JP2000026310A - Composition containing germicide and digestive enzyme formulated therein - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply obtain the subject composition capable of preventing the inactivation of a digestive enzyme with time by mixing a sparingly water-soluble germicide with the digestive enzyme which is incompatible with the germicide together with a water-swellable substance and wet granulating the resultant mixture. SOLUTION: This composition is obtained by mixing (A) a sparingly water-soluble germicide (preferably berberine chloride, berberine tannate, creosote and phenyl salicylate) with (B) a digestive enzyme which is incompatible with the ingredient A (preferably an amylase, a protease, a lipase and a complex enzyme thereof) and (C) a water-swellable substance (preferably hydroxypropyl cellulose having a low degree of substitution, carmellose calcium or croscarmellose sodium) and wet granulating the resultant mixture. The formulating ratio of the respective ingredients is preferably (0.5-6):1:(1-10) of the ingredients A:B:C. The composition is preferably a solid pharmaceutical preparation for internal use. Thereby, stabilized effects can be expected and effects on treatment for bacterial diarrhea can be expected.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a fungicide, a composition comprising the fungicide, a digestive enzyme contraindicated in combination with the fungicide, and a water-swellable substance. More specifically, the present invention relates to a technology for stabilizing digestive enzymes which are easily deactivated by the action of a bactericide.

[0002]

2. Description of the Related Art A preparation containing a bactericide and a digestive enzyme is an extremely useful antidiarrheal in that it is effective in treating bacterial diarrhea and promotes intestinal action.

[0003] However, when a water-insoluble disinfectant and a disinfectant and a digestive enzyme contraindicated in combination are mixed and granulated to produce a formulation, the action of the disinfectant degrades the digestive enzyme over time. there were.

[0004] In order to produce a stable solid preparation by mixing a poorly water-soluble disinfectant and a digestive enzyme, which are contraindicated in such a formulation, at least one of the granules is coated with at least one of the granules and then coated. Multigranular powders, granules or tablets, or, by separately producing granules containing a bactericide and digestive enzymes, by forming a multilayer tablet so that the bactericide and digestive enzymes do not contact, Although a method of preventing deactivation is also conceivable, such a manufacturing method increases the number of manufacturing steps, requires time and effort, and has a remarkable disadvantage in manufacturing cost.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a bactericide having poor water solubility and a digestive enzyme which is contraindicated in combination with the bactericide.
It is an object of the present invention to provide a composition that prevents the inactivation of digestive enzymes over time by a simple production method at low cost.

[0006]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, mixed a bactericide with poor water solubility and a digestive enzyme contraindicated in combination with the bactericide together with a water-swellable substance. The present inventors have found that a composition in which the deactivation of digestive enzymes with time is suppressed can be produced by an extremely simple production method of wet granulation, and the present invention has been completed.

That is, the present invention provides a bactericide having poor water solubility.
A composition obtained by mixing the bactericide, a concomitant digestive enzyme and a water-swellable substance, and performing wet granulation.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The poorly water-soluble bactericide of the present invention is
It is a drug having a bactericidal action whose solubility in water is 100 mg / L or less. Such fungicides include, for example, fungicides such as berberine chloride, berberine tannate, creosote and phenyl salicylate. These fungicides may be blended alone,
Moreover, you may mix and mix 2 or more types.

The digestive enzyme of the present invention is an enzyme having a digestive action which is contraindicated in combination with a poorly water-soluble germicide. Examples thereof include amylase, protease, lipase and their complex enzymes (for example, amylase and protease). Complex enzyme). These digestive enzymes may be used alone or in combination of two or more.

The water-swellable substance of the present invention is a fibrous polymer having the property of absorbing water and expanding in volume, and is used mainly as an excipient in solid preparations. is there. Examples include low substituted hydroxypropylcellulose, croscarmellose sodium and carmellose calcium. These water-swellable substances may be used alone or in combination of two or more.

The bactericide of the present invention, the weight ratio of the bactericide to the concomitant concomitant digestive enzyme and water-swellable substance is 0.5 to
6: 1: 1-10, and 1-3: 1: 2 in order to prevent the inactivation of digestive enzymes and obtain a stable digestive enzyme-containing composition.
To 5 are preferred.

[0012] Here, incompatibility means that when two or more drugs are mixed and formulated, the content value of at least one of the drugs is significantly reduced as compared with the case where the drugs are used alone. And the relationship between drugs that causes discoloration of the preparation. In the present invention, when a poorly water-soluble disinfectant and a digestive enzyme are mixed and then granulated to form a formulation, the interaction of the digestive enzyme content value in the formulation with time decreases due to the action of the disinfectant. It is to say.

