JP2016204305A - Preparation method of irbesartan-containing tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide preparation methods of irbesartan-containing tablets in which the adhesion of irbesartan, an active ingredient, to a granulator can body at the time of kneading and granulating is inhibited, and also the adhesion to tableting equipment at the time of tableting is inhibited.SOLUTION: A preparation method of an irbesartan-containing tablet comprises: kneading and granulating, with water/ethanol mixed liquid as a binding liquid, a mixture which contains 48-58% by weight of irbesartan as an active ingredient, 2.5-3.5% by weight of hypromellose as a binder, 7-9% by weight of croscarmellose sodium as a disintegrant, based on a total weight of a tablet, and a diluent, without anti-adhesion agent, to obtain a granulated material; and adding 0.8-1.2% by weight of a lubricant to the material, wherein the adhesion of irbesartan, a principal drug, to a granulator can body is inhibited.SELECTED DRAWING: None

Description

  The present invention relates to a method for preparing a tablet containing irbesartan, and more particularly to a method for preparing an irbesartan-containing tablet in which adhesion of irbesartan, which is an active ingredient, to a granulator can body is suppressed.

Irbesartan having the chemical name 2-n-butyl-4-spirocyclopentane-1-[(2 ′-(tetrazol-5-yl) biphenyl-4-yl) methyl] -2-imidazolin-5-one (general Name: JAN, INN) is a long-acting Angiotensin II Receptor Blocker (ARB), a drug that is clinically used as a long-acting ARB to treat hypertension [Brand name: Avapro (registered trademark), Irbetan (registered trademark)].
For irbesartan, clinically proposed are tablets containing irbesartan alone or diuretics such as trichlormethiazide, and a combination tablet with a long-acting Ca antagonist, amlodipine besylate. Yes.

By the way, irbesartan is a fluffy substance, has a relatively small substantial weight and a very low density, and therefore has poor fluidity and extremely strong adhesion. There is a problem that the tableting efficiency is not good because it adheres to the surface of tableting knives and the mouse.
Therefore, in order to suppress the adhesion to the surface of tableting kinetics and mice, a proposal of a pharmaceutical composition containing irbesartan containing anti-adhesive agents such as silicon dioxide (anhydrous silicic acid), magnesium trisilicate, talc, etc. (Patent Document 1).

  However, with regard to the adhesion of irbesartan, not only does it adhere to the surface of tableting knives and mice at the time of tableting, but also adheres to the granulator can body during the preparation of granules for tableting. If the anti-adhesive agent is simply contained, adhesion to the granulator can body cannot be prevented, and the efficiency of preparation of irbesartan-containing tablets cannot be increased.

Japanese Patent No. 3162626 Japanese Patent No. 2868313

Accordingly, the present invention provides a method for preparing an irbesartan-containing tablet that suppresses the adhesion of irbesartan, which is an active ingredient, to a granulator can under the present situation, and further suppresses the adhesion to a tableting device during tableting. It is an issue to provide.
In order to solve such a problem, the present inventors have intensively studied, and as a result, do not contain the anti-adhesive agent proposed in the prior art, particularly in the granulation of tablets for tableting containing irbesartan. If kneading and granulating by using a water / ethanol mixture as the liquid, it is possible to suppress the adhesion of irbesartan to the granulator can body. As a result, it was found that the adhesion of the resin can be prevented, and the present invention has been completed.

Therefore, the present invention has the basic aspect as follows.
(1) Based on the total weight of the tablet, 48 to 58% by weight of active ingredient irbesartan, 2.5 to 3.5% by weight of hypromellose as binder, 7 to 9% by weight of disintegrant as a disintegrant Granules obtained by kneading and granulating a mixture containing carmellose sodium and a diluent and containing no anti-adhesive agent by using a water / ethanol mixture as a binding solution An irbesartan-containing tablet characterized by suppressing the adhesion of the active ingredient irbesartan to the granulator can body, comprising adding 0.8 to 1.2% by weight of a lubricant to tablets. Preparation method,
It is.

More specifically, the present invention
(2) The method for preparing an irbesartan-containing tablet according to (1) above, wherein the diluent is one or more selected from lactose, crystalline cellulose, and mannitol,
(3) The method for preparing an irbesartan-containing tablet according to the above (1), wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, or talc.
(4) A method for preparing an irbesartan-containing tablet according to (1), further comprising a surfactant and / or a colorant,
(5) The method for preparing an irbesartan-containing tablet according to the above (1) to (4), wherein the water / ethanol mixture as the binding liquid is a 25-55% aqueous ethanol solution,
It is.

