JPS59130812A - Adminiculum for chemotherapy of cancer - Google Patents

Abstract

PURPOSE:To use a perfluorocarbon compound emulsion well-known as a transfusion for transporting oxygen as an adminiculum for chemotherapy of cancers for increasing effect of a carcinostatic agent, by using it with the carcinostatic agent. CONSTITUTION:A perfluorocarbon compound emulsion is used as an adminiculum for chemotherapy of cancers. The fluorocarbon emulsion as a transfusion [Fluosol-DA, Midori Juji K.K] is applied to patients of a large amount of hemorrhage. This time it is found to increase extremely carcinostatic properties of a carcinostatic agent by using it together with the carcinostatic agent. The emulsion increases the effect of the carcinostatic agent on the center of tumor having resistance to carcinostatic agent or cells of low oxygen around it. The emulsion transports oxygen to fine blood vessel of tumor cell, and provides the cell of low oxygen with oxygen. It is considered that the effect is resulted from increase in the concentration of the carcinostatic agent caused by prevention of reduction in viscosity of blood, and slenderization of blood capillary.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a cancer chemotherapy adjuvant comprising a perfluorocarbon compound emulsion. More specifically, the present invention includes:
The present invention relates to a cancer chemotherapy adjuvant that can be used in combination with an anticancer drug to increase the effectiveness of the anticancer drug.

Fluorocarbon emulsions are currently used in oxygen-carrying infusions [Fluo
aol-DA, ■Used as a green cross,
It is safely administered to patients with massive bleeding.

Did the inventors study this fluorocarbon compound emulsion to the utmost? We have repeatedly found that when this fluorocarbon compound emulsion is administered together with an anticancer drug, the anticancer activity of the anticancer drug is significantly increased, and in particular, hypoxic cells existing in and around the tumor center are resistant to anticancer drugs. The fluorocarbon compound can be used as an adjuvant in cancer chemotherapy using an anticancer drug, or in other words, as an agent to enhance the efficacy of an anticancer drug. Did you discover this and invent it? completed.

The perfluorocarbon compound emulsion used in the present invention may be a liquid fluorocarbon compound emulsion preparation that maintains a particle size small enough to be administered into human blood vessels, and does not cause damage to organs or the bloodstream. There are no particular limitations, and for example, those that have been proposed as infusion solutions for oxygen delivery can be widely used.

Preferred emulsions include a single 17'C perfluorocarbon compound, a suitable mixture, a polymeric nonionic surfactant, and/or a phospholipid. As an emulsifier, the number of carbon atoms is 8
-22 Fatty acid compounds (acids, alkali metal salts or monoglycerides) can be used as emulsification aids, such as emulsions made by emulsifying them to a particle size of 0.3 microns or less. These emulsions are like F! Japanese Patent Publication No. Sho F) 0-69219, Japanese Patent Publication No. Sho B
It is described in detail in No. 2-96722, % Gansho 07-110200, % Sonosho 57-151098, and Tokutsumugi No. 57-157677.

As for the fluorocarbon compound used in this book, the fluorocarbon compound derived from wood is a fluorocarbon compound that utilizes the acid accumulation capacity of fluorocarbon compounds as described below, so it has an oxygen transport function and is resistant to living organisms. Any ti) rL with low adverse reactions can be used. Suitable examples of such perfluorocarbon compounds include those having 9 to 9 carbon atoms.
12 perfluorinated hydrocarbons and perfluorinated tertiary amines having 9 to 12 carbon atoms are exemplified. Specific examples of the perfluorocarbon compound 9M include perfluorocycloalkane, perfluoroalkylonchloroalkane, perfluorocyclohexane, perfluorodecalin, halffluoroalkyldecali/, perfluoroalkyltetrahydrobira/, and perfluorocycloalkane. Alkyltetrahyde tetrafuran, perfluoroalkano, perfluorotertiary alkylamine, perfluoroN, N
Examples include -dialkylcyclohexylamine, perfluoroalkylpiperidine, perfluoroalkylmorpholine, perfluoroadamanthine, perfluoroalkyladamantaf, etc. (Japanese Patent Application Laid-open No. 69219/1983). In particular, these perfluorinated hydrocarbons are the main components,
The emulsion containing perfluorinated tertiary amine r is a plasma bath! Cut, for example, text run, Hakaiakiri 2-96722
No. No. Also, perfluoro-N-methylperhydroquino+77, hafluoro-N-methyldecabaytroinquinoline, perfluoro-4-methyloctahydroquinolidine, perfluoro-3-methyloctahydroquinolidine, which were recently developed by the applicant. Perfluoro-2-methyloctahydroquinolidine, nog-fluoro-l-methyloctahydroquinolidine, noζ-fluoro-9a-methyloctahydroquinolidine, perfluoro-4-ethyloctahydroquinolidine, etc. are also preferred. It is a new perfluorocarbon compound.

