JPH0769897A - Agent for depressing blood triglyeride level - Google Patents

Abstract

PURPOSE:To obtain a blood triglyceride depressing agent containing a fat emulsion containing prostaglaiudin E1 as an active component and exhibiting excell. ent sustained releasability, durability, local (focus) accumulation property and storage stability. CONSTITUTION:This blood triglyceride depressing agent contains a fat emulsion containing prostaglandin E1 or its derivative as an active component. The fat emulsion is preferably a mixture of 5-50%(W/V) of vegetable oil, 5-30 pts.wt. (based on 100 pts.wt. of the vegetable oil) of a phospholipid and a proper amount of water. The agent is preferably used in the form of an intravenous injection and preferably 1-50mug of the agent is injected at a rate of 0.02-0.2ng/kg/min.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a blood triglyceride lowering agent.

[0002]

2. Description of the Related Art Generally, hyperlipidemia refers to a state in which serum lipids such as cholesterol, triglyceride or phospholipid in blood are abnormally increased. In actual clinical situations, hypercholesterolemia depends on the type of increased lipid. And hypertriglyceridemia are roughly treated. In both cases, the basis of treatment is diet and moderate exercise, but if symptoms do not improve, drug therapy is given. As a therapeutic agent for hyperlipidemia that is currently used, anion exchange resins, cholesterol synthesis inhibitors (HMG-CoA reductase inhibitors), propcoll, etc. are useful for hypercholesterolemia, and hypertriglyceridemia Clofibrate-based preparations, nicotinic acid preparations and the like are useful for the disease. In addition, hypercholesterolemia eventually causes arteriosclerosis and cerebral thrombosis, and hypertriglyceridemia causes fatty liver and coronary disease. Therefore, the above drugs prevent arteriosclerosis and fatty liver. Also plays a role as an agent.

However, it is also known that these drugs are associated with various side effects. For example, clofibrate, which is an antitriglyceridemic agent, is suspected to cause liver tumor formation in addition to diarrhea and dizziness. Also, with regard to nicotinic acids, adverse effects caused by suppressing the level of cyclic AMP, which is a mechanism of action, have been proposed. Therefore, there is a demand for the development of safe and more preferably durable antihyperlipidemic agents.

On the other hand, prostaglandin (hereinafter referred to as PG) is known as an autacoid 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 very diverse, so that the development of new pharmaceuticals containing this as an active ingredient is expected. .

Regarding the above-mentioned PG, the present inventors have already developed a sustained-release preparation of prostaglandin E ₁ (hereinafter referred to as PGE ₁ ). By containing PGE ₁ in a fat emulsion, it suppresses the inactivation of PGE _{1 in} the lungs, is more stable, has a sustained release (sustained release), and is a preparation with superior focus concentration. There is (JP-A-58-222)
No. 014, JP-A-60-51105, JP-A-59-1
41518 publication).

[0006]

The object of the present invention is to provide a novel antitriglyceridemic agent. Further, the present invention aims to provide a novel pharmaceutical use of a PGE ₁ -containing fat emulsion.

[0007]

Means for Solving the Problems As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that a PGE ₁ -containing fat emulsion newly has a blood triglyceride lowering action and, in addition, its effect. Is more stable and sustained (sustained)
That is, the present invention has been completed.

That is, the present invention relates to prostaglandin E
_It is a blood triglyceride lowering agent containing a fat emulsion containing ₁ or a derivative thereof as a component.

The PGE ₁ derivative used in the present invention is a concept encompassing compounds capable of retaining PGE ₁ activity. Specifically, an alkyl ester of PGE ₁ (JP-A-59-216820), an alkoxycarbonylalkyl ester or an acyloxyalkyl ester (JP-A-59-206344, JP-A-60-1377).
9), 9-acyloxy compounds (JP-A-3-2048)
53), 7-thio compounds (JP-A-58-110562), and the like. In the present invention, PGE ₁ and its derivatives are collectively referred to as PGE _1's .

