JPH02206A - Novel drug preparation containing exifone and water-soluble polymeric compound - Google Patents

Abstract

PURPOSE:To provide a cerebral metabolism improver containing exifone, a water-soluble polymeric compound such as cellulose derivative and, as necessary, conventional additives and giving a solid dispersion, mixed powder, etc., having improved absorbability in oral administration. CONSTITUTION:The objective cerebral metabolism improver effective as a remedy for senile dementia, cerebrovascular dementia, etc., contains exifone of formula and a water-soluble polymeric compound at a weight ratio of 1:(0.01-7) and, as necessary, conventional additives such as disintegrant, lubricant, excipient or colorant. The water-soluble polymeric compound is e.g. cellulose derivative (e.g. hydroxypropyl methylcellulose), water-soluble synthetic polymer compound (e.g. polyvinyl pyrrolidone), etc., and the hardly water-soluble nature of exifone can be improved by the addition of the polymeric compound. Exifone is dissolved in an organic solvent, the water-soluble polymeric compound is added to and dissolved or dispersed in the solution and the solvent is distilled off to obtain a solid dispersion.

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial Utilization of Bone" The present invention provides exiphon (Ex
The present invention relates to a new formulation containing exiphon and a water-soluble polymer compound that improves the difficulty in absorption of (ifon θ) during oral administration, and is useful in the pharmaceutical field.

``Prior art and the problems that the invention attempts to solve.

Exiphon is a compound having the structure shown below, and is useful as a brain metabolism improving agent, for example, senile dementia,
It is effective in treating cerebrovascular dementia, etc.

[2,3,4,3',4',5'-hexahydroxybenzophenone However, exiphone is poorly soluble in water (saturated solubility:
When administered orally as a normal preparation, it has poor absorption into the blood, and therefore has a drawback of low bioavailability. Therefore, a new formulation that overcomes this drawback has been awaited.

The inventors of the present invention discovered that the above-mentioned drawbacks could be overcome by incorporating a water-soluble polymer compound into the exiphone, and as a result of intensive research, they completed the present invention.

The present invention is the first to improve the above-mentioned drawbacks of exiphones.

rMeans for solving problems.

The novel formulation of the present invention is characterized by containing exiphon and a water-soluble polymer compound. The presence of both Exiphon and a water-soluble polymer compound improves the disadvantage of Exiphon, which is that it is poorly soluble in water.
High bioavailability can be obtained even when administered orally.

The preparation of the present invention may further include a disintegrant, a lubricant,
It may contain conventional additives commonly used in the process of formulation, such as excipients and colorants. In addition, the dosage form is not particularly limited, and for oral administration, as desired,
It can be used as powder, fine granules, granules, capsules, tablets, film-coated tablets, etc.

Suitable water-soluble polymer compounds used in this preparation include those commonly used in the art, including cellulose derivatives (e.g.
hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, etc.), synthetic water-soluble polymer compounds (eg, polyvinylpyrrolidone, etc.), and the like. Among these, more preferred are cellulose derivatives, and most preferred are hydroxypropylmethylcellulose and hydroxypropylcellulose.

Suitable disintegrants include, for example, starches (e.g., potato starch, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, etc.), cellulose derivatives (e.g., carboxymethyl cellulose calcium, levoxymethyl cellulose, etc.). Suitable lubricants include:
For example, talc, waxes (e.g. beeswax, hydrogenated oil, etc.), stearic acids (e.g. stearic acid, magnesium stearate, calcium stearate, etc.)
etc., but suitable excipients include, for example, sugars (e.g.
lactose, sucrose, etc.), starches (e.g., corn starch, etc.), cellulose derivatives (e.g., crystalline cellulose, etc.), inorganic calcium salts (e.g., calcium hydrogen phosphate, calcium sulfate, etc.), and as suitable colorants. examples include tar dyes, but are not limited to these, and those commonly used in this field can be used.

