[go: up one dir, main page]

CN104994856A - Administered formulation of Dabigatran etexilate and salt thereof and preparation method thereof - Google Patents

Administered formulation of Dabigatran etexilate and salt thereof and preparation method thereof Download PDF

Info

Publication number
CN104994856A
CN104994856A CN201480008391.XA CN201480008391A CN104994856A CN 104994856 A CN104994856 A CN 104994856A CN 201480008391 A CN201480008391 A CN 201480008391A CN 104994856 A CN104994856 A CN 104994856A
Authority
CN
China
Prior art keywords
acid
elements
victoria
qiang
active material
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
CN201480008391.XA
Other languages
Chinese (zh)
Inventor
唐勇
盛晓霞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SOLIPHARMA LLC
Original Assignee
SOLIPHARMA LLC
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 SOLIPHARMA LLC filed Critical SOLIPHARMA LLC
Priority to CN201480008391.XA priority Critical patent/CN104994856A/en
Publication of CN104994856A publication Critical patent/CN104994856A/en
Pending legal-status Critical Current

Links

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
    • A61K9/48—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

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (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)

Abstract

An orally administered formulation of Dabigatran etexilate and pharmacologically acceptable salt thereof and preparation method thereof.

Description

Administered formulation of Dabigatran etexilate and salt thereof and preparation method thereof
The dispensing preparation of dabigatran etcxilate and its salt and preparation method thereof technical field
The invention belongs to pharmaceutical technology field.In particular to 3-, [(3- [(2- { [4- (own oxygen carbonyl amino-imino-methyl)-phenyl amino]-methyl } -1- methyl isophthalic acid H- benzimidazole -5- carbonyls)-than pyridine -2- bases-amino] ethyl propionate is novel oral dispensing preparation of dabigatran etcxilate and its pharmacological-acceptable salt and preparation method thereof.In particular it relates to combination of oral medication of three kinds of dabigatran etcxilates and its salt and preparation method thereof.Background technology
Dabigatran etcxilate is a kind of new direct thrombin inhibitor, is the pro-drug of dabigatran, belongs to non-peptide batroxobin inhibitor.Developed by German Boehringerlngelheim (Boehringer Ingelheim) company, orally after gastrointestinal absorption, the dabigatran with direct anticoagulant active is converted into vivo.Dabigatran is incorporated into fibrin ferment Xian Victoria albumen specific binding sites, prevents Xian Victoria proteinogens from being cracked into Xian Victoria albumen, so as to block the final step and thrombosis of blood coagulation waterfall network.Dabigatran can be dissociated on the fibrin ferment combination of Cong Xian Victoria albumen one, play reversible anticoagulation.The medicine, first in Germany and Britain's listing, is ratified occur apoplexy and systemic embolism risk for reducing NVAF patient in October, 2010 by FDA again in April, 2008.Listing formulation is capsule at present, and specification is 75 mg and 150 mg, trade name Pradaxa.
The chemical name of dabigatran etcxilate is：3- [(3- [(2- [4- (own oxygen carbonyl amino-imino-methyl)-phenyl amino]-methyl 1- methyl isophthalic acid H- benzimidazole -5- carbonyls) and-pyridine -2- bases-amino] ethyl propionate, the entitled Dabigatranetexilate of English, molecular formula is 〇34¾^705, molecular weight is 627.74, and chemical structural formula is as follows（I shown in)：
Patent document WO 98/37075 discloses dabigatran compound and purposes.Patent document
WO03/074056A1 discloses the composition and dispensing formulation of a kind of dabigatran, and it mainly constitutes as follows：The active material layer of core material, separation layer and outermost that organic acid is constituted.
The present inventor's research finds the composition prepared according to WO03/074056A1, because its active material exists , easily there is active material and occur to turn brilliant and degraded phenomenon in outermost layer.
In view of prior art remains deficiency, the novel oral dispensing preparation of dabigatran etcxilate and its salt of the exploitation with more advantage performances is of great practical significance.The content of the invention
It is an object of the invention to provide a kind of improved formulations being administered orally suitable for dabigatran etcxilate and its salt.According to the purpose of the present invention, the present invention provides combination of oral medication 1 (hereinafter referred to as " composition 1 ") of a kind of dabigatran etcxilate and its salt and preparation method thereof.
The combination of oral medication 1 of dabigatran etcxilate and its salt is included：
A) capsule core containing adhesive and the plain classes of medical acceptable Xian Victoria or carbohydrate or starch or containing the plain classes of mentioned component one or more Wei Jing Xian Victoria or carbohydrate or the one or more almost spherical of starch；And
B) active material layer constituted containing adhesive and active material, the active material is dabigatran etcxilate or its a kind of pharmaceutically acceptable salt；And
C) the water-soluble separation layer of active material layer surface, its material is selected from：The composition of the high-molecular organic material such as Qiang the third Jia Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, starch, resinae or these organic materials；And acid layer d) containing adhesive and medical acceptable organic acid or containing the organic acid, the organic acid means that the water solubility at 20 °C is more than lg/250 milliliters, selected from tartaric acid, fumaric acid, butanedioic acid, citric acid, malic acid, glutamic acid or aspartic acid or its a kind of hydrate or hydrochlorate；And
E) the water-soluble separation layer on acid layer surface, its material is selected from：Water-soluble polymer or its composition such as Qiang the third Jia Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, starch, resinae.
Preferably, the active material layer further includes adhesive, filler and active material.
Preferably, the filler is pharmaceutically acceptable water-soluble material, the preferably one or more in carbohydrate, alcohols, soluble starch class and salt；More preferably lactose, mannitol, maltose, sorbierite.
