KR20240176609A - Composite tablet comprising linagliptin and metformin - Google Patents

Abstract

One aspect of the present invention provides a composite tablet and a manufacturing method thereof, wherein the composite tablet comprises a sustained-release layer containing metformin and a fast-release layer containing linagliptin, wherein the sustained-release layer contains sustained-release granules including metformin or a pharmaceutically acceptable salt thereof, and a sustained-release agent, the fast-release layer contains fast-release granules including linagliptin or a pharmaceutically acceptable salt thereof, and a disintegrant, the weight ratio of the fast-release layer to the sustained-release layer is 10 to 25 wt%, and a 30-minute dissolution rate of linagliptin is 80 % or more in a dissolution test according to the general test method of the Korean Pharmacopoeia.

Description

{Composite tablet comprising linagliptin and metformin}

The present invention relates to a combination tablet containing linagliptin and metformin and a method for manufacturing the same, and more specifically, to a combination tablet capable of securing the release profiles of each of the approved single tablets of linagliptin and metformin, while also having excellent content uniformity of linagliptin and excellent economic efficiency in mass production, and a method for manufacturing the same.

Metformin is a drug widely prescribed to lower blood sugar levels in patients with type 2 diabetes mellitus NIDDM, and is commercially available in the form of hydrochloride (GlucophageXL sustained-release tablets, Merck). Metformin acts on diabetic patients by increasing insulin sensitivity in human peripheral tissues, inhibiting glucose absorption in the intestines, inhibiting hepatic glucose synthesis, and inhibiting fatty acid absorption. A suitable dosage of metformin includes a unit dose of 500 mg administered two to three times a day (which may be increased to five times a day), or 850 mg administered once or twice a day (Non-patent Document 1).

Linagliptin is a hypoglycemic agent of the DPP-IV inhibitor series. It inhibits the inactivation of GLP-1 and GIP by DPP-IV, thereby enabling GLP-1 and GIP to promote insulin secretion from pancreatic beta cells, and inhibits glucagon secretion from alpha cells, thereby lowering blood sugar. Linagliptin is commercially available in tablet form as a base (Trajenta tablets, Boehringer Ingelheim Korea Co., Ltd.).

In addition, to increase the convenience of taking the drug, a combination tablet of the above linagliptin and metformin hydrochloride (Jentadueto XR, Boehringer Ingelheim Co., Ltd.) has been developed and is commercially available.

In the combination tablet of linagliptin and metformin, the content of linagliptin required per unit dosage form is relatively very small compared to the content of metformin, so that the content uniformity of linagliptin must be secured. In addition, in order to exhibit sufficient efficacy, it is necessary to have the dissolution profile of each of the approved single dosage forms of linagliptin and metformin.

Patent Document 1 (Korean Patent Publication No. 2014-0052970) discloses a combination tablet of linagliptin and metformin, which includes an inner extended-release core comprising metformin and one or more excipients, a middle seal coating, and an outer immediate-release coating comprising linagliptin and one or more excipients. In the combination tablet, metformin is introduced as an extended-release core to enable sustained-release of metformin, and linagliptin is introduced as an outer immediate-release coating layer to enable immediate-release of linagliptin, while also attempting to secure uniformity in the content of linagliptin. However, the combination tablet having such an outer coating layer has a problem in that its manufacturing method is relatively difficult, making it not economical for mass production.

1. Korean Patent Publication No. 2014-0052970

1. Martindale, The Complete Drug Reference

One aspect of the present invention is to provide a combination tablet containing metformin and linagliptin, which not only has excellent content uniformity of linagliptin and can secure the dissolution profile of each approved single tablet, but also has excellent tabletability and high economic feasibility in mass production.

Another aspect of the present invention is to provide a method for producing the composite tablet.

Other purposes and advantages of the present application will become more apparent from the detailed description below, together with the appended claims. Contents related to purposes and advantages not described in this specification are sufficiently recognizable and inferable to those of ordinary skill in the art or similar art fields of the present application, and therefore, their description is omitted.

