JPH0412244B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a blood purification agent comprising a perfluorocarbon compound emulsion. More specifically, the present invention relates to a therapeutic agent for drug poisoning and liver failure that requires blood exchange, that is, a blood purifier.

Currently, there are no suitable treatments for diseases caused by poisonous substances mixed into the blood, such as drug poisoning and blood type incompatible blood transfusions for liver failure, and dialysis treatment and whole blood exchange are performed. However, in cases such as drug poisoning caused by high-molecular proteins, dialysis treatment is not sufficiently effective, and whole blood exchange as a treatment for such cases does not require the necessary type of blood. It is difficult to prepare the necessary amount at the time of use, and sometimes the result is the worst.

The present invention utilizes a fluorocarbon emulsion as a blood purification agent during whole blood exchange, and has thereby succeeded in efficiently cleaning blood containing toxic substances.

Fluorocarbon emulsions are currently used as oxygen-carrying infusions (Fluosol-DA, Midori Juji Co., Ltd.) and are safely administered to patients with massive bleeding.

The present inventors have conducted various studies on this fluorocarbon compound emulsion, and have completed the present invention by discovering that if the fluorocarbon compound emulsion is administered to the human body as a blood purification agent, it can be used as a therapeutic agent for drug addiction.

The term "blood purification agent" as used herein refers to an agent that achieves blood purification by leading the blood together with the extracorporeal circulation system, separating it from the blood fraction, and returning the purified healthy blood to the body. be.

The perfluorocarbon compound emulsion used in the present invention is a liquid fluorocarbon compound emulsion that maintains a particle size that can be administered into human blood vessels and does not accumulate in organs or cause damage in organs or bloodstream. There are no particular limitations, and for example, those proposed as oxygen-carrying infusions can be widely used.

Preferred emulsions include a perfluorocarbon compound alone or a suitable mixture thereof, a polymeric nonionic surfactant and/or a phospholipid as an emulsifier;
If necessary, an emulsion prepared by emulsifying the particle size to 0.3 microns or less using a fatty acid compound having 8 to 22 carbon atoms (acid, alkali metal salt, or monoglyceride) as an emulsifying agent can be mentioned. These emulsions are disclosed in, for example, JP-A-50-69219, JP-A-52-96722, and JP-A-Sho 57.
-110200, (Japanese Unexamined Patent Publication No. 1983-225013), Patent Application No. 1983-
No. 151098 (Japanese Unexamined Patent Publication No. 1983-39870), Patent Application No. 1987-
It is described in detail in No. 157677 (Japanese Unexamined Patent Publication No. 59-46218).

Any perfluorocarbon compound used in the present invention can be used as long as it has an oxygen transport function and has a low adverse reaction to living organisms. Suitable examples of such perfluorocarbon compounds include perfluorohydrocarbons having 9 to 12 carbon atoms and perfluoro tertiary amines having 9 to 12 carbon atoms. Specific examples of perfluorocarbon compounds include perfluorocycloalkane, perfluoroalkylcycloalkane, perfluorocyclohexane, perfluorodecalin, perfluoroalkyldecalin, perfluoroalkyltetrahydropyran, perfluoroalkyltetrahydrofuran, and perfluoroalkyltetrahydrofuran. Fluoroalkane, perfluorotertiary alkylamine, perfluoro N,N-dialkylcyclohexylamine, perfluoroalkylpiperidine,
Examples include perfluoroalkylmorpholine, perfluoroadamantane, perfluoroalkyladamantane (Japanese Patent Application Laid-open No. 1983-69219). In particular, emulsions containing these perfluorinated hydrocarbons as a major component and a perfluorinated tertiary amine as a minor component are preferred because they do not cause precipitation when plasma expanders such as dextran, hydroxystarch, and modified gelatin are added. (Tokukai Akira
52-96722). Also, perfluoro-N-methylperhydroquinoline, perfluoro-N-methyldecahydroisoquinoline, recently developed by the applicant.
Perfluoro-4-methyloctahydroquinolidine, perfluoro-3-methyloctahydroquinolidine, perfluoro-2-methyloctahydroquinolidine, perfluoro-1-methyloctahydroquinolidine, perfluoro-9a-
Methyl octahydroquinolidine, perfluoro-4-ethyl octahydroquinolidine, and the like are also preferred perfluorocarbon compounds.

As an emulsifier for the emulsion, a polymeric nonionic surfactant with a molecular weight of about 2,000 to 20,000, such as polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, and/or egg yolk phospholipid and soybean. Phospholipids such as phospholipids are used.

Fatty acid compounds used as emulsification aids include fatty acids having 8 to 22 carbon atoms and physiologically acceptable sodium, potassium, etc. salts or monoglycerides of these fatty acids. These include, for example, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitoleic acid, oleic acid, linoleic acid, arachidonic acid and their sodium or potassium salts and their It is a monoglyceride. These fatty acids can be used alone or in a mixture of two or more, and in the above emulsion, based on 95 to 50 parts by weight of perfluorodecalin or perfluoromethyldecalin, those having an alkyl group having 4 to 6 carbon atoms are used. Perfluorocarbon tertiary amine or perfluoroadamantane selected from the group consisting of perfluoro-N-alkylpiperidine, perfluoro-N-alkylmorpholine having an alkyl group having 5 to 7 carbon atoms, and perfluoro tertiary alkylamine. At present, an emulsion obtained by emulsifying 5 to 50 parts by weight of the following is most preferred.

