JPS6048992A - Oligosaccharide fatty acid ester and transfusion containing the same - Google Patents

Abstract

NEW MATERIAL:The ligosaccharide fatty acid ester wherein the 1-position of the oligosaccharide is esterified with linoleic acid or alpha-linolenic acid. EXAMPLE:Maltose-1-0-linoleic acid ester. USE:A transfusion for transvenous infusion. It is prepared in the form of an agueous solution containing e.g. 50-350g of saccharide, 0.2-8g pf oligosaccharide- 1-0-linoleic acid ester, 0-3g of oligosaccharide-1-0-alpha-linolenic acid ester, 0- 100m-mol of Na, 10-60m-mol of K, 0-100m-mol of Cl, 3-10m-mol of P, 1-6m- mol of Mg, 1-6m-mol of Ca, 0-40mu-mol of Zn and 0-1mu-mol of Cr per 1 liter of the solution. PREPARATION:For example, thiazolidinethione linoleic acid amide is added and reacted with a pyridine solution of maltose.

Description

Detailed Description of the Invention 10 Background Technical Field of the Invention The present invention relates to a carbohydrate containing an oligosaccharide fatty acid Nisdel and an oligosaccharide fatty acid ester in which the first position of the oligosaccharide is esterified with linoleic acid or α-lylunic acid. Contains infusions. More specifically, the oligosaccharide is maltose, lactose, or maltotriose, and an infusion solution containing a carbohydrate containing a linoleic acid ester at the C-1 position or an α-lylunic acid ester at the C-1 position of the oligosaccharide is provided. There is a particular thing.

Prior art and its problems Various infusion preparations containing carbohydrates are commercially available, but some of them contain carbohydrates containing the essential fatty acids linoleic acid and α-lylunic acid in water-soluble form. There are no infusions containing it. Furthermore, there is no example in which linoleic acid or α-linuric acid is subjected to a regioselective esterification reaction to the 1-position hydroxyl group of maltose, lactose, or maltotriose.

ti Conventionally, methods for producing only mixtures of mono-, di-, and triesters, or mixtures of monoesters have been disclosed, and methods for selectively producing single monoesters have not been disclosed. There have been many infusion preparations that are stable in terms of quality and pharmacology using single ester compounds.

■1 Purpose of the Invention As a result of extensive research into the simultaneous inclusion of essential fatty acids in infusion preparations containing carbohydrates, the present inventors discovered that oligosaccharides such as maltose, lactose, and maltotriose
We succeeded in preparing an infusion solution containing a novel oligosaccharide fatty acid ester in which the hydroxyl group is esterified with linoleic acid or α-lylunic acid, and a carbohydrate suitable for intravenous infusion, and the infusion solution is stable. They discovered that it is a highly nutritious infusion solution and completed the present invention.

(6) Detailed Description of the Invention Namely, the present invention is an infusion preparation characterized by containing a carbohydrate and an ester in which the first position of an oligosaccharide is esterified with linoleic acid or α-lylunic acid. The carbohydrate is preferably glucose or glucose/fructose/xylitol. glucose fructose xyl
Although it is not necessary to limit the mixing ratio of G)-glucose to 50% or more, it is preferable to include 50 glucose or more. The oligosaccharide fatty acid ester used in the present invention is maltose, lactose +17? is preferably linoleic acid or α-lylunic acid ester of the 1-position hydroxyl group of maltotriose. The concentration range of the elements in the carbohydrate, oligosaccharide fatty acid ester, and electrolyte in the aqueous solution is 50
~350f/l Oligosaccharide-1-0-linoleic acid ester 0.2~8f
/l oligosaccharide-1-0-α-lylunic acid ester 0-3
Sodium 0-100 mmol/l Potassium 10-60 mmol/l Chlorine 0
~100 mmol/l Phosphorus 3~10 mmol/l Magnesium 1~6 mmol/l Calcium 1
It is desirable that the amount of zinc be 0 to 40 micromol/l and 0 to 1 micromol/l for zinc.

