JPH1171284A - Preparation for injection containing lipid a analog and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preparation for injection, having high clarity and stability, stimulation on macrophage, antitumor action, pyrogenicity, etc., by dissolving a lipid A analog in an alkali aqueous solution and adding a buffer solution to the solution. SOLUTION: A lipid A analog or its pharmacologically permissible salt (e.g. a compound of the formula) is dissolved in an alkali aqueous solution such as 0.001-0.005 M aqueous solution of sodium hydroxide, heated for 10 minutes to 3 hours while heating the solution at 30-60 deg.C and then a buffer solution such as 1-20 mM buffer solution of phosphoric acid is added to the solution and the solution is finally adjusted to pH 4-9. Preferably a saccharide such as lactose is added to the buffer solution. The objective preparation for injection comprises the lipid A analog which is associated and is made into approximately spherical particles having <=30 nm average particle diameter. The associated body can be freeze-dried without being destroyed.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an injectable preparation containing a lipid A analog or a pharmacologically acceptable salt thereof and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION [0002] Lipid A, which is a lipopolysaccharide (LPS) activity expression center, is known to have various biological activities such as macrophage stimulating action, antitumor action, and pyrogenic action (eg, , Haruka Takada, Shozo Kotani, Protein, Nucleic Acid, Enzyme, 31 (4),
361 (1986)).

In recent years, various lipid A analogs have been synthesized,
Its biological activity has been investigated (Yuji Ogawa et al., Metabolism,
26 (5), 415 (1989)), lipid A analogs originally have a glycolipid structure, and many of these analogs are poorly water-soluble or insoluble. In order to obtain a highly transparent aqueous solution, various studies have been made. As a result, it has been proposed to add triethylamine, bovine serum albumin, lipids and the like as solubilizers (YBKim, et al, Eur. J. Biochem.
31,230 (1972) and RBRamsey, et al, Blood, 56,307 (198
0), J. Dijkstra, et al., J. Immunol., 138, 2663 (1987)).

Japanese Patent Application Laid-Open No. 4-198192 discloses a method using a basic amino acid or polyamine as a solubilizing agent, but the pH of the aqueous solution is as high as about 10 in all cases. On the other hand, to disperse lipids such as lecithin in water to form aggregates such as liposomes, there is known a method in which lipids are put in a buffer in a neutral region, heated, and irradiated with ultrasonic waves.

[0005]

The method of solubilizing lipid A analogs using a solubilizing agent is not sufficient in terms of physical stability in water, chemical stability, pharmacological effect and safety. However, it has not been put to practical use. Also, a method of dispersing in a buffer solution in a neutral region and sonication could not obtain a transparent solution of lipid A analog. Therefore, there is a need for an injection that can be used for lipid A analogs in practical use, that is, an injection that has high clarity when prepared as an aqueous solution, has a preferable pH as an injection, and has good stability. In view of the above situation, the present inventors have conducted intensive studies to find a highly clear and stable injectable preparation containing a lipid A analog and a method for producing the same. As a result, it has been found that the desired object can be achieved by the following configuration, and the present invention has been completed.

[0006]

DISCLOSURE OF THE INVENTION The present invention relates to an injectable preparation characterized by dissolving a lipid A analog or a pharmaceutically acceptable salt thereof in an alkaline aqueous solution and then adding a buffer. It is. The present invention also provides a lipid A
This is a method for producing an injectable preparation, comprising dissolving an analog or a pharmaceutically acceptable salt thereof in an alkaline aqueous solution, and then adding a buffer. Furthermore, the present invention
An injectable preparation containing an aggregate having an average particle diameter of 30 nm or less produced by dissolving a lipid A analog or a pharmaceutically acceptable salt thereof in an alkaline aqueous solution and then adding a buffer, and a method for producing the same. .

According to the present invention, the lipid A analog or a pharmacologically acceptable salt thereof (hereinafter simply referred to as lipid A analog) can be prepared into a transparent and stable preparation for injection, which is the present invention. Is the purpose. Representative compounds of lipid A analogs according to the present invention have the following chemical structural formula (I)
Or (II), and can be produced, for example, by the method disclosed in JP-A-5-194470 or WO96 / 39411.