[0013] Inactivation means that the content of digestive enzymes in the composition decreases over time. To prevent the inactivation of digestive enzymes in the present invention means that the residual activity of digestive enzymes is 80% when the composition containing digestive enzymes is stored at 40 ° C. for 6 months.
It is the above.

The mixing according to the present invention refers to mixing a bactericide, a digestive enzyme, and a water-swellable substance.
Various powder mixers such as a mold mixer and a rocking mixer can be used.

The wet granulation of the present invention is a method of granulating a powder by using water or a mixed liquid of water and alcohol as a solvent for granulation, and preparing the mixture by stirring granulation, fluidized bed granulation, Various granulation methods such as kneading granulation and extrusion granulation may be mentioned.

The composition of the present invention can be produced as follows.

The required water-insoluble bactericide, the bactericide, a digestive enzyme contraindicated for incorporation, and a water-swellable substance are mixed and crushed with a crusher to make the powder more uniform. At this time, if the magnesium aluminate metasilicate is mixed before the pulverization, the generation of static electricity during the pulverization can be prevented and the pulverization can be performed smoothly. The obtained mixed powder can be produced by wet granulation using water or a mixed solution of water and alcohol as a granulating solvent.

The poorly water-soluble disinfectant of the present invention, the composition comprising the disinfectant, the contraindicated digestive enzyme, and the water-swellable substance are mainly provided as a solid preparation for internal use, and include tablets, powders, and granules. It can be formulated into various solid preparations such as preparations and capsules.

According to the present invention, the disinfectant can be prepared by separately granulating the poorly water-soluble disinfectant and the disinfectant digestive enzyme and its contraindicated digestive enzymes into separate granules, or by forming a multilayer tablet to form a multi-layer tablet. The stability of the digestive enzyme over time can be ensured even if it is manufactured as the same granules without using a complicated manufacturing method that avoids contact between the digestive enzyme and the digestive enzyme.

The composition according to the present invention may optionally contain vitamins, lactic acid bacteria, bifidobacteria and the like, if necessary, and other excipients, as long as the effects of the present invention are not impaired. For example, crystalline cellulose, lactose, starch and the like can be blended.

[0021]

Industrial Applicability According to the present invention, it is possible to provide a low-cost solid preparation for oral administration in which a poorly water-soluble disinfectant and a disinfectant digestive enzyme are combined with the disinfectant to prevent inactivation of the digestive enzyme. Was.

[0022]

Examples Examples, comparative examples and test examples are given below.
The present invention will be described in more detail. Biodiastase (Amano Pharmaceutical Co., Ltd.) is a complex enzyme of amylase and protease.

Example 1 (Prescription) Berberine chloride 294 g Biodiastase 158 g Low-substituted hydroxypropylcellulose 438 g Magnesium aluminate metasilicate 35 g Hydroxypropylcellulose 35 g After weighing and uniformly mixing the above components and amounts, The powder was pulverized with a pulverizer to make the powder uniform. The obtained mixed powder was granulated with a vertical granulator (manufactured by Powrex Co., Ltd.) using 180 g of SEI SUI as a solvent, and dried with a fluid bed dryer. Tablets were added and mixed with 5 g of magnesium stearate to obtain tablets each weighing 180 mg.

Example 2 (Prescription) Berberine chloride 294 g Biodiastase 158 g Croscarmellose sodium 438 g Magnesium aluminate metasilicate 35 g Hydroxypropylcellulose 35 g The above components and amounts were weighed and uniformly mixed. A tablet weighing 180 mg per tablet was obtained according to Example 1.

Example 3 (Formulation) Berberine chloride 294 g Biodiastase 158 g Carmellose calcium 438 g Magnesium aluminate metasilicate 35 g Hydroxypropylcellulose 35 g The above components and amounts were weighed and uniformly mixed. In accordance with No.1, a tablet weighing 180 mg was obtained.

Comparative Example 1 (Prescription) Berberine chloride 294 g Biodiastase 158 g Microcrystalline cellulose 438 g Magnesium metasilicate aluminate 35 g Hydroxypropylcellulose 35 g The above components and amounts were weighed and uniformly mixed. To obtain a tablet weighing 180 mg per tablet.

Comparative Example 2 (Prescription) berberine chloride 294 g biodiastase 158 g corn starch 438 g magnesium metasilicate aluminate 35 g hydroxypropylcellulose 35 g After weighing and uniformly mixing the above components and amounts, the same procedure as in Example 1 was carried out. As a result, a tablet weighing 180 mg was obtained.

