CN111840245B - Dabigatran etexilate pharmaceutical composition and preparation method thereof - Google Patents
Dabigatran etexilate pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN111840245B CN111840245B CN201910351043.7A CN201910351043A CN111840245B CN 111840245 B CN111840245 B CN 111840245B CN 201910351043 A CN201910351043 A CN 201910351043A CN 111840245 B CN111840245 B CN 111840245B
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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 26
- 229960000288 dabigatran etexilate Drugs 0.000 title claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title description 10
- 239000010410 layer Substances 0.000 claims abstract description 75
- 239000011248 coating agent Substances 0.000 claims abstract description 63
- 238000000576 coating method Methods 0.000 claims abstract description 63
- 239000008188 pellet Substances 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 31
- 150000007524 organic acids Chemical class 0.000 claims abstract description 27
- 239000000853 adhesive Substances 0.000 claims abstract description 17
- 230000001070 adhesive effect Effects 0.000 claims abstract description 17
- 239000011241 protective layer Substances 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 238000002955 isolation Methods 0.000 claims abstract description 13
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 230000000181 anti-adherent effect Effects 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims description 40
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 34
- 239000006187 pill Substances 0.000 claims description 32
- 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 description 26
- 239000011975 tartaric acid Substances 0.000 claims description 26
- 235000002906 tartaric acid Nutrition 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000008187 granular material Substances 0.000 claims description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 15
- 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 description 11
- 238000000889 atomisation Methods 0.000 claims description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 10
- 229960003943 hypromellose Drugs 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 9
- 239000008213 purified water Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 241000220479 Acacia Species 0.000 claims description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 claims description 3
- 239000008119 colloidal silica Substances 0.000 claims description 3
- 229960004951 dabigatran etexilate mesylate Drugs 0.000 claims description 3
- 229950005770 hyprolose Drugs 0.000 claims 1
- 238000001727 in vivo Methods 0.000 abstract description 7
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 150000003839 salts Chemical class 0.000 abstract description 6
- 239000011162 core material Substances 0.000 description 29
- 238000004090 dissolution Methods 0.000 description 23
- 238000003756 stirring Methods 0.000 description 14
- 238000007873 sieving Methods 0.000 description 12
- 238000005507 spraying Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 229960003850 dabigatran Drugs 0.000 description 4
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention specifically relates to a dabigatran etexilate pharmaceutical composition, which comprises the following components: 1) An organic acid layer prepared by coating the organic acid, the adhesive and the anti-adhesive on the pellet core; 2) An isolating layer is arranged outside the organic acid layer; 3) The isolation layer is provided with a medicine feeding layer which is prepared by mixing active ingredient dabigatran etexilate or pharmaceutically acceptable salt or hydrate, an anti-sticking agent and an adhesive; 4) And a protective layer is arranged outside the upper medicine layer. The dabigatran etexilate composition prepared by the invention can be dissolved stably in the in-vivo absorption process, thereby achieving good bioavailability.
Description
Technical Field
The invention relates to the field of medicines, in particular to a dabigatran etexilate pharmaceutical composition and a preparation method thereof.
Background
The chemical name of the dabigatran etexilate active substance is 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester, and salts and hydrates thereof. The structure of dabigatran etexilate is shown in the following figure I. It is a novel synthetic non-peptide thrombin inhibitor, a prodrug of dabigatran (dabigatran), mainly used for the prevention of post-operative venous thrombosis. Dabigatran etexilate is converted in vivo to dabigatran with direct anticoagulant activity after oral administration and gastrointestinal absorption. dabigatran binds to the fibrin-specific binding site of thrombin, preventing cleavage of fibrinogen to fibrin, thus blocking the final step of the coagulation cascade and thrombosis.
Since dabigatran etexilate only has trace dissolution in a medium with a pH of more than 4, the acidic environment is favorable for dissolution and in vivo absorption of the main active ingredient dabigatran etexilate from the pharmaceutical preparation.
The application number is 201310047056.8, the patent name is a pharmaceutical composition containing dabigatran etexilate or a salt and hydrate thereof, and discloses an active substance pellet core material, an isolation layer, an organic acid layer and an isolation layer or an outer coating layer which is arranged outside the organic acid layer.
Disclosure of Invention
The invention aims at solving the problems in the prior art and provides a dabigatran etexilate pharmaceutical composition which can be stably dissolved in the in-vivo absorption process, so that good bioavailability is achieved.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a dabigatran etexilate pharmaceutical composition comprising: 1) An organic acid layer prepared by coating the organic acid, the adhesive and the anti-adhesive on the pellet core; 2) An isolating layer is arranged outside the organic acid layer; 3) The isolation layer is provided with a medicine feeding layer which is prepared by mixing active ingredient dabigatran etexilate or pharmaceutically acceptable salt or hydrate, an anti-sticking agent and an adhesive; 4) And a protective layer is arranged outside the upper medicine layer.
