CN103976957B - A kind of 20 (S)-protopanoxadiol microballoons and its preparation method and application - Google Patents
A kind of 20 (S)-protopanoxadiol microballoons and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of 20 (S) protopanoxadiol microballoon and its preparation method and application.Described microballoon is made up with polylactic-co-glycolic acid and nanometer hydroxyapatite with polylactic-co-glycolic acid or by 20 (S) protopanoxadiol phosphatide complexes of 20 (S) protopanoxadiol, and average grain diameter is 1～5 μm.The preparation of described microballoon is to use emulsion-solvent evaporation method, including the preparation of oil phase, oil phase inject the emulsification after aqueous phase, solvent volatilization and post-processing step.Test result indicate that: the external long-term release profiles of 20 (S) protopanoxadiol microballoon that the present invention provides meets Higuchi equation, release without substantially prominent, external long-term release about 30 days, can reach external long-term sustained release effect, it is expected as active component for preparing the sustained release preparation for the treatment of or prevention of depression medicine, have broad application prospects.
Description
Technical field
The present invention relates to a kind of 20 (S)-protopanoxadiol microballoons and its preparation method and application.
Background technology
It according to World Health Organization's statistics, is likely to become to the year two thousand twenty depression and is only second to cardiopathic second largest illness, depression
Patient is the people at highest risk committing suiside, and therefore there are about the patient of 10%～15% can commit suiside.This kind of serious threat mankind are good for
The disease of health, at present many employing chemical synthetic drug treatments clinically, in terms for the treatment of, Western medicine antidepression is (such as conventional Ah rice
For woods, Prozac etc.) mainly by the heavily absorption of monoamine transmitters in suppression brain, make the mediators such as NE, 5-HT in brain
Content increases.But, these medicines of Long-Time Service have reduction monoamine transmitters synthesis, the side effect of inhibition function.From now
Some research datas are seen, the cause of disease of depression is very complicated, and its treatment should not be limited only to nervous system yet, and this phenomenon carries
Show that treating depression should indeed be more based on by multipath, Mutiple Targets, the conventional medicament playing a role at many levels.
China pharmacy ancient books and records Shennong's Herbal ginseng is classified as top grade, say its have " main tonifying five zang organs, peace spirit, determine soul
Soul, only palpitation with fear, improving eyesight, happy intelligence development, clothes have effect prolonged life of making light of one's life by commiting suicide for a long time ", from ginseng active component, screen antidepressants
Thing has preferable feasibility.Recently scientific investigations showed that, ginsenoside pharmaceutically active in vivo is inhaled not by its prototype
Receipts play a role, and saponin(e is the precursor of medicine, after only passing through the desaccharification metabolism activation of gastrointestinal bacterial flora, just change into
Having the active component of curative effect of medication, some aglycon or the secondary glycosides that obtain after same saponins desaccharification not only change its parent soap
The curative effect of glycosides, but also make its medical active strengthen because eliminating glycogen.20 (S)-protopanoxadiols are protopanaxadiol-type's soap
Aglycon, is metabolite or the acid and alkali hydrolysis product of some ginsenosides, has stronger antidepression and antitumor activity, face
Bed is usually used in prevention and the therapeutic action of depression.
Polymer composite is despite physical blending, but compound shows the character very big with single polymer difference
And feature, the research that therefore polymer composite is applied in a lot of fields is paid attention to.Phosphatide complexes is Italy scholar
The novel drug-loading system of one of Bombardelli discovery when studying liposome, active ingredient of Chinese herbs is with phosphatide under certain condition
After forming phosphatide complexes, medicine lipophilicity can be made to be remarkably reinforced, extended durations of action, bad reaction reduces, and can increase simultaneously
Strong absorption in the gastrointestinal tract, improves bioavilability, strengthens pharmacological action.
Micro-balloon injection is extending medicine release time in vivo and in vitro, maintains steadily effective blood concentration, improves patient and comply with
While property, its framework material has again good biocompatibility, biodegradability and low toxicity, has with dive
In advantage: after drug encapsulation is in microballoon, there is significantly control release and the effect extending curative effect of medication；Micro-balloon injection
Can eliminate and often release the vivo medicine concentration peak valley phenomenon that injection multiple dosing produces, it is thus achieved that steadily long valid density；
Strengthen the targeting of medicine；Will not substantially increase toxicity while slow release long-acting, or reduce toxic and side effect due to targeting.
