CN104162167A - Tamibarotene cyclodextrin or cyclodextrin derivative clathrate and preparation method thereof - Google Patents
Tamibarotene cyclodextrin or cyclodextrin derivative clathrate and preparation method thereof Download PDFInfo
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- CN104162167A CN104162167A CN201410344726.7A CN201410344726A CN104162167A CN 104162167 A CN104162167 A CN 104162167A CN 201410344726 A CN201410344726 A CN 201410344726A CN 104162167 A CN104162167 A CN 104162167A
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- cyclodextrin
- tamibarotene
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- 229950010130 tamibarotene Drugs 0.000 title claims abstract description 139
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 title claims abstract description 134
- 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 116
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 103
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000000725 suspension Substances 0.000 claims abstract description 6
- 239000004570 mortar (masonry) Substances 0.000 claims abstract description 5
- 239000000084 colloidal system Substances 0.000 claims abstract description 3
- 239000012141 concentrate Substances 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 31
- 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 claims description 30
- 239000007924 injection Substances 0.000 claims description 22
- 238000002347 injection Methods 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 13
- 239000000843 powder Substances 0.000 claims description 10
- 239000001116 FEMA 4028 Substances 0.000 claims description 8
- 229960004853 betadex Drugs 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 8
- 238000004108 freeze drying Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 6
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 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 group 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 claims description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 2
- 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 claims description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 235000008504 concentrate Nutrition 0.000 claims description 2
- 239000007919 dispersible tablet Substances 0.000 claims description 2
- 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 claims description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 229940097362 cyclodextrins Drugs 0.000 claims 5
- YZOUYRAONFXZSI-SBHWVFSVSA-N (1S,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-37,39,40,41,42,43,44,45,46,47,48,49-dodecamethoxy-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-diol Chemical compound O([C@@H]([C@H]([C@@H]1OC)OC)O[C@H]2[C@@H](O)[C@@H]([C@@H](O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3O)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O3)O[C@@H]2CO)OC)[C@H](CO)[C@H]1O[C@@H]1[C@@H](OC)[C@H](OC)[C@H]3[C@@H](CO)O1 YZOUYRAONFXZSI-SBHWVFSVSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
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- 239000006191 orally-disintegrating tablet Substances 0.000 claims 1
- 238000001694 spray drying Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 7
- 229920001353 Dextrin Polymers 0.000 abstract description 2
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000000034 method Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- -1 Tamibarotene HP-β-CD derivative Chemical class 0.000 description 5
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- 230000003020 moisturizing effect Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一种他米巴罗汀环糊精或环糊精衍生物包合物，是由他米巴罗汀，以及环糊精或环糊精衍生物制成，他米巴罗汀与环糊精或环糊精衍生物的分子摩尔比为1:1～1:100，制备方法为：将环糊精或环糊精衍生物加入到溶媒中，制成溶液或混悬液，然后加入他米巴罗汀，搅拌、研磨或超声混合，即得。或：将环糊精或环糊精衍生物置于胶体磨或研钵中，加入溶媒搅拌，使其成为糊状物，然后将他米巴罗汀加入糊状物中，研磨1～5小时，得均一的粘稠糊状物，过滤，浓缩或冷冻干燥，即得。本发明还公开了包含他米巴罗汀的组合物。本发明的包合物，提高了他米巴罗汀的溶解度和溶解速率，具有水溶性好、血管刺激性小、崩解快、生物利用度高等特点。
The invention discloses an inclusion compound of tamibarotene cyclodextrin or cyclodextrin derivatives, which is prepared from tamibarotene, cyclodextrin or cyclodextrin derivatives, tamibarotene and cyclodextrin The molecular molar ratio of dextrin or cyclodextrin derivatives is 1:1~1:100. The preparation method is: add cyclodextrin or cyclodextrin derivatives to the solvent to make a solution or suspension, and then add Tamibarotene can be prepared by stirring, grinding or ultrasonic mixing. Or: put cyclodextrin or cyclodextrin derivatives in a colloid mill or mortar, add solvent and stir to make a paste, then add Tamibarotene to the paste, grind for 1 to 5 hours, Obtain a uniform viscous paste, filter, concentrate or freeze-dry, that is. The invention also discloses a composition comprising tamibarotene. The clathrate of the present invention improves the solubility and dissolution rate of tamibarotene, and has the characteristics of good water solubility, small blood vessel irritation, fast disintegration, high bioavailability and the like.