Preferably, the mass ratio of the filler and active material is 1:1~1 :10, more preferably 1:2~1 :5.Preferably, the capsule core is into the plain classes of fine Victoria are divided into, more preferably micro- brilliant fibre Victoria elements.
Preferably, the content of the capsule core material is 10 ~ 60%.
Preferably, the organic acid is tartaric acid, fumaric acid, butanedioic acid or citric acid, more preferably tartaric acid.Preferably, the content of the organic acid is 20 ~ 60%.
Preferably, the content of the dabigatran etcxilate or its salt is 15 60%.
Preferably, described adhesive is selected from：Qiang hydroxypropyl methyl Xian Victoria elements, Qiang propyl group Xian Victoria elements, Jia Ji Xian Victoria elements, Qiang Yi Ji Xian Victoria elements, Suo Jia Ji Xian Victoria elements, polyvinylpyrrolidone, N- vinylpyrrolidones, vinylacetate Copolymer or these copolymers composition, more preferably Qiang propyl group Xian Victoria element.
Preferably, the mean particle size of the core material is 0.2 1.5 mm.
Preferably, the consumption of the active material layer adhesive is 0.5 ~ 20%, more preferably 2 ~ 10%, and the consumption of the organic acid layers of balls adhesive is 0.5 ~ 20%, preferably 2 ~ 10%.
Preferably, the consumption of the active material outer layer separation layer is 2.0 ~ 10%, and the consumption of the organic acid outer layer separation layer is 2.0 ~ 10%.One preferred embodiment of said composition is graininess preparation, and wherein each particle is the structure such as Fig. 1.
In some embodiments, filler, such as lactose, mannitol, maltose, sorbierite are added to improve in the dissolution rate of preparation, the active material layer.
Fig. 1 represents the schematic structure by the pharmaceutical composition shown in the section of the particle suitable for preparing composition 1.The approximate sphericity core area of the particle includes Wei Jing Xian Victoria elements.Then by one layer of active material layer constituted containing adhesive and active material or containing adhesive, water-soluble filler and active material, then outside has one layer to be referred to as water-soluble separation layer, and it isolates active material layer and the layer containing organic acid.Then, the separation layer is surrounded by the identical spherical organic acid layer containing adhesive and organic acid again, and outermost is that water-soluble separation layer layers of balls containing high-molecular organic material again surround by coated, and the coating can increase the wear resistence and storage life of particle.
The preparation method of composition 1 is as follows：
(1) active material layer containing adhesive and active material or containing adhesive, filler and active material is applied into number in capsule core, and dried；
(2) separation layer that number contains high polymer material is applied, and dried；
(3) apply number with lamination method and contain adhesive and the acceptable organic acid layer of medicine, and dry；
(4) separation layer that number contains high polymer material is applied, and dried；
(5) so obtained pill containing active material is packed into hard capsules.
The advantage for the form of administration being made according to composition 1 is as follows：
1) active material layer is in centre, can preferably protection activity material, make it be difficult to turn brilliant or degraded；
2) compared with commercial reference preparation, composition 1 has more preferable chemical stability and physical stability；
3) capsule core is done Yong the plain classes of Xian Victoria, cost is low, prepares simple.
According to the purpose of the present invention, the present invention provides combination of oral medication 2 (hereinafter referred to as " composition 2 ") of another dabigatran etcxilate and its salt and preparation method thereof.
The combination of oral medication 2 of dabigatran etcxilate and its salt is included：
A) core material of the almost spherical constituted containing disintegrant, filler, adhesive and active material, the active material is dabigatran etcxilate or its a kind of pharmaceutically acceptable salt；And B) outer layer containing adhesive and medical acceptable organic acid or containing the organic acid, the organic acid is selected from tartaric acid, fumaric acid, butanedioic acid, citric acid, malic acid, glutamic acid or aspartic acid or its a kind of hydrate or hydrochlorate；And
C) the water-soluble separation layer between outer layer and core material, the water-soluble insolated layer materials include the high-molecular organic materials such as pharmaceutically acceptable the third Jia of Qiang Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, starch, resinae or the composition of these organic materials.
Preferably, the organic acid is tartaric acid, fumaric acid, butanedioic acid or citric acid, more preferably tartaric acid.Preferably, the content of the dabigatran etcxilate or its salt is 20 60%.
Preferably, the dabigatran etcxilate or its salt are dabigatran etcxilate mesylate.
Preferably, the content of the organic acid is 20 ~ 60%.
Preferably, the disintegrant is selected from：Material or its composition such as the plain sodium of Jiao connection Suo Jia Ji Xian Victoria, sodium carboxymethyl starch, Jiao Lian Ju Victoria ketone, low substitution Qiang propyl group Xian Victoria elements.
Preferably, the filler is selected from：Material or its composition such as Xian Victoria elements class, carbohydrate, starch；Preferably, described adhesive is selected from：Qiang hydroxypropyl methyl Xian Victoria elements, Qiang propyl group Xian Victoria elements, Jia Ji Xian Victoria elements, Qiang Yi Ji Xian Victoria elements, the composition of Suo Jia Ji Xian Victoria elements, polyvinylpyrrolidone, N- vinylpyrrolidones, the copolymer of vinylacetate or these copolymers.
Preferably, the mean particle size of the core material is 0.4 1.5 mm.
Preferably, the consumption of adhesive is 0.5 ~ 10% in the core material, and the consumption of adhesive is 0.5 ~ 10%, preferably 2 ~ 10% in the organic acid layers of balls.
Preferably, the consumption of the active material outer layer separation layer is 2.0 ~ 10%, and the consumption of the organic acid outer layer separation layer is 2.0 ~ 10%.
