CN102716491A - 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
- Publication number
- CN102716491A CN102716491A CN2012102230668A CN201210223066A CN102716491A CN 102716491 A CN102716491 A CN 102716491A CN 2012102230668 A CN2012102230668 A CN 2012102230668A CN 201210223066 A CN201210223066 A CN 201210223066A CN 102716491 A CN102716491 A CN 102716491A
- Authority
- CN
- China
- Prior art keywords
- cyclodextrin
- arteannuin
- alkaline
- series
- series matter
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 10
- 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 27
- 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
- 229930191701 arteannuin Natural products 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 23
- 239000002585 base Substances 0.000 claims description 22
- 229930187998 Dihydroarteannuin Natural products 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 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
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 7
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- 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
- 229930101531 artemisinin Natural products 0.000 abstract 1
- 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
- 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 6
- 201000004792 malaria Diseases 0.000 description 6
- 230000006103 sulfonylation Effects 0.000 description 6
- 238000005694 sulfonylation reaction Methods 0.000 description 6
- 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
- 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
- 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
- 230000000078 anti-malarial effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940079593 drug Drugs 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
- 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
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 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
- 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
- 238000010521 absorption reaction Methods 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
- 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
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 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
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 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
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
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 arteannuin series matter and alkaline cyclodextrin thing clathrate and preparation method thereof specifically.
Technical background
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 dead, and nearly all case all is due to the plasmodium.Along with the increase of drug resistance strain, many traditional biological alkali medicines, for example chloroquine and quinine are largely invalid now, cause malaria further to spread.Because the frightening drug resistance diffusion of parasite, The World Health Organization's prophesy if there is not the use of new anti-malaria medicaments, will be doubled to malaria case in 2013.1979, a kind of antimalarial arteannuin of new generation that includes the sesquiterpene lactones class of peroxidating group of from Chinese herbal artemisia, separating had drug-fast plasmodium to chloroquine, is a kind of effective antimalarial agent.The arteannuin series matter, all effective like arteannuin, dihydroartemisinine, Artemether, arteether and artesunate to malaria in the plasmodium of chloroquine drug resistance strain and chloroquine sensitive strain and the brain.Recommended by WHO, 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, discover that the arteannuin series matter has shown the effect of kill cancer cell preferably.It is kill cancer cell through 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 and could pass through gastrointestinal mucosa wall and absorption, 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.
Publication number is the Chinese patent of CN1554336, adopts hydroxypropyl cyclodextrin, and dimethyl cyclodextrin, hydroxypropyl cyclodextrin prepare the arteannuin clathrate as solubilizing agent; Publication number is the Chinese patent of CN101125127, relates to artemisinin derivatives and cyclodextrin and methylates, and hydroxypropylation, thioether groupization, sulphur butylation derivant is processed lyophilized formulations; Publication number is the Chinese patent of CN101954090A, discloses dihydroarteannuin and Benexate Hydrochloride and preparation method thereof and the anti-malaria medicaments that contains this clathrate.
These clathrates have improved the water solublity and the stability of arteannuin series matter to a certain extent, and being convenient to preparation becomes various dosage forms.But these clathrates are limited to the solubilising degree of arteannuin series matter, and having limited this medication preparation becomes liquid preparation (for example oral liquid and injection); Alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin; Hydroxypropyl; The ethoxy beta-schardinger dextrin-, the arteannuin series matter clathrate of methyl beta-schardinger dextrin-and sulfobutyl ether-beta-cyclodextrin, the dissolubility in the time of 25 ℃ in the water is 6 ~ 20mg/mL (amount with the arteannuin series matter is calculated).
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, the 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 amylose a series of cyclic oligosaccharides of generation under the cyclodextrin glycosyltransferase effect that produces by bacillus cereus; Wherein study morely and what have important practical usage is the molecule that contains 6,7,8 glucose units, be called respectively α-, β-and gamma-cyclodextrin.According to the result of X-line crystal diffraction, infrared spectrum and spectral analysis of the nuclear magnetic resonance, confirm that each D (+)-Glucopyranose. of formation cyclodextrin molecular all is a chair conformation, each glucose unit is all with 1, and the 4-glycosidic bond combines ring formation.Because connecting the glycosidic bond of glucose unit can not rotate freely; Cyclodextrin is that the big end of both ends open, an end is little, the cylinder three-dimensional ring structure of hollow; In its empty structure; Intracavity portion has formed hydrophobic region owing to receive the shielding action of c h bond, and all hydroxyls are then outside at molecule, and big opening end is by C
2And C
3Secondary hydroxyl constitute, the osculum end is made up of the primary hydroxyl of C6, has very strong hydrophilic, its structure is:
Q=6 wherein, be respectively in 7,8 o'clock α-, β-, gamma-cyclodextrin.
