JPS6348848B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an immunostimulant containing lysophospholipids and phospholipids and a method for producing the same, an immunostimulant containing lysophospholipids, phospholipids, and oil and a method for producing the same, and a lysophospholipid, phospholipid, and fat emulsion. The present invention relates to an immunostimulant contained therein and a method for producing the same. The aim is to develop a highly safe immunostimulant that reduces the hemolytic effect without affecting the immunostimulatory effect of lysophospholipids and does not cause vascular damage even when used parenterally. It is about providing. Although lysophospholipids have extremely excellent immunostimulatory effects, they have the drawback of strong hemolytic effects. The present inventors believe that if the hemolytic effect of the above-mentioned lysophospholipids is reduced without reducing their immunostimulatory effect, the usefulness of lysophospholipids as pharmaceuticals will be dramatically improved, As a result of extensive research, an immunostimulant containing lysophospholipids and phospholipids, or an immunostimulant containing lysophospholipids, phospholipids, and fats and oils, or an immunostimulant containing lysophospholipids, phospholipids, and fat emulsions. However, the inventors have discovered that the above-mentioned object can be achieved and have completed the present invention. Lysophospholipids and phospholipid-containing immunostimulants according to the present invention, and lysophospholipids,
Immunostimulants containing phospholipids and fats and oils, as well as immunostimulants containing lysophospholipids, phospholipids and fat emulsions, may be simply a mixture of their components or in the form of micelles or lipid vesicles. It may be dispersed in any form, but it is particularly preferable to be dispersed in a micelle state or a lipid vesicle state. The particle size of the immunostimulant of the present invention is 1μ or less,
Particularly preferred is a case of 0.5μ or less. That is, the smaller the particle size, the less hemolytic properties are affected without affecting the main action, the higher the safety, and the better the transferability in the body, the immunostimulatory effect, etc. The phospholipids used in the present invention may be naturally derived phospholipids, such as egg yolk, soybean, cottonseed, rapeseed, corn, or peanut-derived phospholipids, or purely synthetically produced phospholipids, and In the case of a phospholipid having an unsaturated fatty acid residue, it may be used by changing it to a phospholipid having a saturated fatty acid residue by an operation such as hydrogenation. Specific examples of phospholipids include lecithin, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, phosphatidylinositol, and phosphatidic acid, and even if they are a mixture of one or more of them, good. As preferred phospholipids, mention may be made of natural lecithin, especially derived from egg yolk. In addition, lysophospholipids in the present invention include glycerophospholipids (phosphoglycerides) with only one fatty acid removed, such as lysolecithin,
Lysokephalin, Lysoplasmalogen, Lysophosphatidic acid, Lysophosphatidylinositol etc. and the general formula below [In the formula, R ¹ is a C _5-22 acyloxy or C _5-22 alkoxy group, R ² is a hydrogen atom, a hydroxyl group,
C _1-5 acyloxy group or C _1-5 alkoxy group,
^R3 represents a hydrogen atom or a _C1-5 alkyl group. still,
R ¹ and R ² can be converted into each other. ] Compounds represented by these are included, and these may be naturally derived, for example, lysophospholipids derived from pig brain or those derived enzymatically or chemically synthesized from the above-mentioned phospholipids. ()
As the _C5-22 acyloxy group of ^R1 in the formula,
Mention may be made of _C5-22 alkanoyloxy or _C5-22 alkenoyloxy groups. Among these, preferred lysophospholipids include lysolecithin or ether-type lysolecithin having a C _14-18 alkanoyloxy or C _14-18 alkenoyloxy group [(in the formula, R ¹ = octadecyloxy group, R ² =
methoxy group and R ³ =methyl group]. In the present invention, phospholipids and lysophospholipids in the D, L and DL forms are generally used, and the use of the L form is particularly preferred. In addition, the fats and oils that can be used in the immunostimulant containing lysophospholipids, phospholipids, and fats and oils are not particularly limited as long as they are pharmaceutically acceptable, but edible oils, for example, Preference is given to using cottonseed oil, soybean oil, corn oil, coconut oil, rapeseed oil, sesame oil or peanut oil. In addition, fat emulsions that can be used in immunostimulants containing lysophospholipids, phospholipids, and fat emulsions include, in a weight ratio of 10 fats and oils, emulsifiers such as egg yolk phospholipids, 0.1 to 50, and water 5.0 to 50.
