JPS61151116A - Method for producing a pharmaceutical composition containing 5-(3-n-butyloxalylaminophenyl)tetrazole - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] Purpose of the Invention <Industrial Application Field> The present invention provides a 5-(3
= A method for producing a pharmaceutical composition containing n-butyloxarylaminophenyl)tetrazole (hereinafter referred to as MTB) (:
It is related to

<Prior art> MTB is a compound represented by formula (1) and has a molecular weight of 289.3. Melting point approx. 1
It is a white crystalline powder at 55°C and is a known compound useful as an anti-allergic agent.

(Special Publication No. 59-1705) <Problems to be Solved by the Invention> The inventors of the present invention have encountered various problems as a result of their attempts to formulate a pharmaceutical formulation of MTB to develop it as an anti-allergic, anti-allergy drug, and especially as a treatment for asthma. I found the point.

In other words, MTB raw wood (white crystalline powder) has adhesion and agglomeration properties, is poorly soluble, and difficult to wet with water (the powder floats in water), making it extremely difficult to handle during drug processing. It has been found that when the bulk powder of seaweed is made into a formulation as it is by a conventional method, the disintegration and dissolution properties of the formulation are poor, and the bioavailability of the active ingredient is insufficient.

In the event of an asthma attack, it may be necessary to treat the patient by oneself, and it is especially desirable that this type of therapeutic agent not only be easy to take, but also be a formulation that can exert rapid and reliable effects.

For these reasons, the present inventors have completed the present invention as a result of extensive research aimed at producing an MTB formulation with good disintegration and dissolution properties and high bioavailability.

Structure of the Invention and Means for Solving the Problems> The present invention provides r(1) MTB with polysorbate 80. Polyvinylpyrrolidone (hereinafter referred to as PvP), polyoxyethylene hydrogenated castor oil, polyethylene glycol (hereinafter referred to as PE)
G), hydroxymethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose (hereinafter sometimes referred to as specific dispersants), and mixed homogeneously in the coexistence of a non-aqueous solvent. A method for producing an MTB-containing pharmaceutical composition with high bioavailability, characterized by removing the water solvent or dissolving it in liquid PEG. ” and “(2) A method for producing an MTB-containing pharmaceutical composition according to claim 1, wherein the mixing is carried out in the presence of a pharmaceutically acceptable inert carrier.j
(This is related to two things.

In the present invention, the specific dispersant consists of a relatively high-molecular component that can be dispersed or dissolved in both water and non-aqueous solvents, and the amount used varies considerably depending on the type, but 1 part by weight of MTB is 4 parts by weight.
Two to two usually 0. O can be appropriately selected within the range of 1 to 10 parts by weight.

PEG having an average molecular weight of about 200 to 6,000 is preferable. C: Can be used.

The inert carrier is not particularly limited as long as it is pharmaceutically acceptable, but usually crystalline cellulose, corn starch, manilla, light silicic anhydride, kaolin, etc. can be used.

The non-aqueous solvent is not particularly limited as long as it can simultaneously dissolve or disperse both the specific dispersant and MTH components and can be easily removed by evaporation, but usually methanol, ethanol, and isopropyl alcohol are used.

Acetone, dichloromethane, etc. are used alone or in combination.

Note that when a large amount of liquid PEG is used as the specific dispersant, it is not necessary to use a non-aqueous solvent since it dissolves MTB by itself.

According to present invention C2, after dissolving or dispersing MTB and the specific dispersant in a non-aqueous solvent, with the solvent evaporation (forming a dihedral solution or P
In the case of EG, a composition in which MTB is dissolved is provided, and an MTB-containing pharmaceutical composition with excellent bidispersibility and dissolution properties and high bioavailability can be produced.

In measurement using a differential thermal scanning calorimeter (DSC30 type, manufactured by Takafusa Seisakusho) C2, MTB showed an absorption peak indicating crystallinity, and a mere mechanical mixture of MTB and a specific dispersant also showed a peak. The mixture treatment of both components in the coexistence of a non-aqueous solvent did not show any peak.1 The non-aqueous solvent treatment in the present invention not only increases the single C: mixing efficiency but also improves the MT
The crystal structure of H itself (it was observed that two-component formation occurred).

The MTB-containing pharmaceutical composition of the present invention uses a carrier.

It is possible to prepare a premix containing a high concentration of MTB by not using it or using it in a limited manner, and diluting this premix with a carrier to prepare a preparation in any form by a conventional method. It is also possible to formulate a preparation by using a large amount of the agent as a carrier.

