Linagliptin-containing pharmaceutical composition and method for producing the same.

Abstract

To provide linagliptin-containing pharmaceutical compositions to suppress degradation delay, elution delay and analogous substance increase that occur with time by simpler means, in particular, linagliptin-containing film coating tablets and production methods thereof.SOLUTION: Disclosed is a method for producing a linagliptin-containing film coating tablet, by the fluid bed granulation-drying method (a wet granulation method), comprising preparing uncoated tablets using linagliptin as an effective ingredient, an excipient, a disintegrator, a binder selected from polyvinyl alcohol acrylic acid methyl methacrylate copolymer or a polyvinyl alcohol polyethylene glycol graft copolymer, and a lubricant, and coating the tablets with hypromellose as a film coating agent so that the film coat layer does not contain polyethylene glycol.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a linagliptin-containing pharmaceutical composition with improved stability, particularly a linagliptin-containing film-coated tablet, and a method for producing the same.

Background Art

[0002] The following formula I:

[0003]

Chemical formula

[0004] Linagliptin (JAN, INN) having the chemical name: 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine represented by the formula is a drug having an inhibitory effect on bile excretion type selective DPP-4 (dipeptidyl peptidase-4) and is clinically used as a type 2 diabetes drug (trade name: Trajenta (registered trademark) tablets).

[0005] In linagliptin-containing pharmaceutical compositions, delayed disintegration, delayed dissolution, and an increase in related substances have been observed over time due to the influence of storage conditions, etc. For example, many additives generally used in the preparation of formulations, such as microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, sucrose, lactose, and maltodextrin, have shown incompatibility with linagliptin, problems with decomposition, or problems with extraction (for example, Patent Documents 1 and 2 described below). Therefore, in order to solve such problems, many patent applications have been made so far regarding formulations containing linagliptin, particularly additives used in the preparation of formulations (Patent Documents 1 to 8).

Prior Art Documents

Patent Documents

[0006] [Patent Document 1] Patent No. 5478244 [Patent Document 2] Patent No. 6100998 [Patent Document 3] Patent No. 6564720 [Patent Document 4] Patent No. 6839708 [Patent Document 5] Patent No. 6215940 [Patent Document 6] Japanese Patent Publication No. 2020-158435 [Patent Document 7] Japanese Patent Publication No. 2021-134202 [Patent Document 8] Japanese Patent Publication No. 2021-167288 [Overview of the project] [Problems that the invention aims to solve]

[0007] In view of the above situation, the present invention aims to provide a linagliptin-containing pharmaceutical composition, particularly a film-coated tablet, that can suppress the delay in disintegration, the delay in dissolution, and the increase in related substances that occur over time by simpler means. [Means for solving the problem]

[0008] In order to solve these problems, the inventors conducted diligent research and found that in pharmaceutical compositions containing linagliptin, particularly in formulations prepared by fluid bed granulation using a specific polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer or polyvinyl alcohol-polyethylene glycol-graft copolymer as a binder during tablet preparation, no delay in disintegration or dissolution was observed.

[0009] Furthermore, we discovered that the formation of related substances under harsh light conditions is suppressed in film-coated tablets prepared using a formulation that does not contain polyethylene glycol in the film coating, thus completing the present invention.

[0010] Therefore, the present invention specifically comprises the following embodiments. (1) A linagliptin-containing pharmaceutical composition characterized by comprising linagliptin as an active ingredient, an excipient, a disintegrant, a binder, and a lubricant, wherein the binder is a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer or a polyvinyl alcohol / polyethylene glycol / graft copolymer; (2) The linagliptin-containing pharmaceutical composition according to (1) above, wherein the excipient is mannitol; (3) The linagliptin-containing pharmaceutical composition according to (1) above, wherein the disintegrant is corn starch or crospovidone; (4) The linagliptin-containing pharmaceutical composition according to (1) above, wherein the lubricant is magnesium stearate; (5) A linagliptin-containing pharmaceutical composition according to any of (1) to (4) above, in the form of a tablet; (6) The linagliptin-containing pharmaceutical composition described in (5) above, which is a film-coated tablet; (7) The linagliptin-containing pharmaceutical composition according to (6) above, wherein hypromellose is used as the film coating agent and the film coating layer does not contain polyethylene glycol.

