CN113499315A - Stomach retention type dihydroartemisinin sustained-release tablet and preparation method and application thereof - Google Patents
Stomach retention type dihydroartemisinin sustained-release tablet and preparation method and application thereof Download PDFInfo
- Publication number
- CN113499315A CN113499315A CN202111002657.8A CN202111002657A CN113499315A CN 113499315 A CN113499315 A CN 113499315A CN 202111002657 A CN202111002657 A CN 202111002657A CN 113499315 A CN113499315 A CN 113499315A
- Authority
- CN
- China
- Prior art keywords
- tablet
- dihydroartemisinin
- agent
- release
- sustained
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960002521 artenimol Drugs 0.000 title claims abstract description 84
- 229930016266 dihydroartemisinin Natural products 0.000 title claims abstract description 84
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 title claims abstract description 81
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 32
- 230000014759 maintenance of location Effects 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims description 16
- 210000002784 stomach Anatomy 0.000 title abstract description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 34
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 28
- 239000000463 material Substances 0.000 claims abstract description 27
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229960000913 crospovidone Drugs 0.000 claims abstract description 20
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 20
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 20
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 17
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 17
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 16
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 15
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000008101 lactose Substances 0.000 claims abstract description 14
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 13
- 229960001631 carbomer Drugs 0.000 claims abstract description 13
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 13
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 12
- 239000000314 lubricant Substances 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 239000000945 filler Substances 0.000 claims abstract description 10
- 239000000080 wetting agent Substances 0.000 claims abstract description 10
- 239000004088 foaming agent Substances 0.000 claims abstract description 9
- 238000013268 sustained release Methods 0.000 claims abstract description 3
- 239000012730 sustained-release form Substances 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims description 62
- 239000000843 powder Substances 0.000 claims description 18
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 15
- 230000002496 gastric effect Effects 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 10
- 238000005469 granulation Methods 0.000 claims description 9
- 230000003179 granulation Effects 0.000 claims description 9
- 238000003825 pressing Methods 0.000 claims description 9
- 238000007873 sieving Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 206010012442 Dermatitis contact Diseases 0.000 claims description 6
- 238000007906 compression Methods 0.000 claims description 5
- 230000006835 compression Effects 0.000 claims description 5
- 208000010247 contact dermatitis Diseases 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- 208000002440 photoallergic dermatitis Diseases 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 4
- BJDCWCLMFKKGEE-HVDUHBCDSA-N dihydroartemisinin group Chemical group C[C@@]12OO[C@]34[C@@H](CC1)[C@@H](CC[C@H]3[C@H](C(O[C@@H]4O2)O)C)C BJDCWCLMFKKGEE-HVDUHBCDSA-N 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 238000007908 dry granulation Methods 0.000 claims description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 17
- 229940079593 drug Drugs 0.000 abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 206010036087 Polymorphic light eruption Diseases 0.000 description 13
- 239000000243 solution Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 230000008595 infiltration Effects 0.000 description 8
- 238000001764 infiltration Methods 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 229960004191 artemisinin Drugs 0.000 description 7
- 229930101531 artemisinin Natural products 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 206010034972 Photosensitivity reaction Diseases 0.000 description 6
- 206010025135 lupus erythematosus Diseases 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 5
- 206010014025 Ear swelling Diseases 0.000 description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 5
- 229940082484 carbomer-934 Drugs 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 210000005069 ears Anatomy 0.000 description 5
- -1 methoxyl group Chemical group 0.000 description 5
- 210000005087 mononuclear cell Anatomy 0.000 description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000000078 anti-malarial effect Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 4
- 229960004171 hydroxychloroquine Drugs 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229960001076 chlorpromazine Drugs 0.000 description 3
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 210000001198 duodenum Anatomy 0.000 description 3
- 208000007578 phototoxic dermatitis Diseases 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- AKUVRZKNLXYTJX-UHFFFAOYSA-N 3-benzylazetidine Chemical compound C=1C=CC=CC=1CC1CNC1 AKUVRZKNLXYTJX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BJDCWCLMFKKGEE-KDTBHNEXSA-N Dihydroartemisinin (DHA) Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](O)[C@@H]4C BJDCWCLMFKKGEE-KDTBHNEXSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 2
- 229960000981 artemether Drugs 0.000 description 2
- 229960002970 artemotil Drugs 0.000 description 2
- NLYNIRQVMRLPIQ-XQLAAWPRSA-N artemotil Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OCC)O[C@H]4[C@]32OO[C@@]1(C)O4 NLYNIRQVMRLPIQ-XQLAAWPRSA-N 0.000 description 2
- 229960004991 artesunate Drugs 0.000 description 2
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 229960001657 chlorpromazine hydrochloride Drugs 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000001678 irradiating effect Effects 0.000 description 2
- 210000001630 jejunum Anatomy 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Chemical class 0.000 description 2
- 239000002184 metal Chemical class 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 229930009674 sesquiterpene lactone Natural products 0.000 description 2
- 150000002107 sesquiterpene lactone derivatives Chemical class 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 1
- 102220487426 Actin-related protein 2/3 complex subunit 3_K15M_mutation Human genes 0.000 description 1
- 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 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000049464 Artemisia apiacea Species 0.000 description 1
- 235000011570 Artemisia caruifolia var apiacea Nutrition 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241001391944 Commicarpus scandens Species 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 206010033733 Papule Diseases 0.000 description 1
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 1
- 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 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000010398 acute inflammatory response Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 1
- 229940043234 carbomer-940 Drugs 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000012085 chronic inflammatory response Effects 0.000 description 1
- 238000010549 co-Evaporation Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000035617 depilation Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 235000013350 formula milk Nutrition 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008233 hard water Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 208000001875 irritant dermatitis Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001823 pruritic effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 206010041307 solar urticaria Diseases 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 239000000003 vaginal tablet Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Toxicology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a stomach retention type dihydroartemisinin sustained-release tablet, which belongs to the technical field of medicines and consists of dihydroartemisinin and auxiliary materials, wherein the auxiliary materials comprise a release retardant, a foaming agent, a filling agent, a disintegrating agent, a lubricant and a wetting agent, the release retardant comprises hydroxypropyl methyl cellulose, octadecanol and carbomer, the foaming agent is sodium bicarbonate, the filling agent is lactose, the disintegrating agent is crospovidone, the lubricant is magnesium stearate, and the wetting agent is sodium dodecyl sulfate; the sustained-release tablet has long retention time in the stomach, can release medicine continuously, has obvious sustained-release effect, can improve the oral bioavailability of dihydroartemisinin and improve the medication compliance.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a stomach retention type dihydroartemisinin sustained-release tablet and a preparation method and application thereof.
