JPH04273817A - Low density lipoprotein receptor activating agent - Google Patents

Abstract

PURPOSE:To provide a drug containing docosahexaenoic acid as an active ingredient, capable of specifically reducing LDL in plasma without being accom panied by the storage of cholesterol in a liver and further capable of reducing triglycerides in the plasma. CONSTITUTION:The objective agent contains as an active ingredient a purified product from a fish oil or a chemically synthesized product such as docosahexaenoic acid or a pharmaceutically acceptable salt (e.g. Na salt or Ksalt), ester (e.g. glyceride or ascorbic acid ester) or amide (e.g. a derivative bonded to an amino acid, peptide or protein through an amide bond) thereof. The agent is preferably compounded with an antioxidant such as butylhydroxytoluene, propyl gallate or alpha-tocopherol.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to low density lipoprotein (hereinafter referred to as L
DL) receptor activity and is capable of lowering LDL in plasma without increasing liver cholesterol and blood cholesterol.

0002

BACKGROUND OF THE INVENTION A state in which blood cholesterol levels are elevated is called hyperlipidemia, and it has been known that it leads to diseases such as obesity and arteriosclerosis. Since hyperlipidemia is nothing but a state in which cholesterol synthesis in the body is abnormally increased, cholesterol synthesis inhibitors and calcium antagonists are used for drug treatment of hyperlipidemia.

[0003] It has also been known that plasma cholesterol levels are lowered by ingesting unsaturated fatty acids such as linoleic acid, arachidonic acid, and eicosapentaenoic acid and polyene phospholipids (Japanese Patent Laid-Open No. 11832-1983).
3, JP-A-58-38215, etc.). Furthermore, cholesterol exists in plasma mainly in lipoproteins as is or as fatty acid ester, and the increase in plasma cholesterol level is parallel to the increase in various lipoproteins. The main plasma lipoproteins are
High-density lipoprotein (specific gravity 1.063-1.210, hereinafter abbreviated as HDL) works to eliminate cholesterol from tissues, and LDL (specific gravity 1.006-1.019) works to transport cholesterol between tissues. . HDL in plasma
Increasing is rather preferable because it leads to an increase in the flexibility of the cell membrane. On the other hand, an increase in LDL causes obesity, hyperlipidemia, arteriosclerosis, etc. From this point of view, there is a need for pharmaceuticals that promote the absorption and metabolism of LDL in the liver.

0004

[Problems to be Solved by the Invention] Plasma cholesterol levels are reduced by intake of unsaturated fatty acids and polyene phospholipids. However, this effect is due to inhibition of cholesterol absorption from the intestinal tract, and LD
There is a problem in that not only L but also HDL is reduced.

[0005] Cholesterol synthesis inhibitors and calcium antagonists used to improve plasma lipids similarly lower blood cholesterol without distinguishing between LDL and HDL, but do not change blood triglycerides. Therefore, the problem is that it causes a high triglyceride state in the blood. At the same time, none of these drugs is known to increase the activity of the LDL receptor, which is the mechanism by which cells take up LDL.

Furthermore, simply activating LDL receptors in the liver for the purpose of eliminating LDL from plasma does not
It is thought to promote the accumulation of cholesterol in the liver. The liver itself synthesizes a certain amount of cholesterol, and simply increasing absorption without suppressing endogenous cholesterol production will cause cholesterol to concentrate and accumulate in the liver, leading to liver cirrhosis. , which can cause liver damage such as fatty liver.

[0007] An object of the present invention is to provide a drug that reduces LDL cholesterol in plasma by activating LDL receptors in the liver, suppresses endogenous cholesterol production in the liver, and at the same time reduces triglycerides in plasma. It is to be.

[0008]

[Means for Solving the Problems] In view of the above circumstances, the inventors of the present invention have made extensive studies and have found that docosahexaenoic acid (al
lcis 4,7,10,13,16,19-doc
osahexaenoic acid (hereinafter abbreviated as DHA) or its pharmaceutically acceptable salt, ester, or amide specifically reduces LDL in plasma without accumulating hepatic cholesterol, and further reduces triglycerides in plasma. This discovery led to the completion of the present invention.

