CN108703948A - 即用型酮咯酸注射液 - Google Patents
即用型酮咯酸注射液 Download PDFInfo
- Publication number
- CN108703948A CN108703948A CN201810988217.6A CN201810988217A CN108703948A CN 108703948 A CN108703948 A CN 108703948A CN 201810988217 A CN201810988217 A CN 201810988217A CN 108703948 A CN108703948 A CN 108703948A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- ketorolac
- injection
- described pharmaceutical
- medically acceptable
- 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.)
- Pending
Links
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960004752 ketorolac Drugs 0.000 title claims abstract description 74
- 239000000203 mixture Substances 0.000 title claims abstract description 35
- 238000009472 formulation Methods 0.000 title description 8
- 238000002347 injection Methods 0.000 claims abstract description 91
- 239000007924 injection Substances 0.000 claims abstract description 91
- 239000003814 drug Substances 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 19
- 239000007788 liquid Substances 0.000 claims abstract description 8
- 238000009938 salting Methods 0.000 claims abstract 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 47
- 239000000243 solution Substances 0.000 claims description 19
- -1 sorbierite Chemical compound 0.000 claims description 19
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 12
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 12
- 230000003204 osmotic effect Effects 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 10
- 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 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000008103 glucose Substances 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 6
- 238000012856 packing Methods 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 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 239000000811 xylitol Substances 0.000 claims description 5
- 235000010447 xylitol Nutrition 0.000 claims description 5
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 5
- 229960002675 xylitol Drugs 0.000 claims description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 4
- 229930091371 Fructose Natural products 0.000 claims description 4
- 239000005715 Fructose Substances 0.000 claims description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 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 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- 235000011187 glycerol Nutrition 0.000 claims description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 239000004743 Polypropylene Substances 0.000 claims description 2
- 229920000728 polyester Polymers 0.000 claims description 2
- 229920000098 polyolefin Polymers 0.000 claims description 2
- 229920001155 polypropylene Polymers 0.000 claims description 2
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 2
- 239000004800 polyvinyl chloride Substances 0.000 claims description 2
- 230000001954 sterilising effect Effects 0.000 claims description 2
- 238000004659 sterilization and disinfection Methods 0.000 claims description 2
- 150000005846 sugar alcohols Chemical class 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 6
- 239000001103 potassium chloride Substances 0.000 claims 3
- 235000011164 potassium chloride Nutrition 0.000 claims 3
- 125000000647 trehalose group Chemical group 0.000 claims 2
- 235000019441 ethanol Nutrition 0.000 abstract description 9
- 229940090044 injection Drugs 0.000 description 76
- 238000000034 method Methods 0.000 description 23
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- 230000015556 catabolic process Effects 0.000 description 17
- 238000006731 degradation reaction Methods 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 16
- 238000004806 packaging method and process Methods 0.000 description 16
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 15
- 229920000858 Cyclodextrin Polymers 0.000 description 14
- 229960004384 ketorolac tromethamine Drugs 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 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 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 8
- 238000001802 infusion Methods 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 230000000202 analgesic effect Effects 0.000 description 6
- 239000007853 buffer solution Substances 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000890 drug combination Substances 0.000 description 6
- 230000002045 lasting effect Effects 0.000 description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000008896 Opium Substances 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000005815 base catalysis Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229940020756 ketorolac injection Drugs 0.000 description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 5
- 229960001027 opium Drugs 0.000 description 5
- 230000036407 pain Effects 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- CNBGNNVCVSKAQZ-UHFFFAOYSA-N benzydamine Chemical compound C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 CNBGNNVCVSKAQZ-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229960005181 morphine Drugs 0.000 description 4
- 229940127240 opiate Drugs 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 3
- 108090000137 Opioid Receptors Proteins 0.000 description 3
- 102000003840 Opioid Receptors Human genes 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 230000036592 analgesia Effects 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 3
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- 201000010099 disease Diseases 0.000 description 3
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- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound 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 3
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
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- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical class OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
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- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Chemical class O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
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- 239000012535 impurity Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
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Classifications
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- 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
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- 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
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- 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
- A61K9/08—Solutions
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- 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]
Abstract
本发明提供了一种药物组合物注射液,包括剂量为0.1～10mg/mL的酮咯酸及其医学上可接受的盐溶液；医学上可接受的赋形剂；所述的注射液不含有乙醇。
Description
分案申请说明
本申请为申请日：2011年10月21日，申请号：201180050372.X，发明名称：即用型酮咯酸注射液的发明专利申请的分案申请。
相关申请的交叉引用
本申请要求美国临时专利61/405,384的优先权，该申请于2010年10 月21日提交，本申请还要求美国临时专利61/481,602的优先权，该申请于 2011年5月2日提交，这两个申请揭露的全部内容作为本申请的参照。
技术领域
本发明属于医药技术领域，具体涉及一种即用型酮咯酸氨丁三醇注射液。
背景技术
酮咯酸，也称5-苯甲酰-2,3-二氢-1H-吡咯嗪-1-羧酸，是一个已知的非固醇类消炎药，具有镇痛和消炎作用，美国专利4,089,969描述了酮咯酸。
与其他非固醇类消炎药物相比，酮咯酸被认为具有更高的镇痛和消炎活性。更突出的是，它的镇痛活性比吗啡更高，而没有吗啡那些已知的副作用。例如可参考文献“Ketorolac-A review of its pharmacodynamic and pharmacokinetic properties andits therapeutic potential”,Drugs 39(1):86-109, 1990.
