JPH02149531A - Improver for transition into brain tumor - Google Patents

Abstract

PURPOSE:To obtain the title preparation to be used with an antitumor agent such as nimustine, extremely improving transition of antitumor agent into brain tumor, maintaining antitumor agent at high concentration, alleviating side effects of antitumor agent, comprising an emulsion of perfluorocarbon compound. CONSTITUTION:(A) A perfluorocarbon compound is emulsified with (B) an emulsifying agent and optionally (C) an emulsion auxiliary into <=0.3mu particle diameter to give the title preparation. A substance having oxygen transporting function and low harmfulness to organism may be used as the component A and 9-12C perfluorohydrocarbon or perfluoro tertiary amine (e.g. perfluorocyclohexane or perfluoroalkylpiperidine) may be cited as the component A. A polymer nonionic surfactant, phospholipid, etc., may be used as the component A and 8-22C fatty acid, an alkali metallic salt thereof, etc., as the component C.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to an agent for improving brain tumor migration of an antitumor agent comprising a perfluorocarbon compound emulsion.

(Prior art) Perfluorocarbon compounds are known to be substances with excellent oxygen transport ability, and these perfluorocarbon compounds are emulsified using an appropriate emulsifier (hereinafter referred to as perfluorocarbon compound emulsion), which can be used for artificial blood, It can be used clinically as an oxygen-carrying infusion.

By the way, it is known that this perfluorocarbon compound emulsion can be used in combination with an antitumor agent (Japanese Patent Publication No. 59-50166).
No. 5, Japanese Patent Publication No. 59-130812).

However, these documents do not disclose the effect on brain tumors, and only the involvement of oxygen has been confirmed as the mechanism of the combination effect. remains beyond the realm of speculation.

(Problems to be Solved by the Present Invention) In general, the best method for tumor chemotherapy is to administer drugs only within the tumor. However, in the case of brain tumors, direct administration is technically difficult.

In addition, large doses of antitumor drugs affect normal cells and destroy the brain barrier, which tends to cause side effects such as convulsions.

Therefore, it has become important to maintain high concentrations of antitumor agents within brain tumors.

This time, the present inventors used a perfluorocarbon compound emulsion and an antitumor agent in combination to create an antitumor agent called Brain II!
The present invention was completed based on the discovery that it is possible to maintain a high concentration within 1yIj and to reduce the side effects of antitumor agents.

(Means for Solving the Problems) The present invention relates to an agent for improving brain tumor migration of an antitumor agent comprising a perfluorocarbon compound emulsion.

The perfluorocarbon compound emulsion used in the present invention may be 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, a wide variety of fluids that have been proposed as oxygen-carrying infusion fluids can be used.

Preferred emulsions include a perfluorocarbon compound alone or a suitable mixture, a polymeric nonionic surfactant and/or a phospholipid as an emulsifier, and if necessary a carbon atom having 8 to 2 carbon atoms.
Examples include emulsions made by emulsifying the fatty acid compound (acid itself, its alkali metal salt, or monoglyceride) of No. 2 to a particle size of 0.3 microns or less using an emulsification aid. These emulsions are described in detail in, for example, JP-A No. 169219, JP-A 52-96722, JP-A 58-225013, JP-A 58-39870, and JP-A 59-46218. ing.

As the perfluorocarbon compound used in the present invention, since the present invention utilizes the oxygen gas transporting property of the fluorocarbon compound as described later, the perfluorocarbon compound used in the present invention is a perfluorocarbon compound that uses oxygen transporting 89
Any oil can be used as long as it has good properties 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,
Perfluoroalkanes, perfluorotertiary alkylamines, perfluoro-NN-dialkylcyclohexylamines, perfluoroalkylpiperidines, perfluoroalkylmorpholines, perfluoroadamancune, perfluoroalkyladamankune, etc.
No. 69219) is exemplified. In particular, emulsions containing these perfluorinated hydrocarbons as major components and perfluorinated tertiary amines as minor components are preferred because they do not cause precipitation when plasma expanders such as dextran, hydroxystarch, and modified gelatin are added. (Unexamined Japanese Patent Publication No. 5
1-96722). Also, perfluoro-N-methylperhydroquinoline, perfluoro-N-methyldecahyoisoquinoline, perfluoro-4-methyloctahydroquinolidine, perfluoro-3-methyloctahydroquinolidine, perfluoro-2-methyl Octahydroquinolidine, perfluoro-1-methyloctahydroquinolidine, perfluoro-9a-methyloctahydroquinolidine, perfluoro-4-ethyloctahydroquinolidine, and the like are also preferred perfluorocarbon compounds.

