JPH0733667A - Aqueous solution of 4,6-o-hydroxyphosphorylglucosamine derivative and method of making the same derivative water-soluble - Google Patents

Abstract

PURPOSE:To obtain the aqueous solution useful as an immunopotentiator, an antitumor agent, etc., having excellent safety and stability, containing meglumine, etc. CONSTITUTION:The aqueous solution contains a polyamine such as meglumine, piperazine or spermine or a basic amino acid such as lysine. 4,6-O- Hydroxyphosphorylglucosamine derivative is dissolved in water in the presence of meglumine, piperazine, spermine or a basic amino acid to preferably make 4,6-O-hydroxyphosphorylglucosamine derivative water-soluble.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to an aqueous solution of a 4,6- O -hydroxyphosphorylglucosamine derivative and a method of solubilizing it, and more specifically to 4,6- O -hydroxyphosphorylglucosamine derivative in the presence of meglumine, piperazine, polyamine or a basic amino acid. The present invention relates to an aqueous solution of a 4,6- O -hydroxyphosphorylglucosamine derivative, which comprises dissolving the O -hydroxyphosphorylglucosamine derivative in water, and a method for solubilizing the aqueous solution.

[0002]

2. Description of the Related Art The cell surface of Gram-negative bacteria is composed of a cell membrane, cell wall peptide glucans surrounding it, and an outer membrane, which is the main component of endotoxin-causing endotoxin. (Hereinafter, L
It is called PS).

[0003] LPS is composed of three parts, an acidic protein part, a high molecular polysaccharide part and a phospholipid part. In addition to the effects such as fever, hemorrhage, arthritis and encephalomyelitis, LPS is its host. Anti-tumor effect (IF-activating effect such as macrophage activating effect, B cell activating effect, cellular immune activating effect, etc.) and anti-tumor effect (IF
It is known to have N (interferon) inducing action, TNF (tumor necrosis factor) inducing action, etc.

The active expression center of LPS is a phospholipid part called lipid A among the above three parts, which has the following structure in which a fatty acid residue and a phosphoric acid are bound to a disaccharide amine. [Japanese Journal of Bacteriology 40 (1) , 5
7 (1985) and Proc. Natl. Acad.
Sci. USA 80 , 4624 (1983)].

[0005]

[Chemical 1]

According to recent research, various analogs having the same activity as lipid A have been synthesized, but the activity is largely different depending on the substituent and the site of introduction, and there are many problems such as high toxicity. Since it remains, a drug that can be put to practical use has not been developed yet. The inventors of the present invention also tried various syntheses in order to obtain a lipid A analog of low toxicity having a stronger activity, and particularly for a non-ring subunit derivative, a hydroxyphosphoryl group [> P (O)
[OH]] was introduced at the 4th and 6th positions, and many new derivatives were synthesized, including 4,6- O -hydroxyphosphorylglucosamine derivatives. As a result, they have found that these derivatives have strong activity similar to natural lipid A and low toxicity, and have already filed many patent applications (for example, WO91 / 16332, Japanese Patent Application No. 4-5012).
No. 1).

However, while these lipid A analogs have excellent activity as pharmaceuticals as described above, they are sparingly soluble or insoluble in water, and in particular, 4,6- O -hydroxyphosphorylglucosamine derivatives have a low polarity, and therefore are not soluble in water. Is insoluble, and a method for solubilizing it has been strongly desired. Regarding such a water-insoluble or insoluble lipid A analog, conventionally, as a solubilizing agent, for example, bovine serum albumin,
Although triethylamine and the like are used, they are not sufficient in terms of solubilizing ability, stability in preparation and safety, and have not been put into practical use (Eur. J. B.
iochem. 31, 230-233 (1972) and Microbiology-1977, 269-276.
(1977)). The present inventors have also conducted various studies to solve the above-mentioned problems regarding water solubilization of lipid A analogs and 4,6- O -hydroxyphosphorylglucosamine derivatives (Japanese Patent Application No. 2-322332, Japanese Patent Application No. 322332). Flat 4-
32890).

