CN115227663B - Dabigatran etexilate mesylate capsule and preparation method thereof - Google Patents
Dabigatran etexilate mesylate capsule and preparation method thereof Download PDFInfo
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- CN115227663B CN115227663B CN202110434794.2A CN202110434794A CN115227663B CN 115227663 B CN115227663 B CN 115227663B CN 202110434794 A CN202110434794 A CN 202110434794A CN 115227663 B CN115227663 B CN 115227663B
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- dabigatran etexilate
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- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 title claims abstract description 95
- 239000002775 capsule Substances 0.000 title claims abstract description 83
- 238000002360 preparation method Methods 0.000 title claims abstract description 79
- 229960004951 dabigatran etexilate mesylate Drugs 0.000 title claims abstract description 23
- 229960000288 dabigatran etexilate Drugs 0.000 claims abstract description 72
- 239000006187 pill Substances 0.000 claims abstract description 44
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 39
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 39
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 32
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 32
- 239000011975 tartaric acid Substances 0.000 claims abstract description 32
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 25
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 25
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 25
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 18
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000005507 spraying Methods 0.000 claims description 53
- 239000007788 liquid Substances 0.000 claims description 49
- 238000001035 drying Methods 0.000 claims description 48
- 239000000463 material Substances 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 22
- 238000005070 sampling Methods 0.000 claims description 19
- 238000000889 atomisation Methods 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 17
- 239000008188 pellet Substances 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 229960003943 hypromellose Drugs 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000008213 purified water Substances 0.000 claims description 7
- 125000006850 spacer group Chemical group 0.000 claims description 7
- 238000002955 isolation Methods 0.000 claims description 5
- 239000007902 hard capsule Substances 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 30
- 239000012535 impurity Substances 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 8
- 230000001133 acceleration Effects 0.000 abstract description 5
- 239000012738 dissolution medium Substances 0.000 abstract description 3
- 230000000052 comparative effect Effects 0.000 description 40
- 238000010828 elution Methods 0.000 description 17
- 238000001514 detection method Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 206010051055 Deep vein thrombosis Diseases 0.000 description 4
- 208000010378 Pulmonary Embolism Diseases 0.000 description 4
- 206010047249 Venous thrombosis Diseases 0.000 description 4
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 3
- 238000010835 comparative analysis Methods 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000003868 thrombin inhibitor Substances 0.000 description 3
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 206010016948 Food interaction Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 238000011882 arthroplasty Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940127216 oral anticoagulant drug Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The application aims to provide dabigatran etexilate mesylate capsule and a preparation method thereof, wherein the dabigatran etexilate mesylate capsule comprises 130-150 parts of tartaric acid pill cores, 5-6 parts of hydroxypropyl methylcellulose, 5-6 parts of talcum powder, 165-180 parts of dabigatran etexilate mesylate and 25-35 parts of hydroxypropyl cellulose. The dissolution rate of the dabigatran etexilate capsule is more than 90% in a dissolution medium of 0.01N hydrochloric acid solution for 45min, the dissolution rate is high, and the clinical curative effect is stable; stable quality, no obvious change of dissolution rate after being placed for 6 months under the acceleration condition, slow growth of impurities and less than 1% of total impurities.
Description
Technical Field
The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a dabigatran etexilate capsule and a preparation method thereof.
Background
Dabigatran etexilate mesylate is characterized by the chemical name beta-alanine, N- [ [2- [ [ [4- [ [ [ (hexyloxy) carbonyl ] amino ] iminomethyl ] phenyl ] amino ] methyl ] -1-methyl-1H-benzimidazol-5-yl ] carbonyl ] -N-2-pyrimidine-, ethyl ester, and methanesulfonate, and has the chemical structure shown in formula I, and is an oral direct thrombin inhibitor developed by Boringer's Ingham, and is mainly used for: (1) prevention of wind in non-valvular atrial fibrillation patients; (2) Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) prophylaxis in patients who have been treated with anticoagulants by 5-10 days of injection; (3) the treated patient reduces the risk of recurrence of DVT and PE; (4) prevention of DVT and PE following hip arthroplasty.
Dabigatran etexilate is a new generation of oral anticoagulant drug Direct Thrombin Inhibitors (DTIs), can provide effective, predictable and stable anticoagulation effect, has less drug interaction, has no drug-food interaction, does not need to monitor blood coagulation function or adjust dosage conventionally, and has very wide clinical application.
