JPS59175421A - Hemocathartic agent - Google Patents

Abstract

PURPOSE:To provide a hemocathartic agent composed of an emulsion of a perfluorocarbon compound used as an oxygen-carrier transfusion, and capable of effectively cleaning the blood containing toxic substances. CONSTITUTION:The objective hemocathartic agent is composed of a perfluorocarbon compound emulsion obtained by emulsifying a perfluorocarbon compound such as perfluorocylcoalkane, perfluoroalkylcycloalkane, perfluoro-N-methyl perhydroquinoline, etc. to a particle size of <=0.3mu using a polymeric nonionic surface active agent (e.g. polyoxyethylene-polyoxypropylene copolymer) and/or a phospholipid (e.g. egg yolk phospholipid) as an emulsifier and a 8-22C fatty acid compound (e.g. caprylic acid) as an assistant for emulsification. The hemocathartic agent can be applied to the diseases such as hepatic insufficiency, icterus gravis, incompatibility of the blood group in transfusion, drug intoxication, etc. The blood contaminated by intoxication, etc. is released from the body, and at the same time, the perfluoro compound emulsion is infused in the vessel.

Description

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

Currently, there is no suitable treatment system for diseases caused by blood type incompatible blood transfusions for liver failure and other diseases caused by poisonous substances mixed into the blood, and dialysis treatment and whole blood conversion are currently available. However, in cases where macromolecular proteins are the cause, dialysis treatment is not sufficiently effective, and whole blood conversion as a treatment for such cases does not meet the required blood pressure. It is difficult to prepare the required amount of blood at the time of use, and sometimes the results are disastrous.

The present invention utilizes a fluorocarbon emulsion as a blood purification agent during whole blood exchange.
This method succeeded in efficiently cleaning blood containing toxic substances.

Fluorocarbon emulsions are currently used in oxygen-carrying infusions [Fluo
It is used as aol-D8 (stock Nomitori Juji) and is safely administered to patients with massive bleeding.

The inventors of the present invention have conducted various studies on this fluorocarbon compound emulsion, and finally discovered that when administered to the human body as a blood purifying agent, the fluorocarbon compound emulsion can be used as a therapeutic agent for drug addiction, thereby completing the present invention. .

The perfluorocarbon compound emulsion used in the present invention is a hostile 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. Aa is especially limited foot δ
For example, the proposed formula n can be widely used as an oxygen-carrying infusion solution.

Preferred emulsions include a perfluorocarbon compound alone, a suitable mixture of a polymeric nonionic surfactant and/or a phospholipid as an emulsifier, and a carbon number of 8.
~22 fatty acid compounds (including acids and emulsions)
The emulsion of et al.
It is described in detail in the issue.

The perfluorocarbon compound used in the present invention has oxygen transport properties and has low adverse reactions when applied to living organisms, and can be used as is.

Suitable examples of such perfluorocarbon compounds include perfluorohydrocarbons having 9 to 12 carbon atoms;
Specific examples of perfluorocarbon compounds such as 12 perfluoro tertiary amines include perfluorocycloalkane, perfluoroalkylcycloalkane, perfluorocyclohexane, perfluorodecalin, and perfluoroalkyldecalin. , perfluoroalkyltetrahydropyran, perfluoroalkyltetrahydrofuran, perfluoroalkane, perfluorotertiary alkylamine, perfluoroN
, N-dialkylcyclohexylamine, perfluoroalkylpiperidine, perfluoroalkylmorpholine, perfluoroadamafthane, and perfluoroalkyladamanotank (Japanese Patent Application Laid-open No. 69219/1983). In particular, these perfluorinated hydrocarbons are the main components, and perfluorinated tertiary amines? An emulsion containing a small amount of is preferable because it does not cause precipitation when plasma expanders such as dextrough, hydroxystarch, and modified gelatin are added (Japanese Patent Application Laid-Open No. 52-96722). Also, perfluoro-N-methylperhydroquinoline, perfluoro-N-methyldecahydroinquinoline, perfluoro-4-methyloctahydroquinolidine, and perfluoro-3-methyloctahydroquinolidine recently developed by the applicant. , perfluoro-2-methyloctahydroquinolidine, perfluoro-1-methyloctahydroquinolidine, perfluoro-9a-methyloctahydroquinolidine, perfluoro-4-methyloctahydroquinolidine, etc. Al is a perfluorocarbon compound.

As an emulsifier for emulsions with a molecular weight of approximately 2,000 to 20,000
polymeric nonionic surfactants such as polyoxyethylene-polyoxybrobyle 7 copolymer, polyoxyethylene alkyl ether, polyoxyethylene 7-alkyl allyl ether, and/or egg yolk phospholipids and soybean phospholipids. Phospholipids are used.

