CN109498571A - A kind of esomeprazole sodium and preparation method thereof - Google Patents
A kind of esomeprazole sodium and preparation method thereof Download PDFInfo
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- CN109498571A CN109498571A CN201811379933.0A CN201811379933A CN109498571A CN 109498571 A CN109498571 A CN 109498571A CN 201811379933 A CN201811379933 A CN 201811379933A CN 109498571 A CN109498571 A CN 109498571A
- Authority
- CN
- China
- Prior art keywords
- sodium
- solution
- esomeprazole
- esomeprazole sodium
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960000496 esomeprazole sodium Drugs 0.000 title claims abstract description 135
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- RYXPMWYHEBGTRV-JIDHJSLPSA-N sodium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-3-ide Chemical compound [Na+].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C RYXPMWYHEBGTRV-JIDHJSLPSA-N 0.000 title abstract 7
- 239000000243 solution Substances 0.000 claims abstract description 112
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 93
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 64
- 239000000661 sodium alginate Substances 0.000 claims abstract description 64
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 64
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 64
- 238000013268 sustained release Methods 0.000 claims abstract description 55
- 239000012730 sustained-release form Substances 0.000 claims abstract description 55
- 239000000839 emulsion Substances 0.000 claims abstract description 47
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 25
- 239000007864 aqueous solution Substances 0.000 claims abstract description 25
- 239000001110 calcium chloride Substances 0.000 claims abstract description 25
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 25
- 238000004945 emulsification Methods 0.000 claims abstract description 23
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 claims description 135
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 26
- 239000002994 raw material Substances 0.000 claims description 21
- 235000013921 calcium diglutamate Nutrition 0.000 claims description 20
- UMVAYAXXQSFULN-QHTZZOMLSA-L calcium;(2s)-2-aminopentanedioate;hydron Chemical compound [Ca+2].[O-]C(=O)[C@@H](N)CCC(O)=O.[O-]C(=O)[C@@H](N)CCC(O)=O UMVAYAXXQSFULN-QHTZZOMLSA-L 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 20
- 239000004247 glycine and its sodium salt Substances 0.000 claims description 19
- 235000013905 glycine and its sodium salt Nutrition 0.000 claims description 19
- 229940029258 sodium glycinate Drugs 0.000 claims description 19
- WUWHFEHKUQVYLF-UHFFFAOYSA-M sodium;2-aminoacetate Chemical compound [Na+].NCC([O-])=O WUWHFEHKUQVYLF-UHFFFAOYSA-M 0.000 claims description 19
- 239000011780 sodium chloride Substances 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- 239000008215 water for injection Substances 0.000 claims description 16
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 14
- 229910052708 sodium Inorganic materials 0.000 claims description 14
- 230000005686 electrostatic field Effects 0.000 claims description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 239000000654 additive Substances 0.000 claims description 7
- 230000009514 concussion Effects 0.000 claims description 7
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 7
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 7
- 235000019800 disodium phosphate Nutrition 0.000 claims description 7
- 229960004770 esomeprazole Drugs 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- 239000001488 sodium phosphate Substances 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 29
- 229940079593 drug Drugs 0.000 abstract description 24
- 239000002245 particle Substances 0.000 abstract description 7
- 238000011068 loading method Methods 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000009826 distribution Methods 0.000 abstract description 3
- 238000004108 freeze drying Methods 0.000 description 19
- 238000000034 method Methods 0.000 description 16
- 239000004005 microsphere Substances 0.000 description 14
- 108010010803 Gelatin Proteins 0.000 description 13
- 239000008273 gelatin Substances 0.000 description 13
- 229920000159 gelatin Polymers 0.000 description 13
- 235000019322 gelatine Nutrition 0.000 description 13
- 235000011852 gelatine desserts Nutrition 0.000 description 13
- 239000000047 product Substances 0.000 description 10
- 229920001661 Chitosan Polymers 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 230000002459 sustained effect Effects 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 229910021645 metal ion Inorganic materials 0.000 description 7
- 230000011218 segmentation Effects 0.000 description 7
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 208000025865 Ulcer Diseases 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000027119 gastric acid secretion Effects 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 231100000397 ulcer Toxicity 0.000 description 6
- 235000010894 Artemisia argyi Nutrition 0.000 description 5
- 244000030166 artemisia Species 0.000 description 5
- 150000003851 azoles Chemical class 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000002738 chelating agent Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000005261 decarburization Methods 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 210000004400 mucous membrane Anatomy 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229960001126 alginic acid Drugs 0.000 description 4
- 239000000783 alginic acid Substances 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 150000004781 alginic acids Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 210000004211 gastric acid Anatomy 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 208000010643 digestive system disease Diseases 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 210000001711 oxyntic cell Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- 239000004695 Polyether sulfone Substances 0.000 description 2
- 108010083204 Proton Pumps Proteins 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- VEUACKUBDLVUAC-UHFFFAOYSA-N [Na].[Ca] Chemical compound [Na].[Ca] VEUACKUBDLVUAC-UHFFFAOYSA-N 0.000 description 2
- 230000003796 beauty Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000001066 destructive effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 208000011906 peptic ulcer disease Diseases 0.000 description 2
- 229920006393 polyether sulfone Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000000859 sublimation Methods 0.000 description 2
- 230000008022 sublimation Effects 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- BXWLVQXAFBWKSR-UHFFFAOYSA-N 2-methoxy-5-methylsulfonylbenzoic acid Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(O)=O BXWLVQXAFBWKSR-UHFFFAOYSA-N 0.000 description 1
- BHVRHDLXKLRTEY-UHFFFAOYSA-N 2-sulfinyl-1,3-dihydrobenzimidazole Chemical compound C1=CC=C2NC(=S=O)NC2=C1 BHVRHDLXKLRTEY-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000028006 Corneal injury Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- RYXPMWYHEBGTRV-UHFFFAOYSA-N Omeprazole sodium Chemical compound [Na+].N=1C2=CC(OC)=CC=C2[N-]C=1S(=O)CC1=NC=C(C)C(OC)=C1C RYXPMWYHEBGTRV-UHFFFAOYSA-N 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 206010042220 Stress ulcer Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 229940063517 omeprazole sodium Drugs 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000001175 peptic effect Effects 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- -1 stress Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of esomeprazole sodium and preparation method thereof.The preparation method comprises the following steps: S1. prepares esomeprazole sodium water solution；S2. oily phase organic solution is prepared；S3. it is mixed by the esomeprazole sodium water solution prepared by step S1, by the step S2 oily phase organic solution prepared and sodium alginate aqueous solution, and carries out ultrasonic emulsification, obtain the mixed phase emulsion containing sodium alginate；S4. using being reacted by the mixed phase emulsion containing sodium alginate prepared by step S3 with calcium chloride water, sustained release esomeprazole sodium is obtained；S5. the sustained release esomeprazole sodium obtained by step S4 is washed, filtered and is freeze-dried.The present invention can guarantee that esomeprazole sodium has small good stability, particle size, even particle size distribution, drug loading degree high, the excellent advantage of medicament slow release performance.
