JPH0253427B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cyclodextrin clathrate compounds, more particularly 4-(4-biphenyl)-
The present invention relates to a cyclodextrin clathrate compound in which the solubility of 4-oxobutyric acid in water is increased and the absorbability from the gastrointestinal tract is increased.

4-(4-biphenyl)-4-oxobutyric acid, named fenbufen by the International Common Name (WHO), is a non-steroidal anti-inflammatory,
It is widely used around the world as an analgesic and antipyretic (hereinafter referred to as fuenbufuene).

However, since fenbufuene is poorly soluble in water, its therapeutic scope is limited, and in order to fully utilize its usefulness, further improvement in solubility and absorbability is desired.

As a result of intensive research aimed at improving these, the present inventor found that the huenbufuene-cyclodextrin clathrate compound improves the solubility of huenbufuene in water and improves its absorption from the gastrointestinal tract without reducing the efficacy of huenbufuene. The present invention was completed based on the discovery that this can improve the human's sexual orientation.

The fuenbufuene used in the present invention has the formula It is a white crystalline powder with a molecular weight of 254.28 and a melting point of 187°C (decomposed), and is odorless. Its solubility is slightly soluble in acetone, sparingly soluble in glacial acetic acid, methanol, ethanol, chloroform and ether, very sparingly soluble in benzene, and almost insoluble in water and petroleum ether.

The cyclodextrin used in the present invention is a compound having a cyclic structure in which 6 to 8 or more D-glucose units are bonded through α-1,4-glycosidic bonds, which is obtained by acting amylase on starch or dextrin. Inside diameter 6
It has a cavity of ~10 Å. Cyclodextrin has α-
There are three types, i.e., α-type, β-type, and γ-type, each having a different diameter of the cavity inside the molecule.In the present invention, these α-type, β-type, or γ-type, or a mixture thereof Either may be used.

Inclusion can be carried out by various methods known per se; for example, methods such as a solution method and a kneading method are usually suitable.

In the case of the solution method, an aqueous solution of cyclodextrin,
Preferably, to a saturated aqueous solution, the fenbufen is added as such or as a solution of the fenbufen dissolved in a water-miscible organic solvent such as acetone, and at a temperature of about 10 to about 90°C, preferably about 20 to about 60°C. By stirring for several hours to several days, preferably for about 4 hours to about 1 day, fenbufen-
A cyclodextrin clathrate is obtained as a precipitate. After the clathrate precipitate is separated, acetone, methanol, ethanol,
Wash and purify using a solvent such as ether. The amount of bufuene to be used is not particularly limited and can be varied widely depending on the type of cyclodextrin, etc., but in general, it is appropriate to use an equimolar amount or less to the cyclodextrin used, and more preferably an amount equal to or less than 1 mole of cyclodextrin. On the other hand, it is appropriate to use 0.05 to 0.5 times the mole of fenbufuene.

On the other hand, in the case of the kneading method, 0.5 to 5 times the weight of water is usually added to cyclodextrin to form a paste, and an amount of fenbufuene powder approximately equivalent to the clathrate equivalent that has been confirmed in advance is added to the paste. Thoroughly knead using a grinder, mortar, etc. The kneading temperature is not particularly limited, and room temperature is sufficient, and the kneading time is usually 2 to 24 hours, preferably 4 to 12 hours. Dry the paste after kneading,
A powdered clathrate compound is obtained. Thus, by using fenbufuene corresponding to the composition of the desired clathrate compound, a fenbufen-cyclodextrin clathrate compound can be obtained in a nearly quantitative yield. The clathrate compound thus obtained can be further purified, if necessary, in the same manner as in the solution method.

The formation of clathrate compounds can be confirmed in solution by polarization dichroism; spectral means such as ultraviolet absorption and nuclear magnetic resonance absorption; and solubility phase diagram. For example, the attached Figure 1 shows the circular dichroism (CD) of fenbufuene alone and fenbufuene-cyclodextrin clathrate in phosphate buffer.
(Figure 1-a) and ultraviolet absorption spectrum (UV)
(Fig. 1-b), the appearance of positive and negative induced bands in Fig. 1-a, and the appearance of fenbufuene by cyclodextrin in Fig. 1-b.
A decrease in UV absorption intensity suggests the formation of clathrates in aqueous solution. In addition, in the solid state, spectral means such as X-ray diffraction and infrared absorption;
This can be confirmed by differential thermal analysis or the like (see FIGS. 6 and 7).

The ratio of fenbufuene and cyclodextrin in the clathrate compound of the present invention is as follows: fenbufuene:α-cyclodextrin=1
Mol: 1.9-2.1 mol Fenbufuene: β-cyclodextrin = 1
Mol: 0.8 to 1.2 mol Fenbufuene: γ-cyclodextrin = 1
Mol: 0.9 to 1.1 mol The fenbufuene-cyclodextrin clathrate compound provided by the present invention has excellent solubility and dissolution rate in water.

