JPH0242020A - Danazol composition - Google Patents

Abstract

PURPOSE:To obtain a danazol composition, capable of remarkably promoting absorption through digestive tracts, improved in bioavailability and useful for treating endometriosis by blending and dissolving a specific amount of danazol in a surfactant and polyhydric alcohol. CONSTITUTION:A danazol composition obtained by blending and dissolving 0.5-5wt.% danazol (a compound expressed by the formula) in 1-50wt.% surfactant (especially preferably having >=14 HLB, e.g., decaglyceryl monolaurate or polyoxyethylene sorbitan monolaurate) having >=12 HLB and 45-98.5wt.% polyhydric alcohol (e.g., glycerol, pentaerythritol or sorbitol). The above- mentioned composition is readily obtained by mixing the respective ingredients and, as necessary, stirring the resultant mixture while heating. The dissolution ratio of the danazol can be remarkably improved by using the prescribed amount of the surfactant according to the above-mentioned method.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a danazol composition prepared by blending and dissolving danazol, a poorly water-soluble steroid, with a surfactant and a polyhydric alcohol. .

[Conventional technology]

Danazol has the following structural formula: 17α-pregna-2,4-diene-20=
Generic name for ino(2,3-d)inxasil-17-ol, which has anti-gonadotrophic effects on FSH.
It is a compound used in the treatment of endometriosis because it suppresses the secretion of LH and has no sex hormone effect.

Due to the excellent effects of danazol as a therapeutic agent for endometriosis, its use is increasing year by year. Danazol is currently used in the form of hard capsules, and is administered in extremely high doses (for example, 400 mg/day) for a hormone or its derivative preparation (ethisterone derivative). However, since danazol itself is sparingly soluble in water, the amount of danazol eluted from a danazol preparation, and therefore the amount absorbed into the human body, depends on various administration conditions, such as the shape of the danazol preparation, the particle size of danazol in the preparation, and the amount of danazol absorbed into the human body. There are variations depending on the residence time of the preparation in the tube, the amount and type of food, etc., and this variation causes variations in the therapeutic effect.Not only is there a high risk of side effects, but the drug itself is expensive, so large doses cannot be administered. Problems associated with large-dose administration, such as being uneconomical, have long been pointed out.

As a means to solve this problem, for example, Japanese Patent Laid-Open No. 61-1
No. 613 discloses that danazol is finely ground and the particles are treated with a binder that is soluble in water or other aqueous media at the pH of the gastrointestinal tract, such as hydroxypropyl methylcellulose,
A medicinal composition in the form of a large number of beads bonded together with polyvinylpyrrolidone or the like has been disclosed. However, since this prior art means does not increase the solubility of danazol, it still requires improvement in terms of absorbability into the human body.

On the other hand, in order to make nifedipine, which is a poorly water-soluble compound, easily absorbable, a composition consisting of a specific blending ratio of nifedipine, polyethylene glycol, and polyoxyethylene sorbitan monooleate was published in Japanese Patent Publication No. 61.
It is disclosed in the publication No.-40647. The technique disclosed herein is applicable only to nifedipine, and since each drug has its own problems that need to be solved, other methods for making nifedipine more easily absorbed may be used. There is no suggestion in this publication regarding the applicability to drugs.

[Problem that the invention seeks to solve]

Danazol is a substance that is almost insoluble in water regardless of pH, and when we investigated the amount of danazol leached from the formulation, we found that the rate of danazol dissolution is low if it is simply made into a fine powder.

In addition, in an absorption test conducted using a Sartorius absorption tester, danazol in a dissolved state was rapidly transferred from the artificial gastric fluid to the permeable membrane.

Based on this fact, there is a strong possibility that danazol has a low absorption amount due to its slow dissolution in the gastrointestinal tract. Therefore, by increasing the dissolution rate of danazol in the gastrointestinal fluid in the formulation, it can be administered in small doses compared to conventional formulations. It is suggested that it is possible to create a danazol preparation that has similar effects, has less interindividual variation in absorption, and has fewer side effects when absorbed excessively. Therefore, there was a need for a means to solubilize danazol to increase the elution of danazol from danazol formulations.

[Means to solve the problem]

The present inventors further investigated the relationship between the dissolution and absorption of danazol in vitro and in vivo, and found that it was insufficient to simply form danazol into a fine powder, and that danazol was incorporated into a water-soluble base. The absorption rate is high when choosing a base that can dissolve and thus itself act as a dispersant for danazol in water;
The present invention was completed by discovering that it is possible to obtain a danazol composition for oral administration that has high bioability, requires a small dosage, and has little variation in absorption between individuals.

That is, as a result of our research, the present inventors found that danazol 0.5
~5% by weight, 1~50% by weight of a surfactant with an HLB of 12 or higher, and polyhydric alcohol 45% by weight.
When blending ~98.5% by weight, danazol dissolves and a clear and highly stable solution is obtained.This danazol solution has good water dispersibility and has good dissolution test results. that the elution rate is obtained, and i
As a result of in vitro and in vivo tests, it was found that danazol was absorbed very well.