200, especially soybean oil
Intrafat or Intralipid®, which consists of 10 parts egg yolk phospholipid, 86.3 parts water, and the tonicity agent concentrated glycerin 2.5 parts, or Fattogen®, Lipofundin-
S (Germany: Braun Melsungen product),
Lipihysan (France: Egic) etc. may be used. The mixing ratio of lysophospholipids and phospholipids in the immunostimulant containing lysophospholipids and phospholipids may be 1.0 to 500 phospholipids to 1 lysophospholipid in weight ratio, especially 500 phospholipids.
~20 is preferred. In addition, in the immunostimulant containing lysophospholipids, phospholipids, and fats and oils, the mixing ratio of lysophospholipids, phospholipids, and fats and oils is 1.0 to 500 parts of phospholipids and 1.0 to 500 parts of fats and oils to 1 part of lysophospholipids by weight.
0.1-200, especially phospholipids 5-20 and fats and oils 0.5-200
20 is preferred. When these dispersions are used, water may be added in an equivalent or more amount to the lysophospholipids and phospholipids. In addition, the mixing ratio of lysophospholipids, phospholipids, and fat emulsion in an immunostimulant containing lysophospholipids, phospholipids, and fat emulsion is determined by mixing lysophospholipids and phospholipids in the same ratio as described above. The volume ratio of the fat emulsion to 1 part of the dispersion may be 0.5 to 10. In addition to the above-mentioned components, substances commonly used medicinally, such as glycerin, sorbitol, xylitol, isotonic agents such as salt or glucose, antioxidants such as vitamin A or vitamin E, cholesterol, and stearylamine are also used. Alternatively, dicetyl phosphate or the like may be added as appropriate. Next, we will discuss the pharmacological effects. (b) Hemolysis test Hemolysis was determined by mixing the rabbit red blood cell suspension and the test drug, shaking at 37°C for 1 hour, and measuring the absorbance at 550 mμ (hereinafter referred to as OD) of the centrifuged supernatant.
The OD when complete hemolysis was achieved with distilled water was determined as 100%. The results are shown in Table-1 and Table-2.

【table】

【table】

[Table] (b) Immunostimulatory effect () Carbon clearance test Using 5 ddY mice per group, the test drug was administered at 0.2
ml/20g was administered intravenously once a day for 7 days. 24 hours after the end of administration, 0.2 ml of carbon suspension was prepared by mixing 1 ml of Rotring's black drafting ink (Art. 59107) and 4 ml of physiological saline containing 5% gelatin.
20 g was injected into the tail vein of the mouse, and 2, 7, and 12 minutes after injection, 0.02 ml of blood was collected from the orbit using a heparin-coated capillary tube, and the blood was immediately injected.
Hemolyze diluted in 0.1% sodium carbonate aqueous solution and compare the color at a wavelength of 660 nm to determine the phagocytotic index.
index): The K value was determined using the formula of Halpern et al. In addition, 0.2 ml/20 g of physiological saline was administered to the control group. K=logCo-logC/t-to (Co=to amount of charcoal in the blood, C=blood charcoal amount at t) The results are shown in Table 3.

[Table] (Note) L-lysolecithin is highly hemolytic and irritating and should be administered intravenously (dose 100mg/Kg)
continuous administration was not possible.
() Pre-administration effect on L-1210 (L-
1210allograft) Each drug (40 mg/Kg in terms of L-lysolecithin) was administered intraperitoneally to ddN mice (〓, 6 weeks old).
After 7 days of continuous administration, and 1 week off, 1 x 10 ⁶ L-1210 leukemia cells were intraperitoneally inoculated, and the average survival days were determined. The results are shown in Table 4.

[Table] Kg)
(c) Acute toxicity (LD ₅₀ value) Each test drug was administered intraperitoneally or intravenously to ddN mice (♀, 6 weeks old), and the acute toxicity value (LD ₅₀ value)
value) was calculated by the Richfield-Wilkoxon method. The results are shown in Table-5.

[Table] *, ** Both values are expressed by the amount of L-lysolecithin contained in drug No. 1.