In the composition, the organic acid is selected from pharmaceutically acceptable acid and hydrate or acid salt thereof, and is one or more of tartaric acid, fumaric acid, malic acid, citric acid, succinic acid and amino acid; preferably tartaric acid; further, the amino acid is selected from acidic amino acids; the acidic amino acids include aspartic acid and glutamic acid.
In the composition of the invention, the pill core is tartaric acid pill core. The use of a combination of tartaric acid cores and tartaric acid is advantageous in promoting dissolution of the active ingredient dabigatran etexilate or a pharmaceutically-acceptable salt or hydrate thereof. The tartaric acid pill core is adopted as the special pill core, so that the pH value is kept at a proper value, and the dissolution of the active ingredients is promoted.
The pellet cores of the invention can also adopt blank pellet cores, and the amount of the organic acid is correspondingly required to be adjusted and increased. Specifically, the invention is selected from tartaric acid, and the pill core is blank pill core without tartaric acid, so that the amount of tartaric acid is correspondingly screened again.
The tartaric acid pill core selected by the invention is an outsourcing product, the ingredients are tartaric acid and HPMC, and the tartaric acid pill core is prepared by small pills with the size of 0.60-0.71 mm through extrusion and rounding equipment.
The mass sum of the organic acid in the organic acid layer accounts for 34-38% of the total prescription mass; preferably 36%. The organic acid herein includes tartaric acid contained in the pellet core.
The adhesive used in the invention is one or more of HPMC, HPC, PVP and EC; HPMC or HPC is preferred.
The anti-adhesion agent used in the invention is one or more of aerosil, talcum powder and magnesium stearate; preferably, the silica gel micropowder.
The isolating layer or the protecting layer is prepared by mixing pharmaceutically acceptable adhesive and anti-adhesion agent; further, the pharmaceutically acceptable binder comprises HPMC, HPC, PVP and/or EC; the pharmaceutically acceptable anti-sticking agent comprises aerosil, talcum powder and/or magnesium stearate.
The compositions of the present invention may be prepared to include capsule formulations.
The invention also provides a preparation method of the dabigatran etexilate pharmaceutical composition, which comprises the following steps:
1) Coating an acid layer coating liquid containing organic acid, an adhesive and an anti-adhesion agent on the pill core through a fluidized bed to prepare the organic acid layer pill core;
2) Coating an isolating layer coating liquid containing an adhesive and an anti-adhesion agent on the organic acid layer pill core through a fluidized bed to prepare the isolating layer pill core;
3) Coating the pill core of the upper medicine layer with coating liquid of the upper medicine layer containing adhesive and active ingredients by a fluidized bed to prepare the pill core of the upper medicine layer;
4) Coating protective layer coating liquid containing adhesive and anti-adhesion agent on the pill core of the upper medicine layer by a fluidized bed to obtain the pill core of the micropill.
Finally, the pellet cores prepared into the granules are transferred into capsules to prepare capsule preparations, and the capsules are prepared from conventional capsule materials such as gelatin and the like.
In order to ensure the stability of the medicine and increase the effective period, a protective layer can be coated on the surface of the medicine, and the coating layer comprises pharmaceutically acceptable polymers, adhesives and anti-adhesion agents.
Specifically, the organic acid layer, the isolation layer, the medicine applying layer and the protection layer are prepared by a fluidized bed process respectively:
organic acid layer: dissolving acacia in purified water, adding L-tartaric acid after complete dissolution, adding colloidal silica after complete dissolution, stirring uniformly to obtain coating liquid of tartaric acid layer, and coating the coating liquid on tartaric acid pill core. Putting tartaric acid pill core into bottom spray coating pan, drying after coating, sieving, and sieving to remove coarse and fine small pills.
Coating parameters: the air inlet temperature is set to be 40-70 ℃, the atomization pressure is set to be 1.5-2.8 bar, and the rotating speed of a liquid supply pump is set to be 20-150 rpm.
Isolation layer: and dispersing the hypromellose into purified water, adding ethanol after the hypromellose is completely dissolved, stirring uniformly, adding talcum powder, and stirring uniformly to obtain coating liquid of the isolation layer. The coating liquid is coated on the pellets coated with tartaric acid liquid. And (3) putting the pellets coated with the tartaric acid layer into a bottom spray coating pot, drying after coating, sieving, and sieving out the coarser and finer pellets.