In the present invention, the PGE ₁ -containing fat emulsion means a preparation in which an oil component containing PGE ₁ is dispersed as a droplet in a dispersion medium. Hereinafter, it is also referred to as a PGE ₁ -containing fat emulsion. Such a preparation can be produced according to a general emulsion production method. Basically, it is prepared by adding water, particularly purified water, to an oil liquid containing PGE ₁ and other oil components and emulsifying the mixture by a suitable method to make the whole quality uniform.

Examples of other oil components include vegetable oils and phospholipids. The PGE ₁ -containing fat emulsion of the present invention is mainly composed of 5 to 50% (W / V) vegetable oil, 1 to 50 parts by weight of phospholipid, preferably 5 to 30 parts by weight, and an appropriate amount of vegetable oil. It consists of water.

Examples of vegetable oils include soybean oil, sesame oil,
Castor oil, cottonseed oil, olive oil, etc. may be mentioned. High-purity refined soybean oil is preferable, and more preferable is high-purity refined soybean oil obtained by further refining refined soybean oil by, for example, steam distillation (purity: 99.9% or more as triglyceride, diglyceride and monoglyceride). Contained). In addition, medium chain fatty acid triglyceride (so-called MC
T), fish oil, etc. may be included.

Examples of phospholipids include egg yolk phospholipids and soybean phospholipids, and purified phospholipids thereof are particularly preferably used. This purified phospholipid can be prepared by a fractionation method using an organic solvent according to a conventional method. This consists mainly of phosphatidylcholine and phosphatidylethanolamine, and as other phospholipids,
Phosphatidylinositol, phosphatidylserine,
Also contains sphingomyelin. Alternatively, purified phospholipids from which phosphatidylethanolamine has been removed may be used. This is a method in which phospholipids such as egg yolk and soybeans are used, and after organic solvent fractionation by a conventional method, silica gel, alumina, etc. It can be obtained by purification with an inorganic adsorbent. The phospholipid thus obtained mainly consists of phosphatidylcholine (JP-A-60-14952).
4 publication). Furthermore, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol itself can be used.

In addition to the above components, the PGE ₁ -containing fat emulsion used in the present invention may further contain an emulsification auxiliary agent, a preservative, a stabilizer, a polymeric substance, an isotonicity agent, etc., if necessary. .

Examples of the emulsification aid include fatty acids having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms or pharmacologically acceptable salts thereof, and aliphatic amines having 2 to 22 carbon atoms. Here, the fatty acid is not particularly limited as long as it can be added to a pharmaceutical product, and may be linear or branched, and specifically, linear stearic acid, oleic acid, linoleic acid, palmitin. It is preferable to use an acid, linolenic acid, myristic acid, or the like. Examples of these pharmacologically acceptable salts include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), and the like.
Further, the aliphatic amine is not particularly limited as long as it can be added to a pharmaceutical product, and examples thereof include linear or branched C2-C22 primary amines and secondary amines. Examples include ethanolamine, propylamine, octylamine, stearylamine, oleylamine and the like. The blending ratio is PGE ₁ -containing fat emulsion 1
If it is set to 00%, the content of fatty acid or its salt is 0.3% (w
/ V) or less, and 0.1% (w /
v) It is preferable that the amount is the following.

The stabilizer is, for example, 0.5% (w
/ V) or less, preferably 0.1% (w / v) or less of cholesterol, or 5% (w / v) or less, preferably 1% (w / v) or less of phosphatidic acid and the like. Can be mentioned. Any of these cholesterols and phosphatidic acid can be used as long as they can be used for medicine.