The infusion preparation of the present invention can be obtained by adding carbohydrates, oligosaccharide fatty acid esters, and, if necessary, electrolytes shown in Table 1 to distilled water for injection and stirring.

The electrolyte containing sodium in Table 1 is NaC
1. Sodium lactate, sodium citrate, Tact for potassium, K2HPO4.

K2HPO4, potassium glucuronate, potassium acetate,
Potassium citrate, MgCL for magnesium
Z, MgSO4, calcium lactate, CaC4zl calcium glucuronate, zinc ZnSO4, ZnCtz, and chromium Cr(OAc)s, CrCts, and appropriately selected from these. It can be used.

The infusion solution of the present invention is filled into a vial or a plastic container inert to the infusion solution, the filling opening is then sealed, and the container is sterilized by high-pressure steam sterilization.

As a container, it is best to use a plastic container that is inert to the infusion drug because it does not generate flakes, and takes into account the prevention of contamination due to contact with the outside air of the infusion drug and the prevention of deterioration such as oxidation of the infusion drug due to oxygen in the outside air. From this point of view, it is desirable to use a plastic bag that does not require introducing outside air into the container and is inert to the infusion drug.

As the material for this bag, soft vinyl chloride resin, ethylene, vinyl acetate copolymer, etc. are used.

The soft vinyl chloride resin is preferably one obtained by gelasto polymerization or block polymerization of vinyl chloride with a plastic monomer, or one obtained by blending polyvinyl chloride with a plastic polymer.

When sterilizing, gas is removed from the container before sterilization, so even if the reactivity of the infusion solution increases due to heat, there will be very little deterioration.

When sterilizing an infusion solution filled in a plastic container with high-pressure steam, remove gases that are active against the infusion solution from around the container, for example, by sterilizing the infusion solution in an inert gas atmosphere. This overcomes the disadvantages of plastic containers, where gas permeability increases with high temperatures.

■1 Specific Effects of the Invention The infusion preparation of the present invention has a 7-oligosaccharide fatty acid ester having a serum action that is ester-bonded with linoleic acid or α-lylunic acid at the 1-position of the oligosaccharide. Therefore, it is chemically hydrolyzed more quickly than those having an ester bond at the 6th, 4th, or 2nd positions. Therefore, the hemolytic toxicity of the infusion preparation of the present invention was investigated, and no inhibition of blue dissolution was observed when administered intravenously, confirming excellent safety.

In addition, the ester contained in the infusion of the present invention is a monoester in which the 1st position of an oligosaccharide is esterified, and it has a different υ from the conventional mixture of mono-, di-, and triesters, and can be obtained by purification. Unlike a mixture of monoesters, it is possible to obtain a monoester that is selectively esterified at the 1st position, so a uniform infusion solution can be prepared and is superior in terms of quality, safety, and nutritional value. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

= 8- Production Example 1 Dried maltose 1078■ (3,1
thiazolidinethione-linoleic acid amide 400 at room temperature in anhydrous pyridine (20 mJ) solution containing 5 mmot).
'19 (1,05 mmo L) in anhydrous pyridine 0
, 5-. Subsequently, 8.5 q (0.21 mmot) of IJium (60%) was added and allowed to react for 2 hours at room temperature.After adding 0.15 q of ammonium chloride saturated aqueous solution to this reaction solution, , pyridine was distilled off under reduced pressure.The residue was suspended in 20 d of hot acetone, and the insoluble portion was separated.Diacetone was distilled off from the mother liquor to obtain 578 ml of residue.This was subjected to silica gel column chromatography. The chloroform-methanol 9:1 elution fraction was cymaltose-1-0-linoleic acid ester 27.
5 q (0.46 mmot) was obtained. The spectral data of this ester are as follows.

