JPH01143826A - Fat emulsion of fine particle - Google Patents

Abstract

PURPOSE:To obtain a fat emulsion of fine particles slightly reducing blood concentration, having raised pharmaceutical action, containing a fat-soluble pharmaceutical activator. CONSTITUTION:A fat-soluble pharmaceutical activator such as vitamin or vasodilator is dissolved in an oil phase component such as soybean oil, an emulsifying agent (e.g. phospholipid) is dispersed into the solution, which is optionally mixed with an emulsifying auxiliary, stabilizer, etc., further blended with water and prepared by a conventional procedure to give the aimed substance. In the operation, the average particle diameter is adjusted to 40-70nm and the aimed substance is obtained in the form of injection. The fat emulsion consists essentially of 5-30W/V% oil phase component, 0.1-20W/V% emulsifying agent and a proper amount of water.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a fat emulsion, and more particularly to a fat emulsion that has fine particles and does not easily reduce the blood concentration of a fat-soluble pharmacologically active substance contained therein.

(Prior Art) Attempts have been made to enhance the pharmacological effects of various pharmacologically active substances by preparing them into fat emulsions.

For example, fat emulsions for steroids, prostaglandins, anticancer drugs, etc. are known, and their pharmacological effects have been shown to increase, but this is still far from sufficient.

(Problems to be Solved by the Invention) An object of the present invention is to enhance the pharmacological action of a fat emulsion containing a fat-soluble pharmacologically active substance.

(Means for Solving the Problems) As a result of intensive research, the present inventors have found that when a fat emulsion containing a fat-soluble pharmacologically active substance is administered intravenously, the blood concentration of the substance rapidly decreases. Nevertheless, the inventors have completed the present invention by discovering that when the particle size of the fat emulsion is set to 70 nm or less, the effects of pharmacologically active substances are significantly enhanced without causing such a phenomenon.

The formulation of the present invention is a fine-grain fat emulsion containing a fat-soluble pharmacologically active substance and having an average particle size of 40 to 70 nm.

In the present invention, the fat-soluble pharmacologically active substance may be any pharmacologically active substance that dissolves in fats and oils, such as anesthetics, sedatives, tranquilizers, analgesics, hypopyretics, central stimulants, Muscle relaxants, sympathomimetic drugs, sympathomimetic drugs, parasensitometric stimulants, parasensory nerve depressants, autonomic blockers.

These include antispasmodics, antihistamines, cardiotonic drugs, antiarrhythmia drugs, vasodilators, antitussives, anticoagulants, hemostatic drugs, vitamins, hormones, chemotherapy drugs, antibiotics, and anticancer drugs.

The fat emulsion of the present invention has an oil phase component of 5 to 30 w/v% and 0.0% w/v.
It mainly consists of 1-20% w/v of emulsifier and an appropriate amount of water.

As oil phase components, vegetable oils such as soybean oil, cottonseed oil, and Panacet 800. Synthetic triglycerides such as 810 [trade name 9 manufactured by Nippon Oil & Fats Corporation] can be used.

As emulsifiers, phospholipids, hydrogenated phospholipids.

lecithin, hydrogenated lecithin, etc., or polyoxyethylene hydrogenated castor oil derivatives [Nilacol HCO-SO,
60 etc. manufactured by Nikko Chemicals ■], polyoxyethylene sorbitan fatty acid ester [Niracol 10-10M
Nonionic surfactants such as 1 Nikko Chemicals Co., Ltd. such as 1 Nikko Chemicals Co., Ltd., 106, etc.), polyoxyethylene polyoxybrobylene glycol (Pluronic F68, etc., manufactured by Asahi Denka Kogyo Co., Ltd.) can be used.

Other emulsification aids, stabilizers, tonicity agents, etc. as necessary.
pH adjusters and the like can also be used.

The fat emulsion of the present invention can be produced, for example, by the method described below.

That is, the fat-soluble pharmacologically active substance is dissolved in the oil phase component heated to 70 to 80°C. After dispersing the emulsifier in this, an emulsifying aid, a stabilizer and other necessary auxiliary components are added as required, an appropriate amount of water is added, and the mixture is roughly emulsified by a conventional method.

This rough emulsion is subjected to bulk emulsification for an appropriate time using a high-pressure emulsifier having a capacity of 700 kg/Qll" or more,
A fat emulsion having an average particle size of 40 to 70 nm is filled into an ampoule and sterilized with high pressure steam to prepare a preparation.

This preparation can be used as an injection.

Examples of emulsifiers that can be used for coarse emulsification include the ultra-high-speed homogenizer Hiscotron N5 manufactured by Nichion Irika Kikai ■.
-60, tabletop quick homo mixer LR-1 manufactured by Mizuha Kogyo ■, etc.

Examples of high-pressure emulsifiers that can be used for emulsification include the Manton-Gorlin injection emulsifier 15M (pressure cuff 00 kg/ell+" or more) manufactured by Manton-Gorlin, and the high-pressure cell crusher French Pressure AFPS-2 manufactured by Aminfu.
0KM (pressure 2200kg 7cm or more), etc.

(Effect of the invention) The fat emulsion of the present invention has an average particle diameter of 40 to 70n1.
11, it is possible to significantly enhance the pharmacological action of the pharmacologically active substance without causing the rapid drop in blood concentration of the drug that occurs in conventional fat emulsions with large particle sizes.

(Example) Hereinafter, the present invention will be specifically explained with reference to Examples and Test Examples.