As is clear from Tables 1 to 5 above, the lysophospholipids and phospholipid-containing immunostimulants of the present invention, the lysophospholipids, phospholipids, and oils and fats-containing immunostimulants, and the lysophospholipids and phospholipids of the present invention. Immunostimulants containing lipids and fat emulsions are
It can be seen that this drug has almost no effect on the immunostimulatory effect that lysophospholipids originally have, exhibits excellent effects, and has a markedly reduced hemolytic property, making it a very safe drug. Generally, methods such as ultracentrifugation, dialysis, or column chromatography have been used to obtain a mixture consisting of particles with small particle sizes, but such operations are extremely complicated, so they cannot be produced in large quantities on an industrial scale. Not desirable as a means. Therefore, as a result of intensive research to find an industrially advantageous method, the present inventors found that the method of filtering a dispersion containing lysophospholipids and phospholipids with a membrane filter yields only small particles. It has been discovered that it has excellent features such as being extremely easy to operate, and can be treated aseptically at the same time. Next, a specific manufacturing method will be described. To obtain immunostimulants containing lysophospholipids and phospholipids, lysophospholipids and phospholipids may be mixed with water (if necessary, an isotonic solution such as glucose solution or physiological saline may be used instead of water). good.)
Mix thoroughly. For example, lysophospholipids and phospholipids can be added to water (an isotonic solution may be used if necessary) and thoroughly mixed mechanically, or lysophospholipids and phospholipids can be added to water (an isotonic solution may be used if necessary), or lysophospholipids and phospholipids can be added to water in chloroform under a nitrogen atmosphere. , halogenated hydrocarbons such as methylene chloride, alcohols such as methanol, ethanol, or a mixed solvent thereof, and then the solvent is distilled off.
The product obtained by adding water (if necessary, an isotonic solution may be used) and mixing thoroughly, or by uniformly dissolving the phospholipid in the above-mentioned organic solvent, and then distilling off the solvent. A suspension is obtained by adding a solution obtained by uniformly dissolving lysophospholipids in water (if necessary, an isotonic solution may be used) and mixing thoroughly.
The amount of organic solvent used in the above operation is not particularly limited, but may be at least an amount that can completely dissolve the solute. Distillation of the used solvent is carried out at a low temperature, preferably 40°C or lower. The temperature and mixing time during mixing are generally preferably room temperature or lower, and 30 minutes to 3 hours is sufficient. For the mixing operation itself, for example, a method of adding an appropriate amount of glass beads and mixing by rotating the container itself, or mechanically mixing with a mixer or the like is used. To further reduce the particle size of lysophospholipids and phospholipid-containing suspension particles, mechanical dispersion such as sonication or pressure jetting (after removal if glass beads are used) can be used. Processing, e.g. 9~200KHz, 50~
Ultrasonic treatment is performed under 1500W conditions for 10 minutes to 10 hours to obtain a dispersion. Furthermore, membrane filter filtration, for example, pore size 0.1 μ to 1 μ, preferably 0.1 μ to
The most preferred dispersion is obtained by filtration using a 0.5μ membrane filter under normal, elevated or reduced pressure. Further, the above-mentioned dispersion can also be vacuum freeze-dried to a solid product by a conventional method, preferably by keeping the secondary drying temperature at 30° C. or lower. In addition, to obtain an immunostimulant containing lysophospholipids, phospholipids, and fats and oils, lysophospholipids and phospholipids can be mixed with halogenated hydrocarbons such as chloroform and methylene chloride or alcohols such as methanol and ethanol under a nitrogen stream. or a mixed solvent thereof, the solvent is distilled off, and the resulting product is dissolved in water (if necessary, an isotonic solution such as glucose solution or physiological saline may be used instead of water). After adding fats and oils to the suspension obtained by adding (good) and thoroughly mixing or the dispersion obtained by the above-mentioned manufacturing method and thoroughly mixing, the same ultrasonic treatment and membrane filter filtration as described above are carried out. Alternatively, the lysophospholipids, phospholipids, and fats and oils can be uniformly dissolved in the same organic solvent as above, the solvent is distilled off, and the resulting product is diluted with water (if necessary, water is added to the solution). An isotonic solution such as glucose solution or physiological saline may be used in place of the above solution) and thoroughly mixed. Furthermore, mechanical dispersion treatment and membrane filter filtration may be performed. To obtain an immunostimulant containing lysophospholipids, phospholipids, and a fat emulsion, the fat emulsion is added to the dispersion containing lysophospholipids and phospholipids obtained by the method described above, and the mixture is shaken 2 to 3 times. do it. The conditions for performing these operations are the same as those for the manufacturing method described above. The immunostimulants containing the lysophospholipids and phospholipids or lysophospholipids, phospholipids and oils or lysophospholipids, phospholipids and fat emulsions of the present invention may be generally known depending on the intended use or formulation. It can be prepared into conventional dosage forms using additives. When administering the immunostimulant of the present invention to a patient, the administration method, frequency of administration, and dose are generally selected to suit the optimal conditions depending on the patient's symptoms, but usually 0.1 lysophospholipid per day for adults.
