JPS58121241A - Isoprenylcarboxylic acid clathrate compound - Google Patents

Abstract

PURPOSE:To prepare a clathrate compound of isoprenylcarboxylic acid useful as a carcinostatic agent and a remedy for psoriasis and having improved thermal stability of the medicine, by including the isoprenylcarboxylic acid with cyclodextrin. CONSTITUTION:The lowering of the titer of isoprenylcarboxylic acid of formula by the thermal oxidation is prevented, and the thermal stabilization of the compound can be achieved by forming a clathrate compound of the isoprenyl-carboxylic acid with cyclodextrin, especially gamma-cyclodextrin. The molar ratio of cyclodextrin to isoprenylcarboxylic acid is >=0.9, preferably 2-3 to 1.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an inclusion compound composed of isoprenylcarboxylic acid and cyclodextrin according to the present invention number ζ.

The isoprenyl carboxylic acid according to the present invention has the formula:

indicated by an-trsuus-3,7,11
,15-t@tram@thyl 2e 4t 6.1
0.14-heXadecapentaenoicac
id-1, and is expected to have medicinal uses as an anticancer agent and a treatment for psoriasis. however.

As is clear from its chemical structure, this substance is susceptible to oxidation, and in fact, as shown in the control sample in the experimental example below, it undergoes oxidation and its potency decreases.

In view of these circumstances, the inventors of the present invention have investigated various means for preventing oxidation of the substance concerned, and have presented the following results.

The present invention was completed after learning that a predetermined objective can be achieved by using a cyclodextrin-hosted clathrate compound.

In other words, the technology of stabilizing pharmaceuticals using cyclodextrins is already widely known,9 and it is most useful in stabilizing pharmaceutical compounds with aliphatic carbon chains, such as prostaglandins and ubidecarenone. It is known. However, its usefulness cannot be easily estimated for pharmaceuticals in general, and can only be achieved by finding appropriate methods for each individual pharmaceutical. In the application of the present invention to isoprenylcarboxylic acid, the invention was completed by adding a separate technology to the drug and confirming the formation of clathrate compounds and the resulting stability.

Next, the present invention will be explained.

The clathrate compound of the present invention is composed of the imprenylcarboxylic acid and cyclodextrin according to the present invention. Although any type of cyclodextrin may be used here, γ-cyclodextrin is particularly preferred.

In order to distinguish the clathrate compounds of the present invention from isoprenylcarboxylic acid itself or a mere mixture of isoprenylcarboxylic acid and cyclodextrin.

In particular, differential thermal analysis (DSG) will be shown in the examples below.
), is made possible by analyzing the results of X-ray diffraction and infrared absorption spectrum analysis. That is, first of all, the isoprenylcarboxylic acid according to the present invention itself exhibits a remarkable melting phenomenon at around (100°C), so it shows a clear endothermic pattern at psc.

In the clathrate compound of the present invention, since each molecule of isoprenylcarboxylic acid is already fixed in the clathrate compound, there is no need for endotherm and therefore no corresponding endothermic pattern is exhibited. Further, the isoprenylcarboxylic acid itself according to the present invention is in advanced crystallization.

However, it shows a remarkable diffraction pattern due to xm diffraction.

In the clathrate compound of the present invention, each molecule remains clathrated,
It is irregularly aggregated and shows an amorphous diffraction pattern.

9 In addition, the imprenylcarboxylic acid itself according to the present invention has an infrared absorption spectrum of 1590 as-1 and 1
It shows a characteristic absorption at 655 CI+-', but the clathrate compound of the present invention has a characteristic absorption at 1590 am-' and 1680 AM-', which shifts to the higher wave number side.

This is because isoprenylcarboxylic acid molecules form dimers by hydrogen bonding through their mutual carbonyl groups, whereas the imprenylcarboxylic acids in the clathrate compounds of the present invention are inhibited from forming hydrogen bonds with each other. It is presumed that this is because of this. Even in a simple mixture of imprenylcarboxylic acid and cyclodextrin, the results of DSC, X-ray diffraction, and infrared absorption spectrum are the same as those of imprenylcarboxylic acid itself, so DSC and X-ray diffraction are also applied.

It can be distinguished from the clathrate compounds of the present invention based on its infrared absorption spectrum.

For the production of the clathrate compound of the present invention, a conventional method for producing a clathrate compound may be carried out.

Therefore, 9 For example, an ethanol solution of imprenylcarboxylic acid and an aqueous cyclodextrin solution are mixed.

The mixture may be stirred at room temperature for 1 to 2 days, and the resulting precipitate of the clathrate compound may be collected and dried. In this case, it is appropriate to use cyclodextrin in a molar ratio of 1 or more, preferably 2 to 3 molar ratio, per 1 molar ratio of isoprenylcarboxylic acid.

The usefulness of the clathrate compound of the present invention is thermal stabilization of imprenylcarboxylic acid, and as shown in the experimental examples below, it is seen that it prevents isoprenylcarboxylic acid from undergoing oxidation when heated.

The present invention will be explained in detail using the following experimental examples.

Experimental Example 1 A clathrate compound produced by the method described in Sample Example 1 was used as a test sample. This sample was produced by the reaction of 1 molar ratio of imprenylcarboxylic acid according to the present invention and 2 molar ratios of γ-schizolodextrin. In addition, the contents of isoprenylcarboxylic acid and γ-cyclodextrin are the same as in the specimen sample.

A simple mixture of both was prepared and used as a control sample.

Method Samples were placed in the open at 45°C and 55°C for 3 days.

