CN101352412A - 肠溶性非甾体解热镇痛抗炎药及其制备 - Google Patents
肠溶性非甾体解热镇痛抗炎药及其制备 Download PDFInfo
- Publication number
- CN101352412A CN101352412A CNA2008102120962A CN200810212096A CN101352412A CN 101352412 A CN101352412 A CN 101352412A CN A2008102120962 A CNA2008102120962 A CN A2008102120962A CN 200810212096 A CN200810212096 A CN 200810212096A CN 101352412 A CN101352412 A CN 101352412A
- Authority
- CN
- China
- Prior art keywords
- acid
- enteric
- compositions
- inflammatory agent
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002260 anti-inflammatory agent Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229940121363 anti-inflammatory agent Drugs 0.000 title claims description 19
- 230000003637 steroidlike Effects 0.000 title claims description 14
- 239000011248 coating agent Substances 0.000 claims description 26
- 238000000576 coating method Methods 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 22
- 239000002702 enteric coating Substances 0.000 claims description 19
- 238000009505 enteric coating Methods 0.000 claims description 19
- 239000000463 material Substances 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 12
- 229960001193 diclofenac sodium Drugs 0.000 claims description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 10
- 229960003943 hypromellose Drugs 0.000 claims description 10
- 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 10
- 229920002301 cellulose acetate Polymers 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- -1 acetic acid phthalic acid ester Chemical class 0.000 claims description 6
- 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 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- ARCGXLSVLAOJQL-UHFFFAOYSA-N trimellitic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(C(O)=O)=C1 ARCGXLSVLAOJQL-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 5
- 229960000991 ketoprofen Drugs 0.000 claims description 5
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 4
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 4
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 4
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 4
- CNBGNNVCVSKAQZ-UHFFFAOYSA-N benzydamine Chemical compound C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 CNBGNNVCVSKAQZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 229960001680 ibuprofen Drugs 0.000 claims description 4
- 229960001929 meloxicam Drugs 0.000 claims description 4
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- AEQDJSLRWYMAQI-KRWDZBQOSA-N tetrahydropalmatine Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3C[C@H]2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-KRWDZBQOSA-N 0.000 claims description 4
- 229920003139 Eudragit® L 100 Polymers 0.000 claims description 3
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 claims description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 claims description 3
- 229960000590 celecoxib Drugs 0.000 claims description 3
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 3
- 229940120889 dipyrone Drugs 0.000 claims description 3
- LUJQXGBDWAGQHS-UHFFFAOYSA-N ethenyl acetate;phthalic acid Chemical compound CC(=O)OC=C.OC(=O)C1=CC=CC=C1C(O)=O LUJQXGBDWAGQHS-UHFFFAOYSA-N 0.000 claims description 3
