravenous Alzheimer's disease preventive / therapeutic agent.

Example 2 An emulsion (pH 6.3) was obtained in the same manner as in Example 1 except that 100 g of caprylic acid was used without using purified soybean oil (LCT). The average grain size of this emulsion is 0.2-0.
It was 4 μm. This emulsion was placed in a glass bottle of appropriate quality, and then heat-sterilized by a conventional method to obtain a milk-like intravenous Alzheimer's disease preventive / therapeutic agent.

Example 3 50 g of refined soybean oil (LCT), caprylic acid ethyl ester
50 g, Japanese Pharmacopoeia glycerin 22.1 g, sucrose 50 g, a small amount of fragrance and an appropriate amount of distilled water for injection were taken, 12 g of egg yolk phospholipid was mixed as an emulsifier, and the total amount was 1 liter, followed by rough emulsification using a homomixer. . Thereafter, emulsification was performed in the same manner as in Example 1. This gave a homogenized very fine emulsion (pH 6.3). The average grain size of this emulsion is 0.2-
It was 0.4 μm. This emulsion was placed in a glass bottle of appropriate quality, and then heat-sterilized by a conventional method to obtain a milk-like intravenous Alzheimer's disease preventive / therapeutic agent.

Example 4 19.7 g of acid caseinate was dissolved in an appropriate amount of an aqueous solution of sodium carbonate or potassium carbonate, and 12 g of sodium caprylate and 3 g of safflower oil were added to this aqueous solution and homogenized, followed by spray drying or freezing. It was dried by drying. Next, 0.3 g of DL-methionine, 64 g of dextrin, 1 g of vitamins and 5 g of minerals were mixed in a V blender to obtain a powdery oral therapeutic agent for Alzheimer's disease.

Example 5 5.4 g ethyl caprylic acid, 1.3% safflower oil
g, casein hydrolyzate 8.87 g, DL-methionine 0.14
g, dextrin 28.8g, Japanese Pharmacopoeia glycerin 0.2
g, 1 g of vitamins, 5 g of minerals and 0.2 g of egg yolk phospholipid were added to 100 ml of purified water and mixed by a homogenizer to obtain a liquid prophylactic / therapeutic agent for Alzheimer's disease for tube.

Example 6 5.4 g of sodium caprylate, 3 g of safflower oil, 19.7 g of acid casein, 0.3 g of DL-methionine, 54 g of α-corn starch, 10 g of sucrose, 1 g of vitamins and 5 g of minerals were homogeneously mixed, By solidifying with a molding machine or an extruder that can be humidified and heated, a solid oral Alzheimer's disease prophylactic / therapeutic agent was obtained.

EXPERIMENTAL EXAMPLE 1 Sodium caprylate was forcibly orally administered to a rat using a metal probe, and the time-dependent change of the acetylcholine content in the brain homogenate was examined.

1. Animals Used Twenty-five 4-week-old male rats were subjected to the test. The body weight at the time of test use was 118.4 g to 158.4 g.

2. Dosage Sodium caprylate (manufactured by Sigma) was administered at 2.38 g / kg to prepare a 7.93% aqueous solution with a volume of 30 ml / kg, which was 4 ml / min / animal. 5 animals for each test
The animals were used.

3. Determination of acetylcholine [Pretreatment] Before administration, 10 minutes, 30 minutes, 1 hour and 2 after administration
At the time point, each rat was decapitated and the brain was immediately removed to measure the wet weight of the brain. Next, 500 μl for 100 mg of brain
0.2 M perchloric acid (containing 100 μM EDTA2Na)
Was added, and 100 μl of 10 ⁻⁴ M ethyl homocholine was added as an internal standard per 500 μl of perchloric acid.
The mixture was homogenized with a potter type Teflon homogenizer at 000 rpm. Then, after allowing to stand on ice for 30 minutes to completely perform the slow protein, it was centrifuged at 10,000 g × 15 minutes at 0 ° C., and 200 μl of the supernatant was neutralized by adding 200 μl of 0.2 M KHCO ₃ . . After leaving it on ice for 30 minutes, add 0.45μ of the supernatant.
The product filtered with the m filter was injected into a high performance liquid chromatograph equipped with an electrochemical detector.

[Test Results] Acetylcholine and choline content in the brain homogenate are shown in Table 1 below. The statistical processing was carried out by using the Ft test method, and the value before administration was used as a control ( ^** P <0.01).

[0041]

[Table 1]

Acetylcholine significantly increased 10 minutes after administration, gradually increased until 30 minutes after administration, and recovered to the pre-administration value 2 hours after administration.

The reason why acetylcholine increases is that fatty acids having 6 to 10 carbon atoms, especially caprylic acid (octanoic acid), are transferred to the cerebrospinal fluid. It is considered that a minute of acetyl CoA is synthesized into acetylcholine together with choline.

Therefore, the prophylactic / therapeutic agent for Alzheimer's disease according to the present invention stimulates the synthesis of acetylcholine as in the case of conventional agents for Alzheimer's disease, or stimulates the receptor with an agonist of muscarinic acetylcholine receptor. The mechanism of action is fundamentally different from that of acetylcholine, which increases acetyl-CoA, which is also a raw material of acetylcholine, and produces acetylcholine in the brain, which is useful as a preventive and / or therapeutic agent for Alzheimer's disease. is there.

[0045]

[Effects of the Invention] Since the acetylcholine is produced in the brain cells by orally or parenterally administering the preventive / therapeutic agent for Alzheimer's disease of the present invention to humans, etc., this agent shows that the acetylcholine content in the brain is decreased. It can be used for the purpose of improving the symptoms of disease patients and preventing Alzheimer's disease.

Claims (1)

[Claims] 1. A prophylactic / therapeutic agent for Alzheimer's disease, which comprises, as a main component, at least one selected from fatty acids having 6 to 10 carbon atoms, salts thereof and esters thereof (excluding triglyceride).