CN107501211A - The common amorphous substance of Docetaxel flavones - Google Patents
The common amorphous substance of Docetaxel flavones Download PDFInfo
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- CN107501211A CN107501211A CN201710554273.4A CN201710554273A CN107501211A CN 107501211 A CN107501211 A CN 107501211A CN 201710554273 A CN201710554273 A CN 201710554273A CN 107501211 A CN107501211 A CN 107501211A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides common amorphous substance of Docetaxel flavones and preparation method thereof.The common amorphous substance is the amorphous state material for being totally different from Docetaxel crystal and chromocor compound crystal.Wherein, amorphous substance has single glass transition temperature to Docetaxel altogether.Using Cu K α radiations, there is no sharp diffraction maximum in the x-ray diffractogram of powder spectrum represented with 2 θ angles.The peak position of amorphous substance is total in FTIR spectrum, there occurs significant changes for peak intensity.With Docetaxel crystal phase ratio, solubility, dissolution rate and the oral administration biaavailability of Docetaxel are significantly improved in amorphous substance altogether.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to Docetaxel and chromocor compound are made at 1: 1 in molar ratio
Docetaxel amorphous substance and preparation method thereof altogether.
Background technology
The chemical name of Docetaxel is：(2R, 3S) -3- t-butoxycarbonyl aminos-PLA -4-
The α of acetate-2-benzoyloxy-5 β, 20- epoxy-1,7 β, 10 β-trihydroxy-9- oxygen-α -ester of yew-11- alkene-13, it is second
For taxane class of anti-cancer agents thing, good control is respectively provided with for oophoroma, prostate cancer, liver cancer, advanced breast cancer and stomach cancer etc.
Therapeutic effect.However, Docetaxel has relatively low solubility (~6.5 μ gmL-1, 37 DEG C) and dissolution rate, oral bio profit
Expenditure is low, seriously limits the exploitation of its oral formulations.
For low solubility, the Docetaxel of low dissolution rate, just like liposome (CN 1931157A), inclusion compound (CN
103505737A), technologies such as amorphous (WO 2008102374A1) is improved.Amorphous substance is to be based on amorphous drug altogether
The shortcomings that thermodynamic instability, medicine is set to be formed with another compound by interactions such as hydrogen bond, Van der Waals forces single-phase
Binary system, each component uniformly mix on a molecular scale, in thermodynamics upper state, have in terms of drug dissolution is improved
Unique advantage, and also more amorphous monomer is high for its stability.
Chromocor compound is distributed widely in natural plants, is existed in the form of glycosides or free state etc. in nature, is had anti-
The multiple pharmacological effect such as tumour, anti-oxidant, protection is neural, hypoglycemic, anti-liver injury, preventing and treating osteoporosis.Chromocor compound with
Docetaxel is used in combination, and there may be collaboration pharmacological action in drug effect, has potential application value.In patent CN
In 105708832 A, we protect a kind of pharmaceutical composition for improving Docetaxel oral administration biaavailability.Wherein, group
Docetaxel is administered with chromocor compound for physical mixture in compound.
We are by largely studying discovery, after chromocor compound and Docetaxel are prepared into common amorphous substance, with
Docetaxel is in itself and its compared with the physical mixture of chromocor compound, the Docetaxel dissolution in amorphous substance altogether
Degree and oral administration biaavailability have obtained conspicuousness raising.
The content of the invention
It is an object of the invention to by introduce flavones (such as myricetin, naringenin) prepare Docetaxel altogether it is amorphous
Thing, the common amorphous substance can significantly improve the solubility and dissolution rate of Docetaxel, and improve its oral administration biaavailability.
Amorphous substance altogether of the present invention has following feature：
1st, powder x-ray diffraction (PXRD)
Instrument：XTRA/3KW X-ray diffractometers (Arl Inc. of Switzerland)
Target：Cu-K α are radiated
Wavelength：1.5406A
Pipe pressure：40KV
Guan Liu：40mA
Step-length：0.02°
Sweep speed：10°/min
As a result show：The PXRD of the common amorphous substance of Docetaxel myricetin and the common amorphous substance of Docetaxel naringenin
Collection of illustrative plates is diffraction ring, without sharp diffraction maximum.
2nd, differential scanning calorimetry (DSC)
Instrument：The thermal analyzers of Pyris 1 (PerkinElmer companies of the U.S.)
Scope：5~400 DEG C
As a result show：The endothermic fusion peak of Docetaxel crystal is at 169.7 DEG C.
The endothermic fusion peak of red bayberry cellulose crystal is at 355.1 DEG C.
