CN108498469A - Dexmedetomidine hydrochloride freeze-dried powder and preparation method thereof - Google Patents
Dexmedetomidine hydrochloride freeze-dried powder and preparation method thereof Download PDFInfo
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- CN108498469A CN108498469A CN201810535416.1A CN201810535416A CN108498469A CN 108498469 A CN108498469 A CN 108498469A CN 201810535416 A CN201810535416 A CN 201810535416A CN 108498469 A CN108498469 A CN 108498469A
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- China
- Prior art keywords
- dexmedetomidine hydrochloride
- freeze
- dried powder
- hours
- dexmedetomidine
- 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.)
- Withdrawn
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- VPNGEIHDPSLNMU-MERQFXBCSA-N dexmedetomidine hydrochloride Chemical compound Cl.C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CNC=N1 VPNGEIHDPSLNMU-MERQFXBCSA-N 0.000 title claims abstract description 61
- 229960002746 dexmedetomidine hydrochloride Drugs 0.000 title claims abstract description 61
- 239000000843 powder Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000003756 stirring Methods 0.000 claims abstract description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000011049 filling Methods 0.000 claims abstract description 15
- 238000004108 freeze drying Methods 0.000 claims abstract description 14
- 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 abstract description 12
- 239000008101 lactose Substances 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 230000003750 conditioning effect Effects 0.000 claims abstract description 8
- 238000010792 warming Methods 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 13
- 239000008215 water for injection Substances 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 6
- 239000003610 charcoal Substances 0.000 claims description 5
- 239000003708 ampul Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 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
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 240000004307 Citrus medica Species 0.000 claims 1
- 210000000481 breast Anatomy 0.000 claims 1
- 239000002075 main ingredient Substances 0.000 claims 1
- 238000007789 sealing Methods 0.000 claims 1
- 238000005303 weighing Methods 0.000 claims 1
- 238000002347 injection Methods 0.000 abstract description 14
- 239000007924 injection Substances 0.000 abstract description 14
- 239000003814 drug Substances 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 8
- 238000003860 storage Methods 0.000 abstract description 7
- 239000007853 buffer solution Substances 0.000 abstract description 4
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000010521 absorption reaction Methods 0.000 abstract 1
- 229960004253 dexmedetomidine Drugs 0.000 description 23
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 239000004615 ingredient Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 210000002700 urine Anatomy 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000002932 luster Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 235000015165 citric acid Nutrition 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical group O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- 108060003345 Adrenergic Receptor Proteins 0.000 description 3
- 102000017910 Adrenergic receptor Human genes 0.000 description 3
- NVTRPRFAWJGJAJ-UHFFFAOYSA-L EDTA monocalcium salt Chemical compound [Ca+2].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O NVTRPRFAWJGJAJ-UHFFFAOYSA-L 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010039897 Sedation Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012857 radioactive material Substances 0.000 description 3
- 230000036280 sedation Effects 0.000 description 3
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Chemical group O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 239000004695 Polyether sulfone Substances 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical group C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 2
- 229960005156 digoxin Drugs 0.000 description 2
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Chemical group C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 230000023611 glucuronidation Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- HRLIOXLXPOHXTA-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CN=C[N]1 HRLIOXLXPOHXTA-UHFFFAOYSA-N 0.000 description 2
- 229960002140 medetomidine Drugs 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 229920006393 polyether sulfone Polymers 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 230000002889 sympathetic effect Effects 0.000 description 2
- 229960000278 theophylline Drugs 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000003849 Cytochrome P450 Human genes 0.000 description 1
- 102100036194 Cytochrome P450 2A6 Human genes 0.000 description 1
- 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 description 1
- 101000875170 Homo sapiens Cytochrome P450 2A6 Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical group CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000002181 anti-sympathetic effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical group OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229930182480 glucuronide Natural products 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- -1 iron ion Chemical class 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical group OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical compound [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Dexmedetomidine hydrochloride freeze-dried powder provided by the invention, belong to field of medicaments, dexmedetomidine hydrochloride freeze-dried powder is 1 part of dexmedetomidine hydrochloride, 30 150 parts of lactose, 10 50 parts of propylene glycol, 0.1~0.9 part of activated carbon, PH conditioning agents are appropriate and water for injection forms, method provided by the invention first lactose is added in the buffer solution of citric acid sodium citrate, stirring and dissolving；Propylene glycol, stirring and dissolving is added；Dexmedetomidine hydrochloride is added, stirring is completely dissolved；Then absorption and condition pH value, it is last it is filling, be lyophilized and draw envelope.Stability is high during storage for dexmedetomidine hydrochloride freeze drying powder injection obtained by preparing, and preparation process is simply suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of injection and preparation method thereof more particularly to a kind of dexmedetomidine hydrochloride injection and its
Preparation method belongs to technical field of medicine.