One aspect of the present invention is

A combination tablet comprising a sustained-release layer containing metformin and an immediate-release layer containing linagliptin,

The above-mentioned layer comprises sustained-release granules comprising metformin or a pharmaceutically acceptable salt thereof, and a sustained-release agent; and

The above-mentioned fast-release layer comprises fast-release granules comprising linagliptin or a pharmaceutically acceptable salt thereof, and a disintegrant,

The weight ratio of the above-mentioned fast-acting layer to the western layer is 10 to 25 wt%,

We provide a composite tablet in which the linagliptin dissolution rate after 30 minutes is 80% or higher in the first solution (pH 1.2) when tested according to the paddle method in the general test methods of the 12th revised edition of the Korean Pharmacopoeia.

Another aspect of the present invention is

A method for manufacturing a composite tablet according to one aspect of the present invention,

A step of manufacturing metformin sustained-release granules by granulating metformin or a pharmaceutically acceptable salt thereof with a sustained-release agent;

A step of preparing linagliptin immediate-release granules by granulating linagliptin or a pharmaceutically acceptable salt thereof with a disintegrant; and

The present invention provides a manufacturing method, comprising the step of compressing the metformin granules as a first layer and the linagliptin granules as a second layer using a two-layer tablet compression machine.

According to one aspect of the present invention, it is possible to provide a composite tablet having excellent content uniformity of linagliptin and securing the dissolution profile of each approved single tablet, as well as excellent tabletability and being more economical in mass production than conventional composite tablets.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless otherwise defined, have the same meaning as generally understood by a person of ordinary skill in the art related to the present invention.

The contents of all publications cited as references in this specification are incorporated herein by reference in their entirety.

Each description and embodiment disclosed in this application can also be applied to each other description and embodiment. That is, all combinations of various elements disclosed in this application fall within the scope of this application. In addition, the scope of this application cannot be considered limited by the specific description described below.

In addition, although the present specification describes preferred methods and samples, similar or equivalent ones are also included in the scope of the present invention. In addition, the term "comprising" is intended to be inclusive, meaning that additional elements may be present in addition to the listed elements.

As used herein, the term “comprising” is used in the same manner as is commonly used.

All numbers expressing quantities of ingredients, properties such as molecular weights, reaction conditions, and the like used herein are to be understood as being modified in all instances by the term "about" unless otherwise specified. Accordingly, the numbers set forth herein are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. The term "about" as used herein is within a specific value or between 1% and 2%. For example, "about 10%" means between 9.8% and 10.2%. As another example, "about 100° C." means between 98° C and 102° C.

One aspect of the present invention is:

A combination tablet comprising a sustained-release layer containing metformin and an immediate-release layer containing linagliptin,

The above-mentioned layer comprises sustained-release granules comprising metformin or a pharmaceutically acceptable salt thereof, and a sustained-release agent; and

The above-mentioned fast-release layer comprises fast-release granules comprising linagliptin or a pharmaceutically acceptable salt thereof, and a disintegrant,

The weight ratio of the above-mentioned fast-acting layer to the western layer is 10 to 25 wt%,

We provide a composite tablet in which the linagliptin dissolution rate after 30 minutes is 80% or higher in the first solution (pH 1.2) when tested according to the paddle method in the general test methods of the 12th revised edition of the Korean Pharmacopoeia.

When the weight ratio of the sustained-release layer to the rapid-release layer of the above-mentioned rapid-release layer is less than 10 wt%, the content uniformity is not sufficiently high and the desired rapid-release property of linagliptin is not obtained (see Experimental Example 3). It seems that the low content uniformity when the weight ratio of the rapid-release layer to the sustained-release layer is less than 10 wt% is because it is difficult to secure content uniformity when a relatively small amount is contained.

The above composite tablet may have a content uniformity test judgment value of 15 or less according to the general test method of the 12th revised edition of the Korean Pharmacopoeia. A lower judgment value means better content uniformity, and the present application can provide a composite tablet having excellent content uniformity due to the technical feature, that is, the weight ratio of the immediate-release layer to the sustained-release layer being 10 to 25 wt%.

In addition, when the weight ratio of the sustained-release layer of the immediate-release layer is less than 10 wt%, the 30-minute dissolution rate of linagliptin in the first solution (pH 1.2) did not show 80% or higher in the dissolution test according to the paddle method in the general test methods of the Korean Pharmacopoeia, and the immediate-release of linagliptin was found to be inhibited (see Experimental Example 3). It seems that the reason why the immediate-release of linagliptin is inhibited when the weight ratio of the immediate-release layer to the sustained-release layer is less than 10 wt% is because the thickness of the immediate-release layer is too thin and the proportion directly adjacent to the sustained-release layer is large, so that it is relatively more affected by the extended-release agent present in the sustained-release layer.

