JPH0513926B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to prostaglandin fat emulsions.

Prostaglandins are generally known to have pharmacological properties. For example, they stimulate smooth muscle, have hypotensive and antilipolytic effects, and inhibit platelet aggregation. It is therefore effective in the treatment of hypertension, thrombosis, asthma, ulcers of the stomach and intestines, induction of labor and abortion in pregnant mammals, and prevention of arteriosclerosis. They are fat-soluble substances;
It is obtained in small amounts from each organ of animals that secrete prostaglandins in vivo.

Among prostaglandins, prostaglandins
F ₂ α (hereinafter abbreviated as PGF ₂ α) prostaglandin
E ₂ (hereinafter abbreviated as PGE ₂ ) prostaglandin F ₁ α
(hereinafter abbreviated as PGF ₁ α) (hereinafter, these prostaglandins are collectively abbreviated as PG) are each represented by the following structural formula, In addition to smooth muscle contraction, hypotensive, and pressor effects in the uterine muscle and isolated small intestine, antilipolytic effects, inhibition of gastric juice secretion, effects on the central nervous system, decreased platelet adhesion, and platelet aggregation and thrombus formation. It has biological effects such as inhibition of epidermal proliferation, stimulation of epidermal proliferation, and keratinization.

However, when applying this useful PG to medicine, its chemical instability poses an obstacle.

The present inventors have conducted various studies to solve the instability of PG, and as a result, the fat emulsion containing PG (hereinafter abbreviated as PG/lipo) has been developed as described above.
The present invention was completed by discovering that PG can be stabilized and can be administered intravenously.

The present invention aims to provide a stable PG preparation, and its gist is a fat emulsion containing at least one prostaglandin selected from PGF ₂ α, PGE ₂ and PGF ₁ α.

The PG used in the present invention is PGF ₂ α, FGE ₂ ,
PGF ₁ α.

In the present invention, examples of the fat emulsion include:
Examples include those mainly composed of oil components (for example, soybean oil), phospholipids, water, etc. In this example, the blending amount of each component is from 5 to 50% of the oil component (soybean oil).
500w/v%, 1~1 phospholipid per 100 parts of oil component
50 parts, preferably 5 to 30 parts, and an appropriate amount of water. Furthermore, if necessary, add an emulsifying agent [for example, 0.3%
(w/v) up to 6 to 22 carbon atoms, preferably
12-20 fatty acids or physiologically acceptable salts thereof], stabilizers [e.g. 0.5% (w/v),
Cholesterols preferably in an amount of 0.1% (w/v) or less or 5% (w/v), preferably 1%
(w/v) or less amount of phosphatidic acid], polymeric substance [for example, 0.1 to 1 part by weight of PG]
5 parts by weight, preferably 0.5 to 1 part by weight of albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, hydroxyethyl starch, etc.], isotonic agent (for example, glycerin, glucose, etc.) are added. You can also. The content of PG in a fat emulsion can be increased or decreased as appropriate depending on the form of the emulsion and its intended use, but it is generally sufficient to contain a very small amount, for example 100 to 0.2 μg/ml, in the emulsion.

Here, as the oil component, for example, soybean oil, highly purified refined soybean oil is used, and preferably,
Highly purified refined soybean oil (purity: contains 99.9% or more as triglyceride, diglyceride, and monoglyceride) obtained by further refining refined soybean oil by, for example, steam distillation is used.

Examples of phospholipids include phosphatidylserine, phosphatidylglycerin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, etc.
Mixtures of these (egg yolk phospholipids, soybean phospholipids, etc.) are used. Purified egg yolk phospholipids, soybean phospholipids, and the like are preferably purified, and can be prepared by a conventional fractionation method using an organic solvent. i.e., for example, crude egg yolk phospholipids
130g to 200ml of cold n-hexane and cold acetone
After dissolving in 100ml, gradually cool acetone 1170 under stirring.
ml, the insoluble matter was collected by filtration, and dissolved again in 260 ml of cold n-hexane and 130 ml of cold acetone.
While stirring, 1,170 ml of cold acetone was added again, and after filtering and collecting insoluble matter, the solvent was distilled off to obtain 60 g of a dry product. This one contains 70 to 70 phosphatidylcholine.
80% phosphatidylethanolamine 12-25
%, and other phospholipids include phosphatidylinositol, phosphatidylserine, and sphingomyelin. [DJ Hanahan,
et al. J. Biol. Chem., 192 , 623-628 (1951)].

Fatty acids having 6 to 22 carbon atoms as emulsification aids are
It can be used as long as it can be added to medicines. This fatty acid may be linear or branched, but
It is preferable to use linear stearic acid, oleic acid, linoleic acid, valmitic acid, linolenic acid, myristic acid, and the like. These salts are
Physiologically acceptable salts, such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, etc.), etc. can be used.

Cholesterol and phosphatidic acid as stabilizers can be used as long as they can be used medicinally.

As the albumin, vinyl polymer, and nonionic surfactant used as the polymeric substance, the following are preferable. That is, albumin of human origin is used due to antigenicity issues.

Examples of vinyl polymers include polyvinylpyrrolidone.