Background
Artemisinin is inspired by Youyou subject group of Chinese institute of traditional Chinese medicine of Chinese academy of sciences of traditional Chinese medicine from Chinese ancient books, sesquiterpene lactone type antimalarial specific drugs found in traditional Chinese medicine artemisia apiacea have the characteristics of high efficiency, quick effect and low toxicity, Dihydroartemisinin (DHA), Artemether (AM), Arteether (AE) and Artesunate (AS) researched and developed on the basis of the sesquiterpene lactone type antimalarial specific drugs become marketed drugs, and at present, a compound drug based on artemisinin drugs is a first-choice drug recommended by WHO for treating malaria.
With the continuous and deep pharmacological research, it is found that the artemisinin and the derivatives thereof have the pharmacological actions of schistosomiasis resistance, tumor resistance, immunosuppression, fibrosis resistance, arrhythmia resistance and the like besides the antimalarial action, so that the expansion of the artemisinin adaptation disease has important significance for improving the utilization of the artemisinin and increasing the economic value and the social benefit of the artemisinin.
The Dihydroartemisinin (DHA) introduces a hydroxyl structure at the C-10 position of ART, is a first generation derivative of artemisinin, and has antimalarial effect 10 times higher than that of artemisinin; the pharmacokinetics research of the dihydroartemisinin shows that the dihydroartemisinin has good oral absorption, wide distribution in vivo, quick effect, excretion and metabolism, 2mg/kg of dihydroartemisinin is orally taken, the blood concentration reaches the peak value within 1.33h, the maximum blood concentration is 0.71mg/L, and the t1/2 of plasma is 1.57 h. The existing commonly used dihydroartemisinin preparation formulations mainly comprise common tablets, suppositories and suspensions, the preparations are all prepared aiming at the medication characteristics of malaria patients, and the blood concentration of the patients is required to reach the onset threshold as soon as possible, so the original preparations are all quick-release common tablets, and the original preparations cannot meet the requirements of stable onset for some new indications requiring stable blood concentration of dihydroartemisinin in the body.
Disclosure of Invention
The existing research shows that the effective permeability coefficient P of dihydroartemisinin in duodenum under the same drug concentrationeffCompared with the jejunum and ileum, the dihydroartemisinin has better absorption in duodenum compared with other intestinal sections, wherein the absorption constant Ka is obviously higher; the absorption rate of dihydroartemisinin in stomach is obviously higher than that of each section of small intestine, and the difficulty of absorption of dihydroartemisinin by different parts is from strong to weak: stomach > duodenum > jejunum ≈ ileum, i.e. dihydroartemisinin is a drug with narrow absorption window, and is better absorbed in the first half of gastrointestinal tract. Based on the above, the invention provides a gastric retention type dihydroartemisinin sustained release tablet, a preparation method and an application thereof, aiming at the problems that dihydroartemisinin is fast to absorb, metabolize and excrete and the existing dihydroartemisinin preparation cannot meet the requirement of stable effect, so as to achieve a lasting effective concentration of the medicine in vivo and improve the clinical curative effect.
The purpose of the invention is realized by adopting the following technical scheme:
a gastric retention type dihydroartemisinin sustained release tablet is composed of dihydroartemisinin and adjuvants, wherein the adjuvants include release retardant, foaming agent, filler, disintegrating agent, lubricant and wetting agent.