The samples were stored for 8 days and 16 days, and the remaining imprenylcarboxylic acid was measured by liquid chromatography. That is, after storage, 1*L of white birch (a 1.6% ethanol solution of di-n-amyl phthalate) was added to 30 μm of the sample, and the sample was heated to 25% with ethanol, exposed to F, and measured at 254 nm.

Results The results are shown in FIGS. 1 and 2. Figure 1 shows the change over time in the survival rate at 45°C. Figure 2 shows the change over time in the survival rate at 55°C.
The marked line indicates that of the control sample.

It is clear from FIG. 11 and FIG. 2 that the clathrate compound of the present invention increases the thermal stability of isoprenylcarboxylic acid.

Experimental Example 2 Sample and Method The γ-cyclodextrin used during preparation was in a 1 molar ratio, 2 molar ratio,
Three types of clathrate compounds having a molar ratio of 3 were prepared according to the method of Example 1 and used as samples.

Experiments were conducted on each sample according to the method described in the section of Experimental Example 1, Method.

Results The results are shown in Table IK. In the table, the numerical value within 0 indicates the survival rate with respect to the initial value. Table 1 shows that the required amount of γ-cyclodextrin is at least 0.9 molar ratio per 1 molar ratio of isoprenylcarboxylic acid.

The present invention will be explained in more detail with reference to the following examples.

Example 1 200 mg of imprenylcarboxylic acid according to the present invention was dissolved in 50 sL of ethanol, and separately, 1718N r-cyclodextrin was dissolved in 50 ml of water.The two were mixed and stirred at room temperature for 1 hour. Collect the formed precipitate.

Vacuum dried under phosphorus pentoxide. What is the molar ratio of γ-cyclodextrin used in this production?

The ratio is 2 molar to 1 molar of isoprenylcarboxylic acid.

DSC the obtained precipitate under the following conditions.

X-ray diffraction and infrared absorption spectrum analysis were performed.

DSC: Temperature increase rate 5℃/min, Range±4mc
alX-ray diffraction: Target Cm/Monochr
Infrared absorption spectrum: KBr method As a control, the contents of the imprenylcarboxylic acid itself and the imprenylcarboxylic acid and γ-cyclodextrin used in the present invention are the same as in the precipitate, and the same is true for a simple mixture. D.S.C.

X-ray diffraction and infrared absorption spectrum analysis were performed.

The results are shown in FIGS. 3 to 7. FIG. 3 is a graph showing the results of DSC. In the figure, the line indicated by symbol A is for the precipitate obtained in this example, and the line indicated by symbol B is for the isoprenyl carboxylic acid itself according to the present invention. The line indicated by symbol C is the isoprenyl carboxylic acid and γ-
The content of cyclodextrin is the same as in the precipitate, and the respective DSC results are shown for just the mixture.

Figure 4 shows an X-ray diffraction image of the precipitate obtained in this example; Figure 5 shows an X-ray diffraction image of the isoprenylcarboxylic acid itself according to the present invention; and Figure 6 shows an X-ray diffraction image of the isoprenylcarboxylic acid itself. and the content of γ-cyclodextrin is the same as in the precipitate.

3 is a graph showing X-ray diffraction images of simple mixtures.

FIG. 7 is a graph showing the results of infrared absorption spectrum analysis. In the figure, the line indicated by symbol A is for the precipitate obtained in this example, and the line indicated by symbol B is for the imprenyl carboxylic acid itself according to the present invention. , and the line indicated by the symbol C shows the results of the respective infrared absorption spectra of the isoprenylcarboxylic acid and γ-cyclodextrin in a simple mixture, the contents of which are the same as in the precipitate.

From Figures 3 to 7, it was found that in the precipitate obtained in this example, the intervention of γ-cyclodextrin inhibited the mutual aggregation of imprenylcarboxylic acid molecules and crystallization to a high degree. do.

Therefore, the precipitate contains imprenylcarboxylic acid and r-
It is an inclusion compound composed of cyclodextrin.

Example 2 The same procedure as described in Example 1 was carried out except that α-cyclodextrin was used instead of γ-cyclodextrin in Example 1.9 Isoprenylcarboxylic acid and α-cyclodextrin according to the present invention A clathrate compound composed of was obtained.

Example 3 The same procedure as described in Example 1 was carried out except that β-cyclodextrin was used instead of γ-cyclodextrin in Example 1. Imprenylcarboxylic acid and β-cyclodextrin according to the present invention A clathrate compound composed of was obtained.

[Brief explanation of the drawing]

Figure 19 Figure 2 corresponds to Figure 1 and Figure 2 described in the Results section of Experimental Example 1, and Figure 1 shows the change over time in the survival rate at 45°C, and Figure 2 shows the change over time in the survival rate at 55°C. It is a graph. FIG. 3 corresponds to FIG. 3 described in Example 1,
It is a graph showing the results of DSC in differential thermal analysis. 42, 52, and 6 correspond to FIGS. 41, 59, and 6 described in Example 1, and all of them are graphs showing X-ray diffraction images. FIG. 7 corresponds to FIG. 7 described in Example 1,
It is a graph showing a spectrum in infrared absorption spectrum analysis. Patent Application - Zai Co., Ltd. Figure 1 Storage days (at A5° (K) Figure 2 Storage days (qt 55”C) Figure 3 Figure 4 3Figure
5 ψ

Claims (3)

[Claims] (1) A clathrate compound composed of isoprenylcarboxylic acid and cyclodextrin represented by the formula (2) The clathrate compound according to claim 1, wherein the cyclodextrin is γ-cyclodextrin. (3) Claim 1 consisting of 1 molar ratio of isoprenylcarboxylic acid and 0.9 molar ratio or more of cyclodextrin.
clathrate compound according to item or item 2