Description
Technical field
The present invention relates to biomedicine fields, and in particular to a kind of esomeprazole sodium and preparation method thereof.
Background technique
Peptic ulcer refer to gastrointestinal mucosa by peptic digest liquid autodigestion and caused by be more than muscular layer of mucosa tissue damage,
Gastral any position can be betided, wherein most commonly seen with stomach and duodenum, i.e. gastric ulcer and duodenal ulcer.
Gastric ulcer is one of common disease in population of China, frequently-occurring disease, and the mainly damage with gastroduodenal mucous membrane occurs
Loss of equilibrium is related between factor and mucous membrane self-defense reparation factor.The protection mechanism of the gastroduodenal mucous membrane of normal person is enough
The erosion of gastric acid and pepsin is resisted, but stomach may occur when certain factors compromise some part in protection mechanism
Acid and protease corrode itself mucous membrane and lead to the formation of ulcer, when excessive gastric acid secretion is considerably beyond the defence and reparation of mucous membrane
Effect may also lead to ulcer.Helicobacter pylori and non-steroidal anti-inflammatory drugs are that damage stomach and intestine protection mechanism causes ulcer to be fallen ill
Most commonly encountered diseases because, drug, stress, hormone may also lead to the generation of ulcer, various psychological factors and undesirable dietetic life are practised
It is used can induced ulcer appearance.
In the forming process of digestive diseases, gastric acid plays a crucial role in ulcer is formed, and gastroxia easily draws
Send out such as peptic ulcer (including stress ulcer), gastroesophageal reflux disease (including reflux esophagitis), gastrinoma, part
The diseases such as functional dyspepsia FD.Stomach lining parietal cell secretes the final step proton pump of gastric acid, and proton pump inhibitor makes any
Gastric acid secretion caused by stimulating is blocked, and has stronger acid suppression effect, is had in terms for the treatment of gastric acid related disease prominent
Curative effect out.
Entitled (S) -5- methoxyl group -2- [[(the 4- methoxy of esomeprazole sodium (Esomeprazole sodium) chemistry
Base -3,5- dimethyl -2- pyridyl group) methyl] sulfinyl-1 H-benzimidazole) sodium.Esomeprazole passes through specificity
Targeting mechanism reduces gastric acid secretion, and parietal cell proton pump is inhibited to reduce gastric acid secretion.Site of action and mechanism are Chinese mugwort department
Omeprazole is dense in the high acid environment that parietal cell secretes sour micro-pipe and is converted into active form, to inhibit the H+/K at the position
+-ATP (proton pump) generates inhibition to basal gastric acid secretion and gastric acid secretion.
The drug for the disease of digestive system that esomeprazole sodium causes as treatment gastroxia, sustained release performance
It is vital.The patent of invention of Publication No. CN103222962A provides a kind of injection esomeprazole composition
And preparation method thereof, the injection esomeprazole composition includes the sustained-release micro-spheres of active ingredient, this passes through
Esomeprazole composition medicine microballoon is prepared, the proton pump inhibitor for capableing of 2 dual controlled releases to release the drug is obtained, is improved
The therapeutic index of drug, improves the quality of formulation products.
However, problems of the prior art are: esomeprazole sodium is as sodium salt, favorable solubility in water,
But it easily goes out the matter such as colour changed into yellow and related substance are exceeded, clarity is unqualified in long-term storing process or in hot conditions
Amount problem, experiments have shown that esomeprazole sodium is more stable under alkaline condition, it is all very sensitive to light, heat, oxygen, water etc., especially
, in acid condition, destructive variation can occur for chemical structure for it, occur changing colour and polymerism.
It include esomeprazole sodium, edetate sodium and hydroxide in esomeprazole sodium drug in the prior art
Sodium.Edetate sodium is outstanding metal ion network mixture, can be complexed under alkaline condition with most metal ions, to protect
Hold the stabilization of preparation.But edetate sodium can be complexed simultaneously with calcium, may cause calcium loss, internal blood calcium after inputting human body
Decline may cause a series of clinical problem.Therefore, edetate sodium and sodium hydroxide are replaced using new ingredient, prepares Chinese mugwort department
Omeprazole Sodium is of great significance.In addition, the prior art is by adding various freeze-drying proppants, metal ion chelation agent and resisting
The additives such as oxygen agent, to solve the problems, such as that esomeprazole stable sodium is poor；However, antioxidant sodium hydrogensulfite to skin,
Eye, respiratory tract are irritant, can cause allergic reaction, corneal injury, blindness, asthma, carry out hidden danger to patient medication safety belt.Cause
This, stability and safety issue of the esomeprazole sodium after long-time is stored still do not obtain adequate solution.
Summary of the invention
To overcome defect and deficiency existing in the prior art, the invention discloses a kind of esomeprazole sodium and its systems
Preparation Method.
The invention is realized by the following technical scheme:
A kind of preparation method of esomeprazole sodium, comprising the following steps:
S1. esomeprazole sodium water solution is prepared；
S2. oily phase organic solution is prepared；
S3. by the esomeprazole sodium water solution prepared by step S1, the oil prepared by step S2
Phase organic solution and sodium alginate aqueous solution mixing, and ultrasonic emulsification is carried out, obtain the mixed phase emulsion containing sodium alginate；
S4. it is carried out using the mixed phase emulsion containing sodium alginate and calcium chloride water that are prepared by step S3
Reaction obtains sustained release esomeprazole sodium；
S5. active carbon stirring and adsorbing, decarburization are carried out to the sustained release esomeprazole sodium obtained by step S4
Filter is sterile filtered and is freeze-dried.