The solubility of dabigatran etexilate mesylate is pH dependent and almost insoluble in a medium with pH more than 4.0, so that the acidic environment is favorable for the dissolution and in vivo absorption of the main active ingredient dabigatran etexilate from the pharmaceutical preparation. However, the active ingredient has poor storage stability under acidic conditions and is susceptible to degradation.
Disclosure of Invention
The present application provides a dabigatran etexilate capsule and a preparation process thereof, which are unexpectedly discovered in the research, the prepared dabigatran etexilate capsule has stable quality, and the dissolution rate is obviously improved, and the clinical curative effect is stable.
In order to achieve the above purpose, the present application provides the following technical solutions:
firstly, the application provides a dabigatran etexilate capsule which comprises a content and a hard capsule shell, wherein the content comprises the following components in parts by weight:
the main component of the hard capsule shell is HPMC, and the moisture content is lower than 6.0%.
Further, the particle size of the tartaric acid pill core is 600-800 mu m.
Further, the talcum powder is 600 meshes of talcum powder.
Further, the hypromellose is 2% aqueous solution (20 ℃) and has a viscosity of 3-6 mPa.s; preferably hypromellose having a viscosity of 5 mPas in a 2% aqueous solution (20 ℃).
Further, the hydroxypropyl cellulose is a 5% aqueous solution (25 ℃) and has a viscosity of 75 to 150 mPa.s.
Further, the dabigatran etexilate capsule contains 100-150mg, preferably 110mg and 150mg of dabigatran etexilate.
Further, the application provides a dabigatran etexilate capsule which comprises the following components in parts by weight:
173 parts of dabigatran etexilate mesylate is equivalent to 150 parts of dabigatran etexilate.
Further, the application provides a preparation method of the dabigatran etexilate capsule.
The preparation method of the dabigatran etexilate capsule is characterized by using a fluidized bed granulator and comprising the following steps of:
(1) Preparation of an isolating layer containing tartaric acid pill cores:
the isolation layer is composed of:
the preparation method comprises the following steps:
(1) preparation of the spacer layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder by absolute ethyl alcohol and purified water;
(2) spraying liquid: setting the air inlet temperature of a fluidized bed granulator to 55.0+/-5.0 ℃; controlling the air inlet quantity to be 2000+/-500 m 3 /h; controlling the liquid spraying speed to be 140-220 g/min; the atomization pressure is 0.20-0.30 Mpa; spraying the isolating layer solution prepared in the step (1) onto tartaric acid pill cores at the material temperature of 41.0+/-3 ℃ to obtain the product containingPellets 1 of the isolation layer.
(3) And (3) drying: setting the air inlet temperature at 22-27 ℃, drying the pellets 1 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is less than or equal to 1.50% (105 ℃ for 10 min).
(2) Preparation of the active layer
Active layer composition:
(1) preparation of liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) spraying liquid: setting the air inlet temperature of a fluidized bed granulator to be 35.0+/-5.0 ℃; controlling the air inlet quantity to be 2000+/-500 m 3 /h; controlling the liquid spraying speed to be 140-220 g/min; the atomization pressure is 0.20-0.30 Mpa; spraying the liquid medicine prepared in the step (1) to an isolating layer containing tartaric acid pill cores at the material temperature of 29.0+/-3 ℃ to obtain pills 2 containing active ingredients;
(3) and (3) drying: setting air inlet temperature at 22-27 ℃, drying the pellets 2 prepared in the step (2), sampling and measuring Loss On Drying (LOD) until the LOD is less than or equal to 1.50% (105 ℃ for 10 min).
(3) And (5) subpackaging: subpackaging into capsule shells to obtain the dabigatran etexilate capsule.
In the preparation of the isolating layer containing the tartaric acid pill core in the step (1), a spraying step is carried out, and the air inlet temperature is 55 ℃.
The step (1) comprises a spraying step in the preparation of the isolating layer containing the tartaric acid pill core (2), and the spraying speed is 180g/min.
The step (1) comprises a spraying step in the preparation of the isolating layer containing the tartaric acid pill core (2), and the atomization pressure is 0.25Mpa.
In the preparation of the isolating layer containing the tartaric acid pill core in the step (1), the drying step is carried out, and the air inlet temperature is 25 ℃.
In the preparation of the active layer in the step (2), the spraying step is carried out, and the air inlet temperature is 35 ℃.
In the preparation of the active layer in the step (2), the liquid spraying step is carried out in the step (2), and the material temperature is 29 ℃.
And (3) a drying step in the preparation of the active layer in the step (2), wherein the air inlet temperature is 25 ℃.