Example 1 Vitamin A25 was added to 25g of soybean oil preheated to 80℃.
00,000 1. U, , phosphorus, lipid 4.5g, HCO-6
025 g was added, and the mixture was stirred and dispersed. This and glycerin 5
．． 5 g of sodium hydroxide and 1.51 g of sodium hydroxide were added thereto, and sterile distilled water for injection was added to bring the total amount to 250 td. This liquid was emulsified for 10 minutes at 10,000 rpm using an ultrahigh-speed homogenizer Hiscotron N5-60 to obtain a rough emulsified liquid.

This crude emulsion was refined and emulsified for 15 minutes using a Manton-Gorlin injection emulsifier 15M with a pressure cuff of 00kg 7cm'' to obtain a fat emulsion with an average particle size of 60nm.The fat emulsion B was divided into 1ml ampoules. The mixture was poured and sterilized using high-pressure steam in a conventional manner to obtain a vitamin A injection.

Example 2 In Example 1, vitamin A was 2.5 million 1. Vitamin D250,011 instead of U. Using LJ, emulsify 1
This was carried out for 0 minutes to obtain a vitamin D injection having an average particle size of 701.

Example 3 In Example 1, vitamin A was 2.5 million 1. Use 12.5 g of vitamin E instead of U, and 12.5 g of soybean oil.
The amount was reduced to 5 g, and emulsification was performed for 15 minutes to obtain a vitamin E injection having an average particle size of 63 nm.

Example 4 In Example 1, vitamin A was 2.5 million 1. U, (7)
Use 2.5 g of vitamin K per ft and emulsify 1
This was carried out for 5 minutes to obtain a vitamin injection having an average particle size of 50 nm.

Example 5 In Example 1, vitamin A was 2.5 million 1. U, (7)
Instead, 2.5 g of coenzyme Q was used and emulsification was performed for 15 minutes to obtain an injection of phenzyme Q with an average particle size of 48 nm.

Example 6 In Example 1, vitamin A was 2,500,000 1. Prostaglandin E+ 2.5 nt was used instead of υ, and emulsification was performed for 15 minutes to obtain a prostaglandin E+ injection having an average particle size of 55 nm.

Example 7 In Example 1, vitamin A was 2.5 million 1. Prostaglandin E□ethyl 1.25□ was used instead of U, and emulsification was carried out for 12 minutes to obtain a prostaglandin E□ethyl injection having an average particle size of 6 on-.

Test Example 1 (Sample Preparation) 1 as a tracer was added to 4 g of soybean oil preheated to 70°C.
40 μC of 4C-glycerol triolate and 0.72 g of 1° phospholipid were added and stirred to uniformly disperse.

To this, lIC0-604g, sodium hydroxide 0.3
After adding and dispersing the mixture, sterile distilled water for injection was added to bring the total volume to 40 ml. Use an ultra-high-speed homogenizer to homogenize this liquid.
Emulsification was performed for 10 minutes using a Hiscotron N5-60 at 7 minutes of rotation to obtain a rough emulsion.

This rough emulsion was processed using the high-pressure cell crusher French Bressie V-A.
Using FPS-20KM, pressure 2200kg 7cm
"The emulsification was carried out nine times to prepare a fat emulsion with an average particle size of 70 nm. This was designated as Sample 1.

Samples 2 to 7 were prepared according to the method for preparing the samples described above, changing the type and amount of emulsifier and the number of times of emulsification as shown in Table 1.

Table 1 shows the average particle diameter of each sample.

Table 1 Average particle diameter (soybean oil 10w/v%) Test example 2 child blood (Preparation of sample) Labeled samples 1 to 7 prepared in Test Example 1 were used as they were.

(Test animals) Three male Wistar rats weighing 250 to 270 g were made into one group, and one group of animals was prepared for each sample.

(Test) 1 ml of the labeled sample was taken from the left femoral vein of the animals in each assigned group! /kg was administered silently. Blood was collected over time from the arteries of animals in each group, and its radioactivity was measured to examine changes in blood fat particle concentration over time.

The results are shown in FIG.

From Figure 1, the group with an average particle diameter of 70 nm or less and the 90
It was observed that there was a clear difference in the change in fat particle blood concentration over time between the nano group and the larger group.

Test Example 3 Coenzyme Qso blood change over time (sample preparation) In the sample preparation of Test Example 1, I' was used as a tracer.
Using 40 μCi of 140-phenzyme Q+e instead of 40 μCi of C-glycerol triolate, sample 1
．． Samples corresponding to 3.6 were prepared as sample 8, respectively.
It was set as 9.10.

(Test animal) Test animals were prepared according to Test Example 2.

(Test) Perform a test similar to Test Example 2 on the labeled sample,
Coenzyme Q1. Changes in blood concentration over time were investigated.

The results are shown in FIG.

From Figure 2, Fuenzyme Q8. It was observed that the change in blood concentration over time showed the same tendency as that of fat particles.

It is thought that this tendency appears similarly for other fat-soluble pharmacologically active substances.

[Brief explanation of the drawing]

FIG. 1 is a graph showing changes over time in blood concentration of fat particles due to differences in particle diameter of fat emulsions. FIG. 2 is a graph showing changes over time in the blood concentration of Fenzyme Q1° depending on the particle size of the fat emulsion. Patent applicant Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1) Contains a fat-soluble pharmacologically active substance and has an average particle diameter of 40
Fine grain fat emulsion with ~70 nm. 2) The fine-grain fat emulsion according to claim 1, wherein the fat-soluble pharmacologically active substance is a fat-soluble vitamin. 3) The fine-grain fat emulsion according to claim 1, wherein the fat-soluble pharmacologically active substance is a vasodilator.