CN113893356A - Dabigatran etexilate mesylate inclusion compound, preparation method and application - Google Patents
Dabigatran etexilate mesylate inclusion compound, preparation method and application Download PDFInfo
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- CN113893356A CN113893356A CN202111264977.0A CN202111264977A CN113893356A CN 113893356 A CN113893356 A CN 113893356A CN 202111264977 A CN202111264977 A CN 202111264977A CN 113893356 A CN113893356 A CN 113893356A
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- Prior art keywords
- dabigatran etexilate
- etexilate mesylate
- cyclodextrin
- inclusion
- mesylate
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- 229960004951 dabigatran etexilate mesylate Drugs 0.000 title claims abstract description 99
- 150000001875 compounds Chemical class 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 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 description 111
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 48
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 18
- 229960000288 dabigatran etexilate Drugs 0.000 claims description 17
- 239000001116 FEMA 4028 Substances 0.000 claims description 16
- 229960004853 betadex Drugs 0.000 claims description 16
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 239000008188 pellet Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- 239000003146 anticoagulant agent Substances 0.000 claims description 3
- -1 glidants Substances 0.000 claims description 3
- CPKOXUVSOOKUDA-UHFFFAOYSA-N 1-bromo-5-fluoro-2-iodo-4-methylbenzene Chemical compound CC1=CC(I)=C(Br)C=C1F CPKOXUVSOOKUDA-UHFFFAOYSA-N 0.000 claims description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 2
- 239000002250 absorbent Substances 0.000 claims description 2
- 230000002745 absorbent Effects 0.000 claims description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 2
- 230000000181 anti-adherent effect Effects 0.000 claims description 2
- 239000002518 antifoaming agent Substances 0.000 claims description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 239000006184 cosolvent Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 229960002919 dronedarone hydrochloride Drugs 0.000 claims description 2
- 239000003995 emulsifying agent Substances 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
- 239000008394 flocculating agent Substances 0.000 claims description 2
- 239000004088 foaming agent Substances 0.000 claims description 2
- 235000013355 food flavoring agent Nutrition 0.000 claims description 2
- 239000003205 fragrance Substances 0.000 claims description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000003906 humectant Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 2
- 230000003204 osmotic effect Effects 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 239000004014 plasticizer Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 239000007939 sustained release tablet Substances 0.000 claims description 2
- 239000002562 thickening agent Substances 0.000 claims description 2
- 239000000080 wetting agent Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000008393 encapsulating agent Substances 0.000 claims 1
- 239000003352 sequestering agent Substances 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 abstract description 5
- 230000007794 irritation Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000012545 processing Methods 0.000 abstract description 3
- XETBXHPXHHOLOE-UHFFFAOYSA-N dabigatran etexilate methanesulfonate Chemical compound CS(O)(=O)=O.C1=CC(C(\N)=N/C(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C XETBXHPXHHOLOE-UHFFFAOYSA-N 0.000 abstract 5
- 210000000813 small intestine Anatomy 0.000 abstract 1
- 210000002784 stomach Anatomy 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000004108 freeze drying Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 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
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 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
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical group 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 229940127216 oral anticoagulant drug Drugs 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Diabetes (AREA)
Abstract
The invention provides a dabigatran etexilate mesylate inclusion compound, a preparation method and application thereof. The invention provides a dabigatran etexilate mesylate inclusion compound which comprises dabigatran etexilate mesylate and cyclodextrin. The dabigatran etexilate mesylate inclusion compound can effectively improve the solubility of a medicament, is improved by 2-5 times compared with the solubility of dabigatran etexilate mesylate, improves the bioavailability, and avoids small intestine and stomach irritation caused by using an organic acid. The method has the advantages of continuous processing, high production efficiency, good process reproducibility and good marketization prospect.
Description
This application claims priority to the following prior applications: application number 202011363686.2 filed 11/27/2020 to the intellectual property office of China, entitled "dabigatran etexilate mesylate clathrate, preparation method and application". The entirety of the above-mentioned prior application is incorporated herein by reference.
Technical Field
The invention relates to a dabigatran etexilate mesylate clathrate compound, a preparation method and application thereof.