Description
Technical field
The present invention relates to Tamibarotene cyclodextrin or cyclodextrin derivant clathrate, its preparation method, the pharmaceutical composition that contains Tamibarotene cyclodextrin or cyclodextrin derivant clathrate and the purposes in preparing medicine.Belong to medical technical field.
Background technology
Tamibarotene (Tamibarotene, Am80), chemistry 4-[(5 by name, 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2) carbamyl] benzoic acid.It is colourless prism or white crystalline powder, is soluble in oxolane and dichloromethane, water insoluble.Its structural formula is as follows:
Tamibarotene is the new selective retinoic acid α receptor promoter of Nippon Shinyaku Co., Ltd. (JP) Tokyo To, Japan (Nippon Shinyaku) exploitation, is applicable to the treatment of acute promyelocytic leukemia relapsed or stubborn sexually transmitted disease (STD).Tamibarotene tablet, in June, 2005 in Japan listing (trade name: Amnolake), there is the features such as efficient, low drug resistance and side effect be little.But because it is insoluble in water, with ordinary preparation oral administration, absorption difference, bioavailability is lower, has therefore limited its application.
Medicine can be increased to the dissolubility of medicine with cyclodextrin inclusion compound, improve the bioavailability of medicine, in addition all right: to increase medicine stability; Cover the bad smell of medicine; Reduce zest or the toxic and side effects of some drugs; Regulating drug rate of releasing drug; Promote medicine per mucous membrane absorption etc.There is at present multiple cyclodextrin clathrate launch, but there are no the report of the cyclodextrin clathrate about Tamibarotene.
Summary of the invention
For above-mentioned prior art, water insoluble for solving in prior art Tamibarotene, oral absorption is poor, the technical problem that is difficult to oral or drug administration by injection, the invention provides Tamibarotene cyclodextrin or cyclodextrin derivant clathrate, with and preparation method thereof, and the pharmaceutical composition that contains Tamibarotene cyclodextrin or cyclodextrin derivant clathrate and the purposes in preparing medicine.
The present invention is achieved by the following technical solutions:
Tamibarotene cyclodextrin or cyclodextrin derivant clathrate, be by Tamibarotene, and cyclodextrin or cyclodextrin derivative make, the molecule mol ratio of Tamibarotene and cyclodextrin or cyclodextrin derivative is 1:1～1:100, preferred 1:1～1:10, dosage form is solid dosage forms or liquid dosage form.
Described cyclodextrin includes but not limited to alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, preferably beta-schardinger dextrin-.
Described cyclodextrin derivative includes but not limited to hydroxyethyl-β-cyclodextrin, HP-β-CD, dihydroxypropyl-beta-schardinger dextrin-, first group-beta-cyclodextrin, glucose-cyclodextrin, maltose-cyclodextrin, maltotriose-cyclodextrin, carboxymethyl-cyclodextrin, sulfoalkyl-cyclodextrin, preferably HP-β-CD.
The preparation method of described Tamibarotene cyclodextrin or cyclodextrin derivant clathrate is: cyclodextrin or cyclodextrin derivative are joined in solvent, make concentration and be the cyclodextrin of 1～90% (mass percent) (preferably 30～90%) or solution or the suspension of cyclodextrin derivative, then add Tamibarotene, stirring, grinding or ultrasonic mixing, obtain Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate (solution or suspension) of liquid.
Further, by the Tamibarotene cyclodextrin of liquid or cyclodextrin derivant clathrate lyophilization spraying is dry or distillation and concentration except desolventizing, obtain Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate of solid.
Preferably, before lyophilization, first that the Tamibarotene cyclodextrin of liquid or cyclodextrin derivant clathrate is concentrated, the concentration that is concentrated into dextrin or cyclodextrin derivative is 10～50% (mass percents).
The present invention also provides another preparation method: cyclodextrin or cyclodextrin derivative are placed in to colloid mill or mortar, add appropriate suitable solvent to stir, become pastel, then Tamibarotene is added in pastel, grind 1～5 hour, obtain the viscous pastes of homogeneous, filter, concentrate or lyophilization, obtain Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate of solid.
In above-mentioned two kinds of preparation methoies, described solvent (dissolving the suitable solvent of cyclodextrin or cyclodextrin derivative) is selected from one or more the mixture in water, ethanol, methanol, propanol, isopropyl alcohol, ethylene glycol, glycerol, acetone, preferred water.