[0008]

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[Wherein at least one of R ¹ , R ² , R ³ or R ⁴
One is

[0010]

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[0011]

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[0012]

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Wherein each L is O, N or C; each M
It is O or N; each E is independently an integer from 0 to 14; each G is N independently, O, S, be a SO or SO _2; each m is independently Each n is independently an integer from 0 to 14; each p is an integer from 0 to 14;
Are independently integers from 0 to 10; each q is independently an integer from 0 to 10); and the remaining R ¹ , R ² , R ³
And each of R ⁴ is independently

[0014]

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Wherein each L is O, N or C;
Is O or N; each x is independently an integer from 0 to 14; each y is independently an integer from 0 to 14; each z is independently from 0 to An integer up to 10; each
G is independently N 2, O 2, S ₂ , SO or SO ₂ ); each A ¹ and A ² is independently H 2, OH, OCH ₃ ,

[0016]

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Wherein each d is independently an integer from 0 to 5; each f is independently an integer from 0 to 5; each g is independently an integer from 0 to 5. Each A ³ is independently:

[0018]

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Wherein each j is independently an integer from 0 to 14; and X is H, (CH ₂ ) _t CH ₃ , (C
H ₂ ) _t OH, (CH ₂ ) _t O (CH ₂ ) _v CH ₃ , (CH ₂ ) _t OPO (OH) ₂ , (CH ₂ ) _t −C
H = CH− (CH ₂ ) _v CH ₃ , (CH ₂ ) _t −O−R ⁵ ,

[0020]

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(Wherein each t and v are independently
Is an integer from 0 to 14; R ⁵ is an either defined above) with respect to R ¹ ~R ^4; Y is _{H, OH, O (CH 2} ) w C
H ₃ , a halogen atom,

[0022]

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(Where w is an integer from 0 to 14)

[0024]

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Wherein R ¹ is

[0026]

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(Wherein, J, K and Q are each a straight-chain or branched alkyl group having 1 to 15 carbon atoms, L is O, NH ₂ or CH ₂ , and M is O or NH And G is NH, O, S,
SO or SO ₂ ).
R ² is a linear or branched alkyl group having 5 to 15 carbon atoms;
R ³ is

[0028]

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Wherein E is N, O, S, SO or SO ₂ , and A, B and D are each a straight-chain or branched carbon atom having 1 carbon atom.
R ⁴ is a straight-chain or branched alkyl group having 4 to 20 carbon atoms;
as well as

[0030]

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(Wherein, U and V are each a straight-chain or branched alkyl group having 2 to 15 carbon atoms, W is a hydrogen atom,
Or a linear or branched alkyl group having 1-5 carbon atoms); R ⁵ is a hydrogen atom,
J ', -J'-OH, -J'-O-K', -J'-O-K'-OH and -J'-0-P0 (O
H) ₂ (wherein J ′ and K ′ each represent a straight-chain or branched carbon atom of 1)
R ⁶ is a group selected from the group consisting of a hydroxyl group, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, and an acyloxy group having 1 to 5 carbon atoms. A ¹ and A ² are each independently:

[0032]

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(Wherein Z is a straight-chain or branched C 1 -C 10)
Is a group selected from the group consisting of In the present invention, a preferred lipid A analog is 6-
O- [2-deoxy-6-O-methyl-4-O-phosphono-3-O-[(R)
-3-Z-dodec-5-enoyloxydecyl] -2- [3-oxo-tetradecanoylamide] -β-0-phosphono-α-D-glucopyranose] tetrasodium, α-D-glucopyranose , 3
-O-decyl-2-deoxy-6-O- [2-deoxy-3-O- (3-methoxydecyl) -6-O-methyl-2-[(1-oxo-11-octadecenyl) amino]- 4-O-phosphono-β-D-glucopyranosyl]
-2-[(1,3-dioxotetradecyl) amino]-, 1- (dihydrogen phosphate), disodium [6 (2Z, 3
R)], and α-D-glucopyranose, 3-O-decyl-2-deoxy-6-O- [2-deoxy-3-O- (3-methoxydecyl) -6-O-methyl-2- [(1-oxo-11-octadecenyl) amino] -4-O-phosphono-β-D-glucopyranosyl] -2-[(1,3-dioxotetradecyl) amino]-, 1- (dihydrogenphos Fate) and tetrasodium [6 (2Z, 3R)]. These chemical structural formulas are represented by the following formulas (III) and (I
V).