Need long term administration owing to depression exists, therefore, develop the microsphere sustained-release preparation for depression long-term treatment, can
To reach to reduce times for spraying and dosage, reduce toxic and side effect, improve the compliance of patient medication.
Content of the invention
The problems referred to above existing for prior art, it is an object of the invention to provide a kind of can be applicable to and prepare the slow of depression
20 (S)-protopanoxadiol microballoons releasing pharmaceutical preparation and preparation method thereof, using meet active component 20 (S)-protopanoxadiol as
The application of sustained release antidepressant requires.
For achieving the above object, the technical solution used in the present invention is as follows:
A kind of 20 (S)-protopanoxadiol microballoons, by 20 (S)-protopanoxadiols and poly lactic-co-glycolic acid (PLGA) or by 20 (S)-
Protopanoxadiol phosphatide complexes is made with poly lactic-co-glycolic acid (PLGA) and nanometer hydroxyapatite (nHAP), average grain diameter
It is 1～5 μm.
A kind of method preparing 20 described (S)-protopanoxadiol microballoons, including operate as follows:
A) by 20 (S)-protopanoxadiols and poly lactic-co-glycolic acid or 20 (S)-protopanoxadiol phosphatide complexes and PLA-
Hydroxyacetic acid and nanometer hydroxyapatite are dissolved in the mixed solvent being made up of ethyl acetate and dichloromethane, form oil phase；Its
In: 20 (S)-protopanoxadiols and 20 (S)-protopanoxadiol phosphatide complexes are with the mass ratio of poly lactic-co-glycolic acid
1:4～1:8；Poly lactic-co-glycolic acid is 80mg:1mL～120mg:1mL with the mass volume ratio of mixed solvent；Nano-hydroxy
Apatite is 1:6～1:3 with the mass ratio of poly lactic-co-glycolic acid；
B) with polyvinyl alcohol (PVA) aqueous solution that mass percent concentration is 0.1～0.5% as aqueous phase, control at 35～45 DEG C
Under, it is slowly injected into oil phase prepared for step a) in aqueous phase；Wherein: oil phase is 1:10～1:50 with the volume ratio of aqueous phase；
C) at 35～45 DEG C, high-speed stirred makes emulsification；
D) continue stirring, make the organic solvent in system volatilize completely；
E) centrifugation, with the collected solid of distilled water washing, is then vacuum dried, and obtains described 20 (S)-former
Panoxadiol microballoon.
Described mixed solvent is preferably made up of by 1:4 volume ratio with dichloromethane ethyl acetate.
The described polyvinyl alcohol preferably less than degree of polymerization, the polyvinyl alcohol of partial alcoholysis type, more preferably the 500th, the degree of polymerization is
Alcoholysis degree is the polyvinyl alcohol of 88%.
Mixing speed described in step c) is preferably 1000～1500 revs/min.
Mixing speed described in step d) is preferably 850～2000 revs/min.
Centrifugal speed described in step e) is preferably 2000～4000 revs/min.
Vacuum drying temperature described in step e) is preferably 35～40 DEG C.
A kind of application of above-mentioned 20 (S)-protopanoxadiol microballoons, for preparation with 20 (S)-protopanoxadiols as active component
The sustained release preparation of anti-depression drug.
Described sustained release preparation is preferably subcutaneously or intramuscularly ejection preparation.
20 heretofore described (S)-protopanoxadiol phosphatide complexes are by 20 (S)-protopanoxadiols and answering that phosphatide is formed
Compound；Described phosphatide can be lecithin or Fabaceous Lecithin, is preferably lecithin, including injection lecithin PL-100M and note
Penetrate and use high purity lecithin PC-98T, optimum for injection high purity lecithin PC-98T.Injection lecithin PL-100M
It is all purchased from Shanghai Advanced viecle Technology Co., Ltd. with injection high purity lecithin PC-98T.Japan Patent technology
The PC-98T that (Patent No.3844508) produces, is to use special extraction process to make phosphatidylcholine content more than 98%,
For the natural phospholipid of fine white powder shape, the shelf-life, SFDA authentication code was F20090024 up to 36 months；Lecithin
The phosphatidylcholine content of PL-100M is 80%, and SFDA authentication code is F20090025.