One preferred embodiment of said composition is graininess preparation, and wherein each particle is the structure such as Fig. 2.Fig. 2 represents the schematic structure by the pharmaceutical composition shown in the section of the particle suitable for preparing composition 2.The approximate sphericity core area of the particle includes disintegrant, filler, adhesive and active material.Then one layer is referred to as water-soluble separation layer, its isolated core area and the floor containing organic acid.Then, the separation layer is surrounded by the identical spherical layer containing adhesive and organic acid again, and the layers of balls again surround by coated, and the coating can increase the wear resistence and storage life of particle.
The preparation method of composition 2：
(1) by extruding Gun Round method Huo Gun Round methods by active material, disintegrant, filler and adhesive is optionally added, the core material is formed；
(2) separation layer that number contains high polymer material is applied, and dried； (3) apply number with lamination method and contain adhesive and the acceptable organic acid layer of medicine, and dry；
(4) separation layer that number contains high polymer material is applied, and dried；
(5) so obtained pill containing active material is packed into hard capsules.
The advantage for the form of administration being made according to composition 2 is as follows：
1) can preferably protection activity material, make it be difficult to turn brilliant or degraded；
2) compared with commercial reference preparation, composition 1 has more preferable chemical stability and physical stability；
3) preparation technology is simple.
According to the purpose of the present invention, the present invention provides combination of oral medication 3 (hereinafter referred to as " composition 3 ") of the third dabigatran etcxilate and its salt and preparation method thereof.
The combination of oral medication 3 of dabigatran etcxilate and its salt is included：
A) the capsule core material of the almost spherical containing adhesive and pharmaceutically acceptable organic acid or containing the organic acid, the organic acid system is selected from tartaric acid, fumaric acid, butanedioic acid, citric acid, malic acid, glutamic acid or aspartic acid or a kind of above-mentioned organic acid hydrate or hydrochlorate；And
B) micropill or particle or powder containing filler, disintegrant, adhesive and active material, the active material are dabigatran etcxilate or its a kind of pharmaceutically acceptable salt；And
C) separation layer on organic acid particles surface, its material is selected from：The composition of the high-molecular organic material such as Qiang the third Jia Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, starch, resinae or these organic materials；And
D) micropill containing active material or particle or the separation layer on powder surface, its material are selected from：The composition of the high-molecular organic material such as Qiang the third Jia Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, starch, resinae or these organic materials.
Preferably, the organic acid is tartaric acid, fumaric acid, butanedioic acid or citric acid, more preferably tartaric acid.Preferably, the content of the dabigatran etcxilate or its salt is 15 60%.
Preferably, the dabigatran etcxilate or its salt are dabigatran etcxilate mesylate.
Preferably, the content of the organic acid is 20 ~ 60%.
Preferably, the disintegrant is selected from：Material or its composition such as the plain sodium of Jiao connection Suo Jia Ji Xian Victoria, sodium carboxymethyl starch, Jiao Lian Ju Victoria ketone, low substitution Qiang propyl group Xian Victoria elements.
Preferably, the filler is selected from：Material or its composition such as Xian Victoria elements class, carbohydrate, starch.Preferably, described adhesive is selected from：Qiang hydroxypropyl methyl Xian Victoria elements, Qiang propyl group Xian Victoria elements, Jia Ji Xian Victoria elements, Qiang Yi Ji Xian Victoria elements, the composition of Suo Jia Ji Xian Victoria elements, polyvinylpyrrolidone, N- vinylpyrrolidones, the copolymer of vinylacetate or these copolymers.
Preferably, the mean particle size of the core material is 0.4 1.5 mm. Preferably, consumption of the described adhesive in micropill containing active material or particle or powder is 0.5 ~ 10%, and more preferably 2 ~ 10%, consumption of the described adhesive in containing sour capsule core material is 0.5 ~ 10%, and more preferably 2 ~ 10%.
Preferably, the consumption of the active material outer layer separation layer is 2.0 ~ 10%, and the consumption of the organic acid outer layer separation layer is 2.0 ~ 10%.
One preferred embodiment of said composition is two kinds of granular mix preparations, and wherein each particle is the structure such as Fig. 3.
Fig. 3 represents the schematic structure by the pharmaceutical composition shown in the section of the particle suitable for preparing composition 3.The approximate sphericity core area of one of which particle is the capsule core material of organic acid, and the capsule core material is surrounded by the separation layer containing high-molecular organic material；The approximate sphericity core area of another micropill or particle or powder is the particle for including disintegrant, filler, adhesive and active material; the micropill or particle or powder are surrounded by the separation layer containing high-molecular organic material, and the separation layer can increase the wear resistence and storage life of particle.
The preparation method of composition 3：
(1) by extruding Gun Round method method Huo Gun Round methods by one or more pharmaceutically acceptable organic acids, adhesive is optionally added, the core material is formed, and dry；
(2) separation layer that number contains high polymer material is applied in organic acid core material, and is dried；
(3) by active material, disintegrant, filler and adhesive are optionally added, particle is formed, and dry；
(4) separation layer that number contains high polymer material is applied on active material particle surface, and is dried；
(5) will（2) and（4) two kinds of particles is mixed by a certain percentage, is packed into hard capsules.
The advantage for the form of administration being made according to composition 3 is as follows：
1) according to the ratio of two kinds of particles, the mixed powder of different size is prepared；
2) organic acid particles are dissolved rapidly, and target pH environment can be reached at once；
3) separation layer energy protection activity material, makes it be difficult to turn brilliant or degraded；
4) compared with commercial reference preparation, composition 1 has more preferable chemical stability and physical stability；
5) preparation technology is simple.Brief description of the drawings