In addition, when the weight ratio of the sustained-release layer of the immediate-release layer exceeds 25 wt%, binding to the metformin sustained-release layer occurred when compressing into a bilayer tablet, and layer separation occurred between the metformin sustained-release layer and the linagliptin immediate-release layer when measuring tablet friability (see Experimental Example 3). In contrast, when the weight ratio of the immediate-release layer to the sustained-release layer was 25 wt% or less, no particular tableting problems occurred.

Therefore, in order to secure a 30-minute dissolution rate of linagliptin of 80% or more in a dissolution test according to the general test method of the Korean Pharmacopoeia, while also securing excellent content uniformity and tabletability, the weight ratio of the immediate-release layer to the sustained-release layer needs to be 10 to 25 weight%.

In addition, it is widely known that a bilayer tablet among composite tablets has superior productivity compared to a coated tablet. Therefore, the composite tablet of the present application has significantly superior productivity in mass production compared to a conventionally known coated tablet, which is a composite tablet. However, in the case of a coated tablet, since linagliptin exists in the outer coating layer and is released immediately, the release of linagliptin is not inhibited by the sustained-release agent present in the core, but in the case of a bilayer tablet, the linagliptin-containing immediate-release layer is adjacent to the sustained-release layer, so that the release of linagliptin may be inhibited by the sustained-release agent. As described above, in the composite tablet of the present application, the weight ratio of the immediate-release layer to the sustained-release layer is 10 wt% or more so that the release inhibition by the sustained-release agent does not occur. In addition, the weight ratio of the linagliptin-containing immediate-release layer to the metformin-containing sustained-release layer is adjusted to 25 wt% or less so that a tablet size is maintained without tableting problems and with high convenience of taking medication.

The pharmaceutically acceptable salts of the above linagliptin include, but are not limited to, known acid addition salts of linagliptin, such as besylate, hydrochloride, nitrate, acetate, etc., and hereinafter, unless specifically indicated otherwise, "linagliptin" is collectively referred to as including all of the above salts and free base forms. In one specific embodiment, the linagliptin is linagliptin besylate.

Pharmaceutically acceptable salts of the above metformin include but are not limited to the hydrochloride, metformin (2:1) fumarate, metformin (2:1) succinate, bromate, p-chlorophenoxy acetate or embonate, and other known acid addition salts of metformin with mono- and dibasic carboxylic acids, and unless specifically stated otherwise, "metformin" is collectively referred to as including all of the above salts and free base forms. In one embodiment, the metformin is metformin hydrochloride.

In one specific embodiment, the combination tablet may contain linagliptin besylate and metformin hydrochloride as active ingredients.

The disintegrant included in the above-described immediate-release granules may be any disintegrant that can ensure a 30-minute dissolution rate of linagliptin of 80% or higher in a dissolution test according to the General Test Methods of the Korean Pharmacopoeia. The disintegrant may include, for example, at least one selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, and crospovidone. The disintegrant may be included in an amount of 0.5 to 10 wt% of the total weight of the immediate-release granules, and may vary depending on the type of the specific disintegrant contained. In one specific example, the disintegrant includes a combination of croscarmellose sodium and carboxymethylcellulose calcium. In one specific example, the disintegrant includes a combination of 0.3 to 3 wt% of croscarmellose sodium and 2 to 5 wt% of carboxymethylcellulose calcium with respect to the total weight of the immediate-release granules.

The above combination tablet should exhibit sustained-release dissolution similar to that of the approved metformin single tablet for the metformin component, and therefore, should exhibit a dissolution rate of 20 to 40% in 1 hour, 45 to 65% in 3 hours, and 85% or more in 10 hours in a dissolution test according to the General Test Methods of the Korean Pharmacopoeia (Metformin sustained-release tablet analysis standards of the United States Pharmacopoeia). The sustained-release granules may contain any sustained-release agent capable of exhibiting such sustained-release dissolution, and the sustained-release agent may include at least one selected from the group consisting of hypromellose, carbomer, povidone, and eudragit. The sustained-release agent may be included in an amount of 15 to 30 wt% of the total weight of the sustained-release granules, and may vary depending on the type of specific sustained-release agent contained. In one specific example, the sustained-release agent includes hypromellose in an amount of 10 to 20 wt% of the total weight of the sustained-release granules.