[0008]

The present inventors have found that 4,6-
As a result of earnestly researching a method for solubilizing the 4,6- O -hydroxyphosphorylglucosamine derivative using various solubilizing agents for the purpose of adjusting an aqueous solution of the O -hydroxyphosphorylglucosamine derivative, particularly an injectable preparation, meglumine, It was found that an aqueous solution of a 4,6- O -hydroxyphosphorylglucosamine derivative having excellent solubility, stability and safety can be obtained by using piperazine, polyamine, or basic amino acid as a solubilizing agent. The present invention has been completed. That is, an object of the present invention is to provide an aqueous solution of a 4,6- O -hydroxyphosphorylglucosamine derivative containing meglumine, piperazine, polyamine or a basic amino acid, and particularly a liquid agent such as an injection or an internal solution. The "4,6- O -hydroxyphosphorylglucosamine derivative" used in the present invention means the above-mentioned Escherichia coli (Escherichia C).
oli) -derived lipid A having a non-reducing moiety as a basic skeleton and a hydroxyphosphoryl group [> P (O) OH] of 4
The compounds introduced at the 6- and 6-positions include, for example, derivatives represented by the following general formula.

[0009]

[Chemical 2]

[In the formula, R ₁ is a hydrogen atom, a hydroxyl group, or -OC.
_{O (CH 2) l + 2} CH 3 or -OCOCH ₂ CH (OH)
(CH ₂ ) ₁ CH ₃ , R ₂ is a hydrogen atom or a hydroxyl group,
R _3, while the hydrogen atoms of R _4, a hydroxyl group, --OCO (C
_{H 2) m CH 3, -CH} 2 (CH 2) m CH 3, or -OCH ₂
(CH ₂ ) _m CH ₃ , the other is a hydrogen atom, and l is 6 to 14
, M is an integer of 6 to 18, n is an integer of 4 to 16, and p is an integer of 4 to 16. ]

More specifically, the following 4,6- O-
Examples thereof include hydroxyphosphoryl glucosamine derivatives, but the present invention is not limited to these derivatives. 1,5-anhydro-2-deoxy-4,6-O - hydroxy phosphoryl -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide} -3- O - {(2 R ) -2- tetradeca alkanoyloxy tetradecanoyl} - D - glucitol 1,5-anhydro-2-deoxy -3- O - {(2 R
S) -2- dodecyl hexa big Le}-4,6-O - hydroxy phosphoryl -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide} - D - glucitol 1,5-anhydro-2-deoxy - 3- O -{(2 R
S) -2- dodecyl tetra big Le}-4,6-O - hydroxy phosphoryl -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide} - D - glucitol 1,5-anhydro-2-deoxy - 3- O -{(2 R
S ) -2-Dodecanoyloxyhexadecanoyl} -2
- {(3 R) -3- hydroxy-dodeca cyanamide} 4,6
- O - hydroxy phosphoryl - D - glucitol 1,5-anhydro-2-deoxy -3- O - {(2 R
S ) -2-Hexadecanoyl oxide decanoyl} -2
-{( 3RS ) -3-hydroxyhexadecanamide}-
4,6-O - hydroxy phosphoryl - D - glucitol 1,5-anhydro-2-deoxy -3- O - {(2 R
S ) -2-dodecyloctadecyl} -2-{(3 R ).
-3-Hydroxydodecanamide} -4,6- O -hydroxyphosphoryl- D -glucitol 1,5-anhydro-3- O -{( 2RS ) -2-decyloctadecayl} -2-deoxy-2 -{(3 RS )
3-hydroxy-hexadecanol cyanamide}-4,6-O - hydroxy phosphoryl - D - glucitol 1,5-anhydro-2-deoxy-4,6-O - hydroxy phosphoryl -2 - {(3 R) -3 - hydroxy tetradecanoyl cyanamide} -3- O - {(3 R ) -3- tetradecanoyloxy-tetradecanoyl} - D - glucitol 1,5-anhydro-2-deoxy-4,6-O - hydroxy phosphoryl -2-{( 3R ) -3-hydroxytetradecanamido} -3- O -{( 3RS ) -3-undecylheptadecanoyl} -D -glucitol 1,5-anhydro-2-deoxy- 4,6-O - hydroxy phosphoryl -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide} -3- O - {(3 RS ) -3- tetradecyloxy Tet Decanoyl} - D - glucitol

