CN102716491B - Clathrate compound of artemisinin series and alkaline cyclodextrin and method for preparing same - Google Patents
Clathrate compound of artemisinin series and alkaline cyclodextrin and method for preparing same Download PDFInfo
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- CN102716491B CN102716491B CN201210223066.8A CN201210223066A CN102716491B CN 102716491 B CN102716491 B CN 102716491B CN 201210223066 A CN201210223066 A CN 201210223066A CN 102716491 B CN102716491 B CN 102716491B
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- arteannuin
- cyclodextrin
- alkaline
- clathrate
- series
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- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 88
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical class 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 title claims abstract description 84
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 238000000034 method Methods 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 title abstract description 5
- 239000000243 solution Substances 0.000 claims abstract description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000002360 preparation method Methods 0.000 claims abstract description 29
- 229960004191 artemisinin Drugs 0.000 claims abstract description 24
- 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 claims abstract description 19
- 229960004991 artesunate Drugs 0.000 claims abstract description 19
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims description 23
- 239000002585 base Substances 0.000 claims description 22
- 229930191701 arteannuin Natural products 0.000 claims description 19
- 229930187998 Dihydroarteannuin Natural products 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- 229930101531 artemisinin Natural products 0.000 abstract description 5
- 239000007788 liquid Substances 0.000 abstract description 5
- 229960002521 artenimol Drugs 0.000 abstract description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 2
- 230000003993 interaction Effects 0.000 abstract description 2
- 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 abstract 1
- 229930016266 dihydroartemisinin Natural products 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 9
- 201000004792 malaria Diseases 0.000 description 6
- 230000006103 sulfonylation Effects 0.000 description 6
- 238000005694 sulfonylation reaction Methods 0.000 description 6
- 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 5
- 230000000694 effects Effects 0.000 description 5
- -1 hydroxypropyl cyclodextrin Chemical compound 0.000 description 5
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229960003677 chloroquine Drugs 0.000 description 4
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 4
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 3
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 241000224016 Plasmodium Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 3
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 3
- 230000000078 anti-malarial effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 2
- 229950005162 benexate Drugs 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
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- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 230000006872 improvement Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- PCWPQSDFNIFUPO-VDQKLNDWSA-N (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-37,39,41,43,45,47,49-heptakis(2-hydroxyethoxy)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38,40,42,44,46,48-heptol Chemical compound OCCO[C@H]1[C@H](O)[C@@H]2O[C@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O[C@H]5O[C@H](CO)[C@@H](O[C@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O[C@H]8O[C@H](CO)[C@@H](O[C@H]1O[C@@H]2CO)[C@@H](O)[C@@H]8OCCO)[C@@H](O)[C@@H]7OCCO)[C@@H](O)[C@@H]6OCCO)[C@@H](O)[C@@H]5OCCO)[C@@H](O)[C@@H]4OCCO)[C@@H](O)[C@@H]3OCCO PCWPQSDFNIFUPO-VDQKLNDWSA-N 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 235000003826 Artemisia Nutrition 0.000 description 1
- 235000003261 Artemisia vulgaris Nutrition 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- 241000252983 Caecum Species 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 108010025880 Cyclomaltodextrin glucanotransferase Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229960000981 artemether Drugs 0.000 description 1
- 244000030166 artemisia Species 0.000 description 1
- 235000009052 artemisia Nutrition 0.000 description 1
- 229960002970 artemotil Drugs 0.000 description 1
- 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 1
- 230000008901 benefit Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000006208 butylation Effects 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- IAXUQWSLRKIRFR-SAABIXHNSA-N chembl2104696 Chemical compound C1C[C@@H](CNC(=N)N)CC[C@@H]1C(=O)OC1=CC=CC=C1C(=O)OCC1=CC=CC=C1 IAXUQWSLRKIRFR-SAABIXHNSA-N 0.000 description 1
- BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 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-CMDXXVQNSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 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 1
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- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
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- 230000002496 gastric effect Effects 0.000 description 1
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- 230000000968 intestinal effect Effects 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
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- 229920001542 oligosaccharide Polymers 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229930009674 sesquiterpene lactone Natural products 0.000 description 1
- 150000002107 sesquiterpene lactone derivatives Chemical class 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
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Abstract
The invention discloses a clathrate compound of artemisinin series (artemisinin, dihydroartemisinin and artesunate) and alkaline cyclodextrin and a method for preparing the same. The alkaline cyclodextrin in the clathrate compound refers to an amido-substituted cyclodextrin; and due to the amido substituting of the cyclodextrin, an alkaline environment is formed in an aqueous solution apart from clathration between the cavity of the cyclodextrin and the artemisinin series, and forms ionic interaction with hydroxyls or carboxyls on the artemisinin series; and therefore, the artemisinin series can be dissolved in water to form a solution within an extremely wide concentration range so that liquid artemisinin series preparations can be formed. The clathrate compound provided by the invention is high in stability, high in bioavailability, simple in preparation, easy for operation, moderate in condition, and suitable for industrial production.
