[go: up one dir, main page]

WO2016070696A1 - 达比加群酯或其盐的投药制剂及其制备方法 - Google Patents

达比加群酯或其盐的投药制剂及其制备方法 Download PDF

Info

Publication number
WO2016070696A1
WO2016070696A1 PCT/CN2015/091437 CN2015091437W WO2016070696A1 WO 2016070696 A1 WO2016070696 A1 WO 2016070696A1 CN 2015091437 W CN2015091437 W CN 2015091437W WO 2016070696 A1 WO2016070696 A1 WO 2016070696A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
layer
binder
active material
dabigatran etexilate
Prior art date
Application number
PCT/CN2015/091437
Other languages
English (en)
French (fr)
Inventor
唐勇
徐银荣
盛晓霞
Original Assignee
杭州领业医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州领业医药科技有限公司 filed Critical 杭州领业医药科技有限公司
Priority to US15/308,014 priority Critical patent/US10675276B2/en
Priority to CN201580002607.6A priority patent/CN105764509B/zh
Priority to CA3001495A priority patent/CA3001495C/en
Publication of WO2016070696A1 publication Critical patent/WO2016070696A1/zh

Links

Images

Classifications

    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61K9/5089—Processes
    • 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 or a pharmacologically acceptable salt thereof, and a process for the preparation thereof.
  • the present invention relates to two An oral pharmaceutical composition of dabigatran etexilate and a salt thereof and a process for the preparation thereof.
  • Dabigatran etexilate is a novel direct thrombin inhibitor and a prodrug of dabigatran, a non-peptide thrombin inhibitor. Developed by Boehringer Ingelheim, Germany, after oral absorption by the stomach, it is converted into dabigatran with direct anticoagulant activity in vivo. Dabigatran binds to the fibrin-specific binding site of thrombin, preventing fibrinogen from cleavage into fibrin, thereby blocking the final step of the coagulation cascade 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 currently marketed dosage form is a capsule with a specification of 75 mg and 150 mg under the trade name 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 C 34 H 41 N 7 O 5 , molecular weight 627.74, chemical structural formula is as follows (I ) shown:
  • Patent document WO 98/37075 discloses dabigatran compounds and uses.
  • the patent document CN1638771A and WO03/074056A1 disclose a composition of dabigatran and a dosage form, the main composition of which is as follows: a core material composed of an organic acid, a release layer and an active material layer.
  • Patent document CN 103127109 A discloses a pharmaceutical combination comprising a dabigatran etexilate compound.
  • the main components are as follows: a core material containing an active material, a separator, and an organic acid layer.
  • composition prepared according to WO 03/074056 A1 is susceptible to crystal transformation and degradation of the active material due to the active material in the outer layer.
  • the composition prepared according to CN 103127109 was found to have similar dissolution in an acidic medium to that of the reference preparation (CN1638771A), but in the medium water, the dissolution result was too large compared with the reference preparation (CN1638771A), and the dissolution results in vitro were not similar. .
  • 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 1 of dabigatran etexilate or a salt thereof comprises:
  • a binder comprising a pharmaceutically acceptable cellulosic or saccharide or starch or an approximately spherical one or more microcrystalline celluloses or saccharides or starches comprising the above components Pill core;
  • an active material layer comprising an active substance, and/or a disintegrant, and/or a filler, and a binder, the active substance being dabigatran etexilate or a pharmaceutically acceptable salt thereof; as well as
  • 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;
  • a binder and a pharmaceutically acceptable organic acid or an acid layer containing the organic acid said organic acid being at a water solubility of greater than 1 g / 250 ml at 20 ° C, 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, cysteine hydrochloride;
  • 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, resins, or the like;
  • an active material layer comprising an active substance, and/or a disintegrant, and/or a filler, and a binder composition, the active substance being dabigatran etexilate or a pharmaceutically acceptable salt thereof ;as well as
  • a barrier layer on the surface of the active material layer the material of which is selected from the group consisting of organic polymer materials such as hydroxypropylmethylcellulose, hydroxypropylcellulose, starch, and resins, or a combination of these organic materials.
  • 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 component of the pellet core is a saccharide, more preferably sucrose.
  • the pellet core is present in an amount of from 10 to 60%.
  • the organic acid is cysteine hydrochloride.
  • the content of the organic acid is 15 to 60%.
  • the dabigatran etexilate or a salt thereof is contained in an amount of 15 to 60%.
  • 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 is more preferably hydroxypropylcellulose.
  • the core material has an average particle size of from 0.2 to 1.5 mm.
  • the active material layer binder is used in an amount of from 0.5 to 20%, more preferably from 2 to 10%.
  • the organic acid layer binder is used in an amount of from 0.5 to 20%, more preferably from 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 1.
  • a filler such as lactose, mannitol, maltose, sorbitol is added to the active layer.
  • Figure 1 shows the pictorial structure of a pharmaceutical composition as indicated by the cross-section of the particles suitable for the preparation of Composition 1.
  • the approximately spherical pellet core of the granule comprises sucrose; followed by a layer of active material comprising a binder and an active substance or comprising a binder, a water-soluble filler and an active substance; and a layer of water-soluble barrier layer on the outside It separates the active material layer from the organic acid-containing layer; the barrier layer is then surrounded by the same spherical organic acid layer containing the binder and the organic acid; and a layer of water-soluble barrier layer is isolated on the outside, which isolates the active material a layer and an organic acid-containing layer; followed by a layer of an active material comprising a binder and an active material or comprising a binder, a water-soluble filler and an active material; and an outermost layer of an organic polymer-containing barrier layer,
  • the barrier layer increases the abrasion resistance and shelf life of the particles.
  • the preparation method of the composition 1 is as follows:
  • the structure described in the composition 1 has an acid layer located between the two active material layers, which can better utilize the acid environment formed by the acidic substance and reduce the amount of the acidic substance, thereby Avoid other physiological effects of acidic substances on the body;
  • composition 1 has a better dissolution amount in a multi-media system, especially in a near-neutral environment, such as water, indicating that it has a higher bioavailability in people with insufficient gastric acid secretion. high;
  • 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 acid core comprising an acidic substance, and/or a disintegrant, and/or a filler, and a binder, the acidic substance being sodium dihydrogen phosphate, cysteine hydrochloride;
  • an active material layer comprising an active substance, and/or a disintegrant, and/or a filler, and a binder, the active substance being dabigatran etexilate or a pharmaceutically acceptable salt thereof; as well as
  • a water-soluble barrier layer between the active material layer and the acid core comprising an organic polymer material such as pharmaceutically acceptable hydroxypropylmethylcellulose, hydroxypropylcellulose, starch, or resin A composition of these organic materials.
  • the material of which is selected from the group consisting of organic polymer materials such as hydroxypropylmethylcellulose, hydroxypropylcellulose, starch, and resins, or a combination of these organic materials.
  • the acidic substance is cysteine hydrochloride.