Coating parameters: the air inlet temperature is set to be 35-50 ℃, the atomization pressure is set to be 1.6-2.8 bar, and the rotating speed of a liquid supply pump is set to be 20-200 rpm.
And (3) a medicine feeding layer: and (3) dispersing the hydroxypropyl cellulose into isopropanol through a 20-mesh sieve, stirring until the hydroxypropyl cellulose is completely dissolved, adding talcum powder and dabigatran etexilate mesylate raw materials (micro powder) to completely disperse the hydroxypropyl cellulose, stirring uniformly, shearing the coating liquid at a high speed for 10min, and circulating every 30min to obtain the coating liquid of the medicine feeding layer. The coating liquid is coated on the pellets coated with the isolating layer. And (3) putting the pellets coated by the isolation layer into a bottom spray coating pot, drying after coating, sieving, and removing the coarser and finer pellets.
Coating parameters: setting the air inlet temperature to be 35-55 ℃ and the atomization pressure to be 1.8-2.8 bar, and maintaining the air outlet quantity to be 1400m 3 And the rotating speed of the liquid supply pump is 20-400 rpm above/h.
And (3) a protective layer: and dispersing the hypromellose into purified water, adding ethanol after the hypromellose is completely dissolved, stirring uniformly, adding talcum powder, and stirring uniformly to obtain coating liquid of the protective layer. The coating liquid is coated on the pellets with the medicine coating. And (3) putting the pellets coated by the upper medicine layer into a bottom spraying coating pot, drying after coating, sieving, and sieving out the coarser and finer pellets.
Coating parameters: the air inlet temperature is set to be 35-50 ℃, the atomization pressure is set to be 1.8-2.8 bar, and the rotating speed of a liquid supply pump is set to be 20-300 rpm.
The invention has the beneficial effects that:
1. the dabigatran etexilate composition prepared by the invention can be dissolved out stably in the in-vivo absorption process, so that good bioavailability is achieved.
2. According to the invention, the preparation process and the formula process of the composition are optimized, the pellet core of the product is high in roundness, the average value of self-made samples is 0.94, which is 0.80 higher than that of original ground medicaments (reference preparations), the product prepared by the invention is more beneficial to uniform dissolution of active ingredients, the RSD (reactive toxicity) of the in vitro dissolution is smaller than that of the reference preparations, the self-made samples are stable, the in vivo variation is reduced compared with that of the reference, and the number of the in vivo BE test can BE reduced.
Drawings
FIG. 1 is a dissolution profile of a reference formulation;
FIG. 2 is a dissolution profile of a formulation of the present invention;
FIG. 3 is a graph of dissolution profile with a barrier layer;
FIG. 4 is a microscopic view of a reference formulation;
FIG. 5 is an electron microscope image of a homemade product;
fig. 6 is a schematic diagram of a self-made product.
In fig. 6, 1 is a pellet core; 2 is an organic acid layer; 3 is an isolation layer; 4 is a medicine feeding layer; and 5 is a protective layer.
Detailed Description
The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are only some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
According to the pH solubility curve of the bulk drug, the solubility is obviously increased when the pH is less than 3.0, so that an acidic microenvironment is needed to be provided for the bulk drug to achieve the solubilization effect, tartaric acid is selected to achieve the aim, and the dosage of the tartaric acid needs to be screened. Samples were prepared according to the different amounts of tartaric acid cores and L-tartaric acid in the following formulation, and the amounts of tartaric acid cores and L-tartaric acid were finally obtained by comparing dissolution curves in a citrate buffer at pH3.0 and an acetate buffer at pH4.5, and the dissolution results are shown in Table 1.
* Solvent removed during the process
The preparation process comprises the following steps:
organic acid layer: dissolving 0.65kg of acacia in 8.80kg of purified water, adding 2.89kg of L-tartaric acid after complete dissolution, adding 0.49kg of colloidal silica after complete dissolution, stirring uniformly to obtain coating liquid of a tartaric acid layer, and coating the coating liquid on a tartaric acid pill core. 8.84kg of tartaric acid pill cores are put into a bottom spray coating pot, and after coating, the pill cores are dried and sieved to remove the coarse and fine pills.
Coating parameters: setting air inlet temperature at 45-70 deg.c, atomizing pressure at 1.5-2.8 bar and rotation speed of liquid feeding pump at 20-150 rpm.
Isolation layer: dispersing 0.33kg of hypromellose into 3.50kg of purified water, adding 26.40kg of ethanol after the hypromellose is completely dissolved, stirring uniformly, adding 2.06kg of talcum powder, and stirring uniformly to obtain coating liquid of the isolation layer. The coating liquid is coated on the pellets coated with tartaric acid liquid. And (3) putting the pellets coated with the tartaric acid layer into a bottom spray coating pot, drying after coating, sieving, and sieving out the coarser and finer pellets.