LOD is the loss on drying, and the determination method is that the LOD is dried for 10 minutes at 105 ℃ and the weight of the sample is reduced.
The application has the beneficial technical effects that:
(1) The dissolution rate of the dabigatran etexilate capsule disclosed by the application in a 0.01N hydrochloric acid solution dissolution medium for 45min is more than 90%, the dissolution rate is high, and the clinical curative effect is stable.
(2) The dabigatran etexilate capsule disclosed by the application has stable quality, the dissolution rate is not obviously changed after being placed for 6 months under an acceleration condition, the impurities are slowly grown, and the total impurities are all lower than 1%.
Detailed Description
The application discloses a dabigatran etexilate capsule and a preparation method thereof, and a person skilled in the art can refer to the content of the application and combine the related principles of pharmaceutical preparations to properly improve the technological parameters. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the scope of the present application.
For a better understanding of the present application, and not to limit its scope, all numbers expressing quantities, percentages, and other values used in the present application are to be understood as being modified in all instances by the term "about". Each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; the reagents, materials, etc. used in the examples described below are commercially available unless otherwise specified.
Dissolution profile determination method:
(1) Dissolution medium: 0.01N hydrochloric acid solution.
(2) Dissolution device: the method comprises the steps of carrying out a first treatment on the surface of the Basket method; rotational speed: 100 revolutions per minute; volume of medium: 900ml; temperature: 37.0deg.C+ -0.5deg.C; sampling volume: 7ml;
(3) Sampling time: 10. 15, 20, 30 and 45min;
(4) Standard: a. taking 12 tablets of the sample and the reference preparation prepared in the example respectively, and measuring the dissolution curve of the sample and the reference preparation; b. taking the average dissolution value of each time point on the two curves, and calculating a similarity factor (f 2); c. no more than one sampling point is used for the drug dissolution amount exceeding 85%; d. the relative standard deviation of the elution amount at the first sampling time point (5 minutes) should not exceed 20%, and the relative standard deviation of the elution amount at the remaining sampling time points should not exceed 10%.
And (3) sources of auxiliary materials:
the structural formula of impurities in the dabigatran etexilate capsule is as follows:
impurity 1:
the molecular formula: c (C) 27 H 29 N 7 O 3
Impurity 2:
the molecular formula: c (C) 32 H 37 N 7 O 5
Impurity 3:
the molecular formula: c (C) 34 H 41 N 7 O 5
Impurity 4:
the molecular formula: c (C) 29 H 31 N 7 O 5
Impurity 5:
the molecular formula: c (C) 34 H 40 N 6 O
Example 1: dabigatran etexilate capsule
1. Prescription composition:
the dabigatran etexilate capsules are prepared by feeding according to the prescription amount of 10000 granules, and the following is the same.
2. The preparation method comprises the following steps:
(1) Preparation of an isolating layer containing tartaric acid pill cores:
(1) preparation of the spacer layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder by absolute ethyl alcohol and purified water;
(2) spraying liquid: setting the air inlet temperature of the fluidized bed granulator to 55 ℃; controlling the air inlet quantity to be 2000/h; controlling the liquid spraying speed to be 180g/min; the atomization pressure is 0.25Mpa; spraying the isolating layer solution prepared in the step (1) onto tartaric acid pill cores at the material temperature of 41 ℃ to obtain isolating layer-containing pills 1.
(3) And (3) drying: setting the air inlet temperature at 25 ℃, drying the pellets 1 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.2% (105 ℃ for 10 min).
(2) Preparation of active layer:
(1) preparation of liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) spraying liquid: setting the air inlet temperature of a fluidized bed granulator to be 35.0 ℃; controlling the air inlet quantity to be 2000/h; controlling the liquid spraying speed to be 180g/min; the atomization pressure is 0.25Mpa; spraying the liquid medicine prepared in the step (1) to an isolating layer containing tartaric acid pill cores at the material temperature of 29 ℃ to obtain pills 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature to 25 ℃, drying the pellets 2 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.2% (105 ℃ for 10 min).
(3) And (5) subpackaging: subpackaging into HPMC capsule shell with water content of 5.5% to obtain capsule containing 150mg dabigatran etexilate.
