CN1279897C - Freeze dry preparation containing diclofenac salt and lidocaine and its preparation method - Google Patents
Freeze dry preparation containing diclofenac salt and lidocaine and its preparation method Download PDFInfo
- Publication number
- CN1279897C CN1279897C CN 200410024064 CN200410024064A CN1279897C CN 1279897 C CN1279897 C CN 1279897C CN 200410024064 CN200410024064 CN 200410024064 CN 200410024064 A CN200410024064 A CN 200410024064A CN 1279897 C CN1279897 C CN 1279897C
- Authority
- CN
- China
- Prior art keywords
- solution
- freeze
- lignocaine
- powder preparation
- diclofenac
- 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.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 229960004194 lidocaine Drugs 0.000 title claims abstract description 52
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical class OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 239000000843 powder Substances 0.000 claims abstract description 31
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 18
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000000463 material Substances 0.000 claims abstract description 4
- 230000007928 solubilization Effects 0.000 claims abstract description 3
- 238000005063 solubilization Methods 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 31
- 238000009472 formulation Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 229960001193 diclofenac sodium Drugs 0.000 claims description 25
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 claims description 25
- 238000004108 freeze drying Methods 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 229960004393 lidocaine hydrochloride Drugs 0.000 claims description 9
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 claims description 9
- 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 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 229940035676 analgesics Drugs 0.000 claims description 3
- 239000000730 antalgic agent Substances 0.000 claims description 3
- 230000002421 anti-septic effect Effects 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 3
- 229960004515 diclofenac potassium Drugs 0.000 claims description 3
- KXZOIWWTXOCYKR-UHFFFAOYSA-M diclofenac potassium Chemical compound [K+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KXZOIWWTXOCYKR-UHFFFAOYSA-M 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
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 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 2
- 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 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
- 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 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 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
- 239000008103 glucose Substances 0.000 claims description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229940096636 lidamantle Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 15
- 238000003860 storage Methods 0.000 abstract description 3
- 238000001035 drying Methods 0.000 abstract description 2
- 206010067484 Adverse reaction Diseases 0.000 abstract 1
- 230000006838 adverse reaction Effects 0.000 abstract 1
- 230000008014 freezing Effects 0.000 abstract 1
- 238000007710 freezing Methods 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 56
- 230000000052 comparative effect Effects 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- 229940090044 injection Drugs 0.000 description 21
- 238000002347 injection Methods 0.000 description 21
- 239000007924 injection Substances 0.000 description 21
- 239000007788 liquid Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000003814 drug Substances 0.000 description 12
- 206010020565 Hyperaemia Diseases 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 239000008215 water for injection Substances 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 230000003110 anti-inflammatory effect Effects 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 210000003314 quadriceps muscle Anatomy 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000013558 reference substance Substances 0.000 description 7
- MDNWOSOZYLHTCG-UHFFFAOYSA-N Dichlorophen Chemical compound OC1=CC=C(Cl)C=C1CC1=CC(Cl)=CC=C1O MDNWOSOZYLHTCG-UHFFFAOYSA-N 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 229960003887 dichlorophen Drugs 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000036407 pain Effects 0.000 description 6
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- 238000005262 decarbonization Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 239000003513 alkali Substances 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 4
- 235000010265 sodium sulphite Nutrition 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 230000000622 irritating effect Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 238000011003 system suitability test Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 229960004369 flufenamic acid Drugs 0.000 description 2
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 2
- 239000002085 irritant Substances 0.000 description 2
- 231100000021 irritant Toxicity 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 229940025300 lidocaine injection Drugs 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 1
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022078 Injection site inflammation Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- DNOWPGDHLKQUPV-UHFFFAOYSA-N [NH4+].CC#N.OP(O)([O-])=O Chemical compound [NH4+].CC#N.OP(O)([O-])=O DNOWPGDHLKQUPV-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
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- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940100853 diclofenac sodium 25 mg Drugs 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 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 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
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- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a frozen dry powder preparation containing diclofenac salt and lidocaine. The frozen dry powder preparation is prepared by freezing and drying tween 80, pH regulator and solution of diclofenac salt and lidocaine for effective dose for treatment, wherein the tween 80 has solubilization; the pH regulator can be accepted on the pharmacy and is used for regulating the pH value of the solution so that the pH value of the solution is higher than 7.0. The solution can also contain other auxiliary materials which can be accepted on the pharmacy. The preparation of the present invention has the advantages of stable performance, easy transportation and long storage cycle, and adverse reaction resulted from organic solvent, such as ethanol, etc. does not exist when the frozen dry powder preparation is used.