The preparation containing the exyphon and water-soluble polymer compound of the present invention can be prepared by blending the above-mentioned water-soluble polymer compound and, if necessary, the above-mentioned conventional additives into the exyphon, and then leading to the desired dosage form. It can be manufactured by

Examples of methods for manufacturing the formulation of the present invention by blending a water-soluble polymer compound etc. with exiphon include a manufacturing method by introducing it into a solid dispersion and a manufacturing method by mixing. Each method will be explained in detail.

Method of production by dispersion into solids The formulations of the present invention can be produced by introducing the exiphone into a solid dispersion.

Methods commonly used in the art are used to blend the exiphone with a water-soluble polymer compound and, if necessary, conventional additives to form a solid dispersion.

For example, after dissolving exiphone in a suitable organic solvent (e.g., ethanol), adding a water-soluble polymer compound to this solution and dissolving it or uniformly dispersing it,
It can be produced by distilling off the solvent and drying using a conventional method.

If the water-soluble polymer compound does not dissolve when added, another organic solvent (e.g., methylene chloride) may be added to dissolve it. The selection depends on the water-soluble polymer compound used. This may be carried out as appropriate depending on the type of molecular compound.

The above-mentioned conventional additives may be added at the same time as the water-soluble polymer compound is dispersed, or after the solid dispersion consisting of the exiphon and the water-soluble polymer compound is prepared. , may be added thereto.

The thus obtained solid dispersion containing exiphone and a water-soluble polymer compound can be processed through various processes commonly used in the art, such as pulverization, filtration, kneading, granulation, tableting, and coating. can lead to a dosage form of Each of these steps can be performed by conventional methods.

The formulation of the present invention can be produced by mixing Exyphon with a water-soluble polymer compound and, if necessary, conventional additives.

The mixing method used in this method includes methods commonly used in the art. Further, the mixture may be pulverized for the purpose of further reducing the particle size, and pulverization can be carried out by a conventional method.

The mixed powder of Exiphone and water-soluble polymer compound etc. produced in this way can be prepared as desired.
Various dosage forms can be derived by the methods described in .

This mixing method is suitable for industrial production because of its simplicity.

In addition, in producing the formulation of the present invention by this method, after kneading the mixed powder using an appropriate kneading solvent,
Examples of suitable kneading solvents that are particularly preferred for leading to desired dosage forms include water, ethanol, and mixed solutions thereof.

By the method described above, a preparation containing the exiphon of the present invention and a water-soluble polymer compound can be produced. In its production, the types and amounts of the water-soluble polymer compounds and additives used are determined by, for example, the desired dosage form, the content of exiphon in it, or the elution pattern of exiphon. It can be selected as appropriate.

When the water-soluble polymer compound used is, for example, a cellulose derivative, the compounding ratio of exipone and the water-soluble polymer compound is 1:0.01 to 1 in terms of weight ratio.
It is preferably about 1.0.05 to 1.
:5.

Even when using other water-soluble polymer compounds, those skilled in the art can easily determine a suitable blending ratio by examining their elution patterns and the like.

1 Example j Hereinafter, the present invention will be explained in detail with reference to Examples.

[1] Production method by introducing into a solid dispersion 1 Kaniexyphon (10 g) is dissolved in ethanol (150111). xc-sR (5 g) (trademark: manufactured by Shin-Etsu Chemical Co., Ltd., general name: hydroxypropyl methylcellulose) is added to this solution and dispersed with stirring. moreover,
□Methylene chloride (501m2) is added to completely dissolve IC-5R, and then the solvent is distilled off.

After vacuum drying the residue overnight at room temperature, it was pulverized and sized (20
mesh ) L to obtain a solid dispersion.

A solid dispersion was obtained in the same manner as in Example 1 by adding Siphon (10 g) and TC-5R (2 g) to 1 porcelain.

11] 1 Engineering*shin*shin (10g) and TC-5R (10g),
A solid dispersion is obtained in the same manner as in Example 1.

Yomu 31 Exiphone (10g) ToTC-5R (30g)
Toyo? ), a solid dispersion is obtained in the same manner as in Example 1.

A solid dispersion was obtained in the same manner as in Example 1 from Exiphone (10 g) and TC-5R (50 g).

