JPS58110522A - Agent for vasography - Google Patents

Abstract

PURPOSE:An agnet for vasography having low side effects, capable of adjusting osmotic pressure to a physiologically isotonic state, comprising a specific brominated perfluorocarbon, an emulsifying agent such as phospholipid of egg yolk, etc., and a specific emulsifying auxiliary. CONSTITUTION:5-100w/v% 6-7C brominated perfluorocarbon[e.g., BrCF2 (CF2)4CF2Br, etc.]containing 2 bromines atoms in the molecule is blended with 2-6w/v% emulsifying agent selected from phospholipid of egg yolk or phosholipid of soybean and/or a nonionic surface active agent of high polymer (e.g., polyoxyethylene polyoxypropylene copolymer, etc.) having a molecular weight of about 2,000-20,000 and 0.001-0.1w/v% emulsifying auxiliary consisting of 8- 22C fatty acid ester (e.g., capric acid, caprylic acid, etc.) or fatty acid salt or fatty acid monoglyceride, and the blend is adjusted to physiologically isotonic state with a highly isotonic electrolytic solution, to give an agent for vasography having particle diameters of 0.05-0.4mu. A required amount of the agent can be fed depending upon the purpose.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an angiographic 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 xII transmittance between an organ and the surrounding tissue when observing an organ in the body using an X-ray photograph, making it possible to observe the organ morphologically and functionally. There are positive contrast agents and negative A1 agents, but the former are currently mainly used as angiographic contrast agents, and among them, those containing organic l-do compounds as their main components are the most commonly used. There is.

Important conditions for use as an angiographic contrast agent are high yield of X1ll@, but also chemical stability, efficient excretion, possibility of large-scale administration, and low viscosity. In addition, it is required to 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, Tri
Although preparations of 1odobenzoicmcld derivatives are frequently used, many other short compounds and monoiodo compounds have also been developed. However, there are currently many side effects associated with these angiographic contrast agents, such as vascular pain (burning sensation) in the injected blood vessel, burning sensation in the mouth, bitterness, whole body sensation, flushing, nausea, vomiting, abdominal pain, Heart palpitations,
Chest pressure, rash, etc. often occur. Among them, radiating pain related to vascular pain is a symptom that occurs in almost all cases, and although it is temporary, it can cause great pain to the patient. In addition, anxiety, vomiting, abdominal pain, etc. occur as quite strong side effects. The incidence of this side effect is 8
There are also reports that it is ~10%, which cannot be ignored. One of the causes of these side effects is that conventional angiographic contrast agents are luxuriously hyperosmotic (hypertonic). Therefore, if the osmotic pressure of the angiographic agent is lowered to approach the physiological osmotic pressure, side effects can be greatly reduced.

Furthermore, it is safe to choose the angiographic contrast agent depending on the area to be examined; however, when activating a certain area, such as the coronary artery, the angiographic contrast agent may accumulate for only a few seconds [because of LIJ].
Particularly with respect to the heart, arrhythmia and decreased cardiac function are often observed side effects.

This is an anoxic condition (Ann*xia) based on angiographic agents.
It is presumed that this is due to cardiac arrest or severe debilitating symptoms due to angiography. Sufficient preoperative testing is essential when using drugs.

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 endeavored to improve angiographic contrast agents and have conducted various studies. As a result, when a fluorocycarbon compound emulsion having an oxygen transporting function is added to known contrast agents as an additive, side effects can be minimized and the results can be adjusted depending on the purpose. They discovered that it was possible to inject the required amount, and developed an angiographic contrast agent (Japanese Unexamined Patent Publication No. 10031/1989) consisting of a composition of a contrast agent and a fluorocarbon compound emulsion.
-2) has already been proposed.

