JPH0128727B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to intravenous lipid emulsions of steroids with anti-inflammatory activity.

For the treatment of inflammation, such as that caused by rheumatism, steroid preparations are the most effective drugs, such as ointments,
Although they have been frequently used in the form of injections, tablets, etc., continuous use of steroid preparations brings about various side effects, and there is a recent trend to reconsider steroid therapy itself.

Side effects of steroids are caused by the continuous administration of large doses of steroids in cases such as chronic rheumatism that require long-term treatment. If a suitable formulation is developed, the side effects caused by steroids can be significantly reduced.

From this point of view, the present inventors conducted various studies in order to obtain a steroid preparation that exhibits high anti-inflammatory activity at a small dose. As a result, intravenous fat emulsions that do not contain emulsion particles of 1μ or more of the specific steroids mentioned below that have anti-inflammatory activity, especially those that contain emulsion particles of 1μ or more that contain these steroids, soybean oil, phospholipids, and an appropriate amount of water, are found. The inventors have now completed the present invention by discovering that a fat emulsion for intravenous administration, which is free from steroids, exhibits high anti-inflammatory activity even when administered in small amounts, and therefore does not cause the side effects of conventional steroid preparations.

It is an object of the present invention to provide a lipid emulsion for intravenous administration of a steroid having anti-inflammatory activity and having a specific particle size.

Another object of the present invention is to provide a new formulation of a steroid having anti-inflammatory activity that lasts longer in the inflamed area than conventional formulations and can be specifically concentrated in the inflamed area, i.e. intravenous administration of the steroid. An object of the present invention is to provide a fat emulsion for use.

Further objects and advantages of the present invention will become apparent from the following description.

According to the invention, dexamethasone palmitate or betamethasone palmitate, dexamethasone stearate or betamethasone stearate, dexamethasone myristate or betamethasone myristate, hydrocortisone palmitate, hydrocortisone stearate, hydrocortisone myristate , prednisolone palmitate, prednisolone stearate and prednisolone myristate, and is characterized in that it contains no emulsion particles larger than 1 μm (hereinafter simply referred to as emulsion), especially An effective amount of said steroid having anti-inflammatory activity, soybean oil 5-50% (W/
V), preferably 8-30% (W/V), soybean oil 100
A fat emulsion is provided containing an amount of phospholipid and a suitable amount of water in a weight ratio of 1 to 50, preferably 5 to 30.

The fat emulsion of the present invention is useful for rheumatism, immunological hemolytic anemia, idiopathic thrombocytopenic purpura,
purpura), Paget disease,
It is particularly useful as a therapeutic/preventive agent for kidney transplantation, etc.

The fat emulsion of the present invention may further contain up to 0.3% (W/V) of a fatty acid having 6 to 22 carbon atoms, preferably 12 to 20 carbon atoms, or a physiologically acceptable salt thereof as an emulsification aid. Well, also 0.5% (W/
V), preferably in an amount of up to 0.1% (W/V) or 5% (W/V), preferably 1
% (W/V) or less of phosphatidic acid as a stabilizer.

In addition, in the formulation of the present invention, a polymeric substance selected from albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, and hydroxyethyl starch may be added for formulation, and the amount of addition may be adjusted. , 0.1 to 5 parts by weight, preferably 0.5 to 1 part by weight, per 1 part by weight of the steroid having anti-inflammatory activity.

As albumin, when the purpose is to obtain a preparation for humans, it is preferable to use one derived from humans due to antigenicity issues. Examples of vinyl polymers include polyvinylpyrrolidone. Examples of nonionic surfactants include polyalkylene glycols (e.g., polyethylene glycol with an average molecular weight of 1000 to 10,000, preferably 4,000 to 6,000), polyoxyalkylene copolymers (e.g., average molecular weights of 1,000 to 20,000, preferably 6,000 to 10,000 polyoxyethylene-polyoxypropylene copolymer), hydrogenated castor oil polyoxyalkylene derivatives (e.g. hydrogenated castor oil polyoxyethylene-(40)-ether, hydrogenated castor oil-(20)
-ether, (100)-ether, etc.), castor oil polyoxyalkylene derivatives (e.g., castor oil polyoxyethylene-(40)-ether,
(100)-ether, (20)-ether, etc.).