3. Detection result: the results of the dissolution profile test in 0.01N HCl are shown in Table 1.
Table 1: dissolution profile of dabigatran etexilate capsules prepared in example 1
| Time | Elution amount | RSD |
| /min | (％) | (％) |
| 10 | 13 | 12.5 |
| 15 | 56 | 8.3 |
| 20 | 77 | 6.5 |
| 30 | 97 | 1.0 |
| 45 | 98 | 0.2 |
Example 2: dabigatran etexilate capsule
1. Prescription composition:
2. the preparation method comprises the following steps:
(1) Preparation of an isolating layer containing tartaric acid pill cores:
(1) preparation of the spacer layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder by absolute ethyl alcohol and purified water;
(2) spraying liquid: setting the air inlet temperature of the fluidized bed granulator to be 50 ℃; controlling the air inlet quantity to 2500m3/h; controlling the liquid spraying speed to be 220g/min; the atomization pressure is 0.30Mpa; spraying the isolating layer solution prepared in the step (1) onto tartaric acid pill cores at the material temperature of 44 ℃ to obtain isolating layer-containing pills 1.
(3) And (3) drying: setting the air inlet temperature at 22 ℃, drying the pellets 1 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.5% (105 ℃ for 10 min).
(2) Preparation of active layer:
(1) preparation of liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) spraying liquid: setting the air inlet temperature to be 30 ℃; controlling the air inlet quantity to 2500m3/h; controlling the liquid spraying speed to be 220g/min; the atomization pressure is 0.30Mpa; spraying the liquid medicine prepared in the step (1) to an isolating layer containing tartaric acid pill cores at the material temperature of 32 ℃ to obtain pills 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature at 22 ℃, drying the pellets 2 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.5% (105 ℃ for 10 min).
(3) And (5) subpackaging: subpackaging into HPMC capsule shell with water content of 4.3% to obtain capsule containing 150mg dabigatran etexilate.
3. Detection result: the results of the dissolution profile test in 0.01N HCl are shown in Table 2.
Table 2: dissolution profile of dabigatran etexilate capsules prepared in example 2
| Time | Elution amount | RSD |
| /min | (％) | (％) |
| 10 | 16 | 13.4 |
| 15 | 54 | 7.2 |
| 20 | 73 | 6.6 |
| 30 | 92 | 4.2 |
| 45 | 98 | 1.8 |
Example 3: dabigatran etexilate capsule
1. Prescription composition:
2. the preparation method comprises the following steps:
(1) Preparation of an isolating layer containing tartaric acid pill cores:
(1) preparation of the spacer layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder by absolute ethyl alcohol and purified water;
(2) spraying liquid: setting the air inlet temperature of the fluidized bed granulator to 60 ℃; control the air inlet volume of 1500m 3 /h; controlling the spraying speed to 140g/min; the atomization pressure is 0.20Mpa; spraying the isolating layer solution prepared in the step (1) onto tartaric acid pill cores at the material temperature of 38 ℃ to obtain isolating layer-containing pills 1.
(3) And (3) drying: setting the air inlet temperature at 27 ℃, drying the pellets 1 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.0% (105 ℃ for 10 min).
(2) Preparation of active layer:
(1) preparation of liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) spraying liquid: setting the air inlet temperature to 40 ℃; control the air inlet volume of 1500m 3 /h; controlling the spraying speed to 140g/min; the atomization pressure is 0.20Mpa; the atomization pressure is 0.20-0.30 Mpa; spraying the liquid medicine prepared in the step (1) to an isolating layer containing tartaric acid pill cores at the material temperature of 26 ℃ to obtain pills 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature at 27 ℃, drying the pellets 2 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.0% (105 ℃ for 10 min).
(3) And (5) subpackaging: subpackaging into HPMC capsule shell with water content of 3.8% to obtain capsule containing 150mg dabigatran etexilate.
3. Detection result: the results of the elution profile in 0.01N HCl are shown in Table 3.
Table 3: dissolution profile of dabigatran etexilate capsules prepared in example 3
| Time | Elution amount | RSD |
| /min | (％) | (％) |
| 10 | 21 | 14.0 |
| 15 | 51 | 6.9 |
| 20 | 67 | 5.8 |
| 30 | 84 | 3.0 |
| 45 | 97 | 2.3 |
Example 4: dabigatran etexilate capsule
1. Prescription composition:
2. the preparation method comprises the following steps:
(1) Preparation of an isolating layer containing tartaric acid pill cores:
(1) preparation of the spacer layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder by absolute ethyl alcohol and purified water;
(2) spraying liquid: setting the air inlet temperature of a fluidized bed granulator to be 52 ℃; control the air inlet volume of 1800m 3 /h; controlling the spraying speed to 160g/min; the atomization pressure is 0.23Mpa; spraying the isolating layer solution prepared in the step (1) onto tartaric acid pill cores at the material temperature of 40 ℃ to obtain isolating layer-containing pills 1.