The preparation technology of 20 heretofore described (S)-protopanoxadiol phosphatide complexes, can refer to following technique and prepares:
Weigh 20 (S)-protopanoxadiols and phosphatide (rate of charge is 1:1) in 100mL ground round-bottomed flask, add methyl alcohol,
Adjusting 20 (S)-protopanoxadiol concentration is 20mg/mL, then 40 DEG C of stirred in water bath 4h, and recovered under reduced pressure organic solvent,
Residue is fully dissolved by appropriate ethyl acetate, filters, separating filtrate, reclaims ethyl acetate, and residue is vacuum dried,
Obtain 20 (S)-protopanoxadiol phosphatide complexes；Collect precipitation, be dried and weigh, calculating 20 (S)-protoplasts as follows
Ginseng glycol and the combination percentage of phosphatide: Percentage bound %=(A1-AD)/A1 × 100% of 20 (S)-protopanoxadiols and phosphatide,
Wherein, A1 is the initial dosage of 20 (S)-protopanoxadiols, and AD is precipitation capacity.
Compared with prior art, there is advantages that
20 (S)-protopanoxadiol microballoons that the present invention provides, show outside it to be compact structure under ESEM, smooth surface,
Outward appearance rounding, good dispersion；Its average grain diameter below 5 μm, good fluidity；And its external long-term release profiles meets
Higuchi equation, releases without substantially prominent, and external long-term release about 30 days can reach external long-term sustained release effect；Therefore, originally
20 described (S)-protopanoxadiol microballoons of invention can be as active component for preparing the sustained release for the treatment of or prevention of depression medicine
Preparation, to reduce the times for spraying of patients with depression and dosage, reduces toxic and side effect, improves the compliance of medication；Separately
Outward, preparation method of the present invention is simple, it is not necessary to special installation, is suitable to large-scale production.
Brief description
Fig. 1 is the stereoscan photograph of of the present invention 20 (S)-protopanoxadiol microballoons；
Fig. 2 is by the external long-term release profiles of the 20 made microballoons of (S)-protopanoxadiol；
Fig. 3 is by the external long-term release profiles of the 20 made microballoons of (S)-protopanoxadiol phosphatide complexes.
Detailed description of the invention
The present invention made further in detail, intactly illustrate below in conjunction with embodiment and accompanying drawing.
Embodiment 1
20mg20 (S)-protopanoxadiol and 100mg PLGA are dissolved in 1mL by ethyl acetate-dichloromethane (by volume
In mixed solvent 1:4) forming, prepare oil phase；In 40 DEG C of water-baths, prepared oil phase is slowly injected into the aqueous phase of 50mL
(by the degree of polymerization be the 500th, alcoholysis degree be 88% the mass percent concentration that formed of polyvinyl alcohol be 0.5% the aqueous solution) in；
Emulsify 5min with 1300r/min high-speed stirred；Continue stirring 4h with 850r/min again, make the organic solvent (acetic acid in system
Ethyl ester and dichloromethane) volatilize completely；Centrifugal (rotating speed 3000r/min, 10min) separates, and is collected by distilled water washing
Solid 3 times, be vacuum dried 36h after 37 DEG C, it is micro-that gained white powder is 20 described (S)-protopanoxadiols of invention
Ball.
1st, ocular estimate
Take 20 obtained (S)-protopanoxadiol microballoons and be suspended in ultrasonic 1min in the solution of 0.02% (w/w) Tween 80 in right amount,
Making it dispersed, laser particle size analyzer measures the particle diameter of microballoon, and the average grain diameter of this example thus obtained microsphere is 1.16 μm.
The stereoscan photograph of 20 (S)-protopanoxadiol microballoons by being obtained for the Fig. 1, as seen from Figure 1: the outside of microballoon is close
Real structure, smooth surface, outward appearance rounding, good dispersion.
2nd, drug loading, envelop rate and yield measure
(1) chromatographic condition
Agilent Eclipse XDB-C18 chromatographic column (4.6mm × 150mm, 5 μm), flowing is acetonitrile-water (88:12) mutually, stream
Speed is 1.0mL min-1, column temperature is 25 DEG C, and detection wavelength is 203nm.Theoretical cam curve is calculated not by 20 (S)-PPD peak
Less than 7000.