As an emulsifier for emulsions with a molecular weight of approximately 2,000 to 20,000
polymeric nonionic surfactants such as polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene alkyl ethers, polyoxyethylene alkyl allyl ethers, and/or phospholipids such as egg yolk phospholipids and soybean phospholipids. Lipids are used.

The fatty acid compound used as an emulsification aid has 8 to 2 carbon atoms.
The two fatty acids and physiologically acceptable salts of these fatty acids are sodium, potassium, etc. salts or monoglycerides. These include, for example, caprylic acid, capric acid, lauric acid, myristic acid, balmitic acid, stearic acid, pehe7 acid, halumidoleic acid, oleic acid, linoleic acid, arachidonic acid and their sodium or Potassium salt and monoglyceride of -tn et al. These fatty acids can be used alone or in a mixture of two or more, and those having 4 carbon atoms per 9b to 50 parts by weight of perfluorodecalin or barfluoromethyldecalin in the above emulsion.
Perfluorocarbons selected from the group consisting of bars having ~6 alkyl groups, fluoro-N-alkylpiperidines, perfluoro-N-alkylmorpholines having alkyl groups having 5 to 7 carbon atoms, and perfluorotertiary alkylamines. An emulsion prepared by emulsifying 5 to 50 parts by weight of tertiary amine or perfluoroadamanta Z is most preferred at present.

A preferable composition of these emulsions is perfluorocarbon 1
0-b Ow/v%, emulsifier 2-5 w/v%, phosphorus fJ purchase p 0.1-1 w/v% as an emulsification aid.
and fatty acid compounds i0.004-0.1 w/v%
It is an emulsified aqueous solution consisting of a physiological aqueous solution, for example, its composition is Na043-7%, CaCl20.15
~0.4%, MgCl20.1-0.5%, D-curcose 0.7-2.0%, KCl0.3-0.6%, Na
Suitable formulations are obtained by adjusting to physiological isotonicity with a hypertonic electrolyte solution consisting of 32-4% HCO, optionally with a plasma expander.

When the cancer chemotherapy adjuvant of the present invention is used in combination with an anticancer drug, it exhibits extremely strong anticancer properties2, and the sound effect is even higher than that of anticancer drugs that have been put to practical use in the past. There is also the inherent possibility of the practical application of anticancer drugs that have not been put into practical use due to their weak effects.

Therefore, a wide range of compounds can be used in combination with the uninvented auxiliary agent as an anticancer agent, and a particularly preferred one is [BCNU (
carmustine), CCNU (lomustine la, spadeicomycin (5,10,11111a-tetrahydro-9-).]hydroxy-8-methyl-5-oxo11-sulfino-IH-pyrrolo(2,1-C) C1
, 4) benzodiazepine-2-acetylaminotono, etc. 60 The adjuvant of the present invention can be administered to humans and animals (cows, horses, rats, mice, dogs, etc.); 1 It is generally administered intravenously. For example, for an adult human, 100~2000*/ (*The content of perfluorocarbon compound in the emulsion is 10~2000*/)
/v%).