Description
Described technical field
The present invention belongs to field of pharmaceutical preparations, specifically, relates to pain that osteoarthritis, rheumatoid arthritis and other all kinds of non-rheumatic inflammations cause etc. and contains lyophilized formulations of diclofenac salt and lignocaine and preparation method thereof.
Technical background
Diclofenac is the representative anti-inflammatory analgesic of phenylacetic acid apoplexy due to endogenous wind, mainly be to suppress Cycloxygenase, stop arachidonic acid to be converted into prostaglandin, it is close to the effect of 2 isomer C OX-1 of Cycloxygenase and COX-2, compare with many traditional NSAID (non-steroidal anti-inflammatory drug) (effect that suppresses COX-1 is apparently higher than COX-2), under equivalent antiinflammatory dosage, its gastrointestinal reaction is lighter relatively.Diclofenac sodium or diclofenac potassium are one of medicines that anti-inflammatory and analgesic effect is stronger in the NSAID (non-steroidal anti-inflammatory drug) of using always at present, has significant rheumatism, antiinflammatory, pain relieving and refrigeration function, its antiinflammatory action is stronger than flufenamic acid, mefenamic acid, than the strong 26-50 of aspirin doubly, analgesic activity is stronger than aspirin, indometacin, flufenamic acid, can well remove arthralgia, detumescence, improve its activity, have good tolerability simultaneously.Characteristics are good effects, and untoward reaction is light, and dosage is reckling in the fenamic acids.
Clinical practice shows that diclofenac and its esters medicine have good antiinflammatory, analgesia, refrigeration function.Use its oral formulations clinically at present more, as capsule, tablet, and exterior-applied formulation, as gel, emulsifiable paste etc.To these dosage forms, drug effect is subjected to health very big to the influence of extent of drug absorption, and in addition, the time difference of administration and absorption makes effective ingredient postpone the effect of certain hour competence exertion.Simultaneously because first pass effect of hepar, and oral gastrointestinal is directly stimulated and curative effect is reduced, side effect increases.The injection untoward reaction of diclofenac salt is lighter, general well-tolerated, and common side effect also has the patient of 42%-45% the local strong pain of intramuscular injection to occur except gastrointestinal reaction.If added lignocaine, can effectively reduce injection point pain, reduce the injection site tissue damage.And, lignocaine onset speed is fast, the action intensity height, but action effective is lacked (＜2 hours), diclofenac sodium onset speed is slow, but action effective is long, action intensity height, the combination of two kinds of pharmacokineticss complementary (antiinflammatory) analgesic make its curative effect perfect more, behind the drug administration by injection, at first lidocaine hydrochloride onset in 5 minutes, rapid releasing arthritis patient's pain symptom, its potent anti-inflammatory analgesic action is brought into play in diclofenac sodium onset subsequently, reach 12～24 hours action time, can better control arthritis patient's the state of an illness.The diclofenac sodium lidocaine injection beautifies (Mepha) pharmaceutical factory development and production by Switzerland, and Bureau of Drugs Supervision's approval is in China's listing, and specification is 2ml:(75mg diclofenac sodium, 20mg lignocaine).
Diclofenac salt such as diclofenac sodium are molten in the water part omitted, and the prior art that is made into aqueous solution has for example adopted that lower alcohol such as ethanol, isopropyl alcohol, propylene glycol, Polyethylene Glycol and polyhydric alcohol dissolve diclofenac salt and further gained solution be used for useful in preparing drug formulations (as injection).This has just greatly limited its clinical practice, in use to patient's zest and side effect big (for example pain, injection site inflammation, allergy etc.).In addition, contain the solution of diclofenac salt and lignocaine to photo-labile.Usually, need to add stabilizing agent in the solution.Commercially available injection adopts the packaging material of lucifuge, and cost is increased.Therefore, but to make the preparation with good solubility and stability of injection be the problem that people attempt to solve to the medicine that how will contain diclofenac salt always.
