CN109821027A - A method of preparing hesperetin/HP- beta-CD inclusion - Google Patents
A method of preparing hesperetin/HP- beta-CD inclusion Download PDFInfo
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- CN109821027A CN109821027A CN201910307186.8A CN201910307186A CN109821027A CN 109821027 A CN109821027 A CN 109821027A CN 201910307186 A CN201910307186 A CN 201910307186A CN 109821027 A CN109821027 A CN 109821027A
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Abstract
Hesperetin/HP- beta-CD inclusion method is prepared the invention discloses a kind of, the following steps are included: (1) prepares hesperetin-carrier mixed solution: weighing hesperetin bulk pharmaceutical chemicals and water-solubility carrier is dissolved in organic solvent, obtain hesperetin-carrier mixed solution；(2) by CO2It is passed through crystallization kettle, adjusts temperature and pressure in crystallization kettle；(3) continue to be passed through CO2, while the hesperetin-carrier mixed solution of step (1) preparation being sprayed into inside crystallization kettle at the top of crystallization kettle by nozzle by high pressure pump；(4) after sample introduction, continue to be passed through CO2Crystallization kettle is opened in certain time, release, collects product.Hesperetin prepared by the present invention/HP- beta-CD inclusion dissolution rate with higher, bioavilability and stability overcomes the generally existing organic solvent residual problem of traditional technology, and operating condition is easily controllable, biotic component not easy in inactivation, and process green high-efficient.
Description
Technical field
The invention belongs to field of pharmaceutical engineering, and in particular to a method of prepare hesperetin/HP- beta-CD inclusion.
Background technique
Hesperetin (Hesperetin) is a kind of natural flavonoid compound, is mainly derived from Rutaceae Citrus young fruit.
Hesperetin has a variety of pharmacological activity such as antitumor, anti-oxidant, reducing blood lipid, anti-inflammatory and improvement blood-brain barrier, is widely used in
The every field of medicine.Hesperetin has stomach invigorating, eliminating the phlegm, antibechic, wind dispelling, diuresis, antiviral, antibacterial, non-return and only stomach simultaneously
A series of medicinal functions such as pain have very high economic value.Since hesperetin is not readily dissolved in water, cause its dissolution rate slow,
Bioavilability reduces, and possessed bioactivity cannot fully play.Therefore improve the dissolution that dissolving out capability improves drug
Degree, to improve bioavilability with definite meaning.
Hydroxypropyl-β-cyclodextrin (HP- β-CD) is a kind of etherification derivative of current common cyclodextrin, Cheng Wuding
Shape is highly soluble in water.Its intramolecular has a hydrophobic pocket, can embed to active material, has very to slightly solubility substance
Good solubilizing effect, and its stability is improved, promote active material to discharge in vivo, increase and absorb, improves bioavilability.
Its is highly-safe simultaneously, injection irritation is small, reduce toxic side effect, without hemolytic or many advantages, such as irritation, becomes and grinds
Study carefully most, the widest beta-cyclodextrin derivative of application range.Preparing medicinal inclusion compound by hydroxypropyl-β-cyclodextrin at present is
The solubility for improving insoluble drug, to improve one of effective ways of bioavilability.
Supercritical anti-solvent (SupercriticalAnti-solvent, SAS) technology, which refers to, is dissolved in organic solution solute
Middle formation solution selects a kind of supercritical fluid that can dissolve each other well with solvent, but does not dissolve in solute, supercritical fluid conduct
Anti-solvent, when supercritical fluid contacts with each other with solution, fluid is diffused into solution, and solvent volume is caused to expand rapidly, molten
The solubility of matter in a solvent declines rapidly, forms higher degree of supersaturation within a short period of time, promotes lolute crystallization that grain is precipitated
A kind of novel particle preparation method of the lesser ultrafine dust of diameter, has shown in terms of preparing ultra-fine grain and composite particles in recent years
Huge application potential is shown.Compared to traditional handicraft, it has operating condition easily controllable, prepare resulting diameter of particle it is small and
The advantages that narrowly distributing, composite particles have high homogeneity, and bioactivity not easy in inactivation, organic solvent residual is few, environmentally protective.
