JP2017052752A - Pharmaceutical composition containing irbesartan, and production method of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition and a production method thereof in which stability of active ingredients can be secured in all areas from a point of production to a point after a distribution process, and thus can maintain stable physical properties which is a constant elution rate for example.SOLUTION: A pharmaceutical composition contains irbesartan, lactose hydrate and/or crystalline cellulose, and povidone. The pharmaceutical composition may further contain amlodipine besilate. In a method for producing a pharmaceutical composition, mixture containing irbesartan, lactose hydrate and/or crystalline cellulose, and povidone is granulated by stirring granulation or fluidized bed granulation. In the production method, the mixture may further contain amlodipine besilate.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a pharmaceutical composition containing irbesartan and a method for producing the same.

Pharmaceutical compositions containing various active ingredients have been developed. Depending on the type of active ingredient, the pharmaceutical composition can be attributed to the manufacturing method and / or the type of additives such as excipients other than the active ingredient. Changes may be recognized in the physical properties of the composition itself (see, for example, Patent Documents 1 and 2).
Moreover, in the case of a pharmaceutical composition using two or more active ingredients in combination, the stability of any one or a plurality of active ingredients is increased not only due to the type of additive but also due to contact of the active ingredients. In some cases, it may cause damage and induction of related substances (for example, see Patent Document 3).

Special table 2008-501680 JP 2010-053047 A JP 2013-078893 A

There is a need for a pharmaceutical composition that can maintain stable physical properties over the entire distribution process from the time of manufacture, in particular, a constant dissolution rate over a long period of time.
The present invention provides a pharmaceutical composition capable of ensuring the stability of an active ingredient from the time of production to after the distribution process, and thus maintaining stable physical properties, for example, a constant dissolution rate, and a method for producing the same. For the purpose.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have combined polyvinyl pyrrolidone, which is a well-known component, and crystalline cellulose and / or lactose hydrate. It is shown that a pharmaceutical composition containing irbesartan exhibiting good dissolution properties, and particularly exhibiting good dissolution properties under various conditions expected in the distribution process, especially after severe tests, can be obtained. The headline, the present invention has been completed.
Further, the present inventors have found that a pharmaceutical composition containing irbesartan exhibiting better dissolution properties can be obtained by combining croscarmellose sodium and / or magnesium stearate in addition to the above-described components. It was.

That is, this application includes the following inventions.
[1] A pharmaceutical composition comprising irbesartan, lactose hydrate and / or crystalline cellulose, and povidone.
[2] The pharmaceutical composition described above further comprising amlodipine besylate.
[3] The above-mentioned pharmaceutical composition further comprising croscarmellose sodium.
[4] The pharmaceutical composition described above further comprising magnesium stearate.
[5] The pharmaceutical composition described above, wherein the dissolution rate of irbesartan is 80% or more when stored for 30 minutes in accordance with the dissolution test (paddle method) described in the Japanese Pharmacopoeia after storage at 60 ° C. and 75% RH for 2 weeks object.
[6] A method for producing a pharmaceutical composition, comprising granulating a mixture containing irbesartan, lactose hydrate and / or crystalline cellulose, and povidone by stirring granulation or fluidized bed granulation.
[7] The method for producing a pharmaceutical composition as described above, wherein the mixture further contains amlodipine besylate.

According to the pharmaceutical composition containing irbesartan of the present invention, the stability of the active ingredient can be ensured throughout the entire distribution process from the time of manufacture, and thus stable physical properties such as a constant dissolution rate can be maintained.
Moreover, according to the method for producing a pharmaceutical composition of the present invention, the stability of the active ingredient can be ensured throughout the entire distribution process from the time of production, and thus stable physical properties such as a constant dissolution rate can be maintained. A pharmaceutical composition can be produced reliably and simply.

It is a graph which shows the elution rate after 1 week of the severe test of the pharmaceutical composition of the single active ingredient of this invention. It is a graph which shows the elution rate after 2 weeks of the severe test of the pharmaceutical composition of the single active ingredient of this invention. It is a graph which shows the elution rate by the difference in the manufacturing method of the pharmaceutical composition of the single active ingredient of this invention. It is a graph which shows the elution rate of amlodipine besilate in the pharmaceutical composition of 2 types of active ingredient combination of this invention. It is a graph which shows the elution rate of irbesartan in the pharmaceutical composition of 2 types of active ingredient combination of this invention. It is a graph which shows the related substance 2 weeks after the severe test of the pharmaceutical composition of 2 types of active ingredient combination of this invention. It is a graph which shows the related substance 2 weeks after another severe test of the pharmaceutical composition of 2 types of active ingredient combination of this invention.