In order to make the emulsion isotonic, commonly used tonicity agents such as glycerin and glucose can also be added.

The fatty emulsion of steroid with anti-inflammatory activity provided by the present invention is a new formulation, is extremely fine and stable, does not contain emulsion particles larger than 1μ, and contains steroid with anti-inflammatory activity for intravenous administration. It is a fat emulsion.

The lipid emulsion of the present invention is preferably administered parenterally, particularly intravenously. The dosage varies depending on the route of administration, dosage form, symptoms, etc., but for adults it is generally 10 to 1000 ml/dose as an emulsion.

The soybean oil used in the fat emulsion of the present invention is generally a highly purified refined soybean oil, which can be prepared by, for example, steam distillation [HTLips, J.Am.Oil Chemist.
Soc., 27 , 422-423 (1950)].
99.9% or more).

The phospholipid used in the present invention is also generally a purified phospholipid, and can be prepared by a conventional fractionation method using an organic solvent. That is, for example, after dissolving 130 g of crude egg yolk phospholipid in 200 ml of cold n-hexane and 100 ml of cold acetone, 1170 ml of cold acetone was gradually added while stirring, and insoluble matter was collected by filtration.
Again 260 ml of cold n-hexane and 130 ml of cold acetone
dissolve in While stirring, 1170 ml of cold acetone was added again, the insoluble matter was collected by filtration, and the solvent was distilled off.
Obtain 60 g of dry matter. This product contains 70-80% phosphatidylcholine, 12-25% phosphatidylethanolamine, and other phospholipids such as phosphatidylinositol, phosphatidylserine, and sphingomyelin. . [D.
J.Hanahanet al.J.Biol.Chem., 192, 623-628
(1951)].

Fatty acids having 6 to 22 carbon atoms as emulsification aids can be used as long as they can be added to pharmaceuticals. The fatty acid may be either linear or branched, but preferably a linear one is used. Natural fatty acids are also advantageously used. Specific examples of preferred fatty acids include stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, and the like.

The salts of the fatty acids mentioned above include physiologically acceptable salts, such as alkali metal salts (sodium salts,
potassium salts, etc.) and alkaline earth metal salts (calcium salts, etc.).

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

The effective amount of the steroid having anti-inflammatory activity contained in the fat emulsion of the present invention varies depending on the form and use of the emulsion, but is usually 0.01 to 10% (W/V) in the emulsion.
Preferably it is 0.1 to 5% (W/V).

The emulsion of the present invention is produced by using a conventional homogenizer, such as a pressure jet homogenizer or an ultrasonic homogenizer. First, the required amounts of soybean oil, phospholipids, steroids with anti-inflammatory activity, and if necessary cholesterol or phosphatidic acid as a stabilizer are mixed, heated to form a solution, and then homogenized using the homogenizer described above. It can be easily produced by preparing a water-in-oil dispersion, then adding the required amount of water thereto, homogenizing it again with the homogenizer, and converting the dispersion into an oil-in-water emulsion. (Reference: RPGeyer et al, J.Am.Oil Chem.
Soc., 32 , 365-370 (1950)).

Stabilizers and tonicity agents may be added to the resulting emulsion.

The present invention will be explained in more detail using experimental examples and examples, but the present invention is not limited thereto.

Experimental Example 1 The LD ₅₀ value of the formulation of the present invention manufactured according to Example 1 described later 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.

Experimental Example 2 DD mice (♀〓, 14-17 g) were used as animals, and the LD ₅₀ values of dexamethasone palmitate and dexamethasone phosphate as a control were determined. Dexamethasone palmitate was administered intravenously as a fat emulsion formulation according to Example 1, and the control was an aqueous solution formulation. LD ₅₀ was expressed as steroid weight (mg/Kg).

