JP2022171508A - Method for producing linagliptin-containing preparation having excellent stability and uniformity - Google Patents

Abstract

To provide a method for producing a linagliptin-containing preparation having excellent stability and uniformity.SOLUTION: There is provided a method for producing a tablet including a step for directly tableting a composition containing linagliptin, mannitol and crospovidone.

Description

TECHNICAL FIELD The present invention relates to a method for producing a formulation containing linagliptin with excellent stability and uniformity.

Linagliptin has the chemical name 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazoline-2 -yl)-3,7-dihydro-1H-purine-2,6-dione, a tablet containing linagliptin as an active ingredient is known to be a therapeutic agent for type 2 diabetes, and is marketed as Trazenta Tablets 5 mg. (Non-Patent Document 1).

Patent Document 1 discloses a composition comprising linagliptin, carboxymethylstarch sodium, carmellose, carmellose calcium, and croscarmellose sodium, which can easily suppress deterioration in quality of a linagliptin-containing pharmaceutical composition due to the influence of storage environment. and at least one selected from the group.

US Pat. No. 6,200,000 discloses that the elimination of binders combined with the use of direct compression to manufacture pharmaceutical compositions results in rapid industrial manufacturing without negatively impacting dissolution rate or content uniformity. A pharmaceutical composition comprising linagliptin or a pharmaceutically acceptable salt thereof as an active ingredient, wherein said pharmaceutical composition does not contain a binder and said pharmaceutical composition is obtainable by direct compression Inventions relating to compositions are described.

US Pat. No. 6,200,000 discloses linagliptin or its pharmaceutically acceptable ingredients as active ingredients, which are characterized by high bioavailability and are therapeutically effective even when manufactured, handled and/or stored under conditions of high humidity. A directly compressed pharmaceutical composition comprising a salt, mannitol, copovidone and magnesium stearate, wherein said mannitol is present in an amount of 90-95% by weight based on the pharmaceutical composition. is described.

JP 2020-158435 A JP 2018-530566 A Japanese Patent Application Publication No. 2015-524831

Package insert "Tragenta Tablets 5 mg", revised in July 2020 (1st edition)

An object of the present invention is to provide a method for producing a linagliptin-containing formulation with excellent stability and uniformity.

The inventors of the present invention have investigated a method for producing linagliptin, and found that a production method including a step of mixing linagliptin with a specific additive and tableting the resulting mixture has good stability of linagliptin, The inventors have found that a linagliptin-containing preparation with good uniformity can be produced, and have completed the present invention.

That is, the present invention
(1) a method for producing a tablet, comprising mixing linagliptin, mannitol and crospovidone and tableting;
(2) The method for producing a tablet according to (1) above, further comprising adding a lubricant,
(3) The method for producing a tablet according to (2) above, wherein the lubricant is at least one lubricant selected from the group consisting of magnesium stearate, hydrogenated oil and sucrose fatty acid ester,
(4) The method for producing a tablet according to any one of (1) to (3) above, wherein the tablet is an orally disintegrating tablet;
(5) The method for producing the tablet according to any one of (1) to (4), further comprising a coating step,
It is about.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a method for producing a linagliptin preparation having excellent stability and content uniformity in a preparation containing linagliptin.

The term "stability" as used herein means suppressing an increase in the amount of analogues and/or an increase in the amount of unknown substances caused by decomposition of the drug under temperature and humidity conditions. As an evaluation method, for example, after storing the formulation under temperature and humidity conditions, the stability of the formulation is evaluated by performing a test by high performance liquid chromatography (HPLC method) and calculating the amount of related substances.

Uniformity as used herein refers to the extent to which the tablets produced are uniform in content of ingredients between individual formulations. Evaluation methods include, for example, the Japanese Pharmacopoeia uniformity test method. Good uniformity is defined as a judgment value of 15% or less calculated for 10 samples when evaluating formulation uniformity in the content uniformity test.

The method for producing the formulation containing linagliptin of the present invention is described below.

Linagliptin used in the present invention can be produced according to the method described in WO2004/018468. Pharmaceutically acceptable salts of linagliptin are prepared according to WO2004/018468 or WO2010/072776. Linagliptin crystals A, B and C are described in WO2007/128721 and from linagliptin obtained by the method described in WO2004/018468 as starting material, WO2007/018468. /128721.

Linagliptin produced by the method described in WO2004/018468 can be obtained as a mixture of crystal A and crystal B.

A mixture of crystalline linagliptin crystal A and crystalline linagliptin crystal B is obtained by mixing crystalline A prepared according to WO 2007/128721 with crystalline crystalline A prepared according to WO 2007/128721. It can be obtained by mixing with linagliptin crystal B.