The present invention is an LDL receptor activator containing docosahexaenoic acid or a pharmaceutically acceptable salt, ester or amide thereof as an active ingredient.

DHA that can be used in the present invention is a purified product from fish oil, a chemically synthesized product, or the like. DHA can also be used in the present invention as its pharmaceutically acceptable salt, ester or amide.

DHA esters that can be used in the present invention include, for example, glycerides, ascorbic acid esters, sugar esters, and ethyl esters. Pharmaceutically acceptable salts of DHA that can be used in the present invention include, for example, sodium, potassium, and the like. As the amide of DHA that can be used in the present invention, for example, a derivative bound to an amino acid, peptide, protein, etc. through an amide bond can be used. In addition to esters, salts or amides, other derivatives that can be converted into acids in vivo and are also pharmaceutically acceptable, such as alcohols,
Amides, dibasic acids, etc. can also be used.

00
12] The dosage of the LDL receptor activator of the present invention varies depending on the symptoms of the disease, route of administration, dosage form, etc., but is generally about 10 mg to 60 g/dose of the active ingredient itself.
day/body weight 60 kg.

The LDL receptor activator of the present invention preferably contains one or more antioxidants, such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, pharmaceutically acceptable quinones, and α-tocopherol. .

The LDL receptor activator of the present invention can be administered orally and parenterally (tubally, enterally, subcutaneously or intravenously,
(administration as an infusion or suppository, etc.) can be used. The LDL receptor activator of the present invention is administered in the form of soft/hard capsules, tablets, granules, fine granules, aqueous suspensions, oil-based preparations (liposome preparations, lipid microsphere preparations), etc. It can be done.

[0015] The active ingredient of the present invention is formulated using generally pharmaceutically acceptable surfactants, excipients, lubricants, flavoring agents, deodorants, adjuvants, and, if necessary, enteric-coated preparations. Therefore, it can be carried out appropriately using pharmaceutically acceptable film-forming substances, coating aids, etc. Specific examples thereof are as follows.

Components for improving the disintegration and dissolution of drugs include, for example, alcohols, esters, polyethylene glycol derivatives, sorbitan fatty acid esters,
One type or a combination of two or more types of surfactants such as sulfated fatty alcohols can be added.

As the lubricant, for example, one or more of magnesium stearate, talc, hydrogenated oil, etc. can be added. Also as a flavoring and flavoring agent,
Sweeteners, flavors, colorants, preservatives, etc. may also be included.

Adjuvants such as suspending agents and lubricants may include, for example, coconut oil, olive oil, sesame oil, peanut oil, calcium lactate, safflower oil, soybean phospholipid, and the like.

Film-forming substances include, for example, carbohydrate derivatives such as cellulose acetate phthalate;
Examples include methyl acrylate/methacrylic acid copolymer and methyl methacrylate/methacrylic acid copolymer. In addition, when coating the above-mentioned film-forming substances, in addition to commonly used coating aids such as plasticizers, the properties of the film-forming agent can be improved by adding various additives to prevent the chemicals from adhering to each other during coating operations. This can improve the coating process and make coating operations easier. In addition, a dosage form may be prepared in which the active ingredient is microencapsulated using a film-forming substance and then excipients and the like are mixed therein. As excipients, lactose, crystalline cellulose, carboxymethyl cellulose calcium, etc. can be used.

[0020]

Effects of the Invention The LDL receptor activator of the present invention enhances the activity of the receptor that specifically removes LDL, which is involved in obesity and diseases, from plasma, and at the same time suppresses the production of endogenous cholesterol in the liver. This drug does not increase blood cholesterol.

According to the LDL receptor activator of the present invention,
By improving symptoms such as hyperlipidemia associated with an increase in LDL in plasma, obesity, arteriosclerosis, coronary artery disease,
It becomes possible to prevent and treat diseases such as ischemic heart disease, cerebral embolism, stroke, aneurysm, varicose veins, thrombosis, and lower limb artery occlusion.

