CN117624057A - Amorphous levosimendan sodium salt and preparation method and application thereof - Google Patents
Amorphous levosimendan sodium salt and preparation method and application thereof Download PDFInfo
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- CN117624057A CN117624057A CN202311620270.8A CN202311620270A CN117624057A CN 117624057 A CN117624057 A CN 117624057A CN 202311620270 A CN202311620270 A CN 202311620270A CN 117624057 A CN117624057 A CN 117624057A
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- levosimendan
- sodium salt
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- 229960000692 levosimendan Drugs 0.000 title claims abstract description 118
- -1 levosimendan sodium salt Chemical class 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- WHXMKTBCFHIYNQ-SECBINFHSA-N levosimendan Chemical compound C[C@@H]1CC(=O)NN=C1C1=CC=C(NN=C(C#N)C#N)C=C1 WHXMKTBCFHIYNQ-SECBINFHSA-N 0.000 claims description 40
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 20
- 238000004108 freeze drying Methods 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 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 12
- 239000004695 Polyether sulfone Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 229920006393 polyether sulfone Polymers 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 229920000858 Cyclodextrin Polymers 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 229920003078 Povidone K 12 Polymers 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 8
- 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 description 8
- 229930182555 Penicillin Natural products 0.000 claims description 7
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 7
- 238000011049 filling Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 229940049954 penicillin Drugs 0.000 claims description 7
- 238000007789 sealing Methods 0.000 claims description 7
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 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 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229940069328 povidone Drugs 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000005096 rolling process Methods 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 239000008176 lyophilized powder Substances 0.000 claims 1
- 230000003321 amplification Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 229940090044 injection Drugs 0.000 description 16
- 238000002347 injection Methods 0.000 description 16
- 239000007924 injection Substances 0.000 description 16
- 239000000843 powder Substances 0.000 description 14
- 239000007788 liquid Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 9
- 239000008215 water for injection Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 229960004106 citric acid Drugs 0.000 description 5
- 210000004907 gland Anatomy 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 238000003825 pressing Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000002107 myocardial effect Effects 0.000 description 4
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 229960001508 levocetirizine Drugs 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 230000007928 solubilization Effects 0.000 description 3
- 238000005063 solubilization Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 206010007556 Cardiac failure acute Diseases 0.000 description 2
- 229920012266 Poly(ether sulfone) PES Polymers 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000005638 hydrazono group Chemical group 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000036284 oxygen consumption Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HMBHAQMOBKLWRX-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-3-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)COC2=C1 HMBHAQMOBKLWRX-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 229940122434 Calcium sensitizer Drugs 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940075419 choline hydroxide Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000012065 filter cake Substances 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
- 229940093181 glucose injection Drugs 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 1
- 229960004002 levetiracetam Drugs 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229940083608 sodium hydroxide Drugs 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 description 1
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical preparations, and provides an amorphous levosimendan sodium salt, a preparation method and application thereof, wherein the amorphous levosimendan sodium salt has no characteristic diffraction peak in an X-ray powder diffraction spectrogram, and the levosimendan sodium salt provided by the invention has good solubility, purity of over 99.5% and good stability; the preparation method is simple and convenient, easy to realize industrial amplification, has the yield of more than 95 percent, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and provides an amorphous levosimendan sodium salt, a preparation method and application thereof.
Background
Heart failure is the manifestation of the progression of a variety of cardiovascular diseases to the end stage, with the mortality rate remaining high throughout the year, threatening the life safety of the patient. The existing positive myodynamia medicines in the traditional treatment influence myocardial expansion, increase myocardial oxygen consumption and the like, which are limited in clinical use, and the appearance of the calcium ion sensitizer-levosimendan can improve heart failure symptoms under the condition of not increasing myocardial oxygen consumption and stabilizing abnormal hemodynamics. The safety and curative effect of the medicine are reliable as shown by a plurality of experimental data, and the recommendation of the reasonable medicine guidelines for heart failure (second edition) is obtained.