  • the dabigatran etexilate or a salt thereof is contained in an amount of 10 to 65%.
  • the dabigatran etexilate or a salt thereof is dabigatran etexilate mesylate.
  • the content of the acidic substance is from 8 to 65%.
  • 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;
  • 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 acid core has an average particle size of from 0.2 to 1.5 mm.
  • the binder is used in the acid core in an amount of from 0.5 to 20%, more preferably from 2 to 10%.
  • the active material and the acidic spherical layer isolation layer are used in an amount of 2.0 to 10%; the active material The amount of the outer layer of the outer layer is from 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 a pharmaceutical composition as indicated by the cross-section of the particles suitable for the preparation of Composition 2.
  • the approximately spherical acid core of the particle comprises a binder and an acidic material. This is followed by a layer called a water-soluble barrier that separates the active material from the acid core.
  • the barrier layer is then surrounded by the same spherical layer containing the binder and active material, which in turn is surrounded by a coating which increases the abrasion resistance and shelf life of the particles.
  • Composition 1 has a better dissolution in a multi-media system, especially in a near-neutral environment, such as water, as compared to the protocol described in the patent CN 103127109, indicating a higher bioavailability in people with insufficient gastric acid secretion. ;
  • 1 is a schematic structure of a pharmaceutical composition 1.
  • Figure 3 is a comparison of XRPD of the reference formulation (CN1638771A) at 0 days and 15 days under high humidity conditions. (The top-down order in the figure is: 0 days and 15 days).
  • Figure 4 is a graph of XRPD comparison 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 5 is a graph of XRPD comparison 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).
  • X-ray powder diffraction (XRPD): The instrument used was a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm, a ⁇ -2 ⁇ goniometer at a 40 kV and 40 mA operating condition, and a Mo single Colorimeter, 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-reflecting plate. The detailed detection conditions are as follows, the angle range is 3 - 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • High performance liquid phase analysis (HPLC) data was taken from Agilent 1260. Using C 18 column, 150 mm ⁇ 4.6 mm, column temperature 30 ° C, wavelength 220 nm, flow rate 1.0 mL / min, injection volume 20 ⁇ L, running time 70 min.
  • 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:
  • sucrose pellet core can be homemade or commercially available.
  • Isolation layer II preparation take 90.00g of 80% ethanol aqueous solution, add 10.00g of hydroxypropylmethylcellulose, stir to completely dissolve, disperse under IKA disperser, gradually add 6.47g 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 adjusted to 1.5 MPa, the fluidization pressure is 1.5 MPa, the upper separation layer is started, and the pulping speed is about 1.0 ⁇ . 2.0g/min, after the shotcrete is completed, continue to dry at 40 ⁇ 50 ° C for 3 ⁇ 7 hours.
  • the medicine the pellet obtained above is transferred to the fluidized bed, the inlet air temperature is adjusted to 60 ° C, the exhaust air volume is 3 m 3 /min, and when the material temperature reaches 30 to 40 ° C, the atomization pressure is adjusted to 1.5. Mpa, the fluidization pressure is 1.5Mpa, and the drug is started. The speed of the drug is about 1.5-2.5g/min. After the completion of the drug, continue to dry at 40 ⁇ 50 ° C for 3 to 5 hours.
  • Isolation layer III was prepared, taking 160.00 g of 60% ethanol aqueous solution, adding 25.00 g of gastric layer material, stirring to dissolve completely, and dispersing under an IKA disperser.
  • Upper isolation layer III 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 upper separation layer is started.
  • the pulping speed is about 1.0 ⁇ 2.0g/min, after the shotcrete is completed, continue to dry at 40 ⁇ 50 ° C for 3 ⁇ 7 hours.
  • Preparation of acid-containing core take 37.57g of sucrose and 250.00g of cysteine hydrochloride, mix well, and then into the extrusion spheronizer, set the host speed to 150rpm, the mesh number is 600 ⁇ m, open the device, join A 5% hydroxypropylcellulose solution was obtained by extruding the granules into a centrifugal granulator, spheronizing at 400 rpm, and drying at 40 to 50 ° C for 5 to 8 hours.
  • isolation layer I preparation take 800.00% ethanol aqueous solution 90.00g, add 12.00g hydroxypropylmethyl cellulose, stir to dissolve completely, disperse under IKA disperser, gradually add 7.48g talcum powder Disperse for 10 to 15 minutes.
  • Upper active material layer The pellet obtained above is placed into a centrifugal granulator, and the parameters are set: 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 1.0m 3 /min
  • the exhaust speed is 1.5m 3 /min
  • the pulping speed is 3.0g/min
  • the powder feeding speed is 2.0g/min
  • Upper isolation layer II In the fluidized bed, when the temperature of the material reaches 30-40 ° C, the atomization pressure is adjusted to 1.5 MPa, the fluidization pressure is 1.5 MPa, the upper separation layer is started, and the pulping speed is about 1.0 ⁇ . 2.0g/min, after the shotcrete is completed, continue to dry at 40 ⁇ 50 ° C for 3 ⁇ 7 hours.
  • composition prepared by the present invention 1, the composition 2 prepared in the present invention and a commercially available reference preparation were subjected to a 15-day high-humidity test comparative study, 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 (CN1638771A), 5 g each, and placed in a dish. After RH92.5%, after 15 days, the sample was examined by XRPD for the change of crystal form, and the contents of the capsule containing 100 mg of active substance were taken, diluted 250 times, and analyzed by high performance liquid chromatography. 1.
  • Table 1 show that the two pharmaceutical compositions prepared by the present invention did not change in the crystal form after 15 days under high-humidity conditions, and the related substances and contents changed little, while the commercially available reference preparation (CN1638771A) occurred after 15 days.
  • the crystal form transition (unknown diffraction peak appeared at about 23.8 in 2 ⁇ angle), and the related substances and contents vary greatly, indicating that the chemical combination stability of the two drug combinations prepared by the present invention is higher than that of the commercially available reference preparation (CN1638771A). And physical stability is better.
  • composition prepared by the present invention was eluted in a medium water.
  • the results are shown in Table 2.
  • the experimental method is as follows: Take the composition prepared by the invention, the composition prepared by the invention, the commercially available reference preparation and the capsule of the reference 2, respectively, 3 capsules, and under the dissolution apparatus, according to 100 rpm, basket method, medium water The 900 ml dissolution method was inspected, and samples were taken at 5, 10, 15, 20, 30 min sampling points, 10 ml each time, and 5.0 ml of the filtrate was filtered, and analyzed by high performance liquid chromatography. The results are shown in Table 2.
  • the time in Table 2 refers to the time required to deduct the dissolution of the capsule shell.
  • the dissolution values of the two preparations in more than 85% in 15 min indicate that the in vitro dissolution behavior of the two preparations is similar.
  • the results in Table 2 show that in the medium water, the dissolution of Composition 1 and Composition 2 is similar to that of the reference preparation, while the dissolution value of Control 2 is far from satisfactory.
  • the products of Composition 1 and Composition 2 of the present invention are similar in in vitro dissolution behavior to the reference formulation, and their bioavailability in the gastric acid deficient population is higher than that of Control 2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种达比加群酯或其药理上可接受盐的口服投药制剂及其制备方法。