Described while adding Tamibarotene, directly add tamibarotene solid, or with appropriate organic solvent (dehydrated alcohol), dissolve Tamibarotene and obtain after Tamibarotene solution, then add.
The present invention also provides a kind of compositions that comprises medicine Tamibarotene, comprises Tamibarotene cyclodextrin or cyclodextrin derivant clathrate prepared by said method, and acceptable carrier on pharmacopedics.
The dosage form of the described compositions that comprises medicine Tamibarotene, includes but not limited to the liquid dosage forms such as injection, liquid drugs injection, powder pin, oral liquid, syrup (by the directly preparation of the Tamibarotene cyclodextrin of liquid or cyclodextrin derivant clathrate); The many kinds of solids dosage forms (Tamibarotene cyclodextrin or cyclodextrin derivant clathrate by solid are made) such as tablet, capsule, granule, dispersible tablet, oral cavity disintegration tablet, buccal tablet.
In the described compositions that comprises medicine Tamibarotene, single dose specification is for containing active medicine Tamibarotene 0.1～1000mg, and preferably single dose specification is for containing active medicine Tamibarotene 1～100mg.
Preferably, the described compositions that comprises medicine Tamibarotene, dosage form is injection, in injection, Tamibarotene cyclodextrin or cyclodextrin derivant clathrate are specially Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion, concentration is 0.01～3% (g/ml), and the pH value of injection is 3～10; In injection, can contain the pH adjustment agent such as sodium chloride, glucose isosmoticity regulator and hydrochloric acid, sodium hydroxide.
Preferably, the described compositions that comprises medicine Tamibarotene, dosage form is injectable powder, Tamibarotene cyclodextrin or cyclodextrin derivant clathrate are specially Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion, pH value after injectable powder dissolves is 3～10, can contain the pH such as the proppants such as mannitol, lactose and hydrochloric acid, sodium hydroxide and adjust in injectable powder.
Beneficial effect of the present invention is: by cyclodextrin or cyclodextrin derivative, Tamibarotene is carried out to enclose, Tamibarotene molecule is embedded in the tubular structure of cyclodextrin or cyclodextrin derivative molecule, become the clathrate of Tamibarotene cyclodextrin or cyclodextrin derivative, thereby improved dissolubility and the rate of dissolution of Tamibarotene.
Tamibarotene cyclodextrin of the present invention or cyclodextrin derivant clathrate, make this active component of Tamibarotene directly apply to solid, liquid dosage form with the form of clathrate.Cyclodextrin or cyclodextrin derivative are the water solublity pharmaceutic adjuvants that a kind of toxicity is less, and Tamibarotene cyclodextrin or the cyclodextrin derivant clathrate with it, prepared are suitable for making plurality of liquid preparation and solid preparation.Tamibarotene cyclodextrin of the present invention or cyclodextrin derivant clathrate, there is good water solubility, feature that blood vessel irritation is little, be particularly useful for making liquid preparation, solved Tamibarotene water solublity low, can not be directly used in liquid dosage form, especially the technical problem of injection type.In addition, owing to having improved water solublity, the solid preparation of preparing with it has that disintegrate is fast, stripping good, bioavailability high, is more conducive to clinical practice.
Accompanying drawing explanation
The DSC collection of illustrative plates of Fig. 1: Am80, HP-β-CD and both mixture, Am80 clathrate.
Fig. 2: the stripping curve figure of Am80 clathrate and Am80 crude drug.
Fig. 3: the blood drug level-time plot after Am80 inclusion complex in solution and Am80 crude drug suspension are oral in rat body.
The specific embodiment
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1 prepares liquid Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion solution
Step is as follows:
(1) take 61mg HP-β-CD, pour 5ml distilled water into, stirring and dissolving.
(2) separately claim Tamibarotene 5mg, add 5ml anhydrous alcohol solution, this solution is poured in above-mentioned HP-β-CD solution.
(3) mixed liquor stirs 1h with magnetic agitation method at 45 ℃, and vacuum rotary steam is removed ethanol, filters and removes not enclose medicine, obtains Tamibarotene HP-β-CD derivative clathrate solution.
Embodiment 2 prepares solid Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion
Step is as follows:
(1), (2), (3) are with embodiment 1.
(4) Tamibarotene HP-β-CD derivative clathrate solution is carried out to lyophilization again, obtain solid Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion.
