JPS58999A - Proscillaridin-cyclodextrin clathrate - Google Patents

Abstract

NEW MATERIAL:A clathrate of proscillaridin with cyclodextrin. USE:A water-soluble and high-stability carbiotonic of proscillaridin. PREPARATION:For example, proscillaridine of the formula and a cyclodextrin such as gamma-cyclodextrin are dissolved in pure water with heat and the solution is cooled under stirring at room temperature for 24hr. Then, the precipitate formed is filtered off and heated to dryness under reduced pressure to give the objective clathrate. The resultant clathrate is added to an acidic solvent to examine its stability and the result is shown in the figure. Proscillaridin itself (black round points) and alpha-dextrin clathrate (white round points) are hydrolyzed with the acid and remain little, however, beta-cyclodextrin (triangle points) and gamma-cyclodextrin (square points) are resistant and remains in a large amount.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to cyclotextrin inclusion compounds, and more particularly to gross silaridin (Pros), which is useful as a cardiotonic agent.
The present invention relates to a gross silarinone-cyclodextrin clathrate compound that increases the water solubility of cylaridin and its stability.

Grosssillaridin (chemical name: 3β-((6-
zooxy-α-L-mannopyranosyl)-1
4-)', droxypfer 4,20°22-)lienolide) is a cardiac glycoside (molecular weight: 530.66, odorless) obtained from lll[(5cilla@Bulbua), which increases myocardial contractility. It is known to be a useful compound that reduces heart rate and has secondary effects such as improving blood pressure and diuretic effects.

However, gross silaridin is uniportable in water;
Furthermore, the sugar moiety is hydrolyzed in stomach acid, and the above-mentioned effects are significantly reduced. Therefore, it is strongly desired to improve the water solubility and stability of fy sudiraridine.

The present inventors have conducted extensive research to eliminate the above-mentioned drawbacks regarding proscillaridin, and as a result, a cyclotextrin clathrate compound consisting of grosscillaridin and cyclodextrin has been found to be similar to proscillaridin. The present invention was completed based on the discovery that the solubility and stability of the compound can be improved without reducing its efficacy.

That is, the present invention focuses on the cyclotextrin clathrate of Fi-prossilaridin.

The cyclodextrin used in the present invention is obtained by acting on amylase of species that produce starch. It is a compound having a cyclic structure in which one or more D-glucose units are bonded through α-1,4 glycosidic bonds. There are three types of cyclodextrins, α-2β- and γ-, depending on the number of D-glucose constituent units. In the present invention, these α-9β- or γ-cyclodextrins, or a mixture thereof, are preferably -or r-
is used.

There are various methods for clathration, but a solution method and a kneading method are preferred.

In the solution method, Kf gross silaridin alone or mixed with water is added dissolved in a saturated organic solvent such as methanol, ethanol, acetone, etc. at 10 to 90°C, preferably at t120 ~60℃
The mixture is stirred for 4 to 24 hours, preferably for 5 to 10 hours, to obtain the clathrate compound as a precipitate. If necessary, unreacted substances are washed away with a solvent that can dissolve Zorosdiraridine. As the solvent at this time, methanol, ethanol, acetone, etc. are used. There is no particular restriction on the amount of proscillaridin used, but if the amount used is small, the clathrate compound will be obtained only in an amount proportional to the gross silaridin added, and if it is large, the amount of clathrate compound will be proportional to the amount of cyclodextrin. Only a small amount of the clathrate can be obtained, and it is necessary to separate it from unreacted products.

Therefore, the amount of proscillaridin should be in proportion to the inclusion ratio with cyclodextrin, and is suitably less than the number of moles of cifrobukis in the aqueous solution, preferably 0.05~. 0.5 times the mole is appropriate.