Have not yet to see the report that Supercritical anti-solvent prepares hesperetin inclusion compound.
Summary of the invention
It is an object of the invention to overcome in the prior art hesperetin be not readily dissolved in that water, dissolution rate be slow and bioavilability
Reduced deficiency provides a kind of application supercritical anti-solvent technology and prepares hesperetin/HP- beta-CD inclusion method.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A method of application supercritical anti-solvent technology prepares hesperetin/HP- beta-CD inclusion, comprising the following steps:
(1) it prepares hesperetin-carrier mixed solution: weighing hesperetin bulk pharmaceutical chemicals and water-solubility carrier is dissolved in organic solvent
In, obtain hesperetin-carrier mixed solution；The organic solvent is ethyl alcohol, and water-solubility carrier is hydroxypropyl-β-cyclodextrin, orange
The molar ratio of skin element bulk pharmaceutical chemicals and carrier is 1:1；
(2) by CO2It is passed through crystallization kettle with certain flow rate, adjusts temperature and pressure in crystallization kettle；
(3) continue to be passed through CO2, maintain crystallization kettle in temperature and pressure it is constant, while by step (1) prepare orange peel
Element-carrier mixed solution is sprayed into inside crystallization kettle at the top of crystallization kettle by nozzle by high pressure pump；
(4) after sample introduction, continue to be passed through CO2Crystallization kettle is opened in certain time, release, collects product.
Further, mixed solution concentration is 5-7mg/mL in step (1).
Further, CO in step (2)2Flow velocity is 3.5-4.0L/min.
Further, crystallization temperature in the kettle is 40-48 DEG C in step (2).
Further, pressure is 11-15Mpa in crystallization kettle in step (2).
Further, liquor capacity flow is 0.8-1.2mL/min in step (3).
Further, continue to be passed through CO in step (4)245min。
The utility model has the advantages that
Hesperetin prepared by the present invention/HP- beta-CD inclusion dissolution rate with higher, bioavilability and stability,
The generally existing organic solvent residual problem of traditional technology is overcome, operating condition is easily controllable, biotic component not easy in inactivation, and
Process green high-efficient, safety and environmental protection.
Detailed description of the invention
Fig. 1 is experimental facilities structural schematic diagram, in which: 1 is CO2Storage tank；2 be low temperature thermostat bath；3 be CO2Pump；4 be CO2
Preheater；5 be crystallization kettle；6 be high pressure pump；7 be solution reservoir；8 be solvent recovery tank；9 be flowmeter；
Fig. 2 is influence relational graph of the crystallization temperature to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery；
Fig. 3 is influence relational graph of the crystallization pressure to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery；
Fig. 4 is influence relational graph of the liquor capacity flow to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery；
Fig. 5 is influence relational graph of the solution quality solubility to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery；
Fig. 6 is prepared by hesperetin bulk pharmaceutical chemicals, HP- β-CD, hesperetin/HP- β-CD solid mixture and the embodiment of the present invention 3
Hesperetin/HP- beta-CD inclusion FTIR map；
Fig. 7 is prepared by hesperetin bulk pharmaceutical chemicals, HP- β-CD, hesperetin/HP- β-CD solid mixture and the embodiment of the present invention 3
Hesperetin/HP- beta-CD inclusion DSC map；
Fig. 8 is prepared by hesperetin bulk pharmaceutical chemicals, HP- β-CD, hesperetin/HP- β-CD solid mixture and the embodiment of the present invention 3
Hesperetin/HP- beta-CD inclusion XRD spectrum；
Fig. 9 is orange peel prepared by hesperetin bulk pharmaceutical chemicals, hesperetin/HP- β-CD solid mixture and the embodiment of the present invention 3
Dissolution characteristics curve of the element/HP- beta-CD inclusion in 1%SDS solution.
Specific embodiment
It is specific with reference to the accompanying drawings and examples to introduce essentiality content of the present invention, but guarantor of the invention is not limited with this
Protect range.
