JP4357624B2 - Composition containing a disinfectant and digestive enzyme - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a composition comprising a bactericide, a bactericide, a contraindicated digestive enzyme, and a water-swellable substance. More specifically, the present invention relates to a digestive enzyme stabilization technique that is easily deactivated by the action of a bactericide.
[0002]
[Prior art]
A preparation containing a bactericidal agent and a digestive enzyme is an extremely useful antidiarrheal agent in that it is effective in treating bacterial diarrhea and also promotes intestinal regulation.
[0003]
However, when a poorly water-soluble disinfectant and the disinfectant and a contraindicated digestive enzyme are mixed and granulated into a preparation, the digestive enzyme is deactivated over time due to the action of the disinfectant.
[0004]
In order to produce a stable solid preparation by blending such a water-insoluble disinfectant and digestive enzyme, which are incompatible with such a combination, after forming both of them into separate granules, Inactivation of digestive enzymes can be achieved by preparing powders, granules or tablets, or preparing granules containing fungicides and digestive enzymes separately and making multilayer tablets so that the disinfectant and digestive enzymes do not come into contact with each other. Although a method of preventing it is conceivable, such a manufacturing method increases the number of manufacturing steps, takes time, and has a significant disadvantage in terms of manufacturing cost.
[0005]
[Problems to be solved by the invention]
The present invention provides a composition in which a sparingly water-soluble bactericidal agent and a bactericidal agent and a contraindicated digestive enzyme are blended to prevent inactivation of the digestive enzyme over time by a simple production method at a low cost. Is an issue.
[0006]
[Means for Solving the Problems]
As a result of diligent investigations to solve such problems, the present inventors have conducted extremely simple production in which a poorly water-soluble disinfectant and the disinfectant and a contraindicated digestive enzyme are mixed with a water-swellable substance and wet granulated. The present inventors have found that a composition that suppresses the inactivation of digestive enzymes over time can be produced by the method, and the present invention has been completed.
[0007]
That is, the present invention is a composition characterized by mixing a poorly water-soluble disinfectant, the disinfectant with a contraindicated digestive enzyme, and a water-swellable substance and performing wet granulation.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
The poorly water-soluble fungicide of the present invention is a drug having a bactericidal action with a solubility in water of 100 mg / L or less. Examples of such bactericides include bactericides such as berberine chloride, berberine tannate, creosote and phenyl salicylate. These fungicides may be blended alone or in combination of two or more.
[0009]
The digestive enzyme of the present invention is an enzyme having a digestive action having a contraindicated relationship with a poorly water-soluble fungicide, such as amylase, protease, lipase, and a complex enzyme thereof (for example, a complex enzyme of amylase and protease). ). These digestive enzymes may be blended singly or in combination of two or more.
[0010]
The water-swellable substance of the present invention is a fiber-based polymer having the property of absorbing water and expanding its volume, and is mainly used as an excipient in solid preparations. Examples include low-substituted hydroxypropylcellulose, croscarmellose sodium and carmellose calcium. These water-swellable substances may be blended singly or in combination of two or more.
[0011]
The blending weight ratio of the disinfectant of the present invention, the disinfectant and the incompatible digestive enzyme and the water-swellable substance is 0.5 to 6: 1: 1 to 10 and is stable by preventing inactivation of the digestive enzyme. 1 to 3: 1: 2 to 5 is preferable to obtain a digestive enzyme composition.
[0012]
Here, the contraindication is that when two or more drugs are mixed to form a preparation, the content value of at least one of the drugs is significantly reduced compared to the case where the drug is added alone, Refers to the relationship between drugs that change color. In the present invention, when a poorly water-soluble disinfectant and a digestive enzyme are mixed and then granulated into a preparation, the relationship between the content of the digestive enzyme in the preparation decreases with time due to the action of the disinfectant. It means something.
[0013]
Inactivation means that the content value of the digestive enzyme in the composition decreases with time. In the present invention, preventing digestive enzyme deactivation means that the residual activity rate of digestive enzyme is 80% or more when a composition containing the digestive enzyme is stored at 40 ° C. for 6 months.
[0014]
The mixing of the present invention refers to mixing a bactericide, a digestive enzyme, and a water-swellable substance, and various powder mixers such as a V-type mixer and a rocking mixer can be used for this mixing.