As an emulsifier for the emulsion, molecular number 2,000 to 20,
000 polymeric nonionic surfactants (e.g. polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, etc.), phospholipids (e.g. egg yolk phosphorus Rri and soybean phospholipids) etc. are used.

The fatty acid compound used as an emulsification aid has 8 to 2 carbon atoms.
2 fatty acids, physiologically acceptable alkali metal salts such as sodium and potassium salts of these fatty acids, and monoglycerides. These include, for example, caprylic acid, capric acid, lauric acid,
Myristic acid, palmitic acid, stearic acid, hehenic acid, palmitoleic acid, oleic acid, linoleic acid, arachidonic acid, alkali metal salts thereof such as sodium or potassium salts, and monoglycerides thereof. These fatty acids can be used alone or as a mixture of two or more.

Perfluoro-N-alkylpiperidine having an alkyl group having 4 to 6 carbon atoms, perfluoro-N-alkylpiperidine having an alkyl group having 5 to 7 carbon atoms, and 95 to 50 parts by weight of perfluorodecalin or perfluoromethyldecalin in the above emulsion. An emulsion prepared by emulsifying 5 to 50 parts by weight of a perfluorocarbon tertiary amine or perfluoroadamantane selected from the group consisting of perfluoro-N-alkylmorpholine and perfluoro tertiary alkylamine is currently most preferred.

The preferred composition of these emulsions is perfluorocarbon l.
0 to 50 w/v%, emulsifier 2 to 5 w/v% (however, it is preferable that the emulsifier contains 0.1 to 1 w/v% of phospholipid), and if necessary, 0.0% of a fatty acid compound as an emulsification aid. It is an emulsified aqueous solution containing 0.004 to 0.1 w/v%, which can be used as a physiological aqueous solution, e.g.
Cl 3-7%, Ca Cj! zO, 15-0.4
%, MgCfgo, 1-0.5%, D-glucose 0.
7-2%, K Cffi O, 3-0.5%, Na
Suitable formulations are obtained by adjusting to physiological isotonicity with a hypertonic electrolyte solution consisting of 2-4% HCO, optionally with the addition of a plasma expander.

When the perfluorocarbon compound emulsion used in the present invention is used in combination with an antitumor agent, the migration of the antitumor agent into brain tumors is significantly improved, and the antitumor agent provides extremely excellent anti-II tumor properties. . Therefore, the use of the brain tumor internalization improving agent of the present invention will further enhance the effects of antitumor agents that have been put into practical use, and will also improve the effects of antitumor agents that have not been put into practical use due to their weak effects. It also has the potential for practical use as a drug.

Therefore, as antitumor agents, a wide range of compounds can be used in combination with the brain tumor migration improving agent of the present invention, and particularly preferred ones include ACNU (nimustine), BCNU (carmustine), CCNU (lomustine), and spaticomycin (5 ,10,11,lla -tetrahydro-9-
Examples include hydroxy-8-methyl-5-oxo-11-sulfino-IH-pyrrolo(2,1-C)(1,4)benzodiazepine 2-acetylamide).

The emulsion of the present invention can be administered to mammals including humans (humans, cows, horses, rats, mice, dogs, etc.), and is administered intravenously to boat fishing. The dosage is, for example, 100 to 2000 m/dose per adult human (provided that the content of perfluorocarbon compound in the emulsion is 10 to 50 w/w/dose).
v%).

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

Furthermore, in the present invention, radiation therapy can be used in combination. As a method for this, a commonly used method may be used as is.

For example, specific examples include means such as uniform irradiation of about 1 to 10 Gy/mal.

(Effect) By using the brain tumor migration improving agent of the present invention,
The amount of the antitumor agent transferred into the brain III tumor is improved, the antitumor agent can be maintained at a high concentration within the brain tumor, and the side effects of the antitumor agent can also be reduced.

Therefore, the brain tumor internalization improving agent of the present invention is considered to be a useful drug for the treatment of brain MIm, particularly malignant brain tumors.

(Experimental Examples/Examples) Examples and experimental examples are given to explain the present invention in more detail, but the present invention is not limited by these in any way.