Fig. 1 is the schematic structure of pharmaceutical composition 1.
Fig. 2 is the schematic structure of pharmaceutical composition 2.
Fig. 3 is the schematic structure of pharmaceutical composition 3. Fig. 4 is the reference preparation XRPD comparison diagrams of 0 day and 15 days under conditions of high humidity.（It is followed successively by from top to bottom in figure：0 day and 15 days).
Fig. 5 for the present invention the XRPD comparison diagrams of 0 day and 15 days under conditions of high humidity of composition 1.（It is followed successively by from top to bottom in figure：0 day and 15 days).
Fig. 6 for the present invention the XRPD comparison diagrams of 0 day and 15 days under conditions of high humidity of composition 2.（It is followed successively by from top to bottom in figure：0 day and 15 days).
Fig. 7 for the present invention the XRPD comparison diagrams of 0 day and 15 days under conditions of high humidity of composition 3.（It is followed successively by from top to bottom in figure：0 day and 15 days).Embodiment
It will be helpful to further understand the present invention by following embodiments, but be not used in the limitation present invention.Unless otherwise indicated, described percentage is usually weight %.
Instrument and method used in gathered data：
X-ray powder diffraction（XPRD) ：Used instrument is Bmker D8 Advance
Diffractometer, uses copper target wavelength for 1.54nm Ka X-rays, under 40kV and 40mA operating condition, Θ -2 Θ angular instruments, Mo monochromators, Lynxeye detectors.Instrument is calibrated using preceding with diamond dust.Acquisition software is Diffrac Plus XRD Commander.Sample is tested at ambient temperature, and the sample for needing to detect is placed on areflexia plate.Detailed testing conditions are as follows, angular range：3-40 ° of 2 θ, step-length：0.02 ° of 2 Θ, speed：0.2 second/step.
High-efficient liquid phase analysis（HPLC) data are picked up from Agilent 1260.Using C18Chromatographic column, 150mm X 4.6mm, 30 °C of column temperature, wavelength 220nm, flow velocity 1.0mL/min, sample size 20 L, run time 70min.Solvent is 5% di(2-ethylhexyl)phosphate Hydrogen sodium Slow fliud flushings, methanol and 70% above-mentioned Slow fliud flushing of the mobile phase A for 30%, acetonitrile and 40% above-mentioned Slow fliud flushing of the Mobile phase B for 60%, gradient such as following table：
Except no special is indicated, embodiment is operated at room temperature.
Various reagents used or raw material for example illustrate to be commercially available purchase Wu Te Do in embodiment.Wei Jing Xian Victoria element balls Core can be made by oneself or commercially available.
Embodiment 1
The composition 1 of formula such as following table:
Preparation process is as follows:
(1) prepared by medicine-feeding suspension：Take 900.00g aqueous isopropanols, add 8.33g Qiang propyl group Xian Victoria elements, after dissolving completely, add 250.00g dabigatran etcxilate mesylates, after being disperseed 10 ~ 15 minutes with 13000rpm under to IKA dispersion machines, 8.33g talcum powder is added, continues to disperse 10 ~ 15min with IKA dispersion machines, produces.Nitrogen filled protection , Bing Victoria, which are held, during use stirs loop.
(2) add medicine to：Take the μ π ι Wei Jing Xian Victoria element capsule core 41.62g of particle diameter 200 ~ 355 in fluid bed, regulation EAT is 60 °C, and air draft air quantity is 3m3/ min, when temperature of charge is up to 30 ~ 40 °C, regulation atomizing pressure is 1.5Mpa, and fluidized pressure is 1.5Mpa, starts medicine-feeding, medicine-feeding speed is about 1.5 ~ 2.5g/min.After the completion of medicine-feeding, continue to dry 3 ~ 5 hours with 40 ~ 50 °C.
(3) separation layer I is prepared, and takes aqueous isopropanol 60.00g, adds 5.00g Qiang propyl group Xian Victoria elements, and stirring loop makes dissolving completely, to IKA dispersion machines under disperse, be gradually added after 3.26g talcum powder, scattered 10 ~ 15min is produced.
(4) separation layer I on：In fluid bed, when temperature of charge reaches 30 ~ 40 °C, regulation atomizing pressure is 1.5Mpa, fluidized pressure is 1.5Mpa, starts upper separation layer, plus slurry speed is about 1.0 ~ 2.0g/min, after the completion of whitewashing, continue to dry 3 ~ 7 hours with 40 ~ 50 °C.
(5) winestone acid layer on, by above-mentioned gained micropill extremely, in centrifugal granulator, arrange parameter：Engine speed is 350rpm, and atomizing pressure is 1.5Mpa, and thimble pressure is 1.5Mpa, and EAT is 50 °C, and intake velocity is 1.0 m3/ min, ventilation velocity is 1.5 m3/ min, plus slurry speed are 3.0g/min, are that 2.0g/min adds after tartaric acid fine powder 82.23g for powder speed, to 40 ~ 50 °C under dry and produce for 5 ~ 6 hours. (6) separation layer II is prepared：Take aqueous isopropanol 60.00g, add 5.83g Qiang propyl group Xian Victoria elements, stirring loop makes dissolving completely, to IKA dispersion machines under disperse, be gradually added after 2.50g talcum powder, scattered 10 ~ 15min is produced.
(7) separation layer II on：In fluid bed, when temperature of charge reaches 30 ~ 40 °C, regulation atomizing pressure is 1.5Mpa, fluidized pressure is 1.5Mpa, starts upper separation layer, plus slurry speed is about 1.0 ~ 2.0g/min,, after the completion of whitewashing, continue to dry 3 ~ 7 hours with 40 ~ 50 °C.
(8) 1200 μ π ι above micropills are removed, filling capsule is produced.
Embodiment 2
The composition 1 of formula such as following table:
Preparation process be the same as Example 1.
Embodiment 3
The composition 1 of formula such as following table:
Group is into percentage (%)
(based on 50mg containing dabigatran etcxilate）Per capsule title
Active matter (mg) capsule core separation layer I winestone acid layer separation layer II ratios %
Matter layer
Wei Jing Xian Victoria elements
15.0 -- -- 15.0 57.7 capsule core
Up to π groups of esters of specific force
- 15.0 ---15.0 57.7 mesylates
Tartaric acid ---60.0-60.0 230.7 Qiang propyl group Xian Victoria
- 0.5 2.0 3.0 2.0 7.5 28.8 element
Talcum powder-0.1 1.2-1.2 2.5 9.6 Total ~ 100.0 384.4 preparation process be the same as Example 1.
Embodiment 4
The composition 1 of formula such as following table:
Preparation process be the same as Example 1.
Embodiment 5
The composition 1 of formula such as following table:
Preparation process be the same as Example 1.
Embodiment 6
The composition 1 of formula such as following table: Group is into percentage (%)
(based on 75mg containing dabigatran etcxilate）Per capsule title