Levosimendan is a calcium-sensitized anti-acute heart failure drug developed by the company Orion, euclidean, finland, and is an effective positive inotropic calcium sensitizer, and is mainly used for clinically short-term treatment of acute decompensated heart failure requiring an increase in myocardial contractility. The chemical name is (R) - [ [4- (1, 4,5, 6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl ]]Hydrazono group]Malononitrile of formula C 14 H 12 N 6 O has the following structural formula:
levosimendan is a yellow crystalline powder which is poorly soluble in water and readily degradable, with a pKa of 6.26. The existing commercial levosimendan injection uses absolute ethyl alcohol and polyethylene glycol 400 as solvents, and is used after 5% glucose injection is used for clinical use. However, the concentration of ethanol is diluted, which is likely to cause the precipitation of levosimendan from the compatible solution, so that insoluble particles exceed the standard, and the medication safety is affected. In addition, ethanol-containing formulations are irritating to both blood vessels and muscles during intravenous injection, and cause hemolysis in severe cases.
Patent CN108289832B adopts sulfobutyl ether-beta-cyclodextrin sodium for solubilization to prepare Cheng Zuoxi Mondand freeze-dried powder injection, but the cyclodextrin inclusion compound solubilization scheme requires high dosage of solubilizer, drug: the mass ratio of the sodium sulfobutyl ether-beta-cyclodextrin is up to 1:70, and the influence and the dosage of cyclodextrin products on the kidney safety of human bodies are closely related, so that the use of high dosage brings potential safety hazards.
Patent CN111548310B discloses a preparation method of a crystal form of levosimendan Meng Danna, which is to prepare Cheng Zuoxi of a sodium salt of levosimendan, solve the problem of insolubility of levosimendan Meng Danshui, and adopt a salt forming method or a recrystallization method to prepare a crystal form a of levosimendan Meng Danna, so that the yield is low.
Patent CN111718299B discloses a preparation method of a levocetirizine Meng Danna crystal form B, which is the same as patent CN111548310B and has lower actual yield.
Patent CN 112500353B discloses a preparation method of an esterified prodrug of levosimendan, and the designed compound needs to be hydrolyzed and metabolized in a human body to be converted into levosimendan to exert pharmacological effects.
Since different crystal forms of chemical drugs affect the appearance, solubility and bioavailability of the drugs, it is desirable to provide an amorphous levosimendan sodium salt with high solubility, good stability and high yield, and a preparation method and application thereof.
Disclosure of Invention
Aiming at the defects of the technology, the inventor provides an amorphous levosimendan sodium salt, a preparation method and application thereof, wherein the amorphous levosimendan sodium salt has no characteristic diffraction peak in an X-ray powder diffraction spectrogram, and the levosimendan sodium salt provided by the invention has good solubility, purity of over 99.8 percent and good stability; sodium carbonate is commonly used as a stabilizer and a pH regulator of injection, has good safety, is used as weak base, has mild reaction conditions, and has few degradation impurities and high yield. The solvent required by the provided preparation method is water, the preparation method is simple and convenient, the industrial amplification is easy to realize, the yield is more than 98 percent, and the preparation method is suitable for industrial production.
The inventor has submitted a patent application with publication number of CN116473930A, namely levosimendan for injection and a preparation method thereof, the technical scheme uses one or more of anhydrous sodium carbonate, choline hydroxide, sodium hydroxide, tromethamine and arginine as a cosolvent, and the aim of solubilization is achieved by adjusting the pH value by the cosolvent, but the cosolvent in the scheme does not react with the levosimendan and is only a simple composition. After further research, the inventor finds that no related report exists on the salification of sodium carbonate and levosimendan at present, but the preparation of the salt of levosimendan and sodium carbonate can better improve the solubility and the stability and greatly shorten the preparation time compared with the composition, so that the following specific technical scheme is finally obtained:
the invention mainly provides an amorphous levosimendan sodium salt, which has the following structural formula:
in particular, the amorphous levosimendan sodium salt is a salt formed by dehydrogenating the hydrazono group of levosimendan to form an ionic bond.
The above-mentioned compound is an amorphous compound, and its internal molecules are not periodically arranged, so that it has no fixed melting point and no lattice structure. This disordered distribution prevents the amorphous compound from diffracting the X-rays.
Specifically, the amorphous levosimendan sodium salt has no obvious and sharp characteristic diffraction peak in an XRD spectrum, 2 theta has a wide and weak diffraction peak between 20 degrees, the sharp diffraction peak with extremely weak signals is caused by sodium bicarbonate, and equimolar sodium bicarbonate is generated in the process of preparing the levosimendan sodium salt by using sodium carbonate.