As the polymer substance, for example, PGE ₁ 1
0.1 to 5 parts by weight (preferably 0.5
To 1 part by weight) albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, hydroxyethyl starch and the like. Here, as the albumin, a human-derived one is used because of its antigenicity. Moreover, polyvinylpyrrolidone etc. can be mentioned as a vinyl polymer. Further, as the nonionic surfactant, polyalkylene glycol (for example, an average molecular weight of 1,000 to
10,000, preferably 4,000 to 6,000 polyethylene glycol), polyoxyalkylene copolymer (for example, polyoxyethylene-polyoxypropylene copolymer having an average molecular weight of 1,000 to 20,000, preferably 6,000 to 10,000), hydrogenated castor oil polyoxy Alkylene derivatives [eg hydrogenated castor oil polyoxyethylene- (20) -ether, same- (40) -ether, same- (100) -ether, etc.], castor oil polyoxyalkylene derivative [eg castor oil polyoxyethylene -(20) -ether, the same- (40) -ether, the same- (100) -ether, etc.] can be used.

Examples of the tonicity agent include glycerin, glucose and the like.

The amount of PGE ₁ contained in the above fat emulsion can be appropriately increased or decreased depending on the form and use of the emulsion.
Generally, a very small amount, for example 0.2 to 100 μm, is contained in the emulsion.
Inclusion of g / ml is sufficient.

The following are examples of particularly preferable compositions of the PGE ₁ -containing fat emulsion used in the present invention. PGE 1s ₁ to 100 μg Purified soybean oil 50 to 500 mg Highly purified lecithin 5 to 50 mg Oleic acid 0.1 to 5 mg Concentrated glycerin 5 to 50 mg Distilled water Total amount 1 ml

The PGE ₁ -containing fat emulsion can be prepared by various methods, for example, the following method. That is, a predetermined amount of oil component (preferably soybean oil), phospholipid, PGE ₁ and other additives described above are mixed and heated to form a solution, and a conventional homogenizer (for example, high-pressure jet homogenizer, ultrasonic wave) is used. Produced by making a water-in-oil dispersion by homogenizing with a homogenizer, etc., then adding the required amount of water to this, homogenizing again with the homogenizer and converting to an oil-in-water emulsion. can do. Depending on manufacturing circumstances,
Additives such as a stabilizer and a tonicity agent may be added after the formation of the fat emulsion (JP-A-58-22014).

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

The thus-prepared PGE ₁ -containing fat emulsion may be used as it is or by adding other components, if desired, to 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 parenterally administered in the form of an injection or the like. Intravenous administration is particularly preferable. The administration is, for example, PG
E ₁ as ₁ to 50 μg, 0.02 to 0.2 ng / kg
It is performed by continuous intravenous infusion once a day at a rate of 1 / min.

[0025]

INDUSTRIAL APPLICABILITY The agent for lowering blood triglyceride level of the present invention has the effect of lowering blood triglyceride concentration, and therefore has high lipemia in mammals (eg, mouse, rat, rabbit, dog, cat, human, etc.). It is useful for prevention or treatment of diseases and improvement of lipid metabolism. Further, it is also useful for preventing or treating arteriosclerosis and fatty liver caused by hyperlipidemia. Further, since the blood triglyceride lowering agent of the present invention has the form of a fat emulsion, in addition to the above-mentioned effects, it is excellent in sustained release, sustainability, local (focal) concentration, and has good storage stability. .

[0026]

[Examples / Test Examples] The present invention will be specifically described below with reference to Examples and Test Examples, but the present invention is not limited thereto. Example 1 30 g of purified soybean oil, 5.4 g of purified egg yolk phospholipid and PGE
₁ 1.5 mg and oleic acid 0.72 g were added, 40
Dissolved by heating at ~ 75 ° C. To this, 200 ml of distilled water was added, and then 7.5 g of glycerin in the Japanese Pharmacopoeia was added.
The total amount was adjusted to 300 ml with distilled water for injection at -40 ° C, and the mixture was roughly emulsified with a homogenizer. Using a Manton-Gaurin homogenizer, this was 120 kg / cm ^{2 for} the first time, for a total of 50
It was emulsified by passing 10 times under a pressure of 0 kg / cm ² . This gave a homogenized fat emulsion containing very fine PGE ₁ . The average grain size of this emulsion is 0.2 to 0.4 μ.
m, and did not contain particles of 1 μm or larger. The PGE ₁ -containing fat emulsion thus prepared is used as a blood triglyceride lowering agent.

