JPS6156124A - Ubidecarenone-containing emulsion for intravenous injection - Google Patents

Abstract

PURPOSE:In an emulsion which is composed of ubidecarenone, as a heart function improver, vegetable oil and phosphatidyl choline, the particle size of the emulsion is set toa specific value to increase the dissipation rate from blood and improve its utilization in living bodies. CONSTITUTION:In an aqueous emulsion containing, as essential components ubidecarenone generic name (coenzyme Q10), vegetable oil and phosphpatidyl choline, the particle size of the emulsion is selectively and substantially adusted to 0.5-3.0mu to give an emulsion for intravenous injection. It disctributes in blood and heart in high concentration, especially, 10-20 times higher than such a surface active agent such as HCO.

Description

[Detailed description of the invention] The present invention relates to an emulsion for intravenous injection containing ubidecarenone.

Ubidecarenone, also known as coenzyme QIO, is widely used in the field of clinical treatment as a drug effective for improving cardiac function.

However, there is still room for improvement regarding the speed of transfer from the blood to target organs when this substance is administered intravenously.

For example, it is known that when a commonly used surfactant is formulated into a formulation using conventional techniques and administered, the rate of disappearance from the blood is quite low, and the rate and value of transfer to target organs are also low. In the first place, the substance in question is 48-52
Since it is a fat-soluble substance that is solid at room temperature and has a melting point of °C, attempts are often made to solubilize it with HCO (polyoxyethylene hydrogenated castor oil) to make it suitable for intravenous administration; As shown by experimental examples, the rate of disappearance of ubidecarenone from the blood is slow.

As interest in so-called organ-directed preparations gradually increases in the medical and pharmaceutical fields, it is well known that technology that utilizes liposomes is attracting attention as a means to achieve this goal. . In other words, by focusing on the fact that liposomes exist as unique liposomes for each organ, it is possible to selectively and intensively deliver a drug to a target organ by containing a given drug in a given liposome and administering it. Technology that aims to do this is currently being developed.

Examples of such inventions include JP-A-52-143218 and JP-A-52-151718. Japanese Patent Publication No. 53-133616゜Special Publication No. 55-8488. Japanese Patent Publication No. 58-8010. The inventions disclosed in Japanese Patent Application Laid-Open No. 58-201711 and Japanese Patent Application No. 58-106683 can be mentioned. In particular, the last three inventions are characterized by their organ tropism and high rate of disappearance from the blood.

On the other hand, the in vivo utilization of fat emulsions by injection has recently attracted attention. In other words, emulsification systems have conventionally been generally used as dosage forms for oral administration of oil-based substances or as dosage forms for topical administration to the skin, but emulsification systems have been used in so-called valentiral drug delivery systems. From this point of view, it is a dosage form that aims to increase bioavailability when administered by injection, but
Attempts have also been made to use liposomes in a different dosage form from the liposomes. The following literature is shown as a reference for explaining this tendency in detail.

S. S. Davis: Emulsion sy.
stems for the delivery
g delivery, Alfed Benzon
Symposium 17゜Er1itors;
I■ans Bundgaard et al.
Copenhagen (1982) Against this background, the present inventor investigated a technique for increasing the rate of disappearance from the blood and increasing the bioavailability of ubidecarenone by injection in the form of a fat emulsion. The result is an emulsified aqueous liquid containing ubidecarenone, vegetable oil, and phosphatidylcholine as essential components, and by selectively and substantially adjusting the particle size of the emulsified particles to 0.5 to 3.0 μm, it is possible to achieve the desired purpose. The present invention was completed based on the knowledge that this can be achieved. That is, an object of the present invention is to provide a technique for increasing the rate of disappearance from the blood and increasing the bioavailability of ubidecarenone when it is injected with a fat emulsion.

In order to achieve the object, the present invention provides an emulsified aqueous liquid containing ubidecarenone, vegetable oil, and phosphatidylcholine as essential components, in which the particle size of emulsified particles is selectively and substantially 0.
This invention discloses an emulsion for intravenous injection, characterized in that it has a particle size of 5 to 3.0 microns.

Composition of the invention The present invention will be explained in detail below.

In the present invention, the vegetable oil is not particularly limited as long as it is commonly used for injections, and for example, sesame oil, soybean oil, etc. may be used.

In the present invention, phosphatidylcholine is an essential component and is limited thereto. For example, it is possible to substitute sphingomyelin, but as shown in the experimental examples below, the effect is inferior to that of phosphatidylcholine.

The phosphatidylcholine according to the present invention may be blended alone, but it can also be blended as a mixture with other substances. For example, by blending egg yolk lecithin or soybean lecithin, phosphatidylcholine can be contained as an essential component.

The present invention is an emulsified aqueous liquid and therefore an oil-in-water type emulsion. That is, the present invention is a system in which emulsified particles of an oil phase are dispersed in an aqueous phase, and one of the structural features of the present invention is that the particle size of the emulsified particles of the oil phase is selectively and substantially 0.5. ~3.0
It is at a point where μ. The term "selective" is used here to mean that emulsion particles with a predetermined particle size are selected by performing a fractionation operation such as centrifugation on the prepared emulsion, and therefore, it does not mean that the particle size is selective. This means that the particle size has been selected in a particular range by the fractionation operation. Furthermore, "substantially" is used to mean that when looking at the particle size distribution of emulsified particles, substantially most of the emulsified particles are included in a predetermined particle size range, and therefore, the particle size is substantially within a predetermined particle size range. is the particle size of the emulsified particles that occupy a substantial part of the whole,
This means that even if a small number of particles are included in a particular range and have a particle size outside the range, this does not mean that they are excluded.

