JPH06256193A - Oral sustained release preparation of danazol - Google Patents

Abstract

PURPOSE:To obtain a sustained release complex granule preparation of danazol as a therapeutic agent for endometriosis. CONSTITUTION:A sustained release complex granule preparation of danazol is obtained by blending granules soluble in the stomach, having improved absorption, comprising danazol as a pharmacodynamically effective component and a surfactant with enteric granules prepared by subjecting the granules soluble in the stomach to enteric coating. Since effective concentration in blood can be maintained for many hours, a dose and times of administrations can be reduced.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to danazol (chemical name: 17α-pregna-2,4-diene-20-ino [2,3-d] isoxazole-17, which is a steroid drug having a high first-pass effect. -Ol) orally administrable sustained release formulation.

[0002]

BACKGROUND OF THE INVENTION Danazol is a drug marketed mainly as an oral agent for the treatment of endometriosis, whose main mechanism of action is suppression of gonadotropin secretion in the anterior pituitary gland and the resulting decrease in estrogen production in the ovary. Regarding techniques for improving absorption or bioavailability as an oral preparation, JP-A-61-1613 and JP-A-01-28
7094, JP 02-42020, JP 02-283230, or JP 04-14.
It is reported in Japanese Patent No. 9132. However,
No persistence was observed in either case.

On the other hand, as sustained oral administration agents, preparations for gradually releasing the main drug through the matrix and multiple-release preparations are known. For example, US Pat. No. 4,783,337-A describes a drug release controlling preparation using osmotic pressure. Has been done.
However, an oral sustained-release preparation using danazol is not yet known.

[0004]

The danazol preparations currently used clinically are oral immediate release tablets or capsules, and the daily dose is 200 to 400 mg, which must be taken twice a day. I won't. In addition, this drug must be continuously taken for at least 4 months until its action is exhibited, and there is a problem that compliance is deteriorated as well as bothersome due to long-term administration.

Commercially available dansole preparation (trade name: Bonzo-
Le Capsule, Tokyo Tanabe Seiyaku Co., Ltd.)
When an elution test was conducted according to the revised Japanese Pharmacopoeia (general test method 51, B, 458), the time for elution of 75% of danazol (hereinafter referred to as T _75% ) was less than 30 minutes and continued. Showed no sex. In addition, the biological half-life (T _1/2 ) of this preparation when administered orally was 1 hour in dogs and 3.3 hours in humans, and persistence was not observed.

[0006] Danazol is poorly soluble, has a high first-pass effect, and has a low relative bioavailability of about 3% in dogs. Therefore, in order to maintain its durability, the number of doses and the dose should be increased. The dose may be increased, and there was a concern about the side effects.

Therefore, an object of the present invention is to provide an oral sustained-release preparation of danazol, a drug for treating endometrial cells.

As conditions for the sustained-release preparation, the number of doses per day is smaller than that of the immediate-release preparation, and the maximum blood concentration (hereinafter referred to as Cmax) is similar to that of the immediate-release preparation. That the effective blood concentration of the drug is maintained for a long period of time, that the bioavailability is high, that it is physically and chemically stable even after storage for a long period of time, its release is stable, and it is easy to take. Examples include a dosage form having a size.

In order to obtain a danazol sustained-release preparation, the release is time-dependent, for example, in the case of matrix type, and the release occurs depending on the change of pH, for example, complex granular type and nucleated type. However, in the case of the former, the relative bioavailability was low even if it was persistent in vitro, and in the case of the latter, its solubility was pH-dependent, and Satisfactory results could not be obtained because the relative bioavailability was low or the variation in blood concentration was large, although lag time was observed at the rise of the medium concentration.

[0010]

[Means for Solving the Problems] In view of the above problems, the present inventors have conducted diligent research on a danazol sustained-release preparation. As a result, a danazol composition with improved absorption was used to produce elementary granules (stomach-soluble). Granules) were produced, and the granules were coated with an enteric coating, and the composite granules prepared by mixing these gastric and enteric coated granules showed excellent release in the dissolution test, and The present invention has been completed by finding that it also exhibits good sustainability in blood kinetics.

The complex granule type sustained-release preparation of the present invention contains danazol in an amount of 50 to 400 mg, preferably 100 to 200 mg.
The enteric coated granules contain the
It is preferable to contain 30%. As an enteric base, Eudragit (manufactured by Rohm Pharma: methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methacrylic acid) Methyl copolymer), Aquot (manufactured by Shin-Etsu Chemical Co., Ltd .: hydroxypropylmethylcellulose acetate succinate) or HPMCP (manufactured by Shin-Etsu Chemical Co., Ltd .: hydroxypropylmethylcellulose phthalate).

The sustained-release preparation of the present invention contains hydroxypropylmethyl cellulose (HPM) in gastric soluble granules, if necessary.
C), a gastrosoluble film coating base such as hydroxypropyl cellulose (HPC) can be used to apply the coating. Alternatively, a dye usually used for medicine can be added to the gastric and enteric coatings. Furthermore, the sustained-release preparation of the present invention does not produce a decomposition product of danazol even if it is stored in an airtight bottle at high temperature and high humidity for a long period of time, does not change the release property, and has good storage stability. Excellent long-acting danazol preparation.

