WO2015113324A1 - Formulation administrée de dabigatran étexilate, sel associé, et procédé de préparation associé - Google Patents

Formulation administrée de dabigatran étexilate, sel associé, et procédé de préparation associé Download PDF

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Publication number
WO2015113324A1
WO2015113324A1 PCT/CN2014/074112 CN2014074112W WO2015113324A1 WO 2015113324 A1 WO2015113324 A1 WO 2015113324A1 CN 2014074112 W CN2014074112 W CN 2014074112W WO 2015113324 A1 WO2015113324 A1 WO 2015113324A1
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Prior art keywords
acid
binder
organic
organic acid
layer
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Ceased
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PCT/CN2014/074112
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English (en)
Chinese (zh)
Inventor
唐勇
盛晓霞
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Solipharma LLC
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Solipharma LLC
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Priority to CN201480008391.XA priority Critical patent/CN104994856A/zh
Publication of WO2015113324A1 publication Critical patent/WO2015113324A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention belongs to the field of medical technology. Specifically, it relates to 3-[(3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl ⁇ -1-methyl-1H-benzo) Novel orally administered preparation of imidazole-5-carbonyl)-pyridin-2-yl-amino]propanoate, i.e., dabigatran etexilate and a pharmacologically acceptable salt thereof, and a process for the preparation thereof.
  • the present invention relates to Oral pharmaceutical composition of three dabigatran etexilates and salts thereof and preparation method thereof
  • Dabigatran etexilate is a novel direct thrombin inhibitor and a prodrug of dabigatran, a non-peptide thrombin inhibitor. Developed by Boehringer Engelheim, Germany, it is orally absorbed into the body and converted into dabigatran with direct anticoagulant activity. Dabigatran binds to the fibrin-specific binding site of the thrombin, preventing fibrinogen from cleavage into fibrin, thereby blocking the final step of the clotting waterfall network and thrombosis. Dabigatran can be dissociated from the fibrin-thrombin complex and exerts a reversible anticoagulant effect.
  • the drug was first marketed in Germany and the United Kingdom in April 2008 and was approved by the FDA in October 2010 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
  • the specifications are 75 mg and 150 mg, and the trade name is Pradaxa.
  • dabigatran etexilate 3-[(3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl 1-methyl-1H -benzimidazole-5-carbonyl)-pyridin-2-yl-amino]propionic acid ethyl ester, English name Dabigatranetexilate, molecular formula is 3 34 3 ⁇ 4 ⁇ 7 0 5 , molecular weight is 627.74, chemical structural formula is as follows (I) :
  • Patent document WO 98/37075 discloses dabigatran compounds and uses.
  • WO 03/074056 A1 discloses a composition of dabigatran and a dosage form, the main components of which are as follows: a core material composed of an organic acid, a release layer and an outermost active material layer.
  • composition prepared according to WO 03/074056 A1 is active in The outermost layer is prone to crystallized and degraded active substances.
  • composition 1 an oral pharmaceutical composition 1 (hereinafter referred to as "composition 1") of dabigatran etexilate and a salt thereof, and a process for the preparation thereof.
  • Oral pharmaceutical composition of dabigatran etexilate and its salt 1 comprises:
  • a binder comprising a pharmaceutically acceptable cellulosic or saccharide or starch or an approximately spherical one or more of the one or more microcrystalline celluloses or saccharides or starches Pill core;
  • an active material layer comprising a binder and an active substance, the active substance being dabigatran etexilate or a pharmaceutically acceptable salt thereof;
  • a water-soluble barrier layer on the surface of the active material layer, the material of which is selected from the group consisting of: an organic polymer material such as hydroxypropylmethylcellulose, hydroxypropylcellulose, starch, or a resin; or a combination of these organic materials; Containing a binder and a pharmaceutically acceptable organic acid or an acid layer containing the organic acid, the organic acid means a water solubility at 20 ° C greater than lg / 250 ml, selected from the group consisting of tartaric acid, fumaric acid, succinic acid , citric acid, malic acid, glutamic acid or aspartic acid or a hydrate or acid salt thereof;
  • a water-soluble barrier layer on the surface of the acid layer, the material of which is selected from the group consisting of water-soluble polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, starches, and resins, or a combination thereof.
  • the active material layer further comprises a binder, a filler, and an active material.
  • the filler is a pharmaceutically acceptable water-soluble material, preferably one or more of a saccharide, an alcohol, a soluble starch, and a salt; more preferably lactose, mannitol, maltose, sorbitol .