Preferably, the release retardant comprises hydroxypropyl methylcellulose, stearyl alcohol, and carbomer, wherein:
hypromellose is a semi-synthetic, inactive, viscoelastic polymer, in the form of white or off-white fibrous or granular powder, which is practically insoluble in anhydrous ethanol, diethyl ether or acetone; swelling in cold water to obtain clear or slightly turbid colloidal solution, using skeleton material of sustained release preparation as retarder and controlled release agent of hydrophilic gel skeleton sustained release tablet, and dividing hypromellose into four substitution types, i.e. 1828, 2208, 2906, 2910, according to difference of methoxyl group and hydroxypropoxyl group content; the hypromellose-K100M used in the invention is one of 2208 types;
carbomer is white loose powder, has characteristic slightly smelly, is formed by cross-linking polymerization of acrylic acid and alkyl sucrose, can be divided into multiple models according to the difference of its polymerization degree and proportion, such as carbomer 934, 940, 941, etc., wherein carbomer 934 has the least toxicity, compared with carbomer 940, 941, carbomer 934 and gastric mucosa have intermediate adhesive force, the running speed is slowest in gastrointestinal tract, is suitable for the administration of cavitary tracts, and has better compatible use effect with some water-soluble cellulose derivatives; carbomer is used as an auxiliary material of the tablet, shows good zero-order or nearly zero-order release kinetics, can meet the long-time release requirement even under low dosage, is a completely artificial composition, and has high reproducibility and stability;
the octadecanol is white powder, granules, flakes or blocks; has oil smell, and is transparent oily liquid after being melted; is easily soluble in ether, soluble in ethanol and almost insoluble in water; the octadecanol can be used as a retarder of a sustained-release preparation, and the relative density of the octadecanol is low, so that the relative density of the tablet can be properly reduced, and the retention time of the preparation in the stomach can be prolonged;
the filler is lactose, which is a natural disaccharide present in most mammalian milks and consists of galactose and sucrose; are widely used as fillers or diluents for tablets and capsules, and sometimes in lyophilized products and infant formula; lactose is also used as a diluent for powder inhalers;
the disintegrating agent is crospovidone which is a water-insoluble tablet disintegrating agent or dissolving agent, and the use concentration in the direct tabletting and dry or wet granulating and tabletting process is 2-5%; the crospovidone can rapidly show high capillary activity and excellent hydration ability, and almost has no gel tendency; research shows that the size of the crospovidone granules strongly influences the disintegration of the thermal analgesic tablet; the crospovidone with larger particles can play a faster disintegrating role than the crospovidone with smaller particles; crospovidone is also used as a solubility promoter; by adopting a co-evaporation technology, the crospovidone can increase the solubility of the insoluble drug;
the foaming agent is sodium bicarbonate, the sodium bicarbonate is white crystalline powder, is odorless and smelly alkali, is dissolved in water, is insoluble in ethanol and is slowly decomposed in humid air or hot air, the sodium bicarbonate generates carbon dioxide gas in a gastric acid environment and coats the surface of the tablet, so that the preparation density is favorably reduced, the rising and staying time is regulated, the retention time in the stomach is increased, and meanwhile, the release of the carbon dioxide enables the tablet to generate a large number of pores and is also favorable for water infiltration and drug release;
the wetting agent is sodium dodecyl sulfate which is sodium dodecyl sulfate (C)12H25NaO4S) a predominantly sodium alkyl sulfate mixture in the form of white to pale yellow crystals or powder; has characteristic slight odor; it is easily soluble in water, its 10% water solution is opaque at low temperature, and is soluble in hot ethanol, and is almost insoluble in chloroform and diethyl ether; the sodium dodecyl sulfate has good emulsibility, foamability, water solubility, biodegradability, alkali resistance, hard water resistance and wide effect, and is used for foaming agents, detergents, emulsifiers, dispersing agents and wetting agents; in the invention, the sodium dodecyl sulfate mainly plays a role of a wetting agent, and is a soluble lubricant compared with magnesium stearate, so that the disintegration of the tablet and the dissolution rate of insoluble raw material medicines can be promoted;
the lubricant is magnesium stearate which is white fine powder with smooth touch, small bulk density, light and fluffy weight, adsorbability and poor liquidity and is insoluble in water, ethanol and ether; although relatively stable, magnesium stearate can react with oxidants, strong acids, alkali metals and metal salts, and can also react with aspirin, some vitamins and alkaloid salts; magnesium stearate is generally considered safe and non-toxic and is listed in the FDA guidelines for inactive ingredients for oral tablets, capsules and powders, buccal and vaginal tablets and topical formulations.
Preferably, the prescription composition of the dihydroartemisinin sustained-release tablet is as follows according to 185-200 mg/tablet: 40 mg/tablet of dihydroartemisinin, 10-30.4 mg/tablet of hydroxypropyl methylcellulose, 12-16 mg/tablet of octadecanol, 22-30 mg/tablet of sodium bicarbonate, 48-68.3 mg/tablet of lactose, 3.8-20 mg/tablet of crospovidone, 48-16 mg/tablet of carbomer 93, 4-6 mg/tablet of magnesium stearate and 2.85-6mg of sodium dodecyl sulfate.
Preferably, the prescription of the dihydroartemisinin sustained-release tablet comprises the following components in terms of 190 mg/tablet: 40 mg/tablet of dihydroartemisinin, 10 mg/tablet of hydroxypropyl methylcellulose, 12 mg/tablet of octadecanol, 26 mg/tablet of sodium bicarbonate, 63.45 mg/tablet of lactose, 20 mg/tablet of crospovidone, 93410 mg/tablet of carbomer, 5.7 mg/tablet of magnesium stearate and 2.85 mg/tablet of sodium dodecyl sulfate.