Further, in step sl, made using Sodium Glycinate, sodium chloride, calcio-disodium edetate and calcium glutamate
For auxiliary additive, the esomeprazole sodium water solution is prepared.
Further, in step sl, use the mass ratio of raw material for esomeprazole sodium: Sodium Glycinate: sodium chloride:
Calcio-disodium edetate: calcium glutamate: water for injection=(94-96): (1.2-2.0): (0.8-1.2): (1.2-1.8):
(0.8-1)∶(4800-5000)。
Further, step S1 includes following sub-step:
S1-1. the water for injection for measuring 60% dosage, is added the Sodium Glycinate and calcio-disodium edetate,
It is stirred under the conditions of 10 DEG C -15 DEG C of temperature to being completely dissolved, obtains the first solution；
S1-2. the water for injection for measuring 20% dosage, is added the calcium glutamate, in 30 DEG C -35 DEG C of temperature strip
It is stirred under part to being completely dissolved, is cooled to room temperature, obtain the second solution；
S1-3. first solution and the second solution are uniformly mixed, the esomeprazole sodium is added, is warming up to 40
DEG C -45 DEG C of temperature, stirring obtain third solution to being completely dissolved；
S1-4. it is cooled under the conditions of 2 DEG C -6 DEG C of temperature, using disodium phosphate soln by the pH value of the third solution
It is adjusted to 11-12, the sodium chloride is added after adding water to full dose, stirs evenly, obtains the esomeprazole sodium water solution.
Further, in step s 2, using poly lactide-glycolide acid, ethyl acetate and N- crassitude
Ketone is raw material, prepares the oily phase organic solution.
Further, in step s 2, by poly lactide-glycolide acid: ethyl acetate: N-Methyl pyrrolidone
=(50-80): (10-20): the volume ratio of (10-30) prepares mixed solution, is uniformly mixed, and obtains the oily phase organic solution.
Further, step S3 includes following sub-step:
S3-1. press esomeprazole sodium water solution: the volume ratio of oily phase organic solution=(40-60): (40-60) is mixed
Raw material is closed, and carries out ultrasonic emulsification, obtains mixed phase emulsion；
S3-2. by mixed phase emulsion: sodium alginate aqueous solution=(40-60): the volume ratio of (40-60) will pass through step
The mixed phase emulsion and the sodium alginate aqueous solution mixing that S3-1 is obtained, and ultrasonic emulsification is carried out, it obtains and contains sodium alginate
Mixed phase emulsion, wherein the concentration of the sodium alginate aqueous solution be 10wt%-20wt%.
Further, the sodium alginate in the sodium alginate aqueous solution is to pass through chitosan and gelatin modified alginic acid
Sodium.
Further, in step s 4, under high voltage electrostatic field, will be obtained by step S3 described in containing alginic acid
The mixed phase emulsion Uniform jet of sodium, which instills in rotation concussion calcium chloride water, to be reacted, and is sustained after centrifuge separation
Esomeprazole sodium；Wherein, the volume ratio of the mixed phase emulsion and calcium chloride water containing sodium alginate is (40-
60): (40-60)；The concentration of the calcium chloride water is 2wt%-4Wt%.
Further, in step s 5, the active carbon stirring and adsorbing uses concentration to live for 0.05% needle of g/ml
Property charcoal carry out, adsorption temp be 24 DEG C -74 DEG C, adsorption time 22min-28min.
Further, in step s 5, the decarburization filtering is carried out using 0.45 μm of stud filter, the sterile mistake
Filter is carried out using 0.2 μm of polyether sulfone filter core.
Further, in step s 5, before the freeze-drying, intermediates content measurement and acidity assaying are carried out, and
Loading amount is adjusted according to intermediates content measurement result, is freeze-dried after filling.
Further, in step s 5, the freeze-drying is carried out using segmentation freeze-drying method, the segmentation freezing
Drying specifically includes following sub-step:
S5-1. the sustained release esomeprazole sodium is freezed into 60min- under the conditions of -60 DEG C to -40 DEG C of temperature
100min；
S5-2. by the sustained release esomeprazole sodium obtained by step S5-1 at -20 DEG C to 0 DEG C and 30Pa-
60min-100min is freezed under the conditions of the temperature and pressure of 50Pa；
S5-3. by the sustained release esomeprazole sodium obtained by step S5-2 at 0 DEG C to 5 DEG C and 1000Pa-
60min-100min is freezed under the conditions of the temperature and pressure of 1200Pa；
S5-4. by the sustained release esomeprazole sodium obtained by step S3-3 with the liter of 0.1 DEG C -0.2 DEG C/min
Under conditions of temperature and pressure is increased to 20 DEG C -25 DEG C and 10kPa by the rate of pressure rise of warm rate and 40Pa-100Pa/min, protect
Hold 40min-60min.
A kind of esomeprazole sodium, the esomeprazole sodium use the preparation side of the esomeprazole sodium
Method obtains.
Compared with prior art, the present invention the advantage is that: the present invention is by being prepared as microballoon for esomeprazole sodium
Shape improves the sustained release performance and acid resistance of esomeprazole sodium.Also, the present invention is by using Sodium Glycinate, second two
Amine tetraacethyl calcium sodium and calcium glutamate replace edetate sodium in the prior art as metal ion chelation agent, improve Ai Siao
Beauty draws the stability and safety of azoles sodium.
Firstly, auxiliary additive, which is added, in esomeprazole sodium of the present invention prepares esomeprazole sodium water solution, inciting somebody to action
Esomeprazole sodium water solution mixes ultrasonic emulsification with the oily phase organic solvent of poly lactide-glycolide acid, can obtain
Mixed phase emulsion is obtained, so that the dispersion performance and surface energy of esomeprazole sodium in a solvent can be improved.
Then, the present invention is by under high voltage electrostatic field, by with polymolecularity can and surface can Chinese mugwort department Aomei
Azoles sodium and sodium alginate emulsion Uniform jet is drawn to instill rotation concussion calcium chloride water, so that sodium alginate and chlorination
Reaction between calcium is more uniform and efficient, obtains the smooth rounding in surface, the esomeprazole that particle size is small, uniformity is good
Sodium microsphere drug.Finally, the present invention freezes esomeprazole sodium microballoon using ultralow temperature by segmentation freeze-drying
It is dry, enable to the micro-sphere structure of esomeprazole sodium completely to be retained, to be further ensured that it with good
Sustained release performance.