The drug containing ~200 mg/Kg is administered orally or parenterally in 1 to 4 doses. In particular, administration by intravenous or intramuscular injection, especially by intravenous drip, is preferred. Next, the present invention will be explained by giving specific examples of typical formulations. Formulation Example 1 After dissolving 9.6 g of egg yolk lecithin, 1.0 g of L-lysolecithin, and 1.0 g of vitamin E in 40 ml of chloroform, the chloroform is distilled off under reduced pressure at 40° C. or lower, and the solution is vacuum-dried at room temperature for 2 hours. Then,
100g glass beads and 5% glucose solution for injection
Add 100 ml and rotate the container for 1 hour and 30 minutes to obtain a suspension. After removing the glass beads and subjecting the liquid to ultrasonication (28KHz: 150W) for 2 hours and 30 minutes, it was pressurized using a membrane filter with a pore size of 0.3μ, and the resulting liquid was further sterilized and 25ml
Subdivide and seal in vials for intravenous injection to obtain injections. Formulation example 2 50ml of the dispersion for intravenous injection prepared in Formulation example-1
A separately prepared fat emulsion (containing 20 g of soybean oil, 5.0 g of concentrated glycerin, and 2.4 g of egg yolk phospholipid)
200ml of aqueous emulsion) and 50ml of the aqueous emulsion) and subjected to the same ultrasonic treatment and membrane filtering as in Formulation Example-1 to obtain an intravenous drip. Formulation Example 3 20ml of the intravenous dispersion prepared in Formulation Example-1
is added to 200 ml of commercially available fat emulsion Intrafat Injection and shaken 2 to 3 times to obtain an intravenous infusion. Formulation Example 4 10ml of the intravenous dispersion prepared in Formulation Example-1
The product is lyophilized under vacuum to obtain a ready-to-use intravenous infusion solution. Formulation Example 5 After dissolving 1 g of L-lysolecithin, 9.6 g of egg yolk lecithin, and 1 g of sesame oil in 40 ml of chloroform, the chloroform was distilled off under reduced pressure at 40°C or lower,
Further, vacuum drying is performed for 2 hours at room temperature. Next, 100 g of glass beads and 100 g of 5% glucose solution for injection
ml and rotate the container for 1 hour and 30 minutes to obtain a suspension. After removing the glass beads, the solution was subjected to ultrasonication (28KHz: 150W) for 2 hours and 30 minutes, and then pressurized using a membrane filter with a pore size of 0.3μ. Subdivide and seal in injection vials to obtain injections. Formulation example 6 Egg yolk lecithin 9.6g and L-lysolecithin 1.6
After dissolving g in 40 ml of chloroform, chloroform is distilled off under reduced pressure at below 40°C, and the mixture is further vacuum-dried at room temperature for 2 hours. Then 100g of glass beads and 5% for injection
Add 100 ml of glucose solution and rotate the container for 1 hour and 30 minutes to obtain a suspension. After removing the glass beads, the liquid was subjected to ultrasonication (28KHz: 150W) for 2 hours and 30 minutes, filtered through a membrane filter with a pore size of 0.3μ, and the resulting liquid was further sterilized, and
Seal the solution in ml intravenous injection vials to obtain an injection. Formulation Example 7 20ml of the dispersion for intravenous injection prepared in Formulation Example-6
is added to 200 ml of commercially available fat milk intrafat injection and shaken 2 to 3 times to obtain an intravenous drip solution. Formulation example 8 Egg yolk lecithin 9.6g and L-lysolecithin 1
After dissolving g in 40 ml of chloroform, chloroform is distilled off under reduced pressure at below 40°C, and the mixture is further vacuum-dried at room temperature for 2 hours. Then 100 glass beads
g and 100 ml of 5% glucose solution for injection,
Rotate the container for 1 hour and 30 minutes to obtain a suspension. Remove the glass beads and sonicate the solution (28K
Hz: 150 W) for 2 hours and 30 minutes, the solution is filtered through a membrane filter with a pore size of 0.3 μm, and the obtained solution is further sterilized and sealed in 2 ml vials for intravenous injection to obtain an injection. Formulation example 9 Egg yolk lecithin 14.0g, L-lysolecithin 2.0g
Add to 100 ml of 5% glucose solution for injection and mix with a mixer for 30 minutes. Next, this suspension was subjected to ultrasonic treatment (28KHz: 150W) for 3 hours, and then
Pressure filtration (0.8Kg/cm ² ) was performed using a membrane filter with a pore size of 0.3μ, and the obtained filtrate was treated aseptically.