Description
Technical field
Invention relates to the pharmaceutical technology field, relates to specifically arteannuin series matter and alkaline cyclodextrin thing clathrate and preparation method thereof.
Background technology
In the global tropical area, malaria has very tremendous influence to human health.In every year, nearly 3 to 500,000,000 clinical cases, often cause 1,500,000 to 1,700,000 people's death, and nearly all case is all due to plasmodium.Along with the increase of drug resistance strain, many traditional biological alkali medicines, for example chloroquine and quinine are now largely invalid, cause malaria further to spread.Due to the frightening drug resistance diffusion of parasite, the World Health Organization's prophesy, if there is no the use of new anti-malaria medicaments, will be doubled to case survey of malaria in 2013.1979, a kind of antimalarial arteannuin of new generation that includes the sesquiterpene lactones class of peroxidating group of separating from Chinese herbal artemisia, had drug-fast plasmodium for chloroquine, is a kind of effective antimalarial agent.The arteannuin series matter, as all effective to malaria in the plasmodium of chloroquine drug resistance strain and chloroquine sensitive strain and brain as arteannuin, dihydroartemisinine, Artemether, arteether and artesunate.By WHO, recommended, for the malaria infection crowd, the most countries that quick and reliable arteannuin combined therapy scheme (ACT) is spread unchecked in malaria also is widely accepted.
In recent years, research finds that the arteannuin series matter has shown the effect of kill cancer cell preferably.It is kill cancer cell by causing apoptosis, and the arteannuin series matter is to the normal cell not damaged simultaneously.
But the arteannuin series matter is comparatively responsive to high temperature, and it is water insoluble, and for most of oral formulations, generally can only in gastric juice or intestinal juice, form molecularity could pass through the gastrointestinal mucosa wall and absorb, and makes it advance blood circulation generation curative effect.Therefore, this drug dissolution is poor, causes its assimilation effect in human body bad, and bioavailability is low.
The Chinese patent that publication number is CN1554336, adopt hydroxypropyl cyclodextrin, the dimethyl cyclodextrin, and hydroxypropyl cyclodextrin, as solubilizing agent, prepares inclusion complex of artemisinin; The Chinese patent that publication number is CN101125127, relate to artemisinin derivatives and cyclodextrin and methylate, hydroxypropylation, and thioether group, sulphur butylation derivant, make lyophilized formulations; The Chinese patent that publication number is CN101954090A, the anti-malaria medicaments that discloses dihydroarteannuin and Benexate Hydrochloride and preparation method thereof and contained this clathrate.
These clathrates to a certain extent, have improved water solublity and the stability of arteannuin series matter, and being convenient to preparation becomes various dosage forms.But these clathrates are limited to the solubilising degree of arteannuin series matter, having limited this medicine preparation becomes liquid preparation (for example oral liquid and injection); Alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, hydroxypropylβ-cyclodextrin, hydroxyethylβcyclodextrin, the arteannuin series matter clathrate of methyl beta-schardinger dextrin-and sulfobutyl ether-beta-cyclodextrin, the dissolubility in the time of 25 ℃ in water calculates with the amount of arteannuin series matter at 6 ~ 20mg/mL().
Summary of the invention
The object of the present invention is to provide a kind of dissolubility good, the arteannuin series matter that stability is high and the clathrate of alkaline cyclodextrin thing, this inclusion contains arteannuin series matter and alkaline cyclodextrin, and wherein the weight ratio of arteannuin series matter and alkaline cyclodextrin is 1:3～98.
