JPH051245B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a contrast agent comprising a brominated perfluorocarbon emulsion that does not bioaccumulate and has low toxicity. A contrast agent is a drug that creates a difference in X-ray transmittance between the organ and surrounding tissue when observing internal organs using X-ray photography, making it possible to observe the organ's morphology and function. . There are positive contrast agents and negative contrast agents, and this contrast agent belongs to the former. An important condition for a positive contrast agent is high X-ray absorption rate, but also chemical stability,
It is required to have efficient excretion, the possibility of large-scale administration, low viscosity, and low vascular stimulation and hepato-renal damage. A wide variety of contrast agents have already been developed, and their contrast performance and safety have significantly improved. A contrast agent made of brominated perfluorocarbon (hereinafter also referred to as brominated PFC) having 6 to 12 carbon atoms and 1 or 2 bromine atoms in the molecule was also developed by the present inventors. . This brominated PFC is chemically inert, non-toxic,
It has properties such as low viscosity, volatility, and insolubility, and is also radiopaque.
-47031) is an excellent X-ray contrast agent, but its chemical properties make it extremely difficult to formulate it into a contrast agent. For example, when brominated PFC is administered to the human body as an angiography agent, it is used in the form of an emulsion, but unless the average particle size of the emulsion is 0.4μ or less, it cannot be administered to animals to sustain life. However, in general, brominated PFCs are difficult to emulsify and have poor stability, and it has previously been impossible to maintain the particle size of emulsions below 0.4μ for a long period of time, which is necessary for administration to the human body. In order to improve these drawbacks of contrast agents made of brominated PFC, the present inventors have researched various methods of emulsifying brominated PFC, and have discovered suitable emulsifiers, emulsification aids, and others, thereby achieving the present invention. completed. The present invention aims to provide an X-ray contrast agent comprising a fluorocarbon emulsion containing brominated PFC, a specific emulsifier, and a specific emulsification adjuvant, and whose osmotic pressure can be adjusted to physiological isotonicity. That is, the present invention uses a brominated perfluorocarbon (i.e., brominated PFC) having 6 to 12 carbon atoms and 1 or 2 bromine atoms in the molecule, phospholipids, hydrogenated phospholipids, and polymers with a molecular weight of 2,000 to 20,000. It contains at least one emulsifier selected from nonionic surfactants, and if the emulsifier is the above-mentioned hydrogenated phospholipid, vitamin E is used as an emulsification adjuvant, and if the emulsifier is the above-mentioned surfactant, it contains vitamin E. The present invention relates to a contrast agent comprising a brominated perfluorocarbon emulsion containing a phospholipid as an emulsification aid and having a particle size of 0.05 to 0.4μ. In the present invention, carbon number 6 is used as an emulsification aid.
-22 fatty acids, salts of the fatty acids, and monoglycerides of the fatty acids. When the emulsifier is a phospholipid, a physiologically acceptable antioxidant, e.g. It is preferable to contain vitamin E. The brominated PFC with X-ray contrast ability used in the present invention is a perfluorocarbon having 6 to 12 carbon atoms in which the fluorine atom is replaced with one or two bromine atoms, and is used in the liver and Preferably, it does not accumulate in organs such as the spleen. The bromination
PFCs may be chain-like or alicyclic, and specific examples include the following compounds. (Example) 1-bromo-perfluoro-4-propyl-cyclohexane 1-bromo-perfluoro-2-propyl-cyclohexane 1-bromo-perfluoro-3-propyl-cyclohexane (Example) 1-bromo-perfluoro-2-methyl-4-
Propylcyclohexane 1-bromo-perfluoro-3-methyl-4-
Propylcyclohexane 1-bromo-perfluoro-4-methyl-2-
Propylcyclohexane 1-bromo-perfluoro-2-methyl-6-
Propylcyclohexane 1-bromo-perfluoro-3-methyl-2-
Propylcyclohexane 1-bromo-perfluoro-2-methyl-3-
propylcyclohexane (Example) 1-bromo-perfluoro-4-butylcyclohexane 1-bromo-perfluoro-2-butylcyclohexane 1-bromo-perfluoro-3-butylcyclohexane (7) CF ₃ (CF ₂ ) ₆ CF ₂ Br (8) Br・CF ₂ (CF ₂ ) ₆ CF ₂・Br (9) CF ₃ (CF ₂ ) ₈ CF ₂ Br (10) Br・CF ₂ ( CF ₂ ) ₄ CF ₂ Br Brominated PFC is substantially known and can be produced, for example, by the method described in Encyclopedia of Chemical Technology 9, 748-750 (2nd edition) or by a method similar thereto. can do. The phospholipid used as an emulsifier is preferably egg yolk phospholipid or soybean phospholipid, and the hydrogenated phospholipid is preferably one derived from the above-mentioned phospholipids. The molecular weight of polymeric nonionic surfactants