Summary of the invention
The present invention is in order to overcome the deficiency of above technology, a kind of diclofenac salt for the treatment of effective dose and the pharmaceutical preparation of lignocaine, said preparation steady quality, convenient transportation of containing is provided, the storage cycle is long, and does not have the untoward reaction that causes because of organic solvents such as ethanol when using.
Another object of the present invention is to provide a kind of above-mentioned method that contains the pharmaceutical preparation of diclofenac salt and lignocaine for preparing, and method is simple for this, helps big commercial production.
The inventor is through in depth discovering in a large number, adopt freeze drying process can solve the stability of formulation problem effectively, can solve the solubility of diclofenac salt by the measures such as pH value of adding surfactant, regulator solution, and make the solution that contains diclofenac salt and lignocaine effectively suitable and use economically that normal freeze-drying technology comes that preparation quality is stable, convenient transportation and the preparation that contains diclofenac salt and lignocaine easily stored.
The inventor finds that under study for action multiple pharmaceutically acceptable solubilizing agent such as beta-schardinger dextrin-, phospholipid, polyvidone, poloxamer etc. all can increase the dissolubility of diclofenac salt, but produces precipitation during with the lignocaine compatibility.And the use Tween 80 can make the problems referred to above be solved.
The invention provides a kind of freeze-dried powder preparation that contains diclofenac salt and lignocaine, the diclofenac salt of its pharmaceutically acceptable pH regulator agent, treatment effective dose and the solution of lignocaine by the Tween 80 that contains solubilization, regulator solution pH value, the pH value of solution makes after lyophilization greater than 7.0.
Its pH value of solution of the present invention is preferably 7.5～9.0.Described pharmaceutically acceptable pH regulator agent can be at least a pharmaceutically acceptable routine or the known substance that is used to regulate pH.Can be alkali compounds or buffer system.Described pharmaceutically acceptable alkali compounds can be usually at the pharmaceutically acceptable alkali compounds that can be used for the regulator solution pH value, for example alkali compoundss such as sodium hydroxide, potassium hydroxide, tertiary sodium phosphate, tripotassium phosphate.Described buffer system can be commonly used or known in buffer system pharmaceutically acceptable, scalable solution pH value, and preferred buffer system comprises phosphate, citrate, acetate and Lactated buffer system.
The described solution that contains Tween 80, pH regulator agent, excipient, diclofenac salt and lignocaine can be to be the solution of solvent with water, can be to be the solution of solvent with the organic solvent, can be the solution of solvent with water and organic solvent also.Described organic solvent can be pharmaceutically acceptable organic solvent.
The freeze-dried powder preparation that contains diclofenac salt and lignocaine provided by the invention can also contain one or more material of adjuvants such as pharmaceutically acceptable water soluble excipient, stabilizing agent, analgesics, buffer agent and antiseptic.
Described pharmaceutically acceptable water soluble excipient is the routine or the known substances that can be used to prepare lyophilized formulations, for example: mannitol, sorbitol, sodium chloride, glucose, fructose, sucrose, xylitol, lactose or dextran or their mixture, preferred mannitol.The use amount of described excipient is the consumption of this area routine.
Described diclofenac salt and lignocaine are pharmaceutically acceptable salt, preferred diclofenac sodium or diclofenac potassium and lidocaine hydrochloride.
The content of diclofenac salt is 0.75%～5% (g/ml) in the described solution, and the content of lignocaine is 0.2%～1.4% (g/ml).The consumption of described Tween 80 is 2%～10% (g/ml), preferred 5% (g/ml).
The invention provides a kind of preparation method that contains diclofenac salt and Lida-Mantle lyophilized formulations, comprise with step: (1) preparation contains Tween 80, pH regulator agent, pharmaceutically acceptable water soluble excipient, the diclofenac salt of treatment effective dose and the solution of lignocaine, and the pH value of described solution is greater than 7.0; And (1) step of (2) lyophilization gained solution.Described diclofenac salt and lignocaine refer to its pharmaceutically acceptable salt, preferred diclofenac sodium and lidocaine hydrochloride.