In the kneading method, add cyclodextrin KO, 5 to 3 times the amount of water to make it yeast-like, add the equivalent amount of telos silage introduced in advance to the container, and mix in a mortar, a sieve machine, etc. After kneading at 10 to 80°C, preferably 20 to 60°C for 2 to 8 hours, preferably 3 to 5 hours,
Dry to obtain a powdered clathrate compound. By adding proscillaridin in an amount corresponding to the composition of the intended clathrate compound, 100% inclusion of bald spots can be achieved. In addition, it is of course possible to perform screening in the same manner as the solution method. The composition of the clathrate is infrared @ absorption (IR).

Confirmed by various means such as Xa diffraction.

The cyclodextrin clathrate of proscillaridin obtained by the above method is a white microcrystalline powder.
Even in acidic solvents (eg, stomach acid), the sugar moiety of proscillaridin is inhibited from being hydrolyzed, increasing its stability, and its solubility in water is also significantly increased.

For example, Fig. 1 shows only gross sillaridin (marked with ・) and the α-
Cyclodextrin clathrate compound (5X 10-5M, ○
(mark) β-cyclo r kistrin inclusion compound of proscillaridin (5X 10-''M, △ mark) and γ-cyclodextrin inclusion compound of grosscilaridin (5X 10-'
This figure shows the change over time in the residual rate (%) of gross silaridin in four types of compounds (marked with M and square).
! As is clear from J, the residual rate after 90 minutes is approximately 7% for gross sillaridin alone, and for proscillaridin-β.
- Cyclodex) + 3-n clathrate compound 100%
, in the case of the proscillaridin-r-cyclodextrin clathrate compound, it is 95%, and the decomposition of grosscillaridin is greatly suppressed.

In addition, Figure 2 shows proscillaridin, α- (○ mark), and β-
(△ mark) and γ~ (marker) It is a solubility phase diagram with cyclodextrin. It can be seen that the solubility of proscillaridin is greatly improved by inclusion in dextrin. Prossillaridin 0.02 mol/l
By inclusion in γ-cyclodextrin, 12
It was found that the solubility was improved by 10 times by inclusion in β-cyclotetradextrin of 0 times and 0.002 mol/l.

In the clathrate compound of the present invention, 1 mole of gross silaridin molecule and cyclodextrin molecule is 20 moles for α-cyclodextrin clathrate, 1.2 mole for β-cyclodextrin clathrate, and 1.2 mole for β-cyclodextrin clathrate compound. 1 mol = 1.8 to 2.2 mol, γ-cyclodextrin capsule 1 for the junction compound
For 4 compounds, 1 mol: 1.8 to 2.2 mol.

As described above, the cyclodextrin clathrate compound of proscillaridin of the present invention has excellent solubility and stability without reducing the efficacy of zolosdiraridine, and therefore can be expected to improve its physiological usefulness. It is.

The present invention will be explained in more detail below based on examples.

Example 1 Gross silaridin 7.5 f/(1,41X 10-
2 mol) and γ-cyclodextrin 51.8/i (
4,OX (10-2 mol) was dissolved in purified water 1000+4 with heating, and the mixture was stirred at room temperature for 24 hours. The resulting precipitate was counted and dried under reduced pressure at about 50°C for 8 hours to obtain 37.8 g of the desired product.
I got it. The target product was dissolved in a 1/1 mixture of water/ethanol and the absorbance at 2 parts of ultraviolet (215 nm) K was measured to determine the inclusion ratio of 1 proscillaridin to γ-cyclodextrin, which was 1 mol to 2 mol. Met.

Measurement of infrared absorption spectra and X! Measurement of 1st diffraction (
4,0000P 8. glass cell). 3rd v result! J and shown in FIG.

In the figure, (IL) is the clathrate compound of the present invention, Φ)Fi
It was observed that 1 mole of proscillaridin and 2 γ-cyclodextrin were shifted to 17082-' due to inclusion. In addition, X-ray diffraction measurements revealed a pattern of a 1 mol to 2 mol mixture showing characteristic absorption of both gross silaridin and γ-cyclodextrin (unlike (b) Nori →, pattern (a) shows characteristic absorption of both gross silaridin and γ-cyclodextrin). 11g, which is also an clathrate compound, shows a unique pattern.
1g is possible.