The series matter of arteannuin described in the present invention is a kind of in arteannuin, dihydroarteannuin, artesunate, has structure as follows:
Arteannuin dihydroarteannuin artesunate
(the Cyclodextrin of cyclodextrin described in the present invention, be called for short CD) be the general name of a series of cyclic oligosaccharides of generating under the cyclodextrin glycosyltransferase effect produced by bacillus cereus of amylose, wherein study morely and what have important practical usage is the molecule that contains 6,7,8 glucose units, be called α-, β-and gamma-cyclodextrin.According to the result of X-line crystal diffraction, infrared spectrum and spectral analysis of the nuclear magnetic resonance, each D (+)-Glucopyranose. that determine to form cyclodextrin molecular is chair conformation, each glucose unit all with Isosorbide-5-Nitrae-glycosidic bond in conjunction with ring formation.Because the glycosidic bond that connects glucose unit can not rotate freely, cyclodextrin is that the large end of both ends open, an end is little, the cylinder three-dimensional ring structure of hollow, in its empty structure, intracavity section is because the shielding action that is subject to c h bond has formed hydrophobic region, all hydroxyls are in the molecule outside, and big opening end is by C
2and C
3secondary hydroxyl form, the osculum end consists of the primary hydroxyl of C6, has very strong hydrophilic, its structure is:
Q=6 wherein, within 7,8 o'clock, be respectively α-, β-, gamma-cyclodextrin.
The D (+) that the alkalescence cyclodextrin is the formation cyclodextrin molecular-Glucopyranose. C
2, C
3and/or C
6hydroxyl replace to be generated alkaline cyclodextrin by amido, the compound that contains acidic-group is had to solubilizing effect preferably.
The existing document of the synthetic reference of alkalescence cyclodextrin carries out.Cyclodextrin first reacts with sulfonylation agent and generates sulfonylation cyclodextrin [R.C. Petter; J.S. Salek; C.T. Sikorski; G. Kumaravel; and F.-T. Lin:J. Am. Chem. Soc. 112; 3860 – 3868 (1990)], cyclodextrin can be at D (+)-2 of Glucopyranose .s, 3 and/or 6 upper sulfonylations that occur.Sulfonylation agent commonly used is benzene sulfonyl chloride and p-methyl benzene sulfonic chloride.Then at amine under the nucleophilic attack for reagent; sulfonyl on the sulfonylation cyclodextrin breaks away from; by amido, reacted; generate alkaline cyclodextrin [B.L. May; S.D. Kean; C.J. Easton, and S.F. Lincoln:J. Chem. Soc., Perkin Trans. 13157 – 3160 (1997)].Wherein, described amine can be the organic group of all kinds of amino-containeds for reagent, comprises ammonia, methylamine, ethamine, propylamine, butylamine, ethylenediamine, ethanolamine, acetamide and diethylenetriamine etc.As, paratoluensulfonyl chloride reacts with beta-schardinger dextrin-and generates single 6-tolysulfonyl-beta-schardinger dextrin-(6-OTs-β-CD), and 6-OTs-β-CD adds in ethylenediamine or diethylenetriamine solution, and reaction obtains alkaline cyclodextrin, and reaction equation is as follows:
Wherein, as preferably, described alkaline cyclodextrin is for having formula
shown in structure,
Wherein m be 0 to 7, n be 1 to 8 and m+n=6,7 or 8 in one;
R
1, R
2and R
3for-OH or-RNH
2and R
1, R
2and R
3in have one at least for-RNH
2;
R is (CH
2)
x, NH (CH
2)
x, NH (CH
2)
xnH (CH
2)
x, CO (CH
2)
xor O (CH
2)
x, x is more than or equal to 0 integer.
Formula
in middle m+n=6,7 or 8 one, mean cyclodextrin of the present invention can for α-, β-or gamma-cyclodextrin, wherein, n is at least in the described alkaline cyclodextrin molecular of 1 expression has at least a D (+)-Glucopyranose. parent hydroxy to be modified by amido, and now m is 5,6 or 7; And each D (+)-Glucopyranose. that m is the described alkaline cyclodextrin formation cyclodextrin molecular of 0 expression is all modified by amido.