The danazol composition obtained in this way contains the additives necessary as a pharmaceutical, such as tocopherol, antioxidants such as ascorbic acid, sugars, sweeteners such as saccharin, flavoring agents such as peppermint oil and peppermint, etc. It can also be used in the form of a liquid formulation with addition of a coloring agent and the like.

Furthermore, this danazol composition is used as a composition for filling soft capsules, and is used as a raw material for preparing a danazol soft capsule preparation filled into soft capsules. Although this composition can also be used as a composition for filling hard capsules, the following description will mainly be made regarding soft capsules.

That is, the danazol composition for oral administration of the present invention contains 0.5 to 5% by weight of danazol, 1 to 50% by weight of a surfactant with an HLB of 12 or higher, and 45 to 98.5% by weight of a polyhydric alcohol.
It is characterized by being made by dissolving danazol by blending danazol in the amount by weight.

This danazol composition can then be filled into soft capsules for preparing soft capsule formulations.

The surfactant used in the present invention may be any surfactant as long as it can dissolve danazol in combination with a polyhydric alcohol. The properties required for such a surfactant are preferably HLB l 2 or higher, especially HLB 1
4 or more is desirable, but since it is to be filled into soft or hard capsules, the viscosity of the prepared composition is preferably low, and the viscosity is generally 5000 cp or less. The amount of surfactant that can be used for this purpose is preferably up to 50% by weight in view of its physical properties.

Surfactants that meet the above conditions include polyglycerin fatty acid esters such as decaglyceryl monolaurate and hexaglyceryl monolaurate, and polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate and polyoxyethylene sorbitan monooleate. , polyoxyethylene castor oil diglyceride POE(6) sorbitol fatty acid ester such as polyoxyethylene sorbitol fatty acid ester, polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether, polyethylene glycol fatty acid ester such as POE(10) monolaurate, Although there are polyoxyethylene castor oil and mixtures of two or more thereof, decaglyceryl monolaurate and polyoxyethylene sorbitan monolaurate are particularly preferred from the viewpoint of water dispersibility, viscosity stability, etc. of the composition.

Examples of the polyhydric alcohol used in the present invention include glycerin, pentaerythritol, sorbitol, polyethylene glycol, polypropylene glycol, and mixtures of two or more thereof. In consideration of the water dispersibility and irritation of the danazol composition, the molecular weight is 200 to 6,000, preferably 200 to 6,000.
1000 polyethylene glycols.

The composition of the present invention can be easily prepared by mixing predetermined amounts of each of the above-mentioned components and stirring the mixture under heating if necessary. Finely ground dananol is preferable for ease of dissolution, but if the temperature, stirring, time, type and ratio of surfactant and polyhydric alcohol are selected appropriately, danazol can be finely ground. does not require

The composition can be prepared using an apparatus having a suitable heating device and stirring device.

The danazol composition prepared in this manner can be used as it is as a liquid preparation, but if necessary, it can be filled into soft capsules to form a danazol soft capsule preparation.

Filling of soft capsules can be carried out using any filling machine according to known formulations.

Below are examples showing specific examples of the danazol composition and danazol soft capsule formulation of the present invention, the appearance, water dispersibility, and stability elution test results of the specific example compositions, and the blood concentration of danazol according to the present composition. The following shows the results of a comparison test of the transition of

[Example I]

Danazol 3 parts P OE (20) Sorbitan monolaurate
9.7 parts polyethylene glycol 400
87.3 parts Danazol 3g, POE (20) sorbitan monolaurate 9.7y and polyethylene glycol 400 87.9g are mixed and stirred while heating to about 65°C. Danazol was completely dissolved to form a clear liquid, and an amount equivalent to 10 ma of danazol was taken and filled into soft capsules.

[Example 2] Danazol 1 part Decaglyceryl monolaurate 40 parts Polyethylene glycol 400 40 parts Danazol 19 and Decaglyceryl monolaurate 40
g and stir while heating to about 65°C. Once danazol has dissolved, add polyethylene glycol 40
Add 0 409 and stir further to make a clear liquid. An amount of this liquid corresponding to danazol lomy was taken and filled into soft capsules.

[Comparative example l]

Bonzol Capsule 100 (manufactured by Tokyo Tanabe Pharmaceutical Co., Ltd.) [Comparative Example 2] Ponzol Capsule 100 (manufactured by Tokyo Tanabe Pharmaceutical Co., Ltd.)
After taking out the contents and mixing them uniformly, add Danazol 10
An amount corresponding to mg was taken and filled into diurnal gelatin capsules.

[Control example 3] Danazol 3g and polyethylene glycol 4009
7 g were mixed and the following operation was performed in the same manner as in [Example 1].