As shown by the experimental examples described below, particularly when the particle size is selectively and substantially 0.5 to 3.0 microns, an excellent rate of disappearance of ubidecarenone from the blood is shown.

There is no particular limitation on the weight ratio of the essential components ubidecarenone, vegetable oil, and phosphatidylcholine. That is, take the essential ingredients in any weight ratio and add water to create an oil-in-water emulsion.

In short, the particle size of the oil phase emulsified particles may be selected by an appropriate fractionation operation so that the particle size is substantially 0.5 to 3.0 μm. - For example, for 1 part by weight of ubidecarenone.

What is necessary is to take 80 to 120 parts by weight of soybean oil and 10 to 15 parts by weight of lecithin and further add water.

It should be noted that an isotonizing agent such as glycerin may be freely added as a component other than the essential components, and the present invention is not limited thereto. However, addition of surfactants such as HCO is not preferred in the present invention.

The emulsion of the present invention is for intravenous injection.

The emulsion of the present invention can be produced by preparing an emulsion according to a conventional method for producing emulsions, and then centrifuging the emulsion to separate a layer in which emulsion particles having a particle size within a predetermined range are substantially present.

The present invention will be specifically explained with reference to Examples described below.

Example 1 0.1 part by weight of ubidecarenone is dissolved in 10 parts by weight of soybean oil, 2.5 parts by weight of glycerin, 1.2 parts by weight of phosphatidylcholine and further water are added, and an emulsion is prepared by ultrasound. The obtained emulsion was centrifuged at 3000.9 mm, the upper layer separated liquid was collected, and it was confirmed with a microscope that the particle size of the emulsified particles was substantially 0.5 to 3.0 μ. Make an emulsion.

Effect of the invention The effects of the present invention will be demonstrated by the experimental examples described below.

Experimental Example 1 Sample prepared according to the procedure of Example 1, with a particle size of substantially 0.5
The emulsion with ~3.0μ was sample A, and also substantially 0.5
An emulsion having a particle size of less than μ was prepared as sample B.

1. Prepared in the same manner as described in Example 1 by adding 7 parts by weight of HCO-600 to the ingredients of Example 1.

Sample C is an emulsion whose particle size is substantially 0.4 to 3.0μ.
2. Also, an emulsion liquid having a particle size of substantially less than 0.03 μm was prepared as a sample.

An emulsion prepared according to the procedure of Example 1 except that sphingomyelin was used instead of phosphatidylcholine in Example 1, and the emulsion was centrifuged at 1000 g, and the particle size was substantially less than 0.5. was prepared as sample E. In this case, substantially 0.5 to 3.0μ
The emulsion system was unstable, and the oil droplet particles agglomerated and could not be used as a sample. In each sample, +40-labeled ubidecarenone was used.

Method Each sample was intravenously injected into rats, and the blood concentration and tissue distribution of ubidecarenone were determined. Note that ubidecarenone was quantified by radioactivity measurement.

result The results are shown in FIGS. 1 to 6.

1 to 3 are graphs showing changes in plasma concentration of ubidecarenone over time. FIG. 1 is a graph for Sample A and Sample B, and in FIG. 2, the circle mark indicates the result for Sample A, and the mark line indicates the result for Sample B. FIG. 2 is a graph for sample C and the sample sample. In the figure, the circle mark line indicates the result for sample C1 and the mark line indicates the result for sample sample C1. FIG. 3 is a graph for sample E, and the marked lines in FIG. 9 indicate the results.

It is clear from FIGS. 1 to 3 that the structure of the present invention exhibits an excellent rate of elimination from blood. It is known that structures other than those of the present invention 9, for example, those having emulsified particles of 0.5β or less, or those using sphingomyelin instead of phosphatidylcholine do not satisfactorily achieve the object of the present invention. Also.

Addition of surfactants such as HCO is known to inhibit the effectiveness of the present invention.

4 to 6 are graphs showing the tissue distribution of ubidecarenone. FIG. 4 is a graph for Sample A and Sample B, and in FIG. However, for sample A, the tissue distribution is shown 30 minutes after administration, and for sample B, the tissue distribution is shown 6 hours after administration. The reason why the measurement times after administration are different is that the rate of disappearance from the blood of Sample A and Sample B is significantly different. 30 minutes after administration, and for sample B1, 6 hours after administration.

FIG. 5 is a graph for Sample C and Sample Sample, and in one figure, the column shows the result of Sample C and the column shows the result of Sample Sample. Both show tissue distribution 6 hours after administration.

FIG. 6 is a graph for Sample B and Sample E, and in the two figures, one column shows the results for Sample B, and one column shows the results for Sample E. Both show tissue distribution 6 hours after administration.

It is clear from FIGS. 4 to 6 that the structure of the present invention provides a high concentration distribution in the heart as a target organ. Especially H
It is known that it is 10 to 20 times larger than that with CO added.

[Brief explanation of drawings]

1 to 3 are graphs showing changes in plasma concentration of ubidecarenone over time. 4 to 6 are graphs showing the tissue distribution of ubidecarenone.

Claims (1)

[Claims] An emulsion for intravenous injection, which is an emulsified aqueous liquid containing ubidecarenone, vegetable oil, and phosphatidylcholine as essential components, characterized in that the particle size of the emulsified particles is selectively and substantially 0.5 to 3.0μ. liquid