Formula
middle R
1, R
2and R
3in have one at least for-RNH
2meaning that described alkaline cyclodextrin modified D (+)-Glucopyranose. molecule by amido and be at least the monoamine base and modify, can, at 2,3 or 6, can be also that the diamine base is modified or R
1, R
2and R
3all modified.
Formula
in also defined the amido-RNH of modification cyclodextrin
2in R, R is (CH
2)
x, NH (CH
2)
x, NH (CH
2)
xnH (CH
2)
x, CO (CH
2)
xor O (CH
2)
xthe amido that means modification cyclodextrin can be the organic amino group such as ammonia, methylamine, ethamine, ethylenediamine, ethanolamine, acetamide and diethylenetriamine, and wherein, x is more than or equal to 0 integer, is preferably 0 to 10, more preferably 0,1,2,3 or 4.
Preferably, described alkaline cyclodextrin has structure shown in formula II,
II
Wherein n be 1 and m+n=6,7 or 8 in one;
R
1, R
2or R
3for-RNH
2;
R is (CH
2)
x, NH (CH
2)
x, NH (CH
2)
xnH (CH
2)
x, CO (CH
2)
xor O (CH
2)
x, x is 0,1,2,3 or 4.
More preferably, described alkaline cyclodextrin is a kind of in list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[6-(Diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[3-(amino)-6-deoxidation]-beta-schardinger dextrin-, list-[6-(ethanol amido)-6-deoxidation]-gamma-cyclodextrin.
Another object of the present invention provides the preparation method of a kind of arteannuin series matter and alkaline cyclodextrin clathrate, and the method is dissolved in the water the alkaline cyclodextrin ratio that by volume concentration is 0.02 ~ 0.05g/mL, makes alkaline cyclodextrin aqueous solution; The ratio that is 0.03 ~ 0.5g/mL in the volumetric concentration of arteannuin series matter and organic solvent, be dissolved in the arteannuin series matter in organic solvent; Then arteannuin series matter organic solvent solution is added in alkaline cyclodextrin aqueous solution, under 20 ~ 60 ℃ of conditions after stirring reaction 2 ~ 18h, filter, 40 ℃ of lower concentrating under reduced pressure, after drying, obtain arteannuin series matter and alkaline cyclodextrin clathrate, the weight ratio of its neutral and alkali cyclodextrin and arteannuin series matter is 1:3 ~ 1:98.
The organic solvent adopted in preparation method of the present invention is a kind of in ethanol, methanol, dimethyl sulfoxide, DMF, acetone, isopropyl alcohol, chloroform or oxolane.Adopt ethanol, methanol, dimethyl sulfoxide, N, a kind of in dinethylformamide, acetone, isopropyl alcohol, chloroform or oxolane, the arteannuin series matter is had to dissolubility preferably, can make the arteannuin series matter disperse preferably in the inclusion reaction dicyandiamide solution, improve enclose efficiency, shorten the inclusion reaction time.
The inventive method is with respect to advantage and the technique effect of prior art:
1, the present invention is directed to arteannuin series matter water solublity present situation on the low side, synthetic alkaline cyclodextrin is the cyclodextrin that amido replaces, the amido of cyclodextrin replaces, except the clathration of cyclodextrin cavity and arteannuin series matter molecule, owing to forming alkaline environment in aqueous solution, form ionic interaction with hydroxyl or carboxyl on the arteannuin series matter, thereby make the arteannuin series matter form solution in very wide concentration range in water, be convenient to the formation of arteannuin series matter liquid preparation;
2, arteannuin series matter provided by the invention and alkaline cyclodextrin clathrate in the time of 25 ℃ the dissolubility in water at 20-240
Between mg/mL (amount with the arteannuin series matter is calculated), especially artesunate and alkaline cyclodextrin clathrate, dissolubility in the time of 25 ℃ in water is (amount with artesunate is calculated) between 60-240mg/mL, therefore, clathrate disclosed by the invention, can form solution in water in very wide concentration range, be convenient to the formation of arteannuin series matter liquid preparation;
3, clathrate preparation method of the present invention is simple, easy to operate, and the reaction condition gentleness, be suitable for suitability for industrialized production;
4, the clathrate that the present invention makes has good in the property of medicine to straight caecum target spot, and safe, good stability, dissolubility is good, easy to use, avoids lamp-dish flower acetic to be released and to destroy at digestive tract, the bioavailability that improves medicine increases the dissolubility of medicine, improves the stripping of medicine.