- 229960001395 fenbufen Drugs 0.000 claims description 3
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 claims description 3
- 229960000905 indomethacin Drugs 0.000 claims description 3
- 229960000681 leflunomide Drugs 0.000 claims description 3
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 claims description 3
- DJGAAPFSPWAYTJ-UHFFFAOYSA-M metamizole sodium Chemical compound [Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 DJGAAPFSPWAYTJ-UHFFFAOYSA-M 0.000 claims description 3
- 229960004270 nabumetone Drugs 0.000 claims description 3
- 229960002009 naproxen Drugs 0.000 claims description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 3
- 229960000965 nimesulide Drugs 0.000 claims description 3
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 claims description 3
- 229960002739 oxaprozin Drugs 0.000 claims description 3
- 229960002895 phenylbutazone Drugs 0.000 claims description 3
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 claims description 3
- 229920002744 polyvinyl acetate phthalate Polymers 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 229960000371 rofecoxib Drugs 0.000 claims description 3
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims description 3
- 229960000894 sulindac Drugs 0.000 claims description 3
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 claims description 3
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 claims description 3
- 229960002905 tolfenamic acid Drugs 0.000 claims description 3
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 claims description 2
- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 claims description 2
- ZQBMUHABRSEAIK-UXBLZVDNSA-N 1-[4-[(e)-3-phenylprop-2-enyl]piperazin-1-yl]butan-1-one Chemical compound C1CN(C(=O)CCC)CCN1C\C=C\C1=CC=CC=C1 ZQBMUHABRSEAIK-UXBLZVDNSA-N 0.000 claims description 2
- INYYVPJSBIVGPH-UHFFFAOYSA-N 14-episinomenine Natural products C1CN(C)C2CC3=CC=C(OC)C(O)=C3C31C2C=C(OC)C(=O)C3 INYYVPJSBIVGPH-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 2
- OIRAEJWYWSAQNG-UHFFFAOYSA-N Clidanac Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 claims description 2
- RHAXSHUQNIEUEY-UHFFFAOYSA-N Epirizole Chemical compound COC1=CC(C)=NN1C1=NC(C)=CC(OC)=N1 RHAXSHUQNIEUEY-UHFFFAOYSA-N 0.000 claims description 2
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 claims description 2
- 229920003141 Eudragit® S 100 Polymers 0.000 claims description 2
- RBBWCVQDXDFISW-UHFFFAOYSA-N Feprazone Chemical compound O=C1C(CC=C(C)C)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 RBBWCVQDXDFISW-UHFFFAOYSA-N 0.000 claims description 2
- APQPGQGAWABJLN-UHFFFAOYSA-N Floctafenine Chemical compound OCC(O)COC(=O)C1=CC=CC=C1NC1=CC=NC2=C(C(F)(F)F)C=CC=C12 APQPGQGAWABJLN-UHFFFAOYSA-N 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 2
- 241001597008 Nomeidae Species 0.000 claims description 2
- INYYVPJSBIVGPH-QHRIQVFBSA-N Sinomenine Chemical compound C([C@@H]1N(CC2)C)C3=CC=C(OC)C(O)=C3[C@@]32[C@@H]1C=C(OC)C(=O)C3 INYYVPJSBIVGPH-QHRIQVFBSA-N 0.000 claims description 2
- 229960004663 alminoprofen Drugs 0.000 claims description 2