Background technology
Dexmedetomidine hydrochloride is a kind of efficient, highly selective α 2- adrenoceptor agonists, earliest by Finland
Orion Pharma companies and the joint research and development exploitation of Abott companies of the U.S., the medicine is by acting on two kinds of adrenergic receptors
And with anti-sympathetic, analgesia and sedation, it is 8 times of clonidine effect.FDA ratify its for Intensive Care Therapy middle or short term (<24 is small
When) sedation and analgesia drug, especially in early days after surgery.It acts on two kinds of adrenergic receptors, passes through exciting presynaptic membrane α
2- receptors, it is suppressed that the release of norepinephrine, and have ceased the conduction of pain signal；In addition, passing through exciting postsynaptic membrane
Receptor, Dexmedetomidine inhibit sympathetic activity so as to cause the decline of blood pressure and heart rate.Both effects integrate
Calm, alleviation anxiety, sympathetic inhibition and analgesic effect can be generated.
Dexmedetomidine hydrochloride is the active dextroisomer of Medetomidine, in many animals experiment, has no apparent
Toxic side effect.In order, curative effect is good and Small side effects, with other downern phases for clinical application since foreign countries list for the medicine
Than having unique advantage.
Dexmedetomidine hydrochloride (DexmedetomidineHydrochloride), entitled (+) -4- (S)-[1- of chemistry
(2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazole hydrochlorides.Structural formula is as follows：
Dexmedetomidine is a kind of relative selectivity 2- adrenoceptor agonists, has sedation.Animal is slow
The visible selectively acting to 2- adrenocepters when venoclysis 10~300g/kg of Dexmedetomidine, but in higher dosage
Under (1000g/kg) when slowly venoclysis or rapid intravenous injection are administered a pair 1 and 2- receptors have effect.Dexmedetomidine
Vdss (Vss) is about 118 liters.To Dexmedetomidine in normal healthy male and the blood plasma of female volunteers
Protein binding is evaluated.Its average protein Percentage bound is 94% in different concentration tests；The albumen of male and female
Percentage bound is similar.Compared with health volunteer, under function that hepatic injury subject Dexmedetomidine is combined with plasma protein is apparent
Drop.It is protein-bonded that in vitro study observes fentanyl, ketorolac, theophylline, digoxin and lidocaine substitution Dexmedetomidine
May, the change of Dexmedetomidine plasma protein binding rate is not as a result observed.It is external have studied again dilantin sodium, warfarin,
The possibility that is replaced by Dexmedetomidine of protein binding of brufen, Propranolol, theophylline and digoxin, the results showed that do not have drug
Protein binding, it appears that obviously replaced by Dexmedetomidine.Dexmedetomidine almost by bioconversion, seldom with original shape from
It is discharged in urine and excrement.Bioconversion includes the metabolism of direct glucuronidation and cytochrome P 450 mediated.