Usually, commonly used carriers, binders, sweeteners, and other auxiliary substances are simultaneously mixed to obtain granules, powders, powders, etc. using a wet granulation method using a non-aqueous solvent, and these are then filled into capsules as necessary. It can be made into capsules or compressed into tablets (
= It is easy to do.

In this case, even if MTB and the specific dispersant are not completely dissolved by the non-aqueous solvent.

The dissolution properties of MTB preparations are unexpectedly high.

In addition, the MTn-containing pharmaceutical composition of the present invention has excellent dispersibility and solubility, so it can be used as eye drops.

It can also be made into liquids such as injections, suspensions, or poultices.

The present invention will be described in detail below with reference to Examples.

Example 1゜MTB5 (1, crystalline cellulose 44t, cornstarch 10? and low substituted hydroxypropyl cellulose 101
ζ2PVP6t was dissolved in 30% of isopropyl alcohol and added, mixed uniformly and then granulated,
After drying at 40°C for 5 hours, the particles are sized to obtain fine granules.

Example 2゜PVP6f (7) iJl:, PVP4f and poly://
Fine granules were obtained in the same manner as in Example 1, except that 1ZP-802F was used, and the fine granules were filled into hard gelatin capsules to obtain capsules.

Example 3 MTBxoor was dissolved at 500s/(two times) and polysolvate-801Of was added thereto and stirred and mixed.
This solution contains 400f of crystalline cellulose and 50% of low-substituted hydroxypropyl cellulose. and cornstarch 440
After adding f and mixing evenly, the mixture is dried at 50°C for 5 hours and then sieved to obtain a powder.

Example 4゜MTB100? , crystalline cellulose 420F, cornstarch 400? and low-substituted hydroxypropylcellulose 301, PVP5 (1 dissolved in 550 dl of isopropyl alcohol) was added, and kneaded to form a 0.7 m
Extrude it into granules using Roclean and heat it at 50℃ for 5 minutes.
After drying for a period of time, the granules are sized to obtain granules containing MTB of 507Q in 500μ.

Example 5゜MTBloF and Hydroquine Propyl Methyl Cellulose 2
Add 09 to 200 g of dichloromethane/ethanol mixture, and after dissolving, add 20 f of light silicic anhydride, mix uniformly, evaporate the solvent under reduced pressure, and pass through a 40 mesh sieve. and mix uniformly to obtain a powder.

Example 6゜MTBloof was dissolved in 300w4t of dichloromethane/ethanol equivalent mixture, and polysorbate)-8 was added to this.
03t was added and dissolved, and then crystalline cellulose 167f
was added and dried at 50° C. for 4 hours with uniform mixing waves to form a powder. This C: Add 4 f of magnesium stearate and mix uniformly.

Fill a No. 4 capsule with this mixed powder to 1371v,
Hard capsules containing MTB501v in one capsule are obtained.

Example 7 MT Bloof is dissolved in PEG400F having an average molecular weight of 400, and 200 tons of light anhydrous silicic acid and 300 tons of carboxymethylcellulose calcium are mixed thereto to form a powder. Pass this through a 42 mesh sieve to obtain 500n9
A powder containing 9 medium MTBsOa is obtained.

Example 8゜MTB100? , crystalline cellulose 80f, cornstarch 20? and low substituted hydroxypropyl cellulose 1
62, PVP16F and 4t of polyoxyethylene hydrogenated castor oil dissolved in 120% of ethanol were added thereto, uniformly kneaded (twice) and then granulated.
Dry for 4 hours, add 4 tons of talc after grading, and mix evenly (2 mix 1
The mixture is mixed and filled into No. 4 capsules of size 120 to 4 to obtain hard capsules containing MT850.

Example 9〜MTBxoor and average molecular weight 6000] PEG 8
0 f was dissolved in a mixed solution of equal amounts of dichloromethane and ethanol (500 ml), 20 t of light anhydrous silicic acid was added thereto, mixed, dried at 50°C for 4 hours, and then pulverized. , 10f of carboxymethylcellulose and 2t of magnesium stearate were added.

Conventional method C: Compress to obtain tablets containing about 50 M9 of MTB per tablet.