The compositions described in Example 1 and Example 2 above (
Examples of combinations of other compositions, including compositions No. 13 and 22), are shown in Table 1 below. This table-
The composition shown in Table 1 was prepared by mixing the components shown in Table 1 in predetermined amounts and stirring the mixture while heating it to about 65°C to form a clear liquid. The composition of Control Example 3 (composition No. 23) is also listed in Table 1.

The compositions listed in Table-■ above are treated in the following manner.
Water dispersibility and stability tests were conducted.

The stable two-class acid is stored at room temperature, and changes in appearance are observed after 1 day, 1 week, 2 weeks, 1 month, 2 months, and 3 months have elapsed. In the evaluation method, the state of precipitation of crystals is divided into three stages depending on the amount.

Take about 50 to 200 ml of the two water-dispersible compositions, drop them into about 200 m (l) of water kept at about 30°C, and observe the state when stirring.

The test results are shown in Table 2 below.

Table-2 Composition N.

Water dispersibility almost transparent almost transparent almost transparent almost transparent Stability (days) ooooo.

ooooo.

ooooo.

ooooo.

Water dispersibility almost transparent Immediate crystal precipitation almost transparent almost transparent almost transparent almost transparent almost transparent almost transparent almost transparent almost transparent almost transparent almost transparent almost transparent Immediate crystal precipitation 22 is mostly transparent 23 Immediate crystal precipitation Stability (days) ooooo.

ooooo.

ooooo.

ooooo.

ooooo.

ooooo.

ooooo.

ooooo.

ooooo.

ooooo.

ooooo.

ooooo.

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Evaluation of stability Condition of crystal precipitation 0: No precipitation 1: A very small amount of crystals precipitated 2: A large amount of crystals precipitated The compositions listed in Table 1 above were subjected to an elution test using the following method.

Sample preparation: Each composition filled in So7to capsules and diurnal gelatin capsules of Control Example 2 were heated at 37±0.5°C.
Submerge it in a dissolution test container containing water and leave it for 60 minutes.

Elution test 2 Add 0% polysorbate 80 to the above elution test container.
．． The solution was added at a concentration of 15% (v/w), and a dissolution test was conducted using this as a test solution to determine the dissolution rate of danazol.

The operating method is based on the diurnal general test, dissolution test method, and paddle method, and the number of rotations of the paddle is 1100 rpm.

The test results are shown in Table 3 below and Figure 1.

From the results of this dissolution test, it can be seen that the dissolution rate of danazol is not improved simply by dissolving danazol in a polyhydric alcohol, but is significantly improved by the addition of a surfactant.

Therefore, when changing the blending ratio of surfactant, the dissolution rate of danazol increases significantly when the surfactant goes from 0 to 50% (weight ratio), but when it exceeds 50%, the effect reaches a plateau (
Figure 1).

Table Bioavailability - Test <Method> As a specimen sample (Example 1 (Composition No. 3)) (Example 2 (
Composition No. 22)) As control samples (Control Example 1) (Control Example 2) (Control Example 3 (
Composition No. 23)) was orally administered with 30 to 40 mg of drinking water, respectively.
Blood was collected from the forelimb vein at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours after administration, and the danazol concentration in the blood plasma was measured by high performance liquid chromatography. The fasting was continued until the end of blood collection 8 hours after administration, and water was allowed to be taken ad libitum.

The test results are shown in Table 4 and Figure 2.

Table-4 Bioavailability of each sample-Comparative Example 1
10mg 90.0 223
Example 2 10mg 148.8
343 Control Example 1 100mg 108.1
334 Control Example 2 10mg ND
, ND control example 3 10 mg
22.1 50* ND: Detection limit (5
ng/ml) or less.

Figure 2 shows the time course of the blood danazol concentration when the test samples (Example 1) (Example 2) and the control samples (Control Example 1) (Control Example 3) were orally administered to Peagle dogs. show. As is clear from Figure 2 and Table 4, the absorption of bedanazole in the test sample was significantly improved compared to the control sample, and the AUG, which is an indicator of the bioavailability of the drug, was improved by 10 minutes in the test sample compared to the control sample. The drug amount of 1 was equivalent. This indicates that the composition of the present invention significantly promotes gastrointestinal absorption of danazol and greatly improves its bioavailability.

[Brief explanation of the drawing]

Figure 1 shows the results of the dissolution test conducted on the danazol compositions as changes in dissolution rate over time, and Figure 2 shows the results for the danazol compositions of Examples 1 and 2 and the control examples 1 and 3. This figure illustrates the change in blood concentration of danazol when a danazol composition is administered to a pegle dog.

Claims (1)

[Claims] 0.5 to 5% by weight of danazol, 1 to 50% by weight of a surfactant with an HLB of 12 or higher, and 45 to 98% of a polyhydric alcohol.
A danazol composition characterized in that it contains 5% by weight and is dissolved therein.