One, experimental material and equipment
Hesperetin (purity > 98%, Shaanxi Hui Ke plant development corporation, Ltd.)；HP- β-CD (purity >=98%, Shang Haiyuan
Ye Zhiyuan Biotechnology Co., Ltd)；CO2(purity > 99%, Nanjing Shang Yuan industrial gasses factory)；Ethyl alcohol (analyzes pure, upper Haitai
Smooth Science and Technology Co., Ltd.)；Distilled water (China Medicine University's self-control)；1%SDS solution (laboratory preparation).
The overcritical particle preparation system of Helix (Applied Separations company, the U.S.)；Helix Series
1500 type high pressure pumps (Applied Separations company, the U.S.)；TYW-2 type air pressure pump (the same machine in Suzhou City
Electric Co., Ltd)；SDC-6 type low temperature thermostat bath (Nanjing Xin Chen Biotechnology Co., Ltd)；The light splitting of UV-1800 type UV, visible light
Photometer (Japanese Shimadzu Corporation)；Thermo U-3000 type liquid chromatograph (Thermo Fischer Scient Inc., the U.S.)；DSC
204F1 type differential scanning calorimeter (German Nai Chi company)；(German Bruker is public for D8Advance type X-ray powder diffraction instrument
Department)；FT/IR-4100 type Fourier Transform Infrared Spectrometer (Japanese JASCO company)；ZRS-8L type intelligently dissolves out experiment instrument (day
Saliva Tianda Tianfa Science and Technology Co. Ltd.).
Two, experimental method
Supercritical CO2Anti-solvent technology prepares hesperetin/HP- beta-CD inclusion flow chart referring to Fig. 1, and operating process is such as
Under:
(1) airtight test is carried out to whole system first, it is ensured that do not leak；Open low temperature thermostat bath 2 and crystallization kettle 5
Heating device, reach setting value to temperature, open CO2Inlet valve, open CO2It is straight to pump 3 pairs of whole systems progress boost operations
To reaching setting value；
(2) after the pressure and temperature of kettle 5 to be crystallized is all stable, the CO of 5 bottom of crystallization kettle is opened2Outlet valve leads to simultaneously
Cross fine tuning valve control CO2Flow velocity, make CO2Stability of flow；
(3) configured sample solution is passed through into high pressure pump 6 from 5 top jet nozzle of crystallization kettle with one after the system stabilizes
Fixed flow velocity sprays into inside crystallization kettle 5, while supercritical CO2Organic solvent is taken away and is finally recovered in solvent recovery tank 8；
(4) after sample introduction, continue to be passed through CO245min eliminates residual solvent；Finally close CO2Inlet valve and CO2Pump 3,
Release after the pressure in kettle 5 to be crystallized is down to an atmospheric pressure, opens crystallization kettle 5, collects product.
Three, embodiment
Embodiment 1: single_factor method investigates each factor to the influence of hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery
Experiment of single factor: CO2Influence of the flow velocity to hesperetin/HP- beta-CD inclusion rate of recovery and pattern
In crystallization pressure 11MPa, 45 DEG C of crystallization temperature, concentration of polymer solution 5mg/mL, hesperetin bulk pharmaceutical chemicals and HP- β-CD
Molar ratio is that 1:1 investigates CO under conditions of liquor capacity flow is 1.0mL/min2Flow velocity be respectively 2.0-2.5,2.5-3.0,
Influence when 3.0-3.5,3.5-4.0,4.0-4.5L/min, to hesperetin/HP- beta-CD inclusion pattern and the rate of recovery.Wherein
As flow velocity≤2.5L/min, since solvent does not drain, product is attached to crystallization kettle in a yellow transparent viscous solid
Bottom；When flow velocity is respectively 2.5-3.0 and 3.0-3.5L/min, product is in fluffy cotton-shaped, but still has partial cohesive solid attached
In crystallization kettle bottom, the rate of recovery is respectively 69.72%, 73.08%；It is inviscid when flow velocity is 3.5-4.0 and 4.0-4.5L/min
Substance generates, and fluffy fluffy solid is attached to kettle wall and bottom, and yield is respectively 84.77%, 78.61%；As flow velocity > 4.5L/
When mim, product is less, and yield is very low, can not collect a certain amount of effective product.It is comprehensively compared and considers, finally determine CO2Flow velocity
Range is 3.5-4.0L/min.