  The pharmaceutical composition of the present invention contains irbesartan as an active ingredient. The pharmaceutical composition of the present invention contains lactose hydrate and / or crystalline cellulose and povidone in addition to irbesartan. By using a specific combination of such additives, a pharmaceutical composition containing irbesartan exhibiting good dissolution properties can be obtained. That is, it is possible to obtain a pharmaceutical composition that elutes irbesartan by 60% or more at 15 minutes even at least for 1 week of storage under a severe test. Even when this pharmaceutical composition contains other active ingredients, for example, amlodipine besylate, good elution of both active ingredients can be obtained.

Irbesartan has the chemical name 2-Butyl-3- [4- [2- (1H-tetrazol-5-yl) phenyl] benzyl] -1,3-diazaspiro [4.4] non -1-en-4-one It is a long-acting angiotensin II receptor antagonist useful for the treatment of hypertension and the like.
The content of irbesartan in the pharmaceutical composition is 65 w / w% or less, preferably 60 w / w% or less based on the weight of the pharmaceutical composition (the same applies hereinafter). Moreover, 20 w / w% or more is mentioned, for example.
Amlodipine besylate has the chemical name 3-Ethyl 5-methyl (4RS) -2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -6-methyl-1,4-dihydropyridine-3, It is a long-acting Ca antagonist useful for the treatment of hypertension and the like represented by 5-dicarboxylate monobenzenesulfonate.
When the pharmaceutical composition further contains amlodipine besylate, the content thereof is 15 w / w% or less, preferably 12 w / w% or less based on the weight of the pharmaceutical composition. Moreover, 1 w / w% or more is mentioned, for example, and 2 w / w% or more is preferable.
The weight ratio of irbesartan to amlodipine besylate is, for example, irbesartan: amlodipine besylate = 3 to 30: 1, preferably 5 to 28: 1, and more preferably 6 to 20: 1.

Lactose hydrate is used as an excipient, for example. As for content in a pharmaceutical composition, 15 w / w%-70 w / w% are mentioned, 25 w / w%-50 w / w% are preferable.
Crystalline cellulose is used, for example, as an excipient. As for content in a pharmaceutical composition, 2 w / w%-70 w / w% are mentioned, 4 w / w%-50 w / w% are preferable.
When lactose hydrate and crystalline cellulose are used in combination, the weight ratio of lactose hydrate and crystalline cellulose includes lactose hydrate: crystalline cellulose = 10: 0 to 0:10, and 10: 1 to 1:10. Is preferable, 8: 1 to 1: 8 is more preferable, and 8 to 5: 1 is more preferable. The total content of lactose hydrate and crystalline cellulose may be 20 w / w% to 75 w / w%, preferably 25 w / w% to 50 w / w%.

  As an excipient, in the range that does not affect the effect of the present invention, for example, anhydrous lactose, sucrose, sucrose, fructose, fructooligosaccharide, glucose, maltose, reduced maltose, powdered sugar, powdered koji, reduced lactose, etc. Sugars such as erythritol, sorbitol, maltitol, xylitol, D-mannitol, kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, starch (eg, corn starch, potato starch, rice starch, wheat starch, etc.) Or a combination of two or more thereof. When the excipient is further used, the total amount of the excipient is 20 w / w% to 75 w / w%, preferably 23 w / w% to 75 w / w%, and preferably 25 w / w% to 50 w / w. w% is more preferable.