1,5-anhydro-2-deoxy-2-
Dodekanamido -3- O - {(2 RS) -2- hexadecyl oxide decanoyl}-4,6-O - hydroxy phosphoryl - D - glucit - le 1,5-anhydro-2-deoxy-2-Dodekanamido -3 -O -{( 3RS ) -3-hexadecyloxidedecanoyl} -4,6- O -hydroxyphosphoryl- D-
Glucit - Le 1,5-anhydro-2-deoxy -3- O - {(3 R
S) -3- dodecyl hexadecanoyl} -2 Hekisadekanamido-4,6-O - hydroxy phosphoryl - D - glucit - le 1,5-anhydro-2-deoxy -3- O - {(2 R
S ) -2-Dodecyloxyoctadecanoyl} -2-
{(3 R ) -3-hydroxydodecanamide} -4,6-
O -hydroxyphosphoryl- D -glucitol-1,5-anhydro-3- O -{( 3RS ) -3-decyloctadecanoyl} -2-deoxy-2-{( 3R
S ) -3-Hydroxyhexadecanamide} -4,6- O
- hydroxy phosphoryl - D - glucit - le 1,5-anhydro-2-deoxy-2-Dodekanamido -3- O - {(2 RS) -2- dodecyloxy octadecanoyl}-4,6-O - hydroxy phosphoryl -D-
Glucit - Le 1,5-anhydro -3- O - {(3 RS) -3- decyl-octadecanoyl} -2-deoxy-2-Hekisadekanamido}-4,6-O - hydroxy phosphoryl - D - glucit - Le

[0013] 2-deoxy-4,6-O - hydroxy phosphoryl -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide} -3- O - {(2 RS ) -2- tetradecanoyloxy tetra decanoyl} - D - glucopyranose 2-deoxy -3- O - {(2 RS) -2- dodecyl hexadecanoyl}-4,6-O - hydroxy phosphoryl -2 - {(3 R) -3- hydroxy Tetradecanamid}
-D -glucopyranose 2-deoxy-4,6- O -hydroxyphosphoryl-2
-{( 3R ) -3-hydroxytetradecanamide} -3
- O - {(3 R) -3- tetradecanoyloxy-tetradecanoyl} - D - glucopyranose 2-deoxy-4,6-O - hydroxy phosphoryl -2
-{( 3R ) -3-hydroxytetradecanamide} -3
-O -{( 3RS ) -3-undecylheptadecanoyl} -D -glucopyranose 2-deoxy-3- O -{( 2RS ) -2-dodecylhexadecanoyl} -4,6- O- hydroxy phosphoryl-2 Tetoradekanamido - D - glucopyranose - scan 2-deoxy-2-Tetoradekanamido-4,6-O - hydroxy phosphoryl -3- O - {(2 RS) -2- tetradecanoyloxy-tetradecanoyl} - D - glucopyranose - scan deoxy -3- O - {(2 RS) -2- dodecyloxy hexadecanoyl}-4,6-O - hydroxy phosphoryl-2 Tetoradekanamido - D - glucopyranose - scan 2-deoxy - 3- O - {(3 RS) -3- dodecyl hexadecanoyl}-4,6-O - hydroxy phosphoryl-2 Tetorade Kanamido - D - glucopyranose - scan 2-deoxy-2-Tetoradekanamido-4,6-O - hydroxy phosphoryl -3- O - {(3 RS) -3- tetradecanoyloxy-tetradecanoyl} - D - glucopyranose - scan 2-deoxy -3- O - {(3 RS) -3- dodecyloxy-hexadecanoylamino}-4,6-O - hydroxy phosphoryl-2 Tetoradekanamido - D - glucopyranose - scan 2-deoxy-3-O - { (3 RS) -3- dodecyloxy hexadecanoyl} -2 - {(3 RS) -3- hydroxy-octadecadienoic cyanamide}-4,6-O - hydroxy phosphoryl - D - glucopyranose - scan