[0011] Furthermore, in another aspect, the present invention relates to a method for producing a linagliptin-containing pharmaceutical composition, particularly a film-coated tablet, and specifically, (8) A method for producing linagliptin-containing film-coated tablets, characterized by granulating linagliptin as the active ingredient, mannitol as an excipient, corn starch or crospovidone as a disintegrant, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer or polyvinyl alcohol / polyethylene glycol / graft copolymer by a wet granulation method, adding magnesium stearate as a lubricant, compressing the resulting tablets, and using hypromellose as the film coating agent to create a film coating layer that does not contain polyethylene glycol; (9) The method for producing a linagliptin-containing film-coated tablet according to (8), wherein the wet granulation method is a fluidized bed granulation drying method; It is.

Effects of the Invention

[0012] According to the present invention, it is possible to provide a linagliptin-containing pharmaceutical composition that prevents delayed disintegration and delayed dissolution and suppresses the increase of related substances, particularly a linagliptin-containing film tablet, and a method for producing the same.

Modes for Carrying Out the Invention

[0013] The amount of linagliptin contained as an active ingredient in the linagliptin-containing pharmaceutical composition provided by the present invention is preferably 5 mg per preparation already clinically used.

[0014] As described above, the present invention includes linagliptin, an excipient, a disintegrant, a binder, and a lubricant as active ingredients, and uses a polyvinyl alcohol·acrylic acid·methyl methacrylate copolymer or a polyvinyl alcohol·polyethylene glycol graft copolymer as a binder. It is a linagliptin-containing pharmaceutical composition characterized by the above.

[0015] In the linagliptin-containing pharmaceutical composition provided by the present invention, although it contains linagliptin as an active ingredient, one or more other active ingredients may be blended in addition to linagliptin, and examples of such other active ingredients include empagliflozin, which is a selective SGLT2 inhibitor.

[0016] Examples of the excipient, disintegrant, binder, and lubricant to be used include various excipients, disintegrants, binders, and lubricants generally used in the formulation of pharmaceuticals. In the present invention, from the viewpoint of preventing delayed disintegration and delayed dissolution, mannitol is used as the excipient, corn starch or crospovidone is used as the disintegrant, and magnesium stearate is used as the lubricant.

[0017] The tablets, which are pharmaceutical compositions provided by the present invention, can also be prepared by direct compression without the use of a binder. However, when prepared using the direct compression method, delayed disintegration over time and delayed elution of linagliptin from the formulation were observed (see the test examples described below).

[0018] However, in formulations prepared using a specific binder, such as a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer or a polyvinyl alcohol-polyethylene glycol-graft copolymer, and prepared using a wet granulation method called fluidized bed granulation, no delayed disintegration or delayed dissolution was observed. Furthermore, the formation of related substances was suppressed during storage under severe thermal conditions, and the storage stability of the formulations was also good.

[0019] Therefore, the present invention is characterized by the use of a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer or a polyvinyl alcohol-polyethylene glycol-graft copolymer as a binder.

[0020] Furthermore, the present invention provides linagliptin-containing film-coated tablets obtained by film-coating the uncoated tablets prepared as described above. It is important to use hypromellose as the coating agent and, in particular, not to use polyethylene glycol (macrogol) as the film layer. By not including polyethylene glycol (macrogol) in the film layer, the formation of related substances is suppressed during storage under harsh light conditions, resulting in excellent storage stability of the formulation, which is another unique feature of the present invention.

[0021] Furthermore, when film coating the uncoated tablets, various coloring agents can be added in addition to hypromellose as a coating agent. Examples of such coloring agents include ferric oxide, titanium dioxide, and talc. [Examples]

[0022] The present invention will be described in more detail below with reference to examples, comparative examples, and test examples, but the scope of the present invention is not limited thereto.

[0023] Table 1 below shows the formulations of pharmaceutical compositions that were investigated in this invention.

[0024] [Table 1]

[0025] Example 1: Preparation of Linagliptin-Containing Film-Coated Tablets <First step: Granulation drying step> Linagliptin, mannitol, and corn starch were placed in a fluidized bed granulator (Floint Industrial Co., Ltd., model: FLO-1), and a binding solution of polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer dissolved in purified water was sprayed onto the granulated material, followed by drying.

[0026] <Second process: Sizing process> The granulated powder produced in the first step was sieved through a 24-mesh round sieve.

[0027] <Third step: Mixing step> Magnesium stearate was added to the obtained whole granules and mixed.

[0028] <Fourth process: Tableting process> The mixed powder produced in the third step was compressed into tablets using a rotary tablet press (Hata Iron Works Co., Ltd., model: HT-EX6SS-II) to produce tablets with a mass of 180 mg and a thickness of 3.5 mm.