To sum up, the method through the invention can guarantee that esomeprazole sodium has good stability, particle size
Small, even particle size distribution, drug loading degree are high, the excellent advantage of medicament slow release performance.
Specific embodiment
It should be noted that in the absence of conflict, the feature in embodiment and embodiment in the present invention can phase
Mutually combination.Below in conjunction with embodiment, the present invention will be described in detail.
The present invention provides a kind of preparation methods of esomeprazole sodium, comprising the following steps:
S1. using Sodium Glycinate, sodium chloride, calcio-disodium edetate and calcium glutamate as auxiliary additive, preparation
Esomeprazole sodium water solution；
S2. it uses poly lactide-glycolide acid, ethyl acetate and N-Methyl pyrrolidone for raw material, prepares oily phase
Organic solution；
S3. by the esomeprazole sodium water solution prepared by step S1, the oil prepared by step S2
Phase organic solution and sodium alginate aqueous solution mixing, and ultrasonic emulsification is carried out, obtain the mixed phase emulsion containing sodium alginate；
S4. it is carried out using the mixed phase emulsion containing sodium alginate and calcium chloride water that are prepared by step S3
Reaction obtains sustained release esomeprazole sodium；
S5. active carbon stirring and adsorbing, decarburization are carried out to the sustained release esomeprazole sodium obtained by step S4
Filter is sterile filtered and is freeze-dried；The active carbon stirring and adsorbing use concentration for 0.05% needle-use activated carbon of g/ml into
Row, adsorption temp are 24 DEG C -74 DEG C, adsorption time 22min-28min；The decarburization filtering is filtered using 0.45 μm of stud
Device carries out, and described be sterile filtered is carried out using 0.2 μm of polyether sulfone filter core；Before the freeze-drying, intermediates content is carried out
Measurement and acidity assaying, and loading amount is adjusted according to intermediates content measurement result, it is freeze-dried after filling.
S1 to S5 prepares the reason of esomeprazole sodium and is through the above steps: Ai Siao in the prior art
Beauty draws azoles sodium more stable under alkaline condition but all very sensitive to light, heat, oxygen, water etc., especially in acid condition, changes
Destructive variation can be occurred by learning structure, occur changing colour and polymerism.Also, its therapeutic agent as disease of digestive system,
The superiority and inferiority of sustained release performance is also vital.Therefore, the embodiment of the present invention is solid by the way that esomeprazole sodium to be prepared into
Porous 10 μm -35 μm of micro-sphere structure, not only increases the acid resistance of drug, also can effectively extend drug and act in vivo
Time reduces administration frequency, improves its sustained release performance.
In some embodiments of the invention, in step sl, use the mass ratio of raw material for esomeprazole sodium:
Sodium Glycinate: sodium chloride: calcio-disodium edetate: calcium glutamate: water for injection=(94-96): (1.2-2.0): (0.8-
1.2)∶(1.2-1.8)∶(0.8-1)∶ (4800-5000)。
Specifically, step S1 includes following sub-step:
S1-1. the water for injection for measuring 60% dosage, is added the Sodium Glycinate and calcio-disodium edetate,
It is stirred under the conditions of 10 DEG C -15 DEG C of temperature to being completely dissolved, obtains the first solution；
S1-2. the water for injection for measuring 20% dosage, is added the calcium glutamate, in 30 DEG C -35 DEG C of temperature strip
It is stirred under part to being completely dissolved, is cooled to room temperature, obtain the second solution；
S1-3. first solution and the second solution are uniformly mixed, the esomeprazole sodium is added, is warming up to 40
DEG C -45 DEG C of temperature, stirring obtain third solution to being completely dissolved；
S1-4. it is cooled under the conditions of 2 DEG C -6 DEG C of temperature, using disodium phosphate soln by the pH value of the third solution
It is adjusted to 11-12, the sodium chloride is added after adding water to full dose, stirs evenly, obtains the esomeprazole sodium water solution.
The reason of using Sodium Glycinate, sodium chloride, calcio-disodium edetate and calcium glutamate as auxiliary additive, exists
In in the esomeprazole sodium preparation method of the prior art, the edetate sodium as metal ion chelation agent simultaneously can be with
Calcium complexing may cause calcium loss after inputting human body, and internal blood calcium decline may cause a series of clinical problem.Therefore, originally
Inventive embodiments select calcio-disodium edetate and Sodium Glycinate to replace edetate sodium as metal ion chelation agent.Ethylenediamine
Tetraacethyl calcium sodium and calcium glutamate can provide required calcium ion while realizing metal ion chelation agent for human body,
Avoiding other complexing agents complexing intracorporal calcium ion of people leads to the risk of bone calcium loss.In addition, the embodiment of the present invention respectively will
Calcio-disodium edetate dissolves under cryogenic and by calcium glutamate higher than dissolving under room temperature, incites somebody to action after being mutually mixed
Solution heats up and adds esomeprazole sodium active constituent, and drug is cooled to 2 DEG C -6 DEG C again after being uniformly dissolved, and uses phosphorus
Sour disodium hydrogen replaces the sodium hydroxide of the prior art to adjust drug to alkaline environment, and adds sodium chloride.So that it is guaranteed that drug
With good stability, dissolubility, purity and clarity.
In step s 2, the ingredient of the oily phase organic solution is copolymerized with the preparation method comprises the following steps: pressing polylactic acid-hydroxyacetic acid
Object: ethyl acetate: N-Methyl pyrrolidone=(50-80): (10-20): the volume ratio of (10-30) prepares mixed solution, mixing
Uniformly, the oily phase organic solution is obtained.
In step s3, it is prepared by the esomeprazole sodium water solution prepared by step S1, by step S2
The oily phase organic solution and sodium alginate aqueous solution mixing, and carry out ultrasonic emulsification, obtain the mixing containing sodium alginate
Phase emulsion.Specifically, step S3 includes following sub-step:
S3-1. press esomeprazole sodium water solution: the volume ratio of oily phase organic solution=(40-60): (40-60) is mixed
Raw material is closed, and carries out ultrasonic emulsification, obtains mixed phase emulsion；
S3-2. by mixed phase emulsion: sodium alginate aqueous solution=(40-60): the volume ratio of (40-60) will pass through step
The mixed phase emulsion and the sodium alginate aqueous solution mixing that S3-1 is obtained, and ultrasonic emulsification is carried out, it obtains and contains sodium alginate
Mixed phase emulsion, wherein the concentration of the sodium alginate aqueous solution be 10wt%-20wt%.