Another technique for angiography agents that exhibits a shadowing effect is the compound itself, which is brominated perfluorocarbons (referred to as brominated PFCs), in which one or two bromines replace the fluorine in the perfluorocarbon. This brominated P
FC has properties such as perfluoro-solubility and is radiopaque (Japanese Patent Publication No. 53-47031).
issue). Although this brominated PFC itself is an excellent angiographic contrast agent, it is extremely difficult to formulate it into a pharmaceutical product due to its chemical properties. 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 is difficult to emulsify and has poor stability, making it impossible to maintain the emulsion particle size of 0.4 μm or less for a long period of time, which is necessary for administration to the human body.

In order to improve these drawbacks of brominated PFC, the present inventors researched various methods of emulsifying brominated PFC, and completed the present invention by finding a suitable emulsification auxiliary agent.

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.◇ Angiography used in the present invention Brominated PFC is a perfluorocarbon with 6 to 7 carbon atoms in which the fluorine is replaced with two bromines, and it does not accumulate in organs such as the liver or viscera, and is preferable to organs. There are no limitations whatsoever as long as it does not cause any hindrance. These can be collectively referred to as "brominated/<++ fluorocarbons having 6 to 7 carbon atoms and two bromine atoms in the molecule", and some specific examples thereof are listed below.

fll BrCFz((Fg)4cFtBr(21B
rCFl(CFx)3CFBrCF3t6) BrC
Fz(CFs)icFzBrY Brominated PFCs and their production methods are known, and are described, for example, in Encyclopedia Op.
748-750 (2nd edition), and the present invention has nothing to do with the brominated PFC itself or its manufacturing method.

In general, brominated PFC emulsions have poor stability, and even though they have an average particle diameter of 0.4 μm or less after production, it is difficult to store them in this state for long periods of time.

The present invention uses a phospholipid or/and a polymeric nonionic surfactant as an emulsifier for the selected brominated PFC,
By adding a trace amount of a fatty acid, a fatty acid salt, or a fatty acid compound such as a fatty acid monoglyceride as an emulsifying agent, it has become possible to produce a brominated PFC emulsion with ultrafine particles that is stable for a long time.

The phospholipid used as an emulsifier is egg yolk phospholipid or large phospholipid, and the polymeric nonionic surfactant has a molecular weight of 2.
,000 to 20,000, such as polyoxyethylene/polyoxypropylene colimer, polyoxyethylene alkyl ether, polyoxyethylene alkyl ether,
Ruaryl ether etc. are used.

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. Fats with 8 to 22 carbon atoms include, for example, caprylic acid, capric acid, lauric acid, myristic acid, pallic acid, stearic acid, behenic acid, palmitoleic acid, oleic acid, linoleic acid, aratonic acid. These fatty heavy compounds can be used alone or in a mixture of two or more.

The angiographic agent of the present invention contains brominated PFC5-100 W/V-
1 emulsifier 2-6 W/V %, emulsification aid 0.001-
G, IW/V%, and the emulsified aqueous solution with this composition can be used as a physiological aqueous solution, for example, the composition is Ng C13-7%, CaC1 snow 015-0.4 rumor, MgC/l O, 1-0.5%, D
- Glucose 0.7-LO%, KCl 0.3-0.5%
The tonicity is adjusted to physiological isotonicity with a hypertonic electrolyte solution consisting of 2-4 times NaHCO. In the present invention, first, a predetermined amount of a saline solution, such as a physiological saline solution or a lactic acid gel solution, is added.
W/v% emulsifier and 0.001 to 0.1 w/v% emulsification auxiliary agent were added and coarsely emulsified, and brominated P was added to this coarse emulsion.
FC with a final fluorocarbon content of 5 to 100 W/
V%, stir with a mixer to make a coarse emulsion, and use an emulsifier to reduce the particle size to O, OS ~
A brominated PPC emulsion with ultrafine particles is produced by homogenizing the emulsion to a particle size of 0.4μ. In the present invention, 0.
Although particles larger than 4 μm are not substantially formed, in order to remove particles larger than 0.4 μm just in case, one step of centrifugation may be performed after preparing the emulsion.