IRv=:,023cm': 3370,1745
, 1460, 1370° 1150 , 1070 Production example 2 Maltotriose 22.60 r (4
Oily hydrogenation at room temperature in anhydrous pyridine (250d) solution containing 4.8 mmoz) + Jum (6 on) 12
++v (3.0 mrnot) was added and reacted for 10 minutes. Subsequently, 6.00Of (14.9 mmoz) of P-nitrophenol linoleic acid ester was added together with anhydrous pyridine 3-, and the mixture was reacted overnight at room temperature. After adding 1.5 liters of a saturated aqueous solution of ammonium chloride to this reaction solution, the pyridine was distilled off under reduced pressure.
d K was suspended and the insoluble part was separated from P. Ethanol was distilled off from the mother liquor to obtain a residual amount of 9.940 f. This was subjected to silica gel column chromatography, and chloroform/
Methanol 17:3 elution fraction and simaltotriose 1
-0-linoleic acid ester 3.329 f (4,44
mmot) was obtained.

The spectral data of this ester are as follows.

IRshaxt:nn': 3360 r 174
0 r 1640 (W) H1400, ] 140
, 1070, 1020 Production Example 3 Under an argon atmosphere, dry α-lactose 9 was added to a solution of anhydrous pyridine (80 m) containing 928 m 9 (2,43 mmot) of thiazolidinethione linoleic acid amide at room temperature.
28 riq (2,43 mmot) followed by 26 mg (0,65 mmot) of oily sodium hydride (60 mmot)
g was added. After reacting at room temperature for 200 hours, 1.75 td of a saturated aqueous ammonium chloride solution was added. Pyridine was distilled off under reduced pressure, the residue was suspended in hot acetone and chloroform, and the insoluble portion was separated. The residue obtained by evaporation of the solvent from the mother liquor was subjected to silica gel column chromatography, and the fraction eluted with chloroform and methanol (9:1) was obtained as α-lactose-1-〇-linoleic acid ester 514.
I got ■.

The spectral data of this ester are as follows.

IRv';,:,"3 cm-': 3370, 1
740, 1460 +1380 +1135.107
5. cm-” Production Example 4 Dried maltose 4920 my (15
To a solution of anhydrous pyridine (60f11t) containing 1468 to 3.87 mmot of thiazolidinethione α-lylunic acid theamide) was added together with anhydrous pyridine 8- at room temperature. Next, oily sodium hydride (60%)
22111f (0.55 mmot) was added and reacted for 5 hours at room temperature. Ammonium chloride saturated aqueous solution 0
．． After adding 3-, pyridine was distilled off under reduced pressure, and the 0 residue was suspended in hot acetone to separate insoluble tP. Diacetone was distilled off from the mother liquor, leaving a residue of 268°. This was subjected to silica gel column chromatography, and malt-sul 1-0-
α-Ryrunnic acid ester 983~ was obtained. The spectroscopic data of this ester are as follows: OIR%a, "" cr
n': 3380 r 1740 r 1460
r 1360 +1265, 1145, 1070 Production Example 5 Dry α-lactose 724゜q (2
Thiazolidinethione-α-lylunic acid amide 2010~ (5,29 mmot) was added to a solution of anhydrous pyridine (80 mg) containing 2,3 mmoz) at room temperature.
fId! Added with. Subsequently, 30 μm (0.75 mmot) of oily sodium hydride (60 cm) was added and reacted for 8 hours and 10 minutes at room temperature. After adding 0.3 m/ml of a saturated ammonium chloride aqueous solution, pyridine was distilled off under reduced pressure. Remove remaining residue with hot acetone and ethyl acetate.

It was suspended in chloroform and the insoluble portion was separated.

The solvent was distilled off from the mother liquor to obtain 4200 q of residue. This was subjected to silica gel column chromatography, and the fraction eluted with chloroform/methanol (4::1) gave silica-lactose 1-0-α-lylunic acid ester 859.

The spectral data of this ester are as follows.

IRu,:p;'3 cm-': 3400, 17
40, 1460 m 1380.

