JP2714412B2 - Injection containing polyprenyl compound - Google Patents

Description

The present invention relates to an injection containing a polyprenyl compound.

[Problems to be solved by conventional technology and invention] (Where R is A group represented by A group represented by, or Means a group represented by

n means an integer of 1 to 10. The polyprenyl compound represented by the formula (1) acts as a preventive or therapeutic agent for a disease caused by immune dysfunction in humans or animals. In particular, it is effective as a protective agent against human or animal infectious diseases, and is disclosed in JP-A-58-206517, JP-A-58-225014, and JP-A-59-225014.
73513, 59-73533, already known,
It is usually administered as an injection.

Among the polyprenyl compounds, injections of polyprenyl alcohol are prepared using lecithin (JP-A-62-169725).
No. 1), and its durability is 4 to 5 days. However, for the prevention and treatment of diseases due to immune dysfunction for animals, it is necessary to administer to a large number of animals. Development is desired.

[Means for solving the problem]

The present inventors have studied the long-acting preparations for many years, and as a result, by adding cyclodextrin or a derivative thereof to a polyprenyl compound to form a suspension injection, a predetermined improvement in sustainability is achieved. In addition, they have found that the immune protective effect can be enhanced, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula (I): (Where R is A group represented by A group represented by, or Means a group represented by

n means an integer of 1 to 10. The present invention provides a polyprenyl compound-containing injection comprising, as essential components, a polyprenyl compound represented by the formula (1) and cyclodextrin or a derivative thereof.

 Hereinafter, the present invention will be described in detail.

In the present invention, the polyprenyl compound is a compound represented by the general formula (I), and specific examples thereof include the following compounds.

Here, n represents an integer of 1 to 10, preferably 5
~ 7.

Representative compounds of the polyprenyl compounds in the present invention are listed below, but it goes without saying that the present invention is not limited to these.

3,7,11,15,19,23,27-Heptamethyl-2,6,10,14,18,22,
26-octacosaheptaen-1-ol (hereinafter referred to as compound A).

3,7,11,15,19,23-Hexamethyl-6,10,14,18,22-tetracosapentaen-1-ol (hereinafter referred to as compound B).

3,7,11,15,19,23,27-Heptamethyl-6,10,14,18,22,26
-Octacosahexaen-1-ol (hereinafter referred to as compound C)
And).

3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,2
2,26,30-Dotriacontaheptaen-1-ol (hereinafter, referred to as compound D).

6,10,14,18,22,26-Hexamethyl-5,9,13,17,21,25-
Heptacosahexaen-2-one (hereinafter, referred to as compound E).

The cyclodextrin used in the present invention is obtained by hydrolyzing starch with an acid or an amylase. Depending on the degree of polymerization, α- (degree of polymerization 6), β- (degree of polymerization 7), γ- (degree of polymerization 8 Dextrin (Pharmaceutical Magazine, 101,857 (1981), JP-A-53-31223). In the present invention, a cyclodextrin derivative obtained by subjecting cyclodextrin to treatment such as alkylation can also be used. These cyclodextrin derivatives include, for example, carboxylmethylethylcyclodextrin, diethylcyclodextrin and the like.
Cyclodextrin and its derivatives are a kind of cyclic oligosaccharide, and generate an inclusion compound with a fat-soluble drug as a monomolecular host molecule having a hydrophobic cavity in the molecule.

Among the cyclodextrins or derivatives thereof used in the present invention, β-cyclodextrin and γ-cyclodextrin are particularly preferred.

In order to produce the injection of the present invention, the above-mentioned polyprenyl compound is first encapsulated with cyclodextrin or a derivative thereof. As a method for inclusion by cyclodextrin or a derivative thereof, a kneading method and a dissolution method are generally known, and any of the methods can be used for inclusion in the present invention. As a specific example of the clathration, there is a method in which a polyprenyl compound and a cyclodextrin or a derivative thereof are added to and mixed with distilled water, and the other components and distilled water are added thereto to uniformly disperse. Injections may be filled in predetermined ampules and vials and sterilized. It is more preferable that this operation is performed under aseptic conditions.

The compounding amount of the polyprenyl compound and cyclodextrin or a derivative thereof in the injection of the present invention is preferably 1 to 10 mol, more preferably 1 to 4 mol, of cyclodextrin or a derivative thereof per 1 mol of the polyprenyl compound.

In the present invention, when manufacturing an injection for medical use, as other compounding components, auxiliary components usually used in addition to the above essential components, for example, buffers such as sodium citrate and sodium phosphate, sodium chloride And sorbitol, etc., and a dispersing agent such as carboxymethylcellulose, methylcellulose and the like can be freely selected.

The injection of the present invention showed a remarkable effect on immunoprotection as shown in the following experimental examples.

〔The invention's effect〕

Hereinafter, the effects of the present invention will be described in detail in experimental examples.

Experimental Example 1 β-cyclodextrin or γ-cyclodextrin of each weight g shown in Table 1 was mixed with 2 g of each of compounds A, C, and E, mixed, and kneaded for about 30 minutes by adding 20 to 50 ml of distilled water.
Further, 5 g of D-sorbitol and distilled water were added to make 100 ml, filled in a 10 ml ampoule with stirring, further subjected to nitrogen replacement, sealing, and sterilization with flowing steam for 60 minutes. Is prepared.

100 mg / kg of each sample was added to slc: ICR male mice 5 weeks old (25-3
0g) Administered intramuscularly to 10 mice per group, 7 days and 14 days later, subcutaneously inoculated Escherichia coli (Escherichia coli KC-14) into 2.8 × 10 ⁸ CFU / mouse. The remaining rate was determined and the continuity was confirmed.