[0015]
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 granulating solvent, and stirring granulation, fluidized bed granulation, kneading Various granulation methods such as granulation and extrusion granulation can be mentioned.
[0016]
The composition in the present invention can be produced as follows.
[0017]
A required poorly water-soluble disinfectant, the disinfectant, a contraindicated digestive enzyme, and a water-swellable substance are mixed and pulverized with a pulverizer to make the powder more uniform. At this time, if the magnesium aluminate metasilicate is mixed before pulverization, generation of static electricity during pulverization can be prevented and pulverization can be performed smoothly. The obtained mixed powder can be produced by wet granulation using water or a mixture of water and alcohol as a granulating solvent.
[0018]
The composition comprising the poorly water-soluble disinfectant of the present invention, the disinfectant and a contraindicated digestive enzyme and a water-swellable substance is mainly provided as a solid preparation for internal use, and is a tablet, powder, granule, capsule It can be formulated into various solid preparations such as an agent.
[0019]
According to the present invention, a hardly water-soluble disinfectant and the disinfectant and a contraindicated digestive enzyme are separately granulated to form another granule, and then either one is coated or a multilayer tablet is used to disinfect the disinfectant and digestive enzyme. Even if it manufactures as the same granule without using the complicated manufacturing method which avoids contact of this, the stability with time of a digestive enzyme is securable.
[0020]
In addition, vitamins, lactic acid bacteria, bifidobacteria, and the like can be appropriately blended in the composition according to the present invention as necessary, and other excipients, for example, crystals, as long as the effects of the present invention are not impaired. Cellulose, lactose, starch and the like can also be blended.
[0021]
【The invention's effect】
According to the present invention, it has become possible to provide a low-cost oral solid preparation containing a sparingly water-soluble disinfectant and a disinfectant and a contraindicated digestive enzyme to prevent inactivation of the digestive enzyme.
[0022]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
Biodiastase (Amano Pharmaceutical Co., Ltd.) is a complex enzyme of amylase and protease.
[0023]
Example 1
(Prescription)
Berberine chloride 294 g
Biodiastase 158 g
Low substituted hydroxypropylcellulose 438 g
Magnesium aluminate metasilicate 35 g
Hydroxypropylcellulose 35 g
Each of the above components and amounts were weighed and mixed uniformly, and then pulverized with a pulverizer to make the powder uniform. The obtained mixed powder was granulated with a vertical granulator (manufactured by POWREC Co., Ltd.) using 180 g of seiseisui as a solvent, and dried with a fluidized bed dryer. 5 g of magnesium stearate was added, mixed and tableted to obtain a tablet having a tablet weight of 180 mg.
[0024]
Example 2
(Prescription)
Berberine chloride 294 g
Biodiastase 158 g
Croscarmellose sodium 438 g
Magnesium aluminate metasilicate 35 g
Hydroxypropylcellulose 35 g
After weighing and mixing the above components and amounts uniformly, a tablet having a tablet weight of 180 mg was obtained according to Example 1.
[0025]
Example 3
(Prescription)
Berberine chloride 294 g
Biodiastase 158 g
Carmellose calcium 438 g
Magnesium aluminate metasilicate 35 g
Hydroxypropylcellulose 35 g
After weighing and mixing the above components and amounts uniformly, a tablet having a tablet weight of 180 mg was obtained according to Example 1.
[0026]
Comparative Example 1
(Prescription)
Berberine chloride 294 g
Biodiastase 158 g
Crystalline cellulose 438 g
Magnesium aluminate metasilicate 35 g
Hydroxypropylcellulose 35 g
After weighing and mixing the above components and amounts uniformly, a tablet having a tablet weight of 180 mg was obtained according to Example 1.
[0027]
Comparative Example 2
(Prescription)
Berberine chloride 294 g
Biodiastase 158 g
Corn starch 438 g
Magnesium aluminate metasilicate 35 g
Hydroxypropylcellulose 35 g
After weighing and mixing the above components and amounts uniformly, a tablet having a tablet weight of 180 mg was obtained according to Example 1.