The above-described granules further comprise a pharmaceutically acceptable binder for the manufacture of the granules. The binder may be present in an amount of 3 to 10 wt% based on the dry weight of the granules. The pharmaceutically acceptable binder may be selected from, for example, starch, cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxylethyl cellulose, hydroxylpropylmethyl cellulose, sucrose, dextrose, corn syrup, polysaccharides, gelatin, and any combination thereof. In one embodiment, the binder is povidone.

In one specific example, the sustained-release granules contain povidone as a binder and hypromellose as a sustained-release agent, and more specifically, contain 3 to 10 wt% of povidone as a binder and 10 to 20 wt% of hypromellose as a sustained-release agent based on the total weight of the sustained-release granules.

If the above-mentioned western-release granules do not contain the binder and the sustained-release agent in the amounts described above, the required dissolution rates of 20 to 40% in 1 hour, 45 to 65% in 3 hours, and 85% or more in 10 hours may not be shown in the dissolution test according to the general test method of the Korean Pharmacopoeia (see Experimental Example 1).

Each of the sustained-release granules and the immediate-release granules contained in the above-mentioned composite tablet may independently be a wet granule or a dry granule. In one specific example, each of the sustained-release granules and the immediate-release granules are wet granules. Since the metformin contained in the above-mentioned composite tablet has a high unit dosage, it is preferable to formulate it as a wet granule. When manufactured as a wet granule, a large amount of metformin can be manufactured more compactly, thereby improving patient compliance with the composite tablet. In the case of linagliptin, if it is manufactured by simple mixing instead of wet granules and then compressed into a bilayer tablet, layer separation may occur, and if it is manufactured as dry granules, there is a concern that fine powder may occur. The above-mentioned wet granules are preferably dried to a moisture content of 1 to 2% when measured by a loss on drying (LOD) analyzer. If the moisture content is excessive, binding and sticking, etc., may occur, and if it is insufficient, layer separation and capping may occur, which is disadvantageous in terms of tableting properties.

The above-described granules may further comprise a diluent, a binder, and a stabilizer. The diluent may be any diluent and may be selected from mannitol, lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and any combination thereof. In one embodiment, the diluent is mannitol. The binder may be any binder and may be selected from starch, cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxylethyl cellulose, hydroxylpropylmethyl cellulose, sucrose, dextrose, corn syrup, polysaccharides, gelatin, and any combination thereof. In one embodiment, the binder is povidone. The stabilizer may be any stabilizer and may be selected from meglumine, calcium carbonate, magnesium oxide, and any combination thereof. In one embodiment, the stabilizer is meglumine. In one specific example, the diluent is mannitol, the binder is povidone, and the stabilizer is meglumine, and more specifically, the instant granules may contain 70 to 91 wt% of mannitol, 1 to 7 wt% of povidone, and 1 to 6 wt% of meglumine based on the total weight of the instant granules.

The above-mentioned immediate-release granules and sustained-release granules may each independently additionally include a lubricant for the manufacture of the granules, and the lubricant may be selected from the group consisting of magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and any combination thereof, but is not limited thereto.

The above combination tablet may contain 0.5 to 10 mg of linagliptin besylate as a base and 200 to 2,000 mg of metformin hydrochloride per unit tablet. In one specific example, the combination tablet may contain 2.5 mg of linagliptin besylate as a base and 500, 850 mg, or 1,000 mg of metformin hydrochloride.

The above combination tablets may be used for the treatment of any disease or condition that would benefit from the combination of linagliptin and metformin. For example, it may be used for the treatment of type 2 diabetes.

Another aspect of the present application is a method for manufacturing a composite tablet according to the present application,

A step of manufacturing metformin sustained-release granules by granulating metformin or a pharmaceutically acceptable salt thereof with a sustained-release agent;

A step of preparing linagliptin immediate-release granules by granulating linagliptin or a pharmaceutically acceptable salt thereof with a disintegrant; and

The present invention provides a method for manufacturing a composite tablet, comprising the step of compressing the metformin granules as a first layer and the linagliptin granules as a second layer using a two-layer tablet compression machine.

The details of the above manufacturing method can be applied as is to the description of the composite tablet according to all aspects of the present application.