Example 10゜MTBlooF, crystalline cellulose 80f, corn star f36f and low substituted hydroxypropyl cellulose, X
To this, PVPI (l) and polysorbate-802t dissolved in 120 g of ethanol were added, kneaded evenly, extruded through a 0.7 wΩ screen to form granules, and dried at 50°C for 5 hours. After sizing and adding magnesium stearate 22, tablets are compressed by a conventional method to obtain tablets with a diameter of 7a+ and a weight of 1201n9.

Example n゜MTB2F was dissolved in acetone 109, and 2 t of C-dipolysorbate-800 was added thereto and mixed with stirring.

This solution was added to Kao Lin 5n. 8t and then dried to obtain a dry powder. On the other hand, add 10% glycerin 440f
Heat to 0° C. to remove moisture, add and dissolve 45 t of boric acid, mix the above dry powder with it, and after cooling, add 0.5 f of thymol dissolved in 0.52 g of pepper oil, Mix well to obtain poultice.

Example 12゜MTB 10? and hydroxymethylcellulose 20
9 to 200 ml of a mixture of dichloromethane and ethanol in equal amounts
After dissolving the mixture in 1 liter of water, the mixture is heated under reduced pressure to evaporate the solvent and dried, and then pulverized to obtain a fine powder. Anhydrous sodium dihydrogen phosphate 3.2f
, anhydrous phosphoric acid-sodium hydrogen 5.68? and 4.62 kg of sodium chloride were dissolved in sterile purified water, and the fine powder was added thereto to suspend it.

Add sterile purified water and dispense in 2 portions to obtain eye drops.

Effects of the Invention In order to explain that the drug according to the present invention has a significantly higher dissolution rate and bioavailability (blood concentration) than drugs prepared by conventional methods, a test example using hard capsules and tablets as test drugs. is shown below.

Test example 1. (Elution test) Test method: Artificial gastric juice (Japanese Pharmacopoeia liquid 1) 500 W as eluent
Keep the liquid temperature at 37 ± 0.5℃ using t and put the test drug (t50In9 including MTB) into the bottom of the container and press the paddle.
It rotated at rpm, the liquid was sampled at predetermined time intervals, and the amount of MTB eluted into the liquid over time was measured by spectrophotometry (second method).

Test drug Invention A: Hard capsule of Example 7 Invention B: Tablet of Example 1O Comparison A:
・・・・ Comparison B of hard capsules made by conventional method ・・・・
... As shown in Table 1 of the tablet test results according to the conventional method, the drug of the present invention showed a significantly high dissolution rate.

Table 1 The comparative drugs used in this study (2) were prepared according to the following formulation.

Comparison A MTB crystal powder 50F with lactose 68? and magnesium stearate 2? The mixture is mixed uniformly with 120 square capsules and filled into capsules to obtain hard capsules containing 50 to 50 MTB per capsule.

Comparison B MTB crystal powder 502. Lactose 40? , corn star f-
159. Crystalline cellulose 10? , starch paste 32 is mixed, kneaded by adding about 40 mm of water, extruded through a screen with a diameter of 7 m, dried as granules, sized, added 2 tons of magnesium stearate, and compressed into 1 tablet. Middle MT
A tablet containing B501v is obtained.

Test example 2. (Blood concentration measurement test) Test method: Male pegle dog 1, weighing approximately 10Kt, fasted for 24 hours.
The test drug was orally administered to five animals in the group. At a predetermined time after administration of the drug, blood was collected and the blood concentration of MTB was measured by liquid chromatography.

Test drug Same as Test Example 1.

Test results The results of this test are shown in Table 2.

Table 2 Notes: 1) The results in the table are the average values of 5 horses.

2) ND indicates that no detection was possible.

As is clear from the above test examples, according to the present invention (2), it is possible to produce a pharmaceutical composition that has good disintegration and dissolution properties and a significantly high bioavailability.

Patent applicant: Wakamoto Pharmaceutical Co., Ltd. Manual continuation supplementary book More than 1985

Claims (2)

[Claims] (1) 5-(3-n-butyloxalylaminophenyl)tetrazole with a dispersant selected from the group of polysorbate 80, polyvinylpyrrolidone, polyoxyethylene hydrogenated castor oil, polyethylene glycol, hydroxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose 5-(3-n) with high bioavailability characterized by being homogeneously mixed with one or more of A method for producing a pharmaceutical composition containing -butyloxalylaminophenyl)tetrazole. (2) The 5-(3-n-
A method for producing a pharmaceutical composition containing butyl oxarylaminophenyl)tetrazole.