The most specific present invention is:
(6) Based on the total weight of the tablet, 48 to 58% by weight of active ingredient irbesartan, 2.5 to 3.5% by weight of hypromellose as binder, 7 to 9% by weight of disintegrant as a disintegrant A mixture containing carmellose sodium and lactose and crystalline cellulose as diluents and containing no anti-adhesive agent is a water / ethanol mixture of water / ethanol = 25-55 / 75-45 as a binding solution. Granulation of the main ingredient irbesartan, which comprises kneading and granulating, and adding 0.8 to 1.2% by weight of magnesium stearate to the resulting granulated product for tableting A method for preparing an irbesartan-containing tablet characterized by suppressing adhesion to the machine can body,
It is.

  According to the present invention, when preparing an irbesartan-containing tablet, it is possible to suppress the adhesion of irbesartan to the granulator can body, and further, even when the tablet is tableted, it is possible to prevent the tablet from sticking to the surface of the tableting kin and the mouse. The granule efficiency is good, the tableting efficiency of the tablets is improved, and a preparation method excellent in the production efficiency of irbesartan-containing tablets that are extremely useful in pharmacology can be provided, and its usefulness is enormous.

  As described above, the present invention is based on the total weight of the tablet, based on 48 to 58% by weight of active ingredient irbesartan, 2.5 to 3.5% by weight of hypromellose as a binder, 7 to A mixture containing 9% by weight of croscarmellose sodium as a disintegrant and a diluent and containing no anti-adhesive agent is kneaded and formed by using a water / ethanol mixture as a binding solution. It was granulated, and 0.8 to 1.2% by weight of lubricant was added to the resulting granulated product, and tableting was suppressed. Adhesion of the active ingredient irbesartan to the granulator can body was suppressed. This is a method for preparing an irbesartan-containing tablet.

In this specification, irbesartan means irbesartan or a pharmaceutically acceptable salt or solvate thereof.
This irbesartan itself, including its production method, is described in, for example, Japanese Patent No. 2868313 (Patent Document 2).

The content of irbesartan in the irbesartan-containing tablet provided by the present invention may be an amount exhibiting a normal drug effect, and specifically, 48 to 58% by weight based on the total weight of the preparation.
In addition, in the irbesartan-containing tablet that is clinically used, since the content is a tablet containing 50 mg, 100 mg, and 200 mg, the irbesartan-containing tablet provided by the present invention includes The amount is preferably 50 mg, 100 mg and 200 mg containing tablets.
Therefore, the total weight of the irbesartan-containing tablet provided by the present invention is combined with other binders, disintegrants, diluents, etc. that are blended corresponding to each effective content of irbesartan. What is necessary is just to make it 48 to 58 weight% on the basis of the total weight of a tablet.

As a binder compounded in the irbesartan-containing tablet provided by the present invention, for example, among various binders, there is one feature in that hypromellose (old pharmacopeia name: hydroxypropylmethylcellulose) is used.
The blending amount is 2.5 to 3.5% by weight based on the total weight of the tablet. When it is less than 2.5% by weight or exceeds 3.5% by weight, the desired disintegration property of the tablet cannot be obtained in relation to the blending amount with other disintegrants, diluents, etc. There is.

Moreover, croscarmellose sodium is selected as a disintegrating agent blended in the irbesartan-containing tablet of the present invention.
There are various disintegrants in terms of pharmacology, but in the irbesartan-containing tablet of the present invention, croscarmellose sodium is used as a disintegrant in comparison with the combination with hypromellose used as a binder. It has one characteristic.
The amount of the disintegrant is 7 to 9% by weight based on the total weight of the tablet. When it is less than 7% by weight or more than 9% by weight, the desired disintegration property of the tablet cannot be obtained due to the blending amount with other binders, diluents and the like, which is not preferable.

Furthermore, in the irbesartan-containing tablet provided by the present invention, a diluent is blended as the remaining blended component that satisfies the desired tablet weight.
Although it does not specifically limit as a diluent, In this invention, it is good to use 1 or more types selected from lactose, crystalline cellulose, and mannitol as a diluent. Among them, it is preferable to use lactose and crystalline cellulose in combination.

Furthermore, the irbesartan-containing tablet provided by the present invention may contain a surfactant and / or a colorant within a range that does not affect the moldability, disintegration, etc. of the tablet.
Examples of such surfactants include, but are not limited to, sodium lauryl sulfate and poloxamers, and examples of colorants include titanium oxide, yellow ferric oxide, three Can include edible pigments such as iron dioxide, edible red No. 3, edible yellow No. 5, edible blue No. 1, brown iron oxide, black iron oxide, copper chlorophyll, copper chlorophyllin sodium, riboflavin, powdered green tea powder, among others Titanium oxide is preferably used.