Embodiment 3 prepares solid Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion
Step is as follows:
(1) take 122mg HP-β-CD, put into mortar, add 2ml distilled water, grind and make into pasty state;
(2) separately take Tamibarotene 10mg, add 2ml anhydrous alcohol solution, this solution is poured in above-mentioned HP-β-CD solution.
(3) mixed liquor is ground 2 hours, obtain homogeneous pastel, filter, evaporated under reduced pressure, obtains solid Tamibarotene cyclodextrin derivant clathrate.
Embodiment 4 prepares the sodium chloride injection of Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion
Step is as follows:
(1) take 122mg HP-β-CD, pour in 10ml distilled water, stirring and dissolving, adds 0.5
gtransfusion active carbon, is heated with stirring to 80 ℃, is incubated 15 minutes, filtering decarbonization.
(2) separately take Tamibarotene 10mg, add 10ml anhydrous alcohol solution, this solution is poured in above-mentioned HP-β-CD solution.
(3) mixed liquor stirs 1h with magnetic agitation method at 45 ℃, observes solution to clear, obtains Tamibarotene HP-β-CD derivative clathrate solution.
(4) inclusion complex in solution moisturizing, to 800ml, adds sodium chloride for injection 7.5g, and regulates pH to 6 with the hydrochloric acid of 0.05M or the sodium hydroxide of 0.05M, and moisturizing, to 1000ml, adds 0.1g injection active carbon, stirs 20 minutes.
(5) the de-charcoal fill of solution, 115 ℃, 30 minutes pressure sterilizings, obtain.
Embodiment 5 prepares the glucose injection of Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion
Step is as follows:
(1), (2), (3) are with embodiment 4.
(4) take glucose for injection 50g, add water stirring and dissolving and make volume reach 100ml, add 0.1g active carbon, heat micro-boiling 15 minutes, filtering decarbonization, obtains Glucose Liquid.
(5) Glucose Liquid is poured in inclusion complex in solution, and moisturizing, to 800ml, regulates pH to 7 with the hydrochloric acid of 0.05M or the sodium hydroxide of 0.05M, and moisturizing, to 1000ml, adds 0.1g injection active carbon, stirs 20 minutes.
(6) solution carries out coarse filtration, fine straining with filter or sand stick (aperture 1.0 μ m, 0.45 μ m, 0.22 μ m) respectively, then fill, and 115 ℃, 30 minutes pressure sterilizings, obtain.
Embodiment 6 use Tamibarotene hydroxypropyl-beta-cyclodextrin inclusions are prepared aseptic powder injection
Step is as follows:
(1) indoor in sterile working, take 122mg HP-β-CD, be dissolved in water, be settled to 10ml, add 0.1g active carbon, heat micro-boiling 15 minutes, filtering decarbonization.
(2) separately take Tamibarotene 10mg, add 10ml anhydrous alcohol solution, this solution is poured in above-mentioned HP-β-CD solution.
(3) mixed liquor stirs 1h with magnetic agitation method at 50 ℃, stirs, and vacuum rotary steam is removed ethanol, removes by filter the not medicine of enclose, obtains Tamibarotene HP-β-CD derivative clathrate solution.
(4) inclusion complex in solution moisturizing is to 20ml, crosses 0.22 μ m filter membrane, is sub-packed in the cillin bottle of 5ml (1～2ml/ bottle), inserts in freeze dryer, and lyophilization gland, obtains aseptic powder injection.
Embodiment 7 beta-cyclodextrin inclusion compound Tamibarotene
Step is as follows: take 40g beta-schardinger dextrin-, add 100ml distilled water, be heated to 45 ℃, beta-schardinger dextrin-is dissolved, add with 1g Tamibarotene (using in advance 20ml anhydrous alcohol solution), magnetic agitation, after 2.5 hours, is filtered, lyophilization, obtains beta-schardinger dextrin-Tamibarotene clathrate.
The preparation of embodiment 8 beta-cyclodextrin inclusion compound Tamibarotene oral capsules
Step is as follows: take beta-cyclodextrin inclusion compound Tamibarotene 5g, itself and 20g lactose are mixed by equivalent multiplication method, with water dissolution HPMC, as binding agent soft material processed, 20 mesh sieves are granulated, dry at 60 ℃, 30 mesh sieve granulate for dry granule, carry out intermediate check, by encapsulated containing active medicine 2mg/ grain, sampling observation, subpackage, obtains.