(2) calibration curve
Take 20 (S)-protopanoxadiol reference substance about 10mg, accurately weighed, put in 10mL volumetric flask, add methyl alcohol and dissolve and dilute
Releasing to scale, shaking up, obtaining concentration is 1.0680mg mL-1Solution, as reference substance storing solution；Respectively by 20 (S)-former
It is 0.02136,0.1068,0.2136,0.5340,0.8544 that panoxadiol microballoon reference substance storing solution is diluted to mass concentration
mg·mL-1Series standard solution；Precision draws the 20 μ Ls injections each with reference substance storing solution of above-mentioned reference substance solution efficiently respectively
Liquid chromatograph, is measured according to chromatographic condition, records peak area, with mass concentration (mg mL-1) it is abscissa, face, peak
Long-pending A is that ordinate draws calibration curve, obtains regression equation Y=13004X+40.405(r=0.9996).
Result shows, the concentration of 20 (S)-protopanoxadiol microballoons is at 0.02136 ~ 1.0680mg mL-1In the range of in good line
Sexual intercourse.
(3) drug loading and entrapment efficiency determination
Weigh 20 obtained (S)-protopanoxadiol microballoon 5mg, accurately weighed, add 0.5mL dichloromethane vortex, fully
Destroy micro-sphere structure, add methanol constant volume to 5mL, centrifugal collect supernatant, with 0.45 μm of filtering with microporous membrane, according to
Chromatographic condition measures medicament contg.Microballoon drugloading rate and envelop rate according to the following formula, and calculate according to qualified microspheres quality
Yield, formula is:
The drugloading rate (%) of microballoon=(microballoon total amount after actual content of dispersion/drying in microballoon) × 100%
The envelop rate (%) of medicine=(actual drugloading rate/theory drugloading rate) × 100%
The testing result of 20 (S)-protopanoxadiol microballoons that table 1 is obtained by the present embodiment.
Table 1. microspheres quality testing result
| Inspection target | Mean value | RSD/% |
| Drugloading rate/% | 19.61 | 1.89 |
| Envelop rate/% | 41.76 | 5.57 |
| Yield/% | 35.58 | 4.12 |
3rd, external long-term release
(1) release profiles
20 (S)-protopanoxadiol microballoon 3 parts that precision weighing is obtained, containing about 2mg, fills in teat glass in 15mL tool for every part
In, accurately add 10mL phosphate buffer (pH=7.4) dissolution medium (contain 1% methylcellulose, 1%CA-630,0.01%
Sodium azide), after mixing, test tube is placed in constant temperature 37 DEG C shaking, speed 100rpm；Vibration starts rear timing sampling,
Each sample is centrifuged 5min with 4000rpm；Again, after using l0mL fresh dissolution medium suspended the microballoon obtaining, continue
Shaking；Centrifugal gained supernatant, measures the dose of release, and by following equation calculating preparation:
In formula, Q is the accumulative release rate of medicine, and Ci is each time point drug concentration, and V is dissolution medium volume, and V' is sampling
Volume, W is microspheres weight, and F is microballoon drug content.
Fig. 2 is the external long-term release profiles of the present embodiment thus obtained microsphere, from Figure 2 it can be seen that microballoon is in starting 0.5 hour
Burst size is 18.01%, releases without substantially prominent, and when being discharged into 38 days, preparation is up to 83.62%, and release is close completely,
Illustrate that the present embodiment thus obtained microsphere has certain slow release effect.
(2) release Mechanisms
Treatment Analysis is carried out to the release in vitro data of microballoon, can correctly inquire into its release in vitro mechanism and rule.
Common mathematical model has:
Zero level equation: Mt/M ∞=kt
First-order equation: ln (1-Mt/M ∞)=-kt
Higuchi equation: Mt/M ∞=kt1/2
Wherein Mt is the cumulative release amount of t time, cumulative release amount when M ∞ is ∞, accumulation when Mt/M ∞ is t
Release rate, k is constant, and this constant is different with different pharmaceutical or prescription and different release conditions.