  • the mass ratio of the filler to the active material is from 1:1 to 1:10, more preferably from 1:2 to 1:5.
  • the pellet core component is cellulose, more preferably microcrystalline cellulose.
  • the content of the pellet core material is 10 to 60%.
  • the organic acid is tartaric acid, fumaric acid, succinic acid or citric acid, more preferably tartaric acid.
  • the content of the organic acid is 20 to 60%.
  • the content of the dabigatran etexilate or a salt thereof is 15 to 60%.
  • the binder is selected from the group consisting of: hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, N-vinylpyrrolidone Vinyl acetate
  • the copolymer or a combination of these copolymers is more preferably hydroxypropylcellulose.
  • the core material has an average particle size of 0.2 1.5 mm.
  • the active material layer binder is used in an amount of 0.5 to 20%, more preferably 2 to 10%, and the organic acid layer layer binder is used in an amount of 0.5 to 20%, preferably 2 to 10%. .
  • the outer layer of the active material is used in an amount of 2.0 to 10%
  • the outer layer of the organic acid is used in an amount of 2.0 to 10%.
  • a preferred embodiment of the composition is a multiparticulate formulation wherein the individual particles are of the construction of Figure 1.
  • a filler such as lactose, mannitol, maltose, sorbitol is added to the active layer.
  • Figure 1 shows the schematic structure of a pharmaceutical composition shown by a cross section of a pellet suitable for the preparation of Composition 1.
  • the approximately spherical core of the particle comprises microcrystalline cellulose.
  • an active material comprising a binder and an active material or comprising a binder, a water-soluble filler and an active material, and a layer of water-soluble barrier layer on the outside, which separates the active material layer from the organic acid-containing layer.
  • the separation layer is further surrounded by the same spherical organic acid layer containing a binder and an organic acid, and the outermost layer is a water-soluble barrier layer containing an organic polymer material, which is surrounded by a coating layer, which can increase particles. Anti-wear and storage life.
  • the preparation method of the composition 1 is as follows:
  • composition 1 The advantages of the administered dosage form made according to Composition 1 are as follows:
  • the active material layer is in the middle, which can better protect the active material, making it difficult to crystallize or degrade;
  • Composition 1 has better chemical and physical stability than commercially available reference formulations
  • the pellet core is made of cellulose, which is low in cost and simple in preparation.
  • composition 2 an oral pharmaceutical composition 2 (hereinafter referred to as "composition 2") of another dabigatran etexilate and a salt thereof, and a process for the preparation thereof.
  • Oral pharmaceutical composition 2 of dabigatran etexilate and its salt comprises:
  • an approximately spherical core material comprising a disintegrant, a filler, a binder and an active substance, the active substance being dabigatran etexilate or a pharmaceutically acceptable salt thereof;
  • b) comprising a binder and a pharmaceutically acceptable organic acid or an outer layer comprising the organic acid selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid or aspartame An acid or a hydrate or acid salt thereof;
  • a water-soluble barrier layer between the outer layer and the core material comprising an organic polymer material such as pharmaceutically acceptable hydroxypropylmethylcellulose, hydroxypropylcellulose, starch, or resin A composition of these organic materials.
  • the organic acid is tartaric acid, fumaric acid, succinic acid or citric acid, more preferably tartaric acid.
  • the content of the dabigatran etexilate or a salt thereof is from 20 to 60%.
  • the dabigatran etexilate or a salt thereof is dabigatran etexilate mesylate.
  • the content of the organic acid is 20 to 60%.
  • the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropylcellulose, or the like, or a combination thereof.
  • the filler is selected from the group consisting of: cellulose, sugar, starch, etc. or a combination thereof; preferably, the binder is selected from the group consisting of: hydroxypropylmethylcellulose, hydroxypropylcellulose , a copolymer of methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, N-vinyl pyrrolidone, vinyl acetate or a combination of these copolymers.
  • the core material has an average particle size of 0.4 1.5 mm.
  • the amount of the binder in the core material is 0.5 to 10%
  • the amount of the binder in the organic acid layer is 0.5 to 10%, preferably 2 to 10%.
  • the outer layer of the active material is used in an amount of 2.0 to 10%
  • the outer layer of the organic acid is used in an amount of 2.0 to 10%
  • a preferred embodiment of the composition is a multiparticulate formulation wherein the individual particles are of the structure of Figure 2.
  • Figure 2 shows the pictorial structure of the pharmaceutical composition shown by the cross-section of the particles suitable for the preparation of Composition 2.
