JPS60166626A - Vasographic agent - Google Patents

Abstract

PURPOSE:To provide a vasographic agent containing finely divided emulsion particles, having excellent stability, storable for a long period without causing the agglomeration of the particles, and applicable safely, by adding alpha-tocopherol or its ester to a brominated perfluorocarbon emulsion. CONSTITUTION:The vasographic agent is obtained by using a brominated perfluorocarbon containing one or two bromine atoms in one molecule as a main component, mixing the component with an emulsifier (e.g. a phospholipid, a nonionic surfactant having a molecular weight of 2,000-20,000) and an emulsion assistant (e.g. 8-22C fatty acid), added with alpha-tocopherol or its ester as the stabilizer of the emulsion particles, and homogeneously emulsifying the mixture. Preferably, the vasographic agent is added to a prescribed amount of a medium such as physiological saline water, etc. at ratios of 5-50% (W/V) bromonated perfluorocarbon, 2-6% emulsifier, 0.001-0.1% emulsion assistant and 0.004- 0.2% stabilizer, and emulsified homogeneously to attain an average particle diameter of 0.05-0.25mu.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Application The present invention relates to an emulsion-like vascular imaging agent containing brominated perfluorocarbon as a main component, and has several objects.

<Prior Art> Currently, organic iodine compounds are mainly used clinically as angiographic contrast agents. Angiographic contrast agents have high X-ray absorption, chemical stability, efficient excretion, can be administered to large mice, are low in viscosity, and have low vascular irritation and liver damage. In addition, side effects such as circulatory disorders caused by the anoxic state caused by angiographic agents have become a major problem.

The present inventors have worked to improve angiographic contrast agents, and as a result of various studies, they have first discovered that it is possible to inject known angiographic contrast agents into a device (Japanese Patent Application Laid-Open No. 100312/1983). Prior to this research, the present inventors had discovered that brominated perfluorocarbon (abbreviated as brominated PFC) has a contrast effect, and that it is chemically insoluble, nontoxic, low viscosity, and volatile. (Tokuko Sho 53-47031
No.) 9 The present inventors conducted research to formulate this brominated PFC as a vascular contrast agent, and found a suitable emulsification adjuvant, which made it safe to administer the average particle size of the brominated PFC emulsion to the human body. Brominated PFC for blood imaging that can suppress the diameter to 0.4 μ or less and maintain this uniform diameter for a long period of time.
An emulsion was developed (Japanese Unexamined Patent Publication No. 32829/1983).

The present inventors conducted further research on this brominated PFC emulsion and found that α-tocopherol or its ester is effective in making the emulsion particles finer and more stable.Based on this knowledge, the present invention was completed.

<Disclosure of the Invention> The [+11 functional contrast agent according to the present invention] has a main component of brominated PFC having 8 to 12 carbon atoms and at least one or two bromine atoms in one molecule, and contains an emulsifier and an emulsifying agent. Brominated lily particles with a diameter of 0.4μ or less obtained by distributing an auxiliary agent, adding α-tocopherol or its ester as a stabilizer for emulsified particles, and stirring the gore with a medium to obtain 14) It is a PFC emulsion.

The brominated PFC used in the present invention may be any compound that does not accumulate in the liver or other organs of the body, and does not cause undesirable damage to the organs. There are 11 of them as follows.

”~ (2) CF3-[F,',-Ca F7(61CF
3(CF2)acF2Br (7) BrCFz(CFz)60F2Br(B) C
Brominated PFCs such as F3(CF2)80F2Br and their production methods are known and are not relevant to the present invention.

As emulsifiers, phospholipids such as soybean phospholipids and egg yolk phospholipids, and polymeric nonionic surfactants with a molecular number of 2,000 to 20,000 are used. Examples include oxyethylene alkyl ether and polyoxyethylene alkyl allyl ether. Suitable emulsifying agents include fatty acids having 8 to 22 carbon atoms, such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitoleic acid, oleic acid, linoleic acid, and arachidonic acid. It is. In addition, physiologically acceptable salts of each fatty acid, IJum salt,
Potassium salts, calcium salts, etc.) and esters such as monoglycerides are also suitable. These emulsification aids can be used alone or in a mixture of two or more.

The stabilizer for emulsified particles is vitamin E, also known as yl α-
These include tocopherol 1, its acetate ester, and its acetate ester, all of which are listed in the Japanese Pharmacopoeia. These brominated P
It has been found to be extremely effective in making emulsion particles finer and more stable in FC emulsions, and also has a strong antioxidant effect, so it can also suppress peroxide formation and coloring.

Physiologically acceptable saline is used as the medium. Especially about 5mM phosphate buffer (pH 7.4)
has been found to prevent the deterioration of egg yolk phospholipids, suppress the production of free fatty acids and the content of α-tocopherol, and is extremely useful in the present invention.

