WO1995006471A1

WO1995006471A1 - Blood triglyceride lowering agent

Info

Publication number: WO1995006471A1
Application number: PCT/JP1994/001427
Authority: WO
Inventors: Takeshi Uchida
Original assignee: The Green Cross Corporation
Priority date: 1993-09-01
Filing date: 1994-08-30
Publication date: 1995-03-09
Also published as: JPH0769897A

Abstract

A blood triglyceride lowering agent containing an active ingredient comprising a fat emulsion containing prostaglandin E1 or a derivative thereof. It is useful for preventing or treating mammalian hyperlipemia, ameliorating lipid metabolism, and preventing or treating arteriosclerosis and fatty liver caused by hyperlipemia. Further it has excellent sustained-release performance, persistency and capability of local (focal) concentration, and good preservability because of the emulsion form.

Description

Description Blood triglyceride lowering agent Technical field

TECHNICAL FIELD The present invention relates to a blood triglyceride lowering agent. Background art

In general, hyperlipidemia refers to a state in which serum lipids such as cholesterol, triglycerides, and phospholipids in the blood are abnormally increased. Therefore, treatments are roughly divided into hypercholesterolemia and hypertriglyceridemia, each of which is based on diet and moderate exercise. If these measures do not improve the condition, drug therapy has been given. For the treatment of hyperlipidemia with drugs, anion-exchange resins, cholesterol synthesis inhibitors (HMG-CoA reductase inhibitors), or propcol are useful for hypercholesterolemia. For hypertriglyceridemia, clofibrate preparations, nicotinic acid preparations, etc. are useful, and each is used as a therapeutic agent for hyperlipidemia.

Hypercholesterolemia ultimately causes arteriosclerosis and cerebral thrombosis, and hypertriglyceridemia ultimately causes fatty liver and coronary diseases. The above drugs also play a role as agents for preventing diseases such as arteriosclerosis and fatty liver. However, these drugs are also known to have a variety of side effects, such as the antitriglyceridemia agent clofibrate, which has diarrhea, dizziness, etc. In addition, hepatic tumor formation is suspected, and nicotinic acids have been suggested to have the adverse effect of suppressing the level of cyclicAMP, the mechanism of action.

For this reason, there is a need for the development of safe and, more preferably, persistent antihyperlipidemic agents.

On the other hand, prostaglandin (hereinafter referred to as PG) is known as an overnight coil that is widely distributed in living tissues. This PG and its various analogs are involved in the physiology and pathology of biological functions in a complex manner, and their pharmacological actions are quite diverse.Therefore, the development of new drugs using this as an active ingredient is expected. Have been.

Regarding the above-mentioned PG, the present inventors have already developed a sustained-release formulation of Blostar Granine £ (hereinafter, referred to as PGE). This is a fat emulsion containing PGE !, which suppresses the inactivation of PGE, in the lungs, is more stable, has a sustained release (sustained), and It is a preparation with excellent focus concentration (JP-A-58-222, JP-A-60-511, and JP-A-59-141) Gazette).

Disclosure of the invention

An object of the present invention is to provide a novel anti-triglyceridemia agent. In addition, the present invention relates to PGE, The purpose is to provide a new pharmaceutical use of the emulsion.

The present inventors have conducted intensive studies in order to achieve the above object, and as a result, have found a new blood triglyceride lowering effect in PGE and other fat emulsions containing the same, and the effect is further improved. The present invention was found to be stable and sustained-release (sustained), and completed the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

That is, the present invention provides a prostaglandin E! Or, it is a blood triglyceride lowering agent comprising a fat emulsion containing the derivative thereof.

The derivative of PGE, used in the present invention is a concept encompassing compounds that can retain PGE! Activity. Specifically, PGE! Alkyl esters (JP-A-59-216820), alkoxycarbonylalkylesters or acyloxyalkyl esters (JP-A-59-206344, JP-A-59-21664). 60-137 779), 9-Acyloxy form (Japanese Patent Application Laid-Open No. 58-39660, Japanese Patent Application Laid-Open No. Hei 3-204853 and Japanese Patent Application Laid-Open No. Hei 5-2103862) No. bulletin), 7-Cho body (JP-A-58-110562).