Specifically, the Differential Scanning Calorimetry (DSC) spectrum of the amorphous levosimendan sodium salt compound has 2 endothermic peaks at 51.5 ℃ and 138.7 ℃, which are caused by coexisting sodium bicarbonate.
The amorphous levosimendan sodium salt solves the technical problem that the levosimendan is insoluble in water in the prior art, has the advantage of good water solubility, and can avoid the use of ethanol or other organic solvents in the preparation production, thereby avoiding adverse effects caused by the use of the ethanol or other organic solvents.
In addition, the inventor also provides a preparation method of the amorphous levosimendan sodium salt, which comprises the following specific steps: adding levosimendan and sodium carbonate into a reaction solvent, stirring for reaction at 5-40 ℃, filtering by using a 0.22 mu m polyethersulfone filter membrane after the reaction is finished, and freeze-drying to obtain the levosimendan.
Wherein the concentration of levosimendan in the reaction system is 2mg/ml-5mg/ml, and the reaction temperature is preferably 5-15 ℃.
The molar ratio of levosimendan to sodium carbonate is from 1:1.0 to 1:1.5, preferably from 1:1.0 to 1:1.2.
The reaction solvent is water.
The present invention is not particularly limited to the lyophilization step, and either conventional lyophilization methods or the presently disclosed lyophilization methods can be used in the present invention, and the lyophilization profile that can be selected is:
| step (a) | Setting temperature (DEG C) | Heating time (min) | Duration (min) | Vacuum degree (pa) |
| Prefreezing | -50--30 | — | 60-240 | — |
| Primary drying | -40--10 | 10-100 | 600-1440 | 30-10 |
| Analytical drying | 10-40 | 10-120 | 60-480 | 15-5 |
Wherein the preferred lyophilization profile is:
| step (a) | Setting temperature (DEG C) | Heating time (min) | Duration (min) | Vacuum degree (Pa) |
| Prefreezing | -45--35 | — | 60-240 | — |
| Primary drying | -25--15 | 20-80 | 900-1440 | 20-10 |
| Analytical drying | 20-30 | 20-100 | 60-360 | 10-5 |
It is another object of the present invention to provide a pharmaceutical composition comprising the above amorphous levosimendan sodium salt compound, which composition is composed of levosimendan sodium salt and other pharmaceutically acceptable ingredients; the pharmaceutical composition is preferably freeze-dried powder.
The preparation method of the medicinal composition adopts the conventional technology, and the amorphous levosimendan sodium salt prepared by the invention is combined with pharmaceutically common auxiliary materials to prepare a usable dosage form.
For freeze-dried powder, the preferred auxiliary materials in the pharmaceutical composition are selected from one or more of povidone, cyclodextrin, sodium cyclodextrin, mannitol, sucrose, glucose, glycine and lactose as excipients; one or more of citric acid, sodium citrate, acetic acid, sodium acetate, phosphoric acid, dipotassium hydrogen phosphate, sodium hydroxide and hydrochloric acid are used as pH regulator;
still further, preferably the povidone is povidone K12, preferably the cyclodextrin is hydroxypropyl-beta-cyclodextrin, sodium sulfobutyl ether-beta-cyclodextrin.
Based on the above scheme, preferably, the levosimendan sodium salt: the weight ratio of povidone K12 is 1:1-1:40, preferably 1:4-1:20; levosimendan sodium salt: the weight ratio of the hydroxypropyl-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin sodium is 1:1-1:90, preferably 1:10-1:40.
Based on the above-mentioned scheme, the pH is adjusted to 7.0 to 10.0, more preferably 8.5 to 9.5, with a pH adjustor.
The invention further provides a preparation method of the freeze-dried powder of the levosimendan sodium salt, which comprises the following steps:
step (1): weighing levosimendan sodium salt and excipient, dissolving in water, adding a pH regulator to adjust the pH to 7.0-10.0 after the dissolution is completed, adding water to fix the volume to the total volume, and filtering by a 0.22 mu m PES filter membrane;
step (2): and (3) subpackaging the solution obtained in the step (1) into penicillin bottles, freeze-drying, filling nitrogen, rolling and sealing.