(3) And (3) drying: setting the air inlet temperature at 25 ℃, drying the pellets 1 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.4% (105 ℃ for 10 min).
(2) Preparation of the active layer
(1) Preparation of liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) spraying liquid: setting the air inlet temperature to 33.0 ℃; control the air inlet volume of 1800m 3 /h; controlling the spraying speed to 160g/min; the atomization pressure is 0.23Mpa; spraying the liquid medicine prepared in the step (1) to an isolating layer containing tartaric acid pill cores at the material temperature of 27 ℃ to obtain pills 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature to 25 ℃, drying the pellets 2 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.3% (105 ℃ for 10 min).
(3) Subpackaging into HPMC capsule shell with water content of 5.6% to obtain capsule containing 110mg dabigatran etexilate.
3. Detection result: the results of the elution profile in 0.01N HCl are shown in Table 4.
Table 4: dissolution profile of dabigatran etexilate capsules prepared in example 4
| Time | Elution amount | RSD |
| /min | (％) | (％) |
| 10 | 22 | 13.1 |
| 15 | 60 | 8.3 |
| 20 | 79 | 7.1 |
| 30 | 92 | 4.5 |
| 45 | 96 | 3.7 |
Example 5: dabigatran etexilate capsule
1. Prescription composition:
2. the preparation method comprises the following steps:
(1) Preparation of an isolating layer containing tartaric acid pill cores:
(1) preparation of the spacer layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder by absolute ethyl alcohol and purified water;
(2) spraying liquid: setting the air inlet temperature of a fluidized bed granulator to 58 ℃; controlling the air inlet quantity to 2300/h; controlling the liquid spraying speed to be 210g/min; the atomization pressure is 0.27Mpa; spraying the isolating layer solution prepared in the step (1) onto tartaric acid pill cores at the material temperature of 42 ℃ to obtain isolating layer-containing pills 1.
(3) And (3) drying: setting the air inlet temperature at 25 ℃, drying the pellets 1 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.3% (105 ℃ for 10 min).
(2) Preparation of active layer:
(1) preparation of liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) spraying liquid: setting the air inlet temperature to 37.0 ℃; controlling the air inlet quantity to 2300/h; controlling the liquid spraying speed to be 210g/min; the atomization pressure is 0.27Mpa; spraying the liquid medicine prepared in the step (1) to an isolating layer containing tartaric acid pill cores at the material temperature of 31 ℃ to obtain pills 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature to 25 ℃, drying the pellets 2 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.3% (105 ℃ for 10 min).
(3) And (5) subpackaging: subpackaging into HPMC capsule shell with water content of 5.5% to obtain capsule containing 150mg dabigatran etexilate.
3. Detection result: the results of the elution profile in 0.01N HCl are shown in Table 5.
Table 5: dissolution profile of dabigatran etexilate capsules prepared in example 5
| Time | Elution amount | RSD |
| /min | (％) | (％) |
| 10 | 17 | 14.2 |
| 15 | 57 | 9.0 |
| 20 | 81 | 6.8 |
| 30 | 95 | 4.2 |
| 45 | 98 | 2.8 |
Comparative example 1: effect of hydroxypropyl cellulose on dissolution
1. Prescription composition:
the amount or viscosity of the hydroxypropylcellulose was varied as shown in the following Table, and the same as in example 1
| Comparative example | Hydroxypropyl cellulose | Dosage of hydroxypropyl cellulose |
| Comparative examples 1 to 1 | Hydroxypropyl cellulose 3 | 30 |
| Comparative examples 1 to 2 | Hydroxypropyl cellulose 4 | 30 |
| Comparative examples 1 to 3 | Hydroxypropyl cellulose 3 | 20 |
| Comparative examples 1 to 4 | Hydroxypropyl cellulose 1 | 50 |
| Comparative examples 1 to 5 | Hydroxypropyl cellulose 1 | 20 |
2. The preparation method comprises the following steps: as in example 1.
3. Detection result: the results of the elution profile in 0.01N HCl are shown in Table 6.
Table 6: dissolution profile of dabigatran etexilate capsules prepared in comparative example 1
The amount or viscosity of hydroxypropyl cellulose affects the stability and dissolution behavior of dabigatran etexilate capsules:
(1) The dissolution behavior of dabigatran etexilate is affected by hydroxypropyl cellulose with different viscosities, when the viscosity of hydroxypropyl methylcellulose is high (such as comparative examples 1-1 and 1-2), namely the viscosity of a 5% aqueous solution (25 ℃) exceeds 150 mPa.s, the dissolution of the prepared dabigatran etexilate capsule in 0.01N hydrochloric acid is slow, the dissolution rate after 45min is lower than 80%, and the dissolution rate is low. The dissolution rate of the capsules in the same batch is large, the relative standard deviation of dissolution exceeds 20% in 10min, the relative standard deviation of dissolution exceeds 10% in 15min, and the dissolution is unstable.