The described solution that contains Tween 80, pH regulator agent, excipient, diclofenac salt and lignocaine can be to be the solution of solvent with water and/or organic solvent.Described organic solvent can be pharmaceutically acceptable organic solvent.
In described (1) step, can or add before or after the Tween 80 before or after adding diclofenac salt and lignocaine, perhaps add before or after the pH regulator agent, perhaps add before or after the excipient, add acceptable auxiliary, for example stabilizing agent, analgesics, buffer agent and/or antiseptic etc. on the conventional pharmaceutical.
In described (2) step, i.e. before the lyophilization step, describedly contain diclofenac salt and lignocaine solution can be removed pyrogen, filtration sterilization according to conventional method.
Described (2) step can be conventional or known freeze drying process step.Described freeze drying process carries out under aseptic condition, can adjust lyophilization cycle according to conventional or known method according to the demand of clinical preparation and concrete production equipment.
Diclofenac salt and the lignocaine freeze-dried powder preparation of containing of the present invention can be with the very fast redissolution of 2～5ml water for injection, for clinical use.
The present invention is by adding the methods such as pH value of Tween 80, regulator solution, make and contain diclofenac salt and lignocaine is solution-stabilized, the volume that contains diclofenac salt and lignocaine solution is as far as possible little, when solution contains the dissolubility of diclofenac salt and lignocaine and stability problem, energy consumption is significantly reduced, like this can be effectively and use economically that conventional freeze-dry process comes that preparation quality is stable, convenient transportation and the preparation that contains diclofenac salt and lignocaine easily stored.And technology is simple, does not need large-scale, special equipment, and energy consumption is low.
Freeze-dried powder preparation of the present invention under illumination (4500lx), high temperature (60 ℃) condition, is compared with the Comparative formulation for preparing according to prior art, and related substance obviously reduces, and illustrates that freeze-dried powder preparation of the present invention compares preparation stabilization.
Freeze-dried powder preparation of the present invention can both guarantee good dissolubility and stability not only after just preparing, and after Long-term Storage, be convenient to transportation, store and use.
The specific embodiment
Below will the invention will be further described by embodiment, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what content of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.
Embodiment 1
Get the 100g tween 80, add in the water for injection of about 40 ℃ about 1200ml, stir and make dissolving, add the stirring of 75g diclofenac sodium and make dissolving.Lidocaine hydrochloride 23.1g adds in the above-mentioned solution under constantly stirring with a small amount of water for injection dissolving back, with about the sodium hydroxide solution adjust pH to 8.0 of 5mol/L.Adding 240g mannitol, 2g sodium sulfite, 0.2g disodium edetate again stirs and makes dissolving fully; Add the injection water to 2000ml.Add 0.05% (g/ml) needle-use activated carbon to medicinal liquid, stirring at room 30 minutes, decarbonization filtering.Survey pH value and drug content.With 0.22 μ m microporous filter membrane fine straining degerming.Under aseptic condition gained solution is put (every 2ml) in the aseptic cillin bottle, lyophilization is according to a conventional method sealed.Promptly get the freeze-dried powder preparation A that contains dichlorophen hydrochlorate and lignocaine of the present invention.
Embodiment 2
Get the 100g tween 80, add in the water for injection of about 2000ml, stir and make dissolving, add the stirring of 75g diclofenac sodium and make dissolving.Lidocaine hydrochloride 23.1g adds in the above-mentioned solution under constantly stirring with a small amount of water for injection dissolving back, with about the tertiary sodium phosphate sodium solution adjust pH to 8.5 of 5mol/L.Adding 240g mannitol, 2g sodium sulfite again stirs and makes dissolving fully; Add the injection water to 5000ml.Add 0.05% (g/ml) needle-use activated carbon to medicinal liquid, stirred decarbonization filtering 30 minutes.Survey pH value and drug content.With 0.22 μ m microporous filter membrane fine straining degerming.Under aseptic condition gained solution is put (every 5ml) in the aseptic cillin bottle, lyophilization is according to a conventional method sealed.Promptly get the freeze-dried powder preparation B that contains dichlorophen hydrochlorate and lignocaine of the present invention.
