JPH0461854B2 - - Google Patents

Description

[Detailed Description of the Invention] <Field of Application> The present invention relates to an emulsion-like angiography agent containing brominated perfluorocarbon as a main component, and its purpose is to reduce bioaccumulation and toxicity, and to reduce the size of emulsified particles. The purpose of the present invention is to provide an angiographic contrast agent with excellent stability. <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,
It must be able to be administered in large quantities, have low viscosity, and have low vascular stimulation and liver damage. Side effects have become a major problem. The present inventors worked on improving angiographic contrast agents,
As a result of various studies, we first discovered that a composition in which a perfluorocarbon compound emulsion is added to a known angiographic contrast agent reduces side effects caused by oxygen supplementation and makes it possible to inject the required amount according to the purpose. (Japanese Patent Publication No. 55-100312). Prior to this research, the present inventors had discovered that brominated perfluorocarbon (abbreviated as brominated PFC) has a contrast effect and is chemically insoluble, nontoxic, low viscosity, and volatile. (Tokuko Showa 53-47031
issue). The present inventors conducted research to formulate this brominated PFC as a vascular contrast agent, and found a suitable emulsification aid, which led to the average particle size of the brominated PFC emulsion to be 0.4μ, which is safe to administer to the human body. We have developed a brominated PFC emulsion for angiography that can maintain this average particle size over a long period of time. (Japanese Patent Publication No. 58-32829). The present inventors conducted further research on this brominated PFC emulsion and found that α-tocopherol or its ester is effective in making emulsified particles finer and more stable.Based on this knowledge, the present invention was completed. <Disclosure of the Invention> The vascular contrast agent according to the present invention has brominated PFC as a main component having 8 to 12 carbon atoms and at least one or two bromine atoms in one molecule, and contains an emulsifier and an emulsification aid. α as a stabilizer for emulsified particles.
- adding tocopherol or its ester;
This is a brominated PFC emulsion with an average particle diameter of 0.4μ or less obtained by stirring and emulsifying these with a medium. The brominated PFC used in the present invention may be any compound that does not accumulate in organs such as the liver or spleen, and does not cause undesirable damage to the organs. It is as follows. (6) CF ₃ (CF ₂ ) ₆ CF ₂ Br (7) BrCF ₂ (CF ₂ ) ₆ CF ₂ Br (8) CF ₃ (CF ₂ ) ₈ CF ₂ Br Brominated PFCs and their production methods are listed here. These are not related to the present invention. Phospholipids such as soybean phospholipids and egg yolk phospholipids, and polymeric nonionic surfactants with a molecular weight of 2,000 to 20,000 are used as emulsifiers, and surfactants include polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene Examples include alkyl ether and polyoxyethylene alkyl allyl ether. Suitable emulsifying agents include fats 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. be. In addition, physiologically acceptable salts of each fatty acid (sodium salt, potassium salt, calcium salt, etc.) and esters such as monoglycerides are also suitable. These emulsification aids can be used alone or in a mixture of two or more. Stabilizers for the emulsified particles include α-tocopherol itself, known as vitamin E, as well as its acetate ester and succinate ester, all of which are listed in the Japanese Pharmacopoeia. Through research conducted by the present inventors, these compounds have been found to be extremely effective in refining and stabilizing the emulsified particles of brominated PFC emulsions, and have strong antioxidant effects that prevent the formation of peroxides and discoloration. can also be suppressed. As the medium, physiologically acceptable saline, lactated Ringer's solution, isotonic phosphate buffer, or the like is used. In particular, a 5mM phosphate buffer (PH7.4) prevents the deterioration of egg yolk phospholipids,
It has been found to suppress the production of free fatty acids and the decomposition of α-tocopherol, and is extremely useful in the present invention. The invention further provides tonicity agents such as glycerin;
Plasma expanders such as hydroxyethyl starch and dextran were added to adjust the colloid osmotic pressure, and these additions compensated for the buffer solution when mixed with the contrast medium, especially considering the influence of EDTA contained in the contrast medium. Make corrections. The angiography agent of the present invention contains a predetermined amount of physiological saline phosphate Ringer's solution or isotonic phosphate buffer, an emulsifier of 2 to 6 w/v%, and an emulsification adjuvant of 0.001 to 0.1 w/v.
