CN1977974A - Indulion cyclodextrin/hydroxy camptothecin medicinal composition and its preparing method - Google Patents
Indulion cyclodextrin/hydroxy camptothecin medicinal composition and its preparing method Download PDFInfo
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- CN1977974A CN1977974A CN200510122945.1A CN200510122945A CN1977974A CN 1977974 A CN1977974 A CN 1977974A CN 200510122945 A CN200510122945 A CN 200510122945A CN 1977974 A CN1977974 A CN 1977974A
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- cyclodextrin
- hydroxy camptothecin
- beta
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- camptothecin
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- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 title claims abstract description 123
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 72
- 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 69
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Abstract
The present invention relates to an inclusion state cyclodextrin/hydroxycamptothecin medicine composition, in which the mole ratio of cyclodextrin and hydroxycamptothecin is 1:0.1-1.0, the inclusion stability constant Ka is equal to 195 M-1 - 2264 M-1. Said cyclodextrin adopts beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin or sulfo-butyl-beta-cyclodextrin or mixture of their any two kinds or more than two kinds. Its preparation method includes the following steps: mixing cyclodextrin and pure water to obtain mixed suspension or solution, adding hydroxycamptothecin, fully mixing them, stirring for 5-10 hr, press-filtering, water-washing solid substance, drying to obtain solid inclusion compound or filtering to obtain liquid inclusion compound.
Description
Technical field
What the present invention relates to is a kind of cyclodextrin and hydroxy camptothecin pharmaceutical pack compound of containing: Indulion cyclodextrin/hydroxy camptothecin medicinal composition, and the preparation method of said composition.
Background technology
Hydroxy camptothecin is a kind of micro-alkaloid of separation and Extraction in China distinctive a kind of jade field section arbor-camptotheca seed, chemical name: (S)-and 4-ethyl-4,9 dihydroxy-1H-pyrans also [3 ', 4 ': 6,7] indolizine [1,2-b] quinoline-3 also, 14 (4H, 12H)-diketone, molecular formula: C
20H
16N
2O
5, molecular weight: 364.37, be the present the strongest chemical compound of antitumaous effect in isolating more than 20 monomers from Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae).This product suppresses topoisomerase by selectivity and disturbs duplicating of DNA, characteristics with high-efficiency low-toxicity, broad spectrum anticancer, clinical bladder cancer, rectal cancer, hepatocarcinoma, gastric cancer, ovarian cancer, leukemia and the tumor of head and neck etc. of being used for are all obtained good efficacy, intravenous injection, every day dosage 4-10mg.Similar to most of antineoplastic agents, the hydroxy camptothecin dosage form of present clinical use is single injection, and the different preparation specifications of 2mg/2ml-10mg/2ml are arranged.
Under the solution state, there are the balance of two kinds of tautomeric structures in lactonic ring easy open loop becoming carboxylic acid (salt) so molecule in the hydroxy camptothecin structure:
Lactonic ring structure carboxylate structure
System pH＜5 o'clock, hydroxy camptothecin is based on the lactonic ring structure; PH＞7.5 o'clock are based on the open loop carboxylate structure.(Yang Mei, Ceng Yujian: the progress modern medicine health of camptothecine and derivant thereof, 2003,19 (8), 977～978), but the lactonic ring structure of hydroxy camptothecin is an active structure, and low (the Jichao Kang of the carboxylate structure activity of open loop, Vijay Kumar, Dong Yang, PriyankaRoy Chowdhury, Raymond J.Hohl, Cyclodextrin complexation:influence on thesolubility, stability, and cytotoxicity of camptothecin, an antineoplastic agent, European Journal of Pharmaceutical Sciences, 2002,15 (2): 163-170).Because hydroxy camptothecin is insoluble in water, prepare injection so improve its water solublity and add cosolvent with the carboxylate of hydrolysis clinically.For improving active people, the enhancing water solublity carried out multiple research improvement: the one, carry out the dissolubility that the camptothecine structure of modification increases camptothecine by introducing polar group, reach and improve the purpose that curative effect reduces side effect increase use dosage form, as medicines such as Topotecan.CN96112301 discloses and has a kind ofly utilized basic amino acid and do not adopt the method for NaOH solubilising, but can not solve the problem of the performance that the hydroxy camptothecin hydrolysis affects the treatment under the alkali condition.