According to one specific example of the present invention, in the above manufacturing method, the sustained-release granules and the rapid-release granules can be manufactured by a wet granulation method. The manufacturing method of the wet granulation method is not particularly limited, and any wet granulation method known in the art can be used.

The step of pressing a tablet using the above-mentioned double-layer tablet press can be performed according to a conventional double-layer tablet press method using granules known in the art.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only intended to illustrate the present invention and the scope of the present invention is not limited thereto.

The formulations of the examples and comparative examples below were manufactured by manufacturing granules using the respective compositions according to the following steps, and then performing a tableting process.

Manufacturing example

In the experimental examples below, the manufacturing method for each tablet was used as follows.

1) Step 1: Preparation of wet granules containing metformin

A step for making sustained-release granules containing metformin hydrochloride, manufactured as wet granules.

Specifically, metformin was mixed with a high speed mixer (Sejong, Korea; Agitator 200±20 rpm, Chopper 2000±200 rpm, mixing time 5±1 min, kneading time 5±1 min) excluding the sustained-release agent (hypromellose) and the glidant (magnesium stearate), kneaded with purified water, wet-granulated, dried using a fluidized bed dryer (supply air temperature 40±5℃), sieved with Comil (Quadro; 1.2Ψ, 3000 rpm), added with the sustained-release agent, post-mixed, then the glidant was added and glidated to obtain granules.

2) Step 2: Preparation of immediate-release granules containing linagliptin

A step for producing immediate-release granules containing linagliptin or a pharmaceutically acceptable salt thereof, which are manufactured by wet granulation.

Specifically, linagliptin was mixed with mannitol as a diluent using a high speed mixer (Sejong, Korea; Agitator 200±20 rpm, Chopper 2000±200 rpm, mixing time 5±1 min, kneading time 5±1 min), and a kneading solution (povidone + meglumine + purified water) was added to knead and wet granulate, and each was dried using a fluidized bed dryer (supply air temperature 40±5℃), sieved using Comil (Quadro; 1.2Ψ, 3000 rpm), a disintegrant was added, mixed, a lubricant (magnesium stearate) was added, and lubricating was performed to obtain granules.

3) Step 3: Step of making tablets by pressing

Single-layer tablets or double-layer tablets were manufactured by compressing the above metformin granules or linagliptin granules.

In the case of single tablets, they were manufactured using a tableting machine (VANTIX P320D, Sejong).

In the case of a bilayer tablet, a bilayer tablet was manufactured by compressing the obtained metformin granules as the first layer and linagliptin granules as the second layer using a bilayer tablet compressing machine (VANTIX P320D, Sejong).

Experimental Example 1: Dissolution test of single metformin drug according to additive combination

<Manufacturing of Metformin Single Agent>

According to the step 1 above, metformin sustained-release granules of Examples 1 to 8 and Comparative Examples 1 to 6 were manufactured with the compositions and weights shown in [Table 1] below, and then tablets of Examples 1 to 8 and Comparative Examples 1 to 6 were manufactured by compressing them into single tablets according to step 3.

GlucophageXL sustained-release tablets (manufacturer: Merck), a single-dose formulation containing metformin as an active ingredient, were used as comparative example 7.

<Metformin single-agent dissolution evaluation>

The metformin single preparations of Examples 1 to 8 and Comparative Examples 1 to 7 were subjected to a metformin dissolution evaluation. The dissolution evaluation was performed in a pH 1.2 solution, 37°C, 900 mL, and 50 rpm. Since the metformin component exhibits sustained-release dissolution, it should exhibit a dissolution rate of 20 to 40% in 1 hour, 45 to 65% in 3 hours, and 85% or more in 10 hours. The metformin dissolution results of Examples 1 to 8 and Comparative Examples 1 to 7 are shown in [Table 2] below.

As shown in the above [Table 2], the formulations of Examples 1 to 8 all exhibited good sustained-release dissolution in which the dissolution rates of metformin met the above criteria, and the formulation of Example 6 exhibited the most similar dissolution profile to the control drug (Comparative Example 5). In contrast, Comparative Examples 1 to 4 did not contain sufficient amounts of the binder and sustained-release agent, so they did not exhibit sustained-release dissolution meeting the above criteria and instead exhibited rapid dissolution. On the contrary, Comparative Examples 5 and 6 exhibited dissolution that did not meet the above criteria because the amounts of the sustained-release agent were large and the dissolution was delayed.