When the freeze-dried powder injection prepared by the invention is used in specific clinical compatibility, the special stabilizer solution (citric acid solution) is matched for use, the concentration of the citric acid solution is 2-5mg/ml, preferably 3.5mg/ml, one freeze-dried powder injection is matched with one special stabilizer solution, and the stability of the freeze-dried powder injection after compatibility can be greatly improved by adding the special stabilizer solution.
The preparation method of the special stabilizer solution comprises the following steps: weighing anhydrous citric acid with prescription amount, stirring at room temperature for dissolving, constant volume filtering with 0.22 μm microporous membrane, packaging into ampoule bottle with 5 ml/branch, and sterilizing at 121deg.C for 15 min. This special stabilizer has been described in the applicant's prior application and is not described in detail by the inventors.
Compared with the prior art, the invention has the following beneficial effects:
(1) The related patent of levosimendan salt type compound is CN111548310B, CN111718299B, but the alkali used in the two patents is sodium hydroxide, sodium methoxide, sodium ethoxide or a mixture thereof, and the actual yield is below 80%. The alkali used in the invention is sodium carbonate, and the purity of the amorphous levosimendan sodium salt prepared by the invention is above 99.5%, the yield is above 95%, the solubility is high, and the stability is good.
(2) The preparation process of the amorphous levosimendan sodium salt disclosed by the invention is simple and convenient, low in equipment dependence, free from the use of organic solvents, good in reproducibility and suitable for industrial production.
(3) The invention prepares the levosimendan sodium salt and other compositions into the freeze-dried powder injection, the solvent is water, no organic solvent is used, the preparation method is simple, the industrial amplification is easy to realize, and the stability is greatly improved when the levosimendan sodium salt and other compositions are prepared into the freeze-dried powder injection.
Drawings
Figure 1 is an amorphous form of the sodium salt of levosimendan in example 2 of the present invention 1 H-NMR spectrum.
Figure 2 is an X-ray powder diffraction pattern of the amorphous levosimendan sodium salt of example 1 of the present invention.
Figure 3 is a differential scanning calorimetry thermogram of the amorphous levosimendan sodium salt of example 2 of the present invention.
Figure 4 is an HPLC purity profile of amorphous levosimendan sodium salt in example 2 of the present invention.
Detailed Description
The above-described aspects of the present invention will be described in further detail by way of the following embodiments, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following embodiments. All techniques based on the above description of the present invention are within the scope of the present invention, and unless otherwise specified, the following examples are accomplished by conventional techniques, usually under conventional conditions or under conditions recommended by the manufacturer.
EXAMPLE 1 preparation of amorphous Levosimendan sodium salt
400ml of water was added to a reaction flask, 1.0000g of levosimendan and 0.3782g of anhydrous sodium carbonate were added to the above reaction flask, the reaction was stirred at 10.+ -. 2 ℃ for 50 minutes to obtain a yellow clear liquid, which was then filtered through a 0.22 μm polyethersulfone filter (PES filter) and freeze-dried (lyophilization procedure shown in the following table) to obtain 1.0597g of amorphous levosimendan sodium salt with a yield of 98.26% and a purity of 99.97%.
| Step (a) | Setting temperature (DEG C) | Heating time (min) | Duration (min) | Vacuum degree (Pa) |
| Prefreezing | -40 | — | 120 | — |
| Primary drying | -15 | 40 | 1140 | 20 |
| Analytical drying | 30 | 80 | 210 | 10 |
The X-ray powder diffraction pattern of the product is shown in fig. 2, and the X-ray powder diffraction pattern of the levosimendan sodium salt prepared in this example has a broad and weak diffraction peak at 20 ° at 2θ, and no characteristic diffraction peak, so that the levosimendan sodium salt is determined to be amorphous.
EXAMPLE 2 preparation of amorphous Levosimendan sodium salt
350ml of water is measured and added into a reaction bottle, 1.0003g of levosimendan and 0.4160g of anhydrous sodium carbonate are added into the reaction bottle, the mixture is stirred and reacted for 45min at the temperature of 10+/-2 ℃ to obtain yellow clear liquid, after the reaction is finished, the yellow clear liquid is filtered by a PES (polyether sulfone) filter membrane with the thickness of 0.22 mu m, and the amorphous levosimendan sodium salt 1.0745g is obtained through freeze drying, the yield is 99.63%, and the purity is 99.96%.