The main metabolic pathway of Dexmedetomidine is：Direct N- glucuronides are melted into nonactive metabolite；Fat hydroxyl
Change acts on (mainly being mediated by CYP2A6) and generates 3- hydroxyls Dexmedetomidine, 3- hydroxyl Dexmedetomidine glucosiduronic acids and 3- carboxyls
Dexmedetomidine；Dexmedetomidine N-, which methylates, generates the right U.S. support miaow of 3- Hydroxy N-Methyls Dexmedetomidine, 3- carboxyl N- methyl
Fixed and N- methyl O- glucosiduronic acid Dexmedetomidines.The removing of end eventually half-life period (t1/2) of Dexmedetomidine is about 2 hours, clearly
Except rate is about 39L/h.Mass balance research confirms the radiolabeled Dexmedetomidine of venoclysis average 95% after 9 days
Radioactive materials are recycled from urine, and 4% in excrement.Dexmedetomidine original shape can be detected in urine.24 after infusion this product
About 85% radioactive materials are discharged from urine in hour.The radioactive materials segmentation separation being discharged in urine turns out to be N-
Glucuronidation product accounts for 34%.In addition, fat hydroxylization effect product 3- hydroxyls Dexmedetomidine, 3- hydroxyl Dexmedetomidines
Glucosiduronic acid and 3- carboxylic acid Dexmedetomidines account about 14%.
Dexmedetomidine N- methylates 3- Hydroxy N-Methyls Dexmedetomidine, the 3- carboxyl N- methyl Dexmedetomidines of generation
18% is accounted about with N- methyl O- glucosiduronic acid Dexmedetomidines.N- methyl metabolism products itself are secondary circulating components, are being urinated
In be not detected.About 28% urine metabolin is unrecognized.
Dexmedetomidine hydrochloride is white to off-white color crystalline powder；This product easily dissolves, in water in methanol, ethyl alcohol
It is readily soluble, it is almost insoluble in the hydrochloric acid solution, toluene of 0.1mol/L.Salt containing 1 molecule in dexmedetomidine hydrochloride molecular formula
Acid, in the process for preparation of injection easily with the equipment reactions such as Agitation Tank, filter, the iron ion on dissolving part thereof surface,
Increase in the related substance of placement process to form injection, the phenomenon that color and luster is deepened.Color and luster is also dexmedetomidine hydrochloride drop
A kind of reaction of solution, the liquid phase of current UV detector still cannot effectively detect such impurity, need to carry out area by coloration
Point.
CN105168122A discloses a kind of dexmedetomidine hydrochloride injection and its preparation process, uses the right U.S. of hydrochloric acid
The injection for holding in the palm the preparations such as fixed miaow, osmotic pressure regulator and complexing of metal ion agent solves related substance and increases, it is seen that foreign matter
Increased trend, but fail to solve the phenomenon that excessively middle color and luster of long term storage is deepened.
CN103284945A discloses a kind of pre-filled dexmedetomidine hydrochloride injection, solves dexmedetomidine hydrochloride
The case where injection ease of use, but in failing to solve long term storage excessively related substance increase, color and luster intensification the phenomenon that.
It is main that a kind of dexmedetomidine hydrochloride injection injections of CN105534891A, which are with dexmedetomidine hydrochloride,
Ingredient：It is sterilized by the dissolving embedding of dexmedetomidine hydrochloride, fastness composition, sodium hydroxide and water for injection；Described
Fastness composition is prepared as follows：Mosatil, sodium pyrosulfite are uniformly mixed, mosatil and coke
The weight ratio of sodium sulfite is 1:1-3.Color and luster is deepened during the dexmedetomidine hydrochloride injection of the present invention solves storage
The shortcomings that increasing with related substance, improves drug safety, has more preferably therapeutic effect.
At present, although its is significant in efficacy, and sales volume is very big, domestic market vacancy, but due to drug itself be easy by
There is the problems such as visible foreign matters increase in the influence of light and metal ion.Therefore acceleration is caused in study on the stability 6 months and long
9 months phases sample visible foreign matters, which increase, to be failed to solve always.