2-decanamid-1- O -decanoyl-2
-Deoxy-4,6- O -hydroxyphosphoryl-3-
O -tetradecanoyl-α- D -glucopyranose 3- O -decanoyl-2-deoxy-2-dodecanamid-1- O -dodecanoyl-4,6- O -hydroxyphosphoryl-α- D -glucopyranose 2-deoxy -3- O -Dodecanoyl-1- O -hexadecanoyl-4,6- O -hydroxyphosphoryl-2-
Tetradecanamid-α- D -glucopyranose 2-deoxy-3- O -dodecanoyl-4,6- O -hydroxyphosphoryl-2-octadecanamide-1- O-
Octadecanoyl-α- D -glucopyranose 2-decanamid-1- O -decanoyl-2-deoxy-
3- O - {(3 R) -3- hydroxy-hexadecanoyl}-4,6-O - hydroxy phosphoryl-.alpha.-D - glucopyranose 2 Dodekanamido-2-deoxy -3- O - {(3 R)
-3-Hydroxyhexadecanoyl} -4,6- O -hydroxyphosphoryl-1- O -tetradecanoyl-α-
D - glucopyranose 2-deoxy-2-Hekisadekanamido-1-O - hexadecanoyl -3- O - {(3 R) -3- hydroxy-octadecanoyl}-4,6-O - hydroxy phosphoryl -
alpha-D - glucopyranose 2-deoxy -3- O - {(3 R) -3- hydroxy-octadecanoyl}-4,6-O - hydroxy phosphoryl-2 Okutadekanamido-1-O - octadecanoyl -
α- D -glucopyranose

1- O -decanoyl-2-deoxy-3-
O - dodecanoyl -2 - {(3 R) -3- hydroxy-dodeca cyanamide}-4,6-O - hydroxy phosphoryl -α
- D - glucopyranose 3- O - decanoyl-2-deoxy-1-O - dodecanoyl -2 - {(3 R) -3- hydroxy-hexadecanol cyanamide}-4,6-O - hydroxy phosphoryl-.alpha.-D - glucopyranose 3- O - decanoyl-2-deoxy-1-O - hexadecanoyl -2 - {(3 R) -3- hydroxy-octadecadienoic cyanamide}-4,6-O - hydroxy phosphoryl-.alpha.-D
- glucopyranose 2-deoxy -2 - -4,6- {(3 R) -3- hydroxy-dec cyanamide} O - hydroxy phosphoryl-1-O -
Octadecanoyl-3- O -tetradecanoyl-α- D
- glucopyranose 1-O - decanoyl-2-deoxy -2 - {(3 R) -
3-Hydroxydodecanamide} -3- O -{( 3R )-
4,6 3-hydroxy-octadecanoyl} O - hydroxy phosphoryl-.alpha.-D - glucopyranose 2-deoxy-1-O - dodecanoyl -2 - {(3 R)
-3-Hydroxyhexadecanamide} -3- O -{(3
R ) -3-Hydroxyhexadecanoyl} -4,6- O
-Hydroxyphosphoryl-α- D -glucopyranose 2-deoxy-1- O -hexadecanoyl-3- O-
{(3 R ) -3-hydroxyhexadecanoyl} -2-
{(3 R ) -3-hydroxyoctadecanamide} -4,
6- O - hydroxy phosphoryl-.alpha.-D - glucopyranose 2-deoxy -2 - {(3 R) -3- hydroxy-dec cyanamide} -3- O - {(3 R ) -3- hydroxy-octadecanoyl} -4,6- O -Hydroxyphosphoryl-1
- O - octadecanoyl-.alpha.-D - glucopyranose 2-deoxy-3-O - dodecanoyl-2-Hekisadekanamido -1- O - {(3 R) -3- hydroxy-decanoyl}-4,6-O - Hydroxyphosphoryl-α- D -glucopyranose 2-deoxy-3- O -dodecanoyl-1- O -{(3
R ) -3-Hydroxydodecanoyl} -4,6- O -hydroxyphosphoryl-2-octadecanamide-α- D-
Glucopyranose