The endothermic fusion peak of shaddock ped cellulose crystal is at 255.4 DEG C.
The glass transition of the common amorphous substance of Docetaxel myricetin is at 119.6 DEG C.
The glass transition of the common amorphous substance of Docetaxel naringenin is at 145.4 DEG C.
3rd, FTIR spectrum method (FT-IR)
Instrument：The type infrared spectrometers of TENSOR 27 (German Bruker companies)
Absorbing wavelength：400~4000cm-1
As a result show：The infrared spectrum wave number of amorphous substance (pressing potassium bromide troche) is Docetaxel myricetin altogether：
3388.7、2976.0、1710.0、1656.6、1603.4、1505.2、1317.4、1244.5、1201.3、707.3cm-1。
The infrared spectrum wave number of amorphous substance (pressing potassium bromide troche) is Docetaxel naringenin altogether：3398.4、2978.9、
1709.3、1640.9、1519.4、1453.9、1369.2、1245.8、1160.1、708.0cm-1。
It is a further object of the present invention to provide a kind of preparation method of the common amorphous substance of Docetaxel.
The preparation method of the common amorphous substance of the Docetaxel, it is included Docetaxel and myricetin or naringenin
The one or more mixing being dissolved in methanol, ethanol, ether, ethyl acetate, isopropanol, n-butanol, acetone and acetonitrile is molten
In agent, supernatant liquid is obtained, rotary evaporation of solvent is depressurized at 30~70 DEG C, residue vacuum is dried, and produces common amorphous substance.
The organic solvent preferably uses methanol, ethanol or the mixed solvent of the two.
Preferably 45~60 DEG C of the temperature of the decompression rotary evaporation of solvent.
The polyenoid Japanese yew of PXRD, DSC and FT-IR collection of illustrative plates of amorphous substance altogether disclosed by the invention and existing patent report
Alcohol crystals, red bayberry cellulose crystal, shaddock ped cellulose crystal are different.Therefore, the solid forms are that one kind is totally different from prior art
The form of obtained Docetaxel, myricetin or naringenin.
Brief description of the drawings
Fig. 1：The PXRD collection of illustrative plates of Docetaxel crystal
Fig. 2：The PXRD collection of illustrative plates of red bayberry cellulose crystal
Fig. 3：The PXRD collection of illustrative plates of shaddock ped cellulose crystal
Fig. 4：The PXRD collection of illustrative plates of the common amorphous substance of Docetaxel myricetin
Fig. 5：The PXRD collection of illustrative plates of the common amorphous substance of Docetaxel naringenin
Fig. 6：The DSC collection of illustrative plates of Docetaxel crystal
Fig. 7：The DSC collection of illustrative plates of red bayberry cellulose crystal
Fig. 8：The DSC collection of illustrative plates of shaddock ped cellulose crystal
Fig. 9：The DSC collection of illustrative plates of the common amorphous substance of Docetaxel myricetin
Figure 10：The DSC collection of illustrative plates of the common amorphous substance of Docetaxel naringenin
Figure 11：The FT-IR collection of illustrative plates of Docetaxel crystal
Figure 12：The FT-IR collection of illustrative plates of red bayberry cellulose crystal
Figure 13：The FT-IR collection of illustrative plates of shaddock ped cellulose crystal
Figure 14：The FT-IR collection of illustrative plates of the common amorphous substance of Docetaxel myricetin
Figure 15：The FT-IR collection of illustrative plates of the common amorphous substance of Docetaxel naringenin
Figure 16：Docetaxel blood concentration-time curve：Docetaxel control group, Docetaxel and myricetin
Physical mixture group, Docetaxel myricetin amorphous substance group altogether
Figure 17：Docetaxel blood concentration-time curve：Docetaxel control group, Docetaxel and naringenin
Physical mixture group, Docetaxel naringenin amorphous substance group altogether
Embodiment
By detailed description below, the above of the present invention is described in further detail, it is not intended that
Embodiment limitation of the present invention, the beneficial effect of amorphous substance altogether of the present invention is expanded on further by tests below.
The solid-state of amorphous substance is characterized as below altogether in the present invention：
1st, powder x-ray diffraction (PXRD)
Instrument：XTRA/3KW X-ray diffractometers (Arl Inc. of Switzerland)
Target：Cu-K α are radiated
Wavelength：1.5406A
Pipe pressure：40KV
Guan Liu：40mA
Step-length：0.02°
Sweep speed：10°/min
As a result show：The PXRD of the common amorphous substance of Docetaxel myricetin and the common amorphous substance of Docetaxel naringenin
Collection of illustrative plates is diffraction ring, without sharp diffraction maximum (Fig. 4~5).