- FPHLBGOJWPEVME-UHFFFAOYSA-N alminoprofen Chemical compound OC(=O)C(C)C1=CC=C(NCC(C)=C)C=C1 FPHLBGOJWPEVME-UHFFFAOYSA-N 0.000 claims description 2
- 229960000333 benzydamine Drugs 0.000 claims description 2
- 229960000962 bufexamac Drugs 0.000 claims description 2
- MXJWRABVEGLYDG-UHFFFAOYSA-N bufexamac Chemical compound CCCCOC1=CC=C(CC(=O)NO)C=C1 MXJWRABVEGLYDG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 claims description 2
- 229960003184 carprofen Drugs 0.000 claims description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 2
- RARWEROUOQPTCJ-RBUKOAKNSA-N cepharamine Natural products C1CC2=CC=C(OC)C(O)=C2[C@@]2(CCN3C)[C@]13C=C(OC)C(=O)C2 RARWEROUOQPTCJ-RBUKOAKNSA-N 0.000 claims description 2
- 229940060038 chlorine Drugs 0.000 claims description 2
- NKPPORKKCMYYTO-DHZHZOJOSA-N cinmetacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)\C=C\C1=CC=CC=C1 NKPPORKKCMYYTO-DHZHZOJOSA-N 0.000 claims description 2
- 229950011171 cinmetacin Drugs 0.000 claims description 2
- 229950010886 clidanac Drugs 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 229960000616 diflunisal Drugs 0.000 claims description 2
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 claims description 2
- 229950003801 epirizole Drugs 0.000 claims description 2
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 claims description 2
- 229960004943 ergotamine Drugs 0.000 claims description 2
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 claims description 2
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 claims description 2
- 229960001419 fenoprofen Drugs 0.000 claims description 2
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims description 2
- 229960002428 fentanyl Drugs 0.000 claims description 2
- 229960000489 feprazone Drugs 0.000 claims description 2
- 229960003240 floctafenine Drugs 0.000 claims description 2
- 229960000588 flunixin Drugs 0.000 claims description 2
- NOOCSNJCXJYGPE-UHFFFAOYSA-N flunixin Chemical compound C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O NOOCSNJCXJYGPE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229960002390 flurbiprofen Drugs 0.000 claims description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 2
- 229960004752 ketorolac Drugs 0.000 claims description 2
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 claims description 2
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 claims description 2
- 229960002202 lornoxicam Drugs 0.000 claims description 2
- 229960002373 loxoprofen Drugs 0.000 claims description 2
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims description 2
- 239000002398 materia medica Substances 0.000 claims description 2
- 229960003464 mefenamic acid Drugs 0.000 claims description 2
- 229960000649 oxyphenbutazone Drugs 0.000 claims description 2
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 claims description 2
- 229960000851 pirprofen Drugs 0.000 claims description 2
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000011347 resin Substances 0.000 claims description 2
- 229920005989 resin Polymers 0.000 claims description 2
- 229930189907 rotundine Natural products 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229930002966 sinomenine Natural products 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 229960001312 tiaprofenic acid Drugs 0.000 claims description 2