Seal the solution in 25ml intravenous injection vials to obtain an injection. Formulation Example 10 Add 9.6 g of egg yolk lecithin and L-lysolecithin (produced by treating egg yolk lecithin with phospholipase A) to 90 ml of a 5% glucose solution for injection, and stir and mix with a mixer for 30 minutes. This suspension was then sonicated (19KHz:
1200W) for 1 hour, then pressure filtration (0.5-1.0Kg/
cm ² ), and the obtained filtrate is treated aseptically and sealed in 25 ml vials for intravenous injection to obtain an injection. Formulation Example 11 200 mg of 1-myristoyl-DL-3-glycerylphosphorylcholine and 1.8 g of egg yolk lecithin were added to 18 ml of a 5% glucose solution for injection, and mixed and stirred using a mixer. After this mixed solution was subjected to ultrasonic treatment (equipment: Kubota 200M model: conditions: 200W, 3 hours), it was filtered using a membrane filter with a pore size of 0.3μ at a nitrogen pressure of about 0.2Kg/cm ² to obtain a dispersion of about 18ml.
get. This is sterilized and sealed in a vial for intravenous injection to obtain an injection. Formulation Example 12 200 mg of 1-palmitoyl-DL-3-glycerylphosphorylcholine and 1.8 g of egg yolk lecithin were added to 18 ml of a 5% glucose solution for injection, and mixed and stirred using a mixer. After this mixed solution was subjected to ultrasonic treatment (equipment: Kubota 200M model: conditions: 200W, 3 hours), it was filtered using a membrane filter with a pore size of 0.3μ at a nitrogen pressure of about 0.2Kl/cm ² to obtain a dispersion of about 18ml.
get. This is sterilized and sealed in a vial for intravenous injection to obtain an injection. Formulation Example 13 200 mg of 1-decanoyl-3-DL-glycerylphosphorylcholine and 1.8 g of egg yolk lecithin were added to 18 ml of a 5% glucose solution for injection, and mixed and stirred using a mixer. After this mixed solution was subjected to ultrasonic treatment (equipment: Kubota 200M model: conditions: 200W, 3 hours), it was filtered using a membrane filter with a pore size of 0.3μ at a nitrogen pressure of about 0.2Kg/cm ² to obtain a dispersion of about 18ml.
get. This is sterilized and sealed in a vial for intravenous injection to obtain an injection. Formulation Example 14 200 mg of 1-eicosanoyl-3-DL-glycerylphosphorylcholine and 1.8 g of egg yolk lecithin were added to 18 ml of a 5% glucose solution for injection, and mixed and stirred using a mixer. Ultrasonic treatment of this mixed liquid (equipment: Kubota 200M model: conditions: 200W, 3 hours)
After that, the dispersion was filtered using a membrane filter with a pore size of 0.3μ at a nitrogen pressure of about 0.2Kg/ ^cm2 to remove about 18ml of the dispersion.