Background
The dabigatran etexilate is a novel oral anticoagulant drug and has a structural formula shown in a formula I. After oral absorption, the dabigatran etexilate is converted into dabigatran with direct anticoagulant activity in vivo. Dabigatran binds with fibrin specific binding sites of thrombin, preventing fibrinogen from being cracked into fibrin, thereby blocking the final step of a blood coagulation waterfall network and thrombus formation. Dabigatran can be dissociated from a fibrin-thrombin conjugate to exert reversible anticoagulation.
Compared with the traditional oral anticoagulant warfarin, the dabigatran etexilate has the advantages of low adverse reaction incidence rate, no need of conventional monitoring, wide treatment window, no influence of diet and the like.
The dabigatran etexilate is absorbed quickly after being taken orally, the peak reaching time is about 1-2 h, but the oral bioavailability is only 3% -7%. The solubility of the compound in aqueous solution is pH dependent, the solubility in acidic solution is high, and the compound is almost insoluble at pH > 4.0. Dabigatran etexilate has low bioavailability in humans.
Patent US9925174 discloses a process for formulating dabigatran etexilate capsules, which are pellet capsules containing tartaric acid pellet cores, and provide an acidic microenvironment to increase drug solubility through organic acids, but the preparation process is complex, and researches show that the bioavailability of the commercially available preparation is only 3% -7%. In the prior art, most of the preparations related to the dabigatran etexilate capsules provide an acidic microenvironment by organic acid, but have high irritation to gastrointestinal tracts and low bioavailability in intestinal tracts. Therefore, the finding of the dabigatran formulation with low gastrointestinal irritation, high stability, high solubility, in vitro dissolution and in vivo bioavailability is a technical problem to be solved urgently at present.
Disclosure of Invention
The invention aims to solve the technical problems that in the prior art, the dabigatran etexilate mesylate inclusion compound is low in drug solubility, low in bioavailability, large in gastrointestinal irritation due to the need of organic acid and the like, and provides a preparation method and application of the dabigatran etexilate mesylate inclusion compound. The dabigatran etexilate mesylate inclusion compound can effectively improve the solubility of the drug, thereby improving the bioavailability, and can reduce the irritation of the drug to the gastrointestinal tract by avoiding using organic acid. The method has the advantages of continuous processing, high production efficiency, good process reproducibility and good marketization prospect.
The invention provides a dabigatran etexilate mesylate inclusion compound which comprises dabigatran etexilate mesylate and cyclodextrin.
In the invention, the cyclodextrin is preferably one or more of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin, and is further preferably hydroxypropyl-beta-cyclodextrin and/or sulfobutyl-beta-cyclodextrin.
In the present invention, the molar ratio of the cyclodextrin to the dabigatran etexilate mesylate is preferably 0.1 to 100, more preferably 0.2 to 10, still more preferably 0.3 to 5, for example 1 or 2.
In the invention, the dabigatran etexilate mesylate inclusion compound is preferably composed of dabigatran etexilate mesylate and cyclodextrin.
In the invention, the dabigatran etexilate mesylate clathrate compound can further comprise a pH value regulator, a solubilizer and a cosolvent.
The invention also provides a preparation method of the dabigatran etexilate mesylate clathrate compound, which comprises the following steps: and (3) in a solvent, performing inclusion on the dabigatran etexilate mesylate and cyclodextrin to obtain the dabigatran etexilate mesylate inclusion compound.
The dabigatran etexilate mesylate inclusion compound can be prepared by adopting the conventional inclusion conditions in the field, and the following inclusion conditions are preferred in the invention:
the preparation method of the dabigatran etexilate mesylate clathrate compound can be carried out in a solvent or under the condition of no solvent. When carried out in a solvent, the solvent is preferably water or a mixed solvent of water and an organic solvent; the organic solvent is preferably an alcohol solvent and/or a halogenated hydrocarbon solvent; the alcohol solvent is preferably methanol and/or ethanol; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The "mixed solvent of water and an organic solvent" is more preferably a mixed solvent of methanol and water or a mixed solvent of ethanol and water.