酮咯酸目前主要通过外消旋混合物口服或者注射给药，这种方式有利于其商业化生产销售和运输。酮咯酸肌肉或者静脉注射的浓度范围为1.5％ (1ml中15mg)～3％(2ml中60mg)之间。通常在多剂量治疗时，推荐的剂量是每6小时30mg。在特定情况下，该药物的首次剂量为30～60mg，随后每6～8小时剂量减半(15～30mg)。该药物一天的整体剂量在60～120mg之间。多次注射方式对于病人来说不方便或者难以忍受，该药物的肌肉注射或者静脉注射方式更有可能导致副作用。
酮咯酸还可通过口服片剂或者喷雾剂的形式使用。但是，这些注射液不足以有效地治疗剧烈疼痛。剧烈疼痛，例如手术后调整，需要阿片类水平的镇痛药。
尽管一直有考虑酮咯酸连续给药的问题，在急性调整期，这些注射液存在剂量不准，安全和保持注射液无菌、稳定等方面的问题。
本技术领域迫切需要一种能够直接用于病人疼痛治疗，例如手术后调整，即用型酮咯酸注射液。
在此揭露的全部参考文献整体作为本申请的参照。
发明内容
本发明的目的在于提供一种药物组合物注射剂，包括酮咯酸或其医药上可接受的盐以及医药上可接受的赋形剂，其组分在给药前不需要稀释。
本发明的另一目的在于提供一种酮咯酸可治疗的疾病的治疗方法，包括给酮咯酸可治疗的疾病的病人一种提供组合物，该组合物为注射液，包括酮咯酸或其医药上可接受的盐以及医药上可接受的赋形剂，其组分在给药前不需要稀释。
本发明的另一目的在于提供一种减少酮咯酸给药剂量失误的方法，包括提供一种注射液的药物组合物，该组合物包括括酮咯酸或其医药上可接受的盐以及医药上可接受的赋形剂，其组分在给药前不需要稀释。
本发明的另一目的在于提供一种通过使用瓶装而减少酮咯酸药物活性物质损耗的方法，该方法包括提供一种注射液的药物组合物，该组合物包括括酮咯酸或其医药上可接受的盐以及医药上可接受的赋形剂，其组分在给药前不需要稀释。
本发明的另一目的在于提供一种制备药物组合物的方法，该药物组合物由酮咯酸或其医药上可接受的盐与赋形剂组成，以生产一种注射液的药物组合物，该组合物在给药前不需要稀释。
本发明的另一目的在于提供一种镇痛药给药方法，该方法能够减少阿片类物质(如阿片类节约效应)的给药剂量，该方法包括将即用型酮咯酸注射液持续注入需要其的病人体内。
本发明的另一目的在于提供一种使用镇痛药而减少非甾体抗炎药 (NSAIDs，如NSAIDs节约效应)剂量的方法，该方法包括将即用型酮咯酸注射液持续注入需要其的病人体内。
阿片类和NSAID节约效应可能有利于减少呼吸抑制，减少恶心、呕吐和/或减少住院时间。
本发明的另一目的在于提供一种使用镇痛药的方法，包括单次酮咯酸给药以达到迅速镇痛效果，然后通过持续注入即用型酮咯酸注射剂以维持镇痛效果。在本方法中，单次酮咯酸用量可为10～50mg、20～40mg或 30mg，持续注入的用量可为每小时0.5～5mg、每小时1～4mg或每小时2～ 3mg。
本发明的另一目的在于提供一种将酮咯酸多次给药的峰值减少至波谷血浆浓度的方法，包括持续注入即用型酮咯酸注射液以进行镇痛。
本发明的另一目的在于提供一种减少术后疼痛的方法，包括给病人持续注入即用型酮咯酸注射液。
本发明的另一目的在于提供一种镇痛方法(如获得最低有效镇痛药物浓度，MEAC)，包括持续注入在此揭露的即用型酮咯酸注射液。
本发明的另一目的在于提供一种减少酮咯酸有镇痛效果的日常必需用量的方法，包括持续注入即用型酮咯酸注射液。在某个实施例中，能达到镇痛效果的日常剂量为50～100mg、60～60mg或78～102mg。
本发明的另一目的在于提供一种将酮咯酸多次给药的峰值减少至波谷血浆浓度的方法，包括持续注入即用型酮咯酸注射液以进行镇痛。
本发明的另一目的在于提供一种减少酮咯酸相关副作用的方法，包括持续注入即用型酮咯酸注射液。
本发明的上述目的以及本发明某些实施例的目的在于针对一种药物组合物注射剂，包括含有酮咯酸或其医药上可接受的盐(用量为0.1～10mg) 的水溶液，以及医学上可接受的赋形剂，该注射液不含有乙醇。
在某些实施例中，本发明针对一种药物组合物注射剂，包括含有酮咯酸或其医药上可接受的盐(用量为0.1～10mg)的水溶液、0.1％～3％的葡萄糖，该组合物被装在弹性的静脉输液袋中，该组合物的pH值为6.0～ 7.5。储存6个月后，该注射液至少还保留有90％的酮咯酸或其医药上可接受的盐。
在某些实施例中，本发明针对一种药物组合物注射剂，包括含有酮咯酸或其医药上可接受的盐(用量为0.1～10mg)的水溶液、海藻糖，该组合物被装在弹性的静脉输液袋中，该组合物的pH值为6.0～7.5。储存6个月后，该注射液至少还保留有90％的酮咯酸或其医药上可接受的盐。
在某些实施例中，本发明针对一种药物组合物注射剂，包括含有酮咯酸或其医药上可接受的盐(用量为0.1～10mg)的水溶液、0.1％～10％的海藻糖，该组合物被装在弹性的静脉输液袋中，该组合物的pH值为6.5～ 7.3。储存6个月后，该注射液至少还保留有90％的酮咯酸或其医药上可接受的盐。
在某些实施例中，本发明针对一种药物组合物注射剂，包括含有酮咯酸或其医药上可接受的盐(用量为0.1～10mg)的水溶液、医学上可接受的赋形剂，该组合物的活化能至少为60kJ/mol。储存6个月后，该注射液至少还保留有90％的酮咯酸或其医药上可接受的盐。
术语"ketorolac"指酮咯酸游离酸或任何其医学上可接受的盐，例如酮咯酸氨丁三醇。该术语也包括外消旋和右旋、左旋同分异构体。
术语"ready to use"指在给药时或者给药前(如1小时、12小时、24小时、1天、3天或7天)不需要对注射液进行混合。
在此揭露的酮咯酸的浓度能够被计算，基于将其盐形式的量换算成自由酸形式的量。
附图说明
图1是注射液7、8、10在25℃的长期预测稳定性结果图
具体实施方式
本发明针对一种即用型药物组合物注射剂，包括酮咯酸或其医药上可接受的盐以及医学上可接受的赋形剂，例如，该组合物在给药前不需要进行稀释，在生产时已适用于给药，不需要医务人员在使用时进行稀释或者准备注射液。本发明所用的赋形剂包括增溶剂、抗氧化剂(如维生素E、维生素C或谷胱甘肽)、缓冲剂、酸化剂、络合增强剂、盐、葡萄糖、冻干辅助剂、填充剂、稳定剂、电解质、另一种治疗剂、碱化剂、抗菌剂、抗真菌剂以及它们的组合。
本发明满足存储稳定的酮咯酸注射液即用型需要，医务人员不必依赖于混合注射液，该混合注射液为商用浓缩产品。混合浓度产品有可能导致不期望的结果，如产品未消毒、产品不稳定、剂量误差以及操作人员的安全。
在某些实施例中，本发明提供一种存储稳定的非浓缩形式的酮咯酸药物注射液。与浓缩注射液相比，该非浓缩注射液在较长时间内是稳定的，即使溶剂：药物的比率以及容器表面积：药物的比率上升，这些都可能导致药物降解。而且，商用浓缩产品包含了乙醇，通常不希望乙醇被注入病人体内或者在较长时间内被包含在弹性塑料容器中。
在某些实施例中，本发明提供的注射液在存储6个月后仍然至少还保留有90％的酮咯酸或其医药上可接受的盐，存储1年后仍然至少还保留有 90％的酮咯酸或其医药上可接受的盐，或存储2年后仍然至少还保留有90％的酮咯酸或其医药上可接受的盐。
