JPS60166610A - Emulsion composition - Google Patents

Abstract

PURPOSE:To provide an emulsion composition having eliminated or mitigated hemolytic action of a drug, by adding a specific amount of oil or fat to an emulsion composition containing a hemolytic drug. CONSTITUTION:An emulsion composition containing a hemolytic drug such as the compound of formula I or II (R<1> is alkyl; R<2> is H or alkyl; R<3> is inositol residue, saturated or unsaturated N-containing 6-membered heterocyclic group which may have lower alkyl, or trimethylammonio; Y is OH or oxide; m and n are 0 or 1; R is alkyl) or its salt, is added with >=10W/V% oil or fat such as soybean oil, sesame oil, cottonseed oil, etc. to obtain an emulsion composition preferably containing 0.1-10W/V% said drug, 10-40W/V% oil or fat, 1- 15W/V% surfactant and 30-88W/V% water, essentially free from hemolytic activity at a concentration of as high as 1,000-2,500mu/ml, and extremely useful as a drug preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an emulgene composition that eliminates or reduces the hemolytic effect of hemolytic pharmaceuticals.

It is known that when certain drugs dissolve in the blood, their surfactant action dissolves the red blood cell membrane and reduces the oxygen carrying ability of the red blood cells.For this reason, even drugs with excellent medicinal efficacy are Sometimes it could not be used as a medicine, or there were restrictions on how it could be administered.

As one of the attempts to reduce such hemolytic effect, there is a known method of reducing the hemolytic effect by allowing lysolecithin to coexist with phospholipids (Japanese Patent Publication No. 58-409).
No. 29).

The inventors of this invention obtained the new knowledge as a result of Kei X research that the hemolytic effect of hemolytic drugs can be almost eliminated by making them into Emulgene preparations, which are different from the known technology described in "-". completed this invention.

The hemolytic drug in the present invention is not particularly limited as long as it has a hemolytic effect, but the hemolytic drug described in the specification is not limited to any drug that has a hemolytic effect. '
4'j - (No change in content) Specifically, those having a higher alkyl group in the molecule are mentioned.

Specific examples thereof include, for example, the general formula 0 (%) [wherein R1 is an alkyl group, R2 is an elementary atom or a lower alkyl group at 7, and 113 is an inosyto-)V residue];
A saturated or unsaturated N-containing 6-membered heterocyclic group which may be substituted with a lower alkyl group or a trimethylammonio group, Y means a hydroxy group or a haoxide group, m and n each mean O and 1 Examples include glycerin derivatives represented by the following formulas, and kanamycin derivatives represented by the general formula (no change in content) [wherein R represents an alkyl group] or salts thereof.

As the inosyl l-tv residue in the compound of ``2,
Contains Shinu, Shrimp, Alo, Myo, Muco, Neo or Giro-inositol. The alkyl group is a straight chain or branched anolekyl group having 1 to 25 carbon atoms, for example, methyl
, ethyl, propyl, isoproyl, buna, isoguti 7V, 39th butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undashi)V,)-
Examples include tridecyl, tetradecyl, bentadedinone, hexadecyl, hep-4-tadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, tocosyl, trickle, tetradecyl, bentacosyl, and the like. However, a lower alkyl group is a straight or branched alkyl group having 1 to 6 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, butyl,
Examples include isobutyl, tertiary butyl, pentyl, hexyl, and the like.

A saturated or unsaturated N-containing 6-membered heterocyclic group has N. It may contain one atom selected from S or S, and specific examples thereof include pyridinio, virazinio, pyrimidinio, viridacinio, piperazinio, piperidinio, morpholinio, thiazinio, and the like. It is understood that these heterocyclic groups may be substituted with lower alkyl groups as described above.

In addition, the salts of the above compounds may be pharmacologically acceptable salts, and specifically, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, These include inorganic acid salts and organic acid salts such as salts, hydrobromides, and sulfates.

Note that the glycerin derivative in the general formula fIl includes cases where the group Y and group R are in the form of an intermolecular group, and cases where the group is not in the form of an intermolecular salt.