In the method for preparing the dabigatran etexilate mesylate inclusion compound, the cyclodextrin is preferably used in the form of an aqueous solution thereof, the mass concentration of the aqueous cyclodextrin solution is preferably 1% to 50%, more preferably 5% to 20%, for example 9%, and the mass concentration refers to the percentage of the mass of the cyclodextrin to the total mass of the aqueous cyclodextrin solution.
In the method for preparing the dabigatran etexilate mesylate clathrate compound, the mass-volume ratio of the dabigatran etexilate mesylate to the organic solvent is preferably 0.001 g/mL-1 g/mL, more preferably 0.005 g/mL-0.1 g/mL, for example 0.05 g/mL. The mass-to-volume ratio is the ratio of the mass of the dabigatran etexilate mesylate to the volume of the organic solvent.
In the method for preparing the dabigatran etexilate mesylate inclusion compound, the inclusion temperature is preferably 20-80 ℃, more preferably 40-70 ℃, for example 60 ℃.
In the method for preparing dronedarone hydrochloride clathrate, the time for inclusion is preferably 0.5 to 20 hours, more preferably 2 to 10 hours, for example 7 hours.
The preparation method of the dabigatran etexilate mesylate clathrate compound preferably adopts the following post-treatment steps: and after the inclusion is finished, cooling, removing the solvent, filtering and drying to obtain the dabigatran etexilate mesylate inclusion compound.
In the post-treatment step of the preparation method of the dabigatran etexilate mesylate inclusion compound, the cooling temperature is preferably 10-30 ℃, and more preferably 20-25 ℃.
In the post-treatment step of the preparation method of the dabigatran etexilate mesylate inclusion compound, the filtration is preferably performed by using a filter element. The pore size of the filter element is preferably 0.22-0.8 micron, and further preferably 0.45-0.8 micron.
In the post-treatment step of the preparation method of the dabigatran etexilate mesylate inclusion compound, the drying mode is preferably one or more of freeze drying, reduced pressure drying, normal pressure drying and spray drying, and further preferably freeze drying and/or spray drying.
The preparation method of the dabigatran etexilate mesylate clathrate compound further preferably comprises the following specific steps:
a) preparing a cyclodextrin aqueous solution;
b) adding a solution formed by dabigatran etexilate mesylate and an organic solvent or water into the cyclodextrin water solution prepared in the step a) to obtain a dabigatran etexilate mesylate-cyclodextrin solution;
c) performing inclusion on the dabigatran etexilate mesylate-cyclodextrin solution obtained in the step b) to obtain an inclusion solution of the dabigatran etexilate mesylate-cyclodextrin;
d) cooling, removing the solvent, filtering and drying the inclusion solution of dabigatran etexilate mesylate-cyclodextrin prepared in the step c) to obtain the dabigatran etexilate mesylate inclusion compound.
In step c), the temperature of the inclusion is preferably from 20 ℃ to 80 ℃, more preferably from 40 ℃ to 70 ℃, for example, 60 ℃.
In step c), the time for inclusion is preferably 0.5 to 20 hours, more preferably 3 to 10 hours, for example 7 hours.
In step d), the cooling temperature is preferably 10 to 30 ℃, and more preferably 20 to 25 ℃.
In step d), the filtration is preferably performed using a filter membrane. The pore size of the filter membrane is preferably 0.22-0.8 micron, and more preferably 0.45-0.8 micron.
In step d), the drying manner is preferably one or more of freeze drying, reduced pressure drying, normal pressure drying and spray drying, and further preferably freeze drying and/or spray drying.
The invention also provides the dabigatran etexilate mesylate inclusion compound prepared by the preparation method of the dabigatran etexilate mesylate inclusion compound.
The invention also provides application of the dabigatran etexilate mesylate inclusion compound in preparation of a dabigatran etexilate mesylate medicinal preparation. The pharmaceutical preparation can be an oral anticoagulant.
The invention also provides a dabigatran etexilate mesylate pharmaceutical preparation, which comprises the dabigatran etexilate mesylate inclusion compound and pharmaceutic adjuvant.