Invention content
The purpose of the invention is to overcome the deficiencies of the prior art and provide a kind of dexmedetomidine hydrochloride freeze-dried powder,
Suitable propylene glycol is added during making up a prescription, and filling in ampoule bottle, the dexmedetomidine hydrochloride freeze-dried powder water of gained
Divide content relatively low, finds the dexmedetomidine hydrochloride freeze-dried powder containing propylene glycol by long term test, moisture increase is not
Obviously, stability is good, is suitable for long term storage.
Dexmedetomidine hydrochloride freeze-dried powder of the present invention, formula composition：1 part of dexmedetomidine hydrochloride, lactose 30-
150 parts, 10-50 parts of propylene glycol, 0.1~0.9 part of activated carbon, PH conditioning agents are appropriate and water for injection.
Further, the auxiliary material is carried out preferably obtaining 1 part of dexmedetomidine hydrochloride, 80-120 parts of lactose, the third two
20-40 parts of alcohol, 0.1~0.9 part of activated carbon, PH conditioning agents are appropriate, further, 1 part of hydrochloric acid Medetomidine, 100 parts of lactose,
30 parts of propylene glycol, 0.5 part of activated carbon, PH conditioning agents are appropriate.
The pH adjusting agent can be glacial acetic acid, hydrochloric acid, lactic acid or citric acid, and the present invention is preferably citric acid, more
Preferably 1mol/L citric acids.Selected citric acid can act synergistically with propylene glycol, keep dexmedetomidine hydrochloride stability,
Preferred pH value 4.0~6.0, most preferably pH value are 5.0.
Another object of the present invention is to provide a kind of preparation method of dexmedetomidine hydrochloride freeze-dried powder, including it is as follows
Step：
(1) lactose is added in the buffer solution of citric acid-sodium citrate, stirring and dissolving；Propylene glycol, stirring and dissolving is added；
Dexmedetomidine hydrochloride is added, stirring is completely dissolved；
(2) activated carbon stirs, and then takes off charcoal；
(3) plus suitable water for injection adjusts pH value；
(4) filling, it is lyophilized and draws envelope.
Freeze-drying curve is in the step (4)：After filling obtained product inlet, -35 ± 5 DEG C of pre-freezes are cooled to, are protected
It holds 1.5-2.5 hours；- 10 ± 5 DEG C are warming up to, keeps the temperature 1~5 hour, then is cooled to -30 ± 5 DEG C and keeps the temperature 1.5~2.5 hours；It opens
Cold-trap opens vacuum；Baffle temperature is warming up to -17~-10 DEG C, is then kept for 10~15 hours；Baffle temperature is warming up to -5
It~5 DEG C, is then kept for 3~5 hours；Baffle temperature is warming up to 30~40 DEG C again, is then kept for 3.5~5.5 hours.Freeze-drying knot
Shu Hou is filled with inert gas under vacuum state, takes the dish out of the pot.
A kind of preparation method of dexmedetomidine hydrochloride freeze-dried powder of offer of the present invention, is as follows：
(1) lactose is added in the buffer solution of citric acid-sodium citrate, stirring and dissolving；Propylene glycol, stirring and dissolving is added；
Dexmedetomidine hydrochloride is added, stirring is completely dissolved；
(2) activated carbon of recipe quantity is added, stirs 15~30 minutes, takes off charcoal；
(3) it mends and adds to the full amount of water for injection, adjust pH value to 4.0~6.0 using conditioning agent, the process of making up a prescription carries out filling inertia
Gas shield；
(4) filling, freeze-drying；Freeze-drying curve：After filling obtained product inlet, -35 ± 5 DEG C of pre-freezes are cooled to, are kept
1.5-2.5 hour；- 10 ± 5 DEG C are warming up to, keeps the temperature 1~5 hour, then is cooled to -30 ± 5 DEG C and keeps the temperature 1.5~2.5 hours；It opens cold
Trap opens vacuum；Baffle temperature is warming up to -17~-10 DEG C, is then kept for 10~15 hours；Baffle temperature is warming up to -5~5
DEG C, then kept for 3~5 hours；Baffle temperature is warming up to 30~40 DEG C again, is then kept for 3.5~5.5 hours.