(2) The dosage of the hydroxypropyl cellulose influences the dissolution behavior of the dabigatran etexilate, when the dosage of the hydroxypropyl cellulose is large (such as comparative examples 1-4), namely more than 30 parts by weight, the prepared dabigatran etexilate capsule is slowly dissolved in 0.01N hydrochloric acid, the dissolution rate is lower than 90% after 45min, and the dissolution is slow; when the dosage of hydroxypropyl methylcellulose is small (as in comparative examples 1-5), the prepared dabigatran etexilate capsule dissolves out quickly in 0.01N hydrochloric acid, the dissolution rate is 99% after 45min, but the stability is poor (see table 11 of example 6), and after 6 months of acceleration, the impurity 5 is higher than 1.0%; the total impurity is higher than 2%. Thus, the viscosity of a 5% aqueous solution (25 ℃) of hydroxypropyl cellulose is 75-150 mPa.s; 25-35 parts by weight.
Comparative example 2: effect of hypromellose on dissolution
1. Prescription composition:
the amount or viscosity of hypromellose was varied and the same as in example 1 is given in the following table.
| Comparative example | Hydroxypropyl methylcellulose | Dosage of hypromellose |
| Comparative example 2-1 | Hydroxypropyl methylcellulose 3 | 5.5 |
| Comparative examples 2 to 2 | Hydroxypropyl methylcellulose 4 | 5.5 |
| Comparative examples 2 to 3 | Hydroxypropyl methylcellulose | 3 |
| Comparative examples 2 to 4 | Hydroxypropyl methylcellulose | 8 |
2. The preparation method comprises the following steps: as in example 1.
3. Detection result: the results of the elution profile in 0.01N HCl are shown in Table 7.
Table 7: dissolution profile of dabigatran etexilate capsules prepared in comparative example 2
The dosage or viscosity of hypromellose affects the stability and dissolution behavior of dabigatran etexilate capsules:
(1) The dissolution behavior of dabigatran etexilate is affected by the hydroxypropyl methylcellulose with different viscosities, when the viscosity of the hydroxypropyl methylcellulose is high (such as comparative example 2-1 and comparative example 2-2), namely the viscosity of a 2% aqueous solution (20 ℃) exceeds 6 mPa.s, the prepared dabigatran etexilate capsule is slowly dissolved in 0.01N hydrochloric acid, the dissolution rate is lower than 80% after 45min, and the dissolution is slow. The dissolution rate of the capsules in the same batch is large, the relative standard deviation of dissolution exceeds 20% in 10min, the relative standard deviation of dissolution exceeds 10% in 15min, and the dissolution is unstable.
(2) The amount of the hypromellose affects the dissolution behavior of the dabigatran etexilate, and when the amount of the hypromellose is large (such as comparative examples 2-4), namely more than 6 parts by weight, the prepared dabigatran etexilate capsule is slowly dissolved in 0.01N hydrochloric acid, the dissolution rate is lower than 90% after 45min, and the dissolution is slow. And the dissolution rate of the capsules in the same batch is large, the relative standard deviation of dissolution exceeds 20% in 10min, and the dissolution is unstable.
(3) The amount of hypromellose used affects the dissolution behavior of dabigatran etexilate, when the amount of hypromellose used is small (as in comparative examples 2 to 3), i.e., less than 5 parts by weight; the prepared dabigatran etexilate capsule is fast in dissolution in 0.01N hydrochloric acid, the dissolution rate is 99% after 45min, but the stability is poor (see table 11 of example 6), and the impurity 5 is higher than 1.0% after accelerating for 6 months; the total impurity is higher than 2%.
Thus, the viscosity of a 2% aqueous solution (20 ℃) of hypromellose is 3 to 6 mPa.s; preferably a 2% aqueous solution (20 ℃) with a viscosity of 5 mPas; the weight part is preferably 5 to 6 parts.