Povidone is a component known as polyvinyl pyrrolidone (PVP), and is used as a binder. As for content in a pharmaceutical composition, 10 w / w% or less is mentioned, for example, 5 w / w% or less is preferable and 3 w / w% or less is more preferable. The lower limit of the content is, for example, 0.01 w / w% or more.
As a binder, for example, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (hypromellose, HPMC), polyvinyl alcohol, pregelatinized starch, agar, gelatin, sodium carboxymethylcellulose, dextrin, as long as the effect of the present invention is not affected. , Ethyl cellulose, acacia, glucose, guar gum, polyethylene oxide and the like may be used alone or in combination. When the binder is further used, the total amount of the binder is 0.01 w / w% to 10 w / w%, preferably 0.01 w / w% to 5 w / w%, and preferably 1 w / w% to 5 w / w% is more preferable.
The binder promotes granulation of granules containing irbesartan or irbesartan and amlodipine besylate, but high viscosity may reduce dissolution. Therefore, for example, a povidone having a viscosity of 2 to 10 mPa · s at 20 ° C. in an 8 w / w% aqueous solution is preferable. In addition, povidone preferably has a K value of 20 to 100 calculated based on the following Fikentscher equation from a relative viscosity value (25 ° C.) measured by a capillary viscometer.
In the formula, η _rel represents the relative viscosity of the aqueous polyvinylpyrrolidone solution to water,
c represents the polyvinylpyrrolidone concentration (%) in the aqueous polyvinylpyrrolidone solution.

  In the pharmaceutical composition of the present invention, additives commonly used in the pharmaceutical field other than the above may be added as long as the effects of the present invention are not affected. For example, diluents, binders, disintegrants, lubricants, lubricants, wetting agents, fluidizing agents, surfactants, sweeteners, flavoring agents, organic acids, flavoring agents / fragrances, colorants, stabilizers And coating agents. These can be used alone or in combination of two or more.

  Examples of the diluent include calcium carbonate, calcium phosphate, calcium sulfate, dextrate, D-mannitol, lactitol, lactose, starch and talc. Examples of the total content of the diluent include 60 w / w% to 95 w / w%.

  Examples of the disintegrant include carmellose, alginic acid, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, crospovidone, polacrilin potassium, and starch. Of these, croscarmellose sodium is preferred from the viewpoint of elution. Examples of the total content of the disintegrant include 1 w / w% to 20 w / w%.

  Lubricants (magnifying agents) include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, sodium stearyl fumarate, sucrose fatty acid ester, zinc stearate, stearic acid, talc, carnauba wax, Examples thereof include L-leucine and macrogol. Of these, magnesium stearate is preferable. The total content of the lubricant is, for example, 0.01 w / w% to 5 w / w%, and preferably 0.01 w / w% to 4 w / w%.

Examples of the lubricant include calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, and vegetable oil. Examples of the total content of the lubricant include 0.5 w / w% to 2 wt w / w%.
Examples of the wetting agent include sodium lauryl sulfate.
Examples of the fluidizing agent include light anhydrous silicic acid, magnesium aluminate metasilicate, lloyd silicon dioxide, magnesium trisilicate, starch, talc and the like. The content of the fluidizing agent is 3 w / w% or less.

  Surfactants include ionic surfactants such as sodium lauryl sulfate; polysorbates, sucrose fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene hydrogenated castor oil and poloxamers (polyoxyethylene polyoxypropylene glycol) 1 type, or 2 or more types of combinations, such as nonionic surfactants, etc. are mentioned. The surfactant content is 2 w / w% or less.

Examples of the sweetening agent include aspartame, fructose, mannitol, saccharin and the like.
Examples of the flavoring agent include menthol, citric acid, fumaric acid, tartaric acid, artificial or natural fruit flavor, and the like.
Examples of the colorant include caramel, iron oxide (red, yellow, or black), iron sesquioxide, yellow sesquioxide, black sesquioxide, natural or synthetic organic dyes, lakes, and the like.

  Examples of the coating agent (coating agent) include hypromellose, triethyl citrate, titanium oxide, propylene glycol, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate, methyl cellulose, polyethylene glycol, and polyvinyl acetate phthalate. As for content of a coating agent, 0.1 w / w%-3 w / w% are mentioned, for example.