(5) envelope is drawn：Ampoule drawing after freeze-drying is sealed to obtain the final product, ambient humidity is relative humidity 20%~30%, draws seal ring border
Temperature is controlled at 10 DEG C~15 DEG C.
Compared with prior art, the technical effects of the invention are that, dexmedetomidine hydrochloride prepared by embodiment group is lyophilized
Stability is high during storage for powder-injection, and preparation process is simply suitble to industrialized production.
Specific implementation mode：
It further illustrates the present invention by the following examples, but these embodiments are not limit the invention in any way.
Embodiment 1：Dexmedetomidine hydrochloride freeze-dried powder ingredient and preparation method, it is specific as follows：
Prescription：1000
It is as follows：
(1) lactose of recipe quantity is added in the buffer solution of citric acid-sodium citrate, stirring and dissolving；Propylene glycol is added, stirs
Mix dissolving；Dexmedetomidine hydrochloride is added, stirring is completely dissolved；
(2) activated carbon of recipe quantity is added, stirs 20 minutes, takes off charcoal；
(3) it mends and adds to the full amount of water for injection, adjust pH value to 5.0 using conditioning agent, process of making up a prescription carries out filling with inert gas
Protection；
(4) filling, freeze-drying；Freeze-drying curve：After filling obtained product inlet, -35 ± 5 DEG C of pre-freezes are cooled to, are kept
1.5-2.5 hour；- 10 ± 5 DEG C are warming up to, keeps the temperature 1~5 hour, then is cooled to -30 ± 5 DEG C and keeps the temperature 1.5~2.5 hours；It opens cold
Trap opens vacuum；Baffle temperature is warming up to -17~-10 DEG C, is then kept for 10~15 hours；Baffle temperature is warming up to -5~5
DEG C, then kept for 3~5 hours；Baffle temperature is warming up to 35 DEG C again, is then kept for 4.5 hours.
(5) envelope is drawn：Ampoule drawing after freeze-drying is sealed to obtain the final product, ambient humidity is relative humidity 25%, draws envelope environment temperature control
System is at 12 DEG C.
Embodiment 2：Dexmedetomidine hydrochloride freeze-dried powder ingredient and preparation method, it is specific as follows：
Prescription：1000
For preparation process in addition to auxiliary material and dosage are different, other are substantially the same manner as Example 1.
Embodiment 3：Dexmedetomidine hydrochloride freeze-dried powder ingredient and preparation method, it is specific as follows：
Prescription：1000
For preparation process in addition to auxiliary material and dosage are different, other are substantially the same manner as Example 1.
Embodiment 4：Dexmedetomidine hydrochloride freeze-dried powder ingredient and preparation method, it is specific as follows：
Prescription：1000
For preparation process in addition to auxiliary material and dosage are different, other are substantially the same manner as Example 1.
Embodiment 5：Dexmedetomidine hydrochloride freeze-dried powder ingredient and preparation method, it is specific as follows：Prescription：1000
Other are substantially the same manner as Example 1.
Comparative example 1：Dexmedetomidine hydrochloride freeze-dried powder ingredient and preparation method, it is specific as follows：Prescription：1000
Ph values are 0.7, other are substantially the same manner as Example 1.
Comparative example 2：Dexmedetomidine hydrochloride freeze-dried powder ingredient and preparation method, it is specific as follows：Prescription：
For preparation process in addition to auxiliary material and dosage are different, other are substantially the same manner as Example 1.
Comparative example 3：Dexmedetomidine hydrochloride freeze-dried powder ingredient and preparation method, it is specific as follows：
Prescription：1000
For preparation process in addition to auxiliary material and dosage are different, other are substantially the same manner as Example 1.
Comparative example 4：Dexmedetomidine hydrochloride freeze-dried powder ingredient and preparation method, it is specific as follows：
Prescription：
PH value is adjusted to 3.0, other are substantially the same manner as Example 1.