Embodiment 3
Get the 200g tween 80,240g mannitol, 2g sodium sulfite add in the water for injection of about 1500ml, stir and make dissolving, add the stirring of 75g diclofenac sodium and make dissolving.Lidocaine hydrochloride 23.1g adds in the above-mentioned solution under constantly stirring with a small amount of water for injection dissolving back, with about phosphate buffered solution adjust pH to 7.5; Add the injection water to 2000ml.Add 0.05% (g/ml) needle-use activated carbon to medicinal liquid, stirred decarbonization filtering 30 minutes.Survey pH value and drug content.With 0.22 μ m microporous filter membrane fine straining degerming.Under aseptic condition gained solution is put (every 2ml) in the aseptic cillin bottle, lyophilization is according to a conventional method sealed.Promptly get the freeze-dried powder preparation C that contains dichlorophen hydrochlorate and lignocaine of the present invention.
Embodiment 4
Get the 200g tween 80, add 2000ml water for injection, stir, add the stirring of 75g diclofenac sodium and make dissolving.Lidocaine hydrochloride 23.1g adds in the above-mentioned solution under constantly stirring with a small amount of water for injection dissolving back, with about the sodium hydroxide solution adjust pH to 8.0 of 5mol/L.Add the stirring of 480g mannitol again and make dissolving fully; Add the injection water to 10000ml.Adjust pH to 8.0.Add 0.05% (g/ml) needle-use activated carbon to medicinal liquid, stirring at room 30 minutes, decarbonization filtering.Survey pH value and drug content.With 0.22 μ m microporous filter membrane fine straining degerming.Under aseptic condition gained solution is put (every 10ml) in the aseptic cillin bottle, lyophilization is according to a conventional method sealed.Promptly get the freeze-dried powder preparation D that contains dichlorophen hydrochlorate and lignocaine of the present invention.
Embodiment 5
Get the 70g tween 80, add in the water for injection of about 40 ℃ about 1000ml, stir and make dissolving, add the stirring of 75g diclofenac sodium and make dissolving.Lidocaine hydrochloride 23.1g adds in the above-mentioned solution under constantly stirring with a small amount of water for injection dissolving back, with about the sodium hydroxide solution adjust pH to 9.0 of 5mol/L.Adding 180g mannitol, 2g sodium sulfite, 0.2g disodium edetate again stirs and makes dissolving fully; Add the injection water to 1500ml.Add 0.05% (g/ml) needle-use activated carbon to medicinal liquid, stirring at room 30 minutes, decarbonization filtering.Survey pH value and drug content.With 0.22 μ m microporous filter membrane fine straining degerming.Under aseptic condition gained solution is put (every 1.5ml) in the aseptic cillin bottle, lyophilization is according to a conventional method sealed.Promptly get the freeze-dried powder preparation E that contains dichlorophen hydrochlorate and lignocaine of the present invention.
Embodiment 6
Freeze-dried powder preparation A and the commercially available diclofenac sodium lidocaine injection (being called for short Comparative formulation F) that contains dichlorophen hydrochlorate and lignocaine of the present invention that embodiment 1 makes put illumination (4500lx) and 60 ℃ of following placements 10 days of high temperature respectively, respectively at carrying out study on the stability in the 5th day and the 10th day, investigate data such as following table.
The diclofenac sodium related substance is measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-0.01mol/L sodium dihydrogen phosphate (with phosphoric acid adjust pH to 2.5) (66: 34) is mobile phase; The detection wavelength is 254nm; Flow velocity: 1.0ml/min.Number of theoretical plate calculates by the diclofenac sodium peak should be not less than 2000.
Algoscopy is got this product an amount of (being equivalent to diclofenac sodium 25mg approximately), puts in the 50ml measuring bottle, adds the mobile phase dissolving and is diluted to scale, shakes up, as need testing solution (sample introduction immediately); Precision is measured 1ml and is put in the 100ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l and inject chromatograph of liquid, regulate detection sensitivity and make main constituent chromatograph peak height be about 20% of full scale; Precision is measured each 20 μ l of need testing solution and contrast solution and is injected chromatograph of liquid respectively again, the record chromatogram is to 1.5 times of the main peak retention time, as showing impurity peaks, calculate the area percentage of impurity peak area and reference substance solution main peak in the chromatogram of need testing solution.(relative retention time be the peak of diclofenac sodium peak below 0.3 except).