The invention also aims to provide a preparation method of the gastric retention type dihydroartemisinin sustained-release tablet, which comprises the following steps:
s1 preparation of raw materials
Weighing dihydroartemisinin and auxiliary materials according to the prescription amount, sieving the dihydroartemisinin with a 120-mesh sieve, and sieving the auxiliary materials with a 80-mesh sieve for later use;
s2 preliminary mixing
Adding the prepared dihydroartemisinin, the release retardant, the foaming agent, the filling agent, the wetting agent, the 3/4 disintegrating agent and the 1/6 lubricating agent into a mixer, and mixing to obtain a primary mixed material;
s3, dry pressing and granulating
Performing dry pressing granulation on the primary mixed material, sieving the primary mixed material by using a 20-mesh sieve, and repeating the dry pressing granulation until the fine powder amount is less than 20 percent of the primary mixed material after the dry powder of unformed particles passes through a 65-mesh sieve;
s4 Total Mixed compression sheet
And adding the granules prepared in the step S3, the rest fine powder, the rest disintegrant and the lubricant into a mixer, mixing and tabletting to obtain the sustained release tablet.
Preferably, the dry granulation has a granulation pressure of 30 kg.
Preferably, the compression force of the pellets in S4 is 40 kN.
Still another object of the present invention is to provide a method for applying the above-mentioned gastric retention type dihydroartemisinin sustained release tablets, particularly for the new indications of dihydroartemisinin requiring a longer period of treatment, especially for the treatment of polymorphous light eruptions in contact dermatitis, especially photo-sensitive dermatitis.
The invention has the beneficial effects that:
aiming at the problem that the prior commonly used dihydroartemisinin dosage form can not achieve the requirements of stable effect and slow release, the invention provides a gastric retention type dihydroartemisinin sustained-release tablet based on the characteristic of relatively good absorption in the stomach, and the tablet has proper floating time and floating time by matching with a plurality of auxiliary materials which can be used for oral administration, can realize the long-acting slow release in the stomach and good control of in vitro release degree, has obvious sustained-release effect, can meet the different administration characteristics of dihydroartemisinin, reduces the administration times, improves the oral bioavailability of dihydroartemisinin and improves the administration compliance.
Detailed Description
The invention is further described with reference to the following examples.
Example 1
A gastric retention type dihydroartemisinin sustained-release tablet is prepared by the following steps:
s1 preparation of raw materials
Weighing dihydroartemisinin and auxiliary materials according to the following prescription amount (1000 tablets):
40g of dihydroartemisinin, 10g of hydroxypropylmethylcellulose K100M (shandong herda gmbh, approval document No. F20209990423), 12g of octadecanol (jiangxi alpha gaoko liquid medicine gmbh, approval document No. F20209990119), 26g of sodium hydrogen carbonate (sichuan jinshan pharmaceutical limited, approval document No. F20170000521), 26g of lactose (zhenjiang kangfu bioengineering limited, approval document No. F20190057), 63.45g of crospovidone (BASF SE, approval document No. F20190001344), 20g of carbomer 934 (borun advanced materials, approval document No. F20190000377)10g, 5.7g of magnesium stearate (lazhou abdoming seiko pharmaceutical limited, approval document No. F20209990296), 2.85g of sodium dodecyl sulfate (lazhou abdoming pharmaceutical limited, approval document No. F20100590011);
sieving the dihydroartemisinin with a 120-mesh sieve, and sieving the auxiliary material with a 80-mesh sieve for later use;
s2 preliminary mixing
Adding prepared dihydroartemisinin, hydroxypropyl methyl cellulose K100M, octadecanol, sodium bicarbonate, lactose, carbomer 934, sodium dodecyl sulfate, 15g of crospovidone (inner adding 3/4) and 0.95g of magnesium stearate (inner adding 1/6) into a mixer, and mixing for 20min to obtain a primary mixture;
s3, dry pressing and granulating
Performing dry pressing granulation on the primary mixed material, wherein the granulation pressure is 30kg, sieving the primary mixed material by a 20-mesh sieve, and repeating the dry pressing granulation until the fine powder amount is less than 20% of the primary mixed material after the dry powder of unformed particles passes through a 65-mesh sieve;
s4 Total Mixed compression sheet
And adding the granules prepared in the step S3, the residual fine powder, 5g of crospovidone (additionally added 1/4) and 4.75g of magnesium stearate (internally added 5/6) into a mixer, mixing, and tabletting to obtain the sustained release tablets, wherein the weight difference of the tablets is controlled to be +/-7.5%.
Example 2
As in example 1, the prescription amounts were:
40g of dihydroartemisinin, 16g of hydroxypropyl methyl cellulose K100M 16g, 16g of octadecanol, 26g of sodium bicarbonate, 54g of lactose, 20g of crospovidone, 93416g of carbomer, 6g of magnesium stearate and 6g of sodium dodecyl sulfate.
Example 3
As in example 1, the prescription amounts were:
40g of dihydroartemisinin, 100 g of hydroxypropyl methylcellulose K100M 16g, 12g of octadecanol, 26g of sodium bicarbonate, 48g of lactose, 15g of crospovidone, 93416g of carbomer, 6g of magnesium stearate and 6g of sodium dodecyl sulfate.
