JP2019014712A - Stable dabigatran formulation - Google Patents

Abstract

To provide a pharmaceutical composition containing dabigatran etexilate mesylate and having both of high elution properties and stability.SOLUTION: The present invention provides a pharmaceutical composition containing dabigatran etexilate mesylate, the pharmaceutical composition containing hydroxypropyl methylcellulose and substantially free of organic acid.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition having improved stability containing dabigatran etexilate, which is a prophylactic agent for ischemic diseases.

  Dabigatran is a direct thrombin inhibitor and its prodrug, dabigatran etexilate (3-([[2-([[4- (amino [[(hexyloxy) carbonyl] imino] methyl) phenyl] amino] methyl ) -1-Methyl-1H-benzimidazol-5-yl] carbonyl] (pyridin-2-yl) amino) propanoic acid ethyl ester) is a drug for the prevention of ischemic disease in patients with nonvalvular atrial fibrillation Clinically used to control the onset of bloody stroke or systemic embolism ("Plazaxa (registered trademark) capsule" containing dabigatran etexilate methanesulfonate as an active ingredient, manufactured by Nippon Boehringer Ingelheim Co., Ltd. And sales). Overseas, it is also used for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients after parenteral parenteral administration for 5-10 days.

  As the dabigatran etexilate methanesulfonate, two anhydrous crystal polymorphs (type I and type II) described in International Publication WO2005 / 28468 are known. The solubility of this crystalline material in water is pH dependent and exhibits high solubility in acidic media and very low solubility in neutral and basic media, but such physicochemical properties indicate that patients with low gastric acid (e.g. In patients whose gastric acid has a pH of about 5), there is a problem in that elution of dabigatran etexilate methanesulfonate from the preparation becomes insufficient and bioavailability decreases. In order to solve this problem and ensure high bioavailability even in patients with low gastric acid, pharmaceutical compositions containing acidic substances have been proposed (Patent No. 3866715, Patent No. 4974662, and Special Table 2015- 511241).

  However, although dabigatran etexilate methanesulfonate is stable in the solid state, it has a problem that it is hydrolyzed in the presence of moisture and is unstable to acid. Because of this characteristic, any of the above pharmaceutical compositions containing the teacher substance has a significant problem in storage stability. For example, 75 mg and 110 mg capsules of Plazaxa® are provided in two 14-capsule PTP sheets in an aluminum pillow package with a desiccant. Therefore, it is cautioned to instruct them to store it in aluminum pillow packaging as much as possible, and to take it out of the PTP sheet just before taking it (Plazaxa® capsule 75 mg, 110 mg pharmaceutical interview form ( 11th edition), November 2016, X. Items related to administrative matters, 4. Notes on handling of drugs).

International Publication WO2005 / 28468 Japanese Patent No. 3866715 Japanese Patent No. 4974662 Special Table 2015-511241

Plazaxa® capsule 75mg and 110mg pharmaceutical interview form (11th edition), November 2016

  An object of the present invention is to provide a pharmaceutical composition containing dabigatran etexilate methanesulfonate and having both high dissolution property and stability.

  In order to solve the above problems, the present inventors achieved high dissolution and bioavailability even in patients with low gastric acid without using an acidic substance in a pharmaceutical composition containing dabigatran etexilate methanesulfonate. The additive which can be done was earnestly examined. As a result, in the pharmaceutical composition to which hydroxypropylmethylcellulose is added, the decomposition of dabigatran etexilate methanesulfonic acid does not proceed and the same component is stably maintained in the pharmaceutical composition and has high storage stability. It was also found that this pharmaceutical composition has excellent dissolution properties even under weakly acidic conditions of about pH 5 and can achieve high bioavailability even in patients with low gastric acid. The present invention has been completed based on the above findings.

  That is, according to the present invention, there is provided a pharmaceutical composition containing dabigatran etexilate methanesulfonate, which comprises hydroxypropylmethylcellulose and substantially does not contain an organic acid.

  According to a preferred embodiment of the present invention, there is provided the above pharmaceutical composition, wherein hydroxypropylmethylcellulose is a solubilizer for dabigatran etexilate methanesulfonate; and the above pharmaceutical composition in the form of a tablet.

  The pharmaceutical composition of the present invention has excellent dissolution properties even under weakly acidic conditions of about pH 5 because hydroxypropylmethylcellulose exerts a solubilizing action on dabigatran etexilate methanesulfonate. High bioavailability can be achieved even in patients with low gastric acid. Further, since it does not substantially contain an organic acid, dabigatran etexilate methanesulfonic acid is stably maintained in the pharmaceutical composition and has a high storage stability.

A drug containing dabigatran etexilate methanesulfonate has already been used clinically for the prevention of ischemic stroke or systemic embolism in patients with nonvalvular atrial fibrillation. Latomethane sulfonate is readily available to those skilled in the art. The properties of dabigatran etexilate methanesulfonate are not particularly limited, but it is possible to use one of the two anhydrous crystalline polymorphs (type I and type II) or a mixture described in International Publication WO2005 / 28468. preferable. The particle diameter is not particularly limited, but it is preferable to use a particle having D ₅₀ of 100 μm or less, more preferably D ₅₀ of 50 μm or less.