By the way, in preparation of the conventional tablet containing irbesartan, an anti-adhesive agent is blended as an essential component in order to suppress the adhesiveness of irbesartan to the tableting kinetics and the surface of the mouse (Patent Document 1). Examples of such anti-adhesive agents include silicon dioxide (light anhydrous silicic acid), magnesium trisilicate, and the like.
However, according to the study by the present inventors, even when these anti-adhesive agents are blended, in the preparation of tableting granules carried out before tableting, the adhesion of irbesartan to the granulator can body And the workability in the granulation process was significantly reduced.

  As a result of intensive studies to improve the point, as described above without containing an anti-adhesive agent, irbesartan as an active ingredient, hypromellose as a binder, croscarmellose sodium as a disintegrant, and dilution When a mixture containing an agent is kneaded and granulated by using a water / ethanol mixture as a binding liquid, the adhesion of irbesartan to the granulator can body is suppressed, and the granules for tableting are excellent. It was prepared and surprisingly found that there was no irbesartan adherence to the surface of tableting kinetics or mice when tableting using the prepared tableting granules.

  In the preparation of the granules for tableting, when using the commonly used purified water as the binding liquid, it is not only possible to prevent the adhesion of irbesartan to the granulator can body, but also the tableting obtained In the case of tableting using a granule for use, it was difficult to prevent irbesartan from adhering to the surface of tableting knives and mice.

As a result of investigation, the water / ethanol mixture used as the binding liquid has been found to have a water / ethanol mixture ratio of 25 to 55% aqueous ethanol.
If the ethanol ratio is less than 25%, it is not possible to prevent irbesartan from adhering to the granulator can body, and if it exceeds 55%, the ethanol content is high, which is not preferable for work. .
Therefore, in the preparation of the irbesartan-containing tablet provided by the present invention, when mixing and granulating the mixture of the components constituting the tablet, a water / ethanol mixture having a specific ratio, which has not been studied so far, is used. It has one characteristic.

The irbesartan-containing tablet provided by the present invention is prepared, for example, as follows.
That is, the compounding component which comprises a tablet is mixed, the kneading and granulation is carried out using a binding liquid, and the tableting granule for tableting to a tablet is prepared.
Subsequently, using the obtained granule for granulation, a lubricant is added and tableted to prepare an irbesartan-containing tablet.
As the lubricant to be used, there are various pharmaceutically acceptable lubricants, and examples thereof include talc and magnesium stearate. Among them, magnesium stearate is preferably used. The added amount is preferably 0.8 to 1.2% by weight based on the total weight of the target irbesartan-containing tablet of the present invention.

  In the preparation of the irbesartan-containing tablet provided by the present invention, the adhesion of irbesartan to the surface of tableting kinetics or the mouse was suppressed even when the tablet was compressed.

The irbesartan-containing tablet of the present invention prepared as described above can be coated with a coating film based on a normal formulation technique.
Examples of such coating agents include various pharmaceutically acceptable coating agents such as hypromellose, polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropyl cellulose, PVA copolymer, opadry, carnauba wax and the like.

Among them, it is particularly preferable to use hypromellose as a coating film.
The content of the coating agent is 0.05 to 10% by weight, preferably 0.075 to 5% by weight, more preferably 0.1 to 2.5% by weight, based on the total amount of the preparation.

In addition, in this invention, when coating with the said coating agent, you may contain a coloring agent and a plasticizer with a coating agent. Any colorant or plasticizer may be used as long as it is pharmaceutically acceptable.
Specifically, as coloring agents, titanium oxide, yellow ferric oxide, ferric oxide, edible red No. 3, edible yellow No. 5, edible blue No. 1, etc., edible pigments, brown iron oxide, black iron oxide, copper chlorophyll , Copper chlorophyllin sodium, riboflavin, powdered green tea powder, etc. Among them, it is preferable to use titanium oxide.
Examples of the plasticizer include triethyl citrate and polyethylene glycol, and triethyl citrate is particularly preferably used.
Although the usage-amount of a coloring agent and a plasticizer cannot be generally limited with the usage-amount of the coating agent to be used, it is about 1.0 to 3.0 weight%.

  Hereinafter, the present invention will be described in more detail with reference to examples and comparative examples. However, the present invention is not limited to these examples, and various modifications are possible without departing from the technical idea of the present invention. Is possible.

Examples 1-6 :
Irbesartan-containing tablets (Example products) were prepared according to the formulation shown in Table 1 below.

<Preparation of granules for tableting>
That is, the mixture excluding the lubricant in the formulation shown in Table 1 was kneaded and granulated using a vertical granulator and water / ethanol mixed solutions having different ethanol concentrations as a binding solution.
The presence or absence of irbesartan adhesion to the granulator can body during the granulation was evaluated, and the results are shown in the table.

<Preparation of tablets>
A lubricant (magnesium stearate) was added to the granulation granules obtained above, and tableting was performed at a tableting pressure of 4 to 11 kN / cm ² to obtain irbesartan-containing tablets.
The presence or absence of adhesion of irbesartan to the tableting kinetics and the surface of the mouse at the time of tableting was evaluated, and the results are also shown in the table.