- 229960001017 tolmetin Drugs 0.000 claims description 2
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 claims description 2
- 239000000052 vinegar Substances 0.000 claims description 2
- 235000021419 vinegar Nutrition 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- 102100028675 DNA polymerase subunit gamma-2, mitochondrial Human genes 0.000 claims 1
- 101000837415 Homo sapiens DNA polymerase subunit gamma-2, mitochondrial Proteins 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 39
- 229940079593 drug Drugs 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 5
- 241001465754 Metazoa Species 0.000 abstract description 3
- 206010030113 Oedema Diseases 0.000 abstract description 3
- 208000007107 Stomach Ulcer Diseases 0.000 abstract description 3
- 206010047700 Vomiting Diseases 0.000 abstract description 3
- 201000005917 gastric ulcer Diseases 0.000 abstract description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract 2
- 239000003907 antipyretic analgesic agent Substances 0.000 abstract 2
- 206010017815 Gastric perforation Diseases 0.000 abstract 1
- 206010028813 Nausea Diseases 0.000 abstract 1
- 230000008693 nausea Effects 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 description 18
- 239000012738 dissolution medium Substances 0.000 description 15
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 15
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 7
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 6
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 6
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 6
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 4
- 229960002986 dinoprostone Drugs 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 4
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 4
- 230000029087 digestion Effects 0.000 description 3
- 238000011978 dissolution method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000012982 microporous membrane Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 101000862089 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 1A Proteins 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 206010014418 Electrolyte imbalance Diseases 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- 206010000059 abdominal discomfort Diseases 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000036592 analgesia Effects 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
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000007931 coated granule Substances 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 201000006370 kidney failure Diseases 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- XILVEPYQJIOVNB-UHFFFAOYSA-N 2-[3-(trifluoromethyl)anilino]benzoic acid 2-(2-hydroxyethoxy)ethyl ester Chemical compound OCCOCCOC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 XILVEPYQJIOVNB-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 241000218998 Salicaceae Species 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 229960001493 etofenamate Drugs 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及肠溶性非甾体解热镇痛抗炎药及其制备，经包衣的非甾体解热镇痛抗炎药经口服给药时可避免它们对人和动物胃肠道造成的众所周知的副作用，如：恶心、呕吐、胃溃疡、穿孔、出血和水肿等。