2,000 to 20,000, such as polyoxyethylene/polyoxypropylene copolymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, etc. Fatty acids used as emulsification aids are those having 6 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, arachidonic acid. is exemplified. Further, as the salt of the fatty acid, preferably used are alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, etc. of those specifically listed above. Furthermore, monoglycerides of the fatty acids specifically listed above are preferably used as monoglycerides of the fatty acids. Also, as a phospholipid as an emulsification aid,
Egg yolk phospholipids and soybean phospholipids are used. As the physiologically acceptable antioxidant used in the present invention, vitamin E is preferably used. The composition ratio of each component in the contrast medium according to the present invention is preferably 5 to 50 w/v% of brominated PFC, 2 to 6 w/v% of emulsifier, and further the emulsification adjuvant is
0.001~0.1w/v%, and antioxidants 0.002~
Preferably it is 0.006w/v%. The contrast agent of the present invention is produced, for example, as follows. That is, in a predetermined amount of a saline solution such as physiological saline or lactated Ringer's solution, 2 to 6 w/v% of an emulsifier, if necessary, 0.001 to 0.1 w/v% of an emulsifying adjuvant, and if necessary, 0.002 to 0.006 w/v%. V% of antioxidant is added to coarsely emulsify, and this coarsely emulsified liquid is brominated.
Add PFC to a final content of 5 to 50 w/v%, stir with a mixer to prepare a rough emulsion,
This rough emulsion is homogenized using an emulsifying machine so that the particle size is 0.05 to 0.4 μm, thereby producing an ultrafine-grained brominated PFC emulsion. In the present invention, particles larger than 0.4μ are not substantially formed, but just in case, centrifugation may be performed after preparing the emulsion to remove particles larger than 0.4μ.
The brominated PFC emulsion is preferably a physiological aqueous solution, e.g. NaCl 3-7%, CaCl ₂ 0.15-0.4
%, _MgCl2 0.1-0.5%, D-glucose 0.7-2.0
%, KCl 0.3 to 0.5%, and NaHCO ₃ 2 to 4%. The contrast agent of the present invention can be applied to blood vessel X-ray contrast, tracheal X-ray contrast, hepatosplenic X-ray contrast, tumor X-ray contrast, and the like. The administration method depends on the type of contrast area, for example, percutaneous puncture injection into arteries and veins for imaging limb arteries and veins, and percutaneous injection for imaging vena cava and branch arteries in the chest and abdomen. It is injected through a puncture or a translimb arterial catheter; for imaging of cardiovascular or pulmonary vessels, it is injected through a puncture into the cubital vein or through a cardiac catheter. Administer intravenously for liver, spleen, and tumor imaging.
The amount used is 5 to 100 ml at a time, and the entire amount is injected rapidly or continuously as needed. Since the contrast 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 if a large amount is administered over a long period of time, there will be no damage. Computer tomography is possible because it does not produce When the brominated PFC used in the present invention is administered into a living body, it is quickly excreted through exhalation, so no long-term accumulation in the reticuloendothelial organs of the body is observed. Furthermore, the contrast agent according to the present invention has a particle size of 0.05~
Since they are ultrafine particles of 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. Hereinafter, the manufacturing method of the present invention will be specifically explained with reference to Examples. Comparative example 1 Egg yolk phospholipid 350g and sodium palmitate
3.5 g was added to lactated Ringer's solution 8.0 and mixed with a mixer to prepare a rough emulsion. 2.5 kg of perfluorooctyl bromide was added to this liquid and further stirred vigorously with a mixer to prepare a rough emulsion.
This crude emulsified liquid was placed in a liquid tank of a Manton-Gorlin type injection emulsifier and circulated, and emulsification was carried out while maintaining the liquid temperature at 45±5°C. Bromination of the resulting emulsion
The concentration of PFC was 29.9 w/v%. The average particle diameter measured by the centrifugal sedimentation method was 0.15μ, and the vial was dispensed into an injection vial, capped, stored in a rotary sterilizer, sterilized by heat, and stored at 4°C for 3 months. However, no significant increase in particle size was observed.
