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

Abstract

To provide a linagliptin-containing pharmaceutical composition, particularly a linagliptin-containing film-coated tablet, and a method for producing the same, which can suppress the delayed disintegration, delayed dissolution, and increase of related substances that occur over time by simpler means. [Solution] The invention provides linagliptin as an active ingredient, along with excipients, disintegrants, binders, and lubricants. The binder used is a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer or a polyvinyl alcohol / polyethylene glycol / graft copolymer. The uncoated tablets are prepared by a wet granulation method called fluid bed granulation drying. Hypromellose is used as the film coating agent, and the film coating layer does not contain polyethylene glycol, resulting in linagliptin-containing film-coated tablets.

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:

Chemical Formula

[0003] 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 pharmaceutical preparations, 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 of decomposition, or problems of extraction (for example, Patent Documents 1 and 2 described later).

[0004] 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

[0005]

Patent Document 1

[0006] 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]

[0007] 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.

[0008] 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.

[0009] 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.

[0010] 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; 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; is.

Advantages of the Invention

[0011] According to the present invention, it is possible to provide a linagliptin-containing pharmaceutical composition that prevents delayed disintegration and delayed dissolution and suppresses an increase in related substances, particularly a linagliptin-containing film tablet, and a method for producing the same.

Embodiments for Carrying Out the Invention

[0012] In the linagliptin-containing pharmaceutical composition provided by the present invention, the amount of linagliptin contained as an active ingredient is preferably 5 mg per preparation that has already been clinically used.

[0013] 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 the binder, and is a linagliptin-containing pharmaceutical composition.

[0014] 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.

[0015] 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.

[0016] Regarding the tablets which are the pharmaceutical compositions provided by the present invention, it is also possible to prepare the core tablets by tableting directly without using a binder in particular. However, when prepared by the direct tableting method, a delay in disintegration over time and a delay in the elution of linagliptin from the preparation were observed (refer to the test examples described later).

[0017] However, in the preparations prepared by using the fluidized bed granulation method which is a wet granulation method using a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer or a polyvinyl alcohol-polyethylene glycol graft copolymer which is specific as a binder, no delay in disintegration and elution delay were observed. Furthermore, the generation of related substances was suppressed in storage under thermally severe conditions, and the storage stability of the preparation was also good.

[0018] Therefore, in the present invention, it has a specific characteristic point in particular in using a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer or a polyvinyl alcohol-polyethylene glycol graft copolymer as a binder.

[0019] In addition, the present invention provides a linagliptin-containing film-coated tablet obtained by film-coating the core tablets prepared above. However, it is important not to use polyethylene glycol (macrogol) as a film layer in particular when using hypromellose as a coating agent.

[0020] By not containing this polyethylene glycol (macrogol) in the film layer, the generation of related substances is suppressed in storage under light-severe conditions, and it can be said that this is another specific characteristic point of the present invention in that the storage stability of the preparation is excellent.

[0021] In addition, when film-coating the core tablets, various colorants can be added in addition to hypromellose as a coating agent. Examples of such colorants include iron sesquioxide, titanium oxide, talc and the like. [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 step: 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 step: 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. The samples were exposed to light using a standard D65 lamp, and their purity was evaluated after a total illuminance of 1.2 million lux / hr, 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, issued by the Director of the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare)."

[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 method for producing film-coated tablets containing linagliptin, wherein the film-coated tablets are manufactured in which the formation of related substances during storage under harsh light and heat conditions is suppressed by applying a film-coating layer that does not contain polyethylene glycol. (However, this excludes "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 using a wet granulation method, adding magnesium stearate as a lubricant, compressing the resulting tablets, and using hypromellose as a film coating agent to create a film coating layer that does not contain polyethylene glycol.")

2. A method for producing a film-coated tablet according to claim 1, wherein the film-coated layer contains hypromellose and may further contain talc, titanium dioxide, or ferric oxide.

3. A method for manufacturing a film-coated tablet according to claim 1 or 2, wherein the light stress condition is exposure to a total illuminance of 1,200,000 lux·hr using a standard light source D65 lamp, and the heat stress condition is ambient temperature and humidity at 60°C.

4. A method for producing a film-coated tablet according to claim 1 or 2, comprising applying a film coating layer to a tablet core containing an excipient, a disintegrant, a binder selected from the group consisting of polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer and polyvinyl alcohol / polyethylene glycol / graft copolymer, and a lubricant.

5. A method for producing a film-coated tablet according to claim 1 or 2, wherein a film coating layer is applied to a tablet portion containing mannitol as an excipient.

6. A method for producing a film-coated tablet according to claim 1 or 2, wherein a film coating layer is applied to a tablet portion containing corn starch or crospovidone as a disintegrant.

7. A method for producing a film-coated tablet according to claim 1 or 2, wherein a film coating layer is applied to a tablet portion containing magnesium stearate as a lubricant.

8. A film-coated tablet containing linagliptin, wherein the film coating layer does not contain polyethylene glycol, thereby suppressing the formation of related substances during storage under harsh light and heat conditions. (However, this excludes "linagliptin-containing film-coated tablets characterized by containing linagliptin as an active ingredient, excipients, disintegrants, binders, and lubricants, using 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.")

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