Experimental Example 2: Dissolution Test of Metformin and Linagliptin Combination

<Manufacture of Linagliptin-Metformin Combination>

According to the step 1, metformin sustained-release granules of Example 6 were manufactured with the composition and weight shown in [Table 3] below, and linagliptin immediate-release granules of Examples 9 to 11 and Comparative Example 6 were manufactured according to step 2, and then according to step 3, the metformin sustained-release granule part was formed as the first layer and the linagliptin immediate-release granule part was formed as the second layer, thereby manufacturing the composite tablets of Examples 9 to 11 and Comparative Example 6.

Trajenta tablets (manufacturer: Boehringer Ingelheim), a commercially available product containing linagliptin as a single active ingredient, were used as comparative example 7.

<Evaluation of the release of linagliptin>

The dissolution evaluation of linagliptin was analyzed by sampling at 30 minutes under the conditions of pH 1.2 solution, 37℃, 900mL, and 50rpm. Since linagliptin must exhibit rapid dissolution, the dissolution rate must be 80% or higher within 30 minutes. The dissolution results of linagliptin of Examples 9 to 11 and Comparative Examples 6 and 7 are shown in [Table 4] below.

As can be seen from the results in [Table 4] above, linagliptin of Examples 9 to 11 exhibited rapid immediate release, and Example 11 was confirmed to have the most similar dissolution profile to the control drug. In contrast, Comparative Example 6 was confirmed to not exhibit immediate release because it did not contain a disintegrant.

Experimental Example 3: Dissolution test of a composite formulation according to the weight ratio of the linagliptin immediate-release layer

<Manufacture of Linagliptin-Metformin Combination>

According to the step 1 above, metformin sustained-release granules of Example 6 were manufactured according to the composition of [Table 5] below, and linagliptin immediate-release granules of Examples 12 to 15 and Comparative Examples 8 and 9 were manufactured according to step 2, and then according to step 3, the metformin sustained-release granule part was made as the first layer and the linagliptin immediate-release granule part was made as the second layer, thereby manufacturing the composite tablets of Examples 12 to 15 and Comparative Examples 8 and 9 as two-layer tablets. The weight ratios of the linagliptin layer to the metformin layer in the manufactured composite tablets of Examples 12 to 15 and Comparative Examples 8 and 9 are shown in Table 6 below.

<Evaluation of content uniformity, dissolution rate, and tableting properties for compound tablets>

The content uniformity, dissolution, and purification of linagliptin were evaluated for the composite tablets of Examples 12 to 15 and Comparative Examples 8 and 9.

The content uniformity test was performed on linagliptin according to the content uniformity test according to the general test method of the 12th revised edition of the Korean Pharmacopoeia. Measurements were made on 10 samples each.

The analysis conditions for the content uniformity test are as follows.

<Conditions for content uniformity test analysis>

1) Detector: UV-visible spectrophotometer (measurement wavelength: 225 nm)

2) Column: YMC Triart C18 (4.6 x 250 mm, 5 um) or equivalent column

3) Column temperature: 40 ℃

4) Injection volume: 10 uL

5) Flow rate: 1.0 mL/min

6) Analysis time: 10 minutes

7) Mobile phase: Buffer solution, methanol, acetonitrile mixture (50:45:5)

8) Buffer solution: Dissolve 2.0 g of potassium dihydrogen phosphate in 1 L of water and adjust the pH to 3.0 with phosphoric acid.

The judgment value was calculated by multiplying the standard deviation value obtained through measurement by the judgment coefficient (2.4 when n=10). The results are shown in Table 7 below.

The content uniformity test judgment value should be 15 or less (refer to the General Test Methods, Preparation Uniformity Test, 12th Edition of the Korean Pharmacopoeia).

In addition, the tablet thickness was measured for the composite tablets of Examples 12 to 15 and Comparative Examples 8 and 9, and the average thickness was measured when the tableting was performed at the same hardness of 25 Kp during tableting, and the results are shown in Table 7 below. In addition, the tableting pattern during the tableting process was observed, and the properties of the manufactured composite tablets were observed.