Examples 2-5 In place of PGE ₁ of Example 1, butyl-9-acetoxy-11α (Example 2), 15S-dihydroxy-17S.
(Example 3) The procedure of Example 1 was repeated except that 20-dimethylprostar 8 (Example 4) and 13E-diene-1-oate (Example 5) were used. With these, a homogenized extremely fine PGE ₁ -containing fat emulsion was obtained. The average grain size of the emulsion was 0.2 to 0.4 μm. The PGE ₁ -containing fat emulsion thus prepared is used as a blood triglyceride lowering agent.

Example 6 The procedure of Example 1 was repeated except that 5.4 g of the purified egg yolk phospholipid of Example 1 and 3.6 g of egg yolk phospholipid were used instead of 0.72 g of oleic acid. This gave a homogenized very fine fat emulsion. The average grain size of the emulsion was 0.2 to 0.4 μm. PG thus prepared
The E ₁ -containing fat emulsion is used as a blood triglyceride lowering agent.

Example 7 100 g of egg yolk phospholipid was dissolved in 600 ml of a chloroform-methanol (1: 1) mixed solvent, and alumina 6 was added.
00 g was added with stirring. After stirring for 5 minutes, suction filtration was performed using a G4 glass filter, and the separated alumina was washed with 400 ml of a chloroform-methanol mixed solvent. To the combined filtrate and washing solution, 200 g of alumina was newly added with stirring. After stirring for 5 minutes, suction filtration was performed using a G4 glass filter, and the separated alumina was washed with 200 ml of a chloroform-methanol mixed solvent. The filtrate and the washing solution were combined and then centrifuged at 4 ° C. at 10,000 rpm for 10 minutes.
The supernatant was subjected to suction filtration with a 1.0 μ Millipore filter, and then the solvent was distilled off to obtain 60 g or more of phospholipid. The method of Example 1 was followed except that the purified phospholipid obtained as described above was used instead of the egg yolk phospholipid of Example 1.
This gave a homogenized very fine fat emulsion.
The average grain size of the emulsion was 0.2 to 0.4 μm. The PGE ₁ -containing fat emulsion thus prepared is used as a blood triglyceride lowering agent. The content of phosphatidylethanolamine was 0.4% or less.

Test Example 1 Diseases for adults (chronic arterial occlusion, oscillatory disease, blood circulation)
Carried out for patients with collagen disease and diabetes mellitus; 171 in total after reconstruction.
PGE prepared in Example 1₁PGE containing fat emulsion ₁As
5 μg or 10 μg IV once a day for 2 weeks to 1
I used it monthly. As a result, blood triglyceride before treatment
Lido (neutral fat) level was 137 mg / dl (average)
However, it was as low as 128 mg / dl (average) after treatment.
Defeated

Test Example 2 To a patient with gait disorder due to intermittent claudication, 50 μg of the PGE ₁ -containing fat emulsion prepared in Example 1 as PGE ₁ was intravenously injected once a day for 20 consecutive days. As a result, the blood triglyceride (triglyceride) level before administration was 289 mmol / l.
However, it decreased to 121 mmol / l after the administration treatment.

Test Example 3 Toxicity Test Even when the PGE ₁ -containing fat emulsion prepared in Example 1 was intravenously administered to mice, rats and dogs as PGE _{1 up} to 250 μg / kg body weight, there were no deaths and no serious toxicity. It did not develop.

Claims (1)

[Claims] 1. A blood triglyceride lowering agent which comprises a fat emulsion containing prostaglandin E ₁ or a derivative thereof as an active ingredient.