Figure 2 shows Fuenbufuen, α- (○ mark), β-
This is a solubility phase diagram with cyclodextrin (triangle mark) and γ- (● mark), and it is observed that the solubility of fenbufuene is significantly improved by inclusion. In other words, the solubility of fenbufuene in water is 0.08 mol/
The improvement is about 5 times by inclusion in α-cyclodextrin, about 11 times by inclusion in 0.02 mol/β-cyclodextrin, and about 2 times by inclusion in 0.01 mol/γ-cyclodextrin. .

In addition, Figure 3 shows Fuenbufuen and α− (○ mark)
The dissolution behavior of clathrate compounds with and γ- (●) cyclodextrin and fenbufuene alone (□) in water at 25°C was measured using the powder method, and it was found that the dissolution rate increases significantly in the case of clathrate compounds. I understand that.

Furthermore, Figure 4 shows Fuenbufuen and α- (○ mark)
and γ- (marked with ●) for inclusion compounds with cyclodextrin and fenbufuene alone (marked with □),
A 2 g suppository containing 5 mg of fenbufuene was prepared, and the release behavior of fenbufuene into physiological saline was investigated using a suppository release tester.
It can be seen that inclusion increases the release rate.

Due to the improved solubility of the fenbufuene-cyclodextrin clathrate compound of the present invention, the blood concentration increases significantly when administered orally, and the bioavailability improves.

For example, FIG. 5 is a graph showing the relationship between time and plasma fenbufuen concentration when α-cyclodextrin clathrate compound and fenbufuen alone were administered as 30 mg/kg of fenbufuen to a rabbit. As is clear from FIG. 5, the clathrate compound increases the blood concentration of fenbufuene by about 5 times compared to administration of fenbufuene alone, and a remarkable improvement in absorption is observed.

The huenbufuene-cyclodextrin clathrate compound of the present invention has the above-mentioned excellent physicochemical and physiological advantages. It can be applied to dry syrups,
In addition, an increase in blood concentration brought about by improved absorption during oral administration can improve safety by reducing the dose, and an increase in the release rate of fuenbufuene in suppositories. It is expected that the therapeutic usefulness of fuenbufuene will be improved, such as by enabling the use of fuenbufuene. It is also considered to be an advantage that inclusion reduces the pungent taste of fenbufuene.

For example, the currently marketed and used fenbufuene preparations include one capsule or tablet containing
However, according to the present invention, a formulation of the fuenbufuene-cyclodextrin clathrate compound (433.1 mg) of the present invention containing 50 mg of fuenbufuene in one capsule or tablet has been developed, and the therapeutic usefulness has been demonstrated. is highly anticipated.
Examples of the formulation are shown below.

Formulation example 1 Capsule (50 mg/cap.) Fuenbufuene-α-cyclodextrin clathrate compound (50 mg as huenbufuen) 433.1 mg Corn starch 160.9 mg Magnesium stearate 6.0 mg 600.0 mg Excipients are added to the clathrate compound to form a powder. Leave it as is (or make it into granules), add a lubricant, and fill it into hard capsules.

Formulation example 2 Tablet (50mg/tab) Fuenbufuene-α-cyclodextrin clathrate (50mg as Fuenbufuen) 433.1mg Crystalline cellulose 43.9mg Corn starch 48.0mg Calcium/carboxymethylcellulose 60.0mg Hydroxypropyl cellulose 12.0mg Magnesium stearate 3.0mg 600.0 After adding an excipient, a disintegrant, and a binder to the clathrate compound and mixing them evenly, it is made into granules, and then a lubricant is added and compression molded.

Formulation Example 3 Granules (50 mg/g) Fuenbufuen-α-cyclodextrin clathrate compound (50 mg as Fuenbufuen) 433.1 mg Corn starch 100.0 mg Lactose 436.9 mg Hydroxypropylcellulose 30.0 mg 1000.0 mg The present invention will be further illustrated by Examples below. Explain in detail.

Example 1 0.50 g (1.97 x 10 ^-3 mol) of fenbufen and 11.66 g (1.2 x 10 ^-2 mol) of α-cyclodextrin were dissolved in 100 ml of purified water under heating, and then stirred at room temperature for 24 hours.
The resulting precipitate was collected by filtration, washed with ether and cold water, and then dried under reduced pressure at about 50°C for 10 hours to obtain 4.2 g of the target product. Yield 97%.

The product was dissolved in a pH 7.5 phosphate buffer, and the absorbance in the ultraviolet region (283 nm) was measured, and the inclusion ratio of fenbufuene to α-cyclodextrin was determined to be 1 mole to 2 moles.

Infrared absorption spectroscopy and X-ray diffraction measurements (400 cps, glass cell) were performed on the product and a 1 to 2 mole mixture of fenbufen and α-cyclodextrin. The results are shown in Figure 6-a and Figures 7-a and 7-b, respectively. The infrared absorption spectrum shows carbonyl (-
It is observed that the absorption at 1708 cm ^-1 based on COOH) is shifted to 1725 cm ^-1 due to inclusion.
Also, X-ray diffraction measurements show a pattern unique to clathrate compounds, unlike a 1 mole to 2 mole mixture which exhibits characteristic absorptions of both fenbufuene and α-cyclodextrin.