Experiment of single factor: influence of the crystallization temperature to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery
In crystallization pressure 11MPa, concentration of polymer solution 5mg/mL, liquor capacity flow is 1.0mL/min, hesperetin raw material
Medicine and HP- β-CD molar ratio are 1:1, CO2Under conditions of flow velocity is 3.5-4.0L/min, investigate crystallization temperature be respectively 36,40,
44,48,52 DEG C when, the influence to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery.As a result as shown in Fig. 2, drugloading rate
Respectively 12.32%, 14.48%, 15.81%, 14.84%, 13.53%, the rate of recovery is respectively 70.48%, 74.91%,
83.73%, 77.34%, 72.83%.It is comprehensively compared and considers, it is final to determine that crystallization temperature preferred scope is 40-48 DEG C, and select
40,44,48 DEG C three horizontal progress orthogonal optimizations.
Experiment of single factor: influence of the crystallization pressure to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery
At 44 DEG C of crystallization temperature, concentration of polymer solution 5mg/mL, liquor capacity flow is 1.0mL/min, hesperetin raw material
Medicine and HP- β-CD molar ratio are 1:1, CO2Under conditions of flow velocity is 3.5-4.0L/min, investigate crystallization pressure be respectively 9,11,
13, influence when 15,17MPa, to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery.As a result as shown in figure 3, drugloading rate
Respectively 12.86%, 15.10%, 15.65%, 13.64%, 12.34%, the rate of recovery is respectively 67.39%, 83.70%,
84.78%, 77.17%, 70.65%.It is comprehensively compared and considers, it is final to determine that crystallization pressure preferred scope is 11-15MPa, and select
Select 11,13,15MPa tri- horizontal progress orthogonal optimizations.
Experiment of single factor: influence of the liquor capacity flow to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery
At 44 DEG C of crystallization temperature, crystallization pressure 13MPa, concentration of polymer solution 5mg/mL, hesperetin bulk pharmaceutical chemicals and HP- β-
CD molar ratio is 1:1, CO2Under conditions of flow velocity is 3.5-4.0L/min, investigate liquor capacity flow be respectively 0.6,0.8,
1.0, influence when 1.2,1.4mL/min, to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery.As a result as shown in figure 4,
Drugloading rate is respectively 11.66%, 13.51%, 14.72%, 13.28%, 11.28%, the rate of recovery is respectively 71.74%,
75.30%, 79.34%, 73.91%, 69.57%.It is comprehensively compared and considers, it is final to determine that liquor capacity flow preferred scope is
0.8-1.2mL/min, and select 0.8,1.0,1.2mL/min tri- horizontal progress orthogonal optimizations.
Experiment of single factor: influence of the solution quality solubility to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery
At 44 DEG C of crystallization temperature, crystallization pressure 13MPa, liquor capacity flow is 1.0mL/min, hesperetin bulk pharmaceutical chemicals with
HP- β-CD molar ratio is 1:1, CO2Under conditions of flow velocity is 3.5-4.0L/min, investigate solution quality solubility be respectively 3,4,5,
6, influence when 7mg/mL, to hesperetin/HP- beta-CD inclusion drugloading rate and the rate of recovery.As a result as shown in figure 5, drugloading rate point
Not Wei 10.35%, 10.84%, 12.88%, 14.54%, 13.19%, the rate of recovery is respectively 63.64%, 68.49%,
82.61%, 80.91%, 74.22%.It is comprehensively compared and considers, it is final to determine that solution quality solubility preferred scope is 5-7mg/mL,
And select 5,6,7mg/mL tri- horizontal progress orthogonal optimizations.
Embodiment 2: the best experimental factor parameter of orthogonal optimization
Using the rate of recovery as index, design orthogonal experiment investigates crystallization temperature (A), crystallization pressure (B), liquor capacity flow
(C), solution quality solubility (D), table 1 design table for factor level, and table 2 is orthogonal and result.