As a result, dexamethasone palmitate was
580, ♀420, while the control is 〓140, ♀115
This demonstrated that dexamethasone palmitate is extremely safe.

Experimental Example 3 A comparative experiment was conducted regarding the sustainability of the in vivo activity of this preparation. The drugs to be administered were an emulsified preparation of dexamethasone palmitate prepared according to Example 1 described later, and an aqueous solution preparation of dexamethasone phosphate and physiological saline as controls. The animals used were Wistar rats (male, 5 rats per group, weight approximately 180 g), and the drug was administered intravenously. In the experiment, carrageenan edema was induced in rats and the effects of the test drugs were compared. Carrageenin edema was induced by administering 0.1 ml of 1% carrageenan dissolved in physiological saline under the footpad of the hind paw.
The drug was administered via the tail vein 18 hours before carrageenin administration.
mg/Kg or 30 mg/Kg was administered, and the effect was measured over time in hindlimb volume. Dexamethasone phosphate was dissolved in 0.1 ml of physiological saline.

The results are shown in Figure 1, where _A2 is dexamethasone palmitate 30mg/
Kg administration group, A ₁ is the same drug 3 mg/Kg administration group, B ₂ is dexamethasone phosphate 30 mg/Kg administration group,
B ₁ is the same drug 3 mg/Kg administration group, C is physiological saline 0.1
ml administration group.

As is clear from FIG. 1, the emulsified formulation of dexamethasone palmitate showed a significant sustained release effect and local concentration in the inflamed area compared to the control dexamethasone phosphate aqueous solution formulation.

Experimental Example 4 A comparative experiment was conducted regarding the distribution of the formulation of the present invention to inflamed areas, and the results are shown in FIGS.

As the drugs to be administered, a dexamethasone palmitate emulsion preparation and a dexamethasone phosphate aqueous solution preparation were used in accordance with Experimental Example 2. The animals are
4 Wistar rats (weight 180g) per group
It was used as a fish. In the experiment, 0.1 ml of 1% carrageenan dissolved in physiological saline was administered under the hind footpad.
After 30 minutes, ^{the 3} H-labeled preparation was administered through the tail vein, various organs and tissues were removed over time, and their radioactivity was measured using a liquid scintillation counter. The administered drug was labeled with ^3H at the 6th and 7th positions. The administration of the drug was 0.3 mg (radioactivity:
30 μCi)/Kg at a rate of 1 ml/min/100 g weight.

In FIGS. 2 to 6, A is a group administered with a dexamethasone palmitate emulsion formulation, and B is a group administered with a dexamethasone phosphate aqueous solution formulation.

From FIG. 2 (disappearance kinetics from the blood), it can be seen that the emulsified preparation of the present invention has better retention in the blood than the aqueous solution preparation for about 2 hours immediately after administration. The intramuscular distribution is shown in Figure 3.

Both preparations showed completely opposite movements for about 2 hours after administration of the drug. The distribution to the liver is shown in Figure 4. The distribution of the emulsified preparation of the present invention to the liver shifted temporally to the right. The distribution to the spleen is shown in Figure 5. The initial uptake of the emulsified formulation of the present invention was remarkable and showed a large difference from the control. This means that
The present invention shows a rapid effect on the antibody production system, suggesting the usefulness of the present invention in kidney transplantation and the like.

The distribution to the inflamed area is shown in Figure 6. The right foot is
The patient has carrageenan edema, and his left foot is in control. The emulsified preparation of the present invention was uptaked into inflamed areas up to 2.5 hours after administration, reaching about 2 to 3 times the amount taken into non-inflamed areas. On the other hand, with the aqueous solution formulation, no specific uptake into the inflamed area was observed.

