JPH04112828A - Preparation of drug containing methoxsalen - Google Patents

Abstract

PURPOSE:To prepare a methoxsalen-containing preparation by crushing methoxsalen to a state to get a median diameter smaller than a specific level when the particle diameter is measured by a particle size distribution tester using a laser-diffraction method, adding a water-soluble and water-insoluble diluents to the crushed product and granulating by fluidized layer granulation process. CONSTITUTION:Methoxsalen is crushed to a median diameter of <=50mum determined by a particle size distribution tester using a laser-diffraction method. The obtained powder is mixed with a water-soluble diluent (e.g. lactose, mannitol, starch or sucrose) and a water-insoluble diluent (e.g. crystalline cellulose and hydroxypropyl cellulose) in a weight ratio of 1:(0.5-2) and the mixture is granulated by a fluidized layer granulation process. The preparation is useful as a remedy for leukoderma vulgaris. A preparation quickly absorbable after administration, exhibiting high absorptivity in the body, having a small size compared with conventional preparation and easy to ingest can be produced by the above method.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for manufacturing a methoxsalen-containing preparation, and more specifically, a method for manufacturing a methoxsalen-containing preparation that improves the bioabsorption rate of methoxsalen and achieves miniaturization of the preparation. Regarding.

Problems to be Solved by the Prior Art and the Invention Methoxsalen is currently used as a treatment for vitiligo vulgaris in Japan. This treatment method involves administering a methoxsalen preparation and irradiating it with ultraviolet rays when the plasma concentration reaches a certain level or higher. Therefore, methoxsalen preparations need to be absorbed quickly after administration and have a high rate of absorption in the body. However, since conventional methoxsalen preparations were mixed with common excipients and granulated using a normal granulation method, the time to reach the maximum plasma concentration was 2 hours or more. , the bioabsorption rate was also poor [Frederick Adewolff,
C11nical pharmacokinetics
, Volume 11.

Pages 62-75 (1985) Ko.

In addition, conventional methoxsalen preparations contain 10 mg, and 2 to 5 preparations must be taken during actual treatment, and there has been a desire for smaller preparations.

An object of the present invention is to improve these drawbacks of conventional methoxsalene formulations.

Means for Solving the Problems The present invention involves pulverizing methoxsalen so that the median diameter is 50 μm or less when measured using a particle size distribution analyzer using a laser diffraction method, and adding a water-soluble This is a method for producing a methoxsalene-containing preparation, which comprises adding a filler and a water-insoluble filler and then granulating it by a fluidized bed granulation method.

Methoxsalen has a median diameter of 50% when measured using a particle size distribution analyzer using a laser diffraction method (for example, using a Laser Particle Size Analyzer Model 715 manufactured by Cirrus).
Although it is necessary to grind the particles so that the particles have a median diameter of 20 μm or less and no particles larger than 150 μm, it is more preferable. Median diameter is 50μm
If the amount exceeds 100%, the bioabsorption rate of methoxsalen will not be improved.

Methods for pulverizing methoxsalen into the above state include a pulverization method using jet pulverization and a pulverization method using a ball mill.

As the water-soluble bulking agent, lactose, mannitol, starch (cornstarch, potato starch, etc.), sucrose, glucose, etc. can be used, and two or more of these may be used in combination.

Further, as the water-insoluble filler, crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, or salts thereof can be used, and two or more of these may be used in combination.

Here, the mixing ratio of the water-soluble extender and the water-insoluble extender is 1 part by weight of the water-soluble extender to 1 part by weight of the water-insoluble extender.
It is within 0 parts by weight, preferably 0.5 to 2 parts by weight.

In the present invention, granulation is performed by a fluidized bed granulation method, but if granulation is performed using any other granulation method, the bioabsorption rate of methoxsalen will not be improved.

The granulated product granulated by the above fluidized bed granulation method can be made into various solid preparations such as granules, tablets, and capsules by conventional methods.

Effects of the Invention According to the present invention, it has become possible to provide a methoxsalen preparation that is rapidly absorbed after administration and has a high bioabsorption rate. In addition, the preparation produced by the production method of the present invention can be made smaller and easier to swallow without reducing the amount of methoxsalen.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples and Test Examples.

Example 1 When 40 g of methoxsalen was measured using a laser particle size analyzer Model Ha5 manufactured by Cirrus, the median diameter was 50 μm.
Grind with a ball mill as follows, add 260 g of mannitol, 248 g of crystalline cellulose, and 28 g of carboxymethyl cellulose calcium, mix, use a solution obtained by dissolving 20 g of hydroxypropyl cellulose in purified water as a binder, and use a fluidized bed granulator. It was granulated using.

Sieve this with a No. 30 sieve and use 4g of calcium stearate.
After addition and mixing, 150 mg was filled into No. 3 capsules to obtain capsules.

Example 2 When 40 g of methoxsalen was measured using a laser particle size analyzer model 715 manufactured by Cirrus, the median diameter was 50 μm.
236 g of lactose, 140 g of potato starch, and 150 g of low-substituted hydroxypropyl cellulose were added and mixed, and then a solution of 30 g of hydroxypropyl methyl cellulose dissolved in purified water was used as a binder. and granulated using a fluidized bed granulator. This was passed through a No. 30 sieve, 4 g of calcium stearate was added and mixed, and 150 mg was filled into No. 3 capsules to obtain capsules.