[0034]

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[0035]

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As the alkaline aqueous solution in the present invention, an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide can be used.
An aqueous sodium hydroxide solution. The concentration is usually 0,1.
0001M to 0.1M, preferably 0.0005M
M to 0.01M, more preferably 0.001M to
0.005M.

In the present invention, after the alkaline aqueous solution is added to the lipid A analog, the mixture can be heated, but the heating temperature is not lower than the phase transition temperature of the lipid A analog or a pharmaceutically acceptable salt thereof. Anything is acceptable, usually 30 ° C to 6
0 ° C, more preferably 45 ° C to 55 ° C. The stirring time while heating is usually 10 minutes to 3 hours. Stirring can be performed by a commonly used device. The stirring time required to obtain a transparent liquid (turbidity of 0.6 NTU or less) varies depending on the lipid A analog. In the case of the compound represented by the formula (III), the heating temperature is usually 40 ° C. or less. 90 minutes or more is required in the case of
It may be within 0 minutes. When dissolving in a heated alkaline aqueous solution, add lipid A to a pre-warmed alkaline aqueous solution.
The analog may be added, or the alkaline aqueous solution may be heated after addition of lipid A. In the present invention,
The purpose of the heating is to raise the phase transition temperature of the lipid A analog or higher to promote the hydration of the lipid A analog and improve the dispersibility, thereby obtaining a clear solution by stirring for a short time. is there.

As a component of the buffer used in the present invention, phosphate, tris (hydroxymethyl) aminomethane, citrate, glycine, or the like can be used. The concentration of the buffer is usually 1 mM to 20 mM.
The pH of the final aqueous solution of lipid A analog is preferably 4
-9, more preferably 6-8, and even more preferably 6.8.
７7.8. The final pH can be adjusted by adding a buffer solution and then further adding a sodium hydroxide solution or a hydrochloric acid solution.

If necessary, saccharides and / or amino acids can be added to the buffer to obtain more favorable results. In this case, one kind of saccharide and / or amino acid may be added, or two or more kinds may be added. Examples of saccharides that can be used include lactose (lactose), sorbitol, glucose, trehalose, mannitol, dextran, and the like.
Examples of amino acids include neutral amino acids such as glycine, acidic amino acids such as aspartic acid, and basic amino acids such as arginine.

In the present invention, the obtained aqueous solution of lipid A analogs can be further converted into a lyophilized preparation by a commonly used means. That is, Lipid A or its analog is dissolved in an alkaline aqueous solution, and the mixture is further heated and stirred as necessary, then a buffer is added to adjust the pH, and after sterile filtration, filled into a vial or the like, and frozen. It can be dried to give a lyophilized preparation. When such an injectable preparation of the present invention is provided as an aqueous solution, the osmotic pressure ratio is desirably a value suitable for administration to humans.
Before and after.

The preparation for injection according to the present invention comprises Lipid A
The analogs are associated to form substantially spherical particles having an average particle diameter of about 30 nm or less. The size of the aggregate does not change between immediately after the preparation of the preparation for injection and after condensing after freeze-drying. Generally, aggregates are often destroyed by lyophilization, but in the present invention, even after condensed water, 30 n
It is one of the remarkable effects of the present invention that the average particle diameter of not more than m can be maintained. According to detailed studies, the aggregate according to the present invention has a concentration of about 0,0 in the case of the compound represented by the formula (III).
It has an internal aqueous phase of 196 liters / mole (pH 11.0), and forms an aggregate having a substantially constant size of about 15 nm by continuing stirring during preparation. Therefore, the range of the average particle diameter of the present invention is about 15 nm to 30 nm in the case of a normal production method.