The preferred composition of these emulsions is 10 to 50 w/v% perfluorocarbon, 2 to 5 w/v% emulsifier,
The key is to add 0.1 to 1w/phospholipid as an emulsification aid.
It is an emulsified aqueous solution consisting of 0.004 to 0.1 w/v% of fatty acid compounds and a physiological aqueous solution,
For example, its composition is NaCl 3-7%, CaCl ₂ 0.15-0.4
%, _MgCl2 0.1-0.5%, D-glucose 0.7-2.0
A suitable preparation is obtained by adjusting the tonicity to physiological isotonicity with a hypertonic electrolyte solution consisting of %, KCl 0.3-0.5%, and NaHCO ₃ 2-4%, optionally with a plasma expander added thereto. It will be done.

The blood purifying agent of the present invention is also effective in cases where hemodialysis or the like cannot be expected to be sufficiently effective in treating toxic symptoms in humans and animals caused by various causes.
That is, the blood purification agent of the present invention can be used to treat liver failure, severe jaundice,
It can be applied to diseases such as blood type incompatibility during blood transfusions and drug addiction. Treatment with the blood purifying agent of the present invention is carried out by injecting the perfluoro compound emulsion at the same time as removing poisoned blood. The dosage is, for example, 100 to 5000 ml per adult human adult.
(However, when the content of the perfluorocarbon compound in the emulsion is 10 to 50 w/v%).

In that case, in order to ensure patient safety, it is desirable that the blood concentration of the dose be less than 10ml/Kg body weight, and that the hemacritt value is 1.
The dose may be administered up to a corresponding amount.

Furthermore, in order to safely administer a large amount of perfluoro compound emulsion (FC), it is preferable to apply plasma pheresis technology. That is, the drained blood is separated into an FC part (average specific gravity 1.8) and a blood part by, for example, centrifugation, the FC part is removed, and the blood part is returned to the human body after an appropriate cleaning treatment. By repeating this process, poisoned blood can be washed away.

The safety of perfluoro compound emulsions has already been established in the field of oxygen-carrying infusions.

Example 1 300 g of polyoxyethylene polyoxypropylene copolymer (molecular weight 8350) was dissolved in 88 g of distilled water,
This solution contains 3 kg of perfluorodecalin, 300 g of perfluorotripropylamine, and 40 g of soybean oil phospholipid.
A mixed fluorocarbon containing 2 g of potassium oleate and 2 g of potassium oleate was added thereto and stirred with a mixer to prepare a rough emulsion. This rough emulsified liquid was put into the liquid tank of a jet emulsifier (manufactured by Manton Colin) and circulated.
Emulsification was carried out under high pressure of 500 Kg/cm ² while maintaining the liquid temperature at 35±5°C. The concentration of perfluorodecalin in the obtained emulsion was 30.5% w/v, and the concentration of perfluorotripropylamine was 2.9% w/v. The average particle diameter measured by centrifugal sedimentation is 0.09~
0.1μ, dispensed into an injection vial and stoppered,
Even when this was placed in a rotary sterilizer and heat sterilized at 115°C for 12 minutes, no increase in particle size was observed.

Example 2 Add 400 g of egg yolk phospholipid to lactated Ringer's solution (8.5 g) and stir with a mixer to prepare a rough emulsion, add 2.5 kg of perfluoro-4-methyloctahydroquinolidine to this liquid, and further stir vigorously with a mixer. A crude emulsion was prepared by stirring. This crude emulsified liquid was placed in a liquid tank of a jet emulsifying machine (manufactured by Manton-Gaulin) and circulated to carry out emulsification while maintaining the liquid temperature at 50±5°C. The concentration of perfluoro compound in the obtained emulsion was 27.3 w/v%. The particle size measured by the centrifugal sedimentation method is 0.05 to 0.25μ, and even if the vial is dispensed into an injection vial, capped, and stored in a rotary sterilizer for heat sterilization, the particle size hardly increases. I didn't approve.

Example 3 Add 400 g of egg yolk phospholipid and 4 g of sodium palmitate to 8.5 ml of lactated Ringer's solution, stir with a mixer to prepare a rough emulsion, and add 2.5 ml of perfluoro compound (perfluoro-N-methylperhydroquinoline) to this liquid. Kg was added and further stirred vigorously with a mixer to prepare a rough emulsion. This crude emulsified liquid was placed in a liquid tank of a jet emulsifying machine (manufactured by Manton-Gaulin) and circulated, and emulsification was carried out while maintaining the liquid temperature at 50±5°C. The concentration of perfluoro compound in the obtained emulsion was 27.3 w/v%. The particle size measured by the centrifugal sedimentation method is 0.05 to 0.25μ, and even if the vial is dispensed into an injection vial, capped, and stored in a rotary sterilizer for heat sterilization, the particle size hardly increases. I didn't approve.

Examples of tests on the medicinal efficacy of perfluoro compound emulsions are shown below.

Test Example 1 Using a male beagle dog weighing 10 kg, experimentally
The common bile duct was ligated and a jaundiced dog was created. In order to wash the dog's blood, blood was removed from the artery, and at the same time, the emulsion of Example 1 was infused intravenously. The removed blood is led to the extracorporeal circulation system and centrifuged (4800 rpm
120 minutes), the perfluorocarbon component fraction and blood fraction were separated, the perfluorocarbon component fraction was discarded outside the body, and healthy blood was transfused. This operation was performed continuously. The processing time was approximately 2 hours and the perfluorocarbon emulsion dose was 2000 ml. This washing treatment lowers the blood total bilirubin level of laboratory dogs from 15μg/dl to 5μg/dl.
It was possible to lower it to dl.

Claims (1)

[Claims] 1. A blood purification agent consisting of a perfluorocarbon compound emulsion.