  The pharmaceutical composition of the present invention is characterized by containing hydroxypropylmethylcellulose. Hydroxypropyl methylcellulose (hypromellose) is widely used as a pharmaceutical additive when producing a pharmaceutical composition for uses such as a base, a binder, a coating agent, an excipient, an adhesive, or a thickener, It can be easily obtained. The compounding amount of hydroxypropylmethylcellulose is not particularly limited, but generally it is about 5 to 25% by weight, more preferably about 10 to 20% by weight, based on the weight of dabigatran etexilate methanesulfonate. About 1 to 10% by weight, more preferably about 2 to 8% by weight, based on the total weight of the product. Hydroxypropyl methylcellulose may be added as a powder in the pharmaceutical composition, but it can also be added as an aqueous solution during preparation of the granulated product, and the method and timing of addition are not particularly limited.

  The pharmaceutical composition of the present invention is prepared free of organic acids in order to enhance the stability of dabigatran etexilate methanesulfonate in the pharmaceutical composition. Examples of the organic acid include organic acids such as tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, and aspartic acid. As used herein, the term “substantially free of organic acids” means dabigatran etexylate methane to prevent degradation of dabigatran etexilate methanesulfonate, as will be apparent from the above purposes. It should be construed that it does not contain organic acids in direct contact with the sulfonate. For example, an organic acid may be used if it is not in direct contact with dabigatran etexilate methanesulfonate. In addition, when the organic acid is a neutral salt (for example, sodium fumarate, sodium citrate, sodium stearate, etc.), the decomposition of dabigatran etexilate methanesulfonate is not promoted. Salt formulation may be allowed. Furthermore, in order to sufficiently enhance the stability of dabigatran etexilate methanesulfonate, it is also preferable not to include an acidic pharmaceutical additive. Examples of acidic pharmaceutical additives include, but are not limited to, light anhydrous silicic acid and sodium dihydrogen phosphate.

  The form of the pharmaceutical composition of the present invention is not particularly limited and is generally provided as a solid preparation suitable for oral administration. For example, the pharmaceutical composition is in the form of a tablet, granule, powder, capsule or the like. It is preferable to prepare as a product. Particularly preferred are tablets. For example, conventional excipients, disintegrants, binders, lubricants, pigments, and other pharmaceutical additives can be used for tablet preparation. The pharmaceutical additive may be used alone or in combination of two or more.

  Examples of excipients include D-mannitol, corn starch, wheat starch, lactose, anhydrous lactose, hydroxypropylcellulose, sucrose, talc, purified gelatin, hydroxypropyl starch, polyvinylpyrrolidone, crystalline cellulose, or calcium silicate. Can be mentioned.

  Examples of the disintegrant include corn starch, sodium starch glycolate, carmellose calcium, crospovidone, croscarmellose sodium, croscarmellose calcium, methylcellulose, sodium carboxymethyl starch, or crystalline cellulose.

  Examples of the binder include partially pregelatinized starch, oxidized starch, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl alcohol / polyethylene glycol / graft copolymer, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, hydroxypropylcellulose, hydroxypropylmethylcellulose. , Hydroxyethylcellulose, sodium hydroxypropylmethylcellulose, sodium starch glycolate, beeswax, or crystalline cellulose.

  Examples of the lubricant include magnesium stearate, calcium stearate, talc, hydrogenated oil, honey beeswax, carnauba wax, polyethylene glycol 6000, or sodium stearyl fumarate.

  Other stabilizers such as sulfite, tocopherol, or dibutylhydroxytoluene, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 60, sodium lauryl sulfate, sucrose fatty acid ester, glycerin, macrogol, lauro as required A surfactant such as macrogol, polysorbate, polyethylene glycol, or triethyl citrate can also be blended. However, the pharmaceutical additives are not limited to those exemplified above, and those skilled in the art can appropriately select them according to the purpose.

  When the pharmaceutical composition of the present invention is in the form of a tablet, a mixture containing one or more appropriate pharmaceutical additives together with dabigatran etexilate methanesulfonate was prepared, and the mixture was granulated. Later, an uncoated tablet can be manufactured by a tableting process. It is also possible to produce an uncoated tablet by directly compressing a mixture containing one or more appropriate pharmaceutical additives together with dabigatran etexilate methanesulfonate without going through the granulation step. The uncoated tablet can be used as a tablet as it is, but the tablet may be produced by applying an appropriate coating such as a film coating, if necessary.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example.

Example 1
Add various additives to 20 mL of diluted McIlvaine buffer (pH 5.0) in the amounts shown in Table 1, add dabigatran etexilate methanesulfonate until it remains undissolved, and overnight at 37 ° C (16 hours A saturated solution was prepared by stirring. The mixture was filtered through a 0.45 μm membrane filter, the first 5 mL was discarded, and the next 5 mL was collected. Filtrate: Diluted solution (diluted MacIlvaine buffer pH 5.0 / acetonitrile = 7/3) = 1: 1, analyzed by high performance liquid chromatography, and measured for solubility.