In step s 4, under high voltage electrostatic field, will be obtained by step S3 described in the mixing containing sodium alginate
Phase emulsion Uniform jet, which instills in rotation concussion calcium chloride water, to be reacted, and sustained release Chinese mugwort department Aomei is obtained after centrifuge separation
Draw azoles sodium；Wherein, the volume ratio of the mixed phase emulsion and calcium chloride water containing sodium alginate is (40-60): (40-
60)；The concentration of the calcium chloride water is 2Wt%-4Wt%.
It is using the reason of step S3 and S4: the digestion that esomeprazole sodium causes as treatment gastroxia
The drug of systemic disease, sustained release performance are vital.However, in the prior art directly by esomeprazole sodium activity
Ingredient addition organic solvent and shelling agent are prepared into sustained-release micro-spheres, the problem is that esomeprazole sodium active constituent exists
Dispersibility in organic solvent is not ideal enough, therefore the partial size of the sustained-release micro-spheres obtained is larger, and size is also not uniform enough, therefore leads
Cause the stability, clarity and sustained release performance of drug not ideal enough.The embodiment of the present invention prepares esomeprazole sodium respectively
Aqueous solution and compound oily phase organic solvent and the aqueous solution of sodium alginate shelling agent, and first by esomeprazole sodium water
Solution and the mixing of compound oily phase organic solvent obtain mixed phase emulsion, guarantee esomeprazole sodium in emulsion uniformly
Distribution and specific surface area, then add the aqueous solution of sodium alginate shelling agent and prepare sustained-release micro-spheres.By the ratio for increasing sustained-release microparticle
Surface area and surface can, ensure that the granularity of reactant is sufficiently small, and size uniformity, be uniformly dispersed.In addition, the present invention is implemented
Example by under high voltage electrostatic field, will with polymolecularity can and surface can the mixed phase emulsion containing sodium alginate it is equal
Even jet stream instills rotation concussion calcium chloride water, so that reacting between sodium alginate and calcium chloride is more uniform and high
Effect obtains the smooth rounding in surface, the esomeprazole sodium sustained-release micro-spheres that particle size is small, uniformity is good, guarantees it in structure
It is upper that there is loose porous form.Therefore, it can guarantee that drug is with good stability, clarity is gentle using step S3 and S4
Release performance.
In step s 5, the freeze-drying is carried out using segmentation freeze-drying method, and the segmentation freeze-drying is specific
Including following sub-step:
S5-1. the sustained release esomeprazole sodium is freezed into 60min- under the conditions of -60 DEG C to -40 DEG C of temperature
100min；
S5-2. by the sustained release esomeprazole sodium obtained by step S5-1 at -20 DEG C to 0 DEG C and 30Pa-
60min-100min is freezed under the conditions of the temperature and pressure of 50Pa；
S5-3. by the sustained release esomeprazole sodium obtained by step S5-2 at 0 DEG C to 5 DEG C and 1000Pa-
60min-100min is freezed under the conditions of the temperature and pressure of 1200Pa；
S5-4. by the sustained release esomeprazole sodium obtained by step S3-3 with the liter of 0.1 DEG C -0.2 DEG C/min
Under conditions of temperature and pressure is increased to 20 DEG C -25 DEG C and 10kPa by the rate of pressure rise of warm rate and 40Pa-100Pa/min, protect
Hold 40min-60min.
The quality of refrigerating process and product has close relationship, and the selection of sublimation temperature directly influences the speed of distillation
Degree influences the formation of material combinations particle, the formation in relation to substance and the wherein content of moisture content, is the weight of stable product quality
Cut factor.Temperature rises the too fast formation influenced into porous matrix, so that underclad portion atrophy is occurred, influences the residual water of product
The content divided, leads to solubility, stability and clarity problem.When pressure difference pressure during distillation is too low, heat transfer is unfavorable for
Heat transfer, rate of sublimation reduce instead, influence drying effect.
The present invention carries out rapid freeze-drying to drug using ultralow temperature first, then uses low temperature by segmentation freeze-drying
Vacuum carries out prolonged secondary distillation to drug, and the increasing temperature and pressure of special speed is finally carried out to drug, enables to drug
Microsphere sustained-release structure completely retained.Compared to the frozen drying directly carried out drug under the conditions of single temperature
The prior art, segmentation freeze-drying can further decrease sustained release esomeprazole sodium water content and impurity contain
Amount.Additionally it is possible to retain the sustained-release micro-spheres structure for being sustained esomeprazole sodium completely, it is further increased
Sustained release performance.
In some embodiments of the invention, the sodium alginate is to pass through chitosan and gelatin modified alginic acid
Sodium.Sodium alginate and chitosan have the substance of opposite charges as surface, and the two is capable of forming poly- electricity by electrostatic force
Matter compound is solved, therefore, by using sodium alginate and chitosan, bilayer is prepared and wraps solution, and by sustained-release micro-spheres described
Bilayer, which wraps, carries out secondary treatment in solution, can form polymer complex on sustained-release micro-spheres surface and alternately wrap layer, thus into
The sustained release performance of one step raising sustained-release micro-spheres.In addition, the polyalcohol hydrogel compound system that chitosan and gelatin are formed has pH
Value stimulation sensibility, enables and is taken load-carrying drug by it and specifically discharged in acidic environment, to guarantee institute
The targeted release for stating sustained release esomeprazole sodium, improves its therapeutic effect and sustained release performance.