In the present invention, PGE! And its derivatives are also collectively referred to as PGE1s.

In the present invention, a fat emulsion containing PGE! And oil components dispersed in a dispersion medium as droplets (oil-in-water emulsions, o Zw type emulsion). Hereinafter, it is also referred to as PGE, a kind-containing fat emulsion.

The constituent components of the PGE, and the like fat emulsion of the present invention are PGE, and the like, an oil component (such as a vegetable oil), an emulsifier (such as a phospholipid), and water.

The fat emulsion containing PGE or the like of the present invention is mainly composed of 5 to 50% (w / V) of vegetable oil, 1 to 50 parts by weight per 100 parts by weight of vegetable oil, preferably 5 to 50 parts by weight. It consists of 30 parts by weight of phosphorus fat and an appropriate amount of water.

Examples of vegetable oils include soybean oil, sesame oil, castor oil, cottonseed oil, and olive oil. Preferably, it is refined soybean oil of high purity, and more preferably, refined soybean oil obtained by further purifying refined soybean oil, for example, by a steam distillation method (purity: g) 99.9% or more as glycerides, diglycerides and monoglycerides). It may also contain medium-chain fatty acid triglycerides (so-called MCT), fish oil and the like.

Examples of phospholipids include egg yolk phospholipids and soybean phospholipids, and these purified phospholipids are particularly preferably used.

The purified phospholipid can be prepared by a conventional method by a fractionation method using an organic solvent. It is mainly composed of phosphatidylcholine and phosphatidylethanolamine, and the other phospholipids are phosphatidyl inositol and phosphatidylinositol. Tidylserine, sphingomye Also contains phosphorus.

Alternatively, purified phospholipids from which phosphatidylethanolamine has been further removed may be used. This can be achieved by using a phospholipid such as egg yolk soybean and extracting the organic solvent in a conventional manner. It is obtained by purifying with an inorganic adsorbent such as silica gel or alumina after performing the painting. The phospholipid thus obtained is mainly composed of phosphatidylcholine (Japanese Patent Application Laid-Open No. 60-149524).

In addition, phosphatidylinositol itself, phosphatidylinoleitol, phosphatidylinolenormin, and phosphatidylserine can also be used.

In addition, the PGE or other fat emulsion containing PGE used in the present invention may further contain, if necessary, an emulsifying aid, a preservative, a stabilizer, a polymer, a tonicity agent, etc., in addition to the above-mentioned components. .

Examples of the emulsifying aid include fatty acids having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms or pharmaceutically acceptable salts thereof, and aliphatic amines having 2 to 22 carbon atoms. And the like.

Here, the fatty acid is not particularly limited as long as it can be added to pharmaceuticals, and may be either linear or branched, but concretely, linear stearic acid or carboxylic acid It is preferable to use oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid and the like.

These pharmacologically acceptable salts include, for example, alkali metal salts (sodium salt, potassium salt, etc.), Lucari earth metal salts (calcium salt, magnesium salt, etc.) and the like.

The aliphatic amine is not particularly limited as long as it can be added to pharmaceuticals. Examples thereof include linear or branched primary amines having 2 to 22 carbon atoms, Examples are secondary amines, such as ethanolamine, propylamine, octinoreamin, stearylamine, oreoleamine, etc. .

The mixing ratio is PGE! If the fatty acid-containing fat emulsion is 100%, the amount of fatty acids or salts thereof is 0.3% (wZv) or less, or the amount of aliphatic amines is 0.1% (wNv) or less. This is preferred.

Stabilizers include, for example, cholesterols in an amount of less than 0.5% (wZV), preferably less than 0.1% (w / V), or 5% (w / V). ) In the following, preferably 1% (w / V) or less of phosphatidic acid and the like are mentioned.

Any of the cholesterols and phosphatidic acids can be used as long as they can be used as pharmaceuticals.

Examples of the high molecular substance include albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, and hydroxyshethyl starch. For example, PGE! These may be used in an amount of 0.1 to 5 parts by weight (preferably 0.5 to 1 part by weight) per part by weight.

It is preferable to use human-derived albumin due to antigenicity. Examples of the vinyl polymer include polyvinylpyrrolidone.