The lignocaine related substance is measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With methanol-acetum (get glacial acetic acid 50ml, add water 930ml, mixing is with 1mol/L sodium hydroxide solution adjust pH to 3.4) (40: 60) is mobile phase; The detection wavelength is 234nm; Flow velocity: 1.0ml/min.Number of theoretical plate is by 2, and 6-dimethylaniline peak calculates and is not less than 2000.
Algoscopy is got this product an amount of (being equivalent to lignocaine 20mg approximately), with water dissolution and be diluted to 10ml, shakes up, as need testing solution; Precision measures 2, and 6-dimethylaniline 10.2 μ l (being equivalent to 2 approximately, 6-dimethylaniline 10mg) put in the 100ml measuring bottle, add mobile phase dissolving and be diluted to scale, shake up, precision is measured 1ml and is put in the 100ml measuring bottle, add mobile phase and be diluted to scale, shake up, in contrast product solution.Get reference substance solution 20 μ l and inject chromatograph of liquid, regulate detection sensitivity and make main constituent chromatograph peak height be about 20% of full scale; Precision is measured each 20 μ l of need testing solution and reference substance solution and is injected chromatograph of liquid respectively again, record chromatogram to diclofenac sodium is washed out, in the chromatogram of need testing solution in reference substance main peak retention time corresponding position as showing impurity peaks, calculate the area percentage of impurity peak area and reference substance solution main peak.
Assay is measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With acetonitrile-ammonium dihydrogen phosphate (get Ammonium biphosphate 1.0g, sodium acetate 1.0g adds 300ml water and makes dissolving) (33: 67) is mobile phase; The detection wavelength is 230nm.Number of theoretical plate calculates by the lignocaine peak should be not less than 2000.
Algoscopy is got the content under the content uniformity item, mixing, and precision takes by weighing in right amount (being equivalent to diclofenac sodium 90mg approximately, lignocaine 24mg), puts in the 50ml measuring bottle, with mobile phase dissolving and be diluted to scale, shakes up; Precision is measured 5ml and is put in the 50ml measuring bottle again, is diluted to scale with mobile phase, shakes up, and as need testing solution, precision is measured 20 μ l and injected chromatograph of liquid, the record chromatogram.Precision takes by weighing the about 24mg of lignocaine reference substance in addition, put in the 50ml measuring bottle, add 0.5mol/L hydrochloric acid solution 0.7ml and make dissolving, add 10ml ethanol, shake up, the accurate more about 90mg of diclofenac sodium reference substance that is dried to constant weight at 105 ℃ that takes by weighing, put in the same 50ml measuring bottle, add dissolve with ethanol again and be diluted to scale, shake up, 10 times of the accurate dilutions of reuse mobile phase are measured with method.Press external standard method with calculated by peak area, promptly.