In some embodiments of the invention, a kind of preparation method of esomeprazole sodium, including following step are provided
It is rapid:
S1. using Sodium Glycinate, sodium chloride, calcio-disodium edetate and calcium glutamate as auxiliary additive, preparation
Esomeprazole sodium water solution；
S2. it uses poly lactide-glycolide acid, ethyl acetate and N-Methyl pyrrolidone for raw material, prepares oily phase
Organic solution；
Described in S3 ' is prepared by the esomeprazole sodium water solution prepared by step S1, by step S2
It oily phase organic solution and is mixed containing sodium alginate with the aqueous solution of gelatin, and carries out ultrasonic emulsification, obtained and contain sodium alginate
Mixed phase emulsion；
S4 ' use by step S3 ' preparation the mixed phase emulsion and calcium chloride water containing sodium alginate into
Row reaction obtains sustained release esomeprazole sodium, and the sustained release esomeprazole sodium is put into containing sodium alginate and shell
The mixing of glycan, which wraps in solution, to be stirred；
S5. active carbon stirring and adsorbing, decarburization are carried out to the sustained release esomeprazole sodium obtained by step S4 '
Filter is sterile filtered and is freeze-dried；
Specifically, step S3 ' includes following sub-step:
S3 ' -1. presses esomeprazole sodium water solution: the volume ratio of oily phase organic solution=(40-60): (40-60) is mixed
Raw material is closed, and carries out ultrasonic emulsification, obtains mixed phase emulsion；
S3 ' -2. is by sodium alginate: gelatin: water=(8-16): (2-4): (80-90) mass ratio weighs raw material, 40 DEG C -
It is evenly stirred until that raw material is completely dissolved under the conditions of 50 DEG C of temperature, is cooled to room temperature, obtain the water containing sodium alginate and gelatin
Solution.
S3 ' -3. presses mixed phase emulsion: the aqueous solution containing sodium alginate and gelatin=(40-60): the body of (40-60)
Product carries out ultrasonic emulsification than mixing by the mixed phase emulsion and containing sodium alginate with the aqueous solution of gelatin, is contained
The mixed phase emulsion of sodium alginate.
Step S4 ' includes following sub-step:
S4 ' -1. is by calcium chloride: glutaraldehyde: water=(2-4): (2-4): the mass ratio of (92-96) weighs raw material, and stirring is equal
It is even, prepare calcium chloride water；
S4 ' -2. will pass through the mixed phase containing sodium alginate of the acquisition of step S3 ' -3 under high voltage electrostatic field
Emulsion Uniform jet, which instills in the calcium chloride water obtained by step S4 ' -1 that rotation is shaken, to be reacted, centrifugation point
Esomeprazole sodium is sustained from rear acquisition, wherein the mixed phase emulsion and calcium chloride water containing sodium alginate
Volume ratio is (40-60): (40-60)；
S4 ' -3. is by sodium alginate: chitosan: acetic acid=(5-10): (5-10): the mass ratio of (80-90) weighs raw material,
It stirs evenly, prepares mixing and wrap solution；
The sustained release esomeprazole sodium obtained by step S4 ' -2 is placed through step S4 ' -3 and obtained by S4 ' -4.
The mixing obtained, which wraps in solution, to be stirred, mixing time 20min-40min, and sustained release Chinese mugwort Si Aomeila is obtained after centrifuge separation
Azoles sodium.
Embodiment 1-3
The sample of 1-3 of the embodiment of the present invention is prepared by following steps:
S1-1. the water for injection of 60% dosage is measured, Sodium Glycinate and calcio-disodium edetate is added, is stirred to complete
Dissolution obtains the first solution；
S1-2. the water for injection of 20% dosage is measured, calcium glutamate is added, is stirred to being completely dissolved, is cooled to room temperature, obtains
Obtain the second solution；
S1-3. the first solution and the second solution are uniformly mixed, esomeprazole sodium are added, stirring to being completely dissolved,
Obtain third solution；
S1-4. the pH value that third solution is adjusted using disodium phosphate soln, is added sodium chloride after adding water to full dose, stirs
Uniformly, esomeprazole sodium water solution is obtained；
S2. measuring poly lactide-glycolide acid, ethyl acetate and N-Methyl pyrrolidone is raw material, is uniformly mixed,
Prepare oily phase organic solution；
S3-1. esomeprazole sodium water solution and oily phase organic solution are mixed, and uses ultrasonic emulsification instrument (power
200W, ultrasound 1s are spaced 1s) ultrasonic emulsification is carried out, obtain mixed phase emulsion；
S3-2. mixed phase emulsion and sodium alginate aqueous solution are mixed, and (power 200W, is surpassed using ultrasonic emulsification instrument
Sound 1s is spaced 1s) ultrasonic emulsification is carried out, obtain the mixed phase emulsion containing sodium alginate；
S4. alginic acid will be contained under high voltage electrostatic field using the high-voltage electrostatic field of electrostatic field generator manufacture 15kV
The mixed phase emulsion Uniform jet of sodium, which instills in rotation concussion calcium chloride water, to be reacted, and is sustained after centrifuge separation
Esomeprazole sodium；
S5-1. sustained release esomeprazole sodium washed, filtered, and carried out at freeze-drying in the first condition
Reason；
S5-2. esomeprazole sodium freeze-drying process under a second condition will be sustained；
S5-3. esomeprazole sodium freeze-drying process under third condition will be sustained；
S5-4. with the rate of pressure rise of the heating rate of 0.1 DEG C -0.2 DEG C/min and 40Pa-100Pa/min by temperature and pressure
Power is increased to isothermal holding under fourth condition.
Wherein, the raw material and process conditions that the sample of 1-3 of the embodiment of the present invention uses during the preparation process are listed in table 1.
Table 1
Embodiment 4-6
The sample of 1-3 of the embodiment of the present invention is prepared by following steps:
S1-1. the water for injection of 60% dosage is measured, Sodium Glycinate and calcio-disodium edetate is added, is stirred to complete
Dissolution obtains the first solution；
S1-2. the water for injection of 20% dosage is measured, calcium glutamate is added, is stirred to being completely dissolved, is cooled to room temperature, obtains
Obtain the second solution；
S1-3. the first solution and the second solution are uniformly mixed, esomeprazole sodium are added, stirring to being completely dissolved,
Obtain third solution；
S1-4. the pH value that third solution is adjusted using disodium phosphate soln, is added sodium chloride after adding water to full dose, stirs
Uniformly, esomeprazole sodium water solution is obtained；
S2. measuring poly lactide-glycolide acid, ethyl acetate and N-Methyl pyrrolidone is raw material, is uniformly mixed,
Prepare oily phase organic solution；
S3 ' -1. mixes esomeprazole sodium water solution and oily phase organic solution, and uses ultrasonic emulsification instrument (power
200W, ultrasound 1s are spaced 1s) ultrasonic emulsification is carried out, obtain mixed phase emulsion；
Sodium alginate, gelatin, water are mixed and stirred for uniformly being completely dissolved to raw material by S3 ' -2., are cooled to room temperature, and are obtained
Aqueous solution containing sodium alginate and gelatin；
S3 ' -3. mixes mixed phase emulsion and sodium alginate with the aqueous solution of gelatin, and uses ultrasonic emulsification instrument (function
Rate 200W, ultrasound 1s are spaced 1s) ultrasonic emulsification is carried out, obtain the mixed phase emulsion containing sodium alginate；
S4 ' -1. weighs calcium chloride, glutaraldehyde, water, stirs evenly, and prepares calcium chloride water；
S4 ' -2. will contain sea under high voltage electrostatic field using the high-voltage electrostatic field of electrostatic field generator manufacture 15kV
The mixed phase emulsion Uniform jet of mosanom instill in the calcium chloride water of rotation concussion obtained by step S4 ' -1 into
Row reaction obtains sustained release esomeprazole sodium after centrifuge separation；
S4 ' -3. weighs sodium alginate, chitosan, acetic acid, stirs evenly, and prepares mixing and wraps solution；
The sustained release esomeprazole sodium obtained by step S4 ' -2 is placed through step S4 ' -3 and obtained by S4 ' -4.