Description
技术领域
本发明涉及非甾体解热镇痛抗炎药肠溶制剂的制备方法。
背景技术
非甾体类抗炎药(nonsteroidal antiinflammatory drugs，NSAIDs)是临床上常用的解热镇痛抗炎药，广泛应用于风湿性疾病、慢性炎性关节炎以及各种原因导致的发热、疼痛性疾病。
自从阿司匹林于1898年上市以来的一个多世纪里，非甾体类镇痛消炎药(nonsteroidal antiinflam-matory drugs，NSAIDs)已增至百余个品种，按化学结构可分为甲酸类也称水杨酸类(代表药物阿司匹林、双氯尼柳等)；乙酸类(代表药物双氯芬酸、吲哚美辛、舒林酸和依托芬那酯)；丙酸类(代表药物布洛芬、酮基布洛芬、芬布芬、奈普生、奥沙普秦和恶丙嗪等)；昔康类也叫苯并噻嗪类(代表药物美洛昔康、罗诺昔康、吡罗西康、替诺昔康等)；昔布类(代表药物罗非昔布、塞来昔布)；吡唑酮类(代表药物安乃近、氨基比林、保泰松、羟基布他酮)；非酸类(萘丁美酮、尼美舒利)；免疫抑制剂类(来氟米特)等，这些药物已成为全球最畅销的药品。
所有的非甾体抗炎药(non-steroidal anti-inflammatory drug，NSAID)的化学结构虽然差别很大，但他们的作用机制主要都是通过抑制PGs环氧化酶(COX)，阻止花生四烯酸转化为PGs而发挥镇痛、消炎和解热作用。COX有两个亚型，即COX-1(体内平衡的常态)和诱导形式(导致受损的)被归为COX-2。COX-1出现在胃(肠)壁、肾脏和血小板中，在细胞内维持机体正常的生理功能，由它催化合前列腺素E2(Prostaglandin E2，PGE2)和前列腺素I2(Prostaglandin I2，PGI2)具有稳定细胞功能和保护细胞的作用。前列腺素在胃肠道和肾中产生维持胃肠道黏膜的完整性，和肾充满。COX-2在正常细胞中较少，但当单核细胞、巨噬细胞、纤维母细胞、血管平滑肌或内皮细胞等细胞接触到内毒素、脂多糖、IL-1等致炎因子或细胞因子后，这些细胞经诱导可产生大量的COX-2，由它催化合成的PGE2和PGI2是原炎性前列腺素，它们具有强的致炎、致痛作用。
非甾体抗炎药(non-steroidal anti-inflammatory drug，NSAID)在人临床上的使用情况经过一个多世纪的不断研究和临床使用发现大多数解热镇痛抗炎药对COX-1及COX-2没有选择性，只是不同的药物在COX-1和COX-2选择效果上的不同。因此在使用NSAIDs类药物时，在对COX-2产生抑制的同时也对COX-1产生抑制作用，因此在使用NSAIDs药物时常因COX-1被抑制而出现胃、肾和血小板功能的障碍，发生胃部不适、恶心、呕吐、血液不易凝结、胃溃疡、穿孔、出血、水肿、电解质紊乱、一过性肾功能不全等不良反应。为了在口服使用过程中减少对胃部的副作用，对该类产品进行肠溶性材料的包被处理，使药物在经过胃部时不发生崩解，仍然完整的通过胃部，而在药物到达肠部时又能迅速崩解，同时被吸收利用。
发明内容
本发明提供一种非甾体解热镇痛抗炎药肠溶组合物，该组合物含有非甾体解热镇痛抗炎药和肠溶包衣材料，
两者的重量百分比为：
非甾体解热镇痛抗炎药70-93％
肠溶包衣材料7～30％。
本发明的肠溶组合物，必要时还可以加入其他材料，如药物学上可接受的辅料。
人和动物胃部的PH值通常＜4.0，肠道PH值通常＞5.0，据此我们选择的肠溶包衣材料必须是在PH＞5.0的溶液中可以快速崩解，而在＜5.0的溶液中不溶解。
本发明的肠溶包衣材料符合上述要求，选自：虫胶(PH＞7.0)、聚乙烯醇乙酸苯二甲酸酯(PVAP)(PH＞5.0)、丙烯酸树脂类(Eudragit L30D-55 PH＞5.5)、Eudragit L100(PH＞6.0)、Eudragit S100(PH＞7.0))、邻苯二甲酸乙酸纤维素(乙酸纤维素肽酸酯，CAP)(PH＞6.0)；1，2，4-苯三甲酸乙酸纤维素(乙酸纤维素苯三酸酯，CAT)(PH＞5.5)；羟丙甲纤维素肽酸酯(HPMCP，有HP50、HP55、HP55S三种规格)(PH＞5.5)；1，2，4-苯三甲酸羟丙基甲基纤维素(HPMCr)；琥珀酸乙酸纤维素(CAS)；琥珀酸乙酸羟丙基甲基纤维素(HPMCAS)(5.5-7.1)、欧巴代等，也可以是它们的混合物。
本发明的非甾体解热镇痛抗炎药选自：双氯芬酸钠、氟尼辛、阿司匹林、二氟尼柳、吲哚美辛、阿昔美辛、桂美辛、单(双)氯芬酸、噻洛芬酸、醋洛芬酸、甲洛芬那酸、甲芬那酸、托芬那酸、氯芬那敏、氟芬那敏、依洛芬那酯、夫洛非宁、舒林酸、丁苯羟酸、环氯茚酸、托美汀、酮咯酸、萘普生、布洛芬、酮洛芬、芬布芬、吡洛芬、阿明洛芬、氟比洛芬、卡洛芬、非诺洛芬、洛索洛芬、奥沙普秦、吡洛昔康、美洛昔康、氯诺昔康、塞来昔布、罗非昔布、尼美舒利、安乃近、保泰松、羟布宗、依匹唑、苄达明、非普拉宗、萘丁美酮、来氟米特、青藤碱、芬太尼、罗通定、麦角胺、布桂嗪等以及它们的衍生物或盐类。
本发明的肠溶包衣材料的用量为被包药物重量(药物组合物)的3～30％，优选为5～10％。
本发明的非甾体解热镇痛抗炎药优选为双氯芬酸钠，优选的肠溶包衣材料为羟丙甲纤维素肽酸酯，
本发明的优选的组合物，组成为双氯芬酸钠70-93％，羟丙甲纤维素肽酸酯7～30％。
本发明更优选的组合物，组成为双氯芬酸钠90-95％，羟丙甲纤维素肽酸酯5-10％。
本发明的组合物，其制备包括将肠溶包衣材料溶解，加入非甾体解热镇痛抗炎药，搅拌混合均匀，浓缩，冷却，烘干得到。
也可以将非甾体解热镇痛抗炎药制备成药物制剂，如片剂，颗粒剂，粉剂等，然后用溶解的肠溶包衣材料对这些制剂进行包衣。
本发明的组合物优选将肠溶包衣材料溶解，加入非甾体解热镇痛抗炎药混合的方法制备。
本发明的组合物，可以进一步加工成药物制剂，如片剂，胶囊，颗粒，混悬，等固体制剂，可以用制剂学的常规方法制备成制剂。
本发明的组合物及制剂，适合人和动物服用，不会发生胃部不适、恶心、呕吐、血液不易凝结、胃溃疡、穿孔、出血、水肿、电解质紊乱、一过性肾功能不全等不良反应，具有稳定，安全，吸收好等特点。
具体实施方式：
下面通过举例说明本发明肠溶药物的制备：
实施例1：先用1000ml(乙醇∶水＝80∶20)溶液加热溶解45g羟丙甲纤维素肽酸酯(HP55)，再加入150g双氯芬酸钠，加热搅拌至溶解澄明，边搅拌边浓缩至稠状，冷却，烘干得肠溶包衣物。包衣增重：22.98％。
包封率测定：根据包衣物在酸性介质中溶出度为0(在以下溶出度测定中可得出此结论)，可取包衣物在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，被包合药物不会溶解，而游离药物将溶解，可测出游离药物的量W游离，另外药物总量W总已知，根据包封率＝(W总-W游离)/W总×100％，计算得包封率为98.1％。
溶出度测定：按照中国药典(2005版)附录XC溶出度测定法中第二法测定。将上述制备好的包衣物先在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，烘干。然后把处理后的包衣物分别加入到装有溶出介质的智能溶出仪中，加入量为：0.3g包衣物加至300ml溶出介质中。溶出介质为：0.1mol/L HCl溶液(PH＝1.0)和0.4mol/L KCl溶液(PH＝5.2)。控制溶出介质温度为37±0.5℃，搅拌速度为50r/min，分别在设定时间(0.5h、1.0h、1.5h、2.5h、4h)取样，同时补加同温等量溶出介质。经0.45μm微孔滤膜过滤，取澄清溶液，测定药物含量，计算出药物溶出度(即药物的溶出量占总量的百分比)。结果见表1