Table 1: freeze-dried powder preparation and the Comparative formulation that contains diclofenac salt and lignocaine of the present invention
In illumination (4500lx) stability contrast down
| Project | Sample | 0 day | 5 days | 10 days |
| Character | Preparation A of the present invention | White lyophilizing block | White lyophilizing block | White lyophilizing block |
| Comparative formulation F | Colourless clear liquid | Colourless clear liquid | Almost colourless clear liquid | |
| Clarity | Preparation A of the present invention | Qualified | Qualified | Qualified |
| Comparative formulation F | Qualified | Qualified | Qualified | |
| Diclofenac sodium related substance (%) | Preparation A of the present invention | 0.09 | 0.38 | 0.70 |
| Comparative formulation F | 0.18 | 0.47 | 0.91 | |
| Lignocaine related substance (%) | Preparation A of the present invention | 0.001 | 0.001 | 0.002 |
| Comparative formulation E | 0.29 | 0.96 | 1.88 | |
| Diclofenac sodium content (%) | Preparation A of the present invention | 99.4 | 97.8 | 96.6 |
| Comparative formulation F | 100.9 | 98.4 | 97.1 | |
| Lignocaine content (%) | Preparation A of the present invention | 100.7 | 99.7 | 99.3 |
| Comparative formulation F | 99.3 | 98.9 | 97.4 |
Table 2: freeze-dried powder preparation and the Comparative formulation that contains diclofenac salt and lignocaine of the present invention
In high temperature (60 ℃) stability contrast down
| Project | Sample | 0 day | 5 days | 10 days |
| Character | Preparation A of the present invention | White lyophilizing block | White lyophilizing block | Little yellow lyophilizing block |
| Comparative formulation F | Colourless clear liquid | Colourless clear liquid | Almost colourless clear liquid | |
| Clarity | Preparation A of the present invention | Qualified | Qualified | Qualified |
| Comparative formulation F | Qualified | Qualified | Qualified | |
| Diclofenac sodium related substance (%) | Preparation A of the present invention | 0.09 | 0.45 | 0.68 |
| Comparative formulation F | 0.18 | 0.66 | 0.89 |
| Lignocaine related substance (%) | Preparation A of the present invention | 0.001 | 0.001 | 0.001 |
| Comparative formulation F | 0.29 | 0.54 | 0.94 | |
| Diclofenac sodium content (%) | Preparation A of the present invention | 99.4 | 98.7 | 98.1 |
| Comparative formulation F | 100.9 | 98.8 | 97.9 | |
| Lignocaine content (%) | Preparation A of the present invention | 100.7 | 99.0 | 99.6 |
| Comparative formulation F | 99.3 | 98.6 | 98.6 |
Annotate: " related substance " is meant synthesis material, intermediate, by-product and the possible impurity such as catabolite that exists in the principal agent.
By above result as seen, freeze-dried powder preparation of the present invention, under same experimental conditions, F compares with Comparative formulation, and related substance obviously reduces, and illustrates that freeze-dried powder preparation comparison of the present invention is more stable than preparation F.
Freeze-dried powder preparation A of the present invention and Comparative formulation F have been carried out the muscular irritation test of continuous three administrations and single-dose respectively, and method and result are as follows:
1, gets 2 of healthy rabbits at random, doe does not have pregnant, about it, respectively inject Comparative formulation F1ml with aseptic manipulation in the two lower limb quadriceps femoris respectively, 48 hours execution animals behind the medicine, dissect and take out quadriceps femoris, vertically cut, observe injection site irritant reaction (should do pathologic finding in case of necessity) and, calculate the summation of 4 quadriceps femoris order of reactions then by the listed standard of the table 3 corresponding order of reaction that converts.The results are shown in Table 4.
2, get 2 of healthy rabbits at random in addition, doe does not have pregnant, about it, respectively inject freeze-dried powder preparation A (time spent every with 2ml sterilized water for injection dissolving) aqueous solution 1ml with aseptic manipulation in the two lower limb quadriceps femoris respectively, once a day, injection is three days continuously, 48 hours execution animals behind the last medicine, dissect and take out quadriceps femoris, vertically cut, observe injection site irritant reaction (should do pathologic finding in case of necessity) and, calculate the summation of 4 quadriceps femoris order of reactions then by the listed standard of the table 3 corresponding order of reaction that converts.The results are shown in Table 5.
Table 3. muscular irritation standards of grading
| Order of reaction | Irritative response |
| 0 1 2 3 4 5 | No significant change mild hyperaemia, its scope is in the following moderate hyperemia of 0.5 * 1.0cm, its scope is in the above severe hyperemia of 0.5 * 1.0cm, necrosis occurs with myodegeneration, have the brown degeneration popularity necrosis to occur |
The administration of table 4 Comparative formulation single injection, four muscle of rabbit are observed the scoring situation
| Rabbit number | The injection site | Irritative response | Order of reaction (score value) |
| No. 1 No. 2 | Right side, left side, right side, left side | Moderate hyperemia, scope 0.7 * 1.0cm mild hyperaemia, the hyperemia of scope 0.6 * 0.9cm moderate, the hyperemia of scope 0.8 * 1.0cm moderate, scope 0.7 * 1.1cm | 2 2 2 2 |
Continuous three drug administration by injection of table 5 freeze-dried powder preparation of the present invention, four muscle of rabbit are observed the scoring situation
| Rabbit number | The injection site | Irritative response | Order of reaction (score value) |
| No. 1 No. 2 | Right side, left side, right side, left side | Moderate hyperemia, the hyperemia of scope 0.9 * 1.2cm moderate, scope 0.7 * 1.2cm mild hyperaemia, scope 0.6 * 0.8cm mild hyperaemia, scope 0.5 * 0.9cm | 2 2 1 1 |
As can be seen from the above results, freeze-dried powder preparation of the present invention, give the rabbit drug administration by injection continuous three times, to four muscle total points of rabbit quadriceps femoris is 6 minutes, and after the administration of Comparative formulation F single injection, to four muscle total points of rabbit quadriceps femoris is 8 minutes, and the zest that freeze-dried powder preparation of the present invention is described is less than Comparative formulation F.