在某些实施例中，本发明提供的注射液在存储6个月后仍然至少还保留有95％的酮咯酸或其医药上可接受的盐，存储1年后仍然至少还保留有 95％的酮咯酸或其医药上可接受的盐，或存储2年后仍然至少还保留有95％的酮咯酸或其医药上可接受的盐。
在某些实施例中，本发明提供的注射液在存储6个月后仍然至少还保留有98％的酮咯酸或其医药上可接受的盐，存储1年后仍然至少还保留有 98％的酮咯酸或其医药上可接受的盐，或存储2年后仍然至少还保留有98％的酮咯酸或其医药上可接受的盐。
在某些实施例中，该注射液中的酮咯酸或其医药上可接受的盐的量为0.01～10mg/mL、0.1～5mg/mL、0.25～1mg/mL或0.3mg/mL、0.4mg/mL、 0.5mg/mL、0.6mg/mL、0.7mg/mL、0.8mg/mL以及0.9mg/mL。
在某些实施例中，即用溶液的pH值为2.5～8.5、3.5～7.5、3.5～5.5、 3.5～4.5、4.5～8.5、4.5～7.5、6.8～7.6以及6.9～7.5。
本发明组合物的pH值可用适量的pH调节剂进行调节，pH调节剂包含酸碱基团。合适的pH调节剂通常至少包括一种酸或其盐，或者至少包含一种碱或其盐。加入酸碱调节以达到期望的pH值。例如，如果pH值高于期望的pH值，则加入酸以使pH值降到期望的pH值。适用于预混合的药物组合物的酸包括但不限于盐酸、磷酸、柠檬酸、抗坏血酸、醋酸、硫酸、碳酸和硝酸。在某些实施例中，用盐酸来调节pH值。反过来，如果pH值低于期望的pH值，则加入碱以使pH值上升到期望的pH值。适用于预混合的药物组合物的碱包括但不限于氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠、柠檬酸钠、乙酸钠、氢氧化镁。
在此描述的注射组合物可采用医学上可接受的缓冲液。合适的缓冲液包括但不限于乙酸、酒石酸、柠檬酸、谷氨酸、乳酸、苯甲酸酯、组氨酸或其他氨基酸、葡萄糖酸、磷酸、苹果酸、琥珀酸、甲酸、丙酸酯和碳酸或它们医学上可接受的盐。在某些实施例中，本发明的组合物可包括缓冲液，缓冲液的量为0.0001～100mg/mL、0.0001～0.001mg/mL、0.001～0.01mg/mL、0.01～0.1mg/mL、0.1～1mg/mL、1～5mg/mL、5～10mg/mL、 10～15mg/mL、15～20mg/mL、20～25mg/mL、25～50mg/mL、50～75 mg/mL、75～100mg/mL。
在其他实施例中，缓冲液至少包含了一种成分，该成分至少包含如下一种基团：(1)羧酸、羟基羧酸、二元羧酸(其酸性基团的pKa值至少大于3.0)或它们的盐，或所述羧酸和羧酸盐的混合物；(2)碱金属或碳酸铵、碱金属或碳酸氢铵，或它们的混合物。
在另一个实施例中，可以是乙酸缓冲液、氨基酸缓冲液、乳糖酸缓冲液或者碳酸缓冲液。
能够用于本发明的氨基酸包括，如精氨酸、甘氨酸、甲硫氨酸或赖氨酸。在某些实施例中，氨基酸至少有一个碱性基团，其pKa值大于5、6、7、8、8.5，或是它们的混合物，或是它们的盐、或是氨基酸和其盐的混合物。本发明中氨基酸的用量为0.1～100mg/mL、1～50mg/mL或5～ 25mg/mL。
能够用于本发明的羧酸包括例如葡糖酸、葡萄糖醛酸、葡糖酸酯、葡萄糖醛酸酯、碳酸碱金属盐、碳酸铵盐以及他们的混合物。
本发明的注射组合物可以是低渗、等渗或高渗的。优选地，该注射液具有250～350mOsm/kg的渗透压。
本发明的注射液可采用任何医学上可接受的渗透压试剂。合适的渗透压试剂包括但不限于无水或含水形式的氯化钠、葡萄糖、蔗糖、果糖、木糖醇、甘油、山梨醇、甘露醇、氯化钾、甘露糖、氯化钙、氯化镁和其他无机盐。优选地，渗透试剂为葡萄糖或者氯化钠。
本发明的注射液采用的渗透压试剂的用量为，例如0.1～100mg/mL、 1～50mg/mL、50～100mg/mL、30～70mg/mL、1～10mg/mL、5～15 mg/mL、65～75mg/mL或70～80mg/mL。
在某些实施例中，葡萄糖的用量为如0.1％～10％、0.2％～5％、 0.3％～3％或0.5％～1.5％。
为获取本发明的即用注射液，可使用酮咯酸助溶剂。助溶剂包括乙二醇(如聚乙二醇、丙二醇)、乙醇或多元醇(如山梨醇、甘露醇,木糖醇)。用于本发明助溶剂的用量为，例如0.1～150mg/mL、1～75mg/mL、50～100 mg/mL、30～90mg/mL、1～10mg/mL、5～15mg/mL、75～100mg/mL或 85～125mg/mL。
优选地，本发明的注射液不含有乙醇。在某些含有乙醇的实施例中，乙醇的优选浓度低于10％、低于7.5％、低于5％、低于2％、低于1％或低于0.5％。
在本发明的某些实施例中，医学上可接受的由海藻糖组成赋形剂，海藻糖的用量为，例如0.1～100mg/mL、1～50mg/mL、50～100 mg/mL、30～70mg/mL、1～10mg/mL、5～15mg/mL、65～75mg/mL 或70～80mg/mL。在本发明的某些实施例中，海藻糖的用量为，如 0.2％～5％、0.3％～3％或0.5％～1.5％。
本发明的注射液还可包括表面活性剂，如非离子型表面活性剂。表面活性剂的用量为，例如0.1～20mg/mL、0.2～10mg/mL或1～5mg/mL。
适用的非离子型表面活性剂包括但不限于乙氧基聚山梨醇酯，如聚山梨酯80、环氧乙烷/环氧丙烷共聚物、聚乙氧基化蓖麻油或聚乙二醇羟基硬脂酸酯。
本发明的注射液还可包括环糊精以增强酮咯酸或其医学上可接受的盐的溶解性。能与环糊精一起形成包合物的活性剂可以是，如α、β或γ环糊精。
酮咯酸或其盐的分子比例可以是，如1:10～10:1、1:5～5:1或1:3～3:1。
在某些实施例中，环糊精是磺化的β环糊精，如磺化环糊精或磺化-β- 环糊精等。环糊精取代物的平均磺化度可为，如2～10或5～8。在其他实施例中，环糊精是羟丙基β环糊精。
优选地，本发明的环糊精基本上是单一物。在某些实施例中，环糊精至少包含如下一种：(i)低于100ppm磷酸盐；(ii)低于20ppm的磺化试剂； (iii)重量含量低于0.5％的环糊精衍生物；(iv)重量含量低于1％的碱金属卤盐；(v)重量含量低于0.25％的水解磺化试剂。
在某些实施例中，环糊精中磷酸盐含量低于50ppm，磺化试剂含量低于10ppm，环糊精衍生物的重量含量低于0.2％，碱金属卤盐的重量含量低于0.5％，水解磺化试剂的重量含量低于0.25％。
在其他实施例中，环糊精中磷酸盐含量低于10ppm，磺化试剂含量低于2ppm，环糊精衍生物的重量含量低于0.1％，碱金属卤盐的重量含量低于 0.2％，水解磺化试剂的重量含量低于0.08％。
更进一步，在某些实施例中，环糊精中磷酸盐含量低于5ppm，碱金属卤盐的重量含量低于0.1％，水解磺化试剂的重量含量低于0.05％。
在某些实施例中，注射液的渗透压可以是，如250～350mOsm/kg、270～ 330mOsm/kg或290～310mOsm/kg。