1 factor level table of table
2 orthogonal design of table and result
| Tested number | A/℃ | B/MPa | C/mL·min-1 | D/mg·mL-1 | Rate of recovery % |
| 1 | 40 | 11 | 0.8 | 5 | 68.48 |
| 2 | 40 | 13 | 1.0 | 6 | 70.91 |
| 3 | 40 | 15 | 1.2 | 7 | 66.41 |
| 4 | 44 | 11 | 1.0 | 7 | 64.06 |
| 5 | 44 | 13 | 1.2 | 5 | 89.13 |
| 6 | 44 | 15 | 0.8 | 6 | 81.81 |
| 7 | 48 | 11 | 1.2 | 6 | 80.91 |
| 8 | 48 | 13 | 0.8 | 7 | 87.50 |
| 9 | 48 | 15 | 1.0 | 5 | 80.43 |
| K1 | 68.600 | 71.150 | 79.263 | 79.347 | |
| K2 | 78.333 | 82.513 | 71.800 | 77.877 | |
| K3 | 82.947 | 76.217 | 78.817 | 72.657 | |
| R | 14.347 | 11.363 | 7.463 | 6.690 |
It is analyzed by table 2 it is found that each factor is followed successively by A > to hesperetin/HP- beta-CD inclusion rate of recovery influence from big to small
B > C > D, i.e. crystallization temperature > crystallization pressure > liquor capacity flow > solution quality solubility.Therefore optimum process group is combined into
A3B2C1D1, i.e. 48 DEG C of crystallization temperature, crystallization pressure 13MPa, liquor capacity flow 0.8mLmin-1, solution quality solubility
5mg/mL。
Embodiment 3: hesperetin/HP- beta-CD inclusion is prepared under optimum process using Supercritical anti-solvent
Hesperetin/HP- beta-CD inclusion method is prepared using Supercritical anti-solvent, is included the following steps:
Hesperetin bulk pharmaceutical chemicals and water-solubility carrier are dissolved in organic solvent by step S1, obtain hesperetin-carrier mixing
Solution；
Step S2, by CO2It is passed through in crystallization kettle, adjusts the temperature and pressure in crystallization kettle；
Step S3 continues to be passed through CO2, maintain constant, while prepared by the step S1 orange of temperature and pressure in crystallization kettle
Pi Su-carrier mixed solution is passed through in crystallization kettle；
Step S4 is continually fed into CO after solution to be mixed is passed through245min, the release after draining residual solvent；When
After pressure is down to an atmospheric pressure in crystallization kettle, opens crystallization kettle and collect hesperetin inclusion compound；
Wherein, water-solubility carrier is HP- β-CD；Organic solvent is dehydrated alcohol；Hesperetin bulk pharmaceutical chemicals rub with HP- β-CD's
You are than being 1:1；Mixed solution mass concentration is 5mg/mL；Crystallizing temperature in the kettle is 48 DEG C, pressure 13MPa；The volume of solution
Flow is 0.8mL/min；CO2Flow velocity is 3.5-4.0L/min.
Gained hesperetin/HP- beta-CD inclusion phenetic analysis:
IR analysis
Hesperetin/HP- beta-CD inclusion IR analysis as shown in fig. 6, compare hesperetin bulk pharmaceutical chemicals infrared absorption spectra,
The characteristic absorption peak of hesperetin presents decrease or disappearance in hesperetin/HP- beta-CD inclusion infrared absorption peak, it was demonstrated that
Hesperetin is by HP- β-CD.
Dsc analysis
Hesperetin/HP- beta-CD inclusion dsc analysis as shown in fig. 7, hesperetin/HP- beta-CD inclusion peak DSC with
HP- β-CD is substantially similar, and the feature endothermic peak of hesperetin completely disappears, this illustrates that hesperetin/HP- beta-CD inclusion is
It is successfully incorporated in HP- β-CD with existing for amorphous state, also demonstrating hesperetin.
XRD analysis
Hesperetin/HP- beta-CD inclusion XRD analysis is as shown in figure 8, compare hesperetin bulk pharmaceutical chemicals, hesperetin/HP- β-
CD inclusion compound almost without characteristic peak presence, illustrate hesperetin/HP- beta-CD inclusion be with existing for amorphous state,
Illustrate hesperetin by HP- β-CD.