Be analyzed the release in vitro data of the present embodiment thus obtained microsphere the results are shown in Table shown in 2:
The fit equation of the external long-term release of table 2.
| Model of fit | Fit equation | R |
| Zero level equation | Mt/M∞=1.6378t+37.663 | 0.8886 |
| First-order equation | ln(1-Mt/M∞)=-0.0421t-0.4555 | 0.9608 |
| Higuchi equation | Mt/M∞=10.658t1/2+26.372 | 0.9807 |
From table 2: in fit equation, the coefficient correlation (r) with Higuchi equation is maximum, and this fitting result is best, further
Show that the external long-term release profiles of microballoon provided by the present invention meets Higuchi equation, there is preferable slow release.
Embodiment 2
20mg20 (S)-protopanoxadiol and 160mg PLGA are dissolved in 2mL by ethyl acetate-dichloromethane (by volume
In mixed solvent 1:4) forming, prepare oil phase；In 40 DEG C of water-baths, prepared oil phase is slowly injected into the aqueous phase of 50mL
(by the degree of polymerization be the 500th, alcoholysis degree be 88% the mass percent concentration that formed of polyvinyl alcohol be 0.25% the aqueous solution)
In；Emulsify 10min with 1000r/min high-speed stirred；Continue stirring 4h with 1500r/min again, make the organic solvent in system
(ethyl acetate and dichloromethane) volatilizees completely；Centrifugal (rotating speed 3000r/min, 10min) separates, and washs with distilled water
The solid collected 3 times, is vacuum dried 36h after 37 DEG C, and gained white powder is 20 described (S)-protoplast ginsengs of invention
Glycol microballoon.The outward appearance of the present embodiment thus obtained microsphere and Evaluation results are with described in embodiment 1.
Embodiment 3
20mg20 (S)-protopanoxadiol and 80mg PLGA are dissolved in 1mL by ethyl acetate-dichloromethane (by volume
In mixed solvent 1:4) forming, prepare oil phase；In 40 DEG C of water-baths, prepared oil phase is slowly injected into the aqueous phase of 50mL
(by the degree of polymerization be the 500th, alcoholysis degree be 88% the mass percent concentration that formed of polyvinyl alcohol be 0.1% the aqueous solution) in；
Emulsify 10min with 1300r/min high-speed stirred；Continue stirring 4h with 850r/min again, make the organic solvent (second in system
Acetoacetic ester and dichloromethane) volatilize completely；Centrifugal (rotating speed 3000r/min, 10min) separates, and is collected by distilled water washing
The solid arriving 3 times, is vacuum dried 36h after 37 DEG C, and gained white powder is 20 described (S)-protopanoxadiols of invention
Microballoon.The outward appearance of the present embodiment thus obtained microsphere and Evaluation results are with described in embodiment 1.
Embodiment 4
136mg20 (S)-protopanoxadiol phosphatide complexes and 600mg PLGA and 170mg HAP are dissolved in 5mL by second
In the mixed solvent that acetoacetic ester-dichloromethane (1:4 by volume) forms, prepare oil phase；In 40 DEG C of water-baths, will prepare
Oil phase to be slowly injected into the aqueous phase of 50mL (be the percent mass that formed of polyvinyl alcohol that the 500th, alcoholysis degree is 88% by the degree of polymerization
Specific concentration is the aqueous solution of 0.25%) in；Emulsify 5min with 1500r/min high-speed stirred；Continue to stir with 2000r/min again
Mix 4h, make the organic solvent in system (ethyl acetate and dichloromethane) volatilize completely；Centrifugal (rotating speed 3000r/min, 10min)
Separating, washing the solid collected 3 times with distilled water, be vacuum dried 36h after 37 DEG C, gained white powder is to be sent out
Bright 20 described (S)-protopanoxadiol microballoons.
1st, drug loading and entrapment efficiency determination
The drug loading recording the present embodiment thus obtained microsphere by method described in embodiment 1 is that the 1.12%th, envelop rate is
34.34%th, the mass yield of qualified microballoon is 81.16%.
2nd, external long-term release
(1) release profiles
20 (S)-protopanoxadiol microballoon 3 parts that precision weighing is obtained, containing about 2mg, fills in teat glass in 15mL tool for every part
In, accurately add 10mL phosphate buffer (pH=7.4) dissolution medium (contain 1% methylcellulose, 1%CA-630,10%
Absolute ethyl alcohol, 0.01% Sodium azide), after mixing, test tube is placed in constant temperature 37 DEG C shaking, speed 100rpm；Vibration is opened
Each sample is centrifuged 5min with 4000rpm by timing sampling after the beginning；The microballoon obtaining is situated between by the fresh release of l0mL again
After matter is suspended, continue shaking；Centrifugal gained supernatant, measures the dose of release, and by following equation calculating preparation:
In formula, Q is the accumulative release rate of medicine, and Ci is each time point drug concentration, and V is dissolution medium volume, and V' is sampling
Volume, W is microspheres weight, and F is microballoon drug content.