The aggregates of the lipid A analog according to the present invention are hardly affected by coexisting magnesium ions or calcium ions in terms of particle diameter, turbidity and the like. On the other hand, the membrane fluidity is affected by magnesium ions or calcium ions, and the presence of these metal ions lowers the membrane fluidity. Membrane fluidity affects in vivo kinetics after administration of lipid A analogs, and when membrane fluidity decreases, the disappearance of lipid A analogs from the living body becomes faster.

[0043]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 45 mg of the lipid A analog represented by the above formula (III)
The solution was added to and dissolved in 90 ml of a 0.003M aqueous sodium hydroxide solution at 90 ° C., and stirred at the same temperature for 30 minutes. 5ml of this
Was collected and the turbidity was measured with a turbidity meter. Turbidity was 0.178 NTU. 30 ml of a 7.08 mM phosphate buffer containing 16.7% lactose was added to 7.5 ml of the alkaline aqueous solution, the pH was adjusted to 7.39 with a 0.3% sodium hydroxide solution, and then distilled water for injection was added. The total volume was adjusted to 50 ml. The turbidity of this aqueous solution was 0.181 NTU. This aqueous solution
5.3 ml was placed in a vial and freeze-dried using a vacuum freeze-drying apparatus (Kyowa Seisakusho's Triomaster A04).

Example 2 60 mg of the lipid A analog used in Example 1 was added to 90 ml of a 0.003 M aqueous sodium hydroxide solution at 55 ° C., dissolved and stirred at the same temperature for 60 minutes. 5 ml of this alkali aqueous solution was sampled, and the turbidity was measured with a turbidity meter. Turbidity is 0.133N
TU. 16.5% in 7.5 ml of this alkaline aqueous solution
30 ml of 7.08 mM phosphate buffer containing lactose was added,
After adjusting the pH to 7.41 with a 0.3% aqueous sodium hydroxide solution, distilled water for injection was added to adjust the total volume to 50 ml. The turbidity of this aqueous solution was 0.212 NTU.

Example 3 60 mg of the lipid A analog used in Example 1 was added to and dissolved in 90 ml of a 0.001 M aqueous sodium hydroxide solution at 50 ° C., followed by stirring at the same temperature for 60 minutes. 5 ml of this alkali aqueous solution was sampled, and the turbidity was measured with a turbidity meter. Turbidity is 0.142N
TU. 8.35% in 7.5 ml of this alkaline aqueous solution
7.08 mM Tris (hydroxymethyl) with mannitol
Add 30 ml of aminomethane buffer and adjust the pH with 1N hydrochloric acid.
After adjusting to 7.39, distilled water for injection was added to make the total volume 50 ml. The turbidity of this aqueous solution was 0.133 NTU.

Example 4 60 mg of the lipid A analog used in Example 1 was added to and dissolved in 90 ml of a 0.005 M aqueous sodium hydroxide solution at 50 ° C., and the mixture was stirred at the same temperature for 60 minutes. 5 ml of this alkali aqueous solution was sampled, and the turbidity was measured with a turbidity meter. Turbidity is 0.150N
TU. 16.5% in 7.5 ml of this alkaline aqueous solution
30 ml of 7.08 mM phosphate buffer containing lactose was added,
After adjusting the pH to 7.37 with a 0.3% aqueous sodium hydroxide solution, distilled water for injection was added to adjust the total volume to 50 ml. The turbidity of this aqueous solution was 0.205 NTU.

Example 5 60 mg of the lipid A analog used in Example 1 was added to and dissolved in 90 ml of a 0.003 M aqueous sodium hydroxide solution at 35 ° C., and the mixture was stirred at the same temperature for 150 minutes. 5 ml of this alkali aqueous solution was sampled, and the turbidity was measured with a turbidity meter. Turbidity is 0.66
9 NTU. 8.35 in 7.5 ml of this alkaline aqueous solution
% Dextran 70 (average molecular weight 70000) 7.
After adding 30 ml of 08 mM phosphate buffer and adjusting the pH to 7.30 with a 0.3% aqueous sodium hydroxide solution, distilled water for injection was added to make a total volume of 50 ml. The turbidity of this aqueous solution was 1.25 NTU.