Example 4
As in example 1, the prescription amounts were:
40g of dihydroartemisinin, 15g of hydroxypropyl methylcellulose K15M 16g, 12g of octadecanol, 26g of sodium bicarbonate, 58.3g of lactose, 20g of crospovidone, 9348g of carbomer, 5.7g of magnesium stearate and 3.8g of sodium dodecyl sulfate.
Example 5
As in example 1, the prescription amounts were:
40g of dihydroartemisinin, 100 g of hydroxypropyl methylcellulose K100M 10g, 12g of octadecanol, 26g of sodium bicarbonate, 62.5g of lactose, 20g of crospovidone, 93410g of carbomer, 5.7g of magnesium stearate and 3.8g of sodium dodecyl sulfate.
The compositions of the raw materials and auxiliary materials of examples 1 to 5 are shown in Table 1.
TABLE 1 raw and auxiliary Material compositions of examples 1-5
Experimental example 1
Index determination of tablets prepared in examples 1 to 5:
1. appearance of the tablet
The appearance of the tablets was evaluated for the integrity of the surface and edges of the tablets. For example, the tablet has a smooth surface, a "good" surface, a "smooth" surface, a "poor" surface, a "incomplete" edge, a "dull" surface, a "incomplete" edge, a "cap-off" surface, a "dull" surface.
2. Float starting time and float holding time
In artificial gastric juice at 37 +/-0.5 deg.C and rotating speed of 100r min-1Simulating the peristalsis of the stomach, investigating the form change of the dihydroartemisinin gastric floating sustained-release tablet, and when investigating the floating performance, requiring the floating time of the sustained-release tablet to be less than 3min and the floating time to be not less than 8h, wherein the floating delay time (floating time) from the time when the sustained-release tablet is put into the solution to the floating to the liquid surface and the lasting floating time (floating time) from the time when the sustained-release tablet floats to the liquid surface to the sinking are included.
3. Degree of release
(1) Dissolution sample stability
And taking the release degree test sample solution, respectively injecting samples for 0, 4, 8, 12, 18, 24, 30 and 50 hours, determining the peak area of the sample, and showing that the RSD value in 50 hours is 1.10 percent and less than 2 percent, which indicates that the stability of the sample solution in 50 hours is good.
(2) Release degree test method
The release rate is as follows: measured according to the dissolution and release assay (sixth method of general rule 0931).
Dissolution conditions: taking 500ml of 0.2mol/L phosphate buffer solution (the pH value of sodium hydroxide test solution is adjusted to 4.5) containing 0.5% of lauryl sodium sulfate as a dissolution medium, setting the temperature at 37 ℃, setting the rotating speed at 100 revolutions per minute, operating according to the method, respectively taking 1.5ml of dissolution liquid after 1h, 4h and 12h, immediately supplementing the dissolution medium with the same temperature and volume, and determining the in-vitro accumulative release rate of the dihydroartemisinin.
Test solution: taking 1.5ml of the dissolution liquid of 1h, 4h and 12h respectively, and filtering to obtain the subsequent filtrate.
Control solution: weighing dihydroartemisinin reference substance about 8mg, precisely weighing, placing in 10ml measuring flask, adding methanol to dissolve, metering to scale, and shaking.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica was used as a filler (WATERS BEH-C182.1X 50mm, 1.7 μm); the mobile phase is acetonitrile: water 45: 55; the flow rate was 0.2ml per minute; the detection wavelength was 216 nm.
The determination method comprises the following steps: and respectively injecting 10 μ l of the test solution and 1 μ l of the reference solution into a liquid chromatograph, and calculating the elution amount of each tablet in 1h, 4h and 12 h.
Limitation: the dissolution amount of each tablet in 1h, 4h and 12h is respectively 20-35%, 50-70% and 70-100% of the marked amount, and the dissolution amounts are in accordance with the specification.
The results are shown in Table 2.
TABLE 2 measurement results of the properties of the tablets prepared in examples 1 to 5
| Measurement items | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 |
| Whether sticking or not | Without sticking | Obvious sticking | Without sticking | Without sticking | Without sticking |
| One-sided appearance | Good taste | Is poor | Is preferably used | Good taste | Good taste |
| Rise time/s | 12.0 | 6 | 9 | 12 | 22 |
| Time to float/h | ＞8 | ＞8 | ＞8 | ＞8 | ＞8 |
| 1h degree of release/%) | 24.02 | 30.73 | 21.21 | 25.04 | 27.78 |
| 4h degree of release/%) | 64.04 | 59.50 | 41.59 | 43.17 | 64.77 |
| 12h degree of release/%) | 79.06 | 80.05 | 65.64 | 60.52 | 81.06 |
Experimental example 2
NaHCO3The influence of the dosage on the floating performance of the sustained-release tablets is as follows:
because of NaHCO in the pharmaceutical excipients3Reacting with acid medium to generate gas in hydrochloric acid solution environment with pH of 1.2, thereby enabling the sustained-release tablet to continuously float, and therefore, the floating performance is mainly examined for NaHCO3The dosage of NaHCO was changed according to the formulation in Table 33The dosage of the dihydroartemisinin sustained release tablet is prepared, 900mL of hydrochloric acid solution with the pH value of 1.2 is taken as a dissolution medium, the temperature is controlled to be 37 +/-0.5 ℃, and the rotating speed is 50r min-1Recording the time of starting floating and the time of continuous floating, and investigating NaHCO with different dosages3For slow-release tabletThe effect of buoyancy, the results are shown in Table 3.