Further, nonionic surfactants include polyalkylene glycols (for example, having an average molecular weight of from 1,000 to 10,000, preferably from 4,000 to 6,6). 000 polyethylene glycol) Polyoxyalkylene copolymer (for example, polyoxyethylene having an average molecular weight of 1,000 to 20,000, preferably 6,000 to 10,000) — Polyoxypropylene non-polymer), hydrogenated castor oil polyoxyalkylene derivative [for example, hydrogenated castor oil polyoxyethylene- (20) -ether, same- (40) -ether, same- (100) -ether etc.), castor oil polyoxyalkylene derivative [for example, castor oil polyoxyethylene mono (20) -ether, same- (40) -ether, same (10 0) —ether etc.] can be used.

Examples of the tonicity agent include glycerin and glucose.

The amount of PGE, contained in the above-mentioned fat emulsion can be appropriately increased or decreased depending on the form and use of the emulsion, but generally, a very small amount, for example, 0.2 to 100 g Zml is contained in the emulsion. It is enough to let them.

Examples of particularly preferred compositions of the PGE and other fat emulsions used in the present invention include the following. PGE! Class 1 \ 0 0 p.g Refined soybean oil 500 500 mg Highly refined lecithin 550 mg Oleic acid 0.15 mg Concentrated glycerin 550 mg Distilled water Proper

A total of 1 ml of PGEi-containing fat emulsion can be prepared by various methods. For example, it is produced by the following method.

That is, a predetermined amount of an oil component (preferably, soybean oil), phospholipid, PGE, and other additives described above are mixed and heated to form a solution, and a conventional homogenizer (for example, a high-pressure spray type) is used. Homogenizer, ultrasonic homogenizer, etc.) to produce a water-in-oil dispersion, then add the required amount of water to the dispersion, homogenize again with the homogenizer, and perform oil-in-water dispersion. It can be manufactured by converting it into a type emulsion. Depending on the production convenience, additives such as a stabilizer and a tonicity agent may be added after the preparation of the fat emulsion (Japanese Patent Application Laid-Open No. 58-222014).

Following the above treatment, a sterilization treatment may be performed. As the sterilization treatment, a usual method is used, and examples thereof include a 0.22 // sterilization filter method, a γ-ray irradiation method, and a high-pressure heat treatment method.

The thus-prepared fat emulsion containing PGE or the like may be added as it is or, if desired, with other components added. Accordingly, it is used as the blood triglyceride lowering agent of the present invention.

Other components include eicosapentaenoic acid (so-called EPA), docosahexaenoic acid (so-called DHA), and the like.

The blood triglyceride lowering agent of the present invention can be administered parenterally in the form of an injection or the like. Intravenous administration is particularly preferred. The administration is, for example, PGE! It is performed by continuous intravenous infusion once a day at a rate of 1 to 50 〃g, 0.02 to 0.SngZkg.

Since the blood triglyceride lowering agent of the present invention has an effect of lowering blood triglyceride concentration, it can be used for mammals (eg, mice, rats, rabbits, dogs). , Cats, humans, etc.) to prevent or treat hyperlipidemia and improve lipid metabolism. It is also useful for preventing or treating arterial sclerosis and fatty liver caused by hyperlipidemia.

Further, since the blood triglyceride lowering agent of the present invention is in the form of a fat emulsion, it is excellent in sustained release, sustainability, and local (lesion) concentration in addition to the above-mentioned effects. Good storage stability.

Examples and test examples

Hereinafter, the present invention will be described specifically with reference to Examples and Test Examples, but the present invention is not limited thereto.

5.4 g of refined egg yolk phospholipids in 3 Og of refined soybean oil, 1.5 mg of PGE and 0.72 g of oleic acid were added and dissolved by heating at 40 to 75 ° C. To this, add 200 ml of distilled water, then add 7.5 g of glycerin of the Japanese Pharmacopoeia, bring the total volume to 300 ml with distilled water for injection at 20 to 40, and use a homogenizer. It was coarsely emulsified.