In the present invention, the pharmaceutical excipients may be conventional in the art, including but not limited to, solubilizers, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, tonicity adjusting agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integration agents, penetration enhancers, pH adjusting agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, encapsulation agents, humectants, absorbents, flocculants and deflocculants, filter aids, release retardants, and the like.
The dabigatran etexilate mesylate pharmaceutical preparation comprises but is not limited to tablets, granules, capsules, pellets, sustained release tablets, osmotic pump tablets, orally disintegrating tablets, oral liquid, injection, freeze-dried powder injection and the like.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the environment temperature of 10-35 ℃.
The positive progress effects of the invention are as follows: the dabigatran etexilate mesylate inclusion compound can effectively improve the solubility of the drug, improves the solubility by 2 to 5 times compared with the dabigatran etexilate mesylate, improves the bioavailability, can reduce the administration dosage, and can effectively reduce the irritation of the drug to the gastrointestinal tract. The method has the advantages of continuous processing, high production efficiency, good process reproducibility and good marketization prospect.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
Dabigatran etexilate mesylate: hydroxypropyl-beta-cyclodextrin ═ 1:1 (molar ratio of materials)
0.050g of dabigatran etexilate mesylate and 0.104g of hydroxypropyl-beta-cyclodextrin are respectively weighed, and the inclusion compound is prepared according to the following method.
Dissolving dabigatran etexilate mesylate with 1ml of methanol, dripping the dissolved dabigatran etexilate mesylate into a hydroxypropyl-beta-cyclodextrin water solution with the mass percent of 9% (the mass percent refers to the mass percent of the hydroxypropyl-beta-cyclodextrin and the mass percent of the hydroxypropyl-beta-cyclodextrin water solution), carrying out inclusion for 7 hours in a magnetic stirrer at 60 ℃ (water bath), cooling to room temperature (20-25 ℃), carrying out rotary evaporation, filtering, and carrying out freeze drying to obtain the dabigatran etexilate mesylate hydroxypropyl-beta-cyclodextrin inclusion compound.
Example 2
Dabigatran etexilate mesylate: hydroxypropyl-beta-cyclodextrin ═ 1:2 (molar ratio of materials)
0.200g of dabigatran etexilate mesylate and 0.832g of hydroxypropyl-beta-cyclodextrin are respectively weighed, and the inclusion compound is prepared according to the following method.
Dissolving dabigatran etexilate mesylate by using 4ml of methanol, dripping the dissolved dabigatran etexilate mesylate into a hydroxypropyl-beta-cyclodextrin water solution with the mass percent of 9% (the mass percent refers to the mass percent of the hydroxypropyl-beta-cyclodextrin and the mass percent of the hydroxypropyl-beta-cyclodextrin water solution), carrying out inclusion for 7 hours in a magnetic stirrer at 60 ℃ (water bath), cooling to room temperature (20-25 ℃), carrying out rotary evaporation, filtering, freezing and drying, and obtaining the hydroxypropyl-beta-cyclodextrin inclusion compound of the dabigatran etexilate mesylate.
Example 3:
dabigatran etexilate mesylate: sulfobutyl-beta-cyclodextrin ═ 1:1 (molar ratio of materials)
0.200g of dabigatran etexilate mesylate and 0.328g of sulfobutyl-beta-cyclodextrin are weighed respectively to prepare the inclusion compound according to the following method.
Dissolving dabigatran etexilate mesylate with 4ml of methanol, dripping the dissolved dabigatran etexilate mesylate into 9 mass percent sulfobutyl-beta-cyclodextrin aqueous solution (the mass percent refers to the mass percent of the mass of the sulfobutyl-beta-cyclodextrin and the mass percent of the sulfobutyl-beta-cyclodextrin aqueous solution), carrying out inclusion in a magnetic stirrer at 60 ℃ (water bath for 7 hours, cooling to room temperature (20-25 ℃), carrying out rotary evaporation, filtering, and freeze-drying to obtain the dabigatran etexilate mesylate hydroxypropyl-beta-cyclodextrin inclusion compound.