In addition, the linagliptin used in the present invention can also use crystal F that can be produced according to the method described in WO2020/042939, and can be produced according to the method described in JP-A-2018-177769. Polymorph F can also be used and AL crystals can be used which can be prepared according to the method described in Indian Patent Application No. 2250/MUM/2014. Furthermore, other novel crystals can also be used.

The indication is "type 2 diabetes", and the dosage and administration is "usually for adults, 5 mg of linagliptin is orally administered once a day."

Additives used in the present invention include mannitol and crospovidone.

Mannitol used in the present invention may be mannitol as a component, preferably D-mannitol conforming to the Japanese Pharmacopoeia. Specifically, Mannitol (trade name, manufactured by Mitsubishi Corporation Life Science), Pearitol (trade name, manufactured by Rocket Japan), Partek M (trade name, manufactured by Merck), Granutol (trade name, manufactured by Freund Corporation), etc. mentioned.

The average particle size (d50) of mannitol is preferably 15 μm or more and 200 μm or less, more preferably 50 μm or more and 160 μm or less, and even more preferably 60 μm or more and 100 μm or less.

The amount of mannitol may be any amount that achieves the object of the present invention. As a mode, it is 30 to 95% with respect to the weight of the whole tablet.

The crospovidone used in the present invention may be crospovidone as a component, preferably crospovidone conforming to the Japanese Pharmacopoeia. Specific examples include Kollidon CL, Kollidon CL-F, Kollidon CL-SF, Kollidon CL-M (trade name, manufactured by BASF Japan), Polyplasdon (trade name, manufactured by Ashland Japan), and the like.

The particle size of crospovidone is classified into type A and type B, but either type may be used.

The amount of crospovidone to be blended may be any amount that achieves the object of the present invention. %, in one embodiment 2-5% of the total tablet weight. In one embodiment, 20% by weight or more and 300% by weight or less with respect to 100% by weight of linagliptin, 30% by weight or more and 200% by weight or less with respect to 100% by weight of linagliptin, and in one embodiment, 50% by weight with respect to 100% by weight of linagliptin. % or more and 150% by weight or less.

The manufacturing method used in the present invention includes a step of mixing mannitol and crospovidone and tableting. Moreover, in this step, optional additives such as lubricants can be added. Specifically, for example, the lubricant includes at least one lubricant selected from the group consisting of magnesium stearate, hydrogenated oil and sucrose fatty acid ester. The lubricant may be applied using an external lubrication method. In addition, the amount of lubricant when using the external lubrication method may be an amount that achieves the object of the present invention. In one embodiment, it is 0.01 to 0.1% of the weight of the whole tablet, and in another embodiment, it is 0.02 to 0.08% of the weight of the whole tablet. Moreover, the mixing time in the mixing step is not particularly limited as long as it is a time that achieves the object of the present invention, and is appropriately set in consideration of the production scale. The pressure during tableting is preferably 2 kN or more and 30 kN or less from the viewpoint of tablet hardness and tableting trouble. The machine used for tableting may be any machine as long as it can achieve the object of the present invention, examples of which include a rotary tableting machine and a single tableting machine.

As the manufacturing method used in the present invention, the uncoated tablet manufactured in the tableting step may be coated with a coating layer, if necessary. The solvent of the coating liquid used in the coating step can be selected from organic solvents such as water and ethanol, and is preferably selected from water alone, a mixture of water and ethanol, or ethanol alone. Examples of coating agents used in the coating liquid include hypromellose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyvinyl alcohol/polyethylene glycol/graft copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, titanium oxide, talc, and the like. mentioned. The concentration of the solid component in the coating liquid may be any concentration that achieves the object of the present invention. , 5% by weight or more and 30% by weight or less, and in one embodiment, 8% by weight or more and 25% by weight or less. The spray rate of the coating liquid in the coating step may be any spray rate that achieves the object of the present invention. Hereinafter, as a certain mode, it is 20 mL/min or more and 500 mL/min or less. Drying conditions after spraying of the coating solution in the coating step are not particularly limited as long as they are appropriately set in consideration of the stability of the formulation.

The tablet of the present invention may be an uncoated tablet, a coated tablet, or an orally disintegrating tablet.

The tablet of the present invention may further contain pharmaceutical excipients, if necessary. Specific examples include binders, surfactants, acidulants, foaming agents, sweeteners, fragrances, colorants, buffers, antioxidants, light stabilizers, coating agents and the like. As for excipients, disintegrants, and lubricants, in addition to specific additives, optional additives may be added.

Examples of surfactants include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil and the like.

Examples of binders include hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol/polyethylene glycol/graft copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, gum arabic, and hydroxyethyl cellulose. .

Acidulants include, for example, citric acid, tartaric acid, and malic acid.