This Ma emissions tons - using Gaussian Li down homogenizer, Me once 1 2 0 kg / cm ^2, was passed through 1 0 times under a pressure of total 5 0 0 kg / cm ^2, and emulsified. As a result, a homogenized fat emulsion containing extremely fine PGE was obtained. The average particle size of this emulsion was from 0.2 to 0.4 m, and contained no particles larger than l〃m. Thus prepared

The PGE1-containing fat emulsion is used as an agent for lowering blood triglycerides.

Examples 2 to 5

In place of PGE! In Example 1, PGE, ethyl ester (Example 2), PGE, bivaloyloxymethyl ester (Example 3), PGE 1-octyloxycarbonyl methyl ester (Example 4), butyl- 9 — Acetoxy-11 a, 15 S — Dihydroxy 17 S, 20 — Dimethyl prostar 8, 13 E — Gen 1 1 — Ore (except for using Example 5) An emulsion was prepared according to the method of Example 1 to obtain a homogenized and very fine fat emulsion containing PGE and derivatives.

The average particle size of the emulsion was from 0.2 to 0.4 m. The PGE thus prepared! Derivative-containing fat emulsion contains blood Medium Used as a triglyceride lowering agent.

Example 6

The emulsion was prepared according to the method of Example 1, except that 5.4 g of the purified yolk lin lipid of Example 1 and 3.6 g of the yolk lin lipid were used instead of 0.72 g of oleic acid. Prepared.

As a result, a very fine fat emulsion homogenized was obtained, and the average particle diameter of the emulsion was 0.2 to 0.4 / m. The PGE i -containing fat emulsion thus prepared is used as a blood triglyceride lowering agent.

Example 7

After dissolving 100 g of egg yolk phospholipid in 600 ml of a mixed solution of form mouth and methanol (1: 1), 600 g of alumina was added with stirring. After stirring for 5 minutes, the mixture was suction-filtered through a G4 glass filter, and the separated aluminum was washed with 400 ml of a mixed solution of formaldehyde and methanol. 200 g of alumina was newly added to the combined filtrate and washing solution with stirring. After stirring for 5 minutes, the mixture was suction-filtered with a G4 glass filter, and the separated aluminum was washed with 200 ml of a mixed solvent of black mouth formum. After the combined filtrate and washings, the mixture was centrifuged at 10000 rpm at 4 ° C for 10 minutes. The supernatant was subjected to suction filtration with a 1.0-Millipore filter, and the solvent was distilled off to obtain 60 g or more of phospholipid. This purified phospholipid is substantially free of phosphatidylethanolamine (the content is 1% or less).

The yolk phospholipid of Example 1 was obtained as described above in place of the phospholipid. An emulsion was prepared according to the method of Example 1 except that the purified phospholipid thus obtained was used.

As a result, an extremely fine fat emulsion homogenized was obtained, and the average particle size of the emulsion was 0.2 to 0.4 / m. The PGE, containing fat emulsion thus prepared is used as an agent for lowering blood triglycerides.

Test example 1

For adults (chronic arterial occlusion, vibration disease, revascularization, collagen disease, diabetic patients; total of 17 1 patients), PGE prepared in Example 1 and fat emulsion containing PGE Then 5 〃g or 10 静 g was administered intravenously once a day, and continued for 2 weeks to 1 month. As a result, the blood triglyceride (triglyceride) value before the treatment was 1337 mg / d1 (average), but after the treatment, the blood triglyceride (triglyceride) value was 128 mg / d1 (average). (Average).

Test example 2

To a patient with gait impairment due to intermittent claudication, 50 g of PGE, containing the fat emulsion prepared in Example 1 as PGE, was intravenously injected once a day and continuously used for 20 days. As a result, the blood triglyceride (neutral fat) value before the administration treatment was 2889 mmol / 1, but decreased to 121 mmo 11 after the administration treatment.

Test Example 3 Toxicity test

The PGE containing fat emulsion prepared in Example 1 was applied to mice, rats and dogs as PGE! There were no deaths even after heavy intravenous administration, and no serious toxicity occurred.

Claims

The scope of the claims

1. A blood triglyceride lowering agent comprising a lipid emulsion containing prostaglandin E or a derivative thereof as an active ingredient.

2. Use of prostaglandin or a derivative thereof for the manufacture of a drug having a blood triglyceride lowering effect.

3. Use of a fat emulsion containing prostaglandin or a derivative thereof to reduce blood triglycerides