[0029] <Fifth Process: Film Coating Process> Using a film coating machine (manufactured by Pawrec Co., Ltd., model: PRC-GTXmini), 5 mg of film coating was applied to each uncoated tablet obtained in the fourth step using a solution in which the coating substrate was dissolved and dispersed in water, thereby obtaining the linagliptin-containing film-coated tablets of Example 1.

[0030] Example 2: Preparation of Linagliptin-Containing Film-Coated Tablets <First step: Granulation drying step> Linagliptin, mannitol, and corn starch were placed in a fluidized bed granulator (Floint Industrial Co., Ltd., model: FLO-1), and a binding solution of polyvinyl alcohol, polyethylene glycol, and graft copolymer dissolved in purified water was sprayed onto the granulated material before drying.

[0031] <Second process: Sizing process> The granulated powder produced in the first step was sieved through a 24-mesh round sieve.

[0032] <Third step: Mixing step> Magnesium stearate was added to the obtained whole granules and mixed.

[0033] <Fourth process: Tableting process> The mixed powder produced in the third step was compressed into tablets using a rotary tablet press (Hata Iron Works Co., Ltd., model: HT-EX6SS-II) to produce tablets with a mass of 180 mg and a thickness of 3.5 mm.

[0034] <Fifth Process: Film Coating Process> Using a film coating machine (manufactured by Pawrec Co., Ltd., model: PRC-GTXmini), 5 mg of film coating was applied to each uncoated tablet obtained in the fourth step using a solution in which the coating substrate was dissolved and dispersed in water, thereby obtaining the linagliptin-containing film-coated tablets of Example 2.

[0035] Comparative Example 1: Preparation of linagliptin-containing film-coated tablets using polyethylene glycol as the coating substrate Using a film coating machine (manufactured by Pawrec Co., Ltd., model: PRC-GTXmini), 5 mg of film coating was applied to one uncoated tablet produced in Example 2 using a solution obtained by dissolving and dispersing a coating substrate containing polyethylene glycol in water, thereby obtaining the linagliptin-containing film-coated tablets of Comparative Example 1.

[0036] Comparative Example 2: Preparation of linagliptin-containing film-coated tablets by direct compression without the addition of a binder, followed by the use of polyethylene glycol as the coating substrate. <First step: Mixing step> Linagliptin, mannitol, crospovidone, and light anhydrous silicic acid were mixed together, and then magnesium stearate was added and mixed.

[0037] <Second process: Direct tabletting process> The mixed powder produced in the first step was compressed into tablets using a rotary tablet press (Hata Iron Works Co., Ltd., model: HT-EX6SS-II) to produce tablets with a mass of 180 mg and a thickness of 3.5 mm.

[0038] <Third step: Film coating process> Using a film coating machine (manufactured by Pawrec Co., Ltd., model: PRC-GTXmini), 5 mg of film coating was applied to each uncoated tablet obtained in the second step using a solution in which a coating substrate containing polyethylene glycol was dissolved and dispersed in water, thereby obtaining the linagliptin-containing film-coated tablets of Comparative Example 2.

[0039] The film-coated tablets prepared in Examples 1 and 2, and Comparative Examples 1 and 2, were stored under the following storage conditions, and disintegration tests, dissolution tests, and purity tests were examined.

[0040] Storage condition A: The tablets were packaged in PTP packaging (polypropylene film and aluminum foil), then in aluminum pillow packaging (aluminum / polyethylene laminate film) to be used as samples for storage. The samples were stored at 60°C with ambient humidity, and their disintegration, elution, and purity were evaluated before storage, after 2 weeks, and after 4 weeks of storage.

[0041] Storage condition B: The tablets were placed in a glass petri dish, opened, and prepared as a sample for preservation. Exposure was performed using a standard D65 lamp, and the total illuminance was set to 1.2 million lux, in accordance with the "Guidelines for Photostability Testing of New Active Pharmaceutical Ingredients and New Formulations (Notification No. 422, May 28, 1997, addressed to the Directors of Health Departments (Bureaus) of Each Prefecture, by the Director of the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare)." · The purity after hr was evaluated.

[0042] Test 1: Collapse Test <Method> Six test tablets were taken, and their disintegration time was measured using a disintegration test machine (manufactured by Toyama Sangyo Co., Ltd., model: NT-20H). <Result> The results are shown in Table 2 below.