get. This is sterilized and sealed in a vial for intravenous injection to obtain an injection. Formulation example 15 Add 200 mg of 2-methyl-1-octadecyl-3-DL-glycerylphosphorylcholine and 1.8 g of egg yolk lecithin to 18 ml of 5% glucose solution for injection,
The mixture was mixed and stirred using a mixer. Ultrasonic treatment of this mixed liquid (equipment: Kubota 200M model: conditions:
After heating at 200W for 3 hours), the solution was filtered using a membrane filter with a pore size of 0.3μ under a nitrogen pressure of about 0.2Kg/cm ² to obtain about 18ml of a dispersion liquid. This is sterilized and sealed in a vial for intravenous injection to obtain an injection. Formulation Example 16 200 mg of 1-decanoyl-3-DL-glycerylphosphorylcholine, 1.8 g of egg yolk lecithin, and 200 mg of corn oil were added to 18 ml of a 5% glucose solution for injection, and mixed and stirred using a mixer. After this mixed solution was subjected to ultrasonic treatment (equipment: Kubota 200M model: conditions: 200W, 3 hours), it was filtered using a membrane filter with a pore size of 0.3μ and about 0.2Kg/cm ² of nitrogen, resulting in about 18ml of the dispersion. get. This is treated aseptically,
Seal it in a vial for intravenous injection to obtain an injection. Formulation Example 17 200 mg of 1-eicosanoyl-3-DL-glycerylphosphorylcholine, 1.8 g of egg yolk lecithin and 200 mg of cottonseed oil were added to 18 ml of a 5% glucose solution for injection, and mixed and stirred using a mixer. Ultrasonic treatment of this mixed liquid (equipment: Kubota 200M model: conditions:
After heating at 200W for 3 hours), the solution was filtered using a membrane filter with a pore size of 0.3μ under a nitrogen pressure of about 0.2Kg/cm ² to obtain about 18ml of a dispersion liquid. This is sterilized and sealed in a vial for intravenous injection to obtain an injection. Formulation example 18 2-methyl-1-octadecyl-3-DL-glycerylphosphorylcholine 200mg, egg yolk lecithin
1.8g and 200mg of sesame oil as 5% glucose solution for injection
The mixture was added to 18 ml and mixed using a mixer.
Ultrasonic treatment of this mixed liquid (equipment: Kubota 200M
Type: Conditions: 200W, 3 hours), then use a membrane filter with a pore size of 0.3μ to reduce the nitrogen pressure to about 0.2
Filter through Kg/cm ² to obtain approximately 18 ml of dispersion. This is sterilized and sealed in a vial for intravenous injection to obtain an injection. Formulation Example 19 18 ml of the intravenous dispersion prepared in Formulation Example 13 is added to 180 ml of the commercially available fat emulsion Intrafat Injection and shaken 2 to 3 times to obtain an intravenous infusion. Formulation Example 20 18 ml of the intravenous dispersion prepared in Formulation Example 14 is added to 180 ml of the commercially available fat emulsion Intrafat Injection and shaken 2 to 3 times to obtain an intravenous infusion. Formulation Example 21 18 ml of the intravenous dispersion prepared in Formulation Example 15 is added to 180 ml of the commercially available fat emulsion Intrafat Injection and shaken 2 to 3 times to obtain an intravenous infusion.