  The results are shown in Table 2. As a result, it was found that elution at pH 5.0 can be enhanced by hypromellose.

Example 2
(a) Dabigatran etexilate methanesulfonate (Laurus, D ₅₀ = 32 μm) 82.44 g, lactose hydrate (trade name: Pharmamatose 200M, DFE) 70.7 g, crystalline cellulose (trade name: Theolas UF- 711, manufactured by Asahi Kasei Chemicals Co., Ltd.) 69.03 g and crospovidone (trade name: XL-10, ISP) 4.88 g were put into a fluidized bed granulator, and this was hypromellose (trade name: TC-5E, Shin-Etsu Chemical). A solution obtained by dissolving 13 g in Kogyo Co., Ltd. in 247 g of water was sprayed to perform granulation and drying. 3.14 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) was added to and mixed with 203.12 g of the obtained granules. The mixture was tableted with a rotary tableting machine so that one tablet was 375 mg to obtain a tablet of Example 2 (a).

As comparative examples, the following tablets (b) and (c) were prepared.
(b) dabigatran etexilate methanesulfonate (Laurus) 152.2g, crystalline cellulose (trade name: Theolas UF-711, Asahi Kasei Chemicals Corporation) 125.96g, crospovidone (trade name: XL-10, ISP) 9 g) was put into a fluidized bed granulator, and a solution obtained by dissolving 24 g of hypromellose (trade name: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in 456 g of water was sprayed to perform granulation and drying. To 142.62 g of the obtained granules, 60.5 g of citric acid and 3.14 g of magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) were added and mixed. The mixture was tableted with a rotary tableting machine so that one tablet was 375 mg to obtain a tablet of Example 2 (b).

(c) Dabigatran etexilate methanesulfonate (Laurus) 152.2g, crystalline cellulose (trade name: Theolas UF-711, Asahi Kasei Chemicals Corporation) 125.96g, crospovidone (trade name: XL-10, ISP) 9g) into a fluidized bed granulator, sprayed with a solution of 24g hypromellose (trade name: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) in water 45g, granulated and dried went. 60.5 g of tartaric acid and 3.14 g of magnesium stearate (produced by Taihei Chemical Sangyo Co., Ltd.) were added to 142.62 g of the obtained granules and mixed. The mixture was tableted with a rotary tableting machine so that one tablet was 375 mg, and the tablet of Example 2 (c) was obtained.

  The storage stability of the obtained tablets was evaluated. The tablets of Examples 2 (a), 2 (b), and 2 (c) were stored for 2 weeks at 50 ° C / 90% relative humidity and 60 ° C for 2 weeks under sealed or open conditions in aluminum packaging. Thereafter, the total amount of related substances in each sample after the storage was measured by high performance liquid chromatography. The results are shown in Table 3. In addition, the numerical value of the total amount of related substances was expressed as a percentage (%) of the peak area ratio of related substances other than dabigatran to the total of all peak areas.

Example 3
(a) Lactose hydrate (trade name: Pharmatose 200M, manufactured by DFE) 124.97g, low-substituted hydroxypropyl cellulose (trade name: LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.) 100g in a fluidized bed granulator 10 g of hypromellose (trade name: TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) and 126.83 g of dabigatran etexylate methanesulfonate (Laurus, D50 = 32 μm) in a mixture of 700 g of water and 1000 g of ethanol. The dissolved liquid was sprayed, granulated and dried. Crospovidone (trade name: XL-10, manufactured by ISP) 4.5 g and magnesium stearate (produced by Taihei Chemical Sangyo Co., Ltd.) 3.42 g were added to and mixed with 217.08 g of the obtained granules. The mixture was tableted with a rotary tableting machine so that one tablet was 375 mg to obtain a tablet of Example 3 (a).
(b) Dabigatran etexilate methanesulfonate (Laurus, D50 = 32μm) 126.83g, lactose hydrate (trade name: Super Tab 30GR, DFE Pharma) 128.77g, crystalline cellulose (trade name: Theolas UF- 711, manufactured by Asahi Kasei Chemicals Corporation), 106.2 g, crospovidone (trade name: XL-10, manufactured by ISP) 7.5 g, and magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) 5.7 g were mixed. The mixture was tableted with a rotary tableting machine so that one tablet was 375 mg to obtain a tablet of Example 3 (b).

The obtained tablets were subjected to a dissolution test under the conditions of 900 mL of diluted McIlvaine buffer (pH 5.0), rotating basket method, 100 rotations, and the dissolution rate after 6 hours was measured by high performance liquid chromatography.

Claims (3)

A pharmaceutical composition comprising dabigatran etexilate methanesulfonate, comprising hydroxypropylmethylcellulose and substantially free of organic acids. The pharmaceutical composition according to claim 1, wherein hydroxypropylmethylcellulose is a solubilizer for dabigatran etexilate methanesulfonate. The pharmaceutical composition according to claim 1 or 2, which is in the form of a tablet.