Description

达比加群酯或其盐的投药制剂及其制备方法 技术领域
本发明属于医药技术领域。具体而言，涉及3-[(3-[(2-{[4-(己氧羰基氨基-亚氨基-甲基)-苯基氨基]-甲基}-1-甲基-1H-苯并咪唑-5-羰基)-吡啶-2-基-氨基]丙酸乙酯即达比加群酯或其药理上可接受盐的新颖口服的投药制剂及其制备方法。具体地，本发明涉及两种达比加群酯及其盐的口服药物组合物及其制备方法。
背景技术
达比加群酯是一种新型的直接凝血酶抑制剂，是达比加群的前体药物，属非肽类凝血酶抑制剂。由德国BoehringerIngelheim(勃林格殷格翰)公司开发，口服经胃肠吸收后，在体内转化为具有直接抗凝血活性的达比加群。达比加群结合于凝血酶的纤维蛋白特异结合位点，阻止纤维蛋白原裂解为纤维蛋白，从而阻断了凝血瀑布网络的最后步骤及血栓形成。达比加群可从纤维蛋白—凝血酶结合体上解离，发挥可逆的抗凝作用。该药于2008年4月首先在德国和英国上市，2010年10月又被FDA批准用于减少非瓣膜性房颤患者发生中风及全身性栓塞风险。目前上市剂型为胶囊剂，规格为75mg和150mg，商品名为Pradaxa。
达比加群酯的化学名称为：3-[(3-[(2-{[4-(己氧羰基氨基-亚氨基-甲基)-苯基氨基]-甲基}-1-甲基-1H-苯并咪唑-5-羰基)-吡啶-2-基-氨基]丙酸乙酯，英文名为Dabigatranetexilate，分子式为C34H41N7O5，分子量为627.74，化学结构式如下(I)所示：
Figure PCTCN2015091437-appb-000001
专利文献WO 98/37075公开了达比加群化合物和用途。专利文献CN1638771A和WO03/074056A1公开了一种达比加群的组合物及投药剂型，其主要组成如下：有机酸组成的芯材料、隔离层和活性物质层。
专利文献CN 103127109A公开了含达比加群酯化合物的药物组合。其主要组成如下：含有活性物质丸芯材料、隔离层和有机酸层。
本发明人研究发现根据WO03/074056A1制备得到的组合物，因其活性物质在外层，易发生活性物质转晶和降解的现象。根据CN 103127109制备得到的组合物，发现其在酸性介质中溶出度与参比制剂(CN1638771A)相似，但在介质水中，其溶出结果与参比制剂(CN1638771A)相差过大，体外溶出结果不相似。
鉴于现有技术尚存不足，开发具有更多优势性能的达比加群酯及其盐的新颖口服的投药制剂具有十分重要的现实意义。
发明内容
本发明的目的是提供一种适于达比加群酯及其盐口服使用的改良制剂。
根据本发明的目的，本发明提供一种达比加群酯及其盐的口服药物组合物1(以下称作“组合物1”)及其制备方法。
达比加群酯或其盐的口服药物组合物1包含：
a)含粘合剂及医药可接受的纤维素类或糖类或淀粉类或含该上述成分一种或多种微晶纤维素类或糖类或淀粉类一种或多种的近似球形的丸芯；以及
b)含有活性物质、和/或崩解剂、和/或填充剂、及粘合剂组成的活性物质层，所述活性物质为达比加群酯或一种其药物上可接受的盐；以及
c)活性物质层表面的水溶性隔离层，其材料选自：羟丙甲基纤维素、羟丙基纤维素、淀粉类、树脂类等有机高分子材料或这些有机材料的组合物；以及
d)含有粘合剂及医药可接受的有机酸或含该有机酸的酸层，所述有机酸系指在20℃的水溶性大于1g/250毫升，选自酒石酸、富马酸、琥珀酸、柠檬酸、苹果酸、谷氨酸或天冬氨酸或一种其水合物或酸盐、半胱氨酸盐酸盐；以及
e)酸层表面的水溶性隔离层，其材料选自：羟丙甲基纤维素、羟丙基纤维素、淀粉类、树脂类等水溶性聚合物或其组合物；以及
f)含有活性物质、和/或崩解剂、和/或填充剂、及粘合剂组成组成的活性物质层，所述活性物质为达比加群酯或一种其药物上可接受的盐；以及
g)以及活性物质层表面的隔离层，其材料选自：羟丙甲基纤维素、羟丙基纤维素、淀粉类、树脂类等有机高分子材料或这些有机材料的组合物。
优选地，所述填充剂为药学上可接受水溶性材料，优选为糖类、醇类、可溶性淀粉类和盐类中的一种或多种；更优选为乳糖、甘露醇、麦芽糖、山梨醇。
优选地，所述填充剂与活性物质的质量比为1:1～1:10，更优选为1:2～1:5。
优选地，所述丸芯的成分为糖类，更优选为蔗糖。
优选地，所述丸芯的含量为10～60％。
优选地，所述有机酸为半胱氨酸盐酸盐。
优选地，所述有机酸的含量为15～60％。
优选地，所述达比加群酯或其盐的含量为15～60％。
优选地，所述粘合剂选自：羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羟乙基纤维素、羧甲基纤维素、聚乙烯吡咯烷酮、N-乙烯吡咯烷酮、醋酸乙烯酯的共聚物或这些共聚物的组合物，更优选为羟丙基纤维素。
优选地，所述芯材料的平均颗粒大小为0.2～1.5mm。
优选地，所述活性物质层粘合剂的用量为0.5～20％，更优选为2～10％。
优选地，所述有机酸层粘合剂的用量为0.5～20％，更优选为2～10％。
优选地，所述活性物质外层隔离层的用量为2.0～10％，所述有机酸外层隔离层的用量为2.0～10％。
该组合物一个优选实施方案为多粒状制剂，其中该各个颗粒是如图1的结构。