在某些实施例中，本发明药物组合物的自由能至少为60kJ/mol、至少为70kJ/mol、至少为80kJ/mol、至少为90kJ/mol、至少为100kJ/mol、至少为110kJ/mol。
在某些实施例中，本发明药物组合物是无菌的，如通过终端灭菌。
某些实施例中，本发明的药物组合物中溶解氧的含量低于15mg/L、低于12mg/L或低于9mg/L。
本发明的组合物注射液被包装在医学上可接受的包装容器中，包装容器可为静脉输液袋或者瓶子。输液袋和瓶可以是玻璃、适用的塑料或高分子材料。包装容器的整体或者大部分区域可包含如下材料：聚氯乙烯、聚烯烃、聚酯、聚丙烯或它们的组合。在其他实施例中，仅仅与药物注射液接触的表面材料含有这些材料。静脉输液袋包括但不限于以下品牌： B.以及在其他实施例中，可采用Pisa生产的包装容器或是利用Technoflex生产的材料制备的包装容器。
输液袋可有一个或多个(如两个)端口。输液袋也可能是分岔的，与另一个输液袋部分相连用于连续输液。分岔输液袋也可用于将酮咯酸和另一种活性剂分隔开来。
在此揭露的注射液外面有一个护套(如箔或者纸)以免活性物质被光照射。在其他实施例中，在注射液包装袋和护套间充有氮气以免组合物发生氧化。在其他实施例中，包装容器(如玻璃或塑料)可能是耐光性的。
本发明的酮咯酸注射液还可包含一定量的阿片类镇痛药。阿片类镇痛药和酮咯酸一起形成即用型形式，能够直接给药给需要其的病人，不需要进行稀释。
阿片类镇痛药可选自：阿芬太尼、烯丙罗定、阿法罗定、安那里丁、阿朴吗啡、阿朴可待因、苄吗啡、苯腈米特、布芬太尼、丁丙诺啡，布托啡诺、卡芬太尼、吗拉米、可待因、环多氯联苯、环丙诺啡、二氢去氧吗啡、地佐辛、地恩丙胺、二氢可待因，地美沙多，地美庚醇、二甲噻丁、二氧苯基丁酸、地匹哌酮、依他佐辛、乙甲噻丁、乙基吗啡、依托尼秦、芬太尼、海洛因、氢可酮、羟甲基吗啡、氢吗啡酮羟、凯托米酮、异美沙酮、左洛啡烷、左啡诺、左芬啡烷、罗芬太尼、杜冷丁、美普他酚、美他佐辛、美沙酮、甲基吗啡、美托酮，米芬太尼、吗啡、吗啡-6-葡萄糖醛酸、麦罗啡、纳布啡、罂粟碱、尼可、去甲左啡诺、去甲美沙酮、烯丙吗啡、孤啡肽/孤啡肽FQ(N/OFQ)、去甲吗啡、诺匹哌酮、羟甲芬太尼、鸦片、羟考酮、羟二氢吗啡酮、阿片全碱、戊唑辛、苯吗庚酮、非诺吗烷、非那佐辛、苯呱利定、羟二氢吗啡酮、去痛定、腈米特、普罗庚嗪、二甲哌替啶、普罗法朵、丙哌利定、丙吡兰、丙氧芬、瑞芬太尼、舒芬太尼、他喷他多、曲马多、曲芬太尼、痛立定以及纳布啡；任何在阿片受体上有激动活性的属于菲、吗啡喃、苯基吗啡类、美沙酮、苯基哌啶、丙酰胺苯-4-苯胺基哌啶、4-芳基哌啶以及4-异芳基哌啶的阿片类物质；任何在阿片受体上有激动活性的具有与纳美芬、纳曲酮、丁丙诺啡、左啡诺、美普他酚、喷他佐辛和地佐辛相同的五环核阿片类物质；任何在阿片受体上有活性的芬太尼类似物、前体物、衍生物或其医学上可接受的盐及它们以外消旋或对映体形式的混合物等药物。
本发明所述的酮咯酸也可包含其他的NSAID，如水杨酸盐、吲哚美辛、萘普生、氟比洛芬、双氯芬酸、布洛芬、吡罗昔康、特丁非隆、依托度酸、纳布美通、替尼达普、氯芬酸、安替比林、氨基比林、安乃近、氨基比林、苯基丁氮酮、氯非宗、戊烯松、阿扎丙宗、苄达明、布可隆、辛可芬、苄达明布可隆、氯尼克辛、四唑、依匹唑、苯氧苯丙酸、夫洛非宁、氟芬那酸、格拉非宁、吲哚洛芬、酮洛芬、环氧洛芬、甲氯灭酸、甲灭酸、尼氟酸、非那西丁、salidifamides,、舒林酸、舒洛芬、托美汀以及其医学上可接受的盐，或它们的混合物。
非阿片类或者非NSAID镇痛药也可与酮咯酸组合在一起。这样的试剂包括但不限于醋氨酚。
以下实施例用于帮助理解本发明，但不应理解为对本发明的限制。对于本领域的一般技术人员，依据本发明内容的思想，在具体实施方式及应用范围上均会有改变之处，本说明书内容不应理解为对本发明的限制，凡依本发明设计思想所作的任何改变都在本发明的保护范围之内。
实施例：
1.材料和方法
表1所列出的材料购买于其指明的供应商。
表1.本发明所用材料
采用表2所示的仪器对所有注射液进行开发、操作以及分析
表2.本发明采用的操作和分析仪器
利用HPLC进行纯化分析的方法如表3所示。
表3.纯化方法中HPLC参数和数据分析方法
当利用HPLC色谱进行纯度分析时，在酸性和碱性条件下使酮咯酸氨丁三醇的降解。这样能够使降解物和杂质区分开来，以及使杂质和降解物的峰值区分。对于酸催化的降解，在预装杯中加入4.92mg的酮咯酸氨丁三醇，然后加入10ml水，用磷酸(H3P04)将所得的无色溶液的pH调整为 1.6。将部分溶液加入有盖的HPLC色谱柱，在85℃的条件下放置指定的时间，然后用表3所示的纯化方法进行HPLC分析。对于碱催化的降解，在预装杯中加入4.92mg的酮咯酸氨丁三醇，然后加入10ml水，用NaOH将所得的无色溶液的pH调整为12.09。将部分溶液加入有盖的HPLC色谱柱，在85℃的条件下放置指定的时间，然后用表3所示的纯化方法进行HPLC 分析。表6列出了指定时间后酮咯酸氨丁三醇的纯度。
光稳定性分析：
将酮咯酸氨丁三醇(4.97mg)加入预装杯中，然后加入10ml水产生无色溶液。盖上干净的预装杯，将溶液放置在环境光和室温条件下。在各个时间点，每次取出等量溶液(500μl)至HPLC光谱柱中，用等量的水稀释。用HPLC分析稀释的溶液中酮咯酸氨丁三醇纯度，结果见表11。 HPLC色谱柱中稳定性分析
在HPLC色谱柱中进行稳定性分析，以消除潜在的注射液与RTU包装材料的不相容性。所有的注射液被装在A等级的25ml容量瓶中。每种注射液中测定成分的含量如表4所示。
表4.注射液1～12的成分
一旦所有组分都被加入至容量瓶中，加水定量至刻度处，用磁力搅拌棒搅拌至混合均匀。用1.0N NaOH或1.0N HCI调节注射液的pH值至表4 所示的pH值。每种注射液用N2吹扫5min，然后用0.2μm的注射器式滤器过滤溶液，1.6ml等量的溶液被转移至14个单独的HPLC色谱柱中。7 个柱子加盖，剩下的7个柱子的顶部空间用N2吹扫后立即加盖。12个柱子被放置于121℃条件下20min以模拟高压条件。在达到模拟高压条件后，样品被转移至40℃/75％RH的稳定箱中以进行稳定性测试。在0、1、4、7、10和14天时间点，从稳定箱中取出样品，然后在24h内用HPLC分析酮咯酸氨丁三醇的纯度，所有注射液的纯度结果如表7所示。
Baxter IntraVia包装袋中稳定性分析
稳定的注射液被装在A等级的2L容量瓶中，用表5所示的成分。
表5.用于RTU包装袋稳定性分析的注射液7、8、10的成分
一旦所有组分都被加入至容量瓶中，加水定量至刻度处，用磁力搅拌棒搅拌至所有组分溶解。如有必要，用1.0N NaOH或1.0N HCI调节注射液的pH值至表5所示的pH值。在灌装过程开始前，将注射液用N2吹扫 5min。用蠕动泵使每个Baxter IntraVia包装袋被溶液(80g±1g)充满。分别在溶液满载线处中放置一个二通阀以进行无菌过滤和调节流量。每一种注射液都装24包。