The levosimendan sodium salt prepared in this example 1 The H-NMR spectrum is shown in figure 1, and the hydrogen of the hydrazono group on the structure of the levosimendan is replaced by sodium ions to generate the levosimendan sodium salt; the differential scanning calorimetric diagram is shown in figure 3, wherein 2 endothermic peaks exist at 51.5 ℃ and 138.7 ℃, and the peaks are caused by coexisting sodium bicarbonate, and other endothermic peaks are absent; the HPLC purity profile is shown in FIG. 4, and the purity of the levosimendan sodium salt is 99.96%.
EXAMPLE 3 preparation of amorphous Levosimendan sodium salt
300ml of water is measured and added into a reaction bottle, 1.0002g of levosimendan and 0.4538g of anhydrous sodium carbonate are added into the reaction bottle, the mixture is stirred and reacted for 50min at the temperature of 10+/-2 ℃ to obtain yellow clear liquid, after the reaction is finished, the yellow clear liquid is filtered by a PES (polyether sulfone) filter membrane with the thickness of 0.22 mu m, and the amorphous levosimendan sodium salt 1.0735g is obtained through freeze drying, and the yield is 99.52 percent and the purity is 99.94 percent.
EXAMPLE 4 preparation of amorphous Levosimendan sodium salt
500ml of water was added to the reaction flask, 1.0005g of levosimendan and 0.3782g of anhydrous sodium carbonate were added to the above-mentioned reaction flask, and the mixture was stirred at 15.+ -. 2 ℃ for 50 minutes to obtain a yellow clear liquid, which was then filtered through a 0.22 μm PES filter membrane after completion of the reaction, and freeze-dried to obtain 1.0416g of amorphous levosimendan sodium salt, with a yield of 96.53% and a purity of 99.91%.
EXAMPLE 5 preparation of amorphous Levosimendan sodium salt
200ml of water was added to a reaction flask, 1.0002g of levosimendan and 0.4538g of anhydrous sodium carbonate were added to the above reaction flask, and the mixture was stirred at 20.+ -. 2 ℃ for 40min to obtain a yellow clear liquid, which was then filtered through a 0.22 μm PES filter membrane after completion of the reaction, and freeze-dried to obtain 1.0691g of amorphous levosimendan sodium salt, with a yield of 99.11% and a purity of 99.86%.
Comparative example 1 preparation of form B of levetiracetam Meng Danna
Into a 100ml flask, 0.7g of sodium hydroxide and 30ml of ethanol were added, and the mixture was stirred to obtain a sodium hydroxide ethanol solution, and into a 250ml flask, 5.0004g of levosimendan, 25ml of ethanol, 25ml of isopropyl alcohol were added, and the mixture was dissolved by stirring at room temperature. Sodium hydroxide methanol solution is added dropwise at room temperature, and the reaction is carried out for about 5 hours after the dropwise addition. The mixture was filtered and the filter cake was washed with 5ml of methanol. Drying under reduced pressure at 40 ℃ for 3 hours to obtain 3.7655g of the levocetirizine Meng Danna crystal form B, wherein the weight yield is 69.82%.
According to CN111718299B, the actual yield is far lower than 94%, the hydrolysis impurity OR-1420 of the sterile freeze-dried powder prepared by the levosimendan sodium crystal form B is over 0.15%, the redissolution time is about 90s, and an alcohol solvent is needed in the preparation process, so that the problem of organic solvent residue possibly exists;
the hydrolysis impurity OR-1420 of the aseptic freeze-dried powder prepared by the amorphous levosimendan sodium of the patent is below 0.1%, the stability is better, the redissolution time is about 40s, and the use is more convenient.