Comparative Example 3 (Prescription) Berberine chloride 294 g Biodiastase 158 g Mannitol 438 g Magnesium metasilicate aluminate 35 g Hydroxypropylcellulose 35 g After weighing and uniformly mixing the above components and amounts, Example 1 was repeated. As a result, a tablet weighing 180 mg was obtained. Comparative Example 4 (Prescription) Upper and Lower Granules Crystalline Cellulose 150 g Aluminum hydroxide / sodium bicarbonate coprecipitate 2880 g Hydroxypropylcellulose 600 g Each of the above components and amounts was weighed and uniformly mixed, and then the obtained mixture was mixed. The powder is granulated with a vertical granulator (manufactured by Powrex Co., Ltd.) using 385 g of ethanol as a solvent, dried with a fluid bed drier, and then 2250 g of biodiastase, 1300 g of low-substituted hydroxypropylcellulose, and aluminum hydroxide. 3000 g of sodium hydrogencarbonate coprecipitate and 25 g of magnesium stearate were added and mixed uniformly to obtain upper and lower granules.

Middle-layer granules Crystalline cellulose 30 g Aluminum hydroxide / sodium bicarbonate coprecipitate 1800 g Berberine chloride 2250 g Hydroxypropylcellulose 300 g After weighing and uniformly mixing the above components and amounts, the obtained mixed powder 1375 g of ethanol
, Using a vertical granulator as a solvent and drying with a fluid bed dryer, 250 g of low-substituted hydroxypropylcellulose and magnesium stearate 12.
5 g was added and mixed uniformly to obtain a middle layer granule.

Each of the above granules is tableted in the order of the lower layer, the middle layer and the upper layer.
Thus, a three-layer tablet weighing 400 mg per tablet was obtained.

(Test Example 1) Examples 1 to 3 and Comparative Example 1
Each of the tablets obtained in (3) to (3) was stored in a constant temperature room at 50 ° C.
The stability of biodiastase in the tablets after a week was compared. The stability of biodiastase was expressed as the residual activity of amylase by the digestion test method and the starch saccharification test method described in the Japanese Pharmacopoeia. The test results are shown in FIG.

Test Example 2 The tablets obtained in Example 1 and the three-layer tablets obtained in Comparative Example 4 were stored in a constant temperature room at 40 ° C., and the stability of biodiastase in the tablets after 6 months from immediately after the production. Was evaluated in the same manner as in Test Example 1. The test results are shown in FIG.

As shown in FIG. 1, when a tablet containing bio-diastase was blended with low-substituted hydroxypropylcellulose (water-swellable substance) and wet-granulated (Examples 1 to 3), a fiber having a small water-swelling property was obtained. Bioplastase deactivation was slower than when wet granulation was carried out by mixing a system excipient (crystalline cellulose) or an excipient that was not a water-swellable substance (corn starch, mannitol) (Comparative Examples 1 to 3). .

FIG. 2 shows that the wet granulation was carried out together with the low-substituted hydroxypropylcellulose (Example 1).
Showed that the same biostability as that of a three-layer tablet (Comparative Example 4) could be secured.

[Brief description of the drawings]

FIG. 1 is a graph showing the stability over time of biodiastase of Examples 1 to 3 and Comparative Examples 1 to 3.

FIG. 2 is a graph showing the stability over time of biodiastase of Example 1 and Comparative Example 4.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/38 A61K 9/14

Claims (6)

[Claims] 1. A composition characterized by mixing a poorly water-soluble disinfectant, a disinfectant digestive enzyme and a water-swellable substance which are contraindicated in combination, and wet granulating the mixture. 2. A bactericide having poor solubility in water, a disinfectant, a concomitant digestive enzyme and a water-swellable substance in a mixing ratio of 0.5 to 6:
The composition according to claim 1, wherein the ratio is from 1: 1 to 10. 3. The composition according to claim 1, wherein the poorly water-soluble fungicide is one or more selected from the group consisting of berberine chloride, berberine tannate, creosote, and phenyl salicylate. 4. The digestive enzyme is an amylase, a protease,
The composition according to claim 1, wherein the composition is at least one member selected from the group consisting of lipases and complex enzymes thereof. 5. The composition according to claim 1, wherein the water-swellable substance is at least one member selected from the group consisting of low-substituted hydroxypropylcellulose, carmellose calcium, and croscarmellose sodium. 6. The composition according to claim 1, which is a solid preparation for internal use.