在某些具体实施方式中，为提高制剂的溶出速率，所述活性物质层中加入了填充剂，如乳糖、甘露醇、麦芽糖、山梨醇。
图1表示通过适于制备组合物1的颗粒的断面所示的药物组合物的图示结构。该颗粒的近似球状丸芯包含蔗糖；接着有一层含有粘合剂和活性物质或含有粘合剂、水溶性填充剂和活性物质组成的活性物质层；再外面有一层称为水溶性隔离层，它隔离活性物质层与含有机酸的层；接着，该隔离层再被含有粘合剂和有机酸的相同球形有机酸层包围；外面再接有一层称为水溶性隔离层，它隔离活性物质层与含有机酸的层；接着有一层含有粘合剂和活性物质或含有粘合剂、水溶性填充剂和活性物质组成的活性物质层；最外面为含有机高分子材料的隔离层，该隔离层可增加颗粒的抗磨性及贮存寿命。
组合物1的制备方法如下：
(1)将含有粘合剂和活性物质或含有粘合剂、填充剂和活性物质的活性物质层涂敷于丸芯上，并干燥；
(2)涂敷含有高分子材料的隔离层，并干燥；
(3)用层积法涂敷含有粘合剂和医药可接受的有机酸层，并干燥；
(4)将含有粘合剂和活性物质或含有粘合剂、填充剂和活性物质的活性物质层涂敷于丸芯上，并干燥；
(5)涂敷含有高分子材料的隔离层，并干燥；
(6)将如此得到的含活性物质丸粒填充入硬质胶囊内。
根据组合物1制成的给药剂型的优点如下：
1)与专利WO 98/37075所描述方案相比，组合物1所描述结构，酸层位于两层活性物质层中间，能更好地利用酸性物质所形成之酸环境，降低酸性物质用量，从而避免酸性物质对身体产生的其它生理作用；
2)与专利CN 103127109所描述方案相比，组合物1在多介质体系具有更好的溶出量，尤其是近中性环境内，例如水，说明其在胃酸分泌不足人群中的生物利用度更高；
3)用糖类做丸芯，成本低，制备简单。
根据本发明的目的，本发明提供另一种达比加群酯及其盐的口服药物组合物2(以下称作“组合物2”)及其制备方法。
达比加群酯及其盐的口服药物组合物2包含：
a)含有酸性物质、和/或崩解剂、和/或填充剂、及粘合剂组成的近似球形的酸芯，所述酸性物质为磷酸二氢钠、半胱氨酸盐酸盐；以及
b)含有活性物质、和/或崩解剂、和/或填充剂、及粘合剂组成的活性物质层，所述活性物质为达比加群酯或一种其药物上可接受的盐；以及
c)活性物质层与酸芯间的水溶性隔离层，所述水溶性隔离层包括医药上可接受羟丙甲基纤维素、羟丙基纤维素、淀粉类、树脂类等有机高分子材料或这些有机材料的组合物。
d)以及活性物质层表面的隔离层，其材料选自：羟丙甲基纤维素、羟丙基纤维素、淀粉类、树脂类等有机高分子材料或这些有机材料的组合物。
优选地，所述酸性物质为半胱氨酸盐酸盐。
优选地，所述达比加群酯或其盐的含量为10～65％。
优选地，所述达比加群酯或其盐为达比加群酯甲磺酸盐。
优选地，所述酸性物质的含量为8～65％。
优选地，所述崩解剂选自：交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚维酮、低取代羟丙基纤维素等物质或其组合物。
优选地，所述填充剂选自：纤维素类、糖类、淀粉类等物质或其组合物；
优选地，所述粘合剂选自：羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羟乙基纤维素、羧甲基纤维素、聚乙烯吡咯烷酮、N-乙烯吡咯烷酮、醋酸乙烯酯的共聚物或这些共聚物的组合物。
优选地，所述酸芯的平均颗粒大小为0.2～1.5mm。
优选地，所述酸芯中粘合剂的用量为0.5～20％，更优选为2～10％。
优选地，所述活性物质与酸性球层间隔离层的用量为2.0～10％；所述活性物 质外层隔离层的用量为2.0～10％。
该组合物一个优选实施方案为多粒状制剂，其中该各个颗粒是如图2的结构。
图2表示通过适于制备组合物2的颗粒的断面所示的药物组合物的图示结构。该颗粒的近似球状酸芯包含粘合剂和酸性物质。接着有一层称为水溶性隔离层，它隔离活性物质与酸芯。接着，该隔离层再被含有粘合剂和活性物资的相同球形层包围，该球层又被涂层包围，该涂层可增加颗粒的抗磨性及贮存寿命。
组合物2的制备方法：
(1)通过挤出滚圆法或滚圆法或流化法将酸性物质，任选添加崩解剂、填充剂和粘合剂，形成酸芯；
(2)涂敷含有高分子材料的隔离层，并干燥；
(3)用层积法涂敷含有粘合剂和活性物质的活性物质层，并干燥；
(4)涂敷含有高分子材料的隔离层，并干燥；
(5)将如此得到的含活性物质丸粒填充入硬质胶囊内。
根据组合物2制成的给药剂型的优点如下：
1)能更好地保护活性物质，使其不易转晶或降解；
2)与专利CN 103127109所描述方案相比，组合物1在多介质体系具有更好溶出量，尤其是近中性环境内，例如水，说明其在胃酸分泌不足人群中的生物利用度更高；
3)制备工艺简单。
附图说明
图1为药物组合物1的图示结构。
图2为药物组合物2的图示结构。
图3为参比制剂(CN1638771A)在高湿条件下0天和15天的XRPD对比图。(图中自上而下依次为：0天和15天)。
图4为本发明的组合物1在高湿条件下0天和15天的XRPD对比图。(图中自上而下依次为：0天和15天)。
图5为本发明的组合物2在高湿条件下0天和15天的XRPD对比图。(图中自上而下依次为：0天和15天)。
具体实施方式