Experimental Example 1 Eleven patients with malignant glioma (19 to 69 years old, WHO malignant grade -3 to 4) were intravenously injected with the perfluorocarbon compound emulsion of Example 1 at 10 ml/kg body weight over 30 to 45 minutes during surgery. After that, nimustine hydrochloride (ACNU) 1
mg/kg body weight was administered intravenously. After administration, lung cancer and venous blood were collected 5 to 60 minutes after administration, and the ACNUfi degree was determined by HP.
Measured by LC method. The results are shown in Table 1.

[Margin below]

Table 1 Time after administration ACNU 4 degrees (μg/miV, ) (min) Blood concentration Tumor white concentration 5 2.5 ±1.2 2.65 ± 0.941
0 2.0 ±0.25 3.06±0.
4215 1.6 ±0.32 3.35
±1.4830 1.0 ±0.2 1.
83±0.7260 0.72±0.1 0
．． 16±0.12 Experimental Example 2 10 ml/kg body weight of the perfluorocarbon compound emulsion of Example 1 was administered intraoperatively to 11 patients with malignant brain tumors, and intratumoral blood flow before and after administration was measured using laser Doppler method. Measured over time. As a result, the intratumoral blood flow increased by 22±11%.

Experimental Example 3 ACNU 1mg/2 patients with malignant brain tumor recurrence
At the time of administration of kg body weight, the perfluorocarbon compound emulsion of Example 1 was administered at 10 ml/kg body weight to enhance drug migration into the tumor, and at the same time, radiotherapy was performed using a uniform irradiation method of 2 Gy/mal.

One patient has died and one is still alive.

Example 1 300 g of polyoxyethylene polyoxypropylene copolymer (molecular weight 8.350) was dissolved in 81 l of distilled water, and in this solution were added 3 kg of perfluorodecalin, 300 g of perfluorotripropylamine, 40 g of soybean oil phospholipid, Mixed fluorocarbon mixed with 2g8 of potassium oleate was added and stirred 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 under high pressure of 200 to 500 kg/d while maintaining the liquid temperature at 35±5''C. The perfluorodecalin concentration in the emulsion was 30.5 w/
v%, perfluorotripropylamine concentration is 2.9
w/V%. The average particle diameter measured by centrifugal sedimentation was 0.09 to 0.1μ, which was dispensed into injection vials, capped, and placed in a rotary sterilizer at 115°C.
No increase in particle size was observed even after heat sterilization for 12 minutes.

Example 2 400 g of egg yolk phospholipid was added to 8.5 l of lactated Ringer's solution, stirred with a mixer to prepare a rough emulsion, and 2.5 kg of perfluoro-4-methyloctahydroquinolidine was added to this liquid, and further A rough emulsion was prepared by stirring vigorously with a mixer. This rough emulsified liquid was placed in a liquid tank of a jet emulsifier (manufactured by Manton-Gaulin) and circulated, and emulsification was carried out while maintaining Wi fA at 50±5°C. The concentration of perfluorinated compounds in the obtained emulsion was 27.3 w/v%
Met. Particle size measured by centrifugal sedimentation method is 0.0
The particle size was 5 to 0.25 μm, and no significant increase in particle size was observed even after dispensing it into an injection vial, capping it, storing it in a rotary sterilizer, and heat sterilizing it.

Example 3 400 g of egg yolk phospholipid and 4 g of sodium balmitate were added to 8.5 g of lactated Ringer's solution and stirred with a mixer to prepare a rough emulsion, and a perfluoro compound (
perfluoro-N-methylperhydroisoquinoline)2
．． 5 kg was added and further stirred with a mixer to make a rough emulsion. This rough emulsion was put into the liquid tank of a jet emulsifier (manufactured by Manton-Gorlin) and circulated until the liquid temperature was 50 ± 5°.
Emulsification was carried out while maintaining the temperature at C. The concentration of perfluoro compound in the obtained emulsion was 27.3 w/v%. The particle size measured by the centrifugal sedimentation method was 0.05 to 0.25μ, and even if the vial was dispensed into an injection vial, capped, and stored in a rotary sterilizer and sterilized by heat, the particle size remained significant. No increase was observed.

Claims (2)

[Claims] (1) An agent for improving brain tumor migration of an antitumor agent comprising a perfluorocarbon compound emulsion. (2) The agent for improving brain tumor migration according to claim (1), wherein the antitumor agent is ACNU (nimustine).