所有用于稳定性分析的包装袋都没有暴露在高压(如模拟高压)条件下。在0、4、7、14、28和42天时间点，所有包装袋在装样前都被铺平放置1天以达到在室温。用于包装袋HPLC分析的样品用带有21号针的5cc 一次性注射器通过药物注射孔注入。每个注射液大约1.5ml样品被转移至 HPLC色谱柱中，在加样后12h内进行分析，纯度分析结果如表8所示。
遵照USP标准指导方针测定每个注射液的渗透压，使用的方程(1)如下：
计算注射液中每种单独组分的渗透压，然后将每个值相加(总渗透压)，玻璃和包装袋的渗透压值分别如表4和表5所示。
用阿伦尼乌斯方程式(Arrhenius Equation)进行稳定性预测
利用基于阿伦尼乌斯方程式(2)的Agere's稳定性预测算法来预测长期稳定性：
其中，k为速率常数，A为指前因子，Ea为表观活化能，T为热力学温度(单位为开尔文)，R为摩尔气体常量(8.31446J.Mol-1.K-1)。绘制获得的HPLC 纯度数据曲线，得出其趋势线，然后在给定的温度下推测阿仑尼乌斯方程参数以确定速率常数。速率常数代表酮咯酸氨丁三醇的降解速度。使用该速率常数，可以预测注射液的长期稳定性。阿仑尼乌斯方程参数的推测值如表10所示。
2.材料和方法
进行了酸、碱催化的降解实验。40h后，两种条件下都发生了显著降解，色谱图上出现了可以辨认的降解峰。如Gu,L.等人(International Journal of Pharmaceutics.(1988),41，95-104)所报道的，酮咯酸氨丁三醇有两条主要的降解途径。
酮咯酸氨丁三醇主要降解机制
表6显示了在酸、碱催化降解实验中通过HPLC测定的酮咯酸氨丁三醇纯度。可以看出，碱催化实验的降解峰值更高，尽管酸催化实验的降解峰面积更大，然而纯度低。
表6.酸、碱催化降解条件下酮咯酸氨丁三醇的HPLC纯度
色谱柱中注射液的纯度如表7所示。顶部空间N2对所有注射液几乎都没有影响，不包括在参数内。
表7.第二阶段注射液的HPLC纯度
本研究包括了在6周内各个时间点、在3种不同温度下(40℃、60℃和80℃)的3种注射液。在理想参数方面，稳定性分析A为结构稳定性分析B提供了信息。这两者的主要的区别是需要从Baxter IntraVia包装袋中取样，其显示了降解。在40℃时，IntraVia包装袋两端是稳定的，没有显示降解，然而60℃和80℃时放置一定时间后，包装袋开始融化到铝箔上。袋口开始变成褐色，在被抽样品袋口的外面观察到盐残渣。表8显示了采用HPLC测定的注射液7、8、10的纯度。
表8.Baxter IntraVia包装袋中注射液7、8、10的HPLC纯度
在稳定性分析A实验中，在40℃时，所有注射液显示出最小化降解；而在60℃时，所有注射液显示出轻微的降解。只有在80℃时，所有注射液开始高速降解。从阿仑尼乌斯方程式推断出相对较高的自由活化能支持这个观察结果(如表10所示)。本研究中观察到酮咯酸氨丁三醇的降解需要大量的能量，只有在高温时才能达到。1年和2年的纯度预测如表9和图1所示。
表9. 25℃时，Baxter IntraVia包装袋中注射液的预测纯度
酮咯酸氨丁三醇存在另一种降解机制，其不需要高温条件，但需要暴露在环境光下。环境光下的稳定性分析结果如表11所示。
表10.阿仑尼乌斯方程式参数的推断值
表11.稳定样品在环境光下的HPLC纯度
注射液7、8、10在Baxter IntraVia包装袋中进行42天稳定性分析后，检测注射液的pH值，并与起始的pH值相比较。比较结果如表12所示。
表12.注射液在Baxter IntraVia包装袋中pH值的改变
许多因素可能对溶液pH值的测量有重大影响。首先，由于包装袋是半透材料，长时间暴露于高温下可能通过蒸发的方式浓缩包装在包装袋内的样品，正如高温下稳定性样品的长期浓度测量证实的那样。另一方面，包装袋材料可能吸收了二氧化碳，二氧化碳在溶液中被转化为碳酸。在注射液8(包含了醋酸铵)中，氨气可以被吸收到袋材料中，剩下醋酸阴离子，醋酸阴离子在溶液中被质子化形成醋酸。所有这些情况都可以改变注射液的 pH值，然而，所有被测的pH值依然在注射液可以接受的范围。
溶解氧的测定
步骤：
1.将样品转入100ml的BOD瓶中，用溶解氧测定仪检测溶解氧(Test 1)；
2.样品在121℃高压蒸汽处理15min，取出瓶子后立刻加盖，水浴冷却至室温(24℃)，然后用溶解氧测定仪检测溶解氧(Test 2,3,4)。
表13.溶解氧
3.结论
酮咯酸氨丁三醇长时间暴露于高温下依然稳定。这个观察结果得到了阿仑尼乌斯方程式推断参数的支持，尤其是活化能参数。含有酮咯酸的注射液的主要的风险是光不稳定性，这种风险可以通过在袋外面使用箔使得注射液免遭环境光照射来缓解。对2年最低稳定性进行了预测，该预测是基于在外面包有一层箔的Baxter IntraVia包装袋中注射液。
Claims (19)
1.一种药物组合物注射液，所述药物组合物注射液包括：
0.1mg/mL～10mg/mL的酮咯酸或其医学上可接受的盐溶液；和
医学上可接受的赋形剂，所述赋形剂选自海藻糖、无水或含水的氯化钠、葡萄糖、蔗糖、木糖醇、果糖、甘油、山梨醇、甘露醇、氯化钾、甘露糖、氯化钙和氯化镁；
其中所述药物组合物不含有乙醇成分，而且在25℃下储存6个月后，所述药物组合物至少还保留有90％的酮咯酸或其医药上可接受的盐；并且
其中所述药物组合物被包装在医学上可接受的静脉输液袋或静脉输液瓶中。
2.一种如权利要求1所述的药物组合物，所述药物组合物在25℃下储存1年后至少还保留有95％的酮咯酸或其医药上可接受的盐。
3.一种如权利要求1所述的药物组合物，所述药物组合物在25℃下储存2年后至少还保留有98％的酮咯酸或其医药上可接受的盐。
4.一种如权利要求1所述的药物组合物，其中所述酮咯酸或其医学上可接受的盐的含量为0.1mg/mL～5mg/mL。
5.一种如权利要求1所述的药物组合物，所述药物组合物的pH值为4.5～8.5。
6.一种如权利要求1所述的药物组合物，其中所述医学上可接受的盐为酮咯酸氨丁三醇。
7.一种如权利要求1所述的药物组合物，其中所述药物组合物的渗透压为250mOsm/kg～350mOsm/kg。
8.一种如权利要求1所述的药物组合物，其中所述药物组合物的包装容器是有弹性的静脉输液袋。
9.一种如权利要求8所述的药物组合物，其中所述有弹性的静脉输液袋的溶液接触面的材料选自聚氯乙烯、聚烯烃、聚酯和聚丙烯。
10.一种如权利要求1所述的药物组合物，其中所述药物组合物不含有糖醇。
11.一种如权利要求1所述的药物组合物，其中所述药物组合物的活化自由能至少为60kJ/mol。
12.一种如权利要求1所述的药物组合物，其中所述药物组合物为终端灭菌。
13.一种如权利要求1所述的药物组合物，其中所述药物组合物的溶解氧含量低于15mg/L。
14.一种药物组合物注射液，所述药物组合物包括：
0.1mg/mL～10mg/mL的酮咯酸或其医学上可接受的盐溶液；和
医学上可接受的赋形剂，所述赋形剂选自海藻糖、无水或含水的氯化钠、葡萄糖、蔗糖、木糖醇、果糖、甘油、山梨醇、甘露醇、氯化钾、甘露糖、氯化钙和氯化镁；
其中所述药物组合物不含有乙醇成分；