As long as the emulsion composition of the present invention contains oil and fat at IOW/V% or more, its composition and composition ratio are not particularly limited, but it is preferable that the hemolytic drug be
~10 W/V%, fats and oils 10-40 W/v%, surfactants 1-15 W/V%, and water 30-88 W/V
Examples include emulsions containing %.

Examples of the fats and oils contained in the emulsion composition of the present invention include edible oils such as soybean oil, sesame oil, cottonseed oil, etc., and commercially available fat emulsions in which fats and oils and water are blended in an emulsion state, such as indirafuto, Intrapolis, Intrapolis, Fatgen, etc. can also be used.

Further, as the surfactant, in addition to egg yolk lecithin, Pluronic F-68 (registered trademark), etc., any substance having a surfactant action that is commonly used as an additive for this yuzu preparation can be used.

In addition to water such as distilled water for injection and sterile water,
Glucose solution, physiological saline, etc. may also be used.

In addition to the above-mentioned compositions, the emulsion composition of the present invention also contains emulsion thread stabilizers such as tonicity agents such as glycerin and glucose, vitamin A, and vitamin E.
Antioxidants such as cholesterol, α- are also 1 to < are β-
Cyclodextrins and the like may be added, and the hemolytic effect may be further reduced by adding these stabilizers.

In addition, Towara's stabilizer is added at a range of up to about IOW/V%, but especially when the content of oil and fat is 10 to 3 ow.
, if it is about Ar%, glycerin, vitamin E1
It is preferable to add one to several kinds of stabilizers selected from cholesterol and cyclodextrin in an amount of about 0.1 to 5 w/v%.

Examples of the emulsion composition of the present invention are given below along with examples and reference examples, and the results of their bathing tests are further explained.
explain in detail.

The following drugs A to E were selected as hemolytic drugs to prepare emulsion compositions.

() (Egg yolk lysolecithin) 9- (In the formula, R1 represents a mixed alkyl group of C17 to C2□) =10- Example 1 4 soybean oil, 3 g of egg yolk lecithin, and vitamin EO, 2
After heating and dissolving 9 at 65 to 75°C, the mixture was returned to room temperature. After adding 0.29 g of drug B and 0.5 g of glycerin to this mixture, distilled water is added to make the total volume 20 #l. This mixture was coarsely emulsified for 1 minute using a boiler, then an ultrasonic generator (2
50 W) for 10 minutes to obtain an emulsion composition.

Examples 2 to 24 Emulgene compositions were obtained by processing in the same manner as in Example 1 with various drugs and various formulations as shown in the table below.

The numbers for each component in the table indicate the proportion of each success in the total emulsion composition acid product in W/V%, and the remainder is distilled water for injection.

The emulsion composition obtained in each example was mixed with sheep red blood cells, subjected to inky bathing at 37°C for 1 hour, and then centrifuged. The amount of red blood cells precipitated in the test tube was visually determined and determined according to the following criteria. I judged it.

The concentration of the hemolytic drug in the test results was adjusted by diluting the Emulgene composition obtained in each example with isotonic lv 9AI solution.

80-100% hemolysis is observed; old (50-80% hemolysis is observed: ''-0 Group I ~ 50% hemolysis is observed) 4-20 L ~ 1% hemolysis is observed :± Example: Test results: Example: Test results: Example: Test results: For comparison, the following formulations were manufactured and a hemolysis test was conducted in the same manner as above.

Reference Examples 1-2 0.2 g each of drug A and drug B are mixed with isotonic phosphate buffer to make a total amount of 2011/.

Reference Examples 3 to 5 Soybean oil, oil yellow lecithin, Shikke Bruronic F, vitamin E1 drug A, glycerin, and water were treated in the same manner as in Example 1 at the proportions listed in the table below to prepare each formulation.