In one embodiment of the present invention, for example, 10-50 parts by weight of lactose hydrate and / or 1-20 parts by weight of crystalline cellulose and 1-20 parts by weight of povidone are preferably combined with 50 parts by weight of irbesartan. In this case, it is more preferable to further combine croscarmellose sodium with 1 to 20 parts by weight and / or magnesium stearate 0.1 to 10 parts by weight.
In still another embodiment, for example, it is preferable to combine 20 to 50 parts by weight of lactose hydrate and / or 1 to 15 parts by weight of crystalline cellulose and 1 to 15 parts by weight of povidone with respect to 50 parts by weight of irbesartan. In this case, it is more preferable to combine 1 to 15 parts by weight of croscarmellose sodium and / or 0.1 to 5 parts by weight of magnesium stearate.
In still another embodiment, for example, it is preferable to combine 25 to 45 parts by weight of lactose hydrate and / or 1 to 10 parts by weight of crystalline cellulose and 1 to 10 parts by weight of povidone with respect to 50 parts by weight of irbesartan. In this case, it is more preferable to combine 1 to 10 parts by weight of croscarmellose sodium and / or 0.1 to 4 parts by weight of magnesium stearate.

In particular, when a composition containing irbesartan and amlodipine besylate is used, in one embodiment, 1 to 10 parts by weight of amlodipine besylate, 10 to 50 parts by weight of lactose hydrate and 50 parts by weight of irbesartan and It is preferable to combine 1-20 parts by weight of crystalline cellulose and 1-20 parts by weight of povidone. In this case, it is more preferable to further combine croscarmellose sodium with 1 to 20 parts by weight and / or magnesium stearate 0.1 to 10 parts by weight.
In still another embodiment, 2-8 parts by weight of amlodipine besylate, 20-50 parts by weight of lactose hydrate and / or 1-15 parts by weight of crystalline cellulose and 1-15 parts by weight of povidone with respect to 50 parts by weight of irbesartan. It is preferable to combine the parts. In this case, it is more preferable to combine 1 to 15 parts by weight of croscarmellose sodium and / or 0.1 to 5 parts by weight of magnesium stearate.
In yet another embodiment, 3-8 parts by weight of amlodipine besylate, 25-45 parts by weight of lactose hydrate and / or 1-10 parts by weight of crystalline cellulose and 1-10 parts by weight of povidone with respect to 50 parts by weight of irbesartan. It is preferable to combine the parts. In this case, it is more preferable to combine 1 to 10 parts by weight of croscarmellose sodium and / or 0.1 to 4 parts by weight of magnesium stearate.

  The pharmaceutical composition of the present invention can be in various dosage forms. Examples include fine granules, granules, powders, tablets, capsules, pills, chewables, suppositories, sachets or lozenges. These dosage forms may be in any form as defined in the Japanese Pharmacopoeia General Rules for Preparations. Moreover, you may attach | subject a secant, an identification mark, etc. to a tablet. The tablet may have any shape such as a round tablet, a round R tablet, a round corner lock, a round two-stage R tablet, various irregular tablets, or a split tablet. The tablet may be an uncoated tablet or may be coated.

  For example, when the pharmaceutical composition of the present invention is used as a tablet, it can be produced by a conventional tablet production method. First, irbesartan or irbesartan and amlodipine besylate and the above-mentioned additive are mixed with an appropriate mixer such as a V-type mixer to produce a tablet mixture. In other words, irbesartan and amlodipine besylate are mixed together to form a mixture without being physically separated. Subsequently, this mixture can be directly compressed and compressed into granules or granules, and the granules can be produced by compression and compression.

The granule used in the method of compressing and compressing the granule may be produced by any of a wet method, a dry method, a spray granulation method, and the like. As the granulation method, for example, it may be formed by either dry granulation or wet granulation, but wet granulation is preferable. Examples of the wet granulation method include a method using an extrusion granulator, a rolling granulator, a stirring granulator, a wet pulverization granulator, a fluidized bed granulator, and the like. Among them, it is preferable to use a stirring granulator and a fluidized bed granulator, and it is particularly preferable to use a stirring granulator. In the case of using an agitation granulator, for example, the rotation of the blade and / or screw may be set to an arbitrary number of rotations or the like as appropriate depending on the type. Specifically, for example, a blade of 500 to 1500 rpm is preferable for a mechano mill, a blade of 100 to 500 rpm is preferable for VG, and a cross screw of 1000 to 4000 rpm is preferable. The granulation time can be set as appropriate. For example, 10 minutes to 10 hours can be mentioned. In particular, when a stirring granulator is used, by adjusting the rotation speed of the blade and / or screw and the granulation time, irbesartan or irbesartan and amlodipine besylate are mixed with other components, and by appropriate stirring action. With the shear / compression force and impact motion, better and more stable dissolution can be obtained. When using a fluidized bed granulator, for example, a method of granulating while spraying a binder solution or the like at an air supply temperature of 30 to 90 ° C. and an exhaust temperature of 20 to 80 ° C. can be mentioned. Examples of the dry granulation method include a method of granulating at a roll rotation number of 1 to 50 rpm using a roller compactor (Freund Sangyo).
The granulated product is preferably sized by sieving after drying. Drying may be performed, for example, at a temperature of 90 ° C. or less for 1 to 60 minutes.