The present invention will be described with reference to experimental examples and examples.

[Method] 1) Dissolution test The dissolution test method of the 12th revised Japanese Pharmacopoeia was applied correspondingly, and a 0.1N hydrochloric acid solution (pH 1.
2) or a phosphate buffer containing a surfactant (pH
Using 900 ml of 7.0 or pH 8.0, 100 mg or 200 mg of a sample corresponding to danazol was added, and a test was conducted at 100 rpm by the paddle method. The amount of danazol in the eluate was measured by the absorbance method.

2) Measurement of the concentration of danazol in blood After the oral administration of 100 mg or 200 mg of danazol to dogs and collecting a certain amount of blood from the vein, the amount of danazol in plasma was measured by high performance liquid chromatography. Microanalysis by.

3) Storage stability The properties, presence / absence of decomposed products, and releasability of the samples stored at 40 ° C. and 75% for 6 months were examined. The properties were visually observed according to the Japanese test method. Thin layer chromatography (TLC) was used to confirm the presence or absence of decomposed products, silica gel was used for the thin layer plate, and cyclohexane: ethyl acetate mixed liquid (3: 2) was used as the developing solvent.

[Experimental Example 1] Danazol 150 g, sucrose stearate 15 g, carboxymethyl cellulose calcium (product name: ECG505) 25 g, crystalline cellulose (product name: Avicel) 25 g, HPC-L
20 g and lactose 265 g were mixed, and kneading was carried out by adding 130 ml of kneading water, and after granulating using an extrusion granulator having a basket hole of 1 mm, it was made heavy using a marumerizer, and at 50 ° It was dried to obtain elementary granules having a particle size of 16 to 32 mesh (stomach-soluble granule 1).

[Experimental Example 2] After dissolving 10 parts of danazol in 420 parts of ethanol, it was previously dissolved in purified water 1200.
1 part of sucrose stearate was added to the mixture, and the mixture was added dropwise to the cooled preparation solution with stirring, and then the suspension was spray-dried to obtain a danazol composition.

Danazol composition 165 g, ECG 505
25 g, Avicel 25 g, HPC-L 20 g, and lactose 265 g were mixed, and kneading was performed by adding 130 ml of kneading water, and after granulating using an extrusion granulator having a basket hole of 1 mm, a Marumerizer was used. And heavier, 50 °
Then, it was dried to obtain elementary granules (stomach-soluble granules 2) having a particle size of 16 to 32 mesh.

[Experimental Example 3] Eudragit L100
7 parts, 0.7 parts of polyethylene glycol 6000 and 3.5 parts of talc were dissolved in a mixed solution of 70 parts of ethanol and 18.8 parts of purified water, and a solid content concentration of 10% was obtained using a fluidized granulation coating apparatus. The above-mentioned gastric-soluble granules 1 and 2 were coated to obtain enteric-coated granules 1 and enteric-coated granules 2.

[0021]

[Table 1]

As a result of the dissolution test for these samples (Table 1), in the dissolution test solution of pH 1.2, danazol was not eluted from enteric-coated granule 1 and enteric-coated granule 2, while gastric-soluble granule 2 was The dissolution rate was much faster than that of soluble granule 1 and the dissolution property was improved (Table 2).

[0023]

[Table 2]

The dissolution property of enteric coated granules 2 at pH 7 is
Similar to enteric-coated granule 1, lag time is seen until the skin is dissolved, but the dissolution rate is much faster than enteric-coated granule 1 and the solubility is improved, and the dissolution rate and amount of gastric-soluble granule 1 are improved. It was significantly improved as compared with (Table 3).

[0025]

[Table 3]

Furthermore, gastric-soluble granule 1, gastric-soluble granule 2 and enteric-coated granule 1, enteric-coated granule 2 were orally administered to beagle dogs and the behavior of blood concentration was examined. The pharmacokinetic parameters of granule 1 and enteric-coated granule 2 were as follows:
0.2 times, 0.9 times, area under blood concentration AUC is 2.9
Times, 0.3 times, 0.9 times, and Tmax is 1.5
2 times, 1.9 times, and 1.8 times slower, gastric-soluble granule 2 and enteric-coated granule 2 showed good bioavailability, and enteric-coated granule 1 had a significantly low utilization rate (Table 4). .

[0027]

[Table 4]

As described above, by applying enteric coating to the granules with improved absorption, the bioavailability equivalent to that of the normal gastric-soluble granules can be obtained, and further, the Tmax is delayed and the release is suppressed. It has been found for the first time that the granules repeat in a pH-dependent manner. Put gastric-soluble granules 2 and enteric-coated granules 2 in an airtight bottle and store them at a storage stability (40 ° C, humidity of 75).
%, For 6 months), no change was observed in the properties of any of the samples, no degradation products were observed (Table 5), and no change was observed in T _75% , indicating an extremely stable formulation. Was confirmed.