% and α-tocopherol from 0.004 to 0.2w/v
% and stirred with a mixer, brominated PFC was added to the resulting crude emulsion at a concentration of 5 to 50 w/v%, further stirred strongly with a mixer, and the coarse emulsion was subjected to Manton-Gaulin injection. A brominated PFC emulsion is prepared by homogeneously emulsifying the emulsion to an average particle size of 0.05 to 0.25μ using a type emulsifier, and as a precaution, particles with a particle size exceeding 0.4μ are removed by centrifugation. A preferred composition in the present invention is perfluorooctyl bromide 25w/v%, egg yolk phospholipid
4w/v%, glycerol 2.21w/v%, α-tocopherol 0.08w/v%, monobasic sodium phosphate
0.012w/v%, dibasic sodium phosphate 0.057w/
v%. 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 injection into the artery and vein for imaging of limb arteries and veins, and percutaneous arteriovenous injection for imaging of the aorta and branch arteries of the chest and abdomen. It is injected through a puncture into the patient's body or through a transfemoral arterial catheter, and for imaging of cardiovascular or pulmonary vessels, it is injected through a puncture into the cubital vein or through a cardiac catheter.
The amount used is 5 to 100 ml at a time, and the entire amount is injected rapidly or continuously as needed. Since the angiography agent according to the present invention provides oxygen supplementation using brominated PFC, it is possible to prevent cardiac arrest and serious shock conditions due to anoxia, and even when administered in large doses over a long period of time, there is no risk of injury. Computer tomography is possible because it does not produce Since the brominated PFC used in the present invention is rapidly excreted through exhalation when administered into a living body, no long-term accumulation in the reticuloendothelial organs of the body is observed. Furthermore, the angiographic contrast agent according to the present invention has a particle size of
Since they are ultrafine particles of 0.05 to 0.4μ and do not coarsen during long-term storage, there are no problems associated with coarsening of the particles to recipient animals, and a high degree 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 phospholipid 400g and α-tocopherol 8.0g
Add to 10% of lactated Ringer's solution and stir with a mixer, add 2.5 kg of perfluorooctyl bromide to the obtained rough emulsion, stir further with a mixer, and put this rough emulsion into a Manton-Gorlin injection emulsifier. The emulsification was carried out for 10 minutes under a total pressure of 500 kg/cm ² while keeping the liquid temperature at about 45°C.
This results in a homogeneous emulsification of extremely fine bromination.
A PFC emulsion was obtained. The average particle diameter measured by centrifugal sedimentation was 0.12μ, and it was dispensed into an injection vial, sealed with a spiral stopper, stored in a rotary sterilizer, sterilized by heat, and stored at 4°C for 3 months. No significant increase in particle size was observed either. Example 2 300g of soybean phospholipids and 3.6g of α-tocopherol
Add to physiological saline solution 9.0 and stir with a mixer,
2.0 kg of monobromperfluorodecalin was added to the obtained crude emulsion, which was further strongly stirred, and the crude emulsion 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 0.16μ, and the particle size remained 0.16μ even after heat sterilization and storage at 4°C for 3 months. was maintained. Example 3 Perfluorooctyl bromide 20%, polyoxyethylene polyoxypropylene copolymer (average molecular weight 8350, Pluronik F68) 3.4%, egg yolk phospholipid 0.6%, tocopheryl acetate 0.12%,
NaCl6%, _NaHCO3 2.1%, KCl0.336%,
_MgCl2 0.427%, _CaCl2 0.356%, D-glucose
A brominated PFC emulsion consisting of 1.8% is prepared and heat sterilized. Its average particle size is 0.11μ. No coarsening of the grains was observed in this emulsion even after it was stored at 4°C for 3 months. Example 4 20% perfluorooctyl bromide, polyoxyethylene octyl ether with an average molecular weight of 3500
3.4%, glycerol 2.2%, tocopherol sodium succinate 0.10%, NaH ₂ PO ₄ 0.012%,
A brominated PFC emulsion consisting of 0.057% Na ₂ HPO ₄ was prepared. Its average particle size is 0.09. No coarsening of the grains was observed in this emulsion even after it was 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 refinement of emulsion particles and their stability. 【table】

Claims (1)

[Claims] 1 The main component is a brominated perfluorocarbon having at least one or two bromine atoms in one molecule, an emulsifier and an emulsification auxiliary are blended, and α-tocopherol or its ester is added as a stabilizer for emulsified particles, An angiographic contrast agent comprising a brominated perfluorocarbon emulsion obtained by homogeneously emulsifying these.