The LD ₅₀ of this product after intravenous administration was greater than 30 g/Kg. Example 1 Add 300 g of soybean phospholipids and 0.3 g of vitamin E to 9.0 g of physiological saline, stir with a mixer to prepare a rough emulsion, add 2.0 kg of β-monobromperfluorodecalin to this liquid, and stir even more vigorously. The mixture was roughly emulsified, and this rough emulsion was emulsified using a Manton-Gorlin emulsifier. The concentration of β-monobromperfluoromethyldecalin in the obtained emulsion is
21.5w/v%, average particle size is 0.12μ, and the particle size remains unchanged even after heat treatment and storage at 4℃ for 3 months.
Maintained 0.14μ. Example 2 Perfluorooctyl bromide 20%, polyoxyethylene polyoxypropylene copolymer (average molecular weight 8350, Pluronik F68) 3.4%, egg yolk phospholipid 0.6%, potassium oleate 0.004%,
NaCl6%, _NaHCO3 2.1%, KCl0.336%,
MgCl ₂ 0.427%, CaCl 0.356%, D-glucose 1.8
% and heat sterilize it. Its average particle size is 0.13μ. This emulsion did not show any coarsening of the grains even after being stored at 4°C for 3 months. Example 3 Hydrogenated soybean phospholipid 5% was used instead of Pluronic F68 as an emulsifier, and egg yolk phospholipid
An emulsion was prepared with the same composition as in Example 3 except that 0.6% was removed. Its average particle size is 0.09μ. This emulsion showed no coarsening of the grains even after being stored at 4°C for 3 months. Experimental Example 1 Table 1 shows a comparison of the average particle diameters of the contrast agents obtained in the Comparative Example and each Example and the contrast agents obtained when no emulsification aid was added.

【table】

[Table] Experimental Example 2 Contrast medium prepared in Example 1 saturated with oxygen and control (Urografin 76 as a contrast medium)
%, alone) was used to selectively perform coronary artery contrast imaging using a male beagle dog weighing approximately 20 kg. A compressed air automatic injector was used to inject the contrast medium, and the injection rate was 50c.c.
was injected into the left coronary artery at a rate of 0.4-0.6 ml/sec. As a result, the control completely developed ventricular fibrillation after 15 seconds of retention and died thereafter, but the beagles injected with the contrast agent according to the present invention showed no notable changes such as side effects even after 240 seconds. Ta. Experimental Example 3 10 ⁶ AH130 cells per rat were intramuscularly transplanted, and 12-month-old tumor-bearing rats with a diameter of 2 to 3 cm were used for experiments. 40 ml of the contrast medium prepared in Example 1 was applied to these rats. /Kg (10g/Kg as brominated PFC) was injected intravenously, and X-ray contrast was performed the next day. As a result, AH130 tumors were significantly contrasted in rats administered with the contrast agent of the present invention compared to controls. After X-ray contrast, brominated PFC in the tumor was quantified by gas chromatography.1
24.3mg/g on day 4;
Significant brominated PFC uptake into the tumor was demonstrated at 8.0 mg/g.

Claims (1)

[Scope of Claims] 1 Brominated perfluorocarbon having 6 to 12 carbon atoms and 1 or 2 bromine atoms in the molecule, phospholipids, hydrogenated phospholipids, and molecular weights of 2000 to 2000.
and at least one emulsifier selected from 20,000 polymeric nonionic surfactants, and if the emulsifier is the above-mentioned phospholipid, vitamin E is used as an emulsification adjuvant, and when the emulsifier is the above-mentioned surfactant, A contrast agent consisting of a brominated perfluorocarbon emulsion containing phospholipids as an emulsification aid and having a particle size of 0.05 to 0.4μ. 2. The contrast imaging according to claim 1, comprising a brominated perfluorocarbon emulsion further containing, as an emulsification adjuvant, at least one selected from a fatty acid having 6 to 22 carbon atoms, a salt of the fatty acid, and a monoglyceride of the fatty acid. agent. 3. The contrast agent according to claim 1 or 2, which is a vascular contrast agent. 4. The contrast agent according to claim 1 or 2, which is a tumor contrast agent.