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明。除非 另有说明，所述的百分比通常为重量％。
采集数据所用的仪器及方法：
X-射线粉末衍射(XRPD)：所使用的仪器为Bruker D8 Advance diffractometer，采用铜靶波长为1.54nm的Ka X-射线，在40kV和40mA的操作条件下、θ-2θ测角仪、Mo单色仪、Lynxeye探测器。仪器在使用前用金刚砂校准。采集软件是Diffrac Plus XRD Commander。样品在室温条件下测试，把需要检测的样品放在无反射板上。详细检测条件如下，角度范围：3–40°2θ，步长：0.02°2θ，速度：0.2秒/步。
高效液相分析(HPLC)数据采自于Agilent 1260。采用C18色谱柱，150mm×4.6mm，柱温30℃，波长220nm，流速1.0mL/min，进样量20μL，运行时间70min。溶剂为5％的磷酸二氢钠缓冲液，流动相A为30％的甲醇和70％的上述缓冲液，流动相B为60％的乙腈和40％的上述缓冲液，梯度如下表：
时间(min) A(％) B(％)
0 70 30
15 60 40
45 50 50
60 45 55
70 60 40
除非特殊注明，实施例均在室温下操作。
实施例中所用的各种试剂或原料如无特别说明均为市售购买。蔗糖丸芯可以自制或市售。
实施例1
配方如下表的组合物1：
Figure PCTCN2015091437-appb-000002
Figure PCTCN2015091437-appb-000003
制备步骤如下：
(1)上药混悬液制备：取400.00g异丙醇溶液，加入4.33g羟丙基纤维素，溶解完全后，再加入110.00g达比加群酯甲磺酸盐，至IKA分散机下以13000rpm分散10～15分钟后，加入4.33g滑石粉，继续以IKA分散机分散10～15min，即得。使用过程中充氮保护，并维持搅拌。
(2)上药：取粒径200～355μm蔗糖丸芯41.62g至流化床内，调节进风温度为60℃，排风风量为3m3/min，待物料温度达30～40℃时，调节雾化压力为1.5Mpa，流化压力为1.5Mpa，开始上药，上药速度约为1.5～2.5g/min。上药完成后，继续以40～50℃烘干3～5小时。
(3)隔离层I配制，取80％乙醇水溶液60.00g，加入5.00g羟丙甲基纤维素，搅拌使溶解完全，至IKA分散机下分散，逐步加入3.26g滑石粉后，分散10～15min即得。
(4)上隔离层I：流化床内，待物料温度达到30～40℃时，调节雾化压力为1.5Mpa，流化压力为1.5Mpa，开始上隔离层，加浆速度约为1.0～2.0g/min，喷浆完成后，继续以40～50℃烘干3～7小时。
(5)上酸层，将上述所得微丸至离心造粒机内，设置参数：主机转速为350rpm，雾化压力为1.5Mpa，顶针压力为1.5Mpa，进风温度为50℃，进风速度为1.0m3/min，排风速度为1.5m3/min，加浆速度为3.0g/min，供粉速度为2.0g/min，加酒石酸细粉82.23g后，至40～50℃下烘干5～6小时即得。
(6)隔离层II配制：取80％乙醇水溶液90.00g，加入10.00g羟丙甲基纤维素，搅拌使溶解完全，至IKA分散机下分散，逐步加入6.47g滑石粉后，分散10～15min即得。
(7)上隔离层II：流化床内，待物料温度达到30～40℃时，调节雾化压力为1.5Mpa，流化压力为1.5Mpa，开始上隔离层，加浆速度约为1.0～2.0g/min，，喷浆完成后，继续以40～50℃烘干3～7小时。
(8)上药混悬液制备：取500.00g异丙醇溶液，加入6.43g羟丙基纤维素，溶解完全后，再加入160.00g达比加群酯甲磺酸盐，至IKA分散机下以13000rpm分散10～15分钟后，加入6.33g滑石粉，继续以IKA分散机分散10～15min，即得。使用 过程中充氮保护，并维持搅拌。
(9)上药：将上述所得微丸至流化床内，调节进风温度为60℃，排风风量为3m3/min，待物料温度达30～40℃时，调节雾化压力为1.5Mpa，流化压力为1.5Mpa，开始上药，上药速度约为1.5～2.5g/min。上药完成后，继续以40～50℃烘干3～5小时。
(10)隔离层III配制，取60％乙醇水溶液160.00g，加入25.00g胃溶层材料，搅拌使溶解完全，至IKA分散机下分散即得。
(11)上隔离层III：流化床内，待物料温度达到30～40℃时，调节雾化压力为1.5Mpa，流化压力为1.5Mpa，开始上隔离层，加浆速度约为1.0～2.0g/min，喷浆完成后，继续以40～50℃烘干3～7小时。
(12)去除1200μm以上微丸，灌装胶囊即得。
实施例2
配方如下表的组合物1：
Figure PCTCN2015091437-appb-000004
备步骤同实施例1。
实施例3
配方如下表的组合物1：
Figure PCTCN2015091437-appb-000005
制备步骤同实施例1。
实施例4
配方如下表的组合物1：
Figure PCTCN2015091437-appb-000006
制备步骤同实施例1。
实施例5