所述药物组合物在25℃下储存6个月后至少还保留有90％的酮咯酸或其医药上可接受的盐；
所述药物组合物的渗透压为250mOsm/kg～350mOsm/kg；
所述药物组合物的活化自由能至少为60kJ/mol；并且
所述药物组合物被包装在医学上可接受的静脉输液袋或静脉输液瓶中。
15.一种药物组合物注射液，所述药物组合物包括：
酮咯酸或其医学上可接受的盐溶液；和
医学上可接受的赋形剂，所述赋形剂选自海藻糖、无水或含水的氯化钠、葡萄糖、蔗糖、木糖醇、果糖、甘油、山梨醇、甘露醇、氯化钾、甘露糖、氯化钙和氯化镁；
其中所述药物组合物不含有乙醇成分，而且所述药物组合物在25℃下储存6个月后至少还保留有90％的酮咯酸或其医药上可接受的盐；并且
所述药物组合物被包装在医学上可接受的静脉输液袋或静脉输液瓶中。
16.一种如权利要求15所述的药物组合物，其中所述赋形剂为海藻糖。
17.一种如权利要求16所述的药物组合物，其中所述海藻糖的含量按重量计为0.1％～10％。
18.一种如权利要求1所述的药物组合物，其中所述赋形剂为海藻糖。
19.一种如权利要求18所述的药物组合物，其中所述海藻糖的含量按重量计为0.1％～10％。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114159384A (zh) * | 2021-02-07 | 2022-03-11 | 南京锐志生物医药有限公司 | 一种化学性质稳定的低刺激性酮咯酸氨丁三醇注射液 |
| CN114432240A (zh) * | 2022-03-04 | 2022-05-06 | 郑州市中心医院 | 一种稳定不刺激的酮咯酸氨丁三醇注射液及其制备方法 |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012054831A2 (en) | 2010-10-21 | 2012-04-26 | Rtu Pharmaceuticals, Llc | Ready to use ketorolac formulations |
| US11559521B2 (en) * | 2013-07-22 | 2023-01-24 | William Bradley Worthington | Analgesic formulations and methods for reduced postoperative nausea and vomiting and enhanced postoperative pain relief |
| US10098872B1 (en) | 2013-07-22 | 2018-10-16 | William Bradley Worthington | Analgesic formulations and methods for reduced postoperative nausea and vomiting and enhanced postoperative pain relief |
| WO2015023675A2 (en) | 2013-08-12 | 2015-02-19 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
| US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
| WO2015095391A1 (en) | 2013-12-17 | 2015-06-25 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
| CN103830171B (zh) * | 2014-03-04 | 2015-11-18 | 鲁南制药集团股份有限公司 | 一种酮咯酸氨丁三醇注射液及其制备方法 |
| WO2016010771A1 (en) | 2014-07-17 | 2016-01-21 | Pharmaceutical Manufacturing Research Services, Inc. | Immediate release abuse deterrent liquid fill dosage form |
| JP2017531026A (ja) | 2014-10-20 | 2017-10-19 | ファーマシューティカル マニュファクチュアリング リサーチ サービシズ，インコーポレーテッド | 徐放性乱用抑止性液体充填剤形 |
| KR102447080B1 (ko) * | 2015-11-25 | 2022-09-23 | 액섬 테라퓨틱스, 인크. | 멜록시캄을 포함하는 약학 조성물 |
| IT201600075246A1 (it) * | 2016-07-19 | 2018-01-19 | Jointherapeutics S R L | Composizioni comprendenti una matrice polisaccaridica per il rilascio controllato di principi attivi. |
| CN117017997A (zh) | 2017-05-10 | 2023-11-10 | 艾克萨姆治疗公司 | 包含美洛昔康的药物组合物 |
| FR3101917B1 (fr) | 2019-10-09 | 2022-07-15 | Ifp Energies Now | Système de refroidissement à radiateur unique |
| CN110812325B (zh) * | 2019-11-13 | 2022-04-05 | 鲁南制药集团股份有限公司 | 一种提高酮咯酸氨丁三醇注射液存储稳定性的方法 |
| CN113679676A (zh) * | 2020-05-19 | 2021-11-23 | 南京海融医药科技股份有限公司 | 一种左酮咯酸的药物组合物及其制备方法 |
| EP4360622A1 (en) * | 2021-06-24 | 2024-05-01 | Shanghai Aurora Biotechnology Co., Ltd. | Ketorolac liquid composition, preparation method therefor, and application thereof |
| CN113384524A (zh) * | 2021-07-05 | 2021-09-14 | 四川尚锐生物医药有限公司 | 一种稳定的酮咯酸氨丁三醇注射液的制备方法 |
| CN114191384A (zh) * | 2021-12-20 | 2022-03-18 | 成都倍特药业股份有限公司 | 一种即用型酮咯酸氨丁三醇和氢溴酸依他佐辛组合液体制剂 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1448184A (zh) * | 2002-04-01 | 2003-10-15 | 永信药品工业股份有限公司 | 包含非－类固醇消炎药剂的可注射医药组合物及其制备方法 |