Example 4:
dabigatran etexilate mesylate: sulfobutyl-beta-cyclodextrin ═ 1:2 (molar ratio of materials)
0.101g of dabigatran etexilate mesylate and 0.332g of sulfobutyl-beta-cyclodextrin are weighed respectively, and the inclusion compound is prepared according to the following method.
Dissolving dabigatran etexilate mesylate with 2ml of methanol, dripping the dissolved dabigatran etexilate mesylate into 9 mass percent sulfobutyl-beta-cyclodextrin aqueous solution (the mass percent refers to the mass percent of the sulfobutyl-beta-cyclodextrin and the mass percent of the sulfobutyl-beta-cyclodextrin aqueous solution), carrying out inclusion in a magnetic stirrer at 60 ℃ (water bath for 7 hours, cooling to room temperature (20-25 ℃), carrying out rotary evaporation, filtering, and freeze-drying to obtain the dabigatran etexilate sulfobutyl-beta-cyclodextrin inclusion compound.
The solubility of the dabigatran etexilate mesylate inclusion compound prepared in examples 1 to 4 in water (37 ℃ C., 24 hours with shaking) is shown in Table 1.
TABLE 1 solubility of dabigatran etexilate mesylate inclusion compound in water
As can be seen from Table 1, the solubility of the dabigatran etexilate mesylate-cyclodextrin inclusion compound in water is remarkably improved.
Claims (15)
1. A dabigatran etexilate mesylate clathrate compound is characterized in that: which comprises dabigatran etexilate mesylate and cyclodextrin.
2. The dabigatran etexilate mesylate clathrate of claim 1, wherein:
the cyclodextrin is one or more of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin.
3. The dabigatran etexilate mesylate clathrate of claim 1, wherein:
the molar ratio of the cyclodextrin to the dabigatran etexilate mesylate is 0.1-100.
4. The dabigatran etexilate mesylate clathrate of claim 3, wherein:
the molar ratio of the cyclodextrin to the dabigatran etexilate mesylate is 0.2-10.
5. The dabigatran etexilate mesylate clathrate of claim 4, wherein:
the molar ratio of the cyclodextrin to the dabigatran etexilate mesylate is 0.3-5.
6. The dabigatran etexilate mesylate clathrate of claim 1, wherein: the dabigatran etexilate mesylate inclusion compound consists of dabigatran etexilate mesylate and cyclodextrin.
7. The dabigatran etexilate mesylate clathrate compound according to any one of claims 1 to 6, wherein: the dabigatran etexilate mesylate clathrate compound further comprises a pH value regulator, a solubilizer and a cosolvent.
8. The preparation method of the dabigatran etexilate mesylate clathrate compound according to any one of claims 1 to 6, characterized by comprising the following steps: and (3) clathrating dabigatran etexilate mesylate with cyclodextrin to obtain the dabigatran etexilate mesylate clathrate compound.
9. The method for preparing the dabigatran etexilate mesylate clathrate compound according to claim 8, wherein the method comprises the following steps:
the preparation method of the dabigatran etexilate mesylate inclusion compound is carried out in a solvent or under the condition of no solvent;
in the preparation method of the dabigatran etexilate mesylate inclusion compound, when the inclusion is carried out in a solvent, the solvent is water or a mixed solvent of water and an organic solvent;
and/or the presence of a gas in the gas,
in the preparation method of the dabigatran etexilate mesylate clathrate compound, the mass volume ratio of the dabigatran etexilate mesylate to the organic solvent is 0.001 g/mL-1 g/mL;
and/or the presence of a gas in the gas,
in the preparation method of the dabigatran etexilate mesylate inclusion compound, the inclusion temperature is 20-80 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the dronedarone hydrochloride clathrate compound, the inclusion time is 0.5 to 20 hours;
and/or the presence of a gas in the gas,
the preparation method of the dabigatran etexilate mesylate clathrate compound comprises the following post-treatment steps: and after the inclusion is finished, cooling, removing the solvent, filtering and drying to obtain the dabigatran etexilate mesylate inclusion compound.