  • the approximately spherical core of the granules contains a disintegrant, a filler, a binder, and an active material.
  • a layer is then referred to as a water-soluble barrier which separates the core from the layer containing the organic acid.
  • the barrier layer is then surrounded by the same spherical layer containing the binder and the organic acid, which in turn is surrounded by a coating which increases the abrasion resistance and shelf life of the particles.
  • Composition 1 has better chemical and physical stability than commercially available reference formulations
  • composition 3 of the third dabigatran etexilate and a salt thereof (hereinafter referred to as "composition 3") and a process for the preparation thereof.
  • Oral pharmaceutical composition 3 of dabigatran etexilate and its salt comprises:
  • pellets or granules or powders comprising a filler, a disintegrant, a binder and an active substance, the active substance being dabigatran etexilate or a pharmaceutically acceptable salt thereof;
  • a separator on the surface of the organic acid particles the material of which is selected from the group consisting of: an organic polymer material such as hydroxypropylmethylcellulose, hydroxypropylcellulose, starch, or a resin; or a combination of these organic materials;
  • a separator containing active material pellets or granules or powder surface selected from the group consisting of: hydroxypropylmethylcellulose, hydroxypropylcellulose, starch, resin, etc., or a combination of these organic materials Things.
  • the organic acid is tartaric acid, fumaric acid, succinic acid or citric acid, more preferably tartaric acid.
  • the content of the dabigatran etexilate or a salt thereof is 15 to 60%.
  • the dabigatran etexilate or a salt thereof is dabigatran etexilate mesylate.
  • the content of the organic acid is 20 to 60%.
  • the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropylcellulose, or the like, or a combination thereof.
  • the filler is selected from the group consisting of cellulose, sugar, starch, and the like or a combination thereof.
  • the binder is selected from the group consisting of: hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, N-vinylpyrrolidone , a copolymer of vinyl acetate or a combination of these copolymers.
  • the core material has an average particle size of 0.4 1.5 mm.
  • the binder is used in an amount of 0.5 to 10%, more preferably 2 to 10%, of the active material-containing pellets or granules or powder, and the amount of the binder in the acid-containing pellet core material is Both are 0.5 to 10%, more preferably 2 to 10%.
  • the outer layer of the active material is used in an amount of 2.0 to 10%
  • the outer layer of the organic acid is used in an amount of 2.0 to 10%
  • a preferred embodiment of the composition is a two granular mixed formulation wherein the individual particles are of the structure of Figure 3.
  • Figure 3 shows the pictorial structure of the pharmaceutical composition shown by the cross-section of the particles suitable for the preparation of Composition 3.
  • the approximate spherical core region of one of the particles is a core material of an organic acid, and the core material is surrounded by a separator containing an organic polymer material;
  • the approximate spherical core region of the other pellet or particle or powder contains disintegration A granule of a filler, a binder, and an active material, the pellet or granule or powder being surrounded by a barrier layer containing an organic polymeric material, the barrier layer increasing the abrasion resistance and shelf life of the granule.
  • composition 3 The advantages of the dosage form made according to composition 3 are as follows:
  • the barrier layer protects the active material from being easily crystallized or degraded
  • Composition 1 has better chemical and physical stability than commercially available reference formulations
  • Figure 1 shows the schematic structure of the pharmaceutical composition 1.
  • Fig. 2 is a diagram showing the structure of the pharmaceutical composition 2.
  • FIG. 3 is a schematic structure of the pharmaceutical composition 3.
  • Figure 4 is a comparison of XRPD of the reference formulation at 0 and 15 days under high humidity conditions. (From top to bottom in the figure are: 0 days and 15 days).
  • Figure 5 is a comparison of XRPD of Composition 1 of the present invention for 0 days and 15 days under high humidity conditions. (The top-down order in the figure is: 0 days and 15 days).
  • Figure 6 is a comparison of XRPD of Composition 2 of the present invention for 0 days and 15 days under high humidity conditions. (The top-down order in the figure is: 0 days and 15 days).
  • Figure 7 is a comparison of XRPD of Composition 3 of the present invention for 0 days and 15 days under high humidity conditions. (The top-down order in the figure is: 0 days and 15 days). detailed description
  • X-ray powder diffraction (XPRD): The instrument used is Bmker D8 Advance
  • the diffractometer uses a Ka X-ray with a copper target wavelength of 1.54 nm, a 40 kV and 40 mA operating condition, a ⁇ -2 ⁇ goniometer, a Mo monochromator, and a Lynxeye detector.