Comparative example 5：Dexmedetomidine hydrochloride freeze-dried powder ingredient and preparation method, it is specific as follows：
Prescription：
Preparation method：The mosatil of recipe quantity, burnt sulfurous is added in the water for injection (50 DEG C~60 DEG C) for taking recipe quantity 75%
Sour sodium, dexmedetomidine hydrochloride, are stirred to dissolve；Be cooled to 35 DEG C hereinafter, with 1mol/L sodium hydroxide solutions adjust pH value to
7.5, then water for injection is mended to recipe quantity, activated carbon stirring and adsorbing is added, through at the beginning of 1 μm of stud, 0.45 μm of polyether sulfone filter core in stirring
Filter；It is filling after 0.22 μm of polyether sulfone filter core refined filtration, it sterilizes to get finished product.
Verify embodiment：
According to 2015 editions《Chinese Pharmacopoeia》Second bulk pharmaceutical chemicals is detected with pharmaceutical preparation stability test guideline,
Long term test such as table 1：
【Assay】It is measured according to high performance liquid chromatography (annex VD)：
Chromatographic condition and system suitability test：It is filler with octadecylsilane chemically bonded silica；It (is taken with phosphoric acid solution
Phosphatase 11 1ml adds water 800ml, with triethylamine tune pH value to 2.3, is diluted with water to 1000ml)~acetonitrile (75：25) it is flowing
Phase；Flow velocity is 1.5ml per minute；Detection wavelength is 215nm；Number of theoretical plate should be not less than by the calculating of dexmedetomidine hydrochloride peak
1500；
Measuring method：Take 5 bottles of this product, respectively plus appropriate amount of water, make contents melting and quantify dilution be made in every 1ml containing about
The solution of 0.1mg, 5 bottles of full doses are mixed and are shaken up, as test solution；Precision measures 20 μ l and injects liquid chromatograph, record
Chromatogram；It separately takes dexmedetomidine hydrochloride reference substance that the solution in every 1ml containing about 0.1mg is made in right amount, is measured in the same method, by external standard
Method with calculated by peak area to get；Bulk pharmaceutical chemicals also can be measured similarly.
【Related substance】It is measured according to high performance liquid chromatography (annex VD)：
This product content is taken, be dissolved in water and the solution containing 0.5mg in every 1ml is made, as test solution；Precision amount
2ml is taken, is set in 100ml measuring bottles, scale is diluted with water to and shakes up, as a contrast solution；Use octadecylsilane chemically bonded silica
For filler, with phosphoric acid solution (phosphatase 11 1ml is taken, water 800ml is added, with triethylamine tune pH value to 2.3, is diluted with water to
1000ml) it is mobile phase A；Acetonitrile is Mobile phase B；Flow velocity is 1.5ml per minute；Detection wavelength is 215nm；According to the form below carries out ladder
Degree elution；Number of theoretical plate is calculated by dexmedetomidine hydrochloride peak should be not less than 1500；
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 79 | 21 |
| 18 | 60 | 40 |
| 20 | 60 | 40 |
| 21 | 79 | 21 |
| 26 | 79 | 21 |
50 μ l injection liquid chromatographs of contrast solution are taken, detection sensitivity is adjusted, makes the about full amount of principal component chromatography peak height
The 20% of journey；Precision measures test solution and each 50 μ l of contrast solution, is injected separately into liquid chromatograph, records chromatogram.
If any impurity peaks in the chromatogram of test solution, in addition to solvent peak, single impurity peak area is not greater than control
The half (1.0%) of solution main peak area；Each impurity peak area and be not greater than contrast solution main peak area (2.0%).
1 embodiment of table, comparative example study on the stability result
The freeze-dried powder of embodiment 1-5 and comparative example 1-5 are put into 40 DEG C ± 2 DEG C, accelerated under RH75% ± 5%
The indices that experiment (detection 1st month, the 3rd month, the 6th month result) is investigated.
