JPS5832829A - Contrast medium for blood vessel - Google Patents

Abstract

PURPOSE:The titled ultrafine particulate pharmaceutical, containing a specific brominated pefluorocarbon, an emulsifying agent, e.g. egg yolk phospholipid, and a specific emulsifying adjuvant, having low toxicity without the accumulation in the living body, and capable of adjusting the osmotic pressure to a physiological isotonicity. CONSTITUTION:An ultrafine particulate contrast medium for blood vessels, containing an 8-12C brominated perfluorocarbon (PFC) having at least one or two bromine atoms in the molecule, an emulsifying agent selected from an egg yolk phospholipd or soybean phospholipid or/and a high polymeric nonionic surfactant, e.g. polyoxyethylene-polyoxypropylene copolymer, having a molecular weight of about 2,000-20,000, and an 8-22C fatty acid or salt thereof or a fatty acid monoglyceride as an emulsifying adjuvant, having a particle diameter of 0.05-0.4mu, and storable for a long term with high safety. The contents of the components are as follows: 5-50W/V% brominated PFC, 2-6W/V% emulsifying agent and 0.001-0.1W/V% emulsifying adjuvant.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an angiographic contrast agent comprising a brominated perfluorocarbon emulsion that has no bioaccumulability and low hostility.

A contrast agent is a drug that creates a difference in KX-ray transmittance between an organ and surrounding tissue when observing an internal body organ using an X-ray photograph, making it possible to observe the organ morphologically and functionally. There are two types of contrast agents: positive contrast agents and negative contrast agents, but the former are currently mainly used as angiographic contrast agents, and among them, those containing organic iodine compounds as the main component are most commonly used.

An important condition for an angiographic contrast agent is high X-ray absorption, but other requirements include chemical stability, efficient excretion,
It is required to be able to administer large amounts, have low viscosity, and have low vascular stimulation and hepato-renal damage.

A wide variety of angiographic contrast agents have already been developed, and their contrast performance and safety have significantly improved. Recently, Trlio
Preparations of dobenzoicacid derivatives are frequently used, but there are many other side effects that are currently a problem, such as vascular pain (burning sensation) in the injection vessel, burning sensation in the mouth,
Bitter taste, general feeling of heat, flushing, nausea, vomiting, abdominal pain, palpitations, chest tightness, rash, etc. often occur. Among them, vascular pain and its associated radiation disease are symptoms that occur in almost all cases, and although they are temporary, they can cause great pain to patients.

Also, nausea, vomiting, abdominal pain, etc. occur as fairly strong side effects. It has been reported that the incidence of this side effect is 8-10%.
It cannot be ignored. One cause of these side effects is that conventional angiographic agents are significantly hyperosmotic (hypertonic). Therefore, by lowering the osmotic pressure of the angiographic agent to bring it closer to physiological osmotic pressure, it is possible to significantly reduce side effects.

Furthermore, angiographic contrast agents can be used as contrast agents depending on the area to be examined, and side effects, particularly with respect to the heart, such as arrhythmia and decreased cardiac function, are often observed. This is presumed to be due to cardiac arrest and severe shock compared to the anoxic state (Annoxla K) caused by angiographic agents, but the frequency of serious side effects that can lead to death is approximately 0. .3
5%'), and sufficient preoperative testing is essential when using angiographic contrast agents.

As described above, angiographic contrast agents have considerable side effects that cannot be ignored, and although various angiographic contrast agents have been developed, many problems remain.

At this stage, the main points of improvement in angiographic contrast agents include minimizing side effects, enabling large-volume injection, and extending the duration of continuous contrast agent injection. The present inventors have worked to improve angiographic contrast agents, and have conducted various studies. 1. As a result, adding a fluorocarbon compound emulsion with an oxygen-carrying function to known contrast agents as an additive reduces side effects and achieves the intended purpose. They discovered that it was possible to inject mice according to their needs, and developed an angiographic contrast agent consisting of a composition of a contrast agent and a fluorocarbon compound emulsion (Japanese Unexamined Patent Publication No. 55-1003).
12) has already been proposed.