The specific embodiment
Below by embodiment, the present invention is described in further detail; but protection domain of the present invention is not limited to described content; the preparation method of embodiment neutral and alkali cyclodextrin is with reference to R.C. Petter; J.S. Salek; C.T. Sikorski; G. Kumaravel; and F.-T. Lin:J. Am. Chem. Soc. 112; 3860 – 3868 (1990) and B.L. May; S.D. Kean; C.J. Easton, and S.F. Lincoln:J. Chem. Soc., in Perkin Trans. 13157 – 3160 (1997), disclosed method is carried out.
embodiment 1:the clathrate of this arteannuin series matter and alkaline cyclodextrin, comprise arteannuin and list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-, and arteannuin is 1:3 with the weight ratio of list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-.
During preparation, carry out as follows:
1, the preparation of sulfonylation cyclodextrin
Get the beta-schardinger dextrin-210g after recrystallization, be dissolved in the 1300mL distilled water, after fully stirring, solution becomes white emulsion, adds sodium hydroxide solution (17.2g, 50mL), stirs 1.5h.Weighing paratoluensulfonyl chloride 26.0g, be dissolved in the 80mL acetonitrile solution, and this solution slowly is added drop-wise in beta-schardinger dextrin-alkali liquor, stirring at room 2h, sucking filtration is removed a small amount of insoluble matter, with 2M hydrochloric acid, regulates filtrate pH value to 7.5, now have a large amount of precipitations to produce, sucking filtration is removed filtrate.To be precipitated and dissolved in 450mL water under heating in, filter while hot insoluble matter, filtrate is at 0 ℃ of recrystallization 12h, and the precipitation reusable heat water recrystallization obtained after filtration repeatedly, 60 ℃ of vacuum drying 12 h obtain the about 18g of pure single 6-tolysulfonyl-beta-schardinger dextrin-, productive rate 8%.
2, the preparation of list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-
Getting single 6-tolysulfonyl-beta-schardinger dextrin-(3g) adds in the 20mL ethylenediamine solution, at 80 ℃ of reaction 8h, after cooling, reactant liquor is splashed in acetone, collecting precipitation can obtain list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-(2.3g), productive rate 84%.
3, the preparation of arteannuin and list-[6-(ethylenediamine base)-6-deoxidation]-Benexate Hydrochloride
The 1g arteannuin is dissolved in 40mL ethanol, forms solution, by 3g mono--[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in 100mL water, prepares and become solution.Under stirring condition, above-mentioned two kinds of solution are mixed, under 60 ℃, stir 2h, the gained solution filter, 40 ℃ of lower concentrating under reduced pressure, after drying, obtain inclusion complex of artemisinin, clathrate dissolubility in water in the time of 25 ℃ is that 20mg/mL(calculates with the amount of arteannuin).
embodiment 2:the clathrate of this arteannuin series matter and alkaline cyclodextrin, comprise arteannuin and list-[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-, and arteannuin is 1:98 with the weight ratio of list-[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-.
During preparation: the 1g arteannuin is dissolved in 30mL methanol, forms solution; By 98g mono--[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in 500mL water, preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, under 40 ℃, stir 9h, the gained solution filter, 40 ℃ of lower concentrating under reduced pressure, after drying, obtain inclusion complex of artemisinin, clathrate dissolubility in water in the time of 25 ℃ is that 38mg/mL(calculates with the amount of arteannuin).
embodiment 3:the clathrate of this arteannuin series matter and alkaline cyclodextrin, arteannuin is 1:50 with the weight ratio of list-[6-(amino)-6-deoxidation]-beta-schardinger dextrin-.
The 1g arteannuin is dissolved in the 20mL dimethyl sulfoxide, forms solution; By 50g mono--[6-(amino)-6-deoxidation]-beta-schardinger dextrin-is dissolved in 200mL water, preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, under 20 ℃, stir 18h, the gained solution filter, 40 ℃ of lower concentrating under reduced pressure, after drying, obtain inclusion complex of artemisinin, clathrate dissolubility in water in the time of 25 ℃ is that 22mg/mL(calculates with the amount of arteannuin).
embodiment 4:the clathrate of this arteannuin series matter and alkaline cyclodextrin, dihydroarteannuin is 1:3 with the weight ratio of list-[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-.