Coating parameters: the air inlet temperature is set to be 35-50 ℃, the atomization pressure is set to be 1.6-2.8 bar, and the rotating speed of a liquid supply pump is set to be 20-200 rpm.
And (3) a medicine feeding layer: 2.61kg of hydroxypropyl cellulose is sieved by a 20-mesh sieve to be dispersed in 151.10kg of isopropanol, after stirring overnight, 0.47kg of talcum powder and 13.06kg of dabigatran etexilate mesylate raw material (micro powder) are added to be completely dispersed, stirring is uniform, the coating liquid is sheared for 10min at a high speed, and circulation is carried out every 30min to obtain the coating liquid of the upper drug layer. The coating liquid is coated on the pellets coated with the isolating layer. And (3) putting the pellets coated by the isolation layer into a bottom spray coating pot, drying after coating, sieving, and removing the coarser and finer pellets.
Coating parameters: setting the air inlet temperature to be 35-55 ℃ and the atomization pressure to be 1.8-2.8 bar, and maintaining the air outlet quantity to be 1400m 3 And the rotating speed of the liquid supply pump is 20-400 rpm above/h.
And (3) a protective layer: dispersing 0.23kg of hypromellose into 1.73kg of purified water, adding 13.08kg of ethanol after the hypromellose is completely dissolved, stirring uniformly, adding 0.38kg of talcum powder, and stirring uniformly to obtain coating liquid of the protective layer. The coating liquid is coated on the pellets with the medicine coating. And (3) putting the pellets coated by the upper medicine layer into a bottom spraying coating pot, drying after coating, sieving, and sieving out the coarser and finer pellets.
Coating parameters: the air inlet temperature is set to be 35-50 ℃, the atomization pressure is set to be 1.8-2.8 bar, and the rotating speed of a liquid supply pump is set to be 20-300 rpm.
The applicant examined the dissolution of the product prepared according to the invention at each pH, the results being shown in Table 1.
TABLE 1 dissolution at different pH values
The applicant further investigated the stability of the pharmaceutical composition of the present application by experiments, which were carried out as follows:
the sample prepared by the prescription and the reference preparation capsule are exposed to light at 40+/-5 ℃ and 60+/-5 ℃ for carrying out influence factor tests, and the dissolution curve and related substances in pH2.0 are detected, wherein the dissolution conditions are as follows: basket, 100rpm, dissolution medium 0.01NHCl (ph 2.0), dissolution medium volume: 900ml, sampling time: the results are shown in Table 2, up to 45 minutes.
The related substance detection method comprises the following steps: chromatographic conditions: a column (recommended Phenomenex Gemini C, 4.6x250mm, 5 μm, or equivalent performance column) with octadecylsilane chemically bonded silica as filler, with 0.2% ammonium acetate solution (glacial acetic acid adjusted to pH 4.3) as mobile phase a, acetonitrile as mobile phase B, and gradient elution as shown in the following table;
column temperature 35 ℃, flow rate 1.0ml/min, detection wavelength: the detection wavelengths are 242nm, 310nm and 340nm by using DAD or a detector with equivalent performance. The detection wavelength of DBC-Z6 is 310nm, the peak area of other impurities (all of which are calculated according to unknown impurities) is calculated by selecting the peak area at the wavelength with the strongest absorption in the three wavelengths, and the result is shown in Table 3.
TABLE 2 stability under different conditions
Wherein the product of lot number 01803 was prepared as prescribed by DB170617 JL.
TABLE 3 Table 3
From the above dissolution results and related material results, the pharmaceutical composition of the present invention is more stable than the reference formulation.
The applicant further examined the effect of the protective layer on the stability of the pharmaceutical composition, the experimental results were as follows:
weight gain screening of different protective layers:
the weight gain of the protective layer was screened and the weight gain and the ratio of HPMC to talc were determined by measuring the dissolution profile of each example at pH 2.0. The formulation of the protective layer of each example is shown in Table 4, and the dissolution in pH2.0 is shown in Table 5.
TABLE 4 protective layer prescriptions
Table 5 dissolution in pH2.0
The applicant further measured the rounding of the drug:
the contents of the reference formulation and the homemade sample were taken separately, pellets 20 were taken randomly, and the minor and major diameters of the pellets were measured by microscopy, respectively, and the minor/major diameters were calculated (wherein the closer the major/minor diameter values were, the more rounded the major/minor diameter ratios were, i.e., the closer the major/minor diameter ratios were, the more rounded the major/minor diameters were, the closer the major/minor diameters were, the more rounded the major/minor ratios were), the average value of the reference formulation was 0.80, the average value of the homemade sample was 0.94, and the specific test results were as shown in table 6 below.