Another technique for angiographic contrast agents is the compound itself that exerts a contrast effect.It is a chemical compound that combines the properties of bromine with the properties of bromine by replacing the fluorine in perfluorocarbon with one or two bromine. physically inert, non-active,
It has properties such as low viscosity, volatility, and insolubility, and is also radially opaque (Japanese Patent Publication No. 53-4703
1) This brominated PFC is itself an excellent angiographic contrast agent, but its chemical properties make it extremely difficult to formulate it into a formulation. 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 0.4 μm or less, it cannot be administered to animals to sustain life. However, brominated PFC
It is difficult to emulsify and has poor stability, and it is difficult to maintain the emulsion particle size of 0.4μ or less for a long period of time, which is necessary for administration to the human body.We have researched various ways to emulsify nonbrominated PFC.
The present invention was completed by finding a suitable emulsification aid.

The present invention aims to provide an angiographic contrast agent that is composed of a fluorocarbon emulsion containing brominated PFC, an emulsifier, and an emulsifying agent, and whose osmotic pressure can be adjusted to physiological isotonicity.

The brominated PFC with angiographic ability used in the present invention is a perfluorocarbon having 8 to 12 carbon atoms in which fluorine is replaced with one or two bromines, and is used in the liver, etc. There are no limitations at all as long as it does not accumulate in organs and does not cause undesirable damage to organs. These can be collectively referred to as brominated perfluorocarbons having 8 to 12 carbon atoms and at least 1 or 2 bromine atoms in the molecule, and some specific examples thereof are listed below.

(61CFB (CF2) 6 CFI Br(71
Br@CFi (CFi)6cr”2@13r, O (8)
CF3(CFi)6CF2Br brominated PFCs and their production methods are known, for example, Encyclopedia of Chemical Technology 9, 748-750.
(2nd edition), and the present invention has nothing to do with the brominated PFC itself or the method of making it.

It is difficult to store it in this state for a long time. The present invention uses a phospholipid or/and a polymeric nonionic surfactant as an emulsifier for the selected brominated PFC, and adds a WI amount of a fatty acid or a fatty acid salt or a fatty acid compound such as a fatty acid monoglyceride to this as an emulsifying aid. This made it possible to produce a brominated PFC emulsion with ultrafine particles that was stable for a long period of time.

The phospholipid used as an emulsifier is egg yolk phospholipid or soybean phospholipid, and the polymeric nonionic surfactant is a molecule ffi.
2,000 to 20,000, such as polyoxyethylene-functional polyoxypropylene copolymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, etc.

The fatty acid compound used as an emulsification aid is a fatty acid having 8 to 22 carbon atoms, or a physiologically acceptable sodium salt, potassium salt, or monoglyceride thereof. Examples of fatty acids with 8 to 22 carbon atoms include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitoleic acid, oleic acid, linoleic acid, and arachidonic acid. ,
These fatty acid compounds can be used alone or in a mixture of two or more.

The angiographic agent of the present invention contains brominated PFC5-50 W/V%,
Emulsifier 2-6 4'%, emulsification adjuvant 0.001-0. I
W/V%, and an emulsified aqueous solution with this composition can be used as a physiological aqueous solution, for example, with a composition of 13-7% NaCl, 20% CaCl.
15-0.4%, MgCIQ 0.1-0.5%, D-
Glucose 0.7-2.0%, KCI! 0.3-0.5
%, adjusted to physiological isotonicity with a hypertonic electrolyte solution consisting of 2-4% NaHCO3. In the present invention, first, a predetermined amount of salt solution, for example, is grown and coarsely emulsified, and then brominated PFC is added to this coarse emulsion.
This rough emulsion is processed into an emulsifier until the particle size is 0.05 to 0.
．． A brominated PFC emulsion with ultrafine particles is produced by homogenizing the emulsion to a particle size of 4μ. In the present invention, 0.4
Particles larger than μ are virtually never formed, but
In order to remove particles larger than 0.4 μm, centrifugation may be performed after preparing the emulsion.

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 puncture injection into arteries and veins for imaging of limb arteries and veins, and percutaneous puncture injection for imaging of the aorta and branch arteries of the chest and abdomen. Alternatively, it can be injected through a transfemoral artery catheter, and for imaging of cardiovascular or pulmonary vessels, it can be injected through a puncture into the cubital vein or through a cardiac catheter. The amount used is 5 to 100+nl' at a time, and the entire amount is injected rapidly or continuously as needed.