2 embodiment of table, comparative example accelerate to investigate as a result, acceleration environment (40 DEG C ± 2 DEG C, RH75% ± 5%)
It can be seen that by above-mentioned Tables 1 and 2：
Freeze-dried powder moisture by long term test Examples 1 to 5 keeps stablizing, and moisture increases unobvious,
It redissolves effect, be superior to pharmacopoeial requirements in relation to substance and visible foreign matters；
Comparative example 1 be not the present invention ratio, appearance color is unqualified during storage.Comparative example 2 uses mannitol,
As a result the redissolution time receives limitation significantly, and comparative example 3 replaces propylene glycol that technique effect of the invention is also not achieved using ethyl alcohol.
The excipient and dosage that comparative example 5 uses are totally different from the present invention, can be seen that it during accelerated test
Appearance, the content in relation to substance are poorer than the effect of the embodiment of the present invention 1-5.
Claims (9)
1. a kind of dexmedetomidine hydrochloride freeze-dried powder, as follows containing forming with weight ratio meter：1 part of dexmedetomidine hydrochloride, breast
30-150 parts sugared, 10-50 parts of propylene glycol, 0.1~0.9 part of activated carbon and PH conditioning agents are appropriate.
2. dexmedetomidine hydrochloride freeze-dried powder as described in claim 1, which is characterized in that with weight ratio meter, the right U.S. of hydrochloric acid
Ask miaow fixed：Lactose：Propylene glycol=1：80-120：20-40.
3. dexmedetomidine hydrochloride freeze-dried powder as described in claim 1, which is characterized in that with weight ratio meter, hydrochloric acid U.S. support
Miaow is fixed：Lactose：Propylene glycol=1：100：30 parts.
4. dexmedetomidine hydrochloride freeze-dried powder as described in claim 1, which is characterized in that the pH adjusting agent is ice vinegar
Acid, citric acid, lactic acid or hydrochloric acid it is one or two kinds of.
5. dexmedetomidine hydrochloride freeze-dried powder as described in claim 1, which is characterized in that the pH adjusting agent is citron
Acid.
6. dexmedetomidine hydrochloride freeze-dried powder as described in claim 1, which is characterized in that comprise the steps of：
(1) by lactose, water for injection, stirring and dissolving is added；Propylene glycol, stirring and dissolving is added；Dexmedetomidine hydrochloride is added,
Stirring is completely dissolved；
(2) activated carbon stirs, and then takes off charcoal；
(3) it mends and adds to the full amount of water for injection, adjust pH value；
(4) filling, it is lyophilized and draws envelope.
7. dexmedetomidine hydrochloride freeze-dried powder preparation method as claimed in claim 6, which is characterized in that the step (4)
Freeze-drying curve is：After filling obtained product inlet, -35 ± 5 DEG C of pre-freezes are cooled to, are kept for 1.5-2.5 hours；It is warming up to -10
± 5 DEG C, 1~5 hour is kept the temperature, then is cooled to -30 ± 5 DEG C and keeps the temperature 1.5~2.5 hours；Cold-trap is opened, vacuum is opened；By baffle temperature
- 17~-10 DEG C are warming up to, is then kept for 10~15 hours；Baffle temperature is warming up to -5~5 DEG C, is then kept for 3~5 hours；
Baffle temperature is warming up to 30~40 DEG C again, is then kept for 3.5~5.5 hours, after freeze-drying, inertia is filled under vacuum state
Gas takes the dish out of the pot.
8. dexmedetomidine hydrochloride freeze-dried powder preparation method as claimed in claim 6, which is characterized in that the step (4)
Draw strip of paper used for sealing part be：Ambient humidity is relative humidity 20%~30%, and temperature is controlled at 10 DEG C~15 DEG C.