Example 6 6.09 mg of the lipid A analog represented by the above formula (IV) was added to 9.0 ml of a 0.01 M aqueous sodium hydroxide solution to give 6
Stirred for 0 minutes. This pH was 12.08. To this solution was added 30 ml of a phosphate buffer containing lactose. pH was 7.46. Distilled water for injection was added to this solution to make the total volume 60 ml. This solution was a pH 7.50 injection containing 0.1 mg / ml of lipid A analog, 10% lactose and 4.25 mM phosphate buffer.

Example 7 The injection solution obtained in Example 6 was sterilized, filtered, dispensed into vials 3 ml each, and freeze-dried to obtain a lyophilized preparation containing a lipid A analog. Lyophilization conditions were as follows (lyophilization apparatus: EDWARD Model Lyo fast S08). Freezing temperature: -40 ° C, primary drying temperature: 20 ° C, primary drying pressure: 0.075 ± 0.025 mbar, secondary drying temperature: 27 ° C, secondary drying pressure: (maximum capacity of the device), secondary Drying time: 18 hours.

Example 8 40.16 mg of the lipid A analog used in Example 6 was added to 9.0 ml of a 0.003 M aqueous sodium hydroxide solution and stirred for 60 minutes. This pH was 11.49. 10 ml of lactose-containing phosphate buffer was added to this solution. pH was 8.44. Further, the pH was adjusted to 7.4 by adding a 4% phosphoric acid solution, and distilled water for injection was added to adjust the total volume to 20 ml. This solution contains 2.0 mg / ml lipid A analog, 10% lactose and 4.25.
It was a pH 7.51 injection containing mM phosphate buffer.

Example 9 The injection solution obtained in Example 8 was sterilized, filtered, dispensed into vials 3 ml each, and freeze-dried to obtain a freeze-dried preparation containing a lipid A analog. Lyophilization conditions were as follows (lyophilization apparatus: EDWARD Model Lyo fast S08). Freezing temperature: -40 ° C, primary drying temperature: 20 ° C, primary drying pressure: 0.075 ± 0.025 mbar, secondary drying temperature: 27 ° C, secondary drying pressure: (maximum capacity of the device), secondary Drying time: 18 hours.

[0053]

Next, experimental examples will be described to show the effects of the present invention. Experimental Example 1 Evaluation of clarity of preparation according to the present invention Experimental method The turbidity of the aqueous solution of the lipid A analog prepared in the comparative example and the present method 1 shown below was measured. The measurement is Hach 2100AN
This was performed using a Turbidimeter.

Comparative Example 60 mg of Lipid A analog used in Example 1 was added to 4.25 mM containing 10% lactose at 50 ° C.
Dissolve in phosphate buffer and continue stirring at the same temperature.
After 0, 60, 120 and 180 minutes, 12.5 ml were sampled. Turbidity was measured using 5 ml of the mixture. In addition, 7.5 ml of each solution contains 10% lactose.
25 mM phosphate buffer was added to bring the total volume to 50 ml. The turbidity and pH of these aqueous solutions were measured.

Method 1 60 mg of the lipid A analog used in Example 1 was added to and dissolved in 90 ml of a 0.003 M aqueous sodium hydroxide solution at 50 ° C., stirred at the same temperature, and stirred for 30 minutes and 6 minutes.
After 0, 120 and 180 minutes, 12.5 ml of an aqueous alkaline solution was collected. Turbidity was measured with a turbidimeter using 5 ml of the mixture. Then add 1 to 7.5 ml of each aqueous alkali solution.
30 ml of 7.08 mM phosphate buffer containing 6.5% lactose
And adjust the pH to about 7.
After adjusting to 4, distilled water for injection was added to make a total volume of 50 ml.
The turbidity and pH of these aqueous solutions were measured.

2. Experimental results Table 1 shows the results obtained from the above experimental method.

[0057]

[Table 1]

From Table 1, it can be seen that the aqueous solution of the lipid A analog prepared according to the comparative example, which is a conventional representative method, is much more excellent in clarity than that obtained by the present method 1 according to the present invention. It is clear that there is.