Since the angiographic agent according to the present invention provides oxygen supplementation through brominated PFC, it is possible to prevent cardiac arrest and severe shock due to anoxia, and there is no damage even when administered in large quantities over a long period of time. Since the brominated PFC used in the present invention is rapidly excreted through exhalation when administered into the body, no long-term accumulation in the reticuloendothelial organs of the body has been observed. Furthermore, the angiographic contrast agent according to the present invention has a particle size of 0.05 to 0.4 microparticles, and the particles do not coarsen during long-term storage, so there is no harm caused to the administered animal due to the coarsening of the particles. A high degree of safety is guaranteed.

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

Example 1 Egg yolk phospholipid 350v and sodium palmitate 3.5
A crude emulsion was prepared by adding the pre-lactic acid Ringer's solution S, Ot into a fist and stirring with a mixer.Perfluorooctyl bromide 2.5 K9 was added to this solution and further stirred vigorously with a mixer to prepare a coarse emulsion. . This crude emulsified liquid was placed in a liquid tank of a Manton-Gorlin injection emulsifier and circulated, and emulsification was carried out while maintaining the liquid temperature at 45±5°C. The concentration of brominated PFC in the obtained emulsion was 29.9 W/V%
Met. The average particle size measured by centrifugal sedimentation is 0.
．． The particle size was 12μ, and no significant increase in particle size was observed even after dispensing into injection vials, capping them, storing them in a rotary sterilizer, heat sterilizing them, and storing them at 4°C for 3 months.

Example 2 300 g of soybean phospholipid and 5 g of capric acid were added to 9 g of physiological saline.
．． A crude emulsion was prepared by stirring with a mixer, and 2.0% of monobromoperfluorodecalin was added to this solution, and the mixture was further stirred vigorously until the concentration of perfluoromethyldecalin was 21.5 W/V%. , average particle size 0
．． The particle size was 16μ, and the particle size remained 0.16μ even after heat treatment and storage at 4°C for 3 months.

Example 3 Perfluorooctyl bromide 20%, polyoxyethylene polyoxypropylene copolymer (average molecular weight 8.350, Pluronic F68) 3.4%, egg yolk phospholipid 0.6%, potassium oleate 0.004%, Na
C16%, NaHCO32.1%, KCl0.336%
, MgCl20.427%, CaCl20.356%,
The emulsion did not show any coarsening of the grains even after being stored at 4°C for 3 months.

Example 4 An emulsion was prepared with the same composition as in Example 3, except that it contained 3.4% of polyoxyethylene octyl ether with an average molecular weight of 3,500 as an emulsifier. Its average particle size is 0
．． It is 09μ. No coarsening of the grains was observed in this emulsion even after it was stored at 4°C for 3 months.

Table 1 shows that the composition and average particle diameter of each example and the average particle diameter when no emulsification aid is added are as shown in Table 1. It can be seen that it has a remarkable effect on

[Margins below] Table 1 Composition and average particle diameter of each example (comparison with and without emulsification aid) Vascular contrast agent prepared in Safety Experiment Example 1 saturated with oxygen and control (angiographic contrast agent) Selective coronary artery imaging was performed using urografin 76% (alone) in a male beagle dog weighing approximately 20-9. A compressed air automatic injector is used to inject the angiographic agent, and 50 cc is injected from 0.4 to 50 cc.
It was injected into the left coronary artery at a rate of 0.6 me 7 seconds. As a result, in the control, ventricular fibrillation completely developed within 15 seconds of retention and the patient died thereafter, but in the pegle dogs injected with the angiographic contrast agent according to the present invention, no notable changes such as side effects were observed even after 240 seconds. There wasn't.

Applicant Mitri Juji Co., Ltd. 2, name of invention Blood! Relationship with the case by the person making the amendment Applicant: Midori Toimo Co., Ltd. 4, Agent 7, Details of the amendment 4sv J Page 8, line 5, insert ``1 quality'' after ``r town''.

Claims (1)

[Scope of Claims] A brominated perfluorocarbon having 8 to 12 carbon atoms and at least 1 or 2 bromine atoms in the molecule, egg yolk phospholipid or soybean phospholipid, or/and a molecular weight of about 2
,000 to 20,000 polymeric nonionic surfactants, and as an emulsification aid, an emulsifier with a carbon number of 8 to 20,000.
Contains 22 fatty acids, fatty sulfates, or fatty acid monoglycerides, and has a particle size of 0.
An angiographic contrast agent consisting of a 0.05-0.4μ fluorocarbon emulsion.