Fig. 3 is the external long-term release profiles of the present embodiment thus obtained microsphere, as seen from Figure 3: microballoon is in starting 0.5 hour
Burst size is only 2.08%, releases without substantially prominent, when being discharged into 33 days, and preparation only up to 50.87%, still have and release further
Putting trend, slow release effect is obvious.
(2) release Mechanisms
Be analyzed the release in vitro data of the present embodiment thus obtained microsphere the results are shown in Table shown in 3:
The fit equation of the external long-term release of table 3
| Model of fit | Fit equation | R |
| Zero level equation | Mt/M∞=0.0165t+0.086 | 0.9321 |
| First-order equation | ln(1-Mt/M∞)=-0.0233t-0.0862 | 0.9521 |
| Higuchi equation | Mt/M∞=0.0976t1/2-0.0005 | 0.9830 |
From table 3: in fit equation, the coefficient correlation (r) with Higuchi equation is maximum, and this fitting result is best, further
Show that the external long-term release profiles of microballoon provided by the present invention meets Higuchi equation, there is preferable slow release.
Embodiment 5
80mg20 (S)-protopanoxadiol phosphatide complexes and 600mg PLGA and 100mg HAP are dissolved in 5mL by acetic acid
In the mixed solvent that ethyl ester-dichloromethane (1:4 by volume) forms, prepare oil phase；In 40 DEG C of water-baths, by prepared
The aqueous phase that oil phase is slowly injected into 50mL (is the mass percent that formed of polyvinyl alcohol that the 500th, alcoholysis degree is 88% by the degree of polymerization
Concentration is the aqueous solution of 0.25%) in；Emulsify 5min with 1300r/min high-speed stirred；Continue stirring 4h with 850r/min again,
The organic solvent in system (ethyl acetate and dichloromethane) is made to volatilize completely；Centrifugal (rotating speed 3000r/min, 10min)
Separating, washing the solid collected 3 times with distilled water, be vacuum dried 36h after 37 DEG C, gained white powder is to be sent out
Bright 20 described (S)-protopanoxadiol microballoons.The Evaluation results of the present embodiment thus obtained microsphere is with described in embodiment 4.
Embodiment 6
140mg20 (S)-protopanoxadiol phosphatide complexes and 600mg PLGA and 200mg HAP are dissolved in 6mL by second
In the mixed solvent that acetoacetic ester-dichloromethane (1:4 by volume) forms, prepare oil phase；In 40 DEG C of water-baths, will prepare
Oil phase to be slowly injected into the aqueous phase of 50mL (be the percent mass that formed of polyvinyl alcohol that the 500th, alcoholysis degree is 88% by the degree of polymerization
Specific concentration is the aqueous solution of 0.25%) in；Emulsify 5min with 1300r/min high-speed stirred；Continue stirring with 850r/min again
4h, makes the organic solvent in system (ethyl acetate and dichloromethane) volatilize completely；Centrifugal (rotating speed 3000r/min, 10min)
Separating, washing the solid collected 3 times with distilled water, be vacuum dried 36h after 37 DEG C, gained white powder is to be sent out
Bright 20 described (S)-protopanoxadiol microballoons.The Evaluation results of the present embodiment thus obtained microsphere is with described in embodiment 4.
To sum up experimental result is visible: the outward appearance rounding of 20 (S)-protopanoxadiol microballoons that the present invention provides, good dispersion；Averagely
Particle diameter below 5 μm, good fluidity；And its external long-term release profiles meets Higuchi equation, release without substantially prominent, body
Outer long-term release about 30 days, can reach external long-term sustained release effect, it is expected to be used for preparing treatment as active component or prevention presses down
The sustained release preparation of strongly fragrant disease drug, has broad application prospects.