Active matter (mg) capsule core separation layer I winestone acid layer separation layer II ratios %
Matter layer
Wei Jing Xian Victoria elements
9.8 -- -- 9.8 35.5 capsule core
Mannitol-2.4 ---2.4 8.7 reach π groups of esters of specific force
- 24.0 ---24.0 86.8 mesylates
Tartaric acid ---19.5-19.5 70.5 Qiang propyl group Xian Victoria
- 9.5 6.3 19.5 6.2 41.5 150.1 elements
Talcum powder-0.5 1.2-1.1 2.8 10.1 is always ~ 100 361.7
(1) prepared by medicine-feeding suspension：Take 900.00g aqueous isopropanols, add 8.33g Qiang propyl group Xian Victoria elements, after dissolving completely, add 250.00g dabigatran etcxilate mesylates and 25.00g mannitol, after being disperseed 10 ~ 15 minutes with 13000rpm under to IKA dispersion machines, 8.33g talcum powder is added, continues scattered with IKA dispersion machines
10 ~ 15min, is produced.Nitrogen filled protection , Bing Victoria, which are held, during use stirs loop.
(2) add medicine to：Take the μ π ι Wei Jing Xian Victoria element capsule core 41.62g of particle diameter 200 ~ 355 in fluid bed, regulation EAT is 60 °C, and air draft air quantity is 3m3/ min, when temperature of charge is up to 30 ~ 40 °C, regulation atomizing pressure is 1.5Mpa, and fluidized pressure is 1.5Mpa, starts medicine-feeding, medicine-feeding speed is about 1.5 ~ 2.5g/min.After the completion of medicine-feeding, continue to dry 3 ~ 5 hours with 40 ~ 50 °C.
(3) separation layer I is prepared, and takes aqueous isopropanol 60.00g, adds 5.00g Qiang propyl group Xian Victoria elements, and stirring loop makes dissolving completely, to IKA dispersion machines under disperse, be gradually added after 3.26g talcum powder, scattered 10 ~ 15min is produced.
(4) separation layer I on：In fluid bed, when temperature of charge reaches 30 ~ 40 °C, regulation atomizing pressure is 1.5Mpa, fluidized pressure is 1.5Mpa, starts upper separation layer, plus slurry speed is about 1.0 ~ 2.0g/min, after the completion of whitewashing, continue to dry 3 ~ 7 hours with 40 ~ 50 °C.
(5) winestone acid layer on, by above-mentioned gained micropill extremely, in centrifugal granulator, arrange parameter：Engine speed is 350rpm, and atomizing pressure is 1.5Mpa, and thimble pressure is 1.5Mpa, and EAT is 50 °C, and intake velocity is 1.0 m3/ min, ventilation velocity is 1.5 m3/ min, plus slurry speed are 3.0g/min, are that 2.0g/min adds after tartaric acid fine powder 82.23g for powder speed, to 40 ~ 50 °C under dry and produce for 5 ~ 6 hours.
(6) separation layer II is prepared：Take aqueous isopropanol 60.00g, add 5.83g Qiang propyl group Xian Victoria elements, stirring loop makes dissolving completely, to IKA dispersion machines under disperse, be gradually added after 2.50g talcum powder, scattered 10 ~ 15min is produced.
(7) separation layer II on：In fluid bed, when temperature of charge reaches 30 ~ 40 °C, regulation atomizing pressure is 1.5Mpa, fluidized pressure is 1.5Mpa, starts upper separation layer, plus slurry speed is about 1.0 ~ 2.0g/min, after the completion of whitewashing, continue to dry 3 ~ 7 hours with 40 ~ 50 °C.
(8) 1200 μ π ι above micropills are removed, filling capsule is produced.
Embodiment 7
The composition 1 of formula such as following table:
Preparation process be the same as Example 6.
Embodiment 8
The composition 1 of formula such as following table:
Group is into percentage (%)
(based on 75mg containing dabigatran etcxilate）Per capsule title
Active matter (mg) capsule core separation layer I winestone acid layer separation layer II ratios %
Matter layer
Wei Jing Xian Victoria elements
8.9 -- -- 8.9 35.4 capsule core
Sorbierite-10.9 ---10.9 43.4 reach π groups of esters of specific force
- 21.8 ---21.8 86.8 mesylates
Tartaric acid ---17.8-17.8 70.9 Qiang propyl group Xian Victoria
- 8.0 5.0 19.5 5.5 38.0 151.3 elements
Talcum powder-0.4 1.1-1.1 2.6 10.4 is always ~ 100 398.2 Preparation process be the same as Example 6.
Embodiment 9
The composition 1 of formula such as following table:
Preparation process be the same as Example 6.
Embodiment 10
It is formulated the composition 2 of ^ following tables:
Preparation process is as follows：
(1) prepared by pellet core：Take Wei Jing Xian Victoria element 37.57g, lactose monohydrate 5.78g, Jiao Lian Ju Victoria ketone 16.36g Dabigatran etcxilate mesylate 250.00g; after mixing is hooked; to extrusion Gun Round machines; engine speed 150rpm is set, and sieve mesh number is 600 μ π ι, opens equipment; add 2% Ju Victoria ketone solution; it must extrude in particulate matter to centrifugal granulator, with 400rpm rotating speed Gun Round, then produce within 5 ~ 8 hours to drying under 40 ~ 50 °C.
(2) separation layer I is prepared：Take aqueous isopropanol 260.00g, add 22.50g Qiang propyl group Xian Victoria elements, stirring loop makes dissolving completely, to IKA dispersion machines under disperse, be gradually added after 2.50g talcum powder, scattered 10 ~ 15min is produced.
(3) separation layer I on：In fluid bed, when temperature of charge reaches 30 ~ 40 °C, regulation atomizing pressure is 1.5Mpa, fluidized pressure is 1.5Mpa, starts upper separation layer, plus slurry speed is about 1.0 ~ 2.0g/min,, after the completion of whitewashing, continue to dry 3 ~ 7 hours with 40 ~ 50 °C.
(4) winestone acid layer on：By above-mentioned gained micropill extremely, in centrifugal granulator, arrange parameter：Engine speed is 350rpm, and atomizing pressure is 1.5Mpa, and thimble pressure is 1.5Mpa, and EAT is 50 °C, and intake velocity is 1.0 m3/ min, ventilation velocity is 1.5 m3/ min, plus slurry speed are 3.0g/ min, after being 2.0g/min, plus tartaric acid fine powder 749.96g for powder speed, to 40 ~ 50 °C under dry and produce for 5 ~ 6 hours.
(5) separation layer II is prepared, and takes aqueous isopropanol 260.00g, adds 22.50g Qiang propyl group Xian Victoria elements, and stirring loop makes dissolving completely, to IKA dispersion machines under disperse, be gradually added after 2.50g talcum powder, scattered 10 ~ 15min is produced.
(6) separation layer II on：In fluid bed, when temperature of charge reaches 30 ~ 40 °C, regulation atomizing pressure is 1.5Mpa, fluidized pressure is 1.5Mpa, starts upper separation layer, plus slurry speed is about 1.0 ~ 2.0g/min,, after the completion of whitewashing, continue to dry 3 ~ 7 hours with 40 ~ 50 °C.
(7) 1200 μ π ι above micropills are removed, filling capsule is produced.
Embodiment 11
It is formulated the composition 2 of ^ following tables:
Group is into percentage (%)