[0022]

EXAMPLES Next, the present invention will be explained in more detail with reference to examples. In the following, percentages represent weight % unless otherwise specified.

[0023]

[Example 1] Weight at the time of acceptance is 125-150
Thirty-six female SD rats (36 g) were given free access to a basic diet (product of Allied Mills, USA, trade name: Wayne Lab Blocks, containing 4.5% total fat by weight) for 3 weeks. These 3 at the start of the experiment 3 weeks later
The 6 rats were divided into 3 groups of 12 rats each, and each group received 10 rats.
Over the course of several days, all fatty acid residues are converted to DHA as an additive.
The triglyceride (hereinafter abbreviated as tri-DHA) is 4
% mixed experimental diet was administered. To prevent fatty acid oxidation, 0.05% of vitamin E and 0.02% of tert-butylhydroquinone (manufactured by Sigma, USA) were added to the feed, and the feed was stored at -20°C for one day and replaced every day.

[0024] After that, LDL labeled with 125I as a radioactive marker (125I-LDL) was given to experimental animals.
), followed by administration of 125I-LDL over a period of 6 hours to keep the plasma LDL concentration constant. 6
LDL labeled with 131I (131
A fixed amount of I-LDL) was administered to each group. 131I-L
Ten minutes after DL administration, the mice were sacrificed due to blood loss from the abdominal aorta, the liver was removed, and radioactivity was measured using a gamma counter (manufactured by Packard Instruments, USA).

[0025] LDL receptor activity in the liver was determined from the amount of 131I-LDL uptake into the liver over 10 minutes. In addition, the amount of endogenous cholesterol production in the liver is 125I-
It was determined from the amount of LDL. Each result was expressed as a ratio (%) to the control example (non-drug administration system).

[0026] Total cholesterol and triglyceride concentrations in plasma were determined using an enzyme method kit (manufactured by Boehringer Mannheim Biochemical, USA). plasma LDL
- Cholesterol content was measured at 164,905 G in the animal's blood taken just before administration of labeled LDL.
Centrifuged for hours, density 1.005-1.020g/m
The cholesterol contained in the 1 fraction was determined by colorimetry. Plasma triglycerides were isolated by thin layer chromatography and quantified colorimetrically. The results are shown in Table 1.

[0027]

Example 2 An experiment was conducted under the same conditions as in Example 1, except that the amount of avian DHA added was 1%. The results are shown in Table 1.

[0028]

[Example 3] Additive is DHA sodium salt (addition amount 1
The experiment was conducted under the same conditions as in Example 1, except that the concentration was changed to (%). The results are shown in Table 1.

[0029]

[Example 4] The additive was DHA glycinamide (addition amount 1
The experiment was conducted under the same conditions as in Example 1, except that the concentration was changed to (%). The results are shown in Table 1.

[0030]

[Example 5] DHA free fatty acid (addition amount 1%) was added as an additive.
) The experiment was conducted under the same conditions as in Example 1, except that The results are shown in Table 1.

[0031]

[Comparative Example] An experiment was conducted under the same conditions as in Example 1 except that avian DHA was not added. The results are shown in Table 1.

Both liver LDL absorption activity and liver LDL cholesterol content were set to 100% for control purposes. Also, plasma LDL cholesterol and plasma triglyceride,
The value here was taken as the reference value.

[0033]

Comparative Example 1 An experiment was carried out under the same conditions as in Example 1, except that the additive was triglyceride (addition amount: 4%) whose fatty acid residues were all α-linolenic acid. The results are shown in Table 1.

[0034]

[Comparative Example 2] An experiment was conducted under the same conditions as in Example 1, except that the additive was triglyceride (addition amount: 4%) whose fatty acid residues were all eicosapentaenoic acid. The results are shown in Table 1.

[0035]

[Table 1]

Claims (1)

[Claims] Claim 1: A low-density lipoprotein receptor activator containing docosahexaenoic acid or a pharmaceutically acceptable salt, ester, or amide thereof as an active ingredient.