| US20090227534A1 (en) * | 2006-04-10 | 2009-09-10 | Laboratorios Senositan S.A. De C.V. | Pharmaceutical Composition Comprising the Combination of a Ketorolac Salt and Vitamins of the-B-Complex for the Treatment of Neuralgia |
Family Cites Families (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4089969A (en) * | 1976-07-14 | 1978-05-16 | Syntex (U.S.A.) Inc. | 5-Aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid derivatives and process for the production thereof |
| US5214052A (en) | 1987-07-28 | 1993-05-25 | Mitsubishi Kasei Corporation | Method for dissolving arginineamides and pharmaceutical compositions containing them |
| US6372755B2 (en) | 1997-07-11 | 2002-04-16 | Toray Industries, Inc. | Stable medicinal compositions containing 4,5-epoxymorphinan derivatives |
| US6608073B1 (en) | 1998-10-14 | 2003-08-19 | New Millennium Pharmaceutical Research, Inc. | Intranasal codeine for the rapid suppression of cough and rapid relief of pain |
| MXPA01009658A (es) | 1999-03-26 | 2003-06-24 | Pozen Inc | Composiciones de dihidroergotamina de alta potencia. |
| US20040022787A1 (en) * | 2000-07-03 | 2004-02-05 | Robert Cohen | Methods for treating an autoimmune disease using a soluble CTLA4 molecule and a DMARD or NSAID |
| US6509027B2 (en) * | 2001-02-12 | 2003-01-21 | Supergen, Inc. | Injectable pharmaceutical composition comprising coated particles of camptothecin |
| US7473432B2 (en) | 2002-10-11 | 2009-01-06 | Idea Ag | NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery |
| PL2368553T3 (pl) | 2003-04-08 | 2015-05-29 | Progenics Pharm Inc | Preparaty farmaceutyczne zawierające metylonaltrekson |
| US20070049552A1 (en) * | 2003-04-14 | 2007-03-01 | Babu Manoj M | Fluoroquinolone formulations and methods of making and using the same |
| US20080317681A1 (en) | 2003-07-11 | 2008-12-25 | Petros Gebreselassie | Compositions containing a stain removing complex, and methods of making and using the same |
| US20050266031A1 (en) | 2004-05-25 | 2005-12-01 | Jay Dickerson | Pharmaceutical suspension composition |
| CA2584184A1 (en) * | 2004-10-15 | 2006-04-27 | Seo Hong Yoo | Methods and compositions for reducing toxicity of a pharmaceutical compound |
| US8148356B2 (en) | 2005-08-24 | 2012-04-03 | Cumberland Pharmaceuticals, Inc. | Acetylcysteine composition and uses therefor |
| KR20150108430A (ko) | 2005-09-01 | 2015-09-25 | 백스터 인터내셔널 인코포레이티드 | 가용화제로서의 산을 포함하는 아가트로반 제제 |
| US20070142478A1 (en) | 2005-12-21 | 2007-06-21 | Erning Xia | Combination antimicrobial composition and method of use |
| WO2007092620A2 (en) | 2006-02-09 | 2007-08-16 | Macusight, Inc. | Stable formulations, and methods of their preparation and use |
| JP2009534409A (ja) | 2006-04-18 | 2009-09-24 | イーケーアール セラピューティクス， インク． | 予備混合即時使用静脈内ボーラス組成物および使用方法 |
| US20100010046A1 (en) | 2006-06-12 | 2010-01-14 | Ironwood Pharmaceuticals, Inc. | Pharmaceutical formulation for parenteral administration |