A sample was prepared by emulsifying and dispersing 2% of each of compounds A, C, and E using an ultrasonic emulsifying apparatus using 1.5% of purified soybean lecithin and 5% of glycerin and isotonicized with sorbitol as a control.

 Table 1 shows the results.

As is clear from Table 1, the injection of the present invention improves the in vivo use of the polyprenyl compound of the present invention.

Experimental Example 2 β or γ of each weight g shown in Table 2 with respect to 1 g of compound C
Take cyclodextrin, mix and add 20-50 ml of distilled water and knead for about 30 minutes. Further, 5 g of D-sorbitol was added to distilled water to make 100 ml, and filled into a 10 ml ampoule with stirring.
Furthermore, nitrogen replacement, sealing, and steam sterilization for 60 minutes are performed, and if necessary, each sample is prepared by cooling while shaking in water.

6.25 mg / kg, 12.5 mg / kg, 25 mg / kg, 50 mg / kg,
100mg / kg slc: ICR male mice 5 weeks old (25-30g) 1 group 10
The mice were administered intramuscularly, and after 24 hours, E. coli (Escherichia co.
liKC-14) was subcutaneously inoculated into 2.8 × 10 ⁸ CFU / mouse, and the ED ₅₀ (mg / kg) was determined from the number of survivors 7 days after infection.

 Table 2 shows the results.

As is clear from Table 2, the injection of the present invention improves the in vivo use of the polyprenyl compound of the present invention.

〔Example〕

Hereinafter, the present invention will be described in more detail by examples,
The present invention is not limited to these examples.

Example 1 2 g of compound A and 15 g of γ-cyclodextrin were mixed, and 50 ml of distilled water was added and kneaded for about 30 minutes, and 5 g of D-sorbitol was added.
Add 0.05 g of citric acid and distilled water to make 100 ml, adjust to pH 7.2 with aqueous sodium hydroxide solution, further stir to make uniform, 1 ml
The ampoule was filled, replaced with nitrogen, sealed, and sterilized with flowing steam for 60 minutes to obtain an injection.

Example 2 1 g of compound B and 9 g of β-cyclodextrin were mixed, 30 ml of distilled water was added, and the mixture was kneaded for about 30 minutes.
Add 0.05 g of citric acid and distilled water to make 100 ml, adjust to pH 7.2 with aqueous sodium hydroxide solution, further stir to make uniform, 1 ml
The ampoule was filled, replaced with nitrogen, sealed, and sterilized with flowing steam for 60 minutes to obtain an injection.

Example 3 1 g of compound C and 10 g of β-cyclodextrin were mixed, kneaded with 30 ml of distilled water and kneaded for about 30 minutes. 0.9 g of sodium chloride and distilled water were added to make 100 ml, and the mixture was stirred to make uniform, filled in a 20 ml ampoule, and replaced with nitrogen. Then, the mixture was sealed and sterilized with flowing steam for 60 minutes to obtain an injection.

Example 4 Compound C (0.1 g) and β-cyclodextrin (1.2 g) were mixed, distilled water (4 ml) was added, and the mixture was kneaded for about 30 minutes. The mixture was then purged with nitrogen, sealed, and sterilized with flowing steam for 60 minutes to obtain an injection.

Example 5 Compound C (2 g) and gamma-cyclodextrin (15 g) were mixed, distilled water (40 ml) was added, and the mixture was kneaded for about 30 minutes.
25 ml of a 0.4% carboxymethylcellulose aqueous solution and distilled water were added to make 100 ml, and the mixture was stirred and made uniform. The mixture was filled in a 10 ml vial, replaced with nitrogen, closed with a rubber stopper, and sterilized with flowing steam for 60 minutes to obtain an injection.

Example 6 Compound C1g and β-cyclodextrin 7.5g were mixed,
Add 30 ml of distilled water, knead for about 30 minutes, and add D-sorbitol 5
g, 0.05 g of citric acid and distilled water were added to make 100 ml, adjusted to pH 7.2 with an aqueous sodium hydroxide solution, further stirred and homogenized, filled in a 1 ml ampoule, purged with nitrogen, sealed, and sterilized with flowing steam for 60 minutes. The injection was obtained.

Example 7 Compound D2g and γ-cyclodextrin 12g were mixed, distilled water 50ml was added and kneaded for about 30 minutes, D-sorbitol 5g,
Add 0.05 g of citric acid and distilled water to make 100 ml, adjust to pH 7.2 with aqueous sodium hydroxide solution, further stir to make uniform, 1 ml
The ampoule was filled, replaced with nitrogen, sealed, and sterilized with flowing steam for 60 minutes to obtain an injection.

Example 8 Compound E1g and β-cyclodextrin 9.5g were mixed,
Add 30 ml of distilled water, knead for about 30 minutes, and add D-sorbitol 5
g, 0.05 g of citric acid and distilled water were added to make 100 ml, adjusted to pH 7.2 with an aqueous sodium hydroxide solution, further stirred and homogenized, filled in a 1 ml ampoule, purged with nitrogen, sealed, and sterilized with flowing steam for 60 minutes. The injection was obtained.

Example 9 0.1 g of compound C and 3 ml of a 40% β-cyclodextrin suspension each sterilized by a membrane filter and high-pressure steam sterilization were kneaded by an aseptic method for about 30 minutes, and further sterilized by high-pressure steam sterilization. After adding 50 ml of the 10% sorbitol solution and distilled water to make 100 ml, the mixture was stirred and homogenized, filled in a 1 ml ampoule, replaced with nitrogen, and sealed to obtain an injection.

Claims (1)

(57) [Claims] (1) General formula (Where R is A group represented by A group represented by, or Means a group represented by n means an integer of 1 to 10. (3) An injection containing a polyprenyl compound, which comprises the polyprenyl compound represented by the formula (1) and cyclodextrin or a derivative thereof as essential components.