表1包衣物在不同溶出介质中的溶出度
| 时间(h) | 0.1mol/L HCl 溶液(PH＝1.0) | 0.4mol/L KCl 溶液(PH＝5.2) |
| 0.5 | 0 | 70.8％ |
| 1.0 | 0 | 72.6％ |
| 1.5 | 0 | 81.3％ |
| 2.5 | 0 | 85.2％ |
| 4.0 | 0 | 88.1％ |
实施例2：先用800ml(乙醇∶水＝80∶20)溶液加热溶解15g羟丙甲纤维素肽酸酯(HP55)，再加入150g双氯芬酸钠，加热搅拌至溶解澄明，边搅拌边浓缩至稠状，冷却，烘干得肠溶包衣物。包衣增重：9.0％。
包封率测定：根据包衣物在酸性介质中溶出度为0(在以下溶出度测定中可得出此结论)，可取包衣物在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，被包合药物不会溶解，而游离药物将溶解，可测出游离药物的量W游离，另外药物总量W总已知，根据包封率＝(W总-W游离)/W总×100％，计算得包封率为92.5％。
溶出度测定：按照中国药典(2005版)附录XC溶出度测定法中第二法测定。将上述制备好的包衣物先在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，烘干。然后把处理后的包衣物分别加入到装有溶出介质的智能溶出仪中，加入量为：0.3g包衣物加至300ml溶出介质中。溶出介质为：0.1mol/L HCl溶液(PH＝1.0)和0.4mol/L KCl溶液(PH＝5.2)。控制溶出介质温度为37±0.5℃，搅拌速度为50r/min，分别在设定时间(0.5h、1.0h、1.5h、2.5h、4h)取样，同时补加同温等量溶出介质。经0.45μm微孔滤膜过滤，取澄清溶液，测定药物含量，计算出药物溶出度(即药物的溶出量占总量的百分比)。结果见表2
表2包衣物在不同溶出介质中的溶出度
| 时间(h) | 0.1mol/L HCl 溶液(PH＝1.0) | 0.4mol/L KCl 溶液(PH＝5.2) |
| 0.5 | 0 | 88.7％ |
| 1.0 | 0 | 91.2％ |
| 1.5 | 0 | 95.3％ |
| 2.5 | 0 | 100％ |
| 4.0 | 0 | 100％ |
实施例3：先用500ml(乙醇∶水＝80∶20)溶液加热溶解5g羟丙甲纤维素肽酸酯(HP55)，再加入100g双氯芬酸钠，加热搅拌至溶解澄明，经喷雾干燥得肠溶包衣物。包衣增重：4.72％。
包封率测定：根据包衣物在酸性介质中溶出度为0(在以下溶出度测定中可得出此结论)，可取包衣物在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，被包合药物不会溶解，而游离药物将溶解，可测出游离药物的量W游离，另外药物总量W总已知，根据包封率＝(W总-W游离)/W总×100％，计算得包封率为90.7％。
溶出度测定：按照中国药典(2005版)附录XC溶出度测定法中第二法测定。将上述制备好的包衣物先在0.1mol/L HCl溶液(PH＝1.0)中搅拌后迅速过滤，烘干。然后把处理后的包衣物分别加入到装有溶出介质的智能溶出仪中，加入量为：0.3g包衣物加至300ml溶出介质中。溶出介质为：0.1mol/L HCl溶液(PH＝1.0)和0.4mol/L KCl溶液(PH＝5.2)。控制溶出介质温度为37±0.5℃，搅拌速度为50r/min，分别在设定时间(0.5h、1.0h、1.5h、2.5h、4h)取样，同时补加同温等量溶出介质。经0.45μm微孔滤膜过滤，取澄清溶液，测定药物含量，计算出药物溶出度(即药物的溶出量占总量的百分比)。结果见表3
表3包衣物在不同溶出介质中的溶出度
| 时间(h) | 0.1mol/L HCl溶液(PH＝1.0) | 0.4mol/L KCl 溶液(PH＝5.2) |
| 0.5 | 0 | 95.8％ |
| 1.0 | 0 | 100％ |
| 1.5 | 0 | 100％ |
| 2.5 | 0 | 100％ |
| 4.0 | 0 | 100％ |
其它肠溶药物的制备：
实施例4：将20g聚丙烯酸树脂Eudragit L100边搅拌边加入到1000ml去离子水中，制成2％的水分散体系，在搅拌下将200g美洛昔康均匀分散于该水分散体系中，然后经喷雾干燥制得均匀包衣颗粒。包衣增重：6.86％。
实施例5：将20g聚乙烯醇乙酸苯二甲酸酯(PVAP)边搅拌边加入到1000ml(乙醇∶水＝50∶50)溶液中，制成2％的水分散体系，在搅拌下将150g托芬那酸均匀分散于该水分散体系中，然后经喷雾干燥制得均匀包衣颗粒。包衣增重：8.25％。
实施例6：先用500ml(乙醇∶水＝80∶20)溶液加热溶解5g琥珀酸乙酸羟丙基甲基纤维素(HPMCAS)，再加入100g酮洛芬，加热搅拌至溶解澄明，经喷雾干燥得肠溶包衣物。包衣增重：5.21％。
Claims (10)
1、一种非甾体解热镇痛抗炎药肠溶组合物，该组合物含有非甾体解热镇痛抗炎药和肠溶包衣材料。
2、权利要求1的组合物，其中非甾体解热镇痛抗炎药70-93％。肠溶包衣材料3～30％。
3、权利要求1的组合物，必要时还可以加入其他材料，如药物学上可接受的辅料。
4、权利要求1的组合物，其中肠溶包衣材料选自：虫胶(PH＞7.0)、聚乙烯醇乙酸苯二甲酸酯(PVAP)(PH＞5.0)、丙烯酸树脂类(Eudragit L30D-55 PH＞5.5)、Eudragit L100(PH＞6.0)、Eudragit S100(PH＞7.0))、邻苯二甲酸乙酸纤维素(乙酸纤维素肽酸酯，CAP)(PH＞6.0)；1，2，4-苯三甲酸乙酸纤维素(乙酸纤维素苯三酸酯，CAT)(PH＞5.5)；羟丙甲纤维素肽酸酯(HPMCP，有HP50、HP55、HP55S三种规格)(PH＞5.5)；1，2，4-苯三甲酸羟丙基甲基纤维素(HPMCr)；琥珀酸乙酸纤维素(CAS)；琥珀酸乙酸羟丙基甲基纤维素(HPMCAS)(5.5-7.1)、欧巴代、或是它们的混合物。
5、权利要求1的组合物，其中非甾体解热镇痛抗炎药选自：双氯芬酸钠、氟尼辛、阿司匹林、二氟尼柳、吲哚美辛、阿昔美辛、桂美辛、单(双)氯芬酸、噻洛芬酸、醋洛芬酸、甲洛芬那酸、甲芬那酸、托芬那酸、氯芬那敏、氟芬那敏、依洛芬那酯、夫洛非宁、舒林酸、丁苯羟酸、环氯茚酸、托美汀、酮咯酸、萘普生、布洛芬、酮洛芬、芬布芬、吡洛芬、阿明洛芬、氟比洛芬、卡洛芬、非诺洛芬、洛索洛芬、奥沙普秦、吡洛昔康、美洛昔康、氯诺昔康、塞来昔布、罗非昔布、尼美舒利、安乃近、保泰松、羟布宗、依匹唑、苄达明、非普拉宗、萘丁美酮、来氟米特、青藤碱、芬太尼、罗通定、麦角胺、布桂嗪等以及它们的衍生物或盐类。
6、权利要求1的组合物，组成为双氯芬酸钠70-93％，羟丙甲纤维素肽酸酯7～30％。
7、权利要求1的组合物，组成为双氯芬酸钠90-95％，羟丙甲纤维素肽酸酯5-10％。
8、权利要求1的组合物的制备方法，包括将肠溶包衣材料溶解，加入非甾体解热镇痛抗炎药，搅拌混合均匀，浓缩，冷却，烘干得到；或将非甾体解热镇痛抗炎药制备成药物制剂，如片剂，颗粒剂，粉剂等，然后用溶解的肠溶包衣材料对这些制剂进行包衣。
9、权利要求1所述的制备方法，其中溶解肠溶包衣材料的溶剂为水、甲醇、乙醇或它们的混合物。