Melting point If1 of the clathrate compound of the present invention obtained in this example
The temperature was 290°C or higher (decomposition). Further, the dissolution rate in water at 25° C. was measured by a rotating disk method in comparison with that of 7o sudiraridine. The results are shown in FIG. 5 and Table 1.

The dissolution rate of the clathrate compound of the present invention in water is:

6.4 times that of proscillaridin alone,
It was found that it dissolves quickly.

Example 2 Gross Silarisin 250ji (4,72X 10-s
mol) and β-cyclodextrin 22.7 g (2,0
After heating and dissolving 1,000,1117 of purified water (100011117 mol), the solution was stirred at room temperature for 24 hours. The resulting precipitate P
The target product 12.9 was removed and dried for 8 hours at about 50°C under reduced pressure.
I got g. The target product was dissolved in a water/ethanol mixture of 1/l and the absorption order in the ultraviolet/external wavelength (215 nm) was measured to determine the inclusion ratio of prosdillarinone to β-cyclodextrin, which was found to be 1 mole to 2 moles. Ta. Infrared @ yield spectrum measurement and xm diffraction measurement (4,000 CPS
, glass cell). The results are shown in FIGS. 6 and 7, respectively. In the figure, (a) represents the clathrate compound of the present invention, and (b) represents an m-compound of 1 mole of proscillaridin and 2 moles of β-cyclodextrin.

In the infrared absorption spectrum, it is based on the carbonyl at position 24.
The absorption of 17180II-' is due to inclusion of 1703
A shift towards cIL-凰 was observed. Also, X
11! Diffraction measurements also revealed that gross silaridin and β
-Cyclodex) Unlike the pattern of the 1 molar to 2 molar mixture ((b), Zetane), which shows characteristic absorption of both IJ and IJ, the pattern (a) showed a pattern peculiar to the clathrate compound of the present invention. The melting point of the compound was 11,290°C or higher (decomposition), and its solubility in water at 25°C was measured in comparison with that of proscillaridin in the same manner as in Example 1. The results are shown in Figure 8 and Table 2. Ta.

Table 2 The dissolution rate of the clathrate compound of the present invention in water was 3.3 times that of crosssilaridine alone.

[Brief explanation of drawings]

#11 [t, Zorosdiraridine alone in acidic solvent (・
Time variation of the residual rate (%) of gross sillaridin in each α-(○ mark), β-(△ mark)′)j and γ-(mouth part) cyclodextrin clathrate compounds of gross sillaridin ．．
FIG. Figure 2 shows gross silaridin and α-(
It is a solubility phase diagram of β-(marked with △), and γ-(marked with lI) cyclodextrin. FIG. 3 and FIG. 4 respectively show gross silaridin of the present invention.
1 is an infrared absorption spectrum and an XIN diffraction pattern of a mixture of an r-cyclodextrin clathrate compound, 1 mole of gross silaridin, and 2 moles of γ-cyclo rkistrin. FIG. 5 is a graph showing the results of the analysis of the 10-sdiraridine-γ-cyclodextrin clathrate compound of the present invention (mouth part) and gross sillaridin (indicated by .) by the rotating disk method (in water, 25°C). be. FIG. 6 and FIG. 7 respectively show proscillaridin of the present invention.
These are red Tato absorption spectra and X-ray diffraction patterns of a β-cyclodextrin clathrate compound and a mixture of 1 mol of gross silaridin and 2 mol of β-cyclof kistrin. FIG. 8 is a graph showing the dissolution behavior (in water, 25° C.) of the gross silaridin-I-cyclodextrin clathrate compound of the present invention (triangle mark) and proscillaridin (mark) by a rotating disk method.

Claims (1)

[Claims] A proscilaridin-cyclotextrin clathrate compound comprising glycillaridin and cyclodextrin.