The alkalescence cyclodextrin is for constituting D (+)-Glucopyranose. C of cyclodextrin molecular
2, C
3And/or C
6Hydroxyl replace to be generated alkaline cyclodextrin by amido, the chemical compound that contains acidic-group is had solubilizing effect preferably.
The existing document of the synthetic reference of alkalescence cyclodextrin carries out.Cyclodextrin generates sulfonylation cyclodextrin [R.C. Petter with the sulfonylation agent reaction earlier; J.S. Salek; C.T. Sikorski, G. Kumaravel, and F.-T. Lin:J. Am. Chem. Soc. 112; 3860 – 3868 (1990)], cyclodextrin can be gone up sulfonylation takes place at D (+)-2,3 and/or 6 of Glucopyranose .s.Sulfonylation agent commonly used is benzene sulfonyl chloride and p-methyl benzene sulfonic chloride.Then under the nucleophilic attack of amine for reagent; Sulfonyl on the sulfonylation cyclodextrin breaks away from, and by the amido reaction, generates alkaline cyclodextrin [B.L. May; S.D. Kean; C.J. Easton, and S.F. Lincoln:J. Chem. Soc., Perkin Trans. 13157 – 3160 (1997)].Wherein, said 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 and the single 6-tolysulfonyl-beta-schardinger dextrin-of beta-schardinger dextrin-reaction generation (6-OTs-β-CD), 6-OTs-β-CD adds in ethylenediamine or the diethylenetriamine solution, and reaction obtains alkaline cyclodextrin, and reaction equation is following:
Wherein, As preferably; Said alkaline cyclodextrin is for having structure shown in the formula
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 at least one to be-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 the integer more than or equal to 0.
In the formula
among the m+n=6,7 or 8 one; Represent cyclodextrin according to the invention can for α-, β-or gamma-cyclodextrin; Wherein, N is at least in the said alkaline cyclodextrin molecular of 1 expression has at least a D (+)-Glucopyranose. parent hydroxy to be modified by amido, and this moment, m was 5,6 or 7; And each D (+)-Glucopyranose. of m to be the said alkaline cyclodextrin of 0 expression constitute cyclodextrin molecular is all modified by amido.
Formula
Middle R
1, R
2And R
3In have at least one to be-RNH
2Representing that said alkaline cyclodextrin modified D (+)-Glucopyranose. molecule by amido and be at least the monoamine base and modify, can also can be that the diamine base is modified or R at 2,3 or 6
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 of expression modification cyclodextrin can be organic amino group such as ammonia, methylamine, ethamine, ethylenediamine, ethanolamine, acetamide and diethylenetriamine, and wherein, x is the integer more than or equal to 0, is preferably 0 to 10, more preferably 0,1,2,3 or 4.
Preferably, said alkaline cyclodextrin has structure shown in the 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 be that said alkaline cyclodextrin is a kind of in list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[2-(Diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[3-(methylamino)-6-deoxidation]-alpha-cyclodextrin, list-[6-(ethanol amido)-6-the deoxidation]-gamma-cyclodextrin.
Another object of the present invention provides a kind of arteannuin series matter and alkaline Preparation methods of cyclodextrin inclusion complexes, this method with alkaline cyclodextrin by volume concentration be that the ratio of 0.02 ~ 0.05g/mL is dissolved in the water, make alkaline cyclodextrin aqueous solution; In arteannuin series matter and volume of organic solvent concentration is the ratio of 0.03 ~ 0.5g/mL, and the arteannuin series matter is dissolved in the organic solvent; Then arteannuin series matter organic solvent solution is added in the alkaline cyclodextrin aqueous solution; Behind stirring reaction 2 ~ 18h under 20 ~ 60 ℃ of conditions; Filter, 40 ℃ of following concentrating under reduced pressure are after the drying; Promptly get 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 that is adopted in the method for preparing according to the invention is ethanol, methanol, dimethyl sulfoxide, N, a kind of in dinethylformamide, acetone, isopropyl alcohol, chloroform or the oxolane.Adopt ethanol, methanol, dimethyl sulfoxide, N; A kind of in dinethylformamide, acetone, isopropyl alcohol, chloroform or the oxolane; The arteannuin series matter all there is dissolubility preferably; The arteannuin series matter is disperseed in the inclusion reaction dicyandiamide solution preferably, improve enclose efficient, shorten the inclusion reaction time.