Reference Example 6 After dissolving 80.05 g of drug and 0.3 g of egg yolk lecithin in 1.25 ml of chloroform, the chloroform was distilled off under reduced pressure at room temperature, and the mixture was further vacuum-dried at room temperature for 2 hours. Next, 3.125 g of glass peas and 3.125 g of 5% glucose solution were added, and the container was rotated for 1 hour and 30 minutes to obtain a suspension. After removing the glass beads 7, the suspension was subjected to ultrasonic treatment (20 KHz: 100 W) for 2 hours and 30 minutes, and then filtered through a membrane filter with a pore size of 0.45/j to obtain P solution.

Reference Example 7 0.5 of the filtered solution obtained in Reference Example 6 was added to commercially available fat emulsion I/TRARIBOS 105i solution 511/ and shaken several times.

Reference Example 8 Add 0.03 g of drug B, 0.279 egg yolk lecithin and 0.03 g of sesame oil to 5% glucose I & 2.7 g/
Mixed using a polytron. This mixed solution was subjected to ultrasonic treatment (Sonif Ding Year 350 model, 100W, 3 hours), filtered using a membrane filter with a pore size of 0.45μ, and P
Achieve a 3-hour test.

17- Reference example: Test results: As shown in Evaluation Reference Examples 1 and 2, hemolysis was clearly observed for drugs A and B simply dispersed in isotonic phosphate buffer even at a low concentration of 100 ml. On the other hand, the number of successful emulsion θ assembly according to this invention (Examples 1 to 26) was 1000.
Almost no hemolytic effect is observed even at high concentrations ranging from 2,500μ to 2,500μ.

As shown in Reference Examples 3 and 4, even if a surfactant is blended at a high concentration, if soybean oil is not blended at all, no emulgene is formed, so the hemolytic effect of the drug is hardly reduced.

As shown in Reference Example 5, even if soybean oil is blended at a high concentration of 30 W/S/%, if no surfactant is blended, no emulgene is formed, so the hemolytic effect is completely reduced. do not have.

Further, as shown in Reference Examples 6 to B, almost no decrease in the hemolytic effect was observed even when liposome preparations were prepared by conventional methods such as portic swing method and ultrasonic method.

As is clear from the above test results, the emulzidine composition of the present invention shows almost no hemolytic effect even at high concentrations of 1000 to 250 o fiAl, and is extremely useful as a pharmaceutical preparation.

Patent applicant: Fujisawa Pharmaceutical Co., Ltd. Procedural amendment (method) 1. Indication of the case Patent Application No. 24047 of 1982 2. Name of the invention Emano V John Group Success 3. Person making the amendment Relationship with the case Patent applicant 4-3 Doshomachi, Higashi-ku, Osaka (524) Fujisawa Pharmaceutical Co., Ltd. Representative Tomoyoshibe Fujisawa 4, Agent 2-1-6 Kashima, Yodoyou-ku, Osaka 532 Telephone: 06-301-1271 5. Amendment order Date: May 9, 1980 (Delivery date: May 29, 1980) 6. Subject of amendment: Meiwa Book I-1-2 and "Document certifying authority of agency" 7. Contents of amendment 1: Meiwa A written copy of pages 1, 4, and 5 of Book 1 (no changes to the content)? Please submit as shown in the attached sheet.

2. Submit a document certifying the authority of representation as shown in the attached sheet.

that's all

Claims (2)

[Claims] (1) An emulsion composition characterized in that 10 W/V% or more of oil and fat are added to the Emafure 23 composition containing a hemolytic drug. (2) The hemolytic drug has the general formula %) [In the formula, R is an alkyl group, R is a hydrogen atom or a lower alkyl group, n3 is an inosyto-)V residue, 'lower aJV
a saturated or unsaturated N-containing 6-membered heterocyclic group or a trimethylammonio group, which may be substituted with a K/V group;
Y [Hydroxy group and oxide group, m and n 0
The emulsion composition according to claim 1), which is a glycerin compound or a derivative thereof. +31 The emulsion composition according to claim 11, wherein the f4 blood-related drug is a kanamycin derivative represented by the general formula (wherein R represents an alkyl group) or a derivative thereof.