The melting point of the clathrate compound obtained in this example is
The temperature was 290℃ or higher (decomposition). In addition, by differential thermal analysis, it was found that fenbufuene and fenbufuene and α
- It was confirmed that the endothermic peak near the melting point of fenbufen observed in a mixture of 1 mole and 2 moles of cyclodextrin disappeared by inclusion.

Example 2 19.46 g of α-cyclodextrin and 2.54 g of fenbufuene were placed in a crusher, and using 30 ml of purified water,
The mixture was kneaded for 12 hours at room temperature. The resulting paste-like reaction mixture was dehydrated by suction on a funnel, washed with ether and cold water, and then dried under reduced pressure at about 50° C. for 10 hours to obtain a white powder. The inclusion ratio of the target product was determined in the same manner as in Example 1 and was found to be 2 moles of α-cyclodextrin per 1 mole of fenbufuene. The results of infrared absorption spectrum and X-ray diffraction showed that it was the same compound as Example 1.

Example 3 Fuenbufuene 0.35g (1.38×10 ^-3 mol) and γ-
After heating and dissolving 5.19 g (4 x 10 ^-3 mol) of cyclodextrin in 100 ml of purified water, the mixture was stirred at room temperature for 24 hours.
The resulting precipitate was collected by filtration, washed with ether and cold water, and then dried under reduced pressure at about 50°C for 48 hours to obtain 2.1 g of the target product.

The target product was dissolved in a pH 7.5 phosphate buffer and the absorbance in the ultraviolet region (283 nm) was measured to determine the inclusion ratio of fenbufuene to γ-cyclodextrin, which was found to be 1 mole to 1 mole.

Infrared absorption spectra and X-ray diffraction measurements (4000 cps, glass cell) were performed on the target product and a 1 mol to 1 mol mixture of fenbufuene and γ-cyclodextrin. The results are shown in Figure 6-b and Figures 7-c and 7-d, respectively.

In the infrared absorption spectrum, it is observed that the absorption at 1708 cm ^-1 shifts to 1717 cm ^-1 due to inclusion. Also, X-ray diffraction measurements show that unlike a 1 mole to 1 mole mixture which exhibits characteristic absorptions of both fenbufuene and γ-cyclodextrin, it exhibits a pattern unique to clathrate compounds.

The melting point of the clathrate compound of the present invention is 290°C or higher (decomposition)
It was hot. Further, it was confirmed by differential thermal analysis that the endothermic peak near the melting point of fenbufen, which is observed in fenbufen and a 1 mol to 1 mol mixture of fenbufen and γ-cyclodextrin, disappears by inclusion.

[Brief explanation of the drawing]

Figure 1 shows Fuenbufuen and Fuenbufuen.
Figure 1-a shows the circular dichroism (Figure 1-a) and ultraviolet absorption spectrum (Figure 1-b) of a cyclodextrin clathrate compound in a phosphate buffer (pH 7.0) at 25°C. -Fuembufene alone, -Fuembufene + α-cyclodextrin, -Fuembufene + β-cyclodextrin, ...Fuembufene + γ-cyclodextrin, Figure 2 is the solubility phase diagram of Fuenbufuene. 〇: α-cyclodextrin, △: β-cyclodextrin,
●: γ-Cyclodextrin, Figure 3 shows the dissolution behavior in water at 25°C by the powder method. 〇:
α-cyclodextrin clathrate compound, ●: γ-cyclodextrin clathrate compound, □: fenbufuen alone, Figure 4 shows a 2g suppository of physiological saline solution containing 5 mg of huenbufuen alone and huenbufen-cyclodextrin clathrate compound as fenbufuene ( 300ml) (37℃, rotation speed 25 rpm), 〇: fenbufen-α-cyclodextrin clathrate compound, ●: fenbufen-
γ-cyclodextrin clathrate compound, □: fenbufen alone, Figure 5 shows fenbufen alone (△
The blood concentration of huenbufuen was measured by liquid chromatography after oral administration of 30 mg/Kg of huenbufuen-α-cyclodextrin clathrate compound (marked with ○) to domestic rabbits (average of 6 rabbits). value). FIG. 6 shows infrared absorption spectra of clathrate compounds and mixtures. 6th
Figure -a: Fuenbufen-α-cyclodextrin clathrate, -: Inclusion compound, ---: Mixture of 1 mol of fenbufen and 2 mol of α-cyclodextrin, Figure 6-b: Fuenbufen-γ-cyclodextrin clathrate Clathrate, --: Clathrate, ---: Mixture of 1 mole of fenbufuene and 1 mole of γ-cyclodextrin. FIG. 7 shows the X-ray diffraction patterns of the clathrate and the mixture. 7th
Figure 7-a: A mixture of 1 mol of huenbufuene and 2 mol of α-cyclodextrin, Figure 7-b: A mixture of 1 mol of huenbufen and 2 mol of α-cyclodextrin, Figure 7-c: A mixture of 1 mol of fenbufen and 1 mol of γ-cyclodextrin. Mixture, Figure 7-d: Fenbufuene-γ-cyclodextrin clathrate.

Claims (1)

[Claims] 1 4-(4-biphenyl)-4-oxobutyric acid-cyclodextrin clathrate.