[0029]

[Table 5]

[0030]

【Example】

[Example 1] Gastric-soluble granules 1 and enteric-coated granules 2 shown in Table 1 were 3: 7, 7: 3 or gastric-soluble granules 2 and enteric-coated granules 2 were 3: 7, 5: 5, 7: 3. Mixed in a ratio to prepare a composite granule.

Each composite granule prepared to 100 mg as danazol was administered to dogs, and the behavior of blood concentration was examined. As a result, a composite granule using gastric-soluble granule 1 and enteric-coated granule 2 with improved absorption was obtained. In contrast, in the case of No. 3, the absorption-improved gastric-soluble granules 2 and the complex granules using the absorption-improved enteric-coated granules 2 exhibited the characteristics of a sustained-release preparation (Table 6).

[0032]

[Table 6]

From the blood concentration parameters of dogs, the sustained-release composite granules of the present invention showed a 2-fold AUC and 2.5-fold effective concentration maintenance time of the usual granules when the dose of 100 mg was taken once. The sustained-release preparation required a half dose of 200 mg, leading to a reduction in the dose, which is a good sustained-release preparation.

Example 2 In the same manner as in Experimental Example 3,
Enteric coated granules 3 were obtained by coating gastric soluble granules 2 with a solid content of 30%. Gastric soluble granule 2 and enteric soluble granule 3
Were weighed so that the respective danazol ratio was 3: 7, mixed well, and further weighed and packaged to 200 mg as danazol from the composite granules to prepare a sustained-release preparation.

[Example 3] In place of Eudragit L100 of Experimental Example 3, Eudragit S100 was used, and by the same operation, enteric coated granules 4 obtained by coating gastric soluble granules 2 with a solid content concentration of 20% were obtained. Stomach-soluble granules 2 and enteric-coated granules 4 were weighed so that the respective danazol ratio was 4: 6, mixed well, and the composite granules were further weighed and packaged to 100 mg as danazol, and continuously A sex preparation was prepared.

Example 4 165 g of the danazol composition of Experimental Example 2, 25 g of ECG505, 25 g of Avicel,
20g of HPC-L and 65g of lactose are mixed, and kneading water 10
After adding 0 ml and kneading, granulating using an extrusion granulator with a hole in the basket of 1 mm, it was made heavy using a marumerizer, dried at 50 ° and dried to a particle size of 16-32 mesh. Granules (gastric soluble granules 3) were obtained.

3 parts of triethyl citrate were dissolved in chilled water, then Aquat fine powder (grade AS-M) 1
Disperse 0 parts and 3 parts of talc, and finally add water to add 10 parts.
Gastric-soluble granules 3 were coated with 25% as a solid content concentration using 0 part of the coating solution to obtain enteric-coated granules 5.

Gastric-soluble granules 3 and enteric-soluble granules 5 were weighed so that the respective danazol ratio was 4: 6, and mixed well, and the composite granules were further mixed with danazol 200
A continuous preparation was prepared by weighing and packaging so as to have mg.

[Example 5] A coating solution in which the Aqua grade AS-M of Example 4 was changed to AS-H was prepared, and 5% of gastric-soluble granules 2 was coated as a solid content concentration to prepare enteric-coated granules 6. Got

The gastric-soluble granules 2 and the enteric-coated granules 6 were weighed so that the respective danazol ratio was 3: 7 and mixed well, and the composite granules were further mixed with 100 danazol.
A continuous preparation was prepared by weighing and packaging so as to have mg.

[Example 6] HPMC was added to 54.7 parts of ethanol, 27.4 parts of dichloromethane, and 9.1 parts of purified water.
Add 6.3 parts of P (HP-55), 0.9 parts of talc, 1 part of titanium oxide, and 0.6 parts of mybaset and stir well,
Prepare a coating liquid and use it to prepare gastric soluble granules 2
Was coated with 20% as a solid content concentration to obtain enteric coated granules 7.

The gastric-soluble granules 3 and the enteric-coated granules 7 were weighed so that the respective danazol ratio was 4: 6 and mixed well, and the composite granules were further mixed with 200 danazol.
A continuous preparation was prepared by weighing and packaging so as to have mg.

[Example 7] Using the coating solution of Example 6, gastric-soluble granules 3 were coated with 20% as a solid content concentration to obtain enteric-coated granules 8.

The gastric-soluble granules 3 and the enteric-coated granules 8 were weighed so that the respective danazol ratio was 2: 8, and then mixed well to prepare 200 danazol from the composite granules.
A continuous preparation was prepared by weighing and packaging so as to have mg.

Claims (2)

[Claims] 1. A continuous oral administration of danazol obtained by mixing gastric-soluble granules using a danazol composition comprising danazol and a surfactant and enteric-coated granules obtained by coating the gastric-soluble granules with an enteric coating. Complex granule formulation 2. The ratio of gastric-soluble granules to enteric-soluble granules is 2: 8.
~ 7: 3 Danazol oral sustained-release complex granules according to claim 1.