[0028]
Comparative Example 3
(Prescription)
Berberine chloride 294 g
Biodiastase 158 g
Mannitol 438 g
Magnesium aluminate metasilicate 35 g
Hydroxypropylcellulose 35 g
After weighing and mixing the above components and amounts uniformly, a tablet having a tablet weight of 180 mg was obtained according to Example 1.
Comparative Example 4
(Prescription)
Upper and lower granular crystalline cellulose 150 g
Aluminum hydroxide / sodium bicarbonate coprecipitate 2880 g
Hydroxypropylcellulose 600 g
After weighing and mixing each of the above components and amounts uniformly, the obtained mixed powder was granulated with a vertical granulator (manufactured by POWREC Co., Ltd.) using 385 g of ethanol as a solvent, and fluidized bed dryer. After drying, 2250 g of biodiastase, 1300 g of low-substituted hydroxypropylcellulose, 3000 g of aluminum hydroxide / sodium bicarbonate coprecipitate and 25 g of magnesium stearate were added and mixed uniformly to obtain upper and lower granules.
[0029]
Medium-granular granular cellulose 30 g
Aluminum hydroxide / bicarbonate coprecipitate 1800 g
Berberine chloride 2250 g
Hydroxypropylcellulose 300 g
After weighing and mixing each of the above components and amounts uniformly, the obtained mixed powder was granulated with a vertical granulator using 1375 g of ethanol as a solvent, dried in a fluidized bed dryer, and then low-substituted hydroxy 250 g of propylcellulose and 12.5 g of magnesium stearate were added and mixed uniformly to obtain intermediate layer granules.
[0030]
Each of the granules described above was tableted in the order of the lower layer, the middle layer, and the upper layer to obtain a three-layer tablet having an upper layer of 110 mg, a middle layer of 180 mg, and a lower layer of 110 mg, each weighing 400 mg.
[0031]
(Test Example 1)
The tablets obtained in Examples 1 to 3 and Comparative Examples 1 to 3 were each stored in a thermostatic chamber at 50 ° C., and the stability of biodiastase in the tablets after 8 weeks was compared.
The stability of biodiastase was expressed as the residual rate of amylase activity by the digestion test method and the saccharification test method described in the Japanese Pharmacopoeia.
The test results are shown in FIG.
[0032]
(Test Example 2)
The tablet obtained in Example 1 and the three-layer tablet obtained in Comparative Example 4 were stored in a thermostatic chamber at 40 ° C., and the stability of biodiastase in the tablet 6 months after the production was the same as in Test Example 1 It was evaluated by.
The test results are shown in FIG.
[0033]
From FIG. 1, in the case of tablets containing biodiastase, when low-substituted hydroxypropylcellulose (water swellable substance) is blended and wet granulated (Examples 1 to 3), fiber-based shaping with low water swellability Inactivation of biodiastase was milder than when wet granulation was carried out by blending an agent (crystalline cellulose) or an excipient (corn starch, mannitol) that was not a water-swellable substance (Comparative Examples 1 to 3).
[0034]
Moreover, from FIG. 2, when wet granulation is performed with low-substituted hydroxypropylcellulose (Example 1), the stability of biodiastase which is almost the same as that of a triple-layer tablet (Comparative Example 4) can be secured. It was.
[Brief description of the drawings]
FIG. 1 is a graph showing the stability over time of biodiastases of Examples 1 to 3 and Comparative Examples 1 to 3.
FIG. 2 is a graph showing the stability over time of the biodiastase of Example 1 and Comparative Example 4.

Claims (3)

One or more selected from the group consisting of (a) berberine chloride, (b) biodiastase, and (c) low-substituted hydroxypropylcellulose, croscarmellose sodium and carmellose calcium, 1-3: 1: A solid preparation for internal use, which is obtained by wet granulating a mixed powder containing 2 to 5 ratios. 1 to 147/79 is selected from the group consisting of (a) berberine chloride, (b) biodiastase, and (c) low-substituted hydroxypropylcellulose, croscarmellose sodium and carmellose calcium. 1: A solid preparation for internal use characterized by wet granulation of a mixed powder containing a ratio of 219 / 79-5. The oral solid preparation according to claim 1 or 2, wherein the residual amylase activity is 60% or more when stored at 50 ° C for 8 weeks.

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