Dissolution in vitro experiment
It is prepared under the appropriate plain hesperetin bulk pharmaceutical chemicals of measurement, hesperetin/HP- β-CD solid mixture and optimum process respectively
Hesperetin/HP- beta-CD inclusion, measured under conditions of temperature is 37 ± 0.5 DEG C, revolving speed is 50r/min using paddle method its
Dissolution rate in 120min, compares its dissolving out capability in the SDS solution that 900mL concentration is 1%.As a result as shown in figure 9, known to analysis
Hesperetin bulk pharmaceutical chemicals in 30min dissolution rate be 21.66%, 120min after also less than 30%；It is molten when solid mixture 30min
Accumulative dissolution is also only 32.61% after out-degree is 23.79%, 120min；But hesperetin/HP- beta-CD inclusion dissolution rate
With regard to can reach 80% or more after reachable 77.48%, 120min when 30min.Therefore it is comprehensively compared and learns, using supercritical anti-solvent
Hesperetin/HP- beta-CD inclusion dissolving out capability of method preparation is greatly improved.
It is above-mentioned experiments have shown that can successfully prepare hesperetin/HP- beta-CD inclusion by supercritical anti-solvent technology, and lead to
Cross analysis IR, DSC, XRD spectrum, it was demonstrated that hesperetin is successfully included in HP- β-CD；In Vitro Dissolution the result shows that, relative to
Hesperetin bulk pharmaceutical chemicals and solid mixture, hesperetin/HP- beta-CD inclusion dissolving out capability are significantly improved.
Hesperetin prepared by the present invention/HP- beta-CD inclusion dissolution rate with higher, bioavilability and stability,
The generally existing organic solvent residual problem of traditional technology is overcome, operating condition is easily controllable, biotic component not easy in inactivation, and
Process green high-efficient, safety and environmental protection.
The effect of above-described embodiment is specifically to introduce essentiality content of the invention, but those skilled in the art should know
Protection scope of the present invention should not be confined to the specific embodiment by road.
Claims (7)
1. a kind of prepare hesperetin/HP- beta-CD inclusion method, which comprises the following steps:
(1) it prepares hesperetin-carrier mixed solution: weighing hesperetin bulk pharmaceutical chemicals and water-solubility carrier is dissolved in organic solvent, obtain
To hesperetin-carrier mixed solution；Wherein organic solvent is ethyl alcohol, and water-solubility carrier is hydroxypropyl-β-cyclodextrin, and hesperetin is former
The molar ratio for expecting medicine and carrier is 1:1；
(2) by CO2It is passed through crystallization kettle with certain flow rate, adjusts temperature and pressure in crystallization kettle；
(3) continue to be passed through CO2, maintain crystallization kettle in temperature and pressure it is constant, while by step (1) prepare hesperetin-carrier
Mixed solution is sprayed into inside crystallization kettle at the top of crystallization kettle by nozzle by high pressure pump；
(4) after sample introduction, continue to be passed through CO2Crystallization kettle is opened in certain time, release, collects product.
2. according to the method described in claim 1, it is characterized by: mixed solution concentration is 5-7mg/mL in step (1).
3. according to the method described in claim 1, it is characterized by: CO in step (2)2Flow velocity is 3.5-4.0L/min.
4. according to the method described in claim 1, it is characterized by: crystallization temperature in the kettle is 40-48 DEG C in step (2).
5. according to the method described in claim 1, it is characterized by: pressure is 11-15Mpa in crystallization kettle in step (2).
6. according to the method described in claim 1, it is characterized by: liquor capacity flow is 0.8-1.2mL/ in step (3)
min。
7. according to the method described in claim 1, it is characterized by: continuing to be passed through CO in step (4)245min。
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| CN111529719A (en) * | 2020-06-26 | 2020-08-14 | 中国药科大学 | Method for preparing lamotrigine/hydroxypropyl-beta-cyclodextrin inclusion compound |
| CN114262316A (en) * | 2021-12-24 | 2022-04-01 | 嘉应学院 | Nano hesperetin, preparation method thereof and double-homogenate cavitation jet system used in preparation method |
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| CN111529719A (en) * | 2020-06-26 | 2020-08-14 | 中国药科大学 | Method for preparing lamotrigine/hydroxypropyl-beta-cyclodextrin inclusion compound |
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Application publication date: 20190531 |