  • the instrument is calibrated with silicon carbide before use.
  • the acquisition software is Diffrac Plus XRD Commander.
  • the sample is tested at room temperature and the sample to be tested is placed on a non-reflective plate.
  • the detailed detection conditions are as follows, angle range: 3-40 ° 2 ⁇ , step size: 0.02 ° 2 ⁇ , speed: 0.2 sec / step.
  • High performance liquid phase analysis (HPLC) data was taken from Agilent 1260. Using C 18 column, 150mm X 4.6mm, column temperature 30 ° C, wavelength 220nm, flow rate 1.0mL / min, injection volume 20 L, running time 70min.
  • the solvent is 5% sodium dihydrogen phosphate buffer
  • mobile phase A is 30% methanol and 70% of the above buffer
  • mobile phase B is 60% acetonitrile and 40% of the above buffer
  • the gradient is as follows :
  • microcrystalline cellulose pellet The core can be homemade or commercially available.
  • the obtained pellets are transferred to a centrifugal granulator.
  • the setting parameters are: the main engine speed is 350 rpm, the atomization pressure is 1.5 MPa, the ejector pressure is 1.5 MPa, and the inlet air temperature is 50 ° C.
  • the wind speed is 1.0 m 3 /min, the exhaust speed is 1.5 m 3 /min, the pulping speed is 3.0 g/min, the powder feeding speed is 2.0 g/min, and the tartaric acid fine powder is 82.23 g, and then 40 to 50 ° C. Dry down for 5 ⁇ 6 hours.
  • Separation layer II preparation Take 60.00g of isopropyl alcohol solution, add 5.83g of hydroxypropyl cellulose, stir to dissolve completely, disperse under IKA disperser, gradually add 2.50g of talc powder, disperse for 10 ⁇ 15min That is.
  • Upper isolation layer II In the fluidized bed, when the temperature of the material reaches 30 ⁇ 40°C, the atomization pressure is 1.5Mpa, the fluidization pressure is 1.5Mpa, and the isolation layer is started. The pulping speed is about 1.0. ⁇ 2.0g/min, After the shotcrete is finished, continue to dry at 40 ⁇ 50 °C for 3 ⁇ 7 hours.
  • Formulations are as follows in the composition of the composition 1:
  • Formulations are as follows in the composition of the composition 1:
  • the obtained pellets are transferred to a centrifugal granulator.
  • the setting parameters are: the main engine speed is 350 rpm, the atomization pressure is 1.5 MPa, the ejector pressure is 1.5 MPa, and the inlet air temperature is 50 ° C.
  • the wind speed is 1.0 m 3 /min, the exhaust speed is 1.5 m 3 /min, the pulping speed is 3.0 g/min, the powder feeding speed is 2.0 g/min, and the tartaric acid fine powder is 82.23 g, and then 40 to 50 ° C. Dry down for 5 ⁇ 6 hours.
  • Separation layer II preparation Take 60.00g of isopropyl alcohol solution, add 5.83g of hydroxypropyl cellulose, stir to dissolve completely, disperse under IKA disperser, gradually add 2.50g of talc powder, disperse for 10 ⁇ 15min That is.
  • Upper isolation layer II In the fluidized bed, when the temperature of the material reaches 30 ⁇ 40 °C, adjust the atomization pressure to 1.5Mpa, the fluidization pressure is 1.5Mpa, start the upper layer, the pulping speed is about 1.0 ⁇ 2.0g/min, and after the shotcrete is finished, continue to dry at 40 ⁇ 50°C for 3 ⁇ 7 hours.
  • Formulations are as follows in the composition of the composition 1:
  • Isolation layer I preparation Take 260.00g of isopropyl alcohol solution, add 22.50g hydroxypropyl cellulose, stir to dissolve completely, disperse under IKA disperser, gradually add 2.50g talcum powder, disperse for 10 ⁇ 15min That is.
  • Upper tartaric acid layer The pellet obtained above is transferred to the centrifugal granulator.
  • the setting parameters are: the main engine speed is 350 rpm, the atomization pressure is 1.5 MPa, the ejector pressure is 1.5 MPa, and the inlet air temperature is 50 ° C.
  • the wind speed is 1.0 m 3 /min, the exhaust speed is 1.5 m 3 /min, the pulping speed is 3.0 g/min, the powder feeding speed is 2.0 g/min, and after adding tartaric acid fine powder 749.96 g to 40 ⁇ 50° Dry under C for 5 ⁇ 6 hours.
  • pellet core Take 50.00g of microcrystalline cellulose, 100.OOg of lactose monohydrate, 6.24g of crospovidone, 250.00g of dabigatran etexilate mesylate, mix evenly, to extrude
  • the host speed 150 rpm
  • the screen mesh number 600 ⁇ ⁇
  • the equipment add 2% povidone solution
  • composition prepared by the present invention composition prepared by the present invention, composition prepared by the present invention, composition 3 prepared by the present invention
  • a 15-day high-humidity test was compared with a commercially available reference preparation, and the results are shown in Table 1.
  • the experimental method is as follows: Take the composition prepared by the present invention, the composition prepared by the present invention, the composition 3 prepared by the present invention and the capsule content of the commercially available reference preparation each 5g, tiled in flat, at RH92.5 After 15 days, the samples were examined by XPRD for 15 days, and the contents of the capsule containing 100 mg of the active substance were diluted 250 times and analyzed by high performance liquid chromatography. The results are shown in Table 1.