The safety of perfluorocarbon compound emulsions has already been established in the field of oxygen-carrying infusions. The rationale for the effect of perfluorocarbon compound emulsions on enhancing the efficacy of anticancer drugs is as follows.

The particle size of the fluorocarbon emulsion is fine, the oxygen carrying capacity is greater than that of red blood cells, and the oxygen dissociated from mohemoglobin J is rapid. Considering this point, by administering the perfluorocarbon compound emulsion, oxygen is sufficiently transported to the minute blood vessels of the 11Il tumor silk fabric, so that, for example, in a hypoxic region in a hypoxic state, it is possible to Oxygen acceptance between the monofluorocarbon compound emulsion grains is sufficient, and the oxygenation is low, even with low rR.
It is thought that this occurs in natural cells, and it is also thought that administration of perfluorocarbon compound emulsions may reduce blood viscosity, prevent capillary narrowing, and increase cerebral blood flow. As a result, it is thought that the mechanism of increased tumor concentration of the anticancer drug also plays a role.Experimental animals were male Wistar rats weighing 2,009 rats, and transplanted JL [111 cells were N-nitrone methyl 2t7'c2 glioma C6 cells (RG-C, cell)' induced in Wistar rats by urea
? f: Used. The transplantation method involved monolayer culture of C6cells in the logarithmic growth phase, and treatment with IJ pushin to obtain an isolated cell suspension, followed by a d7e exclusion test.
After calculating the number of viable cells, l x 10 cells/7μt were transplanted semi-stereotactically into the right white matter of the rat to create a brain tumor model.
Created. On the 10th day of transplantation, randomly assigned to untreated group, BCNU
The animals were divided into three experimental groups: a single administration group, and a flozol-43 (manufactured by Midori Juji Co., Ltd.) (F-43) and BCNU combination group. FC-43 was injected intravenously through the tail vein at 20x//Kpi, and immediately administered 95% O3.5-〇〇20 for 7 times.
O□t300) Do not keep it above 1g, then B after 30 minutes.
CNU k LD to tit (13,31VKN
) 0 oxygen administration administered intraperitoneally is dose 3 after BCNU administration.
After continuing for a long time, the rat was returned to 17' CO. Efficacy evaluation: Calculated by the survival days of the untreated group and the treated group, and the survival rate of the treated group compared to the untreated group (0 to 1 calculated by Chinowo, after gold side transplantation) Rats were sacrificed on day O, and rats in which the presence of tumors could not be confirmed histologically were excluded from the experimental group.

mW transplantation was confirmed in surviving rats on day 50 after transplantation.
'LfC, rats were determined to be long-term survival group and TC.

The results are shown in Table 1. Example 5 to 9 rats in each group (male) weighing 100 to 130 g were implanted with fixed stationary AH130,5X10' cells into the flank. We investigated the suppression of cancer cell growth by administering a perfluorocarbon compound emulsion.

The test system was Fluoaol-DA (Midori Jujisha Rip, manufactured in the same manner as in Example 1) as a barfluoroca compound emulsion preparation at 20 ml/KP 1 day.

lIi! Subadeicomycin 0.321n9 as a cancer drug
Spadeicomycin was administered continuously for 5 days from the 3rd day after cancer cell transplantation.
ao 1-DAkb day and day 2 in an oxygen tent under 100% oxygen 2o, bty min x 18 hours supply
Administered twice.

Cancer cells were examined for size 122 days after transplantation, and the results are shown in the second column.

Margin below Table 2) SP+FD+02: Spadeicomycin 10 Fl
uosol-DA+02 administration group 3J F'D+O,: Fluosol-DA+0.1
From the results of the first administration group and second study, the inhibition rate was 63.8% in the Subadeicomycin/single administration group, while the inhibition rate was 80.8% in the Subadeicomycin, Fluoaol-DA, and 0□ combination group. Met. Also, Fluoaol-
Since the DA alone administration group and the Fluosol-DA+02 administration group had no effect at all, the anticancer drug
The effect of combined use with l-DA and 02 was confirmed.