Examples of foaming agents include multi-layers.

Sweetening agents include, for example, sucralose, sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.

Perfumes include, for example, lemon, lemon-lime, orange, and menthol.

Examples of coloring agents include iron sesquioxide, yellow iron sesquioxide, black iron oxide, titanium oxide, food yellow No. 4, food yellow No. 5, food red No. 3, food red No. 102, and food blue No. 3. be done.

Examples of buffering agents include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, Phosphoric acid, boric acid, salts thereof, and the like can be mentioned.

Examples of antioxidants include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.

Examples of light stabilizers include iron sesquioxide, yellow iron sesquioxide, black iron oxide, titanium oxide, food yellow No. 4, food yellow No. 5, food red No. 3, food red No. 102, food blue No. 3, and the like. is mentioned.

Excipients include, for example, corn starch, crystalline cellulose, trehalose, anhydrous calcium hydrogen phosphate, isomalt, D-sorbitol, lactose, sucrose, starch, pregelatinized starch, low-substituted hydroxypropylcellulose, carmellose sodium, arabic Rubber, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate and the like.

Examples of disintegrants include corn starch, potato starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium starch glycolate, carmellose, carmellose calcium, hydroxypropyl starch, croscarmellose, croscarmellose sodium, and pregelatinized starch. etc.

Lubricants include, for example, stearic acid, sodium stearyl fumarate, sodium stearate, calcium stearate, talc and the like.

The blending amount is not particularly limited as long as it does not affect the achievement of the desired effect of the present invention.

The tablet of the present invention can be produced by a production method known per se. More specifically, for example, when producing tablets, powder for tableting is obtained by mixing linagliptin, D-mannitol, crospovidone and optional additives, adding a lubricant, and further mixing. .

In another embodiment, for example, linagliptin, D-mannitol, crospovidone and optional additives are mixed, then granulated using a granulator or pulverized using a pulverizer, a lubricant is added, and the Mixing gives a powder for tableting. D-mannitol and crospovidone may be added together with a lubricant after sizing or grinding.

Next, the obtained powder for tableting is tableted to produce uncoated tablets. If necessary, it includes a step of coating by spraying a liquid in which a coating agent is dissolved or dispersed on an uncoated tablet. A film-coated tablet can be produced through this process.

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to the following examples.

A mixture of 25 g of linagliptin and 250 g of D-mannitol (manufactured by Merck KGaA: Parteck M100) was sieved using a sizing machine (manufactured by Powrex: QC-U5) equipped with a 0.813 mm screen to obtain a triturated product. . This triturated product, D-mannitol (manufactured by Merck KGaA: Parteck M100) 584.5 g and crospovidone (manufactured by BASF Japan: Kollidon CL-F) 27 g were added and mixed for 16 minutes, and magnesium stearate (manufactured by Taihei Chemical Industry : Magnesium stearate (vegetable)) was added and mixed for 4 minutes to prepare tableting powder, which was then tableted to give round tablets with a tablet weight of 180 mg and a diameter of 8.0 mm.

<Test Example 1>
(Preparation uniformity test)
The tablets of Example 1 were evaluated for tableting aptitude, weight, hardness, and formulation uniformity after continuous tableting for 60 minutes. Formulation uniformity was determined by measuring the linagliptin content in each of 10 tablets by liquid chromatography. For the evaluation, judgment values were obtained with reference to the formulation uniformity test of the 17th revision of the Japanese Pharmacopoeia general test method. Table 2 shows the results.

Formulation uniformity test (content uniformity)
Take 1 tablet of this product, add 60 mL of the diluent, and sonicate for 15 minutes with occasional shaking until the tablet is completely disintegrated. Further, diluent is added to make exactly 100 mL, and filtered through a membrane filter with a pore size of 0.45 μm or less. Remove the first 5 mL of the filtrate and use the next filtrate as the sample solution. Separately, weigh precisely about 25 mg of linagliptin, and add the diluent to make exactly 50 mL. Accurately measure 5 mL of this solution, add a diluent to make exactly 50 mL, and use it as a standard solution. Exactly 40 μL each of the sample solution and the standard solution were taken and tested by liquid chromatography under the following conditions, and the peak areas A _T and A _S of linagliptin in each solution were measured.
Amount ₍ mg) of _{linagliptin ( C25H28N8O2} )
= M _S ×A _T /A _S × 1/5
M _S : Amount (mg) of linagliptin converted to dehydrated product
A _T : Peak area of linagliptin in sample solution _AS : Peak area of linagliptin in sample solution 1/5: Dilution correction factor Dilution solution: Dissolve 5.44 g of potassium dihydrogen phosphate in 1000 mL of water, add phosphoric Adjust to H3.0. 50 mL of methanol is added to 50 mL of this liquid.
Test conditions Detector: UV absorption photometer (measurement wavelength 225 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm is packed with 5 µm octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 40° C. Mobile phase: 5.44 g of potassium dihydrogen phosphate is dissolved in 1000 mL of water, and phosphoric acid is added to adjust the pH to 3.0. 250 mL of acetonitrile is added to 750 mL of this liquid.
Flow rate: 1.0 mL per minute
System suitability System performance: The theoretical plate number and symmetry coefficient of the linagliptin peak are 5,000 or more and 2.0 or less, respectively, per 40 µL of the standard solution and operated under the above conditions.
Reproducibility of the system: The relative standard deviation of the peak area of linagliptin is 1.0% or less when the test is repeated 6 times under the above conditions for 40 μL of the standard solution.