The fatty acid compound used as an emulsification aid has 8 to 2 carbon atoms.
The physiological effects of these fatty acids include salts or monoglycerides such as sodium and potassium, such as caprylic acid, capric acid, lauric acid, myristic acid, Valmitic acid, stearic acid, behenic acid, palmitoleic acid,
Oleic acid, linoleic acid, arachidonic acid, their sodium or potassium salts, and their monoglycerides. These fatty acids may be used alone or in a mixture of two or more. Among the above emulsions, perfluorodecalin or perfluoromethyldecalin is added to 95 to 50 parts by weight of an alkyl group having 4 to 6 carbon atoms. Perfluoro-N-furkylpiperidine having a group, perfluoro-N-alkylmorpholymer having an alkyl group having 5 to 7 carbon atoms/,
An emulsion prepared by emulsifying 5 to 50 parts by weight of a perfluoroadamancune or a perfluorocarbon tertiary amine selected from the group consisting of perfluoro tertiary alkyl amines is currently most preferred. The preferred composition of these emulsions is 10 to 50 w/v of perfluorocarbon.
%, emulsifier 2-5 w/v%, required 7n is 0.1-1 w/v phospholipid as an emulsification aid and 0 fatty acid compound.
．． It is an emulsified aqueous solution consisting of 0.004 to 0.1 w/v%, such as a physiological aqueous solution, for example, whose composition is Na
Cl3-7%, CaC40, .lI5. ~0.4%, M
gC40, 1-0.5%, D-glucose 0.7-2.
0%, KCl0.3-0.5%, NaHCO32-4%
Suitable formulations are obtained by adjusting the hypertonic electrolyte solution F'L to physiological isotonicity with a solution containing a plasma expander.

The blood purifying agent of the present invention is also effective in cases where hemodialysis or the like is not expected to be sufficiently effective in treating toxic symptoms in humans and animals caused by various causes.

In other words, the blood purification agent of the present invention can be applied to diseases such as liver failure, severe jaundice, blood type incompatibility during blood transfusion, and drug addiction. Treatment with the blood purification 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, human adult 1
100 to 5,000 IE/(provided that 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 dose be administered at a blood concentration of 10 w1/~body weight or less, which is equivalent to a hemacrit value of about 1. May be administered.

Furthermore, in order to safely administer a large amount of perfluorinated compound emulsion (FC), it is preferable to apply plasma phniresis technology. That is, the blood is removed, for example, separated into an FC part (average specific gravity 1.8) and a blood part by centrifugation, the FC part is removed, and the blood part is returned to the human body after an appropriate cleaning treatment.

By repeating this rotation, it becomes possible to wash blood that has caused poisoning, etc. Example 1 Polyoxyethylene polyoxypropylene copolymer (molecular weight 8,350) 300. Li' was dissolved in distilled water (8t''T), and perfluorodecalin 3K9 and nof-
Fluorotriprovira < 7300 g, soybean oil phospholipid 4011. Add the mixed fluorocarbon to 2.9' of potassium olei heptaate, stir with a mixer to make a coarse emulsion, and circulate this coarse emulsion into the liquid tank of an injection emulsifier (manufactured by Manton-Gaulin). Chize, 200-500
Emulsification was carried out under high pressure of Ky/crl while keeping the liquid temperature at 35 ± 5°C. The perfluorodecaly/viscosity in the obtained emulsion was 30.5 w/v%, perfluorotripropylamine. The rate was 2.9 w/v%. The average particle diameter obtained by centrifugal sedimentation is 0.09-? −
P1 injection vial was dispensed at 0.1μ, stoppered, and this was placed in a rotary sterilizer and heat sterilized for 12 minutes, but no increase in particle size was observed. 0 Example 2 Lactated Ringer's solution 8.5 to egg yolk phospholipid 400.9'
into the mixture, prepare a coarse emulsion* using a mixer,
This liquid was added with a perfluoro-4-methyloctahydroquinolinolyl 2,5Kp'i knife, and then the whole emulsion was made into a bulk emulsion using a mixer. This crude emulsion was prepared. Samurai et al.
27.3W in summer for the perfluorinated compound in the emulsion
/V% The particle size measured by centrifugal sedimentation was 0.05 to 0.25μ, and the injection vial was sealed under partial pressure and placed in a rotary sterilizer to be heat sterilized. Example 3 Egg yolk phospholipid% 400 # and sodium valmitate 4.
1 Add 8.5 Ky. of lactic oxidation/glue solution into the mixture, strain with a mixer to prepare a rough emulsion, and add 2.5 Kyk of bar 7 Fluoro compound 9 IJ (perfluoro-N-methylita-hydroquinoline) Add to the mixer and mix well
Filled with coarse emulsion. This crude emulsion was put into the liquid tank of a full-injection emulsifier (manufactured by Manton-Gaulin) and circulated, and the liquid temperature was kept at 50 ± 5°C.The emulsion was then emulsified. The concentration was 27.3 w/v%.The particle diameter added by Q centrifugal sedimentation was 0.05 to 0.
．． The particle size was 25μ, and the particles were dispensed into injection vials, capped, and stored in a full-rotation sterilizer for heat sterilization, with almost no increase in particle size observed.

Hereinafter, an example of a clinical trial on the medicinal efficacy of a perfluoro compound emulsion will be shown.

Test Example 1 Weight (We used a male pegle dog with OK2 and experimentally ligated the common bile duct to create a canine dog. The emulsion of Example 1 was injected intravenously. The removed blood was led to the extracorporeal circulation system, centrifuged (4800 ppm x 120 minutes), and the perfluorocarbon tail fraction and both blood cells were separated, and the perfluorocarbon components were separated. The fraction was discarded outside the body, and healthy blood was transfused.This operation was performed continuously.The treatment time was about 2 hours, and the amount of perfluorocarpore emulsion administered was 2000ml. The treatment reduced the total bilirubin value in the experimental dish to 15 μm17 dt.
It was possible to lower it by 5 μi/dt i.

Patent applicant: Mi Tori Juji Co., Ltd.

Claims (1)

[Claims] A blood purifier made of perfluorocarbon compound emulsion.