The 1g dihydroarteannuin is dissolved in to 20mLN, in dinethylformamide, forms solution; By 3g mono--[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in 100mL water, preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 2h under 60 ℃, the gained solution filter, 40 ℃ of lower concentrating under reduced pressure, after drying, obtain the dihydroarteannuin clathrate, clathrate dissolubility in water in the time of 25 ℃ is that 28mg/mL(calculates with the amount of dihydroarteannuin).
embodiment 5:the clathrate of this arteannuin series matter and alkaline cyclodextrin, dihydroarteannuin is 1:98 with the weight ratio of list-[6-(amino)-6-deoxidation]-beta-schardinger dextrin-.
The 1g dihydroarteannuin is dissolved in 30mL acetone, forms solution; By 98g mono--[6-(amino)-6-deoxidation]-beta-schardinger dextrin-is dissolved in 500mL water, preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 8h under 50 ℃, the gained solution filter, 40 ℃ of lower concentrating under reduced pressure, after drying, obtain the dihydroarteannuin clathrate, clathrate dissolubility in water in the time of 25 ℃ is that 35mg/mL(calculates with the amount of dihydroarteannuin).
embodiment 6:the clathrate of this arteannuin series matter and alkaline cyclodextrin, dihydroarteannuin is 1:50 with the weight ratio of list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-.
The 1g dihydroarteannuin is dissolved in the 40mL isopropyl alcohol, forms solution; By 50g mono--[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in 100mL water, preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 18h under 20 ℃, the gained solution filter, 40 ℃ of lower concentrating under reduced pressure, after drying, obtain the dihydroarteannuin clathrate, clathrate dissolubility in water in the time of 25 ℃ is that 32mg/mL(calculates with the amount of dihydroarteannuin).
embodiment 7:the clathrate of this arteannuin series matter and alkaline cyclodextrin, artesunate is 1:50 with the weight ratio of list-[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-.
The 1g artesunate is dissolved in the 40mL chloroform, forms solution; By 50g mono--[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in 200mL water, preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 2h under 60 ℃, the gained solution filter, 40 ℃ of lower concentrating under reduced pressure, after drying, obtain the artesunate clathrate, clathrate dissolubility in water in the time of 25 ℃ is that 150mg/mL(calculates with the amount of artesunate).
embodiment 8:the clathrate of this arteannuin series matter and alkaline cyclodextrin, artesunate is 1:3 with the weight ratio of list-[6-(amino)-6-deoxidation]-beta-schardinger dextrin-.
The 1g artesunate is dissolved in the 30mL oxolane, forms solution; By 3g mono--[6-(amino)-6-deoxidation]-beta-schardinger dextrin-is dissolved in 100mL water, preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, under 30 ℃, stir 4h, the gained solution filter, 40 ℃ of lower concentrating under reduced pressure, after drying, obtain the artesunate clathrate, clathrate dissolubility in water in the time of 25 ℃ is that 60mg/mL(calculates with the amount of artesunate).
embodiment 9:the clathrate of this arteannuin series matter and alkaline cyclodextrin, artesunate is 1:98 with the weight ratio of list-[6-(ethanol amido)-6-deoxidation]-gamma-cyclodextrin.
The 1g artesunate is dissolved in 20mL ethanol, forms solution; By 98g mono--[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in 500mL water, preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 18h under 20 ℃, the gained solution filter, 40 ℃ of lower concentrating under reduced pressure, after drying, obtain the artesunate clathrate, clathrate dissolubility in water in the time of 25 ℃ is that 240mg/mL(calculates with the amount of artesunate).
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (7)
1. the clathrate of an arteannuin series matter and alkaline cyclodextrin, it is characterized in that: it comprises arteannuin series matter and alkaline cyclodextrin, wherein the weight ratio of arteannuin series matter and alkaline cyclodextrin is 1:3 ~ 1:98.