配方如下表的组合物1：
Figure PCTCN2015091437-appb-000007
制备步骤同实施例1。
实施例6
配方如下表的组合物1：
Figure PCTCN2015091437-appb-000008
制备步骤同实施例1。
实施例7
配方如下表的组合物2：
Figure PCTCN2015091437-appb-000009
制备步骤如下：
(1)含酸芯制备：取蔗糖37.57g，半胱氨酸盐酸盐250.00g，混合均匀后，至挤出滚圆机内，设置主机转速150rpm，筛网目数为600μm，开启设备，加入5％羟丙基纤维素溶液，得挤出颗粒物至离心造粒机内，以400rpm转速滚圆，再至40～50℃下烘干5～8小时即得。
(2)隔离层I配制：隔离层I配制：取80％乙醇水溶液90.00g，加入12.00g羟丙甲基纤维素，搅拌使溶解完全，至IKA分散机下分散，逐步加入7.48g滑石粉后，分散10～15min即得。
(3)上隔离层I：流化床内，待物料温度达到30～40℃时，调节雾化压力为1.5Mpa，流化压力为1.5Mpa，开始上隔离层，加浆速度约为1.0～2.0g/min，，喷浆完成后，继续以40～50℃烘干3～7小时。
(4)上药混悬液制备：取900.00g异丙醇溶液，加入8.33g羟丙基纤维素，溶解完全后，再加入250.00g达比加群酯甲磺酸盐，至IKA分散机下以13000rpm分散10～15分钟后，加入8.33g滑石粉，继续以IKA分散机分散10～15min，即得。使用过程中充氮保护，并维持搅拌。
(5)上活性物质层：将上述所得微丸至，离心造粒机内，设置参数：主机转速为350rpm，雾化压力为1.5Mpa，顶针压力为1.5Mpa，进风温度为50℃，进风速度为1.0m3/min，排风速度为1.5m3/min，加浆速度为3.0g/min，供粉速度为 2.0g/min，加酒石酸细粉749.96g后，至40～50℃下烘干5～6小时即得。
(6)隔离层II配制，取60％乙醇水溶液160.00g，加入25.00g胃溶层材料，搅拌使溶解完全，至IKA分散机下分散即得。
(7)上隔离层II：流化床内，待物料温度达到30～40℃时，调节雾化压力为1.5Mpa，流化压力为1.5Mpa，开始上隔离层，加浆速度约为1.0～2.0g/min，，喷浆完成后，继续以40～50℃烘干3～7小时。
(8)去除1200μm以上微丸，灌装胶囊即得。
实施例8
配方如下表的组合物2：
Figure PCTCN2015091437-appb-000010
制备步骤同实施例7。
实施例9
配方如下表的组合物2：
Figure PCTCN2015091437-appb-000011
制备步骤同实施例7。
实施例10
配方如下表的组合物2：
Figure PCTCN2015091437-appb-000012
制备步骤同实施例7。
对比例1
将本发明制备的组合物1、本发明制备的组合物2与市售参比制剂(CN1638771A)进行15天高湿试验对比研究，结果见表1。
实验方法如下：取本发明制备的组合物1、本发明制备的组合物2、本发明制备的组合物3与市售参比制剂(CN1638771A)的胶囊内容物各5g，平铺在平皿内，在RH92.5％条件下放置，于15天后，取样用XRPD检测其晶型变化情况，另各取含100mg活性物质的胶囊内容物，稀释250倍后，用高效液相色谱分析，结果见表1。
表1高湿试验15天结果对比
Figure PCTCN2015091437-appb-000013
表1结果表明，本发明制备的2种药物组合物在高湿条件下15天后，晶型没有发生变化，有关物质及含量变化较小，而市售的参比制剂(CN1638771A)在15天后发生了晶型转变(2θ角在3.8左右出现未知衍射峰)，且有关物质和含量变化较大，说明本发明制备的2种药物组合的物均比市售参比制剂(CN1638771A)的化学稳定性和物理稳定性更好。
对比例2
将本发明制备的组合物1、本发明制备的组合物2、市售参比制剂(CN1638771A)和按专利文献CN 103127109A实施例30制备得到的组合物(对照品2)进行介质水中的溶出值比较，结果见表2。
实验方法如下：分别取本发明制备的组合物1、本发明制备的组合物2、市售参比制剂和对照品2的胶囊各3粒，至溶出仪下，按100rpm、篮法、介质水900ml溶出方法进行检查，按5、10、15、20、30min取样点进行取样，每次取10ml，滤过5.0ml取续滤液，至高效液相色谱下分析，结果见表2。
表2介质水中的溶出值结果对比
Figure PCTCN2015091437-appb-000014
注：表2中的时间是指扣除胶囊壳溶解所需时间的时间。
由体外溶出一致性评价指导原则可知，两种制剂在15min内的溶出值均大于85％以上，则说明此两种制剂的体外溶出行为相似。表2结果表明，在介质水中，组合物1、组合物2的溶出情况与参比制剂相似，而对照品2的溶出值远未达到要求。说明本发明的组合物1和组合物2的产品与参比制剂的体外溶出行为相似，且其在胃酸分泌不足人群中的生物利用度高于对照品2。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。