10、用权利要求1的组合物，进一步加工成药物制剂，如片剂，胶囊，颗粒，混悬，等固体制剂，可以用制剂学的常规方法制备成制剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008102120962A CN101352412B (zh) | 2008-09-17 | 2008-09-17 | 肠溶性非甾体解热镇痛抗炎药及其制备 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008102120962A CN101352412B (zh) | 2008-09-17 | 2008-09-17 | 肠溶性非甾体解热镇痛抗炎药及其制备 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101352412A true CN101352412A (zh) | 2009-01-28 |
| CN101352412B CN101352412B (zh) | 2011-09-21 |
Family
ID=40305588
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008102120962A Expired - Fee Related CN101352412B (zh) | 2008-09-17 | 2008-09-17 | 肠溶性非甾体解热镇痛抗炎药及其制备 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101352412B (zh) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526076A (zh) * | 2011-12-30 | 2012-07-04 | 齐鲁动物保健品有限公司 | 阿司匹林衍生物的动物用途 |
| WO2013170711A1 (zh) * | 2012-05-17 | 2013-11-21 | Gao Tongqiang | 一种用于镇痛的药物组合产品 |
| CN103860568A (zh) * | 2014-04-11 | 2014-06-18 | 崔新明 | 一种防治类风湿性关节炎的药物组合物及其应用 |
| CN104117065A (zh) * | 2012-05-17 | 2014-10-29 | 高同强 | 一种基于青藤碱的用于镇痛的药物组合产品 |
| CN105769822A (zh) * | 2014-12-26 | 2016-07-20 | 广州朗圣药业有限公司 | 一种阿司匹林肠溶微粒胶囊的制备方法 |
| CN105796524A (zh) * | 2016-03-29 | 2016-07-27 | 南京多宝生物科技有限公司 | 一种阿司匹林肠溶片 |
| CN109394732A (zh) * | 2017-08-16 | 2019-03-01 | 安徽中医药大学 | 盐酸青藤碱肠溶定位渗透泵控释胶囊及其制备方法 |
| CN111020880A (zh) * | 2019-12-04 | 2020-04-17 | 广西民族大学 | 结肠靶向盐酸青藤碱缓释纳米纤维膜及其制备方法和应用 |
| CN112004529A (zh) * | 2018-04-06 | 2020-11-27 | 比利时胶囊公司 | 包含聚[(甲基丙烯酸甲酯)-共-(甲基丙烯酸)]的低纵横比颗粒的喷雾干燥方法 |
| CN112603901A (zh) * | 2020-12-02 | 2021-04-06 | 成都锦华药业有限责任公司 | 一种奥沙普秦肠溶微丸、药剂及其制备方法 |
-
2008
- 2008-09-17 CN CN2008102120962A patent/CN101352412B/zh not_active Expired - Fee Related
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526076A (zh) * | 2011-12-30 | 2012-07-04 | 齐鲁动物保健品有限公司 | 阿司匹林衍生物的动物用途 |
| WO2013170711A1 (zh) * | 2012-05-17 | 2013-11-21 | Gao Tongqiang | 一种用于镇痛的药物组合产品 |
| CN104117065A (zh) * | 2012-05-17 | 2014-10-29 | 高同强 | 一种基于青藤碱的用于镇痛的药物组合产品 |
| CN103860568A (zh) * | 2014-04-11 | 2014-06-18 | 崔新明 | 一种防治类风湿性关节炎的药物组合物及其应用 |
| CN103860568B (zh) * | 2014-04-11 | 2016-01-06 | 杨献美 | 一种防治类风湿性关节炎的药物组合物及其应用 |
| CN105769822A (zh) * | 2014-12-26 | 2016-07-20 | 广州朗圣药业有限公司 | 一种阿司匹林肠溶微粒胶囊的制备方法 |
| CN105796524A (zh) * | 2016-03-29 | 2016-07-27 | 南京多宝生物科技有限公司 | 一种阿司匹林肠溶片 |
| CN105796524B (zh) * | 2016-03-29 | 2019-01-01 | 山西兰花药业股份有限公司 | 一种阿司匹林肠溶片 |
| CN109394732A (zh) * | 2017-08-16 | 2019-03-01 | 安徽中医药大学 | 盐酸青藤碱肠溶定位渗透泵控释胶囊及其制备方法 |
| CN112004529A (zh) * | 2018-04-06 | 2020-11-27 | 比利时胶囊公司 | 包含聚[(甲基丙烯酸甲酯)-共-(甲基丙烯酸)]的低纵横比颗粒的喷雾干燥方法 |
| CN112004529B (zh) * | 2018-04-06 | 2023-08-08 | 比利时胶囊公司 | 包含聚[(甲基丙烯酸甲酯)-共-(甲基丙烯酸)]的低纵横比颗粒的喷雾干燥方法 |
| CN111020880A (zh) * | 2019-12-04 | 2020-04-17 | 广西民族大学 | 结肠靶向盐酸青藤碱缓释纳米纤维膜及其制备方法和应用 |
| CN112603901A (zh) * | 2020-12-02 | 2021-04-06 | 成都锦华药业有限责任公司 | 一种奥沙普秦肠溶微丸、药剂及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101352412B (zh) | 2011-09-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101352412B (zh) | 肠溶性非甾体解热镇痛抗炎药及其制备 | |
| JP2022101549A (ja) | Ｌ－オルニチンフェニルアセテート製剤 | |
| AU2012363789B2 (en) | Extended-release formulation for reducing the frequency of urination and method of use thereof | |