Preparation of amorphous Levosimendan sodium salt pharmaceutical composition of application example 1
(1) Prescription of prescription
| Prescription composition | Dosage of |
| EXAMPLE 1 preparation of Levosimendan sodium salt | 0.27g |
| Povidone K12 (Basiff) | 1.00g |
| Mannitol (Merck) | 5.00g |
| Water for injection | To 100ml |
(2) Preparation process
Taking the prescription amount of levosimendan sodium salt, povidone K12 and mannitol in a eggplant-shaped bottle, adding 90ml of water for injection, stirring in a water bath at the temperature of 10+/-2 ℃ for 30min, obtaining clear liquid after complete dissolution, fixing the volume of the water for injection to 100ml, filtering with a 0.22 mu m polyether sulfone (PES) filter membrane, subpackaging into penicillin bottles, 5 ml/bottle, half-pressing, freeze-drying, and sealing by a nitrogen-filled gland, wherein the water content is controlled below 1.5%.
Preparation of amorphous Levosimendan sodium salt pharmaceutical composition
(1) Prescription of prescription
| Prescription composition | Dosage of |
| EXAMPLE 2 preparation of Levosimendan sodium salt | 0.27g |
| Povidone K12 (Basiff) | 2.00g |
| Citric acid (Luo Fu medicine) | Proper amount of |
| Water for injection | Constant volume to 100ml |
(2) Preparation process
Taking the prescription amount of povidone K12 and levosimendan sodium salt in a eggplant-shaped bottle, adding 90ml of injection water, stirring in a water bath at the temperature of 10+/-2 ℃ for 30min, obtaining yellow clear liquid after complete dissolution, slowly dripping a proper amount of 1M citric acid solution to adjust the pH value to 9.0, fixing the volume of the injection water to 100ml, filtering with a 0.22 mu M polyether sulfone (PES) filter membrane, subpackaging into penicillin bottles, 5 ml/bottle, half-pressing a plug, freeze-drying, filling nitrogen and sealing a gland, and controlling the water content to be below 1.5%.
Application example 3 preparation of amorphous Levosimendan sodium salt pharmaceutical composition
(1) Prescription of prescription
| Prescription composition | Dosage of |
| EXAMPLE 3 preparation of Levosimendan sodium salt | 0.27g |
| Hydroxypropyl-beta-cyclodextrin (Zibo Qianlie) | 2.50g |
| Sucrose (Merck) | 10.00g |
| Hydrochloric acid | Proper amount of |
| Water for injection | Constant volume to 100ml |
(2) Preparation process
Taking the prescription amount of hydroxypropyl-beta-cyclodextrin and levosimendan sodium salt, adding 90ml of injection water into a eggplant-shaped bottle, stirring in a water bath at the temperature of 10+/-2 ℃ for 20min, obtaining clear liquid after complete dissolution, slowly dripping 0.1M hydrochloric acid solution to adjust the pH value to 9.1, fixing the volume of the injection water to 100ml, subpackaging into the penicillin bottle, filling 5 ml/bottle, half-pressing, freezing and drying, and sealing by a nitrogen filling gland to obtain the water content of less than 1.5%.
Preparation of amorphous Levosimendan sodium salt pharmaceutical composition
(1) Prescription of prescription
| Prescription composition | Dosage of |
| EXAMPLE 4 preparation of Levosimendan sodium salt | 0.27g |
| Sodium sulfobutyl ether-beta-cyclodextrin (Zibo Qian Hui) | 5.00g |
| Water for injection | Constant volume to 100ml |
(2) Preparation process
Adding sulfobutyl-beta-cyclodextrin sodium and levosimendan sodium salt with the prescription amount into a eggplant-shaped bottle, adding 90ml of water for injection, stirring in water bath at the temperature of 10+/-2 ℃ for 30min, obtaining clear liquid after complete dissolution, fixing the volume of the water for injection to 100ml, subpackaging into penicillin bottles with the volume of 5 ml/bottle, half-pressing plugs, freeze-drying, filling nitrogen and sealing a gland, and controlling the water content to be below 2.0%.
Preparation of amorphous Levosimendan sodium salt pharmaceutical composition
(1) Prescription of prescription
| Prescription composition | Dosage of |
| EXAMPLE 4 preparation of Levosimendan sodium salt | 0.27g |
| Mannitol (Merck) | 5.00g |
| Water for injection | Constant volume to 100ml |
(2) Preparation process
Taking mannitol and levosimendan sodium salt with a prescription amount, adding 90ml of injection water into a eggplant-shaped bottle, stirring in a water bath at the temperature of 10+/-2 ℃ for 30min, obtaining yellow clear liquid after complete dissolution, fixing the volume of the injection water to 100ml, subpackaging into penicillin bottles, 5 ml/bottle, half-pressing, freeze-drying, filling nitrogen and sealing with a gland, and controlling the water content below 1.5%.