  Examples of a method for compressing and compressing a tablet mixture or granule thereof include a method using a single-punch tableting machine, a rotary tableting machine and the like.

The pressure for compression tableting is sufficient to give sufficient hardness to the tablet, and is preferably 100 kgf or more, for example. Moreover, as for the hardness of the tablet obtained, 50-120N is preferable, for example. The “hardness” of the tablet can be measured with a tablet hardness meter (for example, model TH-203MP, Toyama Sangyo Co., Ltd.).
In addition to the above, in order to prepare in the form of a suitable solid pharmaceutical composition, for example, pulverization, crushing, mixing, sugar coating, film coating, capsule filling, etc. can be performed by methods and conditions known in the art. it can.

  The solid pharmaceutical composition described above is a packaging form known in the art such as bottle packaging (for example, polyethylene bottle and polypropylene cap), PTP packaging (for example, polypropylene), aluminum pillow, etc. It is preferable to preserve. In particular, in the case of a composition containing irbesartan and amlodipine besylate, it is preferable to store in a packaging form for each solid or for each dose, and it is more preferable to employ an aluminum pillow packaging that can block moisture. More preferably, the PTP packaging and the aluminum pillow packaging are used in combination. By such storage, even if irbesartan is not physically separated from amlodipine besylate, it is possible to effectively prevent an increase in the total impurity concentration due to physical contact between the two over time. .

In the pharmaceutical composition containing irbesartan of the present invention, by containing the above-described components, 57% or more of irbesartan is eluted at 15 minutes even after one week of storage in a severe test (60 ° C., 75% RH) ( Preferably, the eluate has a pH of 6.8) and elutes 58% or more, more preferably 60% or more, and even more preferably 63% or more. Further, at 30 minutes, 84% or more of irbesartan is eluted, preferably 85% or more, more preferably 86% or more.
Furthermore, even after 2 weeks of storage in a severe test, 53% or more of irbesartan is eluted at 15 minutes, preferably 55% or more, more preferably 58% or more, more preferably 60% or more. Those are even more preferred. In addition, 80% or more of irbesartan is eluted at 30 minutes, preferably 82% or more, more preferably 83% or more, and even more preferably 84% or more.
In particular, in a pharmaceutical composition comprising irbesartan and amlodipine besylate, by containing the above-described components, and in contact with each other in the pharmaceutical composition by the above-mentioned single solid or single dose packaging. Even after 1 week of storage in a severe test (60 ° C., 75% RH), 85% or more of irbesartan and 85% or more of amlodipine besylate are eluted at 30 minutes (eluent pH 6.8) It is preferable that both elute at 90% or more.
Further, even after 2 weeks of storage in a severe test, it is preferable to elute 80% or more irbesartan and 85% or more amlodipine besylate at 30 minutes (eluent pH 6.8), 85% or more irbesartan and 90% Those that elute amlodipine besylate are more preferred. In addition, it is preferable to elute 80% or more of irbesartan and 85% or more of amlodipine besylate (eluate pH 6.8) at 30 minutes even after one month of storage in a severe test (40 ° C., 75% RH). More preferably, it elutes 85% or more of irbesartan and 90% or more of amlodipine besylate.
In addition, the elution rate of said irbesartan or amlodipine besylate can be measured according to the elution test (paddle method, elution test 2nd liquid) described in the Japanese Pharmacopoeia. The details of this measuring method are as described in the examples.