Claims (1)

[Claims] 1. An immunostimulant containing lysophospholipids and phospholipids. 2 formulas [In the formula, R ¹ is a C _5-22 acyloxy or C _5-22 alkoxy group, R ² is a hydrogen atom, a hydroxyl group,
C _1-5 acyloxy group or C _1-5 alkoxy group,
^R3 represents a hydrogen atom or a _C1-5 alkyl group. still,
R ¹ and R ² can be converted into each other. ] The immunostimulant according to claim 1, which contains a lysophospholipid represented by the following or a lysophospholipid containing the same as a main component and a phospholipid. 3. The immunostimulant according to claim 2, wherein the immunostimulant containing lysophospholipids and phospholipids is in the form of a dispersion. 4. The immunostimulant according to claim 3, wherein the dispersed lysophospholipids and phospholipids are in the state of lipid vesicles. 5. The immunostimulant according to claim 4, wherein the particle size of the lipid endoplasmic reticulum is 0.5μ or less. 6. The immunostimulant according to any one of claims 1 to 5, wherein the phospholipid is a naturally derived phospholipid. 7. The immunostimulant according to any one of claims 1 to 6, wherein the lysophospholipid is lysolecithin. 8. The immunostimulant according to claim 7, wherein lysolecithin is obtained by decomposing lecithin. 9. The immunostimulant according to any one of claims 1 to 8, which contains 1.0 to 500 phospholipids in a weight ratio of 1 to 1 lysophospholipids. 10. The immunostimulant according to claim 9, which contains phospholipids in a weight ratio of 5.0 to 20 to 1 of lysophospholipids. 11 Containing lysophospholipids and phospholipids characterized by mixing lysophospholipids, phospholipids and water or an isotonic liquid, subjecting the resulting mixture to mechanical dispersion treatment, and then passing through a membrane filter. A method for producing an immunostimulant. 12 formula [In the formula, R ¹ is a C _5-22 acyloxy or C _5-22 alkoxy group, R ² is a hydrogen atom, a hydroxyl group,
C _1-5 acyloxy group or C _1-5 alkoxy group,
^R3 represents a hydrogen atom or a _C1-5 alkyl group. still,
R ¹ and R ² can be converted into each other. ] Lysophospholipids represented by or lysophospholipids containing it as a main component, phospholipids and water or an isotonic liquid are mixed, the resulting mixture is subjected to mechanical dispersion treatment, and then filtered through a membrane filter. 12. The method for producing an immunostimulant according to claim 11, which contains lysophospholipids characterized by the above, or lysophospholipids containing the same as a main component, and phospholipids. 13. The method for producing an immunostimulant containing lysophospholipids and phospholipids according to claim 11 or 12, wherein the membrane filter has a pore size of 0.5μ or less. 14 An immunostimulant containing lysophospholipids, phospholipids, and fats and oils. 15 formula [In the formula, R ¹ is a C _5-22 acyloxy or C _5-22 alkoxy group, R ² is a hydrogen atom, a hydroxyl group,
C _1-5 acyloxy group or C _1-5 alkoxy group,
^R3 represents a hydrogen atom or a _C1-5 alkyl group. still,
R ¹ and R ² can be converted into each other. ] The immunostimulant according to claim 14, which contains a lysophospholipid represented by the following or a lysophospholipid containing it as a main component, a phospholipid, and an oil or fat. 16. The immunostimulant according to claim 15, wherein the immunostimulant containing lysophospholipids, phospholipids, and fats and oils is in the form of a dispersion. 17 Claim 16, wherein the dispersed lysophospholipids and phospholipids are in the state of lipid vesicles.
The immunostimulant described in Section. 18. The immunostimulant according to claim 17, wherein the particle size of the lipid endoplasmic reticulum is 0.5μ or less. 19. The immunostimulant according to any one of claims 14 to 18, wherein the phospholipid is a naturally derived phospholipid. 20. The immunostimulant according to any one of claims 14 to 19, wherein the lysophospholipid is lysolecithin. 21. The immunostimulant according to claim 20, wherein lysolecithin is obtained by decomposing lecithin. 22 Claim 14 where the fat or oil is an edible oil
The immunostimulant according to any one of items 21 to 21. 23. The immunostimulant according to any one of claims 14 to 22, which contains 1.0 to 500 phospholipids and 0.1 to 200 fats and oils in a weight ratio of 1 to 1 lysophospholipids. 24 An immunostimulant containing lysophospholipids, phospholipids, and fat emulsion. 25 formula [In the formula, R ¹ is a C _5-22 acyloxy or C _5-22 alkoxy group, R ² is a hydrogen atom, a hydroxyl group,
C _1-5 acyloxy group or C _1-5 alkoxy group,
^R3 represents a hydrogen atom or a _C1-5 alkyl group. still,
R ¹ and R ² can be converted into each other. ] The immunostimulant according to claim 24, which contains a lysophospholipid represented by the following or a lysophospholipid containing the same as a main component, a phospholipid, and a fat emulsion. 26. The immunostimulant according to claim 25, wherein the phospholipid is a naturally derived phospholipid. 27. The immunostimulant according to any one of claims 24 to 26, wherein the lysophospholipid is lysolecithin. 28. The immunostimulant according to claim 27, wherein lysolecithin is obtained by decomposing lecithin. 29 The weight ratio of fat emulsion is 10 parts oil to 10 parts emulsifier.
The immunostimulant according to any one of claims 24 to 28, which comprises 0.1 to 50% of water and 5.0 to 200% of water.