TABLE 3 different NaHCO3Influence of dosage on floating performance of dihydroartemisinin sustained-release tablets
The results show that when NaHCO is used3When the dosage is less than 11%, the medicament floats for more than 5min, which does not meet the design requirement. When NaHCO is present3When the dosage of the composition reaches 13%, the medicine can float within 2min and continuously float for more than 8 h. When the dosage reaches and exceeds 15%, the medicine floats within 10s and continuously floats for more than 8 h.
Experimental example 3
Dihydroartemisinin anti-contact dermatitis activity:
contact dermatitis (AD) is an acute or chronic inflammatory response that occurs at the site of skin and mucosal membrane contact following exposure to a substance, including irritant contact dermatitis caused by chemical stimuli and allergic contact dermatitis caused by type iv allergy.
Photoallergic dermatitis is a delayed type hypersensitivity reaction of the skin after exposure to ultraviolet rays, and includes solar urticaria, chemical photosensitive dermatitis, polymorphous light eruptions characterized by pruritic and sudden skin eruptions in the area exposed to sunlight. This light-sensitive constitution can be inherited. The polymorphous light eruption is a photosensitive skin disease related to direct sunlight irradiation named by Rasch in 1900 years, is characterized in that polymorphous damage including erythema, papule, blister, nodule and the like appears on the skin of exposed parts such as face, neck, double forearms and the like after sunlight irradiation, the pathogenesis of the polymorphous light eruption is considered to be related to factors such as immunity, heredity, environment and the like at present, the polymorphous light eruption belongs to delayed anaphylactic reaction, the morbidity in temperate zone reaches 10-20%, accounts for 60% of the photosensitive skin disease, and is better to be developed for middle-aged and young women. Studies have found that polymorphous light eruption (PMLE) and Lupus Erythematosus (LE) may share common pathogenesis, with about 50% to 75% of lupus patients having a history of photosensitivity or once diagnosed as PMLE. ANA being an indicator that early lupus distinguishes PMLE, whereas recent studies have shown that 14% to 19% of PMLE patients have elevated ANA titers without other lupus symptoms.
The invention takes chlorpromazine hydrochloride as a photosensitizer, and a BALB/C female mouse is selected to establish a chlorpromazine photoallergic dermatitis model (CAPD model). The influence of different doses of dihydroartemisinin on the photoallergic dermatitis of the mice is judged by measuring the difference of ear swelling degree, weight difference and the number of single nuclear cells infiltrated in the dermis before and after UVA excitation by adopting an oral gavage administration route.
The test was carried out in three batches. Each test animal was randomly divided into 6 groups of 10 animals each. The experimental animals are healthy and clean BALB/C female mice, the weight is 18-24 g, the experimental animal department of the department of medicine of Beijing university provides, and the qualification number: SCXK (Jing) 2002-.
The dose group design was:
first batch: a dihydroartemisinin high-dose group (135mg/kg), a dihydroartemisinin medium-dose group (45mg/kg), a dihydroartemisinin low-dose group (15mg/kg), a solvent control group (0.5% sodium carboxymethylcellulose) and a hydroxychloroquine positive control group (100 mg/kg); and (4) a negative control group.
And (2) second batch: a dihydroartemisinin high-dose group (45mg/kg), a dihydroartemisinin medium-dose group (15mg/kg), a dihydroartemisinin low-dose group (5mg/kg), a solvent control group (0.5% sodium carboxymethylcellulose) and a hydroxychloroquine positive control group (45 mg/kg); and (4) a negative control group.
And (3) third batch: a dihydroartemisinin high-dose group (5mg/kg), a dihydroartemisinin medium-dose group (2.5mg/kg), a dihydroartemisinin low-dose group (1mg/kg), a solvent control group (0.5% sodium carboxymethylcellulose) and a hydroxychloroquine positive control group (45 mg/kg); and (4) a negative control group.
Wherein, the dihydroartemisinin is provided by Chinese traditional medicine research institute, is white powder, has the batch number of 20031019, and is prepared into suspension by 5 percent of sodium carboxymethylcellulose; hydroxychloroquine is supplied by Shanghai, China and Western pharmaceuticals, Inc., lot number 040501; chlorpromazine hydrochloride was supplied by Tianjin Lisheng pharmaceutical Co., Ltd, lot number 0505005; sodium carboxymethylcellulose was supplied by the chemical reagents development centre of mimiuiou, Tianjin, under batch number 20040605.