1260, 1155, 1070 Example 1 Maltose-1-〇-linoleic acid ester 0.35W/
V % and the ingredients shown in Table 2 were dissolved in decapitated distilled water in the proportions listed under stirring. The resulting aqueous solution was adjusted to pH 5.5. After sterile filtering the aqueous solution,
After dispensing 500 μt into plastic bags and sealing them tightly, the mixture was sterilized using high-pressure steam at 121° C. for 20 minutes to prepare an infusion solution.

Example 2 -r#)-su-1-Q-linoleic acid ester 0
．． 25W/V% Oyobima A7 Tosu 1-Q-a
-Produced in the same manner as in Example 1 except that 0.1 W/V% of linoleic acid ester was contained.

Example 73 Lactol-1-0-IJ nolated ester 0.25W
It was produced in the same manner as in Example 1 with the component composition shown in Table 2 above, except that /V% was added.

Example 4 Maltotriose-1-0-! J nolic acid ester 0.
It was produced in the same manner as in Example 1 with the component composition shown in Table 2 above, except that 35 W/V % was contained.

Test Example 1 A catheter was placed in the jugular vein of a male Wistar rat (approximately 300 r). The first group was divided into two groups, and the first group received an infusion solution containing 10 W/V% glucose having the composition shown in Table 2 of Example 1 as a control. Administered for 4 hours at a flow rate of /hour. The infusion preparation prepared in Example 1 was administered to the second group in the same manner as the first group. In order to examine changes in blood due to infusion drugs, before the start of infusion and after the end of infusion 2
After 4 hours, blood was collected from the vena cava, and changes in the number of red blood cells were examined using a red blood cell measuring device (manufactured by Oats Instruments, USA), which was used as an index of hemolytic toxicity. As shown in Table 3, there was no difference between the groups in changes in the number of red blood cells. After the blood collection was completed, the liver, lungs, kidneys, adrenal glands, lungs, and thymus were examined for lesions, but no abnormalities were found, indicating no toxicity.

Test example 2 The test was conducted in the same manner as in Test Example 1 by dividing into 3 groups.

i1 group H:+n) ant in o-le group, curcose 1°W/
An infusion solution containing V% was continuously infused for 4 hours at a flow rate of 5 nt for 7 hours for 5 days. The infusion solution prepared in Example 2 was administered to the second group, and the infusion solution prepared in Example 3 was administered to the third group. As shown in Table 4, there was no significant difference between the three groups as a result of examining changes in the number of red blood cells due to the infusion.

Abnormally, virtue 11 was not detected for each organ, and the average increase in body 1 was 11.4 f for the first group, 14.2 f for the second group, and 14.2 f for the third group.
In group 11.22, the amount increased to J@-like, no abnormal findings were observed due to infusion, and no toxicity was observed.

Applicant Terumo Corporation

Claims (5)

[Claims] (1) Oligosaccharide fatty acid ester in which the first position of the oligosaccharide is esterified with linoleic acid or α-lylunic acid〇 (2) An infusion preparation, which contains an oligosaccharide fatty acid ester in which the first position of the oligosaccharide is esterified with linoleic acid or α-1) phosphoric acid and a carbohydrate in an aqueous solution. (3) The infusion preparation according to claim 2, wherein the oligosaccharide is maltose, lactose or maltotriose. (4) The infusion preparation according to claim 2 or 3, wherein the carbohydrate is glucose or a mixed sugar of glucose, fructose, and xyl. (5) The concentration range of carbohydrates in the aqueous solution, oligosaccharide fatty acid esters, and elements in the electrolyte is carbohydrate 50-350 f/l Oligosaccharide-1-〇-linoleic acid ester 0.2-5t
7t oligosaccharide-1-0-α-lylunic acid ester 0-3
t/l Sodium 0~100 mmol/l Potassium 10~60 mmol/Base 0~100 mmol/Phosphorus 3~10 mmol/l Magnesium 1~6 mmol 7t Calcium 1~6 mmol 3. The infusion preparation according to claim 2 or 3, wherein Zn/L is 0240 μmol/l to 1 μmol/l.