The dried powder of the above application example was subjected to appearance, reconstitution time, appearance after reconstitution, levosimendan content, OR-1420 impurity detection, and the results are shown in table 1 below.
Table 1 application examples 1-5 test results
Table 1 shows that the sodium salt of levosimendan prepared in this example greatly increases the solubility of levosimendan, and the content of levosimendan is measured to be 98% -102%; the levosimendan sodium salt composition powder injection prepared according to the invention has the moisture below 1.5%, the stability is improved, the content of hydrolysis impurity OR-1420 is below 0.10%, and the stability is good. Compared with the levocetirizine Meng Danna crystal form B prepared by the prior art, the method has obvious progress.
It will be apparent to those skilled in the art that the present invention has been described in detail by way of illustration only, and it is not intended to be limited by the above-described embodiments, as long as various insubstantial modifications of the method concepts and aspects of the invention are employed or the inventive concepts and aspects of the invention are directly applied to other applications without modification, all within the scope of the invention.
Claims (10)
1. An amorphous levosimendan sodium salt characterized by the structural formula:
2. the amorphous levosimendan sodium salt of claim 1, wherein: the X-ray powder diffraction pattern of amorphous levosimendan sodium salt has a broad and weak diffraction peak at 20 deg. 2 theta, without characteristic diffraction peak.
3. The amorphous levosimendan sodium salt of claim 1, wherein: the amorphous levosimendan sodium salt has 2 endothermic peaks at 51.5℃and 138.7℃in a differential scanning calorimetry pattern.
4. A process for the preparation of amorphous levosimendan sodium salt as claimed in claim 1, characterized by the specific steps of: adding levosimendan and sodium carbonate into a reaction solvent, stirring for reaction at 5-40 ℃, filtering by using a 0.22 mu m polyethersulfone filter membrane after the reaction is finished, and freeze-drying to obtain the levosimendan;
wherein the molar ratio of the levosimendan to the sodium carbonate is 1:1.0-1:1.5.
5. The process for preparing amorphous levosimendan sodium salt as claimed in claim 4, wherein the dissolution temperature is 5-15 ℃ with stirring.
6. The process for the preparation of amorphous levosimendan sodium salt as claimed in claim 4, wherein the concentration of levosimendan is from 2mg/ml to 5mg/ml; the molar ratio of levosimendan to sodium carbonate is 1:1-1:1.2, and the reaction solvent is water.
7. A pharmaceutical composition comprising the amorphous levosimendan sodium salt compound of claim 1, consisting of levosimendan sodium salt and other pharmaceutically acceptable ingredients, characterized in that: the medicinal composition is lyophilized powder.
8. The pharmaceutical composition of the amorphous levosimendan sodium salt compound of claim 7, characterized in that: one or more of povidone, cyclodextrin, sodium cyclodextrin, mannitol, sucrose, glucose, glycine and lactose are selected as excipients; one or more of citric acid, sodium citrate, acetic acid, sodium acetate, phosphoric acid, dipotassium hydrogen phosphate, sodium hydroxide and hydrochloric acid are used as pH regulator.
9. The pharmaceutical composition of the amorphous levosimendan sodium salt compound of claim 8, characterized in that: the povidone is povidone K12, levosimendan sodium salt: the weight ratio of povidone K12 is 1:1-1:40; the cyclodextrin is hydroxypropyl-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin sodium, levosimendan sodium salt: the weight ratio of the hydroxypropyl-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin sodium is 1:1-1:90, and the pH regulator regulates the pH to 7.0-10.0.
10. A process for the preparation of a pharmaceutical composition comprising the amorphous levosimendan sodium salt compound of claim 1, characterized in that: the method comprises the following steps:
step (1): weighing levosimendan sodium salt and excipient, dissolving in water, adding a pH regulator to adjust the pH to 7.0-10.0 after the dissolution is completed, adding water to fix the volume to the total volume, and filtering by a 0.22 mu m PES filter membrane;
step (2): and (3) subpackaging the solution obtained in the step (1) into penicillin bottles, freeze-drying, filling nitrogen, rolling and sealing.
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