Example 1: Agitation granulation Each of the following components was weighed and a film-coated tablet was prepared by the following method.
First, irbesartan, lactose hydrate, and crystalline cellulose were charged into a stirring granulator (Okada Seiko Co., Ltd.), and the powder was mixed.
While stirring with blade rotation (800 to 1000 rpm), povidone (“Collidon (registered trademark) 30” manufactured by BASF, K value: 27.0 to 32.4) was added as a solution, and the mixture was made for 1 to 5 minutes. Grained. Then, it set to 80 degreeC with the fluidized-bed granulation dryer (made by Paulec), and dried for 10 minutes.
Croscarmellose sodium and magnesium stearate were added to granules sized with Comil (Pauleck) and mixed in a bag.
Using a rotary tableting machine (manufactured by Kikusui Seisakusho), the tableting pressure was about 1000 kgf, an oval type tablet having a major axis of 8.5 mm and a minor axis of 4.4 mm.
Thereafter, hypromellose, triethyl citrate and titanium oxide were dissolved and dispersed in purified water to prepare a coating solution. The tablets were put into a coating machine (Freund), sprayed with a coating solution, dried and then polished with carnauba wax to form film-coated tablets.

Comparative Examples 1 and 2
A film-coated tablet was prepared in the same manner as in Example 1 except that povidone was changed to hydroxypropylcellulose (HPC) or hypromellose (HPMC) in the formulation of Example 1.

Example 2: Agitation granulation As in Example 1, irbesartan, lactose hydrate, and crystalline cellulose were charged into an agitation granulator (Okada Seiko Co., Ltd.), and the powder was mixed.
Povidone (similar to Example 1) was added as a solution and granulated for 1 to 5 minutes, and then set to 80 ° C. with a fluidized bed granulator / dryer (manufactured by POWREC) and dried for 10 minutes.
In the same manner as in Example 1, croscarmellose sodium and calcium stearate were added to granules sized with Comil (manufactured by POWREC) and mixed in a bag. A single tableting machine (manufactured by Riken Seiki Co., Ltd.) was used to produce tablets with a tableting pressure of about 1000 kgf, an oval type, major axis 8.5 mm, minor axis 4.4 mm.

Example 3: Fluidized bed granulation As in Example 1, irbesartan, lactose hydrate, and crystalline cellulose were charged into a fluidized bed granulator / dryer (manufactured by POWREC), and povidone (similar to Example 1) was used as a solution. Granulated while spraying.
After completion of granulation, drying was performed at 80 ° C. for 10 minutes.
In the same manner as in Example 1, croscarmellose sodium and calcium stearate were added to the granules sized with a sieve (850 μm) and mixed in a bag.
The tablet was molded with a single tableting machine (manufactured by Riken Seiki Co., Ltd.) to give a tableting pressure of about 1000 kgf, an oval type tablet having a major axis of 8.5 mm and a minor axis of 4.4 mm.

Example 4: Dry granulation As in Example 1, irbesartan, lactose hydrate, crystalline cellulose, and povidone were mixed in a bag, and dry granulated with a roller compactor (Freund Corporation).
The granulated product was sized with a comil, and croscarmellose sodium and calcium stearate were added to the resulting granule and mixed in a bag.
A single tableting machine (manufactured by Riken Seiki Co., Ltd.) was used to produce tablets with a tableting pressure of about 1000 kgf, an oval type, major axis 8.5 mm, minor axis 4.4 mm.

Example 5: Direct compression molding Irbesartan, lactose hydrate, crystalline cellulose, povidone, croscarmellose sodium and calcium stearate were mixed in a bag, and the resulting tableting powder was put into a single tableting machine (manufactured by Riken Seiki Co., Ltd.). The tableting pressure was about 1000 kgf, an oval type tablet having a major axis of 8.5 mm and a minor axis of 4.4 mm.

<Evaluation 1>
The film-coated tablets obtained in Example 1 and Comparative Examples 1 and 2 were put in a polyethylene bag and stored under conditions of 60 ° C. and 75% RH. Dissolution tests of film-coated tablets after 1 week and 2 weeks of storage were conducted. The results are shown in FIGS.
As is apparent from FIGS. 1 and 2, in the examples of the present application, dissolution was performed after 15 minutes for any combination of additives and for commercially available irbesartan tablets (reference examples). It can be seen that the rate is higher than 60%, indicating a good dissolution rate.