The judgment value was well below 15% at any point during continuous tableting, indicating good uniformity. Moreover, no tableting failure was observed, and stable production was possible.

<Test Example 2>
(Stability test)
The tablets of Example 1 and 5 mg of Trajenta tablets were stored at 60° C. (±1° C.) and 75% (±5%) RH, and then the total amount of related substances derived from linagliptin was measured by liquid chromatography. Stability was evaluated. Table 3 shows the results.

流量：１．０ｍＬ／ｍｉｎ
面積測定範囲： ６０分
システム適合性
検出の確認：標準溶液１ｍＬを正確に量り、希釈液を加えて正確に１０ｍＬとする。この 液４０μＬから得たリナグリプチンのピーク面積が、標準溶液のリナグリプチンのピ ーク面積の７～１３％になることを確認する。
システムの性能：標準溶液４０μＬにつき、上記の条件で操作するとき、リナグリプチン のピークの理論段数及びシンメトリー係数は、それぞれ７０００段以上、２．０以下 である。
システムの再現性：標準溶液４０μＬにつき、上記の条件で試験を６回繰り返すとき、リ ナグリプチンのピーク面積の相対標準偏差は２．０％以下である。Purity test (related substances)
Take 2 of this product, add 20 mL of the diluted solution, and sonicate with occasional shaking. This liquid is centrifuged, and the supernatant is filtered through a membrane filter with a pore size of 0.45 μm or less. Remove the first 2 mL of the filtrate, measure the next 1 mL of the filtrate, add the diluent to make exactly 10 mL, and use this as the sample solution. Accurately measure 1 mL of this solution, add a diluent to make exactly 100 mL, and use it as a standard solution. Accurately take 40 μL each of the sample solution and the standard solution, and perform the test by liquid chromatography under the following conditions. Each peak area of each liquid is measured by an automatic integration method.
Amount of related substances (%) = A _T / A _S
A _T : Each peak area other than linagliptin obtained from the sample solution A _S : Peak area of linagliptin obtained from the standard solution Diluted solution: mobile phase A/methanol mixture (1:1)
Test conditions Detector: UV absorption photometer (measurement wavelength: 225 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm is packed with 5 μm octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 45° C. Mobile phase A: 2.72 g of potassium dihydrogen phosphate is dissolved in 1000 mL of water, and phosphoric acid is added to adjust the pH to 3.0.
Mobile Phase B: Add 10 mL of methanol to 90 mL of acetonitrile.
Transfer of mobile phase: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.

Flow rate: 1.0 mL/min
Planimetric range: 60 minutes Confirmation of system suitability detection: Accurately measure 1 mL of standard solution and add diluent to make exactly 10 mL. Confirm that the peak area of linagliptin obtained from 40 μL of this solution is 7 to 13% of the peak area of linagliptin in the standard solution.
Performance of the system: For 40 μL of the standard solution, the theoretical plate number and symmetry coefficient of the linagliptin peak are 7000 plates or more and 2.0 or less, respectively, when operated under the above conditions.
System reproducibility: The relative standard deviation of the peak area of linagliptin is 2.0% or less when the test is repeated 6 times per 40 µL of the standard solution under the above conditions.

The tablet of Example 1 had a lower total amount of related substances derived from linagliptin and was more stable than the 5 mg Trajenta tablet.

Claims (5)

A method of manufacturing a tablet comprising direct compression of a composition comprising linagliptin, mannitol and crospovidone. 2. The method of manufacturing a tablet according to claim 1, further comprising a lubricant. 3. The method for producing tablets according to claim 2, wherein the lubricant is at least one lubricant selected from the group consisting of magnesium stearate, hydrogenated oil and sucrose fatty acid ester. The method for producing a tablet according to any one of claims 1 to 3, wherein the tablet is an orally disintegrating tablet. Further comprising a film coating step, the manufacturing method of the tablet according to any one of claims 1 to 4.