Domestic nearest studies show that, hydroxy camptothecin is oral effectively, and hydroxy camptothecin capsule (dosage 5mg/ grain) and tablet (55mg/ grain) are just in clinical trial.The data of having delivered shows: the human body oral administration can be kept the 12h effective blood drug concentration, and prolongs to some extent than intravenously administrable, tablet bioavailability about 32%.The capsule bioavailability is about 37%, and oral administration can improve the local concentration of hydroxy camptothecin in gastrointestinal tissue.The purpose (China Dispensary, 2001,12 (10): 589) that utilize this route of administration can reach the raising chemotherapeutic index, reduce systemic adverse reactions.Oral formulations has made things convenient for extensive patients, good market development prospect is arranged, and still, the dosage of product is higher than drug administration by injection and needs with the high feedstock production of lactonic ring structural content for improving bioavailability, its cost is much higher than injection, has strengthened patient's drug cost.This shows, improve active structure content, increase the hydroxy camptothecin water solubility, reduce the subject matter that preparation cost becomes needs solution, also is the difficult point of present hydroxy camptothecin preparation technique research.
Cyclodextrin is used to increase the existing many successful example of water solublity, raising stability of drug and bioavailability of medicine, is obtaining application more and more widely.Cyclodextrin is not that simple physics is mixed with the effect of medicine, this technology is that main body and medicine object form the clathrate with specific " host-guest " effect with the cyclodextrin, according to bulk of molecule, the object medicine can be in whole or in part by the main body cyclodextrin inclusion compound in cavity, reactive group in the drug molecule is owing to being stablized by the cavity of cyclodextrin parcel, " host-guest " molecular proportion in the enclose system can be 1: 1 or other molecule proportional actions according to molecular size and effect power simultaneously, clathration makes medicine present high dispersion with molecularity, thereby drug solubility is increased.
People such as Jichao Kang have reported the clathration and the performance of cyclodextrin/camptothecine in the aqueous solution, cyclodextrin and derivant thereof can make the camptothecine water solublity improve 5.7 times of (1.5% β-CD) or 33 times (25%HP-β-CD) respectively, wherein the DM-effect is best, 25% DM-solution makes 171 times of camptothecine solubilisings, the cell in vitro activity of camptothecine clathrate has increased about 20%, its reason is that camptothecine lactonic ring structural content increases the stability enhancing behind the enclose, and the half-life of hydrolysis has prolonged about 10 times than non-enclose attitude.The characteristics of camptothecine/cyclodextrin molecular clathrate are to improve the lactonic ring active structure content of medicine dissolution, enhancing medicine stability, protection camptothecine.Jichao Kang does not prepare solid clathrates, but this technical clarification might solve the contradiction of hydroxy camptothecin dissolubility and bioavailability and active structure by cyclodextrin inclusion technique, and the new type antineoplastic medicine dosage form of exploitation high-quality low-cost is served extensive patients.
Hydroxy camptothecin is that 10 of camptothecines connect hydroxy derivative, generally speaking, hydroxyl helps strengthening the insoluble medicine dissolubility, and the hydroxyl in the drug molecule is easily had an effect with the cyclodextrin that contains a plurality of hydroxyls, strengthens drug molecule and cyclodextrin inclusion compound effect and performance.The hydroxyl that increases in the molecule will exert an influence to its clathration and clathrate character (comprising lactonic ring active structure content and stability, deliquescent change etc.).But the cyclodextrin clathrate of hydroxy camptothecin yet there are no report at present; The solid clathrates of cyclodextrin/camptothecine and the solid clathrates of cyclodextrin/hydroxy camptothecin are not all appeared in the newspapers.
Summary of the invention
Purpose of the present invention: the enclose mechanism of exploring cyclodextrin and hydroxy-camptothecin base molecule, provide cyclodextrin and hydroxy camptothecin effect to generate the ratio and the method for clathrate by test, adopt various medicinal cyclodextrin and hydroxy camptothecin effect to generate and stablize clathrate, thereby obtain Indulion cyclodextrin/hydroxy camptothecin medicinal composition, improve dissolubility, the increase hydroxy camptothecin activated lactone ring structure content of hydroxy camptothecin.
The technical scheme of finishing the foregoing invention task is: adopt cyclodextrin to act on common hydroxy camptothecin raw material (63.2% lactonic ring structure) under aqueous conditions, prepare effective hydroxy camptothecin/cyclodextrin clathrate, enhanced activity lactonic ring stability, increase lactonic ring structural content, the dissolubility of raising hydroxy camptothecin.
More particularly, the present invention is: Indulion cyclodextrin/hydroxy camptothecin medicinal composition, the mol ratio of cyclodextrin and hydroxy camptothecin are 1: 0.1～1.0, the inclusion stability constant Ka=195M of different rings dextrin
-1～2264M
-1
Cyclodextrin in the above scheme is recommended to adopt: beta-schardinger dextrin-or HP-or sulphur butyl-beta-schardinger dextrin-, or wherein any two kinds and two or more mixture.
Further qualification to this enclose state combination thing, described Indulion cyclodextrin/hydroxy camptothecin medicinal composition, be meant: in the pure water suspension or solution of cyclodextrin, the hydroxy camptothecin that adds 0.1～1.0 mol ratio, fully mix, stirred filter pressing, washing, drying, the liquid clathrate that solid clathrates that obtains or Direct Filtration obtain 1～10 hour.
Prioritization scheme of the present invention is: the mol ratio of described cyclodextrin and hydroxy camptothecin adopted 1: 0.5; The pure water suspension or the solution of described cyclodextrin are meant: beta-schardinger dextrin-or HP-or sulphur butyl-beta-schardinger dextrin-or above any two or more mixture and the pure water of 1～6 times of quality suspension or solution of being mixed and made into.
The enclose feasibility: in the aqueous solution, cyclodextrin can form stable clathrate with hydroxy camptothecin.By the stability constant that forms clathrate under various cyclodextrin pH 2～7 conditions of the determined by ultraviolet spectrophotometry of classics, result: inclusion stability constant Ka=195M
-1～2264M
-1Illustrate that the effect of cyclodextrin inclusion compound hydroxy camptothecin is obvious, the clathrate good stability of formation.Infrared spectrogram and differential thermal analysis evidence, hydroxy camptothecin and cyclodextrin have formed clathrate, but not the simple physics mixture.The HPLC analysis of experiments shows, almost completely is converted into lactonic ring structure (lactonic ring content reaches more than 96%) with hydroxy camptothecin in the clathrate of the common hydroxy camptothecin feedstock production of lactonic ring structural content 63.2% under the pH7 condition.
Computer Simulation calculation is found, though hydroxy camptothecin lactonic ring structural energy is higher than the about 2.02Kcal/mol of open loop structure, but the Benexate Hydrochloride energy of lactonic ring structure is lower than the about 3.57Kcal/mol of open loop structure clathrate (lactonic ring structure clathrate is more stable), form behind the clathrate lactonic ring structure and discharge more energy (Duoing release 5.50Kcal/mol energy approximately) than the open loop structure clathrate, the result shows, the easier generation clathrate of lactonic ring structure, and because its stability stronger (energy difference 3.57Kcal/mol), the open loop structure clathrate has the possibility that is converted into lactonic ring structure clathrate.
It is as follows that the clathrate of hydroxy camptothecin prepares conventional method:
The pure water of cyclodextrin with 1～10 times of quality mixed, make suspension or solution, add the hydroxy camptothecin of 0.1～1.0 mol ratio, fully mix, filter pressing, stirred 1～10 hour, wash, be drying to obtain solid clathrates or Direct Filtration gets liquid clathrate.
The preferred following scheme of the present invention:
Beta-schardinger dextrin-or HP-or sulphur butyl-beta-schardinger dextrin-or above any two or more mixture are mixed with the pure water of 1～6 times of quality, make into suspension or solution; The hydroxy camptothecin that adds 0.5 mol ratio fully mixes, stirred 5～10 hours, filter pressing, the washing solids, be drying to obtain solid clathrates or filter liquid clathrate.
For verifying result of the present invention, we have carried out following test:
(1) measures hydroxy camptothecin and cyclodextrin inclusion compound constant under the different pH condition
Because the structure type of hydroxy camptothecin is relevant with system pH condition, the pH that considers medication changes probability, in pH2, under 4 and 7 conditions, adopt ultraviolet spectrophotometry (Wang Yana, Lu Yapeng, Ren Yong etc. the assay method of cyclodextrin and derivant/medicine enclose constant and application [J] thereof. the pharmacy progress, 2004,28 (1): 23.) measure the enclose constant of beta-schardinger dextrin-, HP-, sulphur butyl-beta-schardinger dextrin-and hydroxy camptothecin respectively, the results are shown in Table shown in 1.
Table 1: the enclose constant of different rings dextrin and hydroxypropyl camptothecine
| Cyclodextrin | Ka(M -1) | ||
| pH＝2 | pH＝4 | pH＝6.86 | |
| Beta-schardinger dextrin- | 231 | 195 | 2264 |
| HP- | 192 | 311 | 426 |
| Sulphur butyl-beta-schardinger dextrin- | 432 | 401 | 376 |
(2) preparation of clathrate
Hydroxy camptothecin is insoluble in water, and big dissolubility is arranged among the DMSO, can add organic solvent hydrotropy such as DMSO according to routine and prepare clathrate.Owing to organic solvent also can and be difficult to/can not remove the complete use (Wang Yana etc. that are unfavorable for medicine with cyclodextrin generation clathration, phenylpropanol/beta-cyclodextrin inclusion compound effect research [J]. China Medicine University's journal, 2005,36 (1): 13-17), therefore, the present invention adopts the pure water condition to prepare clathrate.
An end is hexa-atomic Alpha-hydroxy lactonic ring in the hydroxy-camptothecin base molecule, the other end is pyrroles's quinoline ring, CAChe 6.1.8 Worksystem Pro. computer molecular simulation program, the energy variation of calculating the clathration system of two kinds of structures of hydroxy camptothecin and beta-schardinger dextrin-sees Table 2.The result shows:
Table 2 hydroxy camptothecin lactonic ring/open loop structure energy and Benexate Hydrochloride energy
| Structure type | Energy (Kcal/mol) | |||
| Free state | Non-enclose attitude | The enclose attitude | Enclose can reduce | |
| Lactonic ring structure open loop structure | 38.0401 36.0246 | 431.6309 429.6534 | 413.5943 417.1646 | 18.0366 12.4888 |
The result shows: 1) hydroxy camptothecin lactonic ring structural energy is higher than the about 2.02Kcal/mol of open loop structure; 2) the Benexate Hydrochloride energy of lactonic ring structure is than the low about 3.57Kcal/mol of open loop structure clathrate; 3) enclose of lactonic ring structure energy (energy difference before and after the enclose) is greater than about 5.50Kcal/mol of open loop structure.Prompting, though two kinds of structures of hydroxy camptothecin can form clathrate with beta-schardinger dextrin-, but the lactonic ring structure has bigger energy advantage (thermodynamics is more favourable), and beta-schardinger dextrin-forms stable clathrate with lactonic ring structure preferential and hydroxy camptothecin.And unsettled open loop structure clathrate under optimum conditions, the possibility that the more stable lactonic ring structure clathrate of oriented energy transforms.
Because there are energy difference in two kinds of structure clathrates of hydroxy camptothecin, simultaneously the lactonic ring structure in water dissolubility less than the open loop structure thing.Therefore, adopt suitable rising system temperature or/and prolong preparation time and can accelerate or increase thaumatropy, reach raising and have the purpose of active lactonic ring structural content.Through the overtesting exploration discovery, prolong the littler lactonic ring structure clathrate of preparation time generation dissolubility and can prepare the high-load clathrate of lactonic ring structure smoothly.
The clathrate preparation method is given an example: the pure water of HP-with 3 times of amounts mixed, make into solution; The hydroxy camptothecin that adds 0.3 mol ratio fully mixes, stirred 7 hours, and placement is spent the night, filter pressing, and the washing solids is drying to obtain solid clathrates.
(3) clathrate differential thermal analysis demonstration test
The result shows: physical mixture has kept the endothermic peak of 96 ℃ of 310 ℃ of HP-and hydroxy camptothecins, is the stack of each chemical compound basically.And clathrate does not have the endothermic peak of 96 ℃ of hydroxy camptothecins, does not have the endothermic peak of 310 ℃ of HP-yet; 290 ℃ of system specific heats begin to increase, and system is promptly decomposed after 305 ℃ of little flex points that occur absorbing heat, and the position at its each peak (temperature) and shape (heat effect) the explanation clathrate have all taken place to change formed.The sample differential thermal analysis curve is seen accompanying drawing 1.
(4) the IR spectrogram is analyzed
In the hydroxy camptothecin IR collection of illustrative plates, ν=1748.26cm
-1Be carbonyl characteristic absorption (by force), in hydroxy camptothecin/hydroxypropyl-beta-cyclodextrin inclusion IR collection of illustrative plates, this characteristic absorption disappears substantially.Prompting: the carbonyl in the hydroxy camptothecin chemical constitution is wrapped up by the cavity of HP-.The IR spectrogram of hydroxy camptothecin and hydroxy camptothecin/hydroxypropyl-beta-cyclodextrin inclusion is seen accompanying drawing 2, Fig. 3.
(5) the phase solubility method is measured the solubilizing effect of each cyclodextrin to hydroxy camptothecin
Precision takes by weighing the 8.0mg hydroxy camptothecin, the DMSO dissolving also is settled to 100ml as storing solution, get the different volumes storing solution, become the serial solution of variable concentrations with pH6.86 mixed phosphate salt buffer dilution storing solution, 380nm measures uv absorption A down, to concentration C (mol/L) mapping drawing standard curve, get A=29920 C+0.0043 (r=1) with A.
Prepare 0.15% respectively, 0.3%, 0.6%, 0.9%, 1.5%, the beta-schardinger dextrin-solution and 2.0% of 1.8% (w/v), 4.0%, 8.0%, 16.0%, 24.0%, 30.0%, the HP-of 40.0% (w/v) (or sulphur butyl-beta-schardinger dextrin-) solution, in above-mentioned solution, add the excess of hydroxyl camptothecine respectively, ultrasonic 30min, 25 ℃ ± 1 ℃ vibration 5d, filter, pipette an amount of filtrate, the buffer dilution, the 380nm place measures optical absorption intensity, get the solubilising multiple of each cyclodextrin according to standard curve, the results are shown in following table hydroxy camptothecin.
Table 4: each cyclodextrin is to the solubilising multiple of hydroxy camptothecin
| Cyclodextrin (%) | Hydroxy camptothecin (mol/l) | The solubilising multiple | |
| Beta-schardinger dextrin-HP-sulphur butyl-beta-schardinger dextrin- | 0 0.15 0.3 0.6 0.9 1.5 1.8 2 4 8 16 24 30 40 25 | 5.49E-7 5.18E-7 6.52E-7 8.86E-7 1.387E-6 1.688E-6 2.86E-6 3.29E-6 6.59E-6 9.88E-6 2.14E-5 4.61E-5 6.81E-5 1.05E-4 7.30E-5 | 1 0.94 1.19 1.61 2.53 3.07 5.21 6 12 18 39 84 124 192 133 |
As can be seen from the table: because beta-schardinger dextrin-autolysis degree is low, the beta-schardinger dextrin-of 1.8% (w/v) (near saturated) can make 5.21 times of hydroxy camptothecin solubilisings; HP-is owing to its high water solublity (＞50%), and 30%～40% concentration can make 100～200 times of hydroxy camptothecin solubilisings.Illustrate, hydroxy camptothecin by the HP-enclose after, water solublity improves greatly, solubilising is up to 192 times, the result is better than the solubilizing effect of document to camptothecine.This is extremely beneficial to improving the hydroxy camptothecin bioavailability.
(6) the HPLC method is measured lactonic ring structural content in the clathrate
Chromatographic condition: chromatographic column: C18 post (Hanbon Science ﹠amp; Technology Co., Ltd; 250 * 4.6mm, 5 μ m); Mobile phase: 55% methanol-phosphate buffer (pH=4.0) flow velocity: 1ml/min; Detector: UV-detector, 25 ℃; Detect wavelength: 359nm; Sample size: 20 μ l; Sampling time: 30min.
The preparation of sample solution: sample solution a: with the pH=6.86 phosphate buffer is the hydroxy-camptothecin aqueous slkali of solvent; Sample solution b: the solid clathrates that treating excess syndrome is tested (2) preparation adds 10 times of ultrasonic 30min of water, filters; Sample solution c: with 0.1M NaOH is the hydroxy-camptothecin aqueous slkali of solvent.
Measure: get a, b, the c sample solution is measured by above-mentioned chromatographic condition sample introduction, the results are shown in Table 5 and accompanying drawing 4,5,6.
Table 5: the measurement result of lactonic ring structural content in the sample solution
| Sample solution | Content (%) | |
| The lactonic ring structure | Open loop structure | |
| a b c | 63.2 ＞96.8 ＜10 | 36.8 ＜3.2 ＞90 |
Found that, contain drug molecule content＞96.8% that exists with lactonic ring version in the pH=6.86 solution of hydroxypropyl-beta-cyclodextrin inclusion, the medicine lactonic ring structural content (63.2%) of hydroxy camptothecin in the aqueous solution that does not have HP-with pH=6.86.Hydroxy camptothecin mainly is a lactonic ring version in the clathrate.Utilize cyclodextrin inclusion technique, can improve hydroxy camptothecin active structure content greatly, this will be very favourable to improving the hydroxy camptothecin bioavailability.
(7) the UV spectrum is measured solution stability testing
Hydroxy camptothecin lactonic ring structure has significantly different UV with open loop structure and absorbs feature, showing as absworption peak wavelength and intensity has than obvious variation, adopting the UV spectrum also can reflect the various versions of hydroxy camptothecin, is the more simple structure determination method of relative HPLC.
With HCl preparation pH2,4 aqueous solutions, other gets the pure water of pH7, adds the excess of hydroxyl camptothecine respectively and is mixed with saturated solution a, b, c, and in addition treating excess syndrome is tested the clathrate that (2) make and is mixed with solution d with pure water, each solution is carried out UV scanning, and (200nm～400m) the results are shown in Table 6 and accompanying drawing 7.
Table 6: each hydroxy-camptothecin aqueous slkali UV scanning curve characteristic peak
| Sample solution | pH | Crest (nm) | Trough (nm) | Structure distribution |
| a b c d | 2 4 7 7 | 379、326、266、217 380、326、266、216 330、246、213 381、327、266、222 | 335、248 334、249 397、294、223 335、247 | The lactonic ring lactonic ring is many-the few lactonic ring of open loop-open ring lactone ring |
Absworption peak shows in the table, and the solution d of the solution a of pH=2 and clathrate preparation has the absorption feature of basically identical, and sample structure mainly is the lactonic ring form in the solution.
Above-mentioned all solution a, b, c and d are placed 4 ℃ of freezer storages after sterilization treatment, while clathrate room temperature preservation, 1.5 a year back UV scans the solution e that each solution and clathrate are prepared again, result of the test shows, the solution d of clathrate preparation almost overlaps with the e of preparation again, and, show that clathrate and stability of solution thereof are good with 0 day basic indistinction of spectrogram; Other sample spectrograms are constant substantially, but change to some extent in 200nm～210nm latter end absorption region peak shape.The result shows that each the hydroxy-camptothecin aqueous slkali that contains cyclodextrin is stable than the hydroxy camptothecin pure water solution, and it is obvious that cyclodextrin inclusion compound improves the medicine stability effect.
Advantage of the present invention
(1) after hydroxy camptothecin and cyclodextrin formed clathrate, the activated lactone ring structure content of hydroxy camptothecin was brought up to more than 96% by 63% of non-enclose attitude under the pH neutrallty condition.
(2) behind the cyclodextrin inclusion compound, the hydroxy-camptothecin alkali solubility is improved significantly, and the dissolubility raising reaches 192 times; Solid-state, the liquid sample stable content of enclose state are suitable for oral and non-peroral dosage form.
(3) clathrate of the present invention prepares under the pure water condition, does not use the organic solvent that is unfavorable for that clathrate forms, and has avoided organic solvent residual, helps improving drug safety.
(4) cyclodextrin clathrate stable in properties of the present invention, solid clathrates and other pharmaceutic adjuvant compatibilitys are good, are easy to compatibility agent processing.Liquid inclusion complex drug level height, the amount of preparation moderate contents is stable, is convenient to the preparation of preparation, and is practical.
(5) preparation method is simple, easy and simple to handle, cost is low and non-environmental-pollution.Clathrate easily stores easily transportation, nonhazardous.
Description of drawings
Fig. 1: differential thermogram.Wherein a is hydroxy camptothecin and hydroxypropyl-beta-cyclodextrin inclusion; B is hydroxy camptothecin and HP-physical mixture; C is a hydroxy camptothecin; D is a HP-.B has kept the endothermic peak of HP-and hydroxy camptothecin, is the stack of each chemical compound basically, and on a collection of illustrative plates, the position at each peak (temperature) and shape (heat effect) the explanation clathrate have all taken place to change formed
Fig. 2: hydroxy camptothecin IR spectrogram.Characteristic absorption peak ν=the 1748.26cm-1 of the carbonyl on the Alpha-hydroxy lactonic ring in the hydroxy camptothecin chemical constitution.
Fig. 3: hydroxy camptothecin/hydroxypropyl-beta-cyclodextrin inclusion IR spectrogram.In this figure, there is not the characteristic absorption peak ν=1748.26cm-1 of the carbonyl on the Alpha-hydroxy lactonic ring in the hydroxy camptothecin chemical constitution.The result proves absolutely that the Alpha-hydroxy lactonic ring in the hydroxy camptothecin chemical constitution is wrapped up by HP-.
Fig. 4: the pH=6.86 phosphate buffer is the HPLC collection of illustrative plates of the hydroxy-camptothecin aqueous slkali of solvent, and R=8.585min is the carboxylate structure form of hydroxy camptothecin among the figure, and R=12.367min is the lactone structure form of hydroxy camptothecin.
Fig. 5: contain the HPLC collection of illustrative plates of the hydroxy camptothecin pure water solution of HP-, R=12.326min is the lactone structure form of hydroxy camptothecin among the figure.This collection of illustrative plates shows hydroxy camptothecin because the parcel of cyclodextrin can effectively be protected the lactonic ring structure, thereby improve the drug molecule content that exists with lactonic ring version.
Fig. 6: with 0.1M NaOH is the HPLC collection of illustrative plates of the hydroxy-camptothecin aqueous slkali of solvent, and R=8.689min is the carboxylate structure form of hydroxy camptothecin among the figure.This collection of illustrative plates shows that in alkaline solution, hydroxy camptothecin mainly exists with carboxylate form.
Fig. 7: the hydroxy-camptothecin aqueous slkali that 0 day UV scintigram: a is pH=2; B is the hydroxy-camptothecin aqueous slkali of pH=4; C is the hydroxy-camptothecin aqueous slkali of pure water preparation; D is the solution of clathrate with the pure water preparation.
The specific embodiment
Embodiment 1: the 0.03mol beta-schardinger dextrin-is mixed with the 205ml pure water, add the 0.015mol hydroxy camptothecin, fully mix and stirred 5 hours, placed 24 hours; Filter, the washing solids, drying under reduced pressure promptly gets white solid inclusion compound.
Embodiment 2: the 0.03mol HP-is mixed with the 45ml pure water, add the 0.015mol hydroxy camptothecin, fully mix and stirred 1 hour, placed 24 hours; Filter, the washing solids, the solids drying under reduced pressure promptly gets white solid inclusion compound.
Embodiment 3: the 0.03mol beta-schardinger dextrin-is mixed with 0.01mol HP-and 55ml pure water, add the 0.015mol hydroxy camptothecin, fully mix and stirred 10 hours, placed 24 hours; Filter, the washing solids, the solids drying under reduced pressure promptly gets white solid inclusion compound.
Embodiment 4: basic identical with EXAMPLE l, but mix with the 340ml pure water.
Embodiment 5: substantially the same manner as Example 1, but add the 0.003mol hydroxy camptothecin, mix and stirred 10 hours.
Embodiment 6: substantially the same manner as Example 2, but use 0.03mol sulphur butyl-beta-schardinger dextrin-.
Embodiment 7: substantially the same manner as Example 2, but use the 0.1mol HP-.
Embodiment 8: substantially the same manner as Example 2, but use 0.1mol sulphur butyl-beta-schardinger dextrin-.
Embodiment 9: substantially the same manner as Example 2, but use the 0.06mol HP-.
Embodiment 10: substantially the same manner as Example 2, but use 0.06mol sulphur butyl-beta-schardinger dextrin-.
Embodiment 11: substantially the same manner as Example 2, but use the 0.09mol HP-, stirred 10 hours, Direct Filtration gets liquid clathrate then.
Embodiment 12: substantially the same manner as Example 2, but with 0.09mol sulphur butyl-beta-schardinger dextrin-, stirring 10 hours, Direct Filtration gets liquid clathrate then.
Embodiment 13: substantially the same manner as Example 11, but use the 0.12mol HP-.
Embodiment 14: substantially the same manner as Example 12, but use 0.12mol sulphur butyl-beta-schardinger dextrin-.
Embodiment 15: substantially the same manner as Example 3, but replace HP-with 0.01mol sulphur butyl-beta-schardinger dextrin-.
Embodiment 16: substantially the same manner as Example 3, but add 0.01mol sulphur butyl-beta-schardinger dextrin-mixed inclusion again.
Embodiment 17: substantially the same manner as Example 3, but use the 0.06mol HP-, add 0.06mol sulphur butyl-beta-schardinger dextrin-mixed inclusion again.
Embodiment 18: substantially the same manner as Example 17, but use 0.06mol HP-and 0.006mol sulphur butyl-beta-schardinger dextrin-mixed inclusion.
Embodiment 19: substantially the same manner as Example 17, but use 0.006mol HP-and 0.06mol sulphur butyl-beta-schardinger dextrin-mixed inclusion.
Claims (6)
1, a kind of Indulion cyclodextrin/hydroxy camptothecin medicinal composition, wherein, the mol ratio of cyclodextrin and hydroxy camptothecin is 1: 0.1～1.0, inclusion stability constant Ka=195M
-1～2264M
-1
2, according to the described Indulion cyclodextrin/hydroxy camptothecin medicinal composition of claim 1, it is characterized in that, described cyclodextrin adopts: beta-schardinger dextrin-or HP-or sulphur butyl-beta-schardinger dextrin-, or wherein any two kinds and two or more mixture.
3, according to the described Indulion cyclodextrin/hydroxy camptothecin medicinal composition of claim 1, it is characterized in that, described Indulion cyclodextrin/hydroxy camptothecin medicinal composition, be meant: in the pure water suspension or solution of cyclodextrin, the hydroxy camptothecin that adds 0.1～1.0 mol ratio fully mixes, filter pressing, stirring 1～10 hour, filter washing, drying, the liquid clathrate that solid clathrates that obtains or Direct Filtration obtain.
According to the described Indulion cyclodextrin/hydroxy camptothecin medicinal composition of claim 1, it is characterized in that 4, the mol ratio of described cyclodextrin and hydroxy camptothecin adopted 1: 0.5; The pure water suspension or the solution of described cyclodextrin are meant: beta-schardinger dextrin-or HP-or sulphur butyl-beta-schardinger dextrin-or above any two or more mixture and the pure water of 1～6 times of quality suspension or solution of being mixed and made into.
5, the preparation method of the described Indulion cyclodextrin/hydroxy camptothecin medicinal composition of a kind of claim 1, step is as follows:
The pure water of cyclodextrin with 1～10 times of quality mixed, make suspension or solution, add the hydroxy camptothecin of 0.1～1.0 mol ratio, fully mix, filter pressing, stirred 1～10 hour, wash, be drying to obtain solid clathrates or Direct Filtration gets liquid clathrate.
According to the preparation method of the described Indulion cyclodextrin/hydroxy camptothecin medicinal composition of claim 1, it is characterized in that 6, described preparation process is:
Beta-schardinger dextrin-or HP-or sulphur butyl-beta-schardinger dextrin-or above any two or more mixture are mixed with the pure water of 1～6 times of quality, make into suspension or solution; The hydroxy camptothecin that adds 0.5 mol ratio fully mixes, stirred 5～10 hours, filter pressing, the washing solids, be drying to obtain solid clathrates or filter liquid clathrate.
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