1 Todoroki] 1 Exyphon (Log) with ethanol (15011111
'), add TC-5R (5g'') to this solution and disperse it, then add methylene chloride (50ml) to completely dissolve TC-5R.Add Explotab to the resulting solution. (2.5 g) (trademark: Mokuzai Sangyo Co., Ltd., generic name: sodium carboxymethyl starch) is added and dispersed. After distilling off the solvent, the residue is vacuum dried overnight at room temperature, pulverized, and sized ( 20mesh) to obtain a solid dispersion.

[1 [] Production method by mixing 1. Mix 100g of Exiphone with TC-5R (5g) and Explotab (2.5g) in a plastic bag and shake well. -5R mixed treated powder is obtained.

Example 8 Exyphon (Log) and TC-5R (5 g) were placed in a plastic bag, mixed by shaking well, and then ground for 5 minutes using a coffee mill. Add this to the Explo tab (2,5
g) is added, placed in a plastic bag, and shaken well to mix well to obtain a TC-5R mixed treated powder of Exiphon.

X star■1 After mixing Exyphon (10g) with τC-5R (0.5g) in a beaker, add a 20% ethanol aqueous solution (4mQ
) for kneading and granulation. After vacuum drying, the mixture is crushed into a suitable size in a mortar and then filled into No. 0 capsules to obtain capsules.

The composition per capsule is as follows.

Exiphone 200mg21
0 ■ Tue m In the same manner as in Example 9, exiphon (10 g) and RPC
-L (0.5g) (trademark Nippon Soda Co., Ltd., generic name:
Hydroxypropyl cellulose) to obtain capsules having the following composition per capsule.

Exiphon 200111g
After mixing 10mg of exiphone (Log) with TC-5R (1.5g) in a beaker, add 20% ethanol aqueous solution (5ml).
x) to knead and granulate. After vacuum drying, the mixture is crushed in a mortar, Explotab (0.35 g) is added, and mixed by shaking well in a plastic bag to obtain a TC-5R treated powder.

This mixed powder is filled into No. 0 capsules to obtain capsules having the following composition per capsule.

Exiphone 200a@IC
-5R3oII1g Explotab 7■37In
Mg Stearate (0.15g)
and tableting by metering using a single tablet press to obtain tablets having the following composition per tablet:

Exiphone 200a@TC
-5R30■ EXPROTAB 7r@Magnesium stearate 3■40mg x181 In the same manner as in Example 9, EXPROTAB (10g) and TC-
5R (2.5 g) to obtain capsules having the following composition per capsule.

Exiphone 200■TC-
5R50mg 250■ and five groups Exiphone (10g), TC in the same manner as in Example 11
-5R (2,5g) and Explotab (2,5g)
Thus, capsules having the following composition per capsule are obtained.

Exiphone 200■TC-
SR50mg Exiphon (10g), τC in the same manner as in Example 11
Capsules having the following composition per capsule are obtained from -C-5R (5) and Explotab (2.5 g).

Exiphone 200■IC-
5R100■ In the same manner as in Example 11, exiphon (log), TC
From -5R (10 books) and Explotab (5g),
Capsules having the following composition per capsule are obtained.

Exiphone loOmgTC
-SRtooq Explotab SO11gzs
oa @ 1 1■ In the same manner as in Example 11, the exiphone (Log), TC
Capsules having the following composition per capsule are obtained from -5R (30 g) and Explotab (20 animals).

Exiphon 50mg Engineering C-
5R150■ In the same manner as in Example 11, the exiphone (Log), 'f
Capsules having the following composition per capsule are obtained from c-5R (50 g) and Explotab (20 g).

Exiphone 50k TC-5
R250＠W Exiphone (200g) and TC-5R (100g) were mixed by putting them in a plastic bag and shaking well, then
% ethanol aqueous solution (801111) as a kneading solvent and kneaded and granulated using a product type granulator. After vacuum drying the obtained grains at 40 ° C., they were crushed using a speed mill (20 mash), and the obtained powder was mixed with Explotab (27 g) in a plastic bag.
The product is filled into No. 0 capsules to obtain capsules having the following composition per capsule.