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Abstract

L'invention concerne une formulation administrée par voie orale de dabigatran étexilate, un sel pharmacologiquement acceptable associé, et un procédé de préparation associé.
PCT/CN2014/074112 2014-01-30 2014-03-26 Formulation administrée de dabigatran étexilate, sel associé, et procédé de préparation associé Ceased WO2015113324A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201480008391.XA CN104994856A (zh) 2014-01-30 2014-03-26 达比加群酯及其盐的投药制剂及其制备方法

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Application Number Priority Date Filing Date Title
CN201410046167 2014-01-30
CN201410046167.1 2014-01-30

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WO2015113324A1 true WO2015113324A1 (fr) 2015-08-06

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106727414A (zh) * 2016-12-27 2017-05-31 哈药集团技术中心 一种甲磺酸达比加群酯微丸及制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103127109A (zh) * 2013-02-05 2013-06-05 南京华威医药科技开发有限公司 含达比加群酯或其盐和水合物的药用组合

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL2588090T3 (pl) * 2010-07-01 2017-12-29 Krka, Tovarna Zdravil, D.D., Novo Mesto Doustne farmaceutyczne postacie dawkowania zawierające eteksylan dabigatranu i jego farmaceutycznie dopuszczalne sole
HUE056194T2 (hu) * 2012-02-21 2022-01-28 Towa Pharmaceutical Europe S L Dabigatrán-etexilát orális gyógyszerészeti készítményei

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103127109A (zh) * 2013-02-05 2013-06-05 南京华威医药科技开发有限公司 含达比加群酯或其盐和水合物的药用组合

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106727414A (zh) * 2016-12-27 2017-05-31 哈药集团技术中心 一种甲磺酸达比加群酯微丸及制备方法

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