2-decanamid-3- O -decanoyl-2
- deoxy -1- O - {(3 R) -3- hydroxy-hexadecanoyl}-4,6-O - hydroxy phosphoryl -
alpha-D - glucopyranose 3- O - decanoyl-2-deoxy-2-Dodekanamido -1- O - {(3 R) -3- hydroxy-octadecanoyl}-4,6-O - hydroxy phosphoryl-.alpha.-D -Glucopyranose 2-deoxy-2-hexadecanamide-1- O -{(3
R ) -3-Hydroxydecanoyl} -3- O -{(3
R ) -3-Hydroxyoctadecanoyl} -4,6- O
- hydroxy phosphoryl-.alpha.-D - glucopyranose 2-deoxy -1- O - {(3 R) -3- hydroxy dodecanoyl} -3- O - {(3 R ) -3- hydroxy-octadecanoyl} -4 , 6- O - hydroxy phosphoryl-2 Okutadekanamido-.alpha.-D - glucopyranose 2 Dekanamido-2-deoxy -1- O - {(3 R) -
3-hydroxyhexadecanoyl} -3- O -{(3
R ) -3-Hydroxyhexadecanoyl} -4,6- O
- hydroxy phosphoryl-.alpha.-D - glucopyranose 2-deoxy -1- O - {(3 R) -3- hydroxy-octadecanoyl} -3- O - {(2 R ) -2- hydroxy-hexadecanoyl} - 4,6- O -Hydroxyphosphoryl-2-dodecanamide-α- D -glucopyranose 3- O -decanoyl-2-deoxy-1- O -{(3
R) -3- hydroxy-decanoyl} -2 - {(3 R) -
4,6 3-hydroxy-octadecadienoic cyanamide} O - hydroxy phosphoryl-.alpha.-D - glucopyranose 2-deoxy-3-O - dodecanoyl -2 - {(3 R)
-3-Hydroxydecanamid} -1- O -{( 3R )-
Hydroxy dodecanoyl}-4,6-3- O - hydroxy phosphoryl-.alpha.-D - glucopyranose 2-deoxy-3-O - dodecanoyl -2 - {(3 R)
-3-Hydroxydodecanamide} -1- O -{( 3R )
-3-hydroxy-hexadecanoyl}-4,6-O - hydroxy phosphoryl-.alpha.-D - glucopyranose 3- O - decanoyl-2-deoxy -2 - {(3 R) -
3-hydroxyhexadecanamide} -1- O -{(3
R ) -3-Hydroxyoctadecanoyl} -4,6- O
-Hydroxyphosphoryl-α- D -glucopyranose