Exiphone 200■TC-
5R1oo Kame 27M 衷Jl Ren (1) In addition to the TC-5R treated powder obtained in Example 19 before capsule filling, Explotab, Avicel (trademark: manufactured by Asahi Kasei Corporation, generic name: crystalline cellulose) and magnesium stearate were added. After adding, tableting is performed by a conventional method to obtain tablets having the following composition per tablet.

Exiphone IC-5R Explotab Avicel 00teg 100Il1g 37@20I@360fi1g (2) This tablet was film-coated by a conventional method to obtain a film-coated tablet. The composition of the film coat layer per tablet is as shown below.

IC-5R 5,4a @ Polyethylene Glyfur 6000 0.8mg Titanium Oxide 1.7■ 8, Oag Higashiori Rui Exiphon (750g), IC-SR (375 animals), Explotab (101,25g'), Lactose (678,
75 g ) and Avicel (678.75 g) are mixed, and the mixed powder is kneaded and granulated using an aqueous solution of citric acid (18.75 g), dried and sized by a conventional method to obtain granules ( The resulting granules were mixed with magnesium stearate (33.08 g) and then tableted in a conventional manner. A film coat layer is applied to the obtained tablet by a conventional method to obtain a film coated tablet having the following composition per tablet.

K-based exiphone τC-5R Explotab citrate lactose Avicel 40 ■ 20 ■ 5,4 mg III@35,6 mg 36.2 mg 140 mg Film coat layer TC-5R3,8 mg Polyethylene glycol 6000 0.5ff1
gTitanium oxide O, 5sff
@Yellow red red red 0.14 o @Carnauba wax Trace amount mg rEffect of the invention In the formulation of the present invention, the solubility of Exiphon is significantly improved compared to its bulk powder, and it has sufficient bioavailability even when administered orally. − is obtained.

In order to clarify this point, dissolution test results and absorption test results in dogs will be described below regarding typical preparations obtained according to the present invention.

[1] Preparations used in the test Formulation A: Solid dispersion obtained in Example 1 (Exyphon: TC-5R Kaku 1:0.5) Formulation B: Obtained in Example 4 Solid dispersion (Exyphon: TC-5R-1: 3) Control preparation: 200 mg of Exyphon bulk powder filled into No. 0 capsules [1] Test method Dissolution test method described in the 11th revised Japanese Pharmacopoeia (Method 2) ) was used to measure the dissolution rate over time. The experimental conditions were as follows.

Elution tester: Toyama Sangyo ■Sample amount: 200mg as an exiphone Eluate and liquid volume: 1st solution (p) 11.2), 900mQ Paddle rotation speed: 100rpa+ Measurement: UV wavelength 385nm [1111 test results at each time] The elution rate was as follows.

From the above test results, it is clear that all of the preparations of the present invention manufactured by the manufacturing method described below have significantly improved dissolution patterns compared to the bulk powder. In other words, it has an exiphon! The drawback of l solubility was significantly improved.

Preparations used in the test [I] Preparation C: TC-5R mixed treatment powder of Exiphon obtained in Example 7 (Exiphon: TC-5R ■ 1:0.5) Formulation D: Example TC-5R of the exiphon obtained in 9.
Mixed processing capsule (exiphon; TC-5R Kaku 1:0.
05) Formulation E: RPC- of Exyphon obtained in Example 10
L mixed-processed capsules (Exyphon: Formulation F HPC-L-1: 0.05): TC-5R mixed-processed tablets of Exyphon obtained in Example 12 (Exyphone: TC-5R HPC-L-1: 0.15) Formulation G : Exyphon TC-5 obtained in Example 13
R mixed treatment capsule (exiphon = IC-51-1:
0.25) Formulation H: τC-5R of Exyphon obtained in Example 15
Mixed processing capsule (Exyphon II TC-5R-1: 0
．． 5) Control formulation: Control formulation used in WI release test 1 [I[] Test method The same method as used in dissolution test 1 was used.

[11[] Test results The elution rate at each time was as follows.

