JPH01287094A - Danazol-cyclodextrin clathrate compound - Google Patents

Abstract

NEW MATERIAL:A clathrate compound of danazol (chemical name; 17alpha- pregna-2,4-dien-20-yno [2,3-d] isoxazol-17-ol)-cyclodextrin. USE:A remedy for endometriosis. PREPARATION:Danazol is added to a saturated aqueous solution of beta- cyclodextrin and the resultant solution is stirred at 5-90 deg.C, preferably 10-60 deg.C for 30min-24hr, preferably 1-5hr and then filtered. The solvent is then distilled from the obtained filtrate under reduced pressure or the filtrate is freeze-dried to produce the aimed clathrate compound.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to danazol (chemical name: 17α-pregna-2,4-diene-20-ino[2,3-d]isoxazole) which is useful as a therapeutic agent for endometriosis. The present invention relates to a danazol-cyclodextrin clathrate compound that has increased solubility of (-17-ol) in water.

It has not been previously known that danazol is made into a cyclodextrin inclusion compound in order to increase the solubility of danazol in water and improve its bioavailability.

JP-A-61-1613 describes an oral pharmaceutical composition of danazol, but this technique involves incorporating danazol into a substance soluble in gastric fluid, such as gelatin. The bioavailability of is 1
．． It is stated that it has been strengthened 91 times.

Problem to be solved by the invention The solubility of danazol in water is 0.05μ at 25°C.
ff/ml, making it a drug that is extremely poorly soluble in water.

When a poorly soluble drug is absorbed from the digestive tract of a living body, its rate of absorption is generally determined by its dissolution rate. One way to increase the dissolution rate is to increase hydrophilicity. Danazol is a drug that is poorly soluble in water, so its absorption rate from the gastrointestinal tract is low, and high doses are used to increase blood concentration and clinical efficacy. For this reason, there have been a few reports of side effects that are presumed to be due to high-dose administration.

Against this background, there is a desire for a danazol preparation with a high absorption rate, that is, a water-soluble preparation, which can reduce the dosage and reduce side effects.

Means for Solving the Problems The present inventors conducted research to obtain a water-soluble danazol preparation that has a high rate of absorption from the gastrointestinal tract, and found that excellent effects can be obtained by including danazol in cyclodextrin. I found out.

The sifurobukis 1-phosphorus used in the present invention is β and γ-cyclodextrin.

The shifrobukis 1-phosphorus clathrate compound of danazol can be produced by a conventional method such as a saturated aqueous solution method or a crosstalk method. For example, when using β-cyclodextrin, β
- addition of hedanazole in a saturated aqueous solution of cyclodextrin, 30 at 5-90'C, preferably 10-60'C;
The solution can be produced by stirring for minutes to 24 hours, preferably 1 to 5 hours, filtering the solution, and removing the solvent from the filtrate under reduced pressure or by freeze-drying the filtrate. When using γ-cyclodextrin, it can be produced by performing the same operation as above, stirring, and then drying the resulting precipitate.

The composition ratio of danazol and β-cyclodextrin is necessarily in a molar ratio of 1:6 to 1:10, preferably 1:7 to 1;
It is 9. The molar ratio of danazol and γ-cyclodextrin is necessarily 1:1 to 1:4, preferably 1:1.
1-1; Must be 2.

Example 1 Danazol 13 and β-cyclodex1-phosphorus 99 were dissolved in water (6.0 OOr, 1 at 10°C in 20°C),...
After stirring for a while, the mixture was centrifuged, the supernatant liquid was filtered off, and the obtained filtrate was dried under reduced pressure to obtain a β-cyclodextrin clathrate of danazol. The molar ratio of danazol and β-cyclodextrin in this clathrate compound was 1:8.5.

Example 2 Danazol 1!7 was added to γ-cyclodextrin at 25°C.
Added to 200 d of saturated aqueous solution and heated at 25°C for 2 hours.
After shaking vigorously for 4 hours, the precipitate was centrifuged and dried to obtain a γ-cyclodextrin clathrate of danazol. The molar ratio of danazol and γ-cyclodextrin in this clathrate was 1:1.

Reference Example Using 1q of the β-cyclodextrin clathrate compound of Danazol prepared in Example 1, 1 m of tablets were prepared according to the following formulation. This tablet contains 1 omg of danazol per tablet.

β-cyclodextrin clathrate compound of danazol 10 parts Crystalline cellulose 1 part Low substituted hydroxypropyl cellulose 1.5 parts Magnesium stearate 0.5 parts The compound of danazol and cyclodextrin subjected to IH in the present invention was analyzed by differential scanning calorimetry and The inclusion was confirmed from the results of the powder X-ray cycle test.

For example, as a result of differential scanning calorimetry of the clathrate compound obtained in Example 1 of the present invention, it was found that the endothermic peak around 225°C, which is characteristic of danazol, had disappeared, and as a result of a powder X-ray diffraction test. , danazol-specific 18.5[2e('
)], the diffraction lines around it disappeared, confirming that it was clathrated.

In addition, the solubility phase diagram of danazol and cyclodextrin clathrate compounds was determined using the solubility method established by Higuchi et al.
)] As shown in FIG. 1, the β-cyclodextrin clathrate compound showed the AL type, and the γ-cyclodestrin clathrate compound showed the [3s type.