Example 3 40 g of methoxsalen was pulverized using a jet pulverizer until the same conditions as in Example 2 were obtained, and 100 g of lactose, 117 g of mannitol, and 100 g of Avicel were added thereto.

After adding and mixing 50 g of low-substituted hydroxypropyl cellulose, the mixture was granulated using a fluidized bed granulator using a solution obtained by dissolving 30 g of hydroxypropyl methyl cellulose in purified water as a binder. This was passed through a No. 30 sieve, 3 g of calcium stearate was added and mixed, and 110 mg was filled into No. 4 capsules to obtain capsules.

Example 4 40 g of methoxsalene was ground using a Schott grinder until the conditions were the same as in Example 2, and 236 g of lactose, 140 g of cornstarch, 50 g of crystalline cellulose, and 100 g of hydroxypropylcellulose were added and mixed, followed by hydroxypropyl cellulose. A solution prepared by dissolving 30 g of methylcellulose in a 1:1 mixture of purified water and ethanol was used as a binder, and the mixture was granulated using a fluidized bed granulator. This was sieved through a No. 30 sieve, 4 g of calcium stearate was added and mixed, and then tablets each weighing 150 mg and having a diameter of 7 mm were obtained using a tablet-tally type tablet machine.

Example 5 40 g of methoxsalene pre-pulverized with a pin mill was pulverized with a jet pulverizer until the conditions were the same as in Example 2. To this was added 100 g of lactose, 117 g of mannitol, 100 g of Avicel, and 50 g of carboxymethyl cellulose, and after mixing, hydroxypropyl Methyl cellulose 3
0 g was dissolved in a 1:1 mixed solution of purified water and ethanol, and the mixture was used as a binder and granulated using a fluidized bed granulator. This is 3
The mixture was sieved through a No. 0 sieve, 3 g of calcium stearate was added and mixed, and 110 mg was filled into No. 4 capsules to obtain capsules.

Test Example (Absorption test of methoxsalen-containing preparation) [Preparation of samples] Sample 1 and control samples 1 to 5 were prepared according to the following.

Sample 1: The capsule of Example 2 was used.

Control sample 1: Example 2, except that instead of jet-pulverizing methoxsalen in Example 2, a normal pulverizer (Yarya pulverizer, manufactured by Yalla Co., Ltd.) was used, and the median diameter of methoxsalen was 100 μm or more. Capsules were produced in the same manner as above.

Control sample 2: Capsules were produced in the same manner as in Example 2, except that instead of granulating using the fluidized bed granulator in Example 2, a normal granulation method (agitation granulation method) was used. .

Control sample 3: Capsules were prepared in the same manner as in Example 2, except that 10 g of light anhydrous silicic acid and 366 g of crystalline cellulose were used instead of 236 g of lactose and 140 g of potato starch (water-soluble filler) in Example 2. Manufactured.

Control sample 4: Instead of jet pulverizing methoxsalen in Example 2, a normal pulverizing method was used, and the median diameter of methoxsalen was 100 μm or more, and instead of granulating using a fluidized bed granulator, a normal pulverizing method was used. Capsules were produced in the same manner as in Example 2, except that the granules were granulated using the granulation method (agitation granulation method).

Control Sample 5: A capsule different from Example 2 in the following points was prepared.

(1) Instead of pulverizing methoxsalen by shedding, a conventional pulverizing method was used, and methoxsalene was used with a median diameter of 100 μm or more.

(10 g of light anhydrous silicic acid instead of 236 g of lactose and 140 g of potato starch (a water-soluble filler)
and 366 g of crystalline cellulose were used.

0) Instead of granulating using a fluidized bed granulator, granulation was performed using a normal granulation method (stirring granulation method).

[Test Method: Six groups of 5 people per group were used. The dose for each sample was 3
It was set to 0 mg. After administration of each sample, 10 me of blood was collected once from the forearm skin vein of the subject at each predetermined time. This blood was analyzed by liquid chromatography to measure the methoxsalen concentration in plasma.

“Result The results are shown in Figure 1.

From these results, the effects of the present invention are as follows: (1) making the median diameter of methoxsalen 50 μm or less; (2) incorporating a water-soluble filler and a water-insoluble filler into the formulation; and 0) fluidized bed. It can be seen that the effect of the present invention is achieved only when the three requirements for granulation by the granulation method are satisfied, and in other cases, the effects of the present invention cannot be achieved.

[Brief explanation of drawings]

FIG. 1 is a diagram showing the amount of methoxsalen absorbed, where the vertical axis represents plasma methoxsalen concentration and the horizontal axis represents time. Note that the area at the bottom of the graph is the absorbed amount of methoxsalen.

Claims (1)

[Claims] (1) Methoxsalen is pulverized so that the median diameter is 50 μm or less when measured using a particle size distribution analyzer using a laser diffraction method, and a water-soluble filler and a water-insoluble filler are added to the methoxsalen. A method for producing a methoxsalen-containing preparation, which comprises adding a bulking agent and then granulating it by a fluidized bed granulation method.