Experimental Example 2 Evaluation of reconstitution of freeze-dried preparation of lipid A analog Experimental Method Method 2 60 mg of lipid A analog used in Example 1 was added to 5
The solution was added to and dissolved in 90 ml of a 0.003 M aqueous sodium hydroxide solution at 0 ° C., and stirred at the same temperature for 30 minutes, 60 minutes, and 120 minutes.
After 1 minute and 180 minutes, 12.5 ml of an aqueous alkaline solution was collected. Turbidity was measured with a turbidimeter using 5 ml of the mixture. Next, 30 ml of a 7.08 mM phosphate buffer solution containing 16.5% lactose was added to 7.5 ml of each alkaline aqueous solution, and the mixture was added with 0.1 ml of a 0.1% lactose solution.
After adjusting the pH to about 7.4 with 3% aqueous sodium hydroxide,
Distilled water for injection was added to make up the total volume to 50 ml. This aqueous solution 5.
3 ml was placed in a vial and freeze-dried using a vacuum freeze dryer (Kyowa Seisakusho's Triomaster A-04). further,
The obtained freeze-dried preparation was re-dissolved by adding 5 ml of distilled water for injection, and the turbidity was measured using a Hach 2100AN Turbidimeter.

Method 3 200 mg of the lipid A analog used in Example 1 was added to 100 ml of a 0.003 M aqueous sodium hydroxide solution at 50 ° C., dissolved, and stirred at the same temperature.
Minutes, 60 minutes, 120 minutes, 180 minutes after alkaline aqueous solution 7.
5 ml were collected. Turbidity was measured with a turbidimeter using 5 ml of the mixture. Then 2.5 m of each alkali aqueous solution
7.08 mM phosphate buffer 3 containing 16.5% lactose in l
0 ml and pH is adjusted with 0.3% aqueous sodium hydroxide solution.
Was adjusted to about 7.4, and distilled water for injection was added to make a total volume of 50 ml. 5.3 ml of this aqueous solution was put into a vial and freeze-dried using a vacuum freeze dryer (Kyowa Seisakusho's Triomaster A-04). Further, 5 ml of distilled water for injection was added to the obtained freeze-dried preparation, and the mixture was redissolved and the turbidity was measured. Turbidity is Ha
It was measured using ch 2100AN Turbidimeter. The results are shown in Table 2.

[0061]

[Table 2]

From Table 2, it is clear that the freeze-dried preparation of the present invention has excellent clarity even when redissolved.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/715 ADU C07H 15/04 D 47/02 A61K 37/20 ABA ADT C07H 15/04 ADU (72) Inventor Kiyoshi Iwamoto Gifu 8-140 Tsutsujigaoka, Kakamigahara City, Prefecture (72) Inventor Yasuo Ishibashi Gifu Prefecture, Gifu City, Nagao, 880-86 (72) Inventor Sumio Watanabe 14-2 Saitonakayoshiike, Fuso-cho, Niwa County, Aichi Prefecture

Claims (18)