Claims (8)

  1. 一种口服的药物组合物，其包含：
    a)含粘合剂及医药可接受的纤维素类或糖类或淀粉类或含该上述成分一种或多种微晶纤维素类或糖类或淀粉类一种或多种的近似球形的丸芯；以及
    b)含有活性物质、和/或崩解剂、和/或填充剂、及粘合剂组成的活性物质层，所述活性物质为达比加群酯或一种其药物上可接受的盐；以及
    c)活性物质层表面的水溶性隔离层，其材料选自：羟丙甲基纤维素、羟丙基纤维素、淀粉类、树脂类等有机高分子材料或这些有机材料的组合物；以及
    d)含有粘合剂及医药可接受的有机酸或含该有机酸的酸层，所述有机酸系指在20℃的水溶性大于1g/250毫升，选自酒石酸、富马酸、琥珀酸、柠檬酸、苹果酸、谷氨酸或天冬氨酸或一种其水合物或酸盐、半胱氨酸盐酸盐；以及
    e)酸层表面的水溶性隔离层，其材料选自：羟丙甲基纤维素、羟丙基纤维素、淀粉类、树脂类等水溶性聚合物或其组合物；以及
    f)含有活性物质、和/或崩解剂、和/或填充剂、及粘合剂组成组成的活性物质层，所述活性物质为达比加群酯或一种其药物上可接受的盐；以及
    e)以及活性物质层表面的隔离层，其材料选自：羟丙甲基纤维素、羟丙基纤维素、淀粉类、树脂类等有机高分子材料或这些有机材料的组合物。
  2. 根据权利要求1的药物组合物，其特征在于，所述酸层处于两层活性物质层中间。
  3. 根据权利要求1～2中任一项所述的酸层，其特征在于，所述有机酸为半胱氨酸盐酸盐。
  4. 根据权利要求1～2中任一项所述的药物组合物，其特征在于，所述丸芯的成分为糖类，更优选为蔗糖；
    优选地，所述丸芯的含量为10～60％；
    优选地，所述有机酸的含量为15～60％；
    优选地，所述达比加群酯或其盐的含量为15～60％；
    优选地，所述达比加群酯或其盐为达比加群酯甲磺酸盐；
    优选地，所述粘合剂选自：羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羟乙基纤维素、羧甲基纤维素、聚乙烯吡咯烷酮、N-乙烯吡咯烷酮、醋酸乙烯酯的共聚物或这些共聚物的组合物，更优选为羟丙基纤维素；
    优选地，所述丸芯的平均颗粒大小为0.2～1.5mm；
    优选地，所述活性物质层粘合剂的用量为0.5～20％，更优选为2～10％；
    优选地，所述活性物质与酸层间的隔离层用量为2.0～10％，所述微丸外层隔离层的用量为2.0～10％。
  5. 根据权利要求1～4中任一项所述的药物组合物，其制备方法如下：
    (1)将含有粘合剂的活性物质涂敷于丸芯上，并干燥；
    (2)涂敷含有高分子材料的隔离层，并干燥；
    (3)用层积法涂敷含有粘合剂和医药可接受的酸层，并干燥；
    (4)涂敷含有高分子材料的隔离层，并干燥；
    (5)用层积法涂敷含有粘合剂的活性物质，并干燥；
    (6)涂敷含有高分子材料的隔离层，并干燥；
    (7)将如此得到的含活性物质丸粒填充入硬质胶囊内。
  6. 一种口服的药用组合，其包含：
    a)含有酸性物质、和/或崩解剂、和/或填充剂、及粘合剂组成的近似球形的酸芯；以及
    b)含有活性物质、和/或崩解剂、和/或填充剂、及粘合剂组成的活性物质层，所述活性物质为达比加群酯或一种其药物上可接受的盐；以及
    c)活性物质层与酸芯间的水溶性隔离层，所述水溶性隔离层包括医药上可接受羟丙甲基纤维素、羟丙基纤维素、淀粉类、树脂类等有机高分子材料或这些有机材料的组合物；以及
    d)以及活性物质层表面的隔离层，其材料选自：羟丙甲基纤维素、羟丙基纤维素、淀粉类、树脂类等有机高分子材料或这些有机材料的组合物。
  7. 根据权利要求6的药物组合物，其特征在于，所述酸性物质为酒石酸、富马酸、琥珀酸或柠檬酸、半胱氨酸盐酸盐，更优选为半胱氨酸盐酸盐；
    优选地，所述达比加群酯或其盐的含量为10～65％；
    优选地，所述达比加群酯或其盐为达比加群酯甲磺酸盐；
    优选地，所述酸性物质的含量为8～65％；
    优选地，所述崩解剂选自：交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚维酮、低取代羟丙基纤维素等物质或其组合物；
    优选地，所述填充剂选自：纤维素类、糖类、淀粉类等物质或其组合物；
    优选地，所述粘合剂选自：羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羟乙基纤维素、羧甲基纤维素、聚乙烯吡咯烷酮、N-乙烯吡咯烷酮、醋酸乙烯酯的共聚物或这些共聚物的组合物；
    优选地，所述酸芯的平均颗粒大小为0.2～1.5mm；
    优选地，所述酸芯中粘合剂的用量为0.5～40％，更优选为2～10％；
    优选地，所述活性物质层与酸芯间的水溶性隔离层的用量为2.0～10％；所述活性物质外层隔离层的用量为2.0～10％。
  8. 根据权利要求6或7中任一项所述的药物组合物，其制备方法如下：
    (1)通过挤出滚圆法或滚圆法或流化法将酸性物质，任选添加崩解剂、填充剂和粘合剂，形成酸芯；
    (2)涂敷含有高分子材料的隔离层，并干燥；
    (3)用层积法涂敷含有粘合剂和活性物质的活性物质层，并干燥；
    (4)涂敷含有高分子材料的隔离层，并干燥；
    (5)将如此得到的含活性物质丸粒填充入硬质胶囊内。
PCT/CN2015/091437 2014-11-03 2015-10-08 达比加群酯或其盐的投药制剂及其制备方法 WO2016070696A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US15/308,014 US10675276B2 (en) 2014-11-03 2015-10-08 Dosing preparation of dabigatran etexilate or a salt thereof and a preparation method thereof
CN201580002607.6A CN105764509B (zh) 2014-11-03 2015-10-08 达比加群酯或其盐的投药制剂及其制备方法
CA3001495A CA3001495C (en) 2014-11-03 2015-10-08 Formulations of dabigatran etexilate or dabigatran etexilate salts and preparation methods thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410610015.X 2014-11-03
CN201410610015 2014-11-03