The dissolution evaluation of linagliptin was analyzed by sampling for 30 minutes under the dissolution conditions of pH 1.2 solution, 37℃, 900mL, and 50rpm according to the dissolution test according to the paddle method in the general test methods of the 12th revised edition of the Korean Pharmacopoeia, and the results are shown in Table 7 below. Since linagliptin must exhibit rapid release, the dissolution rate must be 80% or higher within 30 minutes.

As can be seen from the results in Table 7 above, the content uniformity in Examples 12 to 15 and Comparative Example 9 all showed 15 or less, confirming that the content uniformity of linagliptin was suitable. In contrast, in Comparative Example 8, where the weight ratio of the rapid-release layer to the sustained-release layer was less than 10, the content uniformity was found to be unsuitable since it exceeded the judgment value of 15.

In the composite tablet compression process, Examples 12 to 15 and Comparative Example 8 had no particular problems in the tablet compression process, but in Comparative Example 9 where the weight ratio of the immediate-release layer to the sustained-release layer exceeded 25, binding of the metformin sustained-release layer granules was found, and when measuring tablet wear, separation of layers between the metformin sustained-release layer and the linagliptin immediate-release layer occurred in some tablets. In addition, in Comparative Example 9, the thickness of the tablet exceeded 10 mm, which was confirmed to be disadvantageous in terms of medication convenience. In addition, in the case of Jentadueto XR, a commercially available product containing two components, linagliptin and metformin, the tablet sizes are thickness: 8.8 mm, short axis: 12.9 mm, and long axis: 19.5 mm, whereas the tablets of Examples 12 to 15 had significantly smaller short axis, confirming superior medication convenience.

According to the dissolution evaluation results of linagliptin in Table 7, the 30-minute dissolution rate was 80% or more for all of Examples 12 to 15 and Comparative Example 9, indicating rapid dissolution, but the tablet of Comparative Example 8 showed significantly lower dissolution. This is thought to be because the tablet of Comparative Example 8 has a small weight ratio of the rapid-release layer to the sustained-release layer of less than 10, so the thickness of the rapid-release layer is relatively thin, and accordingly, the ratio of the area directly adjacent to the sustained-release layer is large, which is affected by the sustained-release layer.

The present invention has been described with reference to preferred embodiments thereof. Those skilled in the art will appreciate that the present invention may be implemented in modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated by the claims, not the foregoing description, and all differences within the scope equivalent thereto should be interpreted as being included in the present invention.

Claims (11)

A combination tablet comprising a sustained-release layer containing metformin and an immediate-release layer containing linagliptin,
The above-mentioned layer comprises sustained-release granules comprising metformin or a pharmaceutically acceptable salt thereof, and a sustained-release agent; and
The above-mentioned fast-release layer comprises fast-release granules comprising linagliptin or a pharmaceutically acceptable salt thereof, and a disintegrant,
The weight ratio of the above-mentioned fast-acting layer to the western layer is 10 to 25 wt%,
A composite tablet in which the 30-minute dissolution rate of linagliptin in the first solution (pH 1.2) is 80% or higher when tested according to the paddle method in the general test methods of the 12th revised edition of the Korean Pharmacopoeia. A tablet comprising linagliptin besilate and metformin hydrochloride as active ingredients in claim 1. A composite tablet in claim 1, wherein each of the western-release granules and the rapid-release granules are wet granules. A composite tablet in claim 1, wherein the disintegrant comprises at least one selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, and crospovidone. A composite tablet in claim 4, wherein the disintegrant is contained in an amount of 0.5 to 10 wt% of the total weight of the rapid-release granules. A composite tablet comprising a combination of croscarmellose sodium and carboxymethylcellulose calcium as the disintegrant in claim 5. A combination tablet in claim 4, wherein the release agent comprises at least one selected from the group consisting of hypromellose, carbomer, povidone, and eudragit. A composite tablet in claim 7, wherein the release agent is contained in an amount of 15 to 30 wt% of the total weight of the release granules. A composite tablet in claim 8, wherein the western-release granules further comprise a binder, and the binder comprises at least one selected from the group consisting of povidone, hydroxypropyl cellulose, and sodium carboxycellulose. A composite tablet in claim 9, wherein the binder is contained in an amount of 3 to 10 wt% of the total weight of the western-style granules. A combination tablet comprising povidone as the binder and hypromellose as the sustained-release agent in claim 10.