TABLE 6 measurement results
The foregoing is merely illustrative of the embodiments of the present invention, and the scope of the present invention is not limited thereto, and any changes or substitutions that may be made by those skilled in the art without departing from the inventive concept are intended to be included within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope defined by the claims.
Claims (2)
1. A dabigatran etexilate pharmaceutical composition, comprising: 1) An organic acid layer prepared by coating the organic acid, the adhesive and the anti-adhesive on the pellet core; 2) An isolating layer is arranged outside the organic acid layer; 3) A medicine-feeding layer which is prepared by mixing active ingredients including dabigatran etexilate, an anti-sticking agent and an adhesive is arranged outside the isolation layer; 4) A protective layer is arranged outside the upper medicine layer;
wherein the organic acid layer is tartaric acid layer, and the raw materials and auxiliary materials are as follows: tartaric acid pill core 120.6 mg/granule, acacia 8.86 mg/granule, L-tartaric acid 39.41 mg/granule, colloidal silica 6.7 mg/granule; solvent purified water 120 mg/pellet;
the isolating layer comprises the following raw materials: hypromellose 23.29 mg/granule, talcum powder 6.57 mg/granule; 360 mg/granule of solvent ethanol and 48 mg/granule of purified water;
the raw materials and auxiliary materials of the upper medicine layer are as follows: dabigatran etexilate mesylate 172.95 mg/granule, hyprolose 34.59 mg/granule, talcum powder 16.15 mg/granule; 4000 mg/granule of isopropanol as solvent;
and (3) a protective layer: 3.03 mg/granule of hypromellose and 5.05 mg/granule of talcum powder; 173 mg/grain of solvent ethanol and 23 mg/grain of purified water;
and the solvent is removed in the process; the dabigatran etexilate pharmaceutical composition is prepared by the following method:
1) Coating an acid layer coating liquid containing organic acid, an adhesive and an anti-adhesion agent on the pill core through a fluidized bed to prepare the organic acid layer pill core;
2) Coating an isolating layer coating liquid containing an adhesive and an anti-adhesion agent on the organic acid layer pill core through a fluidized bed to prepare the isolating layer pill core;
3) Coating the pill core of the upper medicine layer with coating liquid of the upper medicine layer containing adhesive and active ingredients by a fluidized bed to prepare the pill core of the upper medicine layer;
4) Coating protective layer coating liquid containing adhesive and anti-adhesion agent on the pill core of the upper medicine layer by a fluidized bed to prepare a pellet core;
wherein,,
coating parameters in step 1): setting the air inlet temperature at 40-70 ℃, atomizing pressure at 1.5-2.8 bar, and rotating speed of a liquid supply pump at 20-150 rpm;
coating parameters in step 2): setting the air inlet temperature to be 35-50 ℃, the atomization pressure to be 1.6-2.8 bar, and the rotating speed of a liquid supply pump to be 20-200 rpm;
coating parameters in step 3): setting the air inlet temperature to be 35-55 ℃ and the atomization pressure to be 1.8-2.8 bar, and maintaining the air outlet quantity to be 1400m 3 Over/h, the rotation speed of the liquid supply pump is 20-400 rpm;
coating parameters in step 4): the air inlet temperature is set to be 35-50 ℃, the atomization pressure is set to be 1.8-2.8 bar, and the rotating speed of a liquid supply pump is set to be 20-300 rpm.
2. The dabigatran etexilate pharmaceutical composition according to claim 1, wherein: the formulation of the composition includes capsules.
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| US20110123635A1 (en) * | 2008-07-14 | 2011-05-26 | Boehringer Ingelheim International Gmbh | Method for manufacturing medicinal compounds containing dabigatran |
| AU2012357956A1 (en) * | 2011-12-22 | 2014-05-22 | Boehringer Ingelheim International Gmbh | Immediate release multi unit pellet system |
| CN103951654B (en) * | 2014-05-13 | 2016-08-24 | 南京生命能科技开发有限公司 | Crystal V of dabigatran etexilate methanesulfonate and preparation method thereof |
| WO2018229784A1 (en) * | 2017-06-14 | 2018-12-20 | Natco Pharma Limited | Pharmaceutical compositions of dabigatran |
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| Design and rationale for the DIVERSITY study: An open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism;Manuela Albisetti MD等;《Res Pract Thromb Haemost》;第2卷(第2期);347-356 * |
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