Effect of the invention 1, Solubility in water 1 [Test method] Danazol (average particle size 1 to 2 μm), the clathrate compound obtained in Example 1, and the clathrate compound obtained in Example 2 were each added to water 20rd! Add excess amount to and incubate at 25°C for 24
Shake for an hour. Next, 0.1 μm membrane filter
The amount of danazol in the filtrate was measured by liquid chromatography to determine the solubility.

[Test results] The results are shown in Table 1.

Table 1 Solubility in Water As is clear from Table 1, the solubility of the cyclodextrin clathrate compound of danazol of the present invention in water is about 1,400 to 15,000 times higher than that of danazol.

2. Solubility in water 2 [Test method] Contents of reference example tablets and commercially available Danazol capsules (
Bunazol 10 mg equivalent), using water or the first liquid 900 of the Japanese Pharmacopoeia disintegration test method as the test liquid,
37° (:,
The test was conducted under the conditions of , 50 r, p, and m.

After the eluate was filtered through a 0.1 μm membrane filter, the filtrate was diluted twice with methanol, and the danazol depth in the solution was measured by an absorbance method to obtain an elution curve.

[Test results] The results are shown in Figure 2.

As is clear from Figure 2, danazol does not dissolve at all in the commercial product, whereas in the reference example tablet, more than 90% of the danazol was released within 15 minutes, indicating that the dissolution of the clathrate compound is excellent. It was confirmed that there is.

3. Bioavailability 1 [Test method] Female peagle-sized (weight 8-14 Kff) was tested 1 before drug administration.
After fasting for 6 hours, the clathrate compound of Example 1 was made into an aqueous solution,
lIom! (equivalent to 25 mtJ of danazol) was administered orally, and 1% of danazol (average particle stop ~ 2 μm) was administered orally.
Hydroxypropylcellulose aqueous suspension 407!
(Danazol 25 mFj equivalent M) was orally administered, and the administration time was 15 minutes, 30 minutes, 1 hour, 1 hour 30 minutes, and 2 hours.
After 3 hours, 4 hours, 6 hours, and 8 hours, blood was collected from the forelimb vein, and the plasma concentration of danazol was measured by liquid chromatography.

゛[Test results] The results are shown in Table 2 and Figure 3.

(n=2) In the table, Cmax is the maximum plasma concentration, AUG is the blood S degree -
The area under the time curve is shown.

As is clear from Table 2 and FIG. 3, the clathrate compound of Example 1 has a Cmax of 12 times and an AUG of 8 times compared to danazol.
showed twice the bioavailability.

4. Bioavailability 2 [Test method] Female peagle-sized (weight 8-14Kff) tablets of the reference example and commercially available Danazol capsules (Danazol 10 (M
+, 9-containing) was orally administered and blood concentrations were compared. The test method was based on the method for bioavailability 1.

Blood collection time is 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours,
The duration was 4 hours, 6 hours, 8 hours, and 12 hours.

[Test results The results are shown in Table 3 and FIG. 4.

Table 3 Parameters related to bioavailability (n=8> In the table, Cmax and AUC have the above meanings.

As is clear from Table 3 and Figure 4, the tablets of the reference example showed a 5 to 10 times improvement in bioavailability compared to commercially available Danazol capsules, and the clathrate compound showed a bioavailability factor even in the solid state. It was confirmed that the utilization rate was excellent.

As mentioned above, the cyclodextrin clathrate compound of danazol of the present invention provides improved solubility and improved bioavailability that could not be predicted by conventional techniques, resulting in a significant reduction in dosage and reduced toxicity. Possible useful compounds.

[Brief explanation of the drawing]

Figure 1 is a solubility phase diagram of danazol and cyclodextrin. In the figure, the ■ mark represents α-cyclodextrin, the * mark represents B-cyclodextrin, and the O mark represents γ-cyclodextrin. FIG. 2 shows the dissolution curves of the tablet of the reference example and the contents of a commercially available danazol capsule (N equivalent to 10 mg of bunazol) in water and the first pharmacopoeial liquid. In the figure, the mark Q indicates the tablet of the reference example, the mark - indicates the contents of a commercially available Danazol capsule, the - line indicates the dissolution curve in water, and the -11111 line indicates the dissolution curve in the first pharmacopoeial liquid. represent. FIG. 3 shows hemostatic concentration curves of the clathrate compound of Example 1 and danazol. In the figure, the ○ mark represents an aqueous solution of the clathrate compound of Example 1, and the * mark represents a suspension of 1% hydroxypropylcellulose aqueous solution of Danazol. Figure 4 shows the tablets of the reference example and the commercially available danazol capsules (Bunazol 1oo). In the figure, the O mark indicates the reference example tablets, and the * mark indicates the commercially available danazol capsules in Table 1. Applicant Tokyo Tanabe Pharmaceutical Co., Ltd. Agent Patent Attorney Matsu ．Yama Naoyuki”o Hayashi’to) Yajibi・(as
1 Shohin Time Zone 4 Time 1 Time n=8

Claims (1)

[Claims] (1) Danazol-cyclodextrin inclusion compound