The method of using the +Th tube contrast 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 abdomen and abdomen. It is injected through a transfemoral arterial catheter, and for imaging of cardiovascular and pulmonary vessels, it is injected through a puncture into the cubital vein or through a cardiac catheter. The amount used is 5 to 100 d 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 to brominated PFC, it is possible to prevent cardiac arrest and serious cardiac arrest due to anoxia, and even when administered in large quantities over a long period of time, there is no risk of injury. computer because it does not cause
Tomography becomes possible.

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.

Further, the angiographic contrast agent according to the present invention has a particle size of 0.05 to 0.
．． Since they are ultrafine particles of 4 μm in size and do not coarsen during long-term storage, there are no problems associated with coarsening of the particles to the 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.

Example 1 Egg yolk phospholipid 35 (l and F barmitate 3.5
2 and pre-lactated Ringer's solution 8. perfluoro-1 and stirred with a mixer to prepare a rough emulsion.
, 6-dipmhexane 2-5 K9 was added, and the mixture was further strongly stirred with a mixer to prepare a crude emulsion. This rough emulsion! The mixture was placed in a liquid tank of a Ntongorin type injection emulsifier and circulated, and emulsification was carried out while maintaining the liquid temperature at 40±5°C.

The concentration of brominated PFC in the obtained emulsion was 30.1 W/V
%Met.

The average particle size measured by 2% cardiac sedimentation method is 0.14μ
No significant increase in particle size was observed even after dispensing into injection vials, capping them, storing them in a rotating DA, heat sterilization, and storing them at 4° C. for 3 months. , Sora sure example 2 Dai uses phospholipid fK30051 and capric acid 5 in physiological saline.
i liquid9. o/, stir with a mixer to prepare a rough emulsion, and add 1,4-dibromperfluorocyclohexane 2. OK was added and further stirred vigorously to form a coarse emulsion, and this coarse emulsion was emulsified using a Manton-Gorlin emulsifier. The concentration of 1,4-dibromperfluorocyclohexane in the obtained emulsion was 21.5 W/V%.
The average particle size was 0.17 μm, and the particle size remained 10.17 μm even after heat treatment and storage at 14° C. for 3 months.

Example 3 Perfluoro 0-1.6-dipromohexane 20-, polyoxyethylene/polyoxypropylene copolymer (average molecular weight 8.350, Pluronic F68) 3.4%
, egg yolk phospholipid 0.6%, potassium oleate 0.00
4%, khcl 6%, NaHCO32,1%, KC7
0,336%, MflC1 0.427%,
An emulsion consisting of 356% CiC/rich G and 1.8% D-glucose is prepared and sterilized by heat. Its average particle size is 0.13μ.

No coarsening of the grains was observed in this emulsion even after it was stored at 4°C for 3 months.

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

Safety Experiment Using the angiographic contrast agent prepared in Example 1 saturated with oxygen and the control (76% urodalafine alone as an angiographic contrast agent), a male beagle dog weighing 20 Kf was selectively injected into the coronal region. Arterial angiography was performed. A compressed air automatic injector is used to inject the angiographic agent, and 30 cc is injected at 0.4~
It was injected into the left coronary artery at a rate of 0.6 mZ/sec. As a result, in the control, ventricular fibrillation completely occurred after 15 seconds of retention;
Although he later died, the dog Peagle injected with the angiographic agent according to the present invention still showed signs of side effects after 240 seconds. No change was observed.

Applicant: Midori Juji Co., Ltd. 11 0

Claims (1)

[Claims] Brominated perfluorocarbon having 6 to 7 carbon atoms and 2 bromine atoms in the molecule, egg yolk phospholipid or soybean phospholipid, or/and a molecular weight of approximately 2°000 to 20,000
It contains an emulsifier selected from polymeric nonionic surfactants with a particle size of 0 and a fatty acid or fatty acid salt or fatty acid monoglyceride having 8 to 22 carbon atoms as an emulsion aid.
．． An angiographic contrast agent consisting of a 0.05-0.4μ fluorocarbon emulsion.