Title is (based on 200mg containing dabigatran etcxilate）Per the micro- crystalline substance fibre Victoria elements 8.0 of capsule (mg) capsule core separation layer I winestone acid layer separation layer II ratios %, -- ---2.0 7.7 reach π groups of esters of specific force to-5.0 19.2 poly- Victoria ketone 0.5 ---0.5 1.9 hands over the poly- Victoria ketone 2.0 of connection -- to-8.0 30.7 lactose monohydrates 5.0
60.0 ---60.0 230.7 mesylates
Tartaric acid -- 20.0-20.0 76.8 Qiang propyl group Xian Victoria
- 1.8 0.5 1.8 4.1 15.7 elements
Talcum powder-0.2-0.2 0.4 1.6 is total ~ the preparation process be the same as Examples 6 of i 100.0 384.5.
Embodiment 12
It is formulated the composition 2 of ^ following tables:
Preparation process be the same as Example 6.
Embodiment 13
It is formulated the composition 3 of ^ following tables:
Group is into percentage (%)
Title is (based on 75mg containing dabigatran etcxilate）Per capsule (mg) capsule core separation layer I tartaric acid capsule core separation layer II ratios %
Wei Jing Xian Victoria elements
4.0 ---4.0 17.3 capsule cores
---8.0 34.6 Ju Victoria ketone 0.5 -- 0.5 2.2 Jiao Lian Ju Victoria ketone 1.5 ---1.5 6.5 reach π groups of esters of specific force to lactose monohydrate 8.0
20.0 ---20.0 86.5 mesylates
Tartaric acid -- 60.0-60.0 259.5 Qiang propyl group Xian Victoria
- 1.8 2.0 1.8 5.6 24.2 elements
Talcum powder-0.2-0.2 0.4 1.7 is total ~ and the preparation processes of i 100.0 432.5 are as follows:
(1) prepared by pellet core：Take Wei Jing Xian Victoria element 50.00g, lactose monohydrate lOO.OOg, Jiao Lian Ju Victoria ketone 6.24g; dabigatran etcxilate mesylate 250.00g; after well mixed, to extrusion Gun Round machines, engine speed 150rpm is set; sieve mesh number is 600 μ π ι; equipment is opened, 2% Ju Victoria ketone solution is added, must extrude in particulate matter to centrifugal granulator; with 400rpm rotating speed Gun Round, then produce within 5 ~ 8 hours to drying under 40 ~ 50 °C.
(2) separation layer I is prepared, and takes aqueous isopropanol 480.00g, adds 22.50g Qiang propyl group Xian Victoria elements, and stirring loop makes dissolving completely, to IKA dispersion machines under disperse, be gradually added after 2.50g talcum powder, scattered 10 ~ 15min is produced.
(3) separation layer I on：In fluid bed, when temperature of charge reaches 30 ~ 40 °C, regulation atomizing pressure is 1.5Mpa, fluidized pressure is 1.5Mpa, starts upper separation layer, plus slurry speed is about 1.0 ~ 2.0g/min,, after the completion of whitewashing, continue to dry 3 ~ 7 hours with 40 ~ 50 °C.
(4) prepared by tartaric acid capsule core：Take tartaric acid 749.96g, plus 10% Qiang propyl group Xian Victoria elements are appropriate, after softwood processed 40 eye mesh screens, in gained particle to centrifugal granulator, arrange parameter：Engine speed is that 350rpm atomizing pressures are 1.5Mpa, and thimble pressure is 1.5Mpa, and EAT is 25 °C, and intake velocity is 0.5 m3/ min, ventilation velocity is 1.0 m3/ min, plus slurry speed is 1.5g/min, after it must play Mu Gun Round, selection particle diameter is about 600 μ π ι tartaric acid capsule cores, then is produced within 5 ~ 6 hours to drying under 40 ~ 50 °C.
(5) separation layer II is prepared, and takes aqueous isopropanol 480.00g, adds 22.50g Qiang propyl group Xian Victoria elements, and stirring loop makes dissolving completely, to IKA dispersion machines under disperse, be gradually added after 2.50g talcum powder, scattered 10 ~ 15min is produced.
(6) separation layer II on：In fluid bed, when temperature of charge reaches 30 ~ 40 °C, regulation atomizing pressure is 1.5Mpa, fluidized pressure is 1.5Mpa, starts upper separation layer, plus slurry speed is about 1.0 ~ 2.0g/min,, after the completion of whitewashing, continue to dry 3 ~ 7 hours with 40 ~ 50 °C.
(7) pellet core and tartaric acid capsule core are taken in right amount by recipe quantity , Fen Do, after being well mixed, filling capsule is produced.
Embodiment 14
It is formulated the composition 3 of ^ following tables: Group is into percentage (%)
Title is (based on 200mg containing dabigatran etcxilate）Per capsule (mg)
Capsule core separation layer I tartaric acid capsule core separation layer II ratio % Wei Jing Xian Victoria element balls
3.5 - - - 3.5 13.3
The heart
---8.0 30.7 Ju Victoria ketone 2.0 ---2.0 7.7 Jiao Lian Ju Victoria ketone 2.0 ---2.0 7.7 dabigatran etcxilate first of lactose monohydrate 8.0
60.0 ---60.0 230.7 sulfonate
Tartaric acid -- 20.0-20.0 76.8 Qiang propyl group Xian Victoria elements-1.8 0.5 1.8 4.1 15.7
Talcum powder-0.2-0.2 0.4 1.6 is total ~ 100.0 384.5 preparation process be the same as Examples 9.
Embodiment 15
It is formulated the composition 3 of ^ following tables:
Preparation process be the same as Example 9.
Comparative example 1
Composition 1, the composition 2 of the invention prepared, the composition 3 of the invention prepared prepared by the present invention 15 days high humidity Test and Comparison Studies are carried out with commercial reference preparation, 1 is the results are shown in Table.
Experimental method is as follows：Take composition 1, the composition 2 of the invention prepared, each 5g of capsule 's content of the composition 3 of the invention prepared and commercial reference preparation prepared by the present invention, in being laid in, placed under the conditions of RH92.5%, in after 15 days, sampling detects its crystal formation situation of change with XPRD, the capsule 's content of the active material containing lOOmg is separately respectively taken, after 250 times of dilution, with efficient liquid phase chromatographic analysis, 1 the results are shown in Table.
15 days Comparative results of high wet test
The result of table 1 shows that 3 kinds of pharmaceutical compositions prepared by the present invention are under conditions of high humidity after 15 days, and crystal formation does not change, and relevant material and changes of contents are smaller, and commercially available reference preparation there occurs crystal transfer after 15 days（There is unknown diffraction maximum 3.8 or so in 2 Θ angles）, and it is larger about material and changes of contents, illustrate that chemical stability and physical stability of the thing of 3 kinds of drug regimens prepared by the present invention than commercial reference preparation are more preferable.It is described above; only embodiment of the invention; but protection scope of the present invention is not limited thereto; any those skilled in the art disclosed herein technical scope in; the change or replacement that can be expected without creative work, should all be included within the scope of the present invention.