2. the clathrate of arteannuin series matter and alkaline cyclodextrin according to claim 1, it is characterized in that: the arteannuin series matter is a kind of in arteannuin, dihydroarteannuin, artesunate.
3. the clathrate of arteannuin series matter and alkaline cyclodextrin according to claim 1 is characterized in that alkaline cyclodextrin has structure shown in formula I:
I
Wherein m be 0 to 7, n be 1 to 8 and m+n=6,7 or 8 in one;
R
1, R
2and R
3for-OH or-RNH
2and R
1, R
2and R
3in have one at least for-RNH
2;
R is (CH2)
x, NH (CH
2)
x, NH (CH
2)
xnH (CH
2)
x, CO (CH
2)
xor O (CH
2)
x, x is more than or equal to 0 integer.
4. the clathrate of arteannuin series matter and alkaline cyclodextrin according to claim 3 is characterized in that alkaline cyclodextrin has structure shown in formula II:
Ⅱ
Wherein n be 1 and m+n=6,7 or 8 in one;
R
1, R
2or R
3for-RNH
2; R is (CH
2)
x, NH (CH
2)
x, NH (CH
2)
xnH (CH
2)
x, CO (CH
2)
xor O (CH
2)
x, x is 0,1,2,3 or 4.
5. the clathrate of arteannuin series matter and alkaline cyclodextrin according to claim 4, it is characterized in that: alkaline cyclodextrin is for a kind of in list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[6-(amino)-6-deoxidation]-beta-schardinger dextrin-, list-[6-(ethanol amido)-6-deoxidation]-gamma-cyclodextrin.
6. the preparation method of the described arteannuin series matter of claim 1 and alkaline cyclodextrin clathrate, is characterized in that: the alkaline cyclodextrin ratio that by volume concentration is 0.03 ~ 0.5g/mL is dissolved in the water, makes alkaline cyclodextrin aqueous solution; The ratio that is 0.02 ~ 0.05g/mL in the volumetric concentration of arteannuin series matter and organic solvent, be dissolved in the arteannuin series matter in organic solvent; Then arteannuin series matter organic solvent solution is added in alkaline cyclodextrin aqueous solution, under 20 ~ 60 ℃ of conditions after stirring reaction 2 ~ 18h, filter, concentrating under reduced pressure, after drying, obtain arteannuin series matter and alkaline cyclodextrin clathrate, the weight ratio of its neutral and alkali cyclodextrin and arteannuin series matter is 1:3 ~ 1:98.
7. the preparation method of arteannuin series matter and alkaline cyclodextrin clathrate according to claim 6, it is characterized in that: organic solvent is a kind of in ethanol, methanol, dimethyl sulfoxide, DMF, acetone, isopropyl alcohol, chloroform or oxolane.
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| CN104013972B (en) * | 2014-06-25 | 2016-12-07 | 东北林业大学 | A kind of preparation method of hydrophilic belulinic acid Betulinic acid preparation |
| CN104857003A (en) * | 2015-04-10 | 2015-08-26 | 昆明理工大学 | Ursolic acid and amine cyclodextrin clathrate compound |
| CN107582529A (en) * | 2016-07-08 | 2018-01-16 | 山东森诺医药科技有限公司 | Artesunate for Injection freeze-dried powder and preparation method thereof |
| CN109833312A (en) * | 2019-04-09 | 2019-06-04 | 栾云鹏 | A kind of cannabidiol and the inclusion compound of alkaline cyclodextrin and preparation method thereof |
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| CN101125127A (en) * | 2007-08-16 | 2008-02-20 | 昆明制药集团股份有限公司 | Artemisinin derivatives freeze-dried preparation and preparation method |
| CN101954090A (en) * | 2010-09-16 | 2011-01-26 | 桂林制药有限责任公司 | Dihydroartemisinin beta-cyclodextrin inclusion compound, preparation method thereof and antimalarialdrug with same |
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| CN101125127A (en) * | 2007-08-16 | 2008-02-20 | 昆明制药集团股份有限公司 | Artemisinin derivatives freeze-dried preparation and preparation method |
| CN101954090A (en) * | 2010-09-16 | 2011-01-26 | 桂林制药有限责任公司 | Dihydroartemisinin beta-cyclodextrin inclusion compound, preparation method thereof and antimalarialdrug with same |
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