Claims (8)
1, a kind of freeze-dried powder preparation that contains diclofenac salt and lignocaine, it is characterized in that: its pharmaceutically acceptable pH regulator agent, the diclofenac salt of treatment effective dose and the solution of lignocaine by the Tween 80 that contains solubilization, regulator solution pH value, the pH value of solution makes after lyophilization greater than 7.0; The envelope-bulk to weight ratio that Tween 80 accounts for solution is 2%～10%.
2, freeze-dried powder preparation according to claim 1 is characterized in that: the pH value of described solution is 7.5～9.0.
3, freeze-dried powder preparation according to claim 1 and 2 is characterized in that: described solution is to be the solution of solvent with water and/or organic solvent, and described organic solvent can be pharmaceutically acceptable organic solvent.
4, freeze-dried powder preparation according to claim 1 and 2 is characterized in that: one or more the material that contains pharmaceutically acceptable water soluble excipient, stabilizing agent, analgesics, buffer agent, antiseptic.
5, freeze-dried powder preparation according to claim 4, described water soluble excipient are one or more of mannitol, sorbitol, sodium chloride, glucose, fructose, sucrose, xylitol, lactose, dextran.
6, freeze-dried powder preparation according to claim 1 and 2 is characterized in that: described diclofenac salt is meant diclofenac sodium or diclofenac potassium, and described lignocaine is meant lidocaine hydrochloride.
7, freeze-dried powder preparation according to claim 1 and 2 is characterized in that: the amount of contained diclofenac salt is 0.75～5g in the described 100ml solution, and the amount of contained lignocaine is 0.2～1.4g, and the consumption of described Tween 80 is 2～10g.
8, the described preparation method that contains the lyophilized formulations of diclofenac salt and Lida-Mantle of a kind of claim 1, it is characterized in that: may further comprise the steps: (1) preparation contains Tween 80, pH regulator agent, pharmaceutically acceptable water soluble excipient, the diclofenac salt of treatment effective dose and the solution of lignocaine, and the pH value of described solution is greater than 7.0; And (1) step of (2) lyophilization gained solution.
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| CN104027315A (en) * | 2014-06-16 | 2014-09-10 | 海南中玉药业有限公司 | Submicron emulsion freeze-dried preparation of diclofenac sodium lidocaine hydrochloride as well as preparation method and application of submicron emulsion freeze-dried preparation |
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| AU2006221633B2 (en) | 2005-02-01 | 2009-07-30 | Troikaa Pharmaceuticals Ltd. | Injectable preparations of diclofenac and its pharmaceutically acceptable salts |
| CN101485650B (en) * | 2009-02-19 | 2013-07-17 | 辰欣药业股份有限公司 | Diclofenac sodium and lidocaine hydrochloride injection and preparation method thereof |
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2004
- 2004-04-30 CN CN 200410024064 patent/CN1279897C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104027315A (en) * | 2014-06-16 | 2014-09-10 | 海南中玉药业有限公司 | Submicron emulsion freeze-dried preparation of diclofenac sodium lidocaine hydrochloride as well as preparation method and application of submicron emulsion freeze-dried preparation |
| CN104027315B (en) * | 2014-06-16 | 2016-02-10 | 海南中玉药业有限公司 | A kind of submicron emulsion lyophilized formulations of diclofenac sodium lidocaine hydrochloride, its preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN1689561A (en) | 2005-11-02 |
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