The inventive method is with respect to the 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 substituted cyclodextrin of amido, and the amido of cyclodextrin replaces, except the clathration of cyclodextrin cavity and arteannuin series matter molecule; Owing in aqueous solution, form alkaline environment; Form ionic interaction with hydroxyl or carboxyl on the arteannuin series matter, thereby make the arteannuin series matter in water, form solution, be convenient to the formation of arteannuin series matter liquid preparation in very wide concentration range;
2, arteannuin series matter provided by the invention and alkaline cyclodextrin clathrate in the time of 25 ℃ the dissolubility in the water at 20-240
Between the mg/mL (amount with the arteannuin series matter is calculated); Especially artesunate and alkaline cyclodextrin clathrate; Dissolubility in the time of 25 ℃ in the water is (amount with artesunate is calculated) between 60-240mg/mL, therefore, and clathrate disclosed by the invention; Can in water, form solution in very wide concentration range, be convenient to the formation of arteannuin series matter liquid preparation;
3, clathrate method for preparing of the present invention is simple, easy to operate, and reaction condition is gentle, is suitable for suitability for industrialized production;
4, the clathrate that makes of the present invention has the good property of medicine of giving to straight caecum target spot, and safe, good stability; Dissolubility is good, and is easy to use, avoids lamp-dish flower acetic to be released and to destroy at digestive tract; Improving bioavailability of medicament increases the dissolubility of medicine, improves the stripping of medicine.
The specific embodiment
Through embodiment the present invention is done further explain below, but protection domain of the present invention is not limited to said content, the method for preparing 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., disclosed method is carried out among Perkin Trans. 13157 – 3160 (1997).
Embodiment 1:The clathrate of this arteannuin series matter and alkaline cyclodextrin comprises 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 behind the recrystallization, be dissolved in the 1300mL distilled water, fully stir back solution and become white emulsion, (17.2g 50mL), stirs 1.5h to add sodium hydroxide solution.Weighing paratoluensulfonyl chloride 26.0g is dissolved in the 80mL acetonitrile solution, and this solution slowly is added drop-wise in the beta-schardinger dextrin-alkali liquor; Stirring at room 2h, sucking filtration remove a small amount of insoluble matter, regulate filtrating pH value to 7.5 with 2M hydrochloric acid; Have this moment a large amount of depositions to produce, sucking filtration is removed filtrating.The heating under with resolution of precipitate in 450mL water; Filter insoluble matter while hot, filtrating is at 0 ℃ of recrystallization 12h, and the deposition reuse hot water recrystallization that obtains after the filtration repeatedly; 60 ℃ of vacuum drying 12 h promptly 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-
Get single 6-tolysulfonyl-beta-schardinger dextrin-(3g) and add in the 20mL ethylenediamine solution, at 80 ℃ of reaction 8h, after the cooling reactant liquor is splashed in the 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 the 40mL ethanol, forms solution, 3g list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in the 100mL water, preparation becomes solution.Under stirring condition, above-mentioned two kinds of solution are mixed, stir 2h down at 60 ℃, gained solution filters, and 40 ℃ of following concentrating under reduced pressure after the drying, obtain the arteannuin clathrate, and clathrate dissolubility in the water in the time of 25 ℃ is 20mg/mL (amount with arteannuin is calculated).
Embodiment 2:The clathrate of this arteannuin series matter and alkaline cyclodextrin comprises 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 the 30mL methanol, forms solution; 98g list-[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in the 500mL water, and preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 9h down at 40 ℃, gained solution filters, and 40 ℃ of following concentrating under reduced pressure after the drying, obtain the arteannuin clathrate, and clathrate dissolubility in the water in the time of 25 ℃ is 38mg/mL (amount with arteannuin is calculated).
Embodiment 3:The clathrate of this arteannuin series matter and alkaline cyclodextrin, arteannuin is 1:50 with the weight ratio of list-[6-(amido)-6-deoxidation]-beta-schardinger dextrin-.
The 1g arteannuin is dissolved in the 20mL dimethyl sulfoxide, forms solution; 50g list-[6-(amido)-6-deoxidation]-beta-schardinger dextrin-is dissolved in the 200mL water, and preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 18h down at 20 ℃, gained solution filters, and 40 ℃ of following concentrating under reduced pressure after the drying, obtain the arteannuin clathrate, and clathrate dissolubility in the water in the time of 25 ℃ is 22mg/mL (amount with arteannuin is calculated).
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 20mLN, in the dinethylformamide, forms solution; 3g list-[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in the 100mL water, and preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 2h down at 60 ℃, gained solution filters; 40 ℃ of following concentrating under reduced pressure; After the drying, obtain the dihydroarteannuin clathrate, clathrate dissolubility in the water in the time of 25 ℃ is 28mg/mL (amount with dihydroarteannuin is calculated).