The preparation of embodiment 9 beta-cyclodextrin inclusion compound Tamibarotene oral tablets
Step is as follows: take beta-cyclodextrin inclusion compound Tamibarotene 2g, itself and 8g lactose and 0.5g carboxymethyl starch sodium mixed by equivalent multiplication method, with water dissolution HPMC as binding agent soft material processed, 20 mesh sieves are granulated, dry at 60 ℃, 30 mesh sieve granulate for dry granule, add micropowder silica gel 0.1g, be mixed evenly, by containing active medicine 2mg/ sheet tabletting, carry out intermediate check, encapsulated, sampling observation, subpackage, obtains.
Experiment 1
The physical mixed of getting respectively appropriate Tamibarotene, HP-β-CD, Tamibarotene hydroxypropyl-beta-cyclodextrin inclusion (by example 2 gained), Tamibarotene and HP-β-CD (takes 5mg Tamibarotene, 61mg HP-β-CD, in mortar, be ground, obtain) totally four parts carry out differential scanning calorimetry.Wherein programming rate is 5 ℃/min, and sweep limits is 20～500 ℃, and test result as shown in Figure 1.As can be seen from the figure, Tamibarotene has a sharp-pointed feature endothermic peak at 231 ℃; HP-β-CD has a larger feature endothermic peak 360 ℃ of left and right; The physical mixture of Tamibarotene and HP-β-CD is respectively having an absworption peak at 217 ℃, 289 ℃ respectively, is the stack peak of Tamibarotene and hydroxypropyl cyclodextrin, may be the peak position difference slightly that both influencing each other causes them; Tamibarotene clathrate all disappears with the peak of 360 ℃ of left and right at 231 ℃, only 325 ℃ of left and right, has an absworption peak, shows that Tamibarotene and hydroxypropyl-beta-cyclodextrin inclusion form.
Experiment 2
Take respectively each six parts of Tamibarotene 2mg, Tamibarotene clathrates appropriate (embodiment 2 preparations, containing Tamibarotene 2mg).According to dissolution method (2010 editions two appendix XC the second methods of Chinese Pharmacopoeia), measure, take purified water 900ml as dissolution medium, temperature is (37 ± 0.5) ℃, rotating speed (100 ± 1) r/min.In 3,7,10,15,20,30,45min samples 5ml, 0.45um filtering with microporous membrane, get subsequent filtrate 2mL, adopt UV method to measure trap, according to the standard curve of setting up, calculate its accumulative releasing degree, take the time as abscissa, accumulation dissolution be vertical coordinate draw Tamibarotene and clathrate thereof stripping curve as shown in Figure 2.As seen from the figure, the dissolution rate of Tamibarotene clathrate Chinese medicine and dissolution, all apparently higher than Tamibarotene crude drug, illustrate that the Tamibarotene clathrate of preparation can obviously improve the stripping of medicine.
Experiment 3
Get 6 of Wistar rats, body weight 200 ± 20g, is divided at random two groups and (for examination, organizes a gavage and give Tamibarotene suspension; For examination, organize two groups of gavages and give Tamibarotene clathrate (by example 2 gained); Dosage is 20mg/kg, and every group parallel three, fasting 12h before experiment, freely drinks water.For examination group and matched group before administration and 0.25 after administration, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24h, from jugular sinus, get blood, add in the centrifuge tube of processing through heparin sodium, the centrifugal 10min of 4000rpm, the accurate 0.1ml supernatant of drawing, add 0.2ml acetonitrile, vortex vibration 30s, the centrifugal 10min of 12000rpm, get the filtering with microporous membrane of 0.22 μ m for supernatant, obtain the plasma sample of different time points, get 20 μ l sample introductions and analyze (utilizing high performance liquid chromatogram to measure), utilize DAS2.0 to process data, draw the blood drug level-time plot in rat body, as shown in Figure 3.Wherein, the AUC of Tamibarotene clathrate and Tamibarotene is respectively 54.812,21.541 (mg/L*h), Cmax is respectively 9.314,2.017 (mg/L), known, Tamibarotene is made after clathrate, bioavailability obviously increases, and can reduce thus the dosage of medicine, thereby can reduce the toxic and side effects of medicine.
Claims (10)
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| CN115337291A (en) * | 2021-05-14 | 2022-11-15 | 香港大学 | Dry powder formulations of tamibarotene for pulmonary and intranasal delivery |
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| CN115337291A (en) * | 2021-05-14 | 2022-11-15 | 香港大学 | Dry powder formulations of tamibarotene for pulmonary and intranasal delivery |
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