According to the above test results, the formulation of the present invention manufactured by 1Tategogo111Ki showed that the dissolution pattern was excellent regardless of whether it was mixed alone, when it was introduced into various drug layers, or when it was mixed at various mixing ratios. It can be seen that it is significantly improved compared to the bulk powder, and the drawback of Exxiphon's poor solubility has been significantly improved.

Conventionally, it was thought that only mixing a poorly soluble drug with a water-soluble polymer compound would hardly improve the solubility; however, just mixing it as in the formulation of the present invention significantly improves the solubility. That is to say, it is completely unexpected.

Naoise Meho 1 [I] Test Preparation Formulation I: The solid dispersion obtained in Example 6 was filled into No. 1: 0.5) Formulation J: Exyphon TC-5Rf obtained in Example 19
i Synthesized capsules (Exyphon; TC-5R-1:
0.5) Formulation K: Exyphon TC-5 obtained in Example 21
R mixed treatment film coated tablet (-r, +siphon: T
C-5R-1: 0.5) Control formulation: Control formulation used in dissolution test 1 CII test method The same method as used in dissolution test 1 was used.

CI[] test results The elution rate at each time was as follows.

In order to clarify that improved dissolution leads to improved absorption upon oral administration, we conducted an absorption experiment in dogs using a representative formulation of the present invention.The results are summarized below. show.

Bunsousha Kiyu [! ] Formulation 11 Formulation J used in Test Formulation Dissolution Test 3 and Control Formulation were used.

[1 [] Test method Male peagle dogs (body weight 9.0 to 1
An absorption experiment was conducted using 6 mice (1.5 kg) using a 3-way-crossover method.

The dose was 200 mg (1 capsule of each test preparation) of exiphone per large animal, and the drug was administered orally. After administration,
Blood samples were collected from the forearm vein over time and immediately subjected to HPL.
Exiphone was quantified by method C.

[1111 test results Plasma concentration at each time after oral administration, maximum plasma concentration (C
max), the time to reach the maximum plasma concentration (Tmax), and the lower end of the plasma concentration-time curve (AUG□-6) are shown in the table below, and each numerical value is shown as "standard error above the mean."

[1 [Test method] Male peagle-sized (weight 9.0-1
An absorption experiment was conducted using 6 mice (1.5 kg) using a 2-way-crossover method.

The dose was 200 mg (preparation J1 capsule; 5 tablets in the preparation) as exiphon per dog, and was administered orally. After administration, blood samples were collected from the forearm vein over time, and the amount of exiphon was immediately determined by HPLC.

CII [ ] test results Plasma concentration at each time after oral administration, maximum plasma concentration (C
max), the time to reach the maximum plasma concentration (Tmax), and the lower end of the plasma concentration-time curve (AUGo-B) are shown in the table below, and each value is expressed as r standard error above the mean.

[I] Test formulations Formulation J and Formulation K used in dissolution test 3 were used.

From the above test results, as expected from the results of dissolution test 3, the preparations of the present invention, both those obtained by -1-deriving and one-kei gokei-go-l, are superior to those obtained by exiphon base production. It is clear that the absorption into the blood is significantly increased compared to the final product.

From the various test results mentioned above, it has been found that the preparation containing the exiphon of the present invention and a water-soluble polymer compound has the disadvantage of being poorly soluble in water, which is the problem that the exiphon has, as well as the fact that there is a problem in blood levels during oral administration. It is clear that both of the low absorption properties have been significantly improved.
It can be said that the preparation containing the exiphon and water-soluble polymer compound of the present invention is extremely useful.

Claims (1)

[Scope of Claims] 1) A preparation characterized by containing exiphon and a water-soluble polymer compound. 2) The preparation according to claim 1, which contains a solid dispersion consisting of exiphon, a water-soluble polymer compound, and, if necessary, conventional additives. 3) The preparation according to claim 1, which contains a mixed powder consisting of exiphone, a water-soluble polymer compound, and, if necessary, a commonly used additive. 4) The preparation according to claim 2 or 3, wherein the water-soluble polymer compound is a cellulose derivative. 5) The formulation according to claim 4, wherein the compounding ratio of exiphon and the water-soluble polymer compound is about 1:0.01 to 1:7 by weight.