Embodiment 5:The clathrate of this arteannuin series matter and alkaline cyclodextrin, dihydroarteannuin is 1:98 with the weight ratio of list-[6-(amido)-6-deoxidation]-beta-schardinger dextrin-.
The 1g dihydroarteannuin is dissolved in the 30mL acetone, forms solution; 98g list-[6-(amido)-6-deoxidation]-beta-schardinger dextrin-is dissolved in the 500mL water, and preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 8h down at 50 ℃, gained solution filters; 40 ℃ of following concentrating under reduced pressure; After the drying, obtain the dihydroarteannuin clathrate, clathrate dissolubility in the water in the time of 25 ℃ is 35mg/mL (amount with dihydroarteannuin is calculated).
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; 50g list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in the 100mL water, and preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 18h down at 20 ℃, gained solution filters; 40 ℃ of following concentrating under reduced pressure; After the drying, obtain the dihydroarteannuin clathrate, clathrate dissolubility in the water in the time of 25 ℃ is 32mg/mL (amount with dihydroarteannuin is calculated).
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; 50g list-[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in the 200mL water, and preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 2h down at 60 ℃, gained solution filters; 40 ℃ of following concentrating under reduced pressure; After the drying, obtain the artesunate clathrate, clathrate dissolubility in the water in the time of 25 ℃ is 150mg/mL (amount with artesunate is calculated).
Embodiment 8:The clathrate of this arteannuin series matter and alkaline cyclodextrin, artesunate is 1:3 with the weight ratio of list-[6-(amido)-6-deoxidation]-beta-schardinger dextrin-.
The 1g artesunate is dissolved in the 30mL oxolane, forms solution; 3g list-[6-(amido)-6-deoxidation]-beta-schardinger dextrin-is dissolved in the 100mL water, and preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 4h down at 30 ℃, gained solution filters, and 40 ℃ of following concentrating under reduced pressure after the drying, obtain the artesunate clathrate, and clathrate dissolubility in the water in the time of 25 ℃ is 60mg/mL (amount with artesunate is calculated).
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 the 20mL ethanol, forms solution; 98g list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-is dissolved in the 500mL water, and preparation becomes solution; Under stirring condition, above-mentioned two kinds of solution are mixed, stir 18h down at 20 ℃, gained solution filters; 40 ℃ of following concentrating under reduced pressure; After the drying, obtain the artesunate clathrate, clathrate dissolubility in the water in the time of 25 ℃ is 240mg/mL (amount with artesunate is calculated).
The explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle 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 claim of 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. according to the clathrate of said arteannuin series matter of claim 1 and alkaline cyclodextrin, it is characterized in that: the arteannuin series matter is a kind of in arteannuin, dihydroarteannuin, the artesunate.
3. according to the clathrate of said arteannuin series matter of claim 1 and alkaline cyclodextrin, it is characterized in that alkaline cyclodextrin has structure shown in the 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 at least one to be-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 the integer more than or equal to 0.
4. according to the clathrate of said arteannuin series matter of claim 3 and alkaline cyclodextrin, it is characterized in that alkaline cyclodextrin has structure shown in the formula II:
Ⅱ
Wherein n be 1 and m+n=6,7 or 8 in one;
R
1, R
2Or R
3For-RNH
2R 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. according to the clathrate of said arteannuin series matter of claim 4 and alkaline cyclodextrin, it is characterized in that: alkaline cyclodextrin is for a kind of in list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[2-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[3-(amido)-6-deoxidation]-alpha-cyclodextrin, list-[6-(ethanol amido)-6-the deoxidation]-gamma-cyclodextrin.
6. said arteannuin series matter of claim 1 and alkaline Preparation methods of cyclodextrin inclusion complexes is characterized in that: with alkaline cyclodextrin by volume concentration be that the ratio of 0.03 ~ 0.5g/mL is dissolved in the water, make alkaline cyclodextrin aqueous solution; In arteannuin series matter and volume of organic solvent concentration is the ratio of 0.02 ~ 0.05g/mL, and the arteannuin series matter is dissolved in the organic solvent; Then arteannuin series matter organic solvent solution is added in the alkaline cyclodextrin aqueous solution; Behind stirring reaction 2 ~ 18h under 20 ~ 60 ℃ of conditions; Filter, concentrating under reduced pressure is after the drying; Promptly get 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. according to said arteannuin series matter of claim 6 and alkaline Preparation methods of cyclodextrin inclusion complexes; It is characterized in that: organic solvent is ethanol, methanol, dimethyl sulfoxide, N, a kind of in dinethylformamide, acetone, isopropyl alcohol, chloroform or the oxolane.
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