The mixing obtained, which wraps in solution, to be stirred, and sustained release esomeprazole sodium is obtained after centrifuge separation.
S5-1. sustained release esomeprazole sodium washed, filtered, and carried out at freeze-drying in the first condition
Reason；
S5-2. esomeprazole sodium freeze-drying process under a second condition will be sustained；
S5-3. esomeprazole sodium freeze-drying process under third condition will be sustained；
S5-4. with the rate of pressure rise of the heating rate of 0.1 DEG C -0.2 DEG C/min and 40Pa-100Pa/min by temperature and pressure
Power is increased to isothermal holding under fourth condition.
Wherein, the raw material and process conditions that the sample of 4-6 of the embodiment of the present invention uses during the preparation process are listed in table 2.
Table 2
Test example 1
It is tested according to 2010 editions two annex XIXC stability test guidelines of Chinese Pharmacopoeia, to embodiment 1-6
The stability of the sample of preparation is investigated.
Experimental example of the present invention is to the sample of the embodiment 1-6 sample prepared and comparative example 1-3 in high temperature, high humidity and illumination
Under the conditions of long-time stability (40 DEG C ± 2 DEG C of temperature, placed under the conditions of humidity RH75% ± 5% 0 month, 2 months January, March, April,
May and June) detected, detection parameters include product characteristics, prepare the clarity of solution, visible foreign matters, basicity, moisture,
The indexs such as content, impurity I, impurity II, impurity III, impurity IV, impurity V, other impurities and total impurities.Wherein, table 3 is listed
Wherein representative test result.
Wherein, the sample of comparative example 1 is to buy (name of product: injection esomeprazole sodium, quotient by commercial sources
The name of an article: resistance to letter, production firm: AstraZeneca AB).Comparative example 2 and 3 is that inventor prepares in laboratory conditions.Comparison
The preparation method of example 2-3 is as follows.
The preparation method of comparative example 2: esomeprazole sodium: Sodium Glycinate: sodium chloride: calcio-disodium edetate is pressed:
Calcium glutamate: mass ratio=94 of water for injection: weigh raw material at 2.0: 1.2: 1.8: 1: 4800, measures the injection of 60% dosage
With water, Sodium Glycinate and calcio-disodium edetate is added, is stirred at 10 DEG C to being completely dissolved, obtains the first solution；It measures
The water for injection of 20% dosage is added calcium glutamate, stirs at 30 DEG C to being completely dissolved, be cooled to room temperature, obtains the second solution；
First solution and the second solution are uniformly mixed, esomeprazole sodium is added, heat up and is stirred at 40 DEG C to being completely dissolved,
Obtain third solution；Third solution is cooled to 2 DEG C, the pH value of third solution is adjusted to 11.5 using disodium phosphate soln,
Sodium chloride is added after adding water to full dose, stirs evenly, obtains esomeprazole sodium water solution；It is water-soluble by esomeprazole sodium
Liquid: sodium alginate aqueous solution=20: 80 volume ratio, by the sodium alginate water of esomeprazole sodium water solution and 10wt%
After mixing, the calcium chloride water of the mixed liquor and 2wt% are mixed and stirred for 2-4 hours again for solution, and stirring is completed
Afterwards, product washed, filtered, is successively freeze-dried under the following conditions: freezing 60min at a temperature of -60 DEG C；-20
DEG C temperature freezes 60min under 50Pa pressure；0 DEG C of temperature freezes 60min under 1000Pa pressure；With 0.1 DEG C -0.2 DEG C/min
Heating rate and 40Pa-100Pa/min rate of pressure rise temperature and pressure is increased to 20 DEG C and 10kPa under conditions of, protect
Hold 60min.
The preparation method of comparative example 3: esomeprazole sodium: Sodium Glycinate: sodium chloride: calcio-disodium edetate is pressed:
Calcium glutamate: mass ratio=94 of water for injection: weigh raw material at 2.0: 1.2: 1.8: 1: 4800, measures the injection of 60% dosage
With water, Sodium Glycinate and calcio-disodium edetate is added, is stirred at 10 DEG C to being completely dissolved, obtains the first solution；It measures
The water for injection of 20% dosage is added calcium glutamate, stirs at 30 DEG C to being completely dissolved, be cooled to room temperature, obtains the second solution；
First solution and the second solution are uniformly mixed, esomeprazole sodium is added, heat up and is stirred at 40 DEG C to being completely dissolved,
Obtain third solution；Third solution is cooled to 2 DEG C, the pH value of third solution is adjusted to 11.5 using disodium phosphate soln,
Sodium chloride is added after adding water to full dose, stirs evenly, obtains esomeprazole sodium water solution；It is water-soluble by esomeprazole sodium
Liquid: sodium alginate aqueous solution=20: 80 volume ratio, by the sodium alginate water of esomeprazole sodium water solution and 10wt%
After mixing, the calcium chloride water of the mixed liquor and 2wt% are mixed and stirred for 2-4 hours again for solution, and stirring is completed
Afterwards, product washed, filtered, the freeze-drying of 180min is carried out at a temperature of -40 DEG C.
Table 3
Long term stability tests the result shows that, the sample of embodiment 1-6 preparation is compared to comparative example 1-3, tool, has more preferable
Stability and clarity.Wherein, the sample of embodiment 4-6 preparation is compared to sample prepared by embodiment 1-3, and stability is more
It is good.