[Claims] 1. A preparation for injection, characterized by dissolving a lipid A analog or a pharmaceutically acceptable salt thereof in an alkaline aqueous solution and then adding a buffer. 2. The injectable preparation according to claim 1, wherein the lipid A analog or a pharmaceutically acceptable salt thereof is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. Embedded image [Wherein at least one of R ¹ , R ² , R ³ or R ⁴ is Embedded image Embedded image Wherein each L is O, N or C; each M is O or N; each E is independently an integer from 0 to 14;
G is independently N, O, S, be a SO or SO _2; each m
Is independently an integer from 0 to 14; each n is independently an integer from 0 to 14; each p is independently an integer from 0 to 14.
Each q is independently an integer from 0 to 10); and each of the remaining R ¹ , R ² , R ³ and R ⁴ is independently 5] Wherein each L is O, N or C; each M is O or N; each x is independently an integer from 0 to 14;
Each y is independently an integer from 0 to 14; each z is independently an integer from 0 to 10; each G is independently N, O, S, SO or SO ₂ ); each of A ¹ and A ²
Is independently H, OH, OCH ₃ , Wherein each d is independently an integer from 0 to 5; each f is independently an integer from 0 to 5; each g is independently from 0 to 5 Each A ³ is
Independently, Wherein each j is independently an integer from 0 to 14; and X is H, (CH ₂ ) _t CH ₃ , (CH ₂ ) _t OH, (C
H ₂ ) _t O (CH ₂ ) _v CH ₃ , (CH ₂ ) _t OPO (OH) ₂ , (CH ₂ ) _t −CH = CH− (CH
₂ ) _v CH ₃ , (CH ₂ ) _t -O-R ⁵ , Wherein each t and v are each independently an integer from 0 to 14; R ⁵ is any of the above definitions for R ^{1 to} R ⁴ ; and Y is H, OH, O (CH ₂ ) _w CH ₃ , a halogen atom, (Where w is an integer from 0 to 14) 3. The injectable preparation according to claim 1, wherein the lipid A analog or a pharmaceutically acceptable salt thereof is a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof. Embedded image Wherein R ¹ is (Wherein, J, K and Q are each a linear or branched alkyl group having 1 to 15 carbon atoms, L is O, NH ₂ or CH ₂ , M is O or NH, and G is Is NH, O, S, SO or SO ₂
R ² is a straight-chain or branched alkyl group having 5 to 15 carbon atoms; R ³ is a group selected from the group consisting of (Wherein E is N 2, O 2, S ₂ , SO or SO ₂ , and A, B and D are each a straight-chain or branched alkyl group having 1 to 15 carbon atoms). R ⁴ is a straight-chain or branched alkyl group having 4 to 20 carbon atoms, and (Wherein U and V each represent a straight-chain or branched carbon atom
W is a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms); R ⁵ is a hydrogen atom, J ′, -J'-OH,
-J'-O-K ', -J'-O-K'-OH and -J'-0-P0 (OH) ₂ (wherein J' and K 'each represent a straight-chain or branched carbon atom having 1 R ⁶ is a group selected from the group consisting of a hydroxyl group, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, and an acyloxy group having 1 to 5 carbon atoms. A ¹ and A ² are each independently: (Wherein, Z is a linear or branched alkyl group having 1 to 10 carbon atoms). ] 4. The preparation for injection according to claim 1, wherein the alkaline aqueous solution is a heated alkaline aqueous solution. 5. The injectable preparation according to claim 4, wherein the warmed alkaline aqueous solution is heated to a temperature not lower than the phase transition temperature of the lipid A analog or a pharmaceutically acceptable salt thereof. 6. The temperature of the heated alkaline aqueous solution is from 30 ° C. to 60 ° C.
The preparation for injection according to claim 4, which is an aqueous alkaline solution at a temperature of ° C. 7. The method according to claim 1, wherein the preparation for injection is an aqueous injection.
The preparation for injection according to any one of claims 3 to 3. 8. The preparation for injection according to claim 1, wherein the preparation for injection is a freeze-dried preparation. 9. The preparation for injection according to claim 1, wherein the buffer is a buffer having a pH of 4 to 9. 10. The buffer according to claim 1, wherein said buffer contains saccharides at pH 4 to pH
The preparation for injection according to claim 1, which is a buffer of H9. 11. A method for producing an injectable preparation, comprising dissolving a lipid A analog or a pharmaceutically acceptable salt thereof in an alkaline aqueous solution, and then adding a buffer. 12. The method according to claim 11, wherein the alkaline aqueous solution is a heated alkaline aqueous solution. 13. The method according to claim 11, wherein the buffer is a buffer having a pH of 4 to 9. 14. A preparation for injection, characterized by dissolving a lipid A analog represented by the formula (III) in a warm alkaline aqueous solution and then adding a buffer. Embedded image 15. An injectable preparation comprising a lipid A analog represented by the formula (IV) dissolved in an alkaline aqueous solution, and then a buffer solution is added. Embedded image 16. An injectable preparation comprising an association of lipid A analog or a pharmaceutically acceptable salt thereof having an average particle diameter of 30 nm or less. 17. An injectable preparation containing an aggregate having an average particle diameter of 30 nm or less, comprising a lipid A analog or a pharmaceutically acceptable salt thereof dissolved in an alkaline solution, and then adding a buffer. 18. An injectable preparation containing an aggregate having an average particle diameter of 30 nm or less produced by dissolving a lipid A analog or a pharmaceutically acceptable salt thereof in an alkaline solution and then adding a buffer. Production method.