It is finally necessary described herein: above example is served only for saying technical scheme in further detail
Bright, it is impossible to be interpreted as limiting the scope of the invention, those skilled in the art makes according to the foregoing of the present invention
Some nonessential improve and adjustment belong to protection scope of the present invention.
Claims (9)
1. (S)-protopanoxadiol microballoon, it is characterised in that: it is by 20 (S)-protopanoxadiol phosphatide complexes and to gather
Lactic-co-glycolic acid and nanometer hydroxyapatite are prepared as follows method and make:
A) it is dissolved in 20 (S)-protopanoxadiol phosphatide complexes and poly lactic-co-glycolic acid and nanometer hydroxyapatite by acetic acid second
Ester, with the mixed solvent of dichloromethane composition, forms oil phase；Wherein: 20 (S)-protopanoxadiol phosphatide complexes and PLA
The mass ratio of-hydroxyacetic acid is 1:4～1:8；The mass volume ratio of poly lactic-co-glycolic acid and mixed solvent be 80mg:1mL～
120mg:1mL；Nanometer hydroxyapatite is 1:6～1:3 with the mass ratio of poly lactic-co-glycolic acid；
B) with polyvinyl alcohol water solution that mass percent concentration is 0.1～0.5% as aqueous phase, control at 35～45 DEG C, will
The prepared oil phase of step a) is slowly injected in aqueous phase；Wherein: oil phase is 1:10～1:50 with the volume ratio of aqueous phase；
C) at 35～45 DEG C, high-speed stirred makes emulsification；
D) continue stirring, make the organic solvent in system volatilize completely；
E) centrifugation, with the collected solid of distilled water washing, is then vacuum dried；
The average grain diameter of 20 obtained (S)-protopanoxadiol microballoons is 1～5 μm；
20 described (S)-protopanoxadiol phosphatide complexes are the compounds being formed by 20 (S)-protopanoxadiols and phosphatide.
2. 20 (S)-protopanoxadiol microballoons as claimed in claim 1, it is characterised in that: described mixed solvent is by second
Acetoacetic ester and dichloromethane press 1:4 volume ratio composition.
3. 20 (S)-protopanoxadiol microballoons as claimed in claim 1, it is characterised in that: described polyvinyl alcohol is selected poly-
Right is the polyvinyl alcohol that the 500th, alcoholysis degree is 88%.
4. 20 (S)-protopanoxadiol microballoons as claimed in claim 1, it is characterised in that: the stirring speed described in step c)
Degree is 1000～1500 revs/min.
5. 20 (S)-protopanoxadiol microballoons as claimed in claim 1, it is characterised in that: the stirring speed described in step d)
Degree is 850～2000 revs/min.
6. 20 (S)-protopanoxadiol microballoons as claimed in claim 1, it is characterised in that: the centrifugal speed described in step e)
Degree is 2000～4000 revs/min.
7. 20 (S)-protopanoxadiol microballoons as claimed in claim 1, it is characterised in that: the vacuum described in step e) is done
Dry temperature is 35～40 DEG C.
8. the application of 20 (S)-protopanoxadiol microballoons described in a claim 1, it is characterised in that: be for preparation with
20 (S)-protopanoxadiols are the sustained release preparation of the anti-depression drug of active component.
9. apply as claimed in claim 8, it is characterised in that: described sustained release preparation is subcutaneously or intramuscularly ejection preparation.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310050858.4A CN103976957B (en) | 2013-02-08 | 2013-02-08 | A kind of 20 (S)-protopanoxadiol microballoons and its preparation method and application |
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| CN201310050858.4A CN103976957B (en) | 2013-02-08 | 2013-02-08 | A kind of 20 (S)-protopanoxadiol microballoons and its preparation method and application |
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| CN103976957B true CN103976957B (en) | 2016-11-09 |
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| CN1895256A (en) * | 2006-06-09 | 2007-01-17 | 上海中药创新研究中心 | Use of 20(S)-protopanoxadiol in preparation of antidepressant medicine |
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| CN1895256A (en) * | 2006-06-09 | 2007-01-17 | 上海中药创新研究中心 | Use of 20(S)-protopanoxadiol in preparation of antidepressant medicine |
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| Title |
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| PLGA微球注射剂的研究进展;高秀娟等;《大连理工大学生物医学工程学术论文集》;20051231;第2卷;参见第418页第1栏,第419页第2.1.1栏 * |
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