Test example 2
The sample of embodiment 1-6 and comparative example 1-3 are subjected to vitro release measurement, measuring method are as follows: weigh 100mg sample
Product are placed in 250ml round-bottomed flask, using the buffer of 200mL as dissolution medium, are placed in water bath with thermostatic control shaking table, are 37 in temperature
Vitro release measurement is carried out under conditions of DEG C ± 0.2 DEG C and hunting speed 120rpm.It is respectively taken at scheduled time point respectively
1mL dissolution medium is used for the content of high effective liquid chromatography for measuring esomeprazole sodium, and supplements fresh dissolution medium, as a result
It is shown in Table 4.Wherein, buffer adds deionized water to prepare using sodium dihydrogen phosphate and hydrochloric acid, and the pH value of the buffer is 2.0.
Table 4
This experimental example simulates stomach acidic environment, and sustained release performance test is carried out under conditions of pH value is 2.0, and the present invention is real
The esomeprazole sodium sample for applying 1-6 preparation has a good slow release effect, and the sustained release period is more than including commercially available medicine
The esomeprazole sodium of comparative example 1-3 will be grown.Also, the esomeprazole sodium sample of 4-6 of embodiment of the present invention preparation exists
Slow release effect in acidic environment is better than the esomeprazole sodium sample of embodiment 1-3 preparation, this is because, embodiment 4-
6 in sample preparation procedure, using chitosan and it is gelatin modified modification has been carried out to sodium alginate, on sustained-release micro-spheres surface
It forms polymer complex and alternately wraps layer, and the polyalcohol hydrogel compound system that chitosan and gelatin are formed to be taken by it
Load-carrying drug can specifically be discharged in acidic environment, to guarantee the slow of the sustained release esomeprazole sodium
Release performance.
Obviously, above-described embodiment is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the present invention
In embodiment, those of ordinary skill in the art without creative efforts to these embodiments carry out it is various
Variation, modification, replacement and improvement, should all be included in the protection scope of the present invention.
Claims (9)
1. a kind of preparation method of esomeprazole sodium, which comprises the following steps:
S1. esomeprazole sodium water solution is prepared；
S2. oily phase organic solution is prepared；
S3. mutually have by the esomeprazole sodium water solution prepared by step S1, by the oil prepared by step S2
Machine solution and sodium alginate aqueous solution mixing, and ultrasonic emulsification is carried out, obtain the mixed phase emulsion containing sodium alginate；
S4. it is carried out using the mixed phase emulsion containing sodium alginate and calcium chloride water that are prepared by step S3 anti-
It answers, obtains sustained release esomeprazole sodium；
S5. the sustained release esomeprazole sodium obtained by step S4 is washed, filtered and is freeze-dried.
2. the preparation method of esomeprazole sodium according to claim 1, which is characterized in that in step sl, use
Sodium Glycinate, sodium chloride, calcio-disodium edetate and calcium glutamate prepare the esomeprazole as auxiliary additive
Sodium water solution.
3. the preparation method of esomeprazole sodium according to claim 2, which is characterized in that in step sl, use
The mass ratio of raw material is esomeprazole sodium: Sodium Glycinate: sodium chloride: calcio-disodium edetate: calcium glutamate: injection
Water=(94-96): (1.2-2.0): (0.8-1.2): (1.2-1.8): (0.8-1): (4800-5000).
4. the preparation method of esomeprazole sodium according to claim 3, which is characterized in that step S1 includes following son
Step:
S1-1. the water for injection for measuring 60% dosage, is added the Sodium Glycinate and calcio-disodium edetate, 10
It is stirred under the conditions of DEG C -15 DEG C of temperature to being completely dissolved, obtains the first solution；
S1-2. the water for injection for measuring 20% dosage, is added the calcium glutamate, under the conditions of 30 DEG C -35 DEG C of temperature
Stirring is cooled to room temperature to being completely dissolved, and obtains the second solution；
S1-3. first solution and the second solution are uniformly mixed, the esomeprazole sodium are added, be warming up to 40 DEG C-
45 DEG C of temperature, stirring obtain third solution to being completely dissolved；
S1-4. it is cooled under the conditions of 2 DEG C -6 DEG C of temperature, is adjusted the pH value of the third solution using disodium phosphate soln
To 11-12, the sodium chloride is added after adding water to full dose, stirs evenly, obtains the esomeprazole sodium water solution.
5. the preparation method of esomeprazole sodium according to claim 3, which is characterized in that in step s 2, use
Poly lactide-glycolide acid, ethyl acetate and N-Methyl pyrrolidone are raw material, prepare the oily phase organic solution.
6. the preparation method of esomeprazole sodium according to claim 5, which is characterized in that in step s 2, by poly-
Poly lactic coglycolic acid: ethyl acetate: N-Methyl pyrrolidone=(50-80): (10-20): the volume ratio of (10-30)
Mixed solution is prepared, is uniformly mixed, the oily phase organic solution is obtained.
7. the preparation method of esomeprazole sodium according to claim 5, which is characterized in that step S3 includes following son
Step:
S3-1. press esomeprazole sodium water solution: the volume ratio of oily phase organic solution=(40-60): (40-60) mixes former
Material, and ultrasonic emulsification is carried out, obtain mixed phase emulsion；
S3-2. press mixed phase emulsion: sodium alginate aqueous solution=(40-60): the volume ratio of (40-60) will pass through step S3-1
The mixed phase emulsion and the sodium alginate aqueous solution mixing obtained, and ultrasonic emulsification is carried out, it obtains mixed containing sodium alginate
Close phase emulsion.
8. the preparation method of esomeprazole sodium according to claim 7, which is characterized in that in step s 4, in height
Press under electrostatic field, will be obtained by step S3 described in mixed phase emulsion Uniform jet containing sodium alginate instill and rotate
It is reacted in concussion calcium chloride water, sustained release esomeprazole sodium is obtained after centrifuge separation.
9. a kind of esomeprazole sodium, it is characterised in that: the esomeprazole sodium is used as any in claim 1-8
The preparation method of esomeprazole sodium described in one obtains.
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| CN115089559A (en) * | 2022-08-08 | 2022-09-23 | 山东济坤生物制药有限公司 | Preparation method of microspheres for injection |
| CN116496250A (en) * | 2023-04-18 | 2023-07-28 | 新沂大江化工有限公司 | Esomeprazole sodium synthesis process |
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