2-deoxy-1- O -{(3 R ) -3-
Hydroxy decanoyl} -3- O - {(2 R ) -2- hydroxy-hexadecanoyl} -2 - {(3 R) -3- hydroxy-octadecadienoic cyanamide}-4,6-O - hydroxy phosphoryl -α - D - glucopyranose 2-deoxy -2 - {(3 R) -3- hydroxy-dec cyanamide} -1- O - {(3 R ) -3- hydroxy dodecanoyl} -3- O - {(3 R ) -3-Hydroxyoctadecanoyl} -4,6- O -hydroxyphosphoryl-
alpha-D - glucopyranose 2-deoxy -2 - {(3 R) -3- hydroxy-dodeca cyanamide} -1- O - {(3 R ) -3- hydroxy-hexadecanoyl} -3- O - {( 3 R) -3-hydroxy-octadecanoyl}-4,6-O - hydroxy phosphoryl-.alpha.-D - glucopyranose 2-deoxy -2 - {(3 R) -3- hydroxy-hexadecanol cyanamide} -3- O - {(3 R) -3- hydroxy-hexadecanoyl} -1- O - -4,6- {(3 R) -3- hydroxy-octadecanoyl} O - hydroxy phosphoryl-.alpha.-D - glucopyranose 2 -Deoxy-4,6- O -hydroxyphosphoryl-2
-Tetradecanamid-1- O -tetradecanoyl-3-
O -tetradecanoyl-α- D -glucopyranose 2-deoxy-4,6- O -hydroxyphosphoryl-3
- O - {(3 R) -3- hydroxy-tetradecanoyl}
-2-tetradecanamid-1- O -tetradecanoyl-
α- D -Glucopyranose 2-deoxy-4,6- O -hydroxyphosphoryl-2
-{( 3R ) -3-hydroxytetradecanamid} -1
- O - tetradecanoyl-3-O - tetradecanoyl -
α- D -Glucopyranose 2-deoxy-4,6- O -hydroxyphosphoryl-2
-{( 3R ) -3-hydroxytetradecanamide} -3
- O - {(3 R) -3- hydroxy-tetradecanoyl}
-1- O -Tetradecanoyl-α- D -glucopyranose 2-deoxy-4,6- O -hydroxyphosphoryl-1
- O - {(3 R) -3- hydroxy-tetradecanoyl}
-2-Tetradecanamide-3- O -tetradecanoyl-
α- D -Glucopyranose 2-deoxy-4,6- O -hydroxyphosphoryl-1
- O - {(3 R) -3- hydroxy-tetradecanoyl}
-3- O - -α- {(3 R ) -3- hydroxy-tetradecanoyl} -2 Tetoradekanamido D - glucopyranose 2-deoxy-4,6-O - hydroxy phosphoryl -2
-{( 3R ) -3-hydroxytetradecanamid} -1
- O - {(3 R) -3- hydroxy-tetradecanoyl}
-3- O -Tetradecanoyl-α- D -glucopyranose 2-deoxy-4,6- O -hydroxyphosphoryl-2
-{( 3R ) -3-hydroxytetradecanamid} -1
- O - {(3 R) -3- hydroxy-tetradecanoyl}
-3- O - {(3 R) -3- hydroxy-tetradecanoyl}-.alpha.-D - glucopyranose

The aqueous solution of the present invention may contain the 4,6- O -hydroxyphosphorylglucosamine derivative as fine particles such as colloids, as well as when it is completely made into an aqueous solution. Examples of the solubilizing agent used in the present invention include meglumine, piperazine, polyamines and basic amino acids. Of these, "polyamine"
Is a linear fatty acid hydrocarbon having two or more primary amino groups, and is an amine that exists in the living body. Specific examples include spermine, spermidine, putrescine and the like. In addition, examples of the "basic amino acid" include lysine, arginine and the like, and these amino acids can be used in the racemic form and the optical isomers in D-form or L-form.

[0019] These solubilizing agents 4,6-O - hydroxy phosphoryl glucosamine derivatives it is sufficient minimum necessary amount that can be dissolved using, for example, 4,6-O - to the hydroxy phosphoryl glucosamine derivative 1 part by weight, normally ,
In the case of meglumine, polyamine or basic amino acid, 3 parts by weight or more can be used, and in the case of piperazine, 10 parts by weight or more can be used. Generally, when preparing an aqueous solution of a 4,6- O -hydroxyphosphorylglucosamine derivative, an auxiliary agent such as a buffer, a surfactant, an isotonicity agent and an additive such as an antioxidant and a preservative are used. However, it is also possible to use only the solubilizer without using these auxiliary agents and additives. Furthermore, using these solubilizers,
The method of solubilizing the 4,6- O -hydroxyphosphorylglucosamine derivative is, for example, a method of directly mixing and dissolving the 4,6- O -hydroxyphosphorylglucosamine derivative and the solubilizing agent, or the solubilizing agent is previously made into an aqueous solution, A method in which a 4,6- O -hydroxyphosphorylglucosamine derivative or a 4,6- O -hydroxyphosphorylglucosamine derivative dissolved in an organic solvent is once evaporated to dryness in order to increase the solubility, and then mixed and dissolved in an aqueous solution. , Or a small amount of water containing organic solvent and solubilizer
- O - dissolved hydroxy phosphoryl glucosamine derivative, or 4,6-O - hydroxy phosphoryl glucosamine derivative in water was added after mixing was evaporated to dryness an aqueous solution of a small amount of solubilizing agent dissolved in an organic solvent solubility Methods and the like.