[0043] Test 2: Dissolution Test <Method> One tablet was taken as a test sample, 900 mL of water was used as the test solution, and the test was performed using the paddle method at 50 rotations per minute.

[0044] <Result> The results are shown in Table 3 below.

[0045] Test 3: Purity Test <Method> One tablet was taken as a test sample and measured by liquid chromatography.

[0046] <Result> The results are shown in Table 4 below.

[0047] The results of each of the above tests are shown in the tables below. Table 2 shows the results of the disintegration test, Table 3 shows the results of the elution test, and Table 4 shows the results of the purity test.

[0048] Table 2: Results of the collapse test (Test 1)

[0049] [Table 2]

[0050] Table 3: Results of the dissolution test (Test 2)

[0051] [Table 3]

[0052] Table 4: Results of the Purity Test (Test 3)

[0053] [Table 4]

[0054] <Consideration> The results in Tables 2 and 3 show that the film-coated tablets of Example 1, Example 2, and Comparative Example 1, which were produced by fluid bed granulation using a specific polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer or polyvinyl alcohol / polyethylene glycol / graft copolymer as a binder, did not show any delay in disintegration or dissolution, and were more stable than those of Comparative Example 2, which was produced by direct compression.

[0055] Furthermore, the purity test results in Table 4 showed that the film-coated tablets of Examples 1 and 2, manufactured by the fluidized bed granulation method, exhibited suppressed generation of related substances under severe thermal conditions compared to the film-coated tablets of Comparative Example 2, manufactured by the direct compression method. Additionally, the film-coated tablets of Example 2, which did not contain polyethylene glycol in the film layer, showed suppressed generation of related substances under severe light conditions compared to the film-coated tablets of Comparative Example 1. This indicates that when preparing uncoated tablets using the fluid bed granulation method and then forming film-coated tablets, removing polyethylene glycol from the film layer is effective in stabilizing the formulation.

[0056] Based on the above, the present invention demonstrates that when a formulation is prepared using a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer or polyvinyl alcohol-polyethylene glycol-graft copolymer as a binder, and prepared using a wet granulation method called fluidized bed granulation, no delayed disintegration or delayed dissolution is observed. Furthermore, the formation of related substances is suppressed during storage under harsh thermal conditions, and the storage stability of the formulation is also good, thus demonstrating the uniqueness of the present invention.

[0057] Furthermore, comparing the results of Example 1 and Example 2 in the purity test shown in Table 4, the increase in related substances was suppressed in Example 1, suggesting that using a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer as the binder is more desirable.

[0058] Furthermore, in preparing the linagliptin-containing film-coated tablets of the present invention, hypromellose is used as the coating agent, and in particular polyethylene glycol (macrogol) is not used as the film layer. This suppresses the formation of related substances during storage under harsh light conditions, resulting in excellent storage stability of the formulation, which is another unique feature of the present invention. [Industrial applicability]

[0059] The present invention provides a linagliptin-containing pharmaceutical composition, particularly a linagliptin-containing film tablet, and a method for producing the same, which prevents delayed disintegration and delayed dissolution and suppresses the increase of related substances, and therefore has great industrial applicability.

Claims

1. A linagliptin-containing film-coated tablet characterized by containing linagliptin as the active ingredient, excipients, disintegrants, binders, and lubricants, using a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer or polyvinyl alcohol / polyethylene glycol / graft copolymer as the binder, using hypromellose as the film coating agent, and not containing polyethylene glycol in the film coating layer.

2. The linagliptin-containing pharmaceutical composition according to claim 1, wherein the excipient is mannitol.

3. The linagliptin-containing pharmaceutical composition according to claim 1 or 2, wherein the disintegrant is corn starch or crospovidone.

4. The linagliptin-containing pharmaceutical composition according to claim 1 or 2, wherein the lubricant is magnesium stearate.

5. A method for producing linagliptin-containing film-coated tablets, characterized by granulating linagliptin as the active ingredient, mannitol as an excipient, corn starch or crospovidone as a disintegrant, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer or polyvinyl alcohol / polyethylene glycol / graft copolymer by a wet granulation method, adding magnesium stearate as a lubricant, compressing the resulting uncoated tablets, and using hypromellose as the film coating agent to create a film coating layer that does not contain polyethylene glycol.

6. A method for producing a linagliptin-containing film-coated tablet according to claim 5, wherein the wet granulation method is a fluid bed granulation-drying method.

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