2nd, differential scanning calorimetry (DSC)
Instrument：The thermal analyzers of Pyris 1 (PerkinElmer companies of the U.S.)
Scope：5~400 DEG C
The glass transition of the common amorphous substance of Docetaxel myricetin is at 119.6 DEG C (Fig. 9).
The glass transition of the common amorphous substance of Docetaxel naringenin is at 145.4 DEG C (Figure 10).
3rd, FTIR spectrum method (FT-IR)
Instrument：The type infrared spectrometers of TENSOR 27 (German Bruker companies)
Absorbing wavelength：400~4000cm-1
The infrared spectrum wave number of amorphous substance (pressing potassium bromide troche) is Docetaxel myricetin altogether：3388.7、2976.0、
1710.0、1656.6、1603.4、1505.2、1317.4、1244.5、1201.3、707.3cm-1(Figure 14).
The infrared spectrum wave number of amorphous substance (pressing potassium bromide troche) is Docetaxel naringenin altogether：3398.4、2978.9、
1709.3、1640.9、1519.4、1453.9、1369.2、1245.8、1160.1、708.0cm-1(Figure 15).
Embodiment 1：The preparation method of the common amorphous substance of Docetaxel myricetin
0.50g Docetaxels and 0.20g myricetins are added in 60mL methanol, stir to clarify solution at room temperature, will
This solution depressurizes rotary evaporation of solvent, 25 DEG C of vacuum drying at 55 DEG C, and products obtained therefrom is Docetaxel myricetin nothing altogether
Amorphous substance.
Embodiment 2：The preparation method of the common amorphous substance of Docetaxel myricetin
0.50g Docetaxels and 0.20g myricetins are added in 40mL absolute ethyl alcohols, stirred to clarify at room temperature molten
Liquid, this solution is depressurized into rotary evaporation of solvent at 40 DEG C, 25 DEG C of vacuum drying, products obtained therefrom is Docetaxel myricetin
Amorphous substance altogether.
Embodiment 3：The preparation method of the common amorphous substance of Docetaxel naringenin
0.50g Docetaxels and 0.17g naringenins are added in 50mL absolute ethyl alcohols, stirred to clarify at room temperature molten
Liquid, this solution is depressurized into rotary evaporation of solvent at 60 DEG C, 25 DEG C of vacuum drying, products obtained therefrom is Docetaxel naringenin
Amorphous substance altogether.
Embodiment 4：The preparation method of the common amorphous substance of Docetaxel naringenin
0.50g Docetaxels and 0.17g naringenins are added in 40mL methanol, stir to clarify solution at room temperature, will
This solution depressurizes rotary evaporation of solvent, 25 DEG C of vacuum drying at 45 DEG C, and products obtained therefrom is Docetaxel naringenin altogether without fixed
Shape thing.
High performance liquid chromatography testing conditions：
Instrument：Shimadzu LC-2010 AHT high performance liquid chromatographs
Chromatographic column：Inertsil ODS-SP chromatographic columns (150 × 4.6mm, 5 μm)
Mobile phase：Acetonitrile: 0.1% aqueous formic acid=55: 45 (v/v)
Flow velocity：1.0mL/min
Detection wavelength：230nm
Solubility test
Docetaxel crystal, Docetaxel myricetin amorphous substance and Docetaxel naringenin altogether are determined respectively
Amorphous substance is in water, 0.1M HCl, pH 4.5 acetate buffer and the phosphate buffers of pH 6.8 (PBS of pH 6.8) altogether
In solubility.50mL solvents are measured respectively in conical flask, are added excess drug, are placed in 37 ± 2 DEG C of constant temperature oscillator
24h is shaken, after reaching balance, solution takes the filtrate after dilution to carry out HPLC detections, the results are shown in Table 1 through 0.22 μm of membrane filtration.
Solubility (the μ gmL of the Docetaxel of table 1-1)
As a result show, two kinds of solubility for being total to Docetaxel in amorphous substances are in any of the above aqueous medium compared with polyenoid
Paclitaxel crystal improves 2.5~3.1 times.