10. The method for preparing the dabigatran etexilate mesylate clathrate compound according to claim 9, wherein: the method comprises the following specific steps:
a) preparing a cyclodextrin aqueous solution;
b) adding a solution formed by dabigatran etexilate mesylate and water or an organic solvent into the cyclodextrin water solution prepared in the step a) to obtain a dabigatran etexilate mesylate-cyclodextrin solution;
c) performing inclusion on the dabigatran etexilate mesylate-cyclodextrin solution obtained in the step b) to obtain an inclusion solution of the dabigatran etexilate mesylate-cyclodextrin;
d) cooling, removing the solvent, filtering and drying the inclusion solution of dabigatran etexilate mesylate-cyclodextrin prepared in the step c) to obtain the dabigatran etexilate mesylate inclusion compound.
11. A dabigatran etexilate mesylate pharmaceutical preparation is characterized in that: the pharmaceutical preparation comprises the dabigatran etexilate mesylate inclusion compound as claimed in any one of claims 1 to 7 and pharmaceutic adjuvants.
12. The pharmaceutical formulation of claim 11, wherein: the dabigatran etexilate mesylate pharmaceutical preparation comprises but is not limited to tablets, granules, capsules, pellets, sustained release tablets, osmotic pump tablets, orally disintegrating tablets, oral liquid, injection and freeze-dried powder injection.
13. The pharmaceutical formulation of claim 11, wherein: the "pharmaceutical excipients" include, but are not limited to, solubilizers, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, tonicity adjusting agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, sequestering agents, permeation enhancers, pH adjusting agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, and release retardants.
14. The use of the dabigatran etexilate mesylate inclusion compound according to any one of claims 1 to 7 in the preparation of a dabigatran etexilate mesylate pharmaceutical preparation.
15. The use of claim 14, wherein: the medicament or the pharmaceutical preparation is an oral anticoagulant medicament.
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| US20130190358A1 (en) * | 2012-01-24 | 2013-07-25 | Boehringer Ingelheim International Gmbh | Novel orally administered dabigatran formulation |
| WO2015071841A1 (en) * | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| WO2017111637A1 (en) * | 2015-12-23 | 2017-06-29 | Zaklady Farmaceutyczne Polpharma Sa | Pharmaceutical composition comprising dabigatran or a pharmaceutically acceptable salt thereof |
| CN109010249A (en) * | 2017-06-08 | 2018-12-18 | 上海美悦生物科技发展有限公司 | Injection dabigatran etcxilate pharmaceutical composition and its preparation method and application |
| WO2019004980A2 (en) * | 2017-05-10 | 2019-01-03 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| CN111150714A (en) * | 2020-03-17 | 2020-05-15 | 南京嘉晨医药科技有限公司 | Dabigatran etexilate mesylate solid pharmaceutical preparation and preparation method thereof |
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- 2021-10-28 CN CN202111264977.0A patent/CN113893356A/en active Pending
Patent Citations (6)
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|---|---|---|---|---|
| US20130190358A1 (en) * | 2012-01-24 | 2013-07-25 | Boehringer Ingelheim International Gmbh | Novel orally administered dabigatran formulation |
| WO2015071841A1 (en) * | 2013-11-12 | 2015-05-21 | Druggability Technologies Holdings Limited | Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| WO2017111637A1 (en) * | 2015-12-23 | 2017-06-29 | Zaklady Farmaceutyczne Polpharma Sa | Pharmaceutical composition comprising dabigatran or a pharmaceutically acceptable salt thereof |
| WO2019004980A2 (en) * | 2017-05-10 | 2019-01-03 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Solid oral pharmaceutical compositions of dabigatran etexilate |
| CN109010249A (en) * | 2017-06-08 | 2018-12-18 | 上海美悦生物科技发展有限公司 | Injection dabigatran etcxilate pharmaceutical composition and its preparation method and application |
| CN111150714A (en) * | 2020-03-17 | 2020-05-15 | 南京嘉晨医药科技有限公司 | Dabigatran etexilate mesylate solid pharmaceutical preparation and preparation method thereof |
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