The test substance dihydroartemisinin and the corresponding control were administered orally by gavage for 1 time/day for 12 days up to the challenge day. Mice were injected intraperitoneally with 150mg/kg cyclophosphamide on day 1 of the experiment. On day 3 of the experiment, paraffin and rosin were used at a ratio of 1: 1, mixing, depilating the neck and shoulder of the mouse, and removing residual hair by sticking a medical adhesive plaster. On the 4 th day of the test, the remaining groups except the negative control group were coated with 50. mu.l of 1% chlorpromazine acetone solution in the depilation region, and after half an hour UVA irradiation (Philips fluorescent lamp, output power per tube 40W/tube, spectral range 315 once again 400nm, peak 365nm) was carried out with an irradiation dose of 22J/cm21 time per day and 2 times continuously. Measuring the thickness of the basic ears of ears by using a engineering caliper rule on the 12 th day of the test, coating a 0.1 percent chlorpromazine ethanol solution on the left ear, irradiating UVA after half an hour, and irradiating with the dose of 22J/cm2. The thickness and weight of ears are measured 48 hours after irradiation by using a caliper. Rat ears were prepared into paraffin blocks, 5 μm-thick tissue sections were cut, HE stained, and the number of monocytes was counted under a light microscope.
The observation indexes include:
(1) degree of ear swelling: and measuring the thickness difference of the middle parts of the ears of the mice, and calculating the thickness difference of the left ear before and after excitation and the thickness difference of the left ear and the right ear after excitation.
(2) Difference in ear weight: a0.6 mm diameter metal punch punches holes in the middle of the ear and the tissue is weighed with an analytical balance and the difference in weight of the left and right ear tissue after excitation is calculated.
(3) Number of mononuclear cell infiltrations: the number of monocytes in one square millimeter dermal tissue was counted under a light microscope and the left and right ear differences were calculated.
The results are shown in tables 7-9.
TABLE 7 Effect of Dihydroartemisinin on ear thickness, weight difference and mononuclear cell infiltration number in mice (A)
Note: p <0.05 compared to solvent control group; p <0.01
TABLE 8 Effect of Dihydroartemisinin on ear thickness, weight difference and mononuclear cell infiltration number in mice (II)
Note: p <0.05 compared to solvent control group; p <0.01
TABLE 9 Effect of Dihydroartemisinin on ear thickness, weight difference and mononuclear cell infiltration number in mice (III)
Note: p <0.05 compared to solvent control group; p <0.01
The experimental result shows that the dihydroartemisinin has the function of resisting the photoallergic dermatitis: compared with a solvent control group, the dihydroartemisinin 2.5, 5, 15 and 45mg/kg dose group has the advantages that the ear swelling degree, the left ear thickness and the right ear thickness are different, the ear weight is different, the infiltration number of single nuclear cells is obviously reduced compared with the control group, and the difference is significant. Within the dosage range of 5-135mg/kg, the ear swelling degree, the difference between the thickness of the left ear and the thickness of the right ear, the difference between the weight of the ears and the infiltration number of mononuclear cells are increased along with the increase of the dosage, and the anti-photosensitivity effect is in negative correlation with the administration dosage. Within the dosage range of 1-5mg/kg, the ear swelling degree, the difference between the left ear thickness and the right ear thickness, the difference between the ear weight and the infiltration number of single nuclear cells are reduced along with the increase of the dosage, and the anti-photosensitivity effect is positively correlated with the administration dosage.
Further, in the research process of dihydroartemisinin for treating lupus erythematosus, 27 dihydroartemisinin tablets are used for clinical pre-tests of treating polymorphous light eruptions (PMLE belongs to photosensitive dermatitis), patients take 60mg or 80mg DHA orally once, the dose is temporarily stopped, 1 treatment course is 4 weeks, 1-3 treatment courses are performed, and of 27 PMLE patients, 25 effective cases and 2 effective cases are obtained, and the effective rate is 100%.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. A gastric retention type dihydroartemisinin sustained release tablet is characterized by comprising dihydroartemisinin and auxiliary materials, wherein the auxiliary materials comprise a release retardant, a foaming agent, a filling agent, a disintegrating agent, a lubricating agent and a wetting agent.
2. The gastric retentive sustained-release dihydroartemisinin tablet of claim 1, wherein the release retardant comprises hydroxypropyl methylcellulose, stearyl alcohol and carbomer, the foaming agent is sodium bicarbonate, the filler is lactose, the disintegrant is crospovidone, the lubricant is magnesium stearate, and the wetting agent is sodium lauryl sulfate.
3. The gastric retentive type dihydroartemisinin sustained release tablet according to claim 2, wherein the prescription composition of the dihydroartemisinin sustained release tablet is as follows according to 185-200 mg/tablet: 40 mg/tablet of dihydroartemisinin, 10-30.4 mg/tablet of hydroxypropyl methylcellulose, 12-16 mg/tablet of octadecanol, 22-30 mg/tablet of sodium bicarbonate, 48-68.3 mg/tablet of lactose, 3.8-20 mg/tablet of crospovidone, 48-16 mg/tablet of carbomer 93, 4-6 mg/tablet of magnesium stearate and 2.85-6mg of sodium dodecyl sulfate.
4. The gastric retentive type dihydroartemisinin sustained release tablet according to claim 2, wherein the prescription composition of the dihydroartemisinin sustained release tablet is as follows, calculated as 190 mg/tablet: 40 mg/tablet of dihydroartemisinin, 10 mg/tablet of hydroxypropyl methylcellulose, 12 mg/tablet of octadecanol, 26 mg/tablet of sodium bicarbonate, 63.45 mg/tablet of lactose, 20 mg/tablet of crospovidone, 93410 mg/tablet of carbomer, 5.7 mg/tablet of magnesium stearate and 2.85 mg/tablet of sodium dodecyl sulfate.