Comparative example 3: influence of material temperature during active layer preparation
1. Prescription composition: as in example 1.
2. The preparation method comprises the following steps:
in the preparation of the active layer in step (2), the material temperature in the spraying liquid in step (2) is shown in the following table, and other preparation methods are the same as in example 1.
| Comparative example | Step (2) livingMaterial temperature in "(2) spray liquid" in preparation of sexual layer |
| Comparative example 3-1 | The temperature of the materials is 37 DEG C |
| Comparative example 3-2 | The temperature of the materials is 40 DEG C |
3. Detection result: the results of the elution profile in 0.01N HCl are shown in Table 8.
Table 8: dissolution profile of dabigatran etexilate capsules prepared in comparative example 3
Comparative analysis examples 1 to 5 and comparative example 3 show that: the material temperature in the preparation process of the active layer influences the stability of the product, and the dissolution rate of the product is not influenced. When the material temperature in the preparation process of the active layer is higher than 32 ℃, such as 37 ℃ in comparative example 3-1 and 40 ℃ in comparative example 3-2, the relevant substances of the prepared dabigatran etexilate capsules grow faster, and after accelerating for 6 months, the impurity 5 is higher than 1.0%; the total impurities are higher than 2 percent. The temperature of the material during the preparation should therefore not be higher than 32℃and preferably 29.0.+ -. 3 ℃.
Comparative example 4: influence of LOD control during preparation
1. Prescription composition: as in example 1.
2. The preparation method comprises the following steps:
LOD values in "(3) drying" during preparation are shown in the following table, and other preparation methods are the same as in example 1.
3. Detection result: the results of the elution profile in 0.01N HCl are shown in Table 9.
Table 9: dissolution profile of dabigatran etexilate capsules prepared in comparative example 4
Comparative analysis examples 1 to 5 and comparative example 4 show that: the control of the drying weight loss in the preparation process influences the stability of the product, and does not influence the dissolution rate of the product. LOD values in the isolation layer containing the tartaric acid pill core in the step (1) and LOD values in the preparation of the active layer in the step (2) both affect the stability of the dabigatran etexilate capsule (table 11 of specific example 6), when the LOD value is higher than 1.5%, the prepared dabigatran etexilate capsule related substances grow faster, and after accelerating for 6 months, the impurity 5 is higher than 1.0%; the total impurities are higher than 2 percent. Thus LOD values should be less than 1.5% during the preparation.
Comparative example 5: preparation of dabigatran etexilate mesylate capsules according to Chinese patent CN03805473.6
1. Prescription composition: as in example 2 of chinese patent CN 03805473.6.
2. The preparation method comprises the following steps: as in example 2 of chinese patent CN 03805473.6.
3. Detection result: the results of the elution profile in 0.01N HCl are shown in Table 10.
Table 10: dissolution profile of dabigatran etexilate capsules prepared in comparative example 5
| Time | Elution amount | RSD |
| /min | (％) | (％) |
| 10 | 16 | 25.8 |
| 15 | 58 | 14.7 |
| 20 | 83 | 7.1 |
| 30 | 94 | 5.2 |
| 45 | 97 | 1.8 |
Comparative analysis examples 1 to 5 and comparative example 5 are shown as follows: dabigatran etexilate mesylate capsules were prepared according to example 2 in chinese patent CN03805473.6, and the dissolution rate was 97% after 45min in 0.01N hydrochloric acid, which is fast. However, the dissolution rate of the capsules in the same batch is large, the relative standard deviation of dissolution exceeds 20% in 10min, and the relative standard deviation of dissolution exceeds 10% in 15min, so that the dissolution is unstable. The related substances of the dabigatran etexilate capsule prepared by the method grow faster, and the total impurities are higher than 1.0% after accelerating for 6 months.
Example 6: stability test
Dabigatran etexilate capsules prepared in examples 1-5, comparative examples 1-6, comparative examples 2-3, comparative examples 3-1-3-2 and comparative examples 4-1-4-3 were prepared at a temperature of 40 ℃ ± 2 ℃; the sample was left for 6 months under conditions of a relative humidity of 75% + -5% (acceleration), and samples were taken at the end of the 0 th and 6 th months, and the substances, elution rates, and the like were measured, and the results are shown in Table 11.
Table 11: stability test results table
As can be seen from Table 11, the dissolution rate of the dabigatran etexilate capsule prepared by the application is not obviously changed after the dabigatran etexilate capsule is placed for 6 months under the acceleration condition, the impurity growth is slow, and the impurity 1-5 is lower than 0.15%; the total impurities are all lower than 1%. Therefore, the dabigatran etexilate capsule disclosed by the application has good dissolution effect and stable quality.