Furthermore, the tablets (plain tablets) obtained by different production methods in Examples 2 and 3 were put in a polyethylene bag and stored under conditions of 60 ° C. and 75% RH. The dissolution test of the tablets after 1 week of storage was conducted. The result is shown in FIG.
As is clear from FIG. 3, it was confirmed that in Examples 2 and 3 of the present application, almost the same elution rate was exhibited in any of the manufacturing methods.

The dissolution test was performed by the method described in the Japanese Pharmacopoeia.
Take uncoated tablets and film-coated tablets obtained in Examples and Comparative Examples, and a commercially available irbesartan tablet (manufactured by Dainippon Sumitomo Pharma Co., Ltd., 50 mg tablet) as a reference example. .8) Using 900 mL, the test was performed at 50 revolutions per minute by the paddle method. The dissolution test was started, and after a specified time, 10 mL of the eluate was accurately collected, and immediately 10 mL of the test solution heated to 37 ± 0.5 ° C. was accurately supplemented with care. The eluate was filtered through a membrane filter having a pore size of 0.45 μm. Except for 5 mL of the first filtrate, the next filtrate was used as a sample solution. Separately, about 28 mg of irbesartan was accurately weighed and dissolved in methanol to make exactly 25 mL. 2.5 mL of this solution was accurately weighed and the test solution was added to make exactly 50 mL, which was used as a standard solution. With respect to the sample solution and the standard solution, respective absorbances AT and AS were measured with an ultraviolet-visible absorptiometer (wavelength: 280 nm). The elution rate (%) with respect to the indicated amount of irbesartan at the time of collecting the eluate at the nth time was calculated by the following formula.
In the formula, MS is a weighed amount of irbesartan (mg),
C is the indicated amount (mg) of irbesartan in one tablet,
Reference numeral 180 denotes a dilution correction coefficient.

Example 6: Agitation granulation Each of the following components was weighed and a film-coated tablet was prepared by the following method.
First, irbesartan, amlodipine besylate, D-mannitol, and crystalline cellulose were put into a stirring granulator (Okada Seiko Co., Ltd.), and the powder was mixed.
While stirring with blade rotation (800 to 1000 rpm), povidone (“Collidon (registered trademark) 30” manufactured by BASF, K value: 27.0 to 32.4) was added as a solution, and the mixture was made for 1 to 5 minutes. Grained. Then, it set to 80 degreeC with the fluidized-bed granulation dryer (made by Paulec), and dried for 10 to 30 minutes.
Croscarmellose sodium and magnesium stearate were added to granules sized with Comil (Pauleck) and mixed in a bag.
A rotary tableting machine (manufactured by Kikusui Seisakusho) was used to form a round tablet having a tableting pressure of about 1000 kgf, a diameter of 8.0 mm, and R12.0 mm.
Thereafter, hypromellose, propylene glycol, titanium oxide, yellow No. 5 and red No. 102 were dissolved and dispersed in purified water to prepare a coating solution. The tablets were put into a coating machine (Freund), sprayed with a coating solution, dried and then polished with carnauba wax to form film-coated tablets.

<Evaluation 2>
A pre-film-coated tablet (uncoated tablet) obtained in Example 6 and a commercial preparation containing irbesartan and amlodipine besylate (“AIMIX (registered trademark) combination tablet HD” manufactured by Dainippon Sumitomo Pharma Co., Ltd.) , Irbesartan 100 mg and amlodipine 10 mg, bottle 500 tablets).
The amlodipine dissolution test was carried out by the following method.
One tablet was taken, and the test was carried out at 50 revolutions per minute by the paddle method using 900 mL of the second solution of JP dissolution (pH 6.8). The dissolution test was started, and after a specified time, 15 mL of the eluate was accurately collected, and immediately 15 mL of the test solution heated to 37 ± 0.5 ° C. was accurately and carefully supplemented. The eluate was filtered through a membrane filter having a pore size of 0.45 μm. Except for 10 mL of the first filtrate, the next filtrate was used as a sample solution.
On the other hand, about 26 mg of amlodipine besylate was accurately weighed and dissolved in methanol to make exactly 50 mL, which was used as an amlodipine standard stock solution. Separately, about 22 mg of irbesartan was accurately weighed and dissolved in 20 mL of acetic acid, 6 m of amlodipine standard stock solution was accurately added, and a test solution was added to make exactly 200 mL to obtain a standard solution.