The present invention further includes adding an isotonizing agent such as glycerin, hydroxyethyl starch for colloid osmotic pressure adjustment, and a liquid additive such as dextran, and adding a buffer solution when mixed with the contrast medium through the addition button. For correction of
~5 w/v%, emulsification aid 0.001~Q, l w
/v% and α-tocopherol from 0.004 to 0.2
In addition to the ratio of W/V%, stir with a mixer, add brominated PFC to the obtained crude emulsion so that it becomes 5 to 5Q w/v%, and further stir strongly with a mixer, and stir this crude emulsion with a mixer. Average particle size is 0.05 with Manton-Gorlin injection emulsifier.
Homogeneously emulsify the brominated PFC to ~0.25μ
An emulsion is prepared and, just in case, particles with a particle size exceeding 0.4 μm are removed by centrifugation.

A preferred composition according to the present invention is perfluorooctyl bromide 25% w/v, egg yolk phospholipid 4% w/v.
, glycerol 2.21 w/v%, α-tocopherol 0.08 w/v%, monobasic sodium phosphate 0.012
W/V%, diphosphorous sodium 0.057W/V%
It is.

The method of using the angiographic agent of the present invention is as follows.

The administration method depends on the type of contrast area, for example, percutaneous imaging for limb arteries and veins! l! Inject by puncture into the IJ # membrane, and if there is a risk of cardiovascular or pulmonary blood vessels, use a puncture injection into the elbow, # membrane, or through a cardiac catheter. Usage fee is 5-100 per time
m, l, the entire amount is injected rapidly or continuously as needed.

The angiographic agent according to the present invention can prevent cardiac arrest and severe shock due to anoxic conditions (Annoxia) due to the ability of brominated PFC to provide oxygen supplementation, and can prevent large doses of oxygen from being administered over a long period of time. Computerized tomography becomes possible because it does not cause any problems.

Brominated PL used in the present invention! When C is administered into a living body, it is rapidly excreted through exhalation, so no long-term accumulation in the reticuloendothelial organs of the body is observed.

Further, the angiographic contrast agent according to the present invention has a particle size of 0.05 to 0.
．． 9. Ultra-fine particles with a diameter of 4 μm, and the particles do not coarsen during long-term storage. There is no problem for animals due to coarse particles, and a high level of safety is guaranteed.

<Example> Hereinafter, the manufacturing method of the present invention will be specifically explained with reference to Examples.

Example 1 Egg yolk phosphorus 400fj and α-tocopherol 8.0
Add 101 K of flk milk and Ringer's solution, stir the liquid with a mixer, add 2.5 cans of the obtained crude milk perfluorooctyl bromide, stir further with a mixer, and pour this rough emulsion into a Manton-Gorlin injection type. Put it in an emulsifier and circulate it, keeping the liquid temperature at about 458C and total pressure 500K.
Emulsification was carried out for 10 minutes under a pressure of 9/cr/1. This homogeneously emulsifies extremely fine brominated p x; c
! % agent was obtained. The average particle diameter measured by the centrifugal sedimentation method was 0.12μ, which was dispensed into an injection vial, capped, and stored in a rotary sterilizer for heat sterilization and incubation at 4°C.
No significant increase in particle size was observed even after storage for 3 months.

Example 2 Soybean phospholipid aooy and α-tocopherol 3.6-2
．． OK9 was added and the mixture was further strongly stirred, and the crude IL solution was emulsified using a Manton-Gorlin emulsifier.

The concentration of monobromperfluorodecalin in the obtained brominated PFC emulsion was 21.5 W/V%, and the average particle size was 0.1.
The diameter of the neck remained 0.16μ even after heat sterilization and storage at 4°C for 3 months.

Example 3 20% perfluorooctyl bromide, 3.4% polyoxyethylene-polyoxypropylene copolymer (average molecular weight 8.350, Pluronic F68), 0.6% egg yolk phospholipid, 0°12% tocopherol acetate, NaC
15%, NaHCO32,1%, KCl, 336%, M
gCgo, 427%, CaCj'2o, 35
Brominated PF consisting of 6%, ■)-glucose 1.8%
Prepare C emulsion and heat sterilize it. Its average particle size is 0.
It is 11μ. No grain coarsening was observed in this emulsion even after storage at 4°C for 3 months.Example 4: Perfluorooctyl bromide 20%, average molecular weight 3
+500 polyoxyethylene octyl ether3.
4%, glycerol 2.2%, succinic acid 1-coffjl-
Roll sodium salt 0.10%, Na 1. (2J'0
A u-substituted PFC7 agent was prepared consisting of 4Q, 012% and Na28PO40,057%. Its average particle size is 0
．． This emulsion, which had a particle size of 0.09μ, showed no coarsening of the grains even after being stored at 4'C for 3 months.

<Comparative Test> The composition and average particle size of each example and the average particle size when no stabilizer was added were compared. The results are shown in Table 1, which shows that α-tocopherol and its esters used in the present invention have a remarkable effect on the fineness of emulsion starters and their stability.

Table 1 909-

Claims (1)

[Claims] The main component is a brominated perfluorocarbon having at least one or two bromine atoms in one molecule, an emulsifier and an emulsification aid are added, α-tocopherol or its ester is added as a stabilizer for emulsified particles, and these An angiographic contrast agent comprising a brominated perfluorocarbon emulsion obtained by homogeneously emulsifying brominated perfluorocarbon.