In addition, as a nonionic surfactant, polyalkylene glycol (for example, an average molecular weight of 1000
~10000, preferably 4000-6000), polyoxyalkylene copolymers (e.g. average molecular weight 1000-20000, preferably
6,000 to 10,000 polyoxyethylene-polyoxypropylene copolymers), hydrogenated castor oil polyoxyalkylene derivatives (for example, hydrogenated castor oil polyoxyethylene-(40)-ether, hydrogenated castor oil polyoxyethylene-(40)-ether, hydrogenated castor-oil polyoxyethylene-(20)-ether, hydrogen-( 100)-ether), castor oil polyoxyalkylene derivatives (e.g. castor oil polyoxyethylene-(20)-ether, castor oil-(40)
-ether, -(100)-ether, etc. can be used.

The fat emulsion of the present invention is produced, for example, by the following method.

That is, by mixing a predetermined amount of oil components (soybean oil), phospholipids, PG, and other additives mentioned above,
A water-in-oil dispersion is prepared by heating to form a solution and homogenizing it using a commonly used homogenizer (for example, a pressure injection homogenizer, an ultrasonic homogenizer, etc.), and then adding the required amount of water to this. In addition, the fat emulsion of the present invention can be produced by again performing homogenization using the homogenizer and converting it into an oil-in-water emulsion. Depending on the manufacturing convenience, additives such as stabilizers and isotonic agents may be added after the production of the fat emulsion.

The thus obtained fat emulsion formulation is extremely fine, with an average particle size of 1 μm or less, and has extremely good storage stability.

The fat emulsion of the present invention is administered parenterally, such as by injection,
Intravenous administration is particularly preferred. For example, its administration
PG is administered by continuous intravenous injection once a day at a rate of 1 to 100 μg, 0.02 to 0.2 ng/Kg/min.

In the fat emulsion of the present invention, the PG contained therein is stabilized, the pharmacological action of PG is strongly exerted, and the emulsion has lesion selectivity, allowing effective treatment.

Furthermore, it can be administered intravenously and has pharmacological effects.
The drug's efficacy is stable, the dosage can be small, and side effects are less likely to occur.

Moreover, swelling and dull pain that tend to occur at the injection site,
There are no side effects such as redness or fever.

The present invention will be specifically explained below with reference to Examples showing experimental examples and manufacturing examples of the fat emulsifier of the present invention, but the present invention is not limited thereto.

Example The LD ₅₀ value of the formulation of the present invention manufactured according to Example 1 below was 10% when administered intravenously to rats.
The amount of fat emulsion was 200 ml/Kg body weight or more, and the amount of 20% fat emulsion was 150 ml/Kg body weight or more, and no hemolysis was observed when injected at a normal rate.

Example 1 30g of refined soybean oil, 3.6g of egg yolk lecithin,
900 μg of PGF ₂ α, 0.15 g of sodium palmitate, and 0.15 g of phosphatidic acid were added and dissolved by heating at 45 to 65°C. Add 200ml of distilled water to this, then add 7.5g of glycerin in the Japanese Pharmacopoeia, and add 200ml of distilled water.
The total volume was made up to 300 ml with distilled water for injection at 40°C, and rough emulsification was performed using a homomixer.

This was emulsified by passing it through a Manton-Caulin homogenizer 10 times under pressure of 120 kg/cm ² in the first stage and a total pressure of 500 kg/cm ² . As a result, a homogenized extremely fine fat emulsion containing PGF ₂ α was obtained. The average grain size of this emulsion is 0.2-0.4μ,
It did not contain particles larger than 1μ.

Example 2 3.0g of soybean lecithin in 35g of refined soybean oil,
850 μg of PGF ₁ α, 0.10 g of sodium linoleate, and 0.15 g of phosphatidic acid were added and dissolved by heating at 40 to 60°C. Add 200ml of distilled water to this, then add 7.5g of glycerin in the Japanese Pharmacopoeia, and add 20 to 40 g of glycerin.
The total volume was made up to 300 ml with distilled water for injection at ℃ and coarsely emulsified using a homomixer.

This was emulsified by passing it through a Manton-Caulin homogenizer 10 times under pressure of 120 kg/cm ² in the first stage and a total pressure of 500 kg/cm ² . As a result, a homogenized extremely fine fat emulsion containing PGF ₁ α was obtained. The average grain size of this emulsion is 0.2-0.4μ,
It did not contain particles larger than 1μ.

Example 3 25g of refined soybean oil, 4.0g of egg yolk lecithin,
800 μg of PGE ₂ , 0.20 g of sodium stearate and 0.20 g of cholesterol were added and dissolved by heating at 50 to 65°C. Add 200ml of distilled water to this, then add 7.5g of glycerin in the Japanese Pharmacopoeia, and add 20 to 40 g of glycerin.
The total volume was made up to 300 ml with distilled water for injection at ℃ and coarsely emulsified using a homomixer.

This was emulsified by passing it through a Manton-Gaulin homogenizer 10 times under pressure of 120 kg/cm ² in the first stage and a total pressure of 500 kg/cm ² . As a result, a homogenized extremely fine fat emulsion containing PGE ₂ was obtained. The average grain size of this emulsion is 0.2-0.4μ,
It did not contain particles larger than 1μ.

Claims (1)

[Claims] 1 A fat emulsion containing at least one prostaglandin selected from prostaglandin F ₂ α, prostaglandin E ₂ and prostaglandin F ₁ α.