| KR20100045509A (ko) | 즉시 방출 및 지속 방출 이부프로펜 투약 계획 | |
| WO2013103389A1 (en) | Delayed-release formulation for reducing the frequency of urination and method of use thereof | |
| CN107157991A (zh) | 用于缓解尿频的延长释放制剂及其使用方法 | |
| CN103285017B (zh) | 复方单硝酸异山梨酯阿司匹林缓释胶囊制剂及制备方法 | |
| CA2609618C (en) | Novel acetylsalicylic acid formulations | |
| CN101265178A (zh) | 一种右旋布洛芬的氨基酸盐及其药用组合物 | |
| EP1726301A1 (en) | Oral pharmaceutical composition for treating a COX-2 mediated condition | |
| TW200918107A (en) | Oral pharmaceutical dosage form and manufacturing method thereof | |
| Jaiswal et al. | pulsatile drug delivery system: An Overview with special Emphasis on Losartan and Captopril | |
| CN103565765B (zh) | 复合香精粉末包衣分层次释药的布洛芬口崩小丸的制备 | |
| CN102294031B (zh) | 含质子泵抑制剂、nsaid和抗酸剂的药物制剂 | |
| CN102697761B (zh) | 一种布洛芬缓释固体组合物及其制备方法 | |
| CN102805742A (zh) | 一种吲哚美辛结肠靶向胶囊及其制备方法 | |
| CN105769773A (zh) | 洛索洛芬钠缓释微丸 | |
| WO2001019350A1 (en) | Controlled release formulation for administration of an anti-inflammatory naphthalene derivative | |
| CN106176648A (zh) | 一种扎托布洛芬分散片的制备方法 | |
| EP2848261B1 (en) | Pharmaceutical formulations comprising a muscle relaxant and an analgesic combination | |
| CN103142618B (zh) | 一种琥珀酸美托洛尔氢氯噻嗪缓释微丸胶囊及其制备方法 | |
| Zhang et al. | Preparation, characterization and in vitro/in vivo evaluation of oral time-controlled release etodolac pellets | |
| TR201802898T4 (tr) | Flurbiprofen ve famotidinin kombine hızlı salım formülasyonları. | |
| CA2624513A1 (en) | Combination | |
| CN106265585A (zh) | 一种扎托布洛芬胃溶型微丸片及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: QINGDAO KDN PHARM SHARES CO., LTD. Effective date: 20120731 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| C56 | Change in the name or address of the patentee |
Owner name: QINGDAO KDN ANIMAL PHARM CO., LTD. Free format text: FORMER NAME: QINGDAO LIUHE PHARMACEUTICAL CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: Dual road Qingda Industrial Park of Chengyang District of Shandong city in Qingdao province 266111 Patentee after: QINGDAO KDN BIOTECH Co.,Ltd. Address before: Dual road Qingda Industrial Park of Chengyang District of Shandong city in Qingdao province 266111 Patentee before: Qingdao Liuhe Pharmaceuticals Ltd. |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20120731 Address after: Dual road Qingda Industrial Park of Chengyang District of Shandong city in Qingdao province 266111 Co-patentee after: QINGDAO KDN PHARMACEUTICAL Co.,Ltd. Patentee after: QINGDAO KDN BIOTECH Co.,Ltd. Address before: Dual road Qingda Industrial Park of Chengyang District of Shandong city in Qingdao province 266111 Patentee before: QINGDAO KDN BIOTECH Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Dual road Qingda Industrial Park of Chengyang District of Shandong city in Qingdao province 266111 Patentee after: QINGDAO KDN BIOTECH Co.,Ltd. Patentee after: QINGDAO VLAND BIOTECH Inc. Address before: Dual road Qingda Industrial Park of Chengyang District of Shandong city in Qingdao province 266111 Patentee before: QINGDAO KDN BIOTECH Co.,Ltd. Patentee before: QINGDAO KDN PHARMACEUTICAL Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110921 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |