CN103611166B - 9-nitrocamptothecin-cyclodextrin clathrate and preparation method thereof and the pharmaceutical composition containing this clathrate - Google Patents
9-nitrocamptothecin-cyclodextrin clathrate and preparation method thereof and the pharmaceutical composition containing this clathrate Download PDFInfo
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Abstract
For 9-nitrocamptothecin poor solubility in prior art, technical problem that bioavailability is low, the invention provides 9-NC-cyclodextrin clathrate, it contains active component 9-NC and inclusion agents β-CD or derivatives thereof that molecule mol ratio is 1:30 ~ 200; Concrete preparation method is: be added drop-wise in CD solution by 9-NC acetone saturated solution, and is stirred to acetone at 25 ~ 60 DEG C of lower magnetic forces and volatilizees completely; Get supernatant after gained suspension is centrifugal to carry out lyophilization and obtain 9-NC-CD clathrate powder.The invention provides the pharmaceutical composition containing above-mentioned 9-NC-CD clathrate and pharmaceutically acceptable excipient simultaneously.Clathrate provided by the invention increases by more than 300 times compared to 9-NC free drug dissolubility; Clathrate shows higher lactone stability and external slow release effect simultaneously; Show that in clathrate, 9-NC is completely by enclose with X-ray diffraction analysis and thermal analysis system, further the reliability of checking technique.Thus, clathrate can be developed to as liquid preparation, also can improve the body absorption of 9-NC solid preparation, improves bioavailability.
Description
Technical field
The invention belongs to Western medicine pharmaceutical arts, be specifically related to 9-nitrocamptothecin-cyclodextrin clathrate and preparation method thereof and the pharmaceutical composition containing this clathrate.
Background technology
9-nitrocamptothecin (9-nitrocamptothecin, 9-NC) have another name called rubitecan, be the novel camptothecin derivatives of Supergen company of U.S. development, be still in clinical experimental stage at present, this medicine of preclinical pharmacology research display of 9-NC is ideal antitumor drug.Camptothecine all also exists the balance (as Fig. 1) of lactone type and these two kinds of forms of carboxylic acid type in humans and animals body, and lactone type is the generally acknowledged chief active form with antitumous effect, and carboxylic acid type is invalid form [1].
But the slightly solubility of 9-NC, unstability, low bioavailability limit the exploitation of its liquid preparation as injection, it is also the main cause hindering its effect; After quiet note, because its slightly solubility can cause 9-NC effective ingredient to be degraded soon in blood.For improving the dissolubility of 9-NC and bioavailability, have researcher to be prepared into liposome, have 9-NC to be loaded in nanoparticle, also useful HP-β-CD be that enclose material freeze-drying prepares 9-NC clathrate.
Wherein, clathrate is point ascus utilizing enclose material to be contained in by drug molecule to be formed in the hole of self.Beta-schardinger dextrin-is conventional enclose material, and it is the cyclic compound being combined the truncated cone formed by 7 glucose units, has the characteristic that the hydrophobic outer wall of inner chamber is hydrophilic.Medicine can improve its dissolubility, stability after enclose, improves the bioavailability of medicine, reduces zest and the toxic and side effects of medicine.The intermediate product that clathrate can be used as preparation makes the various dosage forms such as capsule, granule, tablet, ointment, suppository, injection, oral liquid further.
Jiang Ye, Sha Xianyi, Zhang Wei etc. adopt freeze-drying to prepare 9-nitrocamptothecin HP-β-CD lyophilized injectable powder (Jiang Ye, Sha Xianyi, research [C] .2010 China's pharmacy conference of the .9-nitrocamptothecin hydroxypropyl-cyclodextrin lyophilized injectable powders such as Zhang Wei and the tenth Chinese pharmacists week collection of thesis .2010.1-8), its dissolubility in water reaches 0.52mgml
-1.
Summary of the invention
For solving 9-NC poor solubility, technical problem that bioavailability is low in existing preparation technique, the invention provides 9-nitrocamptothecin-cyclodextrin clathrate, object is the water solublity improving 9-NC, can be developed to as liquid preparation, thus adapts to difference needs clinically; Also can improve the body absorption of 9-NC solid preparation simultaneously, improve its bioavailability.
9-nitrocamptothecin-cyclodextrin clathrate provided by the invention, containing active component 9-nitrocamptothecin and inclusion agents beta-schardinger dextrin-or its derivant, wherein the molecule mol ratio of active component 9-nitrocamptothecin and inclusion agents beta-schardinger dextrin-or its derivant is 1:30 ~ 200; Wherein, the derivant of inclusion agents beta-schardinger dextrin-is selected from HP-β-CD, hydroxyethyl-β-cyclodextrin.2,6-DM-β-CD, 2,3,6-TM-β-CD, 2,6-DE-β-CDs, 2,3,6-triethyl group-beta-schardinger dextrin-or malt sugar group-beta-cyclodextrin.
As a further improvement on the present invention, the molecule mol ratio of active component 9-nitrocamptothecin and inclusion agents beta-schardinger dextrin-or its derivant is 1:120 ~ 180.
Further improve as of the present invention, the molecule mol ratio of active component 9-nitrocamptothecin and inclusion agents beta-schardinger dextrin-or its derivant is 1:120.
Improve as another kind of the present invention, the derivant of inclusion agents beta-schardinger dextrin-is HP-β-CD.
The present invention also provides the preparation method of above-mentioned 9-nitrocamptothecin-cyclodextrin clathrate, comprises the steps:
1) 9-nitrocamptothecin is made acetone saturated solution;
2) take cyclodextrin or derivatives thereof according to corresponding molecule mol ratio, and soluble in waterly make cyclodextrin solution;
3) 9-nitrocamptothecin acetone saturated solution is slowly dropwise added drop-wise in cyclodextrin solution, and is stirred to acetone at 25 ~ 60 DEG C of lower magnetic forces and volatilizees completely to obtain suspension;
4) suspension by obtained is centrifugal, gets supernatant and carries out lyophilization and obtain 9-nitrocamptothecin-cyclodextrin clathrate powder.
As the further improvement of this preparation method, the volume of cyclodextrin solution described in step (2) is 40% ~ 60% of 9-nitrocamptothecin acetone saturated solution.
As the further improvement of this preparation method, the derivant of above-mentioned inclusion agents beta-schardinger dextrin-is HP-β-CD, and its concentration is 0.507mmol/mL (i.e. 700mg/mL); Described in step (3), magnetic agitation temperature is 60 DEG C; The total elapsed-time standards of step (3), namely the enclose time is 2h.
The present invention protects the 9-nitrocamptothecin-cyclodextrin clathrate with gained prepared by above-mentioned preparation method simultaneously.
Finally, the invention provides a kind of pharmaceutical composition, it contains above-mentioned 9-nitrocamptothecin-cyclodextrin clathrate and pharmaceutically acceptable excipient.
Beneficial effect
Compared with prior art, 9-NC-beta-CD inclusion prepared by the present invention, the dissolubility of 9-NC in water is improved greatly: after measured, under 9-NC-HP-beta-CD inclusion provided by the invention 25 DEG C of conditions, the dissolubility of 9-NC is up to 3.8455mg/mL, is that in existing bibliographical information, 9-NC dissolubility is the highest; For Jiang Ye, Sha Xianyi, dissolubility 0.52mg/mL (the Jiang Ye of the disclosed clathrate such as Zhang Wei, Sha Xianyi, the research of the .9-nitrocamptothecin HP-β-CD lyophilized injectable powders such as Zhang Wei .) 7.395 times, more the dissolubility 0.0127mg/mL of specific ionization medicine adds more than 300 times, and effect is significantly beyond thought.Clathrate provided by the invention makes 9-NC dissolubility greatly improve, and improves the water-fast character of 9-NC of single component, improves the dissolution of 9-NC, thus improves bioavailability, and its concentration meets the demand of clinical injection medication completely.
Also significantly increased the lactone stability of 9-NC by the form of clathrate simultaneously, also namely there is through cyclodextrin inclusion compound the effect of stable 9-NC lactone type, thus the direction that the balance between two kinds of forms is improved to the clinical effective form lactone type ratio of checking is moved; Simultaneously 9-NC cyclodextrin clathrate provided by the invention has significant slow release effect compared to free 9-NC medicine, improves condition of storage thus, extends and stores effect duration, is more conducive to its subsequent operations in pharmacy, is convenient to industrialized great production.
This may be because clathration is mainly derived from Van der Waals force; when 9-NC molecule embeds the hydrophobic and molecular cavities that upper and lower both ends open place is hydrophilic of the inner chamber of beta-schardinger dextrin-or its derivant; 9-NC molecule and beta-schardinger dextrin-or its derivant enclose; do not affect the molecular structure of beta-schardinger dextrin-or its derivant; this has just cut off contacting of bioactive molecule and surrounding, serves protection and stable effect.
Accompanying drawing explanation
Figure 19-nitrocamptothecin lactone type (left side) and carboxylic acid type (right side) balance
9-NC medicament contg graph of a relation (n=3) in Figure 29-NC:HP-β-CD molecule mol ratio and clathrate
Fig. 3 X-ray diffraction result
Fig. 4 DSC result figure
The mensuration of Figure 59-NC clathrate Chinese medicine lactone type ratio, the wherein spectrogram of A-total concentration, the spectrogram of beta-lactones type concentration, peak 1-lactone type spectrogram in chromatogram, peak 2-carboxylic acid type spectrogram.
Figure 69-NC clathrate compares (n=3) with free drug lactone stability
Figure 79-NC clathrate compares (n=3) with free drug vitro release
Detailed description of the invention
Further illustrate the present invention below in conjunction with drawings and Examples, wherein part preparation condition is only the explanation as typical case, is not limitation of the invention.
The phase solubility-curve of embodiment 19-NC and HP-β-CD (HP-β-CD) is tested
Not commensurability HP-β-CD is dissolved in 3mLPBS (pH5.0), be mixed with the HP-β-CD solution of a series of concentration, be placed in tool plug test tube, often add excessive 9-NC in pipe, respectively at 25 DEG C, 37 DEG C, 60 DEG C water bath with thermostatic control vibration 48h, get suspension, the centrifugal 10min of 12000rpm, get supernatant, measure absorbance, calculating concentration.With the concentration of 9-NC (mmol/L) for vertical coordinate, the concentration (mmol/L) of HP-β-CD is abscissa, and the equilibrium phase solubility curve at drawing 25 DEG C, 37 DEG C, 60 DEG C, the results are shown in Table 1.
Phase solubility-curve under table 1 different temperatures
Table1Phasesolubilitycurveunderdifferenttemperature
As can be seen from Table 1, phase solubility-curve is all linear, therefore can determine 9-NC and HP-β-CD in clathration process with 1:1 enclose; And stability constant is the highest 60 DEG C time, if control preparation temperature in experimentation to be greater than 60 DEG C, so moisture evaporation is unfavorable for the formation of clathrate too soon, therefore selects 60 DEG C of temperature prepared as clathrate.
Embodiment 2 primary dcreening operation 9-NC:HP-β-CD molecule mol ratio: prepare 9-nitrocamptothecin-cyclodextrin clathrate, step is as follows:
1) 9-NC is made acetone saturated solution 10ml, prepare 13 parts, namely 14.9mg9-NC is dissolved in 10ml acetone soln in every part, and wherein the amount of substance of 9-NC is 0.03788mmol;
2) be the amount that 1:30,50,60,80,100,110,120,130,140,150,160,180,200 takes cyclodextrin according to 9-NC:HP-β-CD molecule mol ratio respectively, and be dissolved in respectively in 5ml water and make cyclodextrin solution;
3) 13 parts of 9-NC acetone saturated solutions are slowly dropwise added drop-wise in the cyclodextrin solution of 13 parts of different cyclodextrin concentrations respectively, and are stirred to acetone at 60 DEG C of lower magnetic forces and volatilize completely to obtain suspension;
4) the centrifugal 10min of suspension 2000r.p.m that will be obtained, get supernatant and carry out lyophilization and obtain 9-NC-cyclodextrin clathrate powder, clathrate powder is soluble in water.
5) precision takes 25.00mg cyclodextrin clathrate powder, with dissolve with methanol standardize solution to 10mL, under 373nm wavelength, measures absorbance, calculates the content of dispersion in clathrate.
Step 1) in the selection of 9-NC solvent: consider that the solvent dissolving insoluble drug 9-NC needs it to have relatively large dissolubility to 9-NC, this solvent needs volatile in follow-up enclose step simultaneously, through the screening of preliminary experiment in advance, cause follow-up enclose product yield too low because the dissolubility of 9-NC in ethanol, methanol is too little, so select dissolubility relatively maximum and volatile acetone as the solvent of 9-NC, and prepare 9-NC acetone saturated solution.
Step 2) in the selection of 9-NC:HP-β-CD molecule mole ratio: from the phase solubility-curve described in embodiment 1,9-NC and HP-β-CD is with ratio 1 ﹕ 1 enclose; But known by trial test in early stage, if select 9-NC and HP-β-CD with mol ratio 1 ﹕ 1 enclose, then clathrate productive rate is very low, does not almost detect, and contacts with it and the chance of enclose so the ratio that need strengthen HP-β-CD increases 9-NC thus.
Step 3) in the selection of dropping method: 1. trial test in early stage compares just drips: be added drop-wise in cyclodextrin solution by 9-NC acetone saturated solution; 2. instead to drip: cyclodextrin solution is added drop-wise in 9-NC acetone saturated solution; Enclose effect, experiment confirm, just dripping enclose better effects if, just dripping so select.
The experimental result of primary dcreening operation 9-NC:HP-β-CD molecule mol ratio is shown in Fig. 2, in figure be classified as the relation of 9-NC medicament contg in 9-NC:HP-β-CD molecule mol ratio and finished product clathrate, as seen from the figure in the scope of mol ratio 1:30 ~ 1:200, the content of 9-NC in clathrate is normal distribution substantially, especially in mol ratio in 1:110 ~ 1:180, medicament contg is higher, can reach more than 1.5mg/g.
Embodiment 3 orthogonal experiment optimizes best preparation technology parameter
By embodiment 2 acquired results, further with the preferred clathrate process of orthogonal, to influence factor: the concentration of aqueous solution (C) of the Host-guest ratio (A) of medicine and HP-β-CD, enclose time (B) and HP-β-CD is investigated.With L9 (3
4) orthogonal table experiment arrangement, preferred for inspection target carries out clathrate process with 9-NC content of dispersion in finished product clathrate.Each factor level table, in table 2, the results are shown in Table 3.
The factor of table 2 orthogonal test and level
Table2Factorsandlevelsoforthogonaltest
The result of table 3 orthogonal test
Table3Theprogramsandresultsoforthogonaltest
Orthogonal experiments shows, and best clathrate process is A
1b
2c
3, i.e. medicine: HP-β-CD=1:120, the enclose time is 2h, HP-β-CD concentration is 700mg/mL (i.e. 0.507mmol/mL).
The reliability of checking Orthogonal experiment results: verify according to best clathrate process condition, result is all higher than Orthogonal experiment results, and absolute medicament contg average out to 2.642mg/g, RSD are 3.0% (n=5), show that this process stabilizing is feasible.
The best preparation technology of embodiment 49-NC-HP-beta-CD inclusion
Determine that the best preparation technology of 9-NC-HP-beta-CD inclusion is as follows by the screening of embodiment 1 ~ 3:
1) 9-NC is made acetone saturated solution;
2) take HP-β-CD according to 9-NC:HP-β-CD molecule mol ratio=1:120, and concentration of making soluble in water is 700mg/mL cyclodextrin solution;
3) be slowly dropwise added drop-wise in cyclodextrin solution by 9-NC acetone saturated solution, and stir at 60 DEG C of lower magnetic forces, the rotating speed of control 500r/min, the enclose time is total up to 2h, and now acetone volatilizees to obtain suspension completely;
4) suspension by obtained is centrifugal, gets supernatant and carries out lyophilization and obtain 9-NC-HP-beta-CD inclusion powder.
The sign of embodiment 59-nitrocamptothecin-cyclodextrin clathrate
(1) preparation of sample
Get 9-NC, HP-β-CD, verify with the physical mixture (i.e. 9-NC:HP-β-CD molecule mol ratio=1:120) of clathrate 9-NC and HP-β-CD in proportion and the 9-NC clathrate powder of preparing gained by embodiment 4.
(2) X-ray diffraction
X-ray diffraction analysis utilizes crystal formation X-ray diffraction, carries out the structure analysis method of interior atoms at spatial distribution state to material.By there is certain wavelength x-ray bombardment to crystal material time, X-ray because running into regularly arranged atom or ion and scattering occurring in crystallization, the X-ray of scattering in a certain direction phase place is strengthened, thus the distinctive diffraction that display is corresponding with crystalline texture.
X-ray diffraction is carried out to sample, the results are shown in Figure 3, be followed successively by physical mixture, 9-NC clathrate, HP-β-CD and 9-NC from top to bottom, by finding out in Fig. 3 that in physical mixture, 9-NC drug level is low, major part diffraction maximum by HP-β-CD cover, but the appearance of identical characteristic peak (being circled part in see figure) is still had in identical position, and in the collection of illustrative plates of clathrate, there is not the characteristic peak of 9-NC, this 9-NC is described by HP-β-cdinclusion, clathrate is outside without free 9-NC.
(3) thermal analysis system
Thermal analyses refers under temperature programmed control, the temperature variant class technology of physical property of measurement of species.By detecting the thermophysical property of sample itself with temperature or the change of time, study the change etc. of the molecular structure of material, aggregated structure, molecular motion.To the sample of thing phase change be had and not undergo phase transition in measured temperature range and the reference substance produced without any heat effect, carry out isothermal heating or cooling at identical conditions, when sample undergoes phase transition, between sample and reference substance, just produce a temperature difference.Namely the one group of differential thermocouple be positioned over below them produces thermoelectric force U Δ T, power back-off amplifier is sent into after differential thermal amplifier amplifies, power back-off amplifier regulates the electric current compensating heater strip automatically, and the temperature difference between sample and reference substance is gone to zero, and both temperature remain identical all the time.This heat compensation is the heat effect of sample, is shown on monitor with electrical power form.
Thermal analysis system scanning is carried out to sample, test condition: differentia scanning calorimetry (DSC), with N
2for protection gas, heating rate 10 DEG C/min, alumina crucible, temperature range 25-300 DEG C; Acquired results is shown in Fig. 4, only has an exothermic peak in the curve of HP-β-CD and 9-NC respectively, has HP-β-CD and 9-NC two exothermic peaks, and only has an exothermic peak in clathrate, 9-NC is described by enclose in physical mixture.
Embodiment 6 clathrate character is investigated
(1) mensuration of clathrate dissolubility
After preparing 9-NC clathrate according to the preparation technology of embodiment 4, get excessive 9-NC and clathrate powder dissolution respectively in 1.0mL pure water, after ultrasonic 1h, vibration 9h, saturated solution being crossed 0.45 μm of microporous filter membrane removes not by after the 9-NC medicine that dissolves, drug level is measured after getting part of dilution certain multiple, as calculated, the dissolubility of 9-NC in 25 DEG C of water is 0.0127mg/mL, the dissolubility of 9-NC clathrate in water is 3.8455mg/mL, and namely after enclose, the dissolubility of 9-NC in water at least increases more than 300 times.Contrast the 9-NC clathrate (Jiang Ye in existing bibliographical information simultaneously, Sha Xianyi, the research of the .9-nitrocamptothecin HP-β-CD lyophilized injectable powders such as Zhang Wei), its dissolubility is 0.52mg/m, the invention provides the dissolubility of 9-NC in clathrate, to compare in it be 7.395 times, and effect is significantly beyond thought.
(2) HPLC analytical method and the result of 9-NC is set up
Chromatographic condition chromatographic column: MerckC18 post (150mm × 4.6mm, 5 μm) (Merck & Co., Inc.); Mobile phase: acetonitrile-0.1% triethylamine (pH6.5 adjusted by glacial acetic acid) (35:65); Flow velocity: 1.0mL/min; Sample size: 20 μ L; Column temperature: 40 DEG C; Determined wavelength: 376nm.
Measure 9-NC lactone type concentration and take 500mg clathrate powder, dissolve with pure water and be settled to 10mL, accurate absorption 1.0mL, join in 9.0mLPBS (pH7.4), 200 μ L are got in mixing immediately, then add 400 μ L ice (-20 DEG C) methanol-acetonitrile (1:1, v/v), the centrifugal 3min of vortex 1min, 12000r/min, gets supernatant and measures.
The supernatant measured after the above-mentioned process of 9-NC total concentration (lactone type+carboxylic acid type) precision absorption is appropriate, by supernatant: glacial acetic acid=9:1 (v/v) precision adds glacial acetic acid acidify, shake up, now all 9-NC medicines are all converted into lactone type, and sample introduction measures immediately; Namely concentration × 10/9 recorded obtains total concentration.
Result: HPLC schemes as Fig. 5, as shown in Figure 5, before sample acidify (B figure), namely lactone type is had also to have carboxylic acid type, after acidify (A figure), 9-NC medicine is all converted into lactone type, loses carboxylic acid type peak, illustrate with this HPLC analytical method measure 9-NC clathrate Chinese medicine lactone type content and total content reliable.
(3) investigation of 9-nitrocamptothecin-cyclodextrin clathrate lactone stability
Employing is prepared the redissolution of gained 9-NC-cyclodextrin clathrate powder water and is mixed with certain density drug solution, with the solution dilution 10 times of the isotonic PBS of pH7.4, place 37 DEG C of water-bath lucifuges, then sample in different time points, standardize solution is diluted with the PBS (=9:1) of methanol: pH6.5, under-20 DEG C of conditions, lucifuge is deposited, and after the freezing high speed centrifugation 5min of 12000rpm, HPLC measures lactone type concentration.
Sample 0.9mL after above-mentioned process adds the acidify of 0.1mL glacial acetic acid, vortex 30s, now in sample, 9-NC is all converted into lactone type, and HPCL working sample content is medicine total concentration (lactone type+carboxylic acid type), then lactone type ratio=lactone type concentration/total concentration × 100%.
Be measured in the same method the lactone stability of free 9-NC medicine, 9-NC DMSO is diluted with water to isoconcentration after dissolving.The results are shown in Figure 6, as shown in Figure 6, its lactone stability of the clathrate that 9-NC is formed after cyclodextrin inclusion compound increases significantly compared to the free 9-NC of non-enclose, the speed that now lactone type open loop changes carboxylic acid type into obviously slows down, that is there is through cyclodextrin inclusion compound the effect of stable 9-NC lactone type, thus the direction that the balance between two kinds of forms is improved to the clinical effective form lactone type ratio of checking is moved.
(4) 9-nitrocamptothecin-cyclodextrin clathrate vitro release test
Adopt magnetic agitation method, employing is prepared the redissolution of gained 9-NC-cyclodextrin clathrate powder water and is mixed with certain density drug solution, get and be placed in different bag filter in right amount, tighten, be placed in release medium (containing the pH7.4 isotonic buffer solution of 0.05% Tween 80, containing 140mMNaCl, 8mMNa in prescription
2hPO
4, 1mMNaH
2pO
4) in, drug release under 37 DEG C of temperature constant magnetic stirring conditions, samples 0.9mL in different time points and adds the acidify of 0.1mL glacial acetic acid, and 1h, HPLC method of placing measures its concentration, calculates cumulative release percent.
Be measured in the same method the accumulation release in vitro percent of free 9-NC medicine, 9-NC DMSO is diluted with water to isoconcentration after dissolving.The results are shown in Figure 7, as shown in Figure 7, the clathrate that 9-NC is formed after cyclodextrin inclusion compound has significant slow release effect compared to the free 9-NC of non-enclose.
Claims (7)
1. the preparation method of 9-nitrocamptothecin-cyclodextrin clathrate, it is characterized in that: containing active component 9-nitrocamptothecin and inclusion agents HP-β-CD, its molecule mol ratio is 1:110 ~ 140, and adopt saturated water solution method preparation, concrete steps are as follows:
1) 9-nitrocamptothecin is made acetone saturated solution;
2) take HP-β-CD according to corresponding molecule mol ratio, and soluble in waterly make cyclodextrin solution;
3) 9-nitrocamptothecin acetone saturated solution is slowly dropwise added drop-wise in cyclodextrin solution, and is stirred to acetone at 25 ~ 60 DEG C of lower magnetic forces and volatilizees completely to obtain suspension;
4) suspension by obtained is centrifugal, gets supernatant and carries out lyophilization and obtain 9-nitrocamptothecin-cyclodextrin clathrate powder.
2. the preparation method of 9-nitrocamptothecin-cyclodextrin clathrate as claimed in claim 1, is characterized in that: the molecule mol ratio of described active component 9-nitrocamptothecin and inclusion agents HP-β-CD is 1:120.
3. the preparation method of 9-nitrocamptothecin-cyclodextrin clathrate as claimed in claim 1 or 2, is characterized in that:
The volume of cyclodextrin solution described in step (2) is 40% ~ 60% of 9-nitrocamptothecin acetone saturated solution.
4. the preparation method of 9-nitrocamptothecin-cyclodextrin clathrate as claimed in claim 1 or 2, is characterized in that:
Described HP-β-CD solution concentration is 0.507mmol/mL; Described in step (3), magnetic agitation temperature is 60 DEG C; The total elapsed-time standards of step (3), namely the enclose time is 2h.
5. the preparation method of 9-nitrocamptothecin-cyclodextrin clathrate as claimed in claim 3, is characterized in that: described HP-β-CD solution concentration is 0.507mmol/mL; Described in step (3), magnetic agitation temperature is 60 DEG C; The total elapsed-time standards of step (3), namely the enclose time is 2h.
6. 9-nitrocamptothecin-cyclodextrin clathrate, is characterized in that: use method any one of claim 1 ~ 5 to prepare gained.
7. a pharmaceutical composition, is characterized in that: contain 9-nitrocamptothecin-cyclodextrin clathrate and pharmaceutically acceptable excipient as claimed in claim 6.
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| CN102000080A (en) * | 2010-09-21 | 2011-04-06 | 江苏先声药物研究有限公司 | Method for solubilizing camptothecin compound |
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