Example 1 100.0g of purified soybean oil, 24.0g of purified egg yolk phospholipid,
Add 20 g of dexamethasone palmitate, 0.5 g of sodium oleate, and 0.5 g of phosphatidic acid, and dissolve by heating at 40 to 75°C. 1000ml for this
of distilled water and using a Manton-Gaulin type homogenizer, the first stage was 100Kg/cm ² and the total pressure was 450.
It is emulsified by passing it 10 times under a pressure of Kg/cm ² . Next, add 5.0g of glycerin to this emulsion, and add 20g of glycerin.
Add 400 ml of distilled water for injection at ~40°C and coarsely emulsify with a homomixer. This is emulsified by passing it through the Manton-Gaulin type homogenizer again 10 times under pressure of 120 kg/cm ² in the first stage and a total pressure of 500 kg cm ² . This resulted in a homogenized, extremely finely divided fat emulsion containing steroids with anti-inflammatory activity. The average grain size of this emulsion is 0.2-0.4μ,
It did not contain particles larger than 1μ.

Example 2 A fat emulsion containing a steroid having anti-inflammatory activity was obtained by carrying out the same treatment as in Example 1, except that sodium oleate was not blended.

Example 3 The same treatment as in Example 1 was carried out except that 0.5 g of cholesterol was added instead of phosphatidic acid to obtain a fat emulsion containing a steroid having anti-inflammatory activity.

Example 4 50g of purified soybean oil, 6g of purified egg yolk phospholipid, 0.25g of sodium oleate, 0.25g of phosphatidic acid
g and 20 g of hydrocortisone palmitate were mixed, and the same procedure as in Example 1 was carried out to obtain a fat emulsion containing a steroid having anti-inflammatory activity.

Example 5 Example 1 was repeated except that prednisolone palmitate was added in place of dexamethasone palmitate in Production Example 1 to obtain a fat emulsion containing a steroid with anti-inflammatory activity.

Example 6 Add 4 g of dexamethasone stearate to 20 g of purified soybean oil and dissolve at 80°C. Next, 5 g of purified egg yolk phospholipid is added and dissolved with vigorous stirring at 80°C. 200 ml of distilled water is added and stirred with a homomixer to form a rough emulsion. The crude emulsion was high-pressure emulsified using a Manton-Gaulin type homogenizer to obtain a fat emulsion containing a very fine steroid having anti-inflammatory activity.

[Brief explanation of drawings]

Figures 1, 2, 3, 4, 5 and 6 show the sustained release effect of the fat emulsion of the present invention, its elimination kinetics from blood, its elimination kinetics in muscle, its elimination kinetics in liver, This figure shows the disappearance dynamics in the spleen and the accumulation dynamics in the inflamed area.

Claims (1)

[Claims] 1 Dexamethasone palmitate or betamethasone palmitate, dexamethasone stearate or betamethasone stearate, dexamethasone myristate or betamethasone myristate, hydrocortisone palmitate, hydrocortisone stearate, hydrocortisone myristate 1. A fat emulsion for intravenous administration, which contains a steroid with anti-inflammatory activity selected from prednisolone palmitate, prednisolone palmitate, prednisolone myristate, and prednisolone myristate, and does not contain emulsion particles of 1 μm or more. 2. Claim No. 2 containing an effective amount of a steroid having anti-inflammatory activity, 5-50% (w/v) soybean oil, phospholipid in an amount of 1-50% by weight to 100% soybean oil, and an appropriate amount of water. Fat emulsion according to item 1. 3. The fat emulsion according to claim 2, which contains an isotonizing agent. 4. The fat emulsion according to claim 2, which contains up to 0.3% (W/V) of a fatty acid having 6 to 22 carbon atoms or a physiologically acceptable salt thereof as an emulsification aid or emulsion stabilizer. 5. The fat emulsion according to claim 2, wherein 0.5% (W/V) or less of cholesterol or 5% (W/V) or less of phosphatidic acid is added as a stabilizer. 6 albumin, dextran, vinyl polymer,
The fat emulsion according to claim 2, which contains at least one selected from a nonionic surfactant, gelatin, and hydroxyethyl starch.