In the present invention, a pH adjusting agent may be used if necessary, and examples thereof include acidic amino acids such as aspartic acid and glutamic acid and gluconic acid, lactic acid, citric acid, oxalic acid, tartaric acid, succinic acid, malic acid and the like. Examples thereof include organic acids. These pH adjusting agents are appropriately selected and used according to the solubilizing agent to be used, but usually 4,6- O-
P of aqueous solution of hydroxyphosphoryl glucosamine derivative
It is desirable to use it so that H is 10 or less.
When preparing the aqueous solution of the 4,6- O -hydroxyphosphorylglucosamine derivative according to the present invention, various liquid preparations such as injectable preparations and oral liquid preparations can be prepared according to the method usually used in the art. .

The present invention will be described in more detail below with reference to Examples and Test Examples, but the present invention is not limited to these Examples. (Example 1) 1,5 in 1% meglumine aqueous solution (1 ml)
- anhydro-2-deoxy -3- O - {(3 R) -3
- dodecyloxy tetradecanoyl}-4,6-O - hydroxy phosphoryl -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide} - D - dissolving glucitol (1 mg), the mixture was stirred Bus (Bath) A solution was obtained after treatment with an ultrasonic wave generator. The pH was 11.

(Example 2) 1% meglumine aqueous solution (1 m
l) to 1,5-anhydro-2-deoxy-4,6- O
- hydroxy phosphoryl -2 - {(3 R) -3- hydroxy-tetradecanoyl cyanamide} -3- O - {(3 R ) -3- tetradecyl tetradecanoyl} - D - glucitol (1
mg) was dissolved, stirred and treated with a bath type ultrasonic generator to obtain a solution. The pH was 11.

(Example 3) 1,5-anhydro-2-deoxy-4,6- O -hydroxyphosphoryl- was added to a 1% meglumine aqueous solution (1 ml) to which an appropriate amount of glutamic acid was added.
2-{(3 R ) -3-hydroxytetradecanamido}-
3- O - {(3 R) -3- tetradecyl tetradecanoyl} - D - dissolving glucitol (1 mg), it was treated with stirring after the bus (Bath) type ultrasonic generator to give a solution. The pH was 9.8.

(Test Example 1) Method: Using the preparations obtained in Examples 1 to 3, changes with time at 4 ° C., room temperature and 37 ° C. were examined using thin layer chromatography (TLC). The TLC conditions were as follows. TLC plate: Whatman silica gel plate (2
With a concentration zone Developing solvent: Chloroform / methanol / water = 65
/ 25/4 Spot amount: 5 μl (Results) Even after 6 months from the preparation of each formulation, formation of another spot was not found.

[0025]

INDUSTRIAL APPLICABILITY The aqueous solution of the 4,6- O -hydroxyphosphorylglucosamine derivative prepared by using the solubilizing agent of the present invention exhibits excellent stability for a long period of time.

[0026]

[Brief description of drawings]

FIG. 1 is a diagram showing the results of thin layer chromatography for showing the stability of the solution of the present invention.

[Procedure amendment]

[Submission date] December 24, 1993

[Procedure Amendment 2]

[Document name to be corrected] Drawing

[Name of item to be corrected] Figure 1

[Correction method] Change

[Correction content]

[Figure 1]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 47/26 G // C07H 13/04 (72) Inventor Kenichi Sugimori Fukuura, Kanazawa-ku, Yokohama, Kanagawa 1-13-2 Japan Tobacco Inc. Pharmaceutical Research Institute

Claims (4)

[Claims] 1. A 4,6- O containing meglumine, piperazine, polyamine or a basic amino acid.
An aqueous solution of a hydroxyphosphoryl glucosamine derivative. 2. The aqueous solution of a 4,6- O -hydroxyphosphorylglucosamine derivative according to claim 1, wherein the polyamine is spermine, spermidine or putrescine. 3. The aqueous solution of the 4,6- O -hydroxyphosphorylglucosamine derivative according to claim 1, wherein the basic amino acid is lysine or arginine. 4. A method for solubilizing a 4,6- O -hydroxyphosphorylglucosamine derivative, which comprises adding meglumine,
In the presence of piperazine, polyamine or basic amino acid,
A method for solubilizing a 4,6- O -hydroxyphosphorylglucosamine derivative, which comprises dissolving in water. [0001]