CN101991560A - Method for preparing WR-2721 enteric-coated microcapsules - Google Patents
Method for preparing WR-2721 enteric-coated microcapsules Download PDFInfo
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- CN101991560A CN101991560A CN2010102759954A CN201010275995A CN101991560A CN 101991560 A CN101991560 A CN 101991560A CN 2010102759954 A CN2010102759954 A CN 2010102759954A CN 201010275995 A CN201010275995 A CN 201010275995A CN 101991560 A CN101991560 A CN 101991560A
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Abstract
The invention relates to a process for preparing WR-2721 enteric-coated microcapsules, which comprises the following steps: using polymer material Eudrgit series, using an appropriate organic solvent for dissolution, preparing emulsion with drugs under the action of a surfactant, and using dry spraying technology to prepare the microcapsules; experiments prove that the identification result of thermodynamics indicates that the microcapsules successfully coat the drugs, the microcapsules are shaped like pellets, and the surface smooth diameter is 0.7 mu m-10mu m through observation by an electronic scanning microscope; in an experiment of preventing radiation damages, 25-100mg/Kg can improve the survival rate of BALB/c mice radiated by 60Co gamma ray 6Gy, indicating that the WR-2721 enteric-coated microcapsules can be used for preventing the radiation damages.
Description
Technical field
The present invention relates to a kind of preparation method of enteric-coated microcapsule, particularly the preparation method of WR-2721 enteric-coated microcapsule.
Background technology
WR-2721 is the cytoprotective of first approval listing, is mainly used in caused side effect when alleviating ovarian cancer and non-small cell lung cancer chemotherapy and the radiotherapy of incidence cancer clinically
[1,2], but because of administering mode is an intravenously administrable, oral absorption is few
[3,4], influenced it and further applied.The present invention intends by preparation WR-2721 oral enteric biodegradation microcapsule, thereby improves its oral availability.
Summary of the invention
The present invention is wrapped