* 1: Evaluation of adhesion of granulator can body +: Many (severe)-: Mild to not recognized * 2: Adhesion evaluation during tableting +: Accepted-: Mild to not recognized

Comparative Examples 1-6 :
According to the formulation shown in Table 2 below. Irbesartan-containing tablets (comparative example products) were prepared in the same manner as in the examples.
The same evaluation was made for the presence or absence of irbesartan adhesion to the granulator can body during its preparation, and the presence or absence of irbesartan tableting kinetics and tablet surface adhesion during granulation granulation, and the results were combined. It is shown in the table.

  As can be seen from the results shown in Table 1 above (Examples 1 to 6), the irbesartan-containing tablet of the present invention does not contain an anti-adhesive agent (light silicic anhydride) and is a granule for tableting. The use of an aqueous 25-55% ethanol solution as a binding solution in the step of preparing irbesartan is suppressed in the granulator can body, and tablets are prepared using the prepared granules. Even at the time of tableting for preparing irbesartan, the adhesion of irbesartan to the surface of tableting kine and the mouse was suppressed.

On the other hand, as shown in Table 2 (Comparative Examples 1 to 6), when it does not contain an anti-adhesive agent (light anhydrous silicic acid), it is kneaded and granulated using purified water as a binding solution , There is much adhesion of irbesartan to the granulator can body, and in the case of tableting using the obtained granule, adhesion of irbesartan to the surface of tableting kinetics and the mouse is recognized at the time of tableting (Comparative Examples 1 and 4).
Furthermore, in the case of containing an anti-adhesive agent (light silicic anhydride), although tableting of irbesartan on tableting kinetics and the surface of the mouse is suppressed during tableting, preparation of granules for tableting At the time of kneading and granulation using purified water as a binder, adhesion to the granulator can body was observed (Comparative Examples 2 and 5).

  In addition, when 10% ethanol aqueous solution in the preparation of tableting granules is used as a binder without containing an anti-adhesive agent (light anhydrous silicic acid), irbesartan can be added to the granulator can body during kneading and granulation. Adhesion was observed (Comparative Examples 3 and 6), and the specificity of the present invention using 25-55% ethanol aqueous solution as the binding solution was confirmed.

Example 7: Preparation of film-coated tablets Film-coated tablets were prepared using the tablets obtained in Examples 1 to 6 described above.
That is, using the tablets obtained in Examples 1 to 6, titanium oxide was used as a colorant, triethyl citrate was used as a plasticizer, and a film coat film was applied with hypromellose to obtain film-coated tablets. Film-coated tablets were prepared.

  As described above, according to the present invention, when preparing an irbesartan-containing tablet, it is possible to suppress the adhesion of irbesartan to the granulator can body, and in addition, even when tableting without containing an anti-adhesive agent, It was possible to provide a preparation method excellent in production efficiency of irbesartan-containing tablets with suppressed adhesion of kine or us to the surface.

Claims (6)

  Based on the total weight of the tablet, 48 to 58% by weight of irbesartan as active ingredient, 2.5 to 3.5% by weight of hypromellose as binder, 7 to 9% by weight of croscarmellose sodium as disintegrant And a mixture containing a diluent and containing no anti-adhesive agent is kneaded and granulated by using a water / ethanol mixed solution as a binding solution. A method for preparing an irbesartan-containing tablet, characterized in that adhesion of the active ingredient irbesartan to a granulator can body is suppressed, which comprises tableting by adding 8 to 1.2% by weight of a lubricant.   The method for preparing an irbesartan-containing tablet according to claim 1, wherein the diluent is one or more selected from lactose, crystalline cellulose, and mannitol.   The method for preparing an irbesartan-containing tablet according to claim 1, wherein the lubricant is one or more selected from magnesium stearate, calcium stearate, or talc.   Furthermore, the preparation method of the irbesartan containing tablet of Claim 1 containing surfactant and / or a coloring agent.   The method for preparing an irbesartan-containing tablet according to any one of claims 1 to 4, wherein the water / ethanol mixture as the binding liquid is a 25-55% aqueous ethanol solution.   Based on the total weight of the tablet, 48 to 58% by weight of irbesartan as active ingredient, 2.5 to 3.5% by weight of hypromellose as binder, 7 to 9% by weight of croscarmellose sodium as disintegrant And a mixture containing lactose and crystalline cellulose as diluents and containing no anti-adhesive agent, and using a water / ethanol mixture of water / ethanol = 25-55 / 75-45 as a binding solution The main ingredient irbesartan granulator can comprising kneading and granulating by adding 0.8 to 1.2% by weight of magnesium stearate and tableting. A method for preparing an irbesartan-containing tablet, characterized in that adhesion to the tablet is suppressed.