The absorbance AT and AS of each of the sample solution and the standard solution were measured with an ultraviolet absorptiometer (wavelength: 270 nm). The elution rate (%) with respect to the displayed amount of amlodipine besil hydrochloride at the time of the n-th eluate collection was calculated by the following formula.
In the formula, MS is a weighed amount (mg) of amlodipine besylate,
C is the indicated amount (mg) of amlodipine besylate in one tablet,
54 represents a dilution correction coefficient.
The dissolution test of irbesartan was carried out in the same manner as in Evaluation 1, except that the same sample solution and standard solution as in the above-described dissolution test of amlodipine besylate were used.

As is clear from FIG. 4 and FIG. 5, the preparation obtained by mixing irbesartan and amlodipine besylate of the examples of the present application together is 30 minutes as in the case of a commercially available product (AIMIX (registered trademark) combination tablet HD). Later, it can be seen that both irbesartan and amlodipine besylate have an elution rate of approximately 100%, indicating a good elution rate.
Moreover, these tablets were packaged one by one with an aluminum pillow and stored under conditions of 60 ° C. and 75% RH or 40 ° C. and 75% RH. Dissolution tests were performed by the method described above for tablets after 1 week, 2 weeks and 1 month after storage. The results are shown in Table 3. In Table 3, the value of elution rate (%) of amlodipine besylate / elution rate (%) of irbesartan is shown.
As is apparent from Table 3, in Example 6 of the present application, it was confirmed that any component showed a stable and good elution rate.

<Evaluation 3>
The tablet before film coating obtained in Example 6 and a commercial product containing “irbesartan” and “amlodipine besylate” (“AIMIX (registered trademark) combination tablet HD” manufactured by Dainippon Sumitomo Pharma Co., Ltd.) from the PTP packaging at the time of marketing. The taken out tablets are each packaged in PTP packaging one by one, each under the conditions of 25 ° C. and 75% RH (see FIG. 6A) and 40 ° C. and 75% RH (see FIG. 6B). The tablets were stored for months, and the initial, one month-old tablets were analyzed by high performance liquid chromatography, and the related substances were evaluated as follows.
That is, among the detected peaks of related substances, for the related substances derived from irbesartan, the value of “(the related substance peak area / irbesartan peak area) × 100” is the value of the related substances derived from amlodipine and related unknowns For the substances, the value of “(the related substance peak area / amlodipine peak area) × 100” was calculated, and the total value thereof was defined as the total related substances (%). These results are shown in FIG. 6A (25 ° C., 75% RH) and FIG. 6B (40 ° C., 75% RH).

  Moreover, the tablet before film coating obtained in Example 6 was packaged for each tablet in PTP packaging or aluminum pillow packaging, or left unpackaged under the conditions of 60 ° C. and 75% RH, respectively. The tablets were stored for 7 days or 14 days, and the tablets after 14 days of storage were analyzed by high performance liquid chromatography, and related substances were evaluated in the same manner as described above. As a result, in the PTP packaging and the aluminum pillow packaging, it was confirmed that the related substances were suppressed to 40% and 7.5%, respectively, very low with respect to the tablets without packaging. In addition, it was confirmed that the initial values of the related substances were all about 0%.

  The pharmaceutical composition of the present invention can ensure stability and a good dissolution rate over a long period of time during production, storage and distribution.

Claims (7)

  A pharmaceutical composition comprising irbesartan, lactose hydrate and / or crystalline cellulose, and povidone.   The pharmaceutical composition according to claim 1, further comprising amlodipine besylate.   The pharmaceutical composition according to claim 1 or 2, further comprising croscarmellose sodium.   Furthermore, the pharmaceutical composition of any one of Claims 1-3 containing magnesium stearate.   The elution rate of irbesartan is 80% or more when eluted for 30 minutes in accordance with the paddle method of the dissolution test described in the Japanese Pharmacopoeia after storage at 60 ° C and 75% RH for 2 weeks. 2. A pharmaceutical composition according to item 1.   A method for producing a pharmaceutical composition, comprising granulating a mixture containing irbesartan, lactose hydrate and / or crystalline cellulose, and povidone by stirring granulation or fluidized bed granulation.   The method for producing a pharmaceutical composition according to claim 6, wherein the mixture further comprises amlodipine besylate.