Claims (1)

  1. Claim
    1st, a kind of oral pharmaceutical composition, it is included：
    A) capsule core containing adhesive and the plain classes of medical acceptable Xian Victoria or carbohydrate or starch or containing the plain classes of mentioned component one or more Wei Jing Xian Victoria or carbohydrate or the one or more almost spherical of starch；And
    B) active material layer containing adhesive and active material, the active material is dabigatran etcxilate or its a kind of pharmaceutically acceptable salt；And
    C) the water-soluble separation layer of active material layer surface, its material is selected from：The composition of the high-molecular organic material such as Qiang the third Jia Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, starch, resinae or these organic materials；And acid layer d) containing adhesive and medical acceptable organic acid or containing the organic acid, the organic acid is selected from tartaric acid, fumaric acid, butanedioic acid, citric acid, malic acid, glutamic acid or aspartic acid or its a kind of hydrate or hydrochlorate；And
    E) the water-soluble separation layer on acid layer surface, its material is selected from：Water-soluble polymer or its composition such as Qiang the third Jia Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, starch, resinae.
    2nd, pharmaceutical composition according to claim 1, it is characterised in that the active material layer further includes adhesive, filler and active material.
    3rd, the active material layer according to claim 2, it is characterised in that the filler is pharmaceutically acceptable water-soluble material, the preferably one or more in carbohydrate, alcohols, soluble starch class and salt；More preferably lactose, mannitol, maltose, sorbierite；
    Preferably, the mass ratio of the filler and active material is 1:1~1 :10, more preferably 1:2~1 :5.
    4th, the pharmaceutical composition according to any one of claim 1 ~ 2, it is characterised in that the capsule core is into the plain classes of fine Victoria are divided into, more preferably micro- brilliant fibre Victoria elements；
    Preferably, the content of the capsule core material is 10 ~ 60%；
    Preferably, the organic acid is tartaric acid, fumaric acid, butanedioic acid or citric acid, more preferably tartaric acid；Preferably, the content of the organic acid is 20 ~ 60%；
    Preferably, the content of the dabigatran etcxilate or its salt is 15 60%；
    Preferably, the dabigatran etcxilate or its salt are dabigatran etcxilate mesylate；
    Preferably, described adhesive is selected from：Qiang hydroxypropyl methyl Xian Victoria elements, Qiang propyl group Xian Victoria elements, Jia Ji Xian Victoria elements, Qiang Yi Ji Xian Victoria elements, the composition of Suo Jia Ji Xian Victoria elements, polyvinylpyrrolidone, N- vinylpyrrolidones, the copolymer of vinylacetate or these copolymers, more preferably Qiang propyl group Xian Victoria elements；
    Preferably, the mean particle size of the core material is 0.2 1.5 mm; Preferably, the consumption of the active material layer adhesive is 0.5 ~ 20%, more preferably 2 ~ 10%, and the consumption of the organic acid layers of balls adhesive is 0.5 ~ 20%, preferably 2 ~ 10%；
    Preferably, the consumption of the active material outer layer separation layer is 2.0 ~ 10%, and the consumption of the organic acid outer layer separation layer is 2.0 ~ 10%.
    5th, the pharmaceutical composition according to any one of claim 1 ~ 4, its preparation method is as follows：
    (1) active material containing adhesive is applied into number in capsule core, and dried；
    (2) separation layer that number contains high polymer material is applied, and dried；
    (3) apply number with lamination method and contain adhesive and the acceptable organic acid layer of medicine, and dry；
    (4) separation layer that number contains high polymer material is applied, and dried；
    (5) so obtained pill containing active material is packed into hard capsules.
    6th, preparation method according to claim 5, it is characterised in that the active material containing adhesive further includes adhesive, filler and active material.
    7th, a kind of oral pharmaceutical compositions, it is included：
    A) core material of the almost spherical constituted containing disintegrant, filler, adhesive and active material, the active material is dabigatran etcxilate or its a kind of pharmaceutically acceptable salt；And
    B) outer layer containing adhesive and medical acceptable organic acid or containing the organic acid, the organic acid is selected from tartaric acid, fumaric acid, butanedioic acid, citric acid, malic acid, glutamic acid or aspartic acid or its a kind of hydrate or hydrochlorate；And
    C) the water-soluble separation layer between outer layer and core material, the water-soluble insolated layer materials include the high-molecular organic materials such as pharmaceutically acceptable the third Jia of Qiang Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, starch, resinae or the composition of these organic materials.
    8th, pharmaceutical composition according to claim 4, it is characterised in that the organic acid is tartaric acid, fumaric acid, butanedioic acid or citric acid, more preferably tartaric acid；
    Preferably, the content of the dabigatran etcxilate or its salt is 20 60%；
    Preferably, the dabigatran etcxilate or its salt are dabigatran etcxilate mesylate；
    Preferably, the content of the organic acid is 20 ~ 60%；
    Preferably, the disintegrant is selected from：Material or its composition such as the plain sodium of Jiao connection Suo Jia Ji Xian Victoria, sodium carboxymethyl starch, Jiao Lian Ju Victoria ketone, low substitution Qiang propyl group Xian Victoria elements；
    Preferably, the filler is selected from：Material or its composition such as Xian Victoria elements class, carbohydrate, starch；Preferably, described adhesive is selected from：Qiang hydroxypropyl methyl Xian Victoria elements, Qiang propyl group Xian Victoria elements, Jia Ji Xian Victoria elements, Qiang Yi Ji Xian Victoria elements, Suo Jia Ji Xian Victoria elements, polyvinylpyrrolidone, N- vinylpyrrolidones, vinylacetate Copolymer or these copolymers composition；
    Preferably, the mean particle size of the core material is 0.4 ~ 1.5 mm；
    Preferably, the consumption of adhesive is 0.5 ~ 10% in the core material, and the consumption of adhesive is 0.5 ~ 10%, preferably 2 ~ 10% in the organic acid layers of balls；
    Preferably, the consumption of the active material outer layer separation layer is 2.0 ~ 10%, and the consumption of the organic acid outer layer separation layer is 2.0 ~ 10%.
    9th, the pharmaceutical composition according to any one of claim 4 or 5, its preparation method is as follows：
    (1) by extruding Gun Round method Huo Gun Round methods by active material, disintegrant, filler and adhesive is optionally added, the core material is formed；
    (2) separation layer that number contains high polymer material is applied, and dried；
    (3) apply number with lamination method and contain adhesive and the acceptable organic acid layer of medicine, and dry；
    (4) separation layer that number contains high polymer material is applied, and dried；
    (5) so obtained pill containing active material is packed into hard capsules.
    10th, a kind of oral pharmaceutical compositions, it is included：
    A) the capsule core material of the almost spherical containing adhesive and pharmaceutically acceptable organic acid or containing the organic acid, the organic acid is selected from tartaric acid, fumaric acid, butanedioic acid, citric acid, malic acid, glutamic acid or aspartic acid or a kind of above-mentioned organic acid hydrate or hydrochlorate；And
    B) micropill or particle or powder containing filler, disintegrant, adhesive and active material, the active material are dabigatran etcxilate or its a kind of pharmaceutically acceptable salt；And
    C) separation layer on organic acid particles surface, its material is selected from：The composition of the high-molecular organic material such as Qiang the third Jia Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, starch, resinae or these organic materials；And
    D) micropill containing active material or particle or the separation layer on powder surface, its material are selected from：The composition of the high-molecular organic material such as Qiang the third Jia Ji Xian Victoria elements, Qiang propyl group Xian Victoria elements, starch, resinae or these organic materials.
    11st, pharmaceutical composition according to claim 7, it is characterised in that the organic acid is tartaric acid, fumaric acid, butanedioic acid or citric acid, more preferably tartaric acid；
    Preferably, the content of the dabigatran etcxilate or its salt is 15 60%；
    Preferably, the dabigatran etcxilate or its salt are dabigatran etcxilate mesylate；
    Preferably, the content of the organic acid is 20 ~ 60%；
    Preferably, the disintegrant is selected from：Material or its composition such as the plain sodium of Jiao connection Suo Jia Ji Xian Victoria, sodium carboxymethyl starch, Jiao Lian Ju Victoria ketone, low substitution Qiang propyl group Xian Victoria elements； Preferably, the filler is selected from：Material or its composition such as Xian Victoria elements class, carbohydrate, starch；Preferably, described adhesive is selected from：Qiang hydroxypropyl methyl Xian Victoria elements, Qiang propyl group Xian Victoria elements, Jia Ji Xian Victoria elements, Qiang Yi Ji Xian Victoria elements, the composition of Suo Jia Ji Xian Victoria elements, polyvinylpyrrolidone, N- vinylpyrrolidones, the copolymer of vinylacetate or these copolymers；
    Preferably, the mean particle size of the core material is 0.4 ~ 1.5 mm；
    Preferably, consumption of the described adhesive in micropill containing active material or particle or powder is 0.5 ~ 10% more preferably 2 ~ 10%；Consumption of the described adhesive in containing sour capsule core material is 0.5 ~ 10%, more preferably 2-10%;
    Preferably, the consumption of the active material outer layer separation layer is 2.0 ~ 10%, and the consumption of the organic acid outer layer separation layer is 2.0 ~ 10%.
    12nd, the pharmaceutical composition according to any one of claim 7 or 8, its preparation method is as follows：
    (1) by extruding Gun Round method method Huo Gun Round methods by one or more pharmaceutically acceptable organic acids, adhesive is optionally added, the core material is formed, and dry；
    (2) separation layer that number contains high polymer material is applied in organic acid core material, and is dried；
    (3) by active material, disintegrant, filler and adhesive are optionally added, particle is formed, and dry；
    (4) separation layer that number contains high polymer material is applied on active material particle surface, and is dried；
    (5) will（2) and（4) two kinds of particles is mixed by a certain percentage, is packed into hard capsules.
CN201480008391.XA 2014-01-30 2014-03-26 Administered formulation of Dabigatran etexilate and salt thereof and preparation method thereof Pending CN104994856A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201480008391.XA CN104994856A (en) 2014-01-30 2014-03-26 Administered formulation of Dabigatran etexilate and salt thereof and preparation method thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201410046167 2014-01-30
CN2014100461671 2014-01-30
CN201480008391.XA CN104994856A (en) 2014-01-30 2014-03-26 Administered formulation of Dabigatran etexilate and salt thereof and preparation method thereof
PCT/CN2014/074112 WO2015113324A1 (en) 2014-01-30 2014-03-26 Administered formulation of dabigatran etexilate and salt thereof and preparation method thereof