Publications (1)

Publication Number Publication Date
WO2016070696A1 true WO2016070696A1 (zh) 2016-05-12

Family

ID=55908545

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/091437 WO2016070696A1 (zh) 2014-11-03 2015-10-08 达比加群酯或其盐的投药制剂及其制备方法

Country Status (4)

Country Link
US (1) US10675276B2 (zh)
CN (1) CN105764509B (zh)
CA (1) CA3001495C (zh)
WO (1) WO2016070696A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR201722186A2 (tr) * 2017-12-27 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Dabi̇gatranin farmasöti̇k kompozi̇syonlari
EP3771465A1 (en) * 2019-08-01 2021-02-03 Zaklady Farmaceutyczne Polpharma SA Pharmaceutical composition comprising dabigatran etexilate

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 (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5395626A (en) * 1994-03-23 1995-03-07 Ortho Pharmaceutical Corporation Multilayered controlled release pharmaceutical dosage form
PE121699A1 (es) 1997-02-18 1999-12-08 Boehringer Ingelheim Pharma Heterociclos biciclicos disustituidos como inhibidores de la trombina
IL146462A (en) * 2001-11-13 2015-02-26 Lycored Bio Ltd Prolonged-release preparations containing as an active compound and analapaxin hydrochloride
US20030181488A1 (en) * 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
NZ546367A (en) 2002-03-07 2008-08-29 Boehringer Ingelheim Pharma Methanesulphonate salt of ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionate to be administered orally
AU2003245504A1 (en) * 2002-06-14 2003-12-31 Andrx Corporation Pharmaceutical compositions for drugs having ph-dependentsolubility
CA2569968C (en) * 2004-06-10 2014-08-19 Glatt Air Techniques, Inc. Controlled release matrix pharmaceutical dosage formulation
JO3616B1 (ar) * 2012-02-21 2020-08-27 Esteve Pharmaceuticals Sa تركيبات دوائية من إيتيكسيلات دابيجاتران تعطى بالفم

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

Also Published As

Publication number Publication date
US20170049764A1 (en) 2017-02-23
CA3001495A1 (en) 2016-05-12
CN105764509A (zh) 2016-07-13
CA3001495C (en) 2021-07-20
US10675276B2 (en) 2020-06-09
CN105764509B (zh) 2019-03-19

Similar Documents

Publication Publication Date Title
CN100528157C (zh) 3-[(2-{[4-(己氧羰基氨基-亚氨基-甲基)-苯基氨基]-甲基}-1-甲基-1h-苯并咪唑-5-羰基)-吡啶-2-基-氨基]-丙酸乙酯及其盐的口服施用的投药剂型
CN108938583B (zh) 包含无定形达格列净的制剂
US20180221359A1 (en) Administration of ethyl 3-[(2-{[4-(hexyloxycarbonyl-aminoiminomethyl)phenyl-amino]methyl}-1-methyl-1h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionate
JP2005526738A (ja) 低溶解度の薬物を経口投与するための投与剤形
CN106102716A (zh) 雄激素受体拮抗剂的固体药物组合物
BRPI0714915A2 (pt) composiÇço farmacÊuticas; formas de dosagem farmacÊutica; e processo para o preparo de uma composiÇço farmacÊutica
KR20140107302A (ko) 즉시 방출형 다중 유닛 펠릿 시스템
EP3646855B1 (en) Oral solid preparation composition comprising proton pump inhibitor, oral solid preparation comprising same, and preparation method therefor
CN104414978A (zh) 一种含有埃索美拉唑镁的肠溶微丸
CN104224754A (zh) 一种达比加群酯药物组合物及其制备方法
CN114569575A (zh) 肠溶微丸、其制备方法和包含它的制剂
AU2020391451A1 (en) AHR inhibitors and uses thereof
WO2016070696A1 (zh) 达比加群酯或其盐的投药制剂及其制备方法
JP2012149066A (ja) 固体分子分散物
MX2013000827A (es) Composicion de tableta de unidad multiple.
CN111265490A (zh) 兰索拉唑肠溶微丸及其制备方法
EP4205729A1 (en) Enteric pellet, preparation method therefor, and preparation comprising same
WO2015069203A1 (en) Capsule comprising rupatadine fumarate and montelukast sodium
CN101632668A (zh) 口服药物组合物
WO2015113324A1 (zh) 达比加群酯及其盐的投药制剂及其制备方法
WO2015121649A1 (en) Pharmaceutical composition comprising vemurafenib
CN114948954B (zh) 一种含甲磺酸仑伐替尼组合物及其制备方法、用途
CN106668018B (zh) 一种右兰索拉唑钠的缓释胶囊及其制备方法
CN103271908A (zh) 含有替米沙坦和苯磺酸氨氯地平的口服片剂及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15857912

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15308014

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15857912

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3001495

Country of ref document: CA