Claims (11)
1. The dabigatran etexilate mesylate capsule comprises a content and a hard capsule shell, wherein the content comprises the following components in parts by weight:
the main component of the hard capsule shell is HPMC, and the moisture content is lower than 6.0%; the particle size of the tartaric acid pill core is 600-800 mu m; the talcum powder is 600 meshes of talcum powder; the hydroxypropyl methylcellulose is 2% hydroxypropyl methylcellulose with the aqueous solution viscosity of 3-6mPa.s; the hydroxypropyl cellulose is 5% hydroxypropyl cellulose with the aqueous solution viscosity of 75-150 mPa.s;
the preparation method comprises the following steps of:
(1) Preparation of an isolating layer containing tartaric acid pill cores:
the isolation layer is composed of:
(1) preparation of the spacer layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder by absolute ethyl alcohol and purified water;
(2) spraying liquid: set fluidized bed granulatorThe air inlet temperature of the air inlet pipe is 55.0+/-5.0 ℃; controlling the air inlet quantity to be 2000+/-500 m 3 /h; controlling the liquid spraying speed to be 140-220 g/min; the atomization pressure is 0.20-0.30 Mpa; spraying the isolating layer solution prepared in the step (1) onto tartaric acid pill cores at the material temperature of 41.0+/-3 ℃ to obtain isolating layer-containing pills 1;
(3) and (3) drying: setting the air inlet temperature at 22-27 ℃, drying the pellets 1 prepared in the step (2), sampling, and measuring the drying loss at 105 ℃ for 10min until the LOD is less than or equal to 1.50%;
(2) Preparation of the active layer
The composition is as follows:
(1) preparation of liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) spraying liquid: setting the air inlet temperature of a fluidized bed granulator to be 35.0+/-5.0 ℃; controlling the air inlet quantity to be 2000+/-500 m 3 /h; controlling the liquid spraying speed to be 140-220 g/min; the atomization pressure is 0.20-0.30 Mpa; spraying the liquid medicine prepared in the step (1) to an isolating layer containing tartaric acid pill cores at the material temperature of 29.0+/-3 ℃ to obtain pills 2 containing active ingredients;
(3) and (3) drying: setting air inlet temperature at 22-27 ℃, drying the pellets 2 prepared in the step (2), sampling, and measuring drying loss at 105 ℃ for 10min until LOD is less than or equal to 1.50%;
(3) And (5) subpackaging: subpackaging into capsule shells to obtain the dabigatran etexilate capsule.
2. The dabigatran etexilate mesylate capsule according to claim 1, wherein the hypromellose is a hypromellose with a viscosity of 5 mPa-s in 2% aqueous solution.
3. Dabigatran etexilate mesylate capsule according to claim 1 or 2, characterized in that the content comprises the following components in parts by weight:
4. the dabigatran etexilate mesylate capsule according to claim 1 or 2, wherein the dabigatran etexilate capsule comprises 100-150mg dabigatran etexilate.
5. The dabigatran etexilate mesylate capsule of claim 4, wherein the dabigatran etexilate capsule comprises 110mg dabigatran etexilate.
6. The dabigatran etexilate mesylate capsule of claim 4, wherein the dabigatran etexilate capsule comprises 150mg dabigatran etexilate.
7. The dabigatran etexilate capsule according to claim 1, wherein the air inlet temperature is 55 ℃ in the preparation of the isolating layer containing the tartaric acid pill core (2) the spraying step.
8. The dabigatran etexilate capsule according to claim 1, wherein the preparation method comprises the step (1) of preparing the isolating layer containing the tartaric acid pill core, wherein the spraying speed is 180g/min.
9. The dabigatran etexilate capsule according to claim 1, wherein the atomization pressure is 0.25Mpa in the preparation of the isolation layer containing the tartaric acid pellet core in the preparation method (1) (2) the spraying step.
10. The dabigatran etexilate capsule according to claim 1, wherein the material temperature is 29 ℃ in the preparation method, the liquid spraying step (2) in the preparation of the active layer in the step (2).
11. The dabigatran etexilate capsule according to claim 1, wherein the air inlet temperature is 25 ℃ in the preparation method, wherein the drying step (3) in the preparation of the active layer in the step (2).
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| CN1638771A (en) * | 2002-03-07 | 2005-07-13 | 贝林格尔英格海姆法玛两合公司 | 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 oral |
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