Publications (1)

Publication Number Publication Date
CN104994856A true CN104994856A (en) 2015-10-21

Family

ID=53756206

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201480008391.XA Pending CN104994856A (en) 2014-01-30 2014-03-26 Administered formulation of Dabigatran etexilate and salt thereof and preparation method thereof

Country Status (2)

Country Link
CN (1) CN104994856A (en)
WO (1) WO2015113324A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106727414B (en) * 2016-12-27 2019-06-07 哈药集团技术中心 A kind of dabigatran etexilate methanesulfonate pellet and preparation method

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012001156A2 (en) * 2010-07-01 2012-01-05 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts
CN103127109A (en) * 2013-02-05 2013-06-05 南京华威医药科技开发有限公司 Pharmaceutical composition containing dabigatran etexilate or salt and hydrate thereof
WO2013124340A1 (en) * 2012-02-21 2013-08-29 Laboratorios Del Dr. Esteve, S.A. Oral pharmaceutical compositions of dabigatran etexilate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012001156A2 (en) * 2010-07-01 2012-01-05 Krka, Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts
WO2013124340A1 (en) * 2012-02-21 2013-08-29 Laboratorios Del Dr. Esteve, S.A. Oral pharmaceutical compositions of dabigatran etexilate
CN103127109A (en) * 2013-02-05 2013-06-05 南京华威医药科技开发有限公司 Pharmaceutical composition containing dabigatran etexilate or salt and hydrate thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
刘耀等: "挤出-滚圆法制备微丸的研究进展", 《中国药学杂志》 *

Also Published As

Publication number Publication date
WO2015113324A1 (en) 2015-08-06

Similar Documents

Publication Publication Date Title
AU2003210400B8 (en) Form of presentation for 3-[(2-{[4-hexyloxycarbonylamino-imino -methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino] propionic acid ethyl ester to be administered orally
US20180221359A1 (en) Administration of ethyl 3-[(2-{[4-(hexyloxycarbonyl-aminoiminomethyl)phenyl-amino]methyl}-1-methyl-1h-benzimidazol-5-carbonyl)pyridin-2-ylamino]propionate
CN103127109B (en) Pharmaceutical composition containing dabigatran etexilate or salt and hydrate thereof
BRPI0714915A2 (en) pharmaceutical compositions; pharmaceutical dosage forms; and process for the preparation of a pharmaceutical composition
EP1010423A2 (en) Oral pharmaceutical preparation comprising an antiulcer activity compound, and process for its production
KR101105042B1 (en) Enteric granules and preparation method thereof
CN101596165B (en) Pantoprazole sodium enteric-coated pellet
JPH09511767A (en) Novel oral pharmaceutical use form
CN1482903A (en) Nateglinide-containing preparation
CN104414978A (en) Enteric-coated micropellet containing esomeprazole magnesium
CN104224754A (en) Dabigatran etexilate medicine composition and preparation method thereof
CN105560206A (en) Preparation of Pradaxa capsule
CN102716090B (en) Sustained-release metformin hydrochloride pellets and preparation method thereof
Yang et al. A novel pH-dependent gradient-release delivery system for nitrendipine: I. Manufacturing, evaluation in vitro and bioavailability in healthy dogs
CN105764509B (en) Dabigatran etcxilate or the dispensing preparation of its salt and preparation method thereof
CN104994856A (en) Administered formulation of Dabigatran etexilate and salt thereof and preparation method thereof
CN105534935B (en) Pantoprazole microplate, preparation method, multiple unit type Pantoprazole enteric sustained-release preparation and preparation method thereof
CN101099762B (en) Zhenju Antihypertensive Sustained Release Preparation
CN105663095A (en) Preparation method of (R)-lansoprazole sustained-release capsule
JP6815109B2 (en) A pharmaceutical composition containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient.
CN106031715A (en) Doxycycline hydrochloride slow-release preparation and preparation method thereof
CN108096220A (en) A kind of sustained-release preparation of tamsulosin hydrochloride and preparation method thereof
KR20090118982A (en) Pharmaceutical preparations
CN104825422B (en) Pharmaceutical composition containing dabigatran etcxilate mesylate and preparation method thereof
CN104434882A (en) Pellet medicine composition containing pradaxa or salt and hydrate thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20151021

RJ01 Rejection of invention patent application after publication