5. A process for preparing a sustained release tablet of gastric retentive dihydroartemisinin as claimed in any of claims 1 to 4, comprising the steps of:
s1 preparation of raw materials
Weighing dihydroartemisinin and auxiliary materials according to the prescription amount, sieving the dihydroartemisinin with a 120-mesh sieve, and sieving the auxiliary materials with a 80-mesh sieve for later use;
s2 preliminary mixing
Adding the prepared dihydroartemisinin, the release retardant, the foaming agent, the filling agent, the wetting agent, the 3/4 disintegrating agent and the 1/6 lubricating agent into a mixer, and mixing to obtain a primary mixed material;
s3, dry pressing and granulating
Performing dry pressing granulation on the primary mixed material, sieving the primary mixed material by using a 20-mesh sieve, and repeating the dry pressing granulation until the fine powder amount is less than 20 percent of the primary mixed material after the dry powder of unformed particles passes through a 65-mesh sieve;
s4 Total Mixed compression sheet
And adding the granules prepared in the step S3, the rest fine powder, the rest disintegrant and the lubricant into a mixer, mixing and tabletting to obtain the sustained release tablet.
6. The process according to claim 5, wherein the dry granulation has a granulation pressure of 30 kg.
7. The process according to claim 5, wherein the compression pressure of the tablet in S4 is 40 kN.
8. Use of a sustained release tablet of gastric retentive dihydroartemisinin according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of contact dermatitis.
9. Use according to claim 8, wherein the contact dermatitis is photoallergic dermatitis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111002657.8A CN113499315A (en) | 2021-08-30 | 2021-08-30 | Stomach retention type dihydroartemisinin sustained-release tablet and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111002657.8A CN113499315A (en) | 2021-08-30 | 2021-08-30 | Stomach retention type dihydroartemisinin sustained-release tablet and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113499315A true CN113499315A (en) | 2021-10-15 |
Family
ID=78016765
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111002657.8A Pending CN113499315A (en) | 2021-08-30 | 2021-08-30 | Stomach retention type dihydroartemisinin sustained-release tablet and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113499315A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101288659A (en) * | 2007-04-18 | 2008-10-22 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
| CN101884627A (en) * | 2010-07-07 | 2010-11-17 | 青岛黄海制药有限责任公司 | Pioglitazone hydrochloride gastric residential sustained release tablet and preparation method thereof |
-
2021
- 2021-08-30 CN CN202111002657.8A patent/CN113499315A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101288659A (en) * | 2007-04-18 | 2008-10-22 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
| CN101884627A (en) * | 2010-07-07 | 2010-11-17 | 青岛黄海制药有限责任公司 | Pioglitazone hydrochloride gastric residential sustained release tablet and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 薛雪等: "双氢青蒿素通过调节肥大细胞浸润减轻小鼠特应性皮炎", 《南方医科大学学报》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2021238978A1 (en) | Pharmaceutical composition containing nitroxoline prodrug, and preparation method and application therefor | |
| CN103705478B (en) | Oral tablet containing tenofovir disoproxil fumarate | |
| CN103893258A (en) | Oral solid preparation containing desmodium styracifolium general flavone and application thereof | |
| CN100389816C (en) | Tibetan medicine formulation for treating hyperlipemia, and its preparing method | |
| CN117547534B (en) | Nicorandil sustained release preparation and preparation method thereof | |
| CN115518066A (en) | Pharmaceutical composition for treating anticoagulation and application | |
| CN102462675B (en) | A kind of Bezafibrate sustained release tablet and preparation method thereof | |
| JPS60255719A (en) | Preparation of nifedipine sustained release pharmaceutical | |
| CN113499315A (en) | Stomach retention type dihydroartemisinin sustained-release tablet and preparation method and application thereof | |
| WO2005039561A1 (en) | Micronized bicyclol and the orally administered controlled release formulation | |
| KR20090086686A (en) | Pharmaceutical composition comprising silymarin with improved dissolution rate and method for preparing the same | |
| CN102266309A (en) | Novel roxithromycin capsule and preparation method thereof | |
| CN101953773B (en) | Lamivudine liposome solid preparation | |
| Tang et al. | Development and evaluation of synchronized and sustained release Tripergium Wilfordii tablets based hot-melt extrusion and direct powder compression | |
| JP3116970B2 (en) | Sustained-release preparation of pemirolast potassium | |
| CN101129358B (en) | Moguisteine sustained-release tablet and method of preparing the same | |
| CN101244068B (en) | Hemsleyadin sustained-release preparation | |
| WO2024022382A1 (en) | Osmotic pump controlled release preparation, osmotic pump controlled release composition, preparation method and use | |
| CN104337783B (en) | A kind of capecitabine tablet and preparation method thereof | |
| CN111214442B (en) | Apixaban co-micropowder | |
| Deepika et al. | Formulation and Evaluation of Miglitol matrix tablets by using Hibiscus rosa sinensis leaves Mucilage | |
| CN112587488B (en) | Silybin composition and preparation method thereof | |
| CN101829121B (en) | Hemsleyadin sustained-release preparation | |
| CA2088273C (en) | Processes for formulating a solid oral dosage form of loperamide compounds | |
| Khatri et al. | Formulation and evaluation of floating matrix tablet of levofloxacin hemihydrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20211015 |