Intrinsic dissolution rate determines
Docetaxel crystal 200mg, Docetaxel myricetin amorphous substance and Docetaxel altogether are weighed respectively
Amorphous substance (equivalent to Docetaxel 200mg amount) carries out pressed powder to naringenin altogether, and it is fine and close to be pressed into a diameter of 13mm
Regular tablet.One bottom surface of tablet and side are wrapped up with beeswax, there was only it, circular surface is exposed, and can be with
Dissolution medium contacts.According to《Chinese Pharmacopoeia》Two methods of annex XC second (paddle method) devices of version in 2015, dissolution medium are respectively
900mL water, 0.1M HCl, pH 4.5 acetate buffer and pH 6.8 PBS, rotating speed 50rpm, 37 ± 2 DEG C of temperature.Point
3mL is not sampled in 2,5,10,15,20,30,45,60 and 90min, and supplements 3mL media in time, sample solution is through 0.22 μm
After membrane filtration, HPLC detections are carried out, estimated performance dissolution rate, the results are shown in Table 2.
Intrinsic dissolution rate (the μ gcm of the Docetaxel of table 2-2·min-1)
As a result show, the intrinsic dissolution rate of Docetaxel is in any of the above aqueous medium in two kinds of common amorphous substances
5.1~7.1 times are improved compared with polyenoid paclitaxel crystal.
Pharmacokinetic experiments (the common amorphous substance of Docetaxel myricetin)
Experimental program：SD rats, 250~280 grams, male, it is randomly divided into control group, physical mixture group and is total to amorphous
Thing group, every group 6, three groups of rat oral gavage samples are as follows：
Control group：The suspension of Docetaxel crystal (40mg/kg).
Physical mixture group：The physical mixture of Docetaxel crystal and red bayberry cellulose crystal (mol ratio 1: 1, press by dosage
Docetaxel 40mg/kg calculate) suspension.
Amorphous substance group altogether：Amorphous substance altogether of Docetaxel myricetin (dosage is by Docetaxel 40mg/kg calculating)
Suspension.
After oral administration, respectively at 0.083,0.5,0.75,1.0,1.5,2,4,8,12 and 24h from rat taking blood from jugular vein
0.2mL, 10000 × g, blood plasma is centrifuged out at 4 DEG C, detect Docetaxel blood concentration, obtain blood concentration-time song
Line and pharmacokinetic parameters.
Experimental result：
Docetaxel plasma drug level-time graph is corresponded to according to pharmacokinetic studies result, sees Figure 16.
The pharmacokinetic parameters of the common amorphous substance of the Docetaxel myricetin of table 3
t1/2：Biological half-life；Tmax：Peak time；Cmax：Maximum plasma concentration；AUC：Area under drug-time curve；
RB%：Relative bioavailability.
As a result show, compared with Docetaxel control group, Docetaxel in its physical mixture with myricetin
Absorption is significantly increased, and the absorption of the Docetaxel myricetin prepared through vacuum rotary steam amorphous substance altogether has and further carried
Height, its relative bioavailability are about 326%.
Pharmacokinetic experiments (the common amorphous substance of Docetaxel naringenin)
Experimental program：SD rats, 250~280 grams, male, it is randomly divided into control group, physical mixture group and is total to amorphous
Thing group, every group 6, three groups of rat oral gavage administration samples are as follows：
Control group：The suspension of Docetaxel crystal (40mg/kg).
Physical mixture group：The physical mixture of Docetaxel crystal and shaddock ped cellulose crystal (mol ratio 1: 1, press by dosage
Docetaxel 40mg/kg calculate) suspension.
Amorphous substance group altogether：Amorphous substance altogether of Docetaxel naringenin (dosage is by Docetaxel 40mg/kg calculating)
Suspension.
After oral administration, respectively at 0.083,0.5,0.75,1.0,1.5,2,4,8,12 and 24h from rat taking blood from jugular vein
0.2mL, 10000 × g, blood plasma is centrifuged out at 4 DEG C, detect Docetaxel blood concentration, obtain blood concentration-time song
Line and pharmacokinetic parameters.
Experimental result：
Docetaxel plasma drug level-time graph is corresponded to according to pharmacokinetic studies result, sees Figure 17.
The pharmacokinetic parameters of the common amorphous substance of the Docetaxel naringenin of table 4
t1/2：Biological half-life；Tmax：Peak time；Cmax：Maximum plasma concentration；AUC：Area under drug-time curve；
RB%：Relative bioavailability.
As a result show, compared with the mixture of Docetaxel and naringenin, Docetaxel after common amorphous substance is made
Oral administration biaavailability be further improved, its relative bioavailability is about 238%.
In summary：The present invention is by depressurizing the common amorphous substance of Docetaxel myricetin that rotary evaporation prepares
The single homogeneous common amorphous substance that amorphous substance is the crystal different from corresponding to, polyenoid Japanese yew are total to Docetaxel naringenin
Solubility, dissolution rate and the oral administration biaavailability of alcohol obtain conspicuousness raising, are advantageous to Docetaxel and orally make
The exploitation of agent.