Example 1 Polyoxyethylene polyoxypropylene copolymer (molecular weight 8,350) 30011 was dissolved in 8 tons of distilled water, and 7300 L of ζ-fluorodecalin and 7300 L of fluorotriglopyramide were added to this solution. Add the mixed fluorocarbon mixed with soybean oil phospholipid + OL potassium oleate 27F1F and stir with a mixer to break up the rough emulsion 1.
This coarse emulsified liquid r injection type emulsifier (manufactured by Manoton Gorif)
The Z-fluorodecalin concentration in the resulting emulsion was 30 Jw.
/v%, no(-fluorotriglobylamine concentration is 2,
9 W/V% and 7j.

The average particle diameter measured by centrifugal sedimentation is 0.09~
Dispense into a 0.1μ injection vial and stopper, c
RT, and heat sterilized at 115°C for 12 minutes in a top rotary sterilizer, but no increase in particle size was observed (7t).

Example 2 Egg yolk phospholipid 400 IIt-lactated Ringer's solution 8.5 l was added and stirred with a mixer to prepare a rough emulsion,
Perfluoro-4-methyloctahydroquinolide 2.5IP was added to this liquid, and a strong (@1) coarse emulsion was prepared using a stirrer. Place the liquid in the liquid tank of company m) and circulate it to raise the liquid temperature to 5.
Emulsification was performed while maintaining the temperature at 0±5°C. The concentration of perfluoro compound in the obtained emulsion was 27.3 w/v%.

Particle size measured by centrifugal sedimentation method is 0.05-0.2
5μ, dispensed into an injection vial, capped, and
L1! Even when the particles were stored in a one-rotation sterilizer and subjected to heat sterilization, no significant increase in particle size was observed.

Example 3 Egg yolk phospholipid 40011 and sodium palmity/acid 4.
Add 8.5 ml of lactated Ringer's solution to 9' and stir with a mixer to make a coarse emulsified liquid! 4 was prepared, 2.5~r of a perfluoro compound (perfluoro-N-methylperhydroquinolite 7) was added to this liquid, and the mixture was further stirred vigorously with a mixer to prepare a crude emulsion. This coarse emulsification was placed in the liquid tank of a noise-reduced injection type emulsifier (manufactured by Manoton Gorin Co., Ltd.) and circulated until the liquid temperature reached t50.
Emulsification was performed while maintaining the temperature at ±5°C. The concentration of perfluoro compound in the obtained emulsion was 27.3% w/y. Particle size measured by centrifugal sedimentation method is 0.05-0.25
μ, and no significant increase in particle size was observed even when the injection vial was dispensed into a vial, capped, stored in a rotary sterilizer, and heat sterilized.0 Patent Applicant: Mitri Co., Ltd. Cross Representative Patent Attorney Takashima - Continued from page 1 9Int, C1,3 identification code Office reference number (A
61K 31/17 31/13) 6408-4C
O Inventor: Takashi Kokuuchi, 7-13-14 Kusunoki-cho, Chuo-ku, Kobe City, Kobe University School of Medicine. 0 Inventor: Norihiko Tamaki. 7-13-14 Kusunoki-cho, Chuo-ku, Kobe City, Kobe University School of Medicine. 0 Author: Matsumoto. Satoru Kobe University School of Medicine, 7-13-14 Kusunobu-cho, Chuo-ku, Kobe City 0 Author: Masao Kagitani 227-227, Yamanobomachi, Kashihara City 0 Author: Kazumasa Yokoyama, 201-201, 2-7-2 Medium Terauchi, Chuo-ku, Kashihara City 1. Indication of the case 1982 Patent application No. 005042 2. Title of the invention Cancer chemotherapy adjuvant 3. Relationship with the amended person case Patent application entry

Claims (1)

[Claims] Consists of perfluorocarbon compound emulsion. Cancer chemotherapy adjuvant.