9. dexmedetomidine hydrochloride freeze-dried powder preparation method as claimed in claim 6, which is characterized in that include following step
Suddenly：
(1) water for injection of recipe quantity is added in the lactose for weighing recipe quantity, and the propylene glycol of recipe quantity is added in stirring and dissolving, stirring
Dissolving, adds the dexmedetomidine hydrochloride of recipe quantity, and stirring makes main ingredient be completely dissolved；
(2) activated carbon of recipe quantity is added, stirs 15~30 minutes, takes off charcoal；
(3) it mends and adds to the full amount of water for injection, pH value is adjusted to 4.0~6.0 using conditioning agent；
(4) filling, freeze-drying；Freeze-drying curve：After filling obtained product inlet, -35 ± 5 DEG C of pre-freezes are cooled to, keep 1.5-2.5
Hour；- 10 ± 5 DEG C are warming up to, keeps the temperature 1~5 hour, then is cooled to -30 ± 5 DEG C and keeps the temperature 1.5~2.5 hours；Cold-trap is opened, is opened true
It is empty；Baffle temperature is warming up to -17~-10 DEG C, is then kept for 10~15 hours；Baffle temperature is warming up to -5~5 DEG C, then
It is kept for 3~5 hours；Baffle temperature is warming up to 30~40 DEG C again, is then kept for 3.5~5.5 hours.
(5) envelope is drawn：Ampoule drawing after freeze-drying is sealed to obtain the final product, ambient humidity is relative humidity 20%~30%, environment temperature control
At 10 DEG C~15 DEG C.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11786508B2 (en) | 2016-12-31 | 2023-10-17 | Bioxcel Therapeutics, Inc. | Use of sublingual dexmedetomidine for the treatment of agitation |
| US11806429B2 (en) | 2018-06-27 | 2023-11-07 | Bioxcel Therapeutics, Inc. | Film formulations containing dexmedetomidine and methods of producing them |
| US11890272B2 (en) | 2019-07-19 | 2024-02-06 | Bioxcel Therapeutics, Inc. | Non-sedating dexmedetomidine treatment regimens |
| US11998528B1 (en) | 2023-01-12 | 2024-06-04 | Bioxcel Therapeutics, Inc. | Non-sedating dexmedetomidine treatment regimens |
| CN119954620A (en) * | 2024-12-27 | 2025-05-09 | 湖北丽益医药科技有限公司 | A new impurity of dexmedetomidine hydrochloride and preparation method thereof |
-
2018
- 2018-05-30 CN CN201810535416.1A patent/CN108498469A/en not_active Withdrawn
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11786508B2 (en) | 2016-12-31 | 2023-10-17 | Bioxcel Therapeutics, Inc. | Use of sublingual dexmedetomidine for the treatment of agitation |
| US11839604B2 (en) | 2016-12-31 | 2023-12-12 | Bioxcel Therapeutics, Inc. | Use of sublingual dexmedetomidine for the treatment of agitation |
| US11931340B2 (en) | 2016-12-31 | 2024-03-19 | Bioxcel Therapeutics, Inc. | Use of sublingual dexmedetomidine for the treatment of agitation |
| US11806429B2 (en) | 2018-06-27 | 2023-11-07 | Bioxcel Therapeutics, Inc. | Film formulations containing dexmedetomidine and methods of producing them |
| US11890272B2 (en) | 2019-07-19 | 2024-02-06 | Bioxcel Therapeutics, Inc. | Non-sedating dexmedetomidine treatment regimens |
| US11998529B2 (en) | 2019-07-19 | 2024-06-04 | Bioxcel Therapeutics, Inc. | Non-sedating dexmedetomidine treatment regimens |
| US12109196B2 (en) | 2019-07-19 | 2024-10-08 | Bioxcel Therapeutics, Inc. | Non-sedating dexmedetomidine treatment regimens |
| US11998528B1 (en) | 2023-01-12 | 2024-06-04 | Bioxcel Therapeutics, Inc. | Non-sedating dexmedetomidine treatment regimens |
| CN119954620A (en) * | 2024-12-27 | 2025-05-09 | 湖北丽益医药科技有限公司 | A new impurity of dexmedetomidine hydrochloride and preparation method thereof |
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Application publication date: 20180907 |
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