Above example is served only for being described in more detail technical scheme, it is impossible to is interpreted as to this hair
The limitation of bright protection domain, those skilled in the art according to the present invention the above make some it is nonessential improvement and
Adjustment belongs to protection scope of the present invention.
Claims (6)
1. Docetaxel flavones amorphous substance altogether, it is characterised in that be by Docetaxel and chromocor compound in molar ratio 1
: 1 is dissolved in organic solvent, and rotary evaporation of solvent is depressurized under certain temperature, and residue vacuum is dried, and it is amorphous altogether to produce this
Thing.
2. Docetaxel flavones as described in claim 1 amorphous substance altogether, it is characterised in that the chromocor compound is
One kind in myricetin and naringenin.
3. the preparation method of the common amorphous substance of Docetaxel flavones as described in claim 1, it is characterised in that described to have
Solvent is one or more of solvents in methanol, ethanol, ether, ethyl acetate, isopropanol, n-butanol, acetone and acetonitrile
Mixing, the preferably mixed solvent of the one or both in methanol and ethanol.
4. the preparation method of the common amorphous substance of Docetaxel flavones as described in claim 1, it is characterised in that described to subtract
It is to carry out at a certain temperature to press dry dry, and temperature is 30~70 DEG C, preferably 45~60 DEG C.
5. the common amorphous substance of Docetaxel flavones as described in claim 1, it is characterised in that prepared polyenoid Japanese yew
There is no sharp diffraction maximum in the x-ray diffractogram of powder spectrum of the common amorphous substance of alcohol myricetin；The common nothing is measured with KBr pressed disc methods
The infrared absorption spectroscopy of amorphous substance is 3388.7,2976.0,1710.0,1656.6,1603.4,1505.2,1317.4,
1244.5、1201.3、707.3cm-1There is absworption peak at place；The glass transition of common amorphous substance in differential scanning amount heat analysis collection of illustrative plates
Temperature is 119.6 DEG C.
6. the common amorphous substance of Docetaxel flavones as described in claim 1, it is characterised in that prepared polyenoid Japanese yew
There is no sharp diffraction maximum in the x-ray diffractogram of powder spectrum of the common amorphous substance of alcohol naringenin；The common nothing is measured with KBr pressed disc methods
The infrared absorption spectroscopy of amorphous substance is 3398.4,2978.9,1709.3,1640.9,1519.4,1453.9,1369.2,
1245.8、1160.1、708.0cm-1There is absworption peak at place；The glass transition of common amorphous substance in differential scanning amount heat analysis collection of illustrative plates
Temperature is 145.4 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108837157A (en) * | 2018-09-10 | 2018-11-20 | 成都医学院 | A kind of double polymer nanoparticles and preparation method thereof for carrying the pure and mild flavone compound of Taxotere |
Citations (3)
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|---|---|---|---|---|
| WO2008102374A1 (en) * | 2007-02-20 | 2008-08-28 | Dabur Pharma Limited | Amorphous form of docetaxel |
| CN103357013A (en) * | 2013-04-23 | 2013-10-23 | 福建省创欣生物科技有限公司 | Composition for enhancing bioavailability of taxane medicament |
| CN105708832A (en) * | 2016-03-08 | 2016-06-29 | 中国药科大学 | Medicine composition for improving docetaxel oral bioavailability |
-
2017
- 2017-07-05 CN CN201710554273.4A patent/CN107501211A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008102374A1 (en) * | 2007-02-20 | 2008-08-28 | Dabur Pharma Limited | Amorphous form of docetaxel |
| CN103357013A (en) * | 2013-04-23 | 2013-10-23 | 福建省创欣生物科技有限公司 | Composition for enhancing bioavailability of taxane medicament |
| CN105708832A (en) * | 2016-03-08 | 2016-06-29 | 中国药科大学 | Medicine composition for improving docetaxel oral bioavailability |
Non-Patent Citations (2)
| Title |
|---|
| TIANYUN HAO ET AL.: "Enhanced oral bioavailability of docetaxel in rats combined with myricetin: In situ and in vivo evidences", 《EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| 郭慧慧等: "共无定形药物——新型单相无定形二元体系", 《化学进展》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108837157A (en) * | 2018-09-10 | 2018-11-20 | 成都医学院 | A kind of double polymer nanoparticles and preparation method thereof for carrying the pure and mild flavone compound of Taxotere |
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