| US20080262017A1 (en) | 2006-06-29 | 2008-10-23 | Ulloa Sergio R | Sugar-Free Storage-Stable Antihistaminic Syrups |
| US20080014274A1 (en) | 2006-07-14 | 2008-01-17 | Wyeth | Enhanced stability phenylephrine liquid compositions |
| TWI489984B (zh) | 2006-08-04 | 2015-07-01 | Wyeth Corp | 用於非經腸道傳輸化合物之配方及其用途 |
| US20080057023A1 (en) | 2006-08-29 | 2008-03-06 | Chynn Emil W | Oxygenated ophthalmic composition |
| US7589106B2 (en) | 2006-09-27 | 2009-09-15 | Eagle Pharmaceuticals, Inc. | Alcohol free formulation of argatroban |
| KR100836624B1 (ko) | 2006-12-08 | 2008-06-10 | 한국전자통신연구원 | 가변 고속 푸리에 변환 장치 및 그 방법 |
| US20080312154A1 (en) | 2007-06-15 | 2008-12-18 | Barbara Lee Peterlin | Administration of adipocytokine and adiponectin for treating headache and methods of diagnosing headache by measuring adiponectin |
| PL2197429T3 (pl) | 2007-09-03 | 2016-09-30 | Kompozycje w postaci cząstek do dostarczania słabo rozpuszczalnych leków | |
| WO2009087658A2 (en) | 2007-11-07 | 2009-07-16 | Sun Pharma Advanced Research Company Limited | Composition suitable for parenteral administration |
| JP5909750B2 (ja) | 2007-11-13 | 2016-04-27 | マリンクロット アイピー | 低用量静脈内アセトアミノフェン |
| US20090239836A1 (en) | 2008-03-24 | 2009-09-24 | Mary Lee Ciolkowski | Multifunctional Ophthalmic Compositions |
| US8956636B2 (en) * | 2008-04-18 | 2015-02-17 | Warsaw Orthopedic, Inc. | Methods and compositions for treating postoperative pain comprosing ketorolac |
| US7635773B2 (en) | 2008-04-28 | 2009-12-22 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
| TWI397038B (zh) * | 2008-11-05 | 2013-05-21 | Au Optronics Corp | 使用半源極驅動架構之顯示面板及其顯示資料供應方法 |
| CA2806069C (en) * | 2010-07-19 | 2021-01-19 | Remedy Pharmaceuticals, Inc. | Methods of intravenous administration of glyburide and other drugs |
| MY173215A (en) | 2010-07-21 | 2020-01-06 | Cumberland Pharmaceuticals Inc | Acetylcysteine compositions and methods of use thereof |
| WO2012054831A2 (en) | 2010-10-21 | 2012-04-26 | Rtu Pharmaceuticals, Llc | Ready to use ketorolac formulations |
-
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- 2011-10-21 WO PCT/US2011/057284 patent/WO2012054831A2/en active Application Filing
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1448184A (zh) * | 2002-04-01 | 2003-10-15 | 永信药品工业股份有限公司 | 包含非－类固醇消炎药剂的可注射医药组合物及其制备方法 |
| US20090227534A1 (en) * | 2006-04-10 | 2009-09-10 | Laboratorios Senositan S.A. De C.V. | Pharmaceutical Composition Comprising the Combination of a Ketorolac Salt and Vitamins of the-B-Complex for the Treatment of Neuralgia |
Non-Patent Citations (1)
| Title |
|---|
| 周建平主编: "《药剂学》", 31 March 2007, 东南大学出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114159384A (zh) * | 2021-02-07 | 2022-03-11 | 南京锐志生物医药有限公司 | 一种化学性质稳定的低刺激性酮咯酸氨丁三醇注射液 |
| CN114159384B (zh) * | 2021-02-07 | 2023-04-07 | 南京锐志生物医药有限公司 | 一种化学性质稳定的低刺激性酮咯酸氨丁三醇注射液 |
| CN114432240A (zh) * | 2022-03-04 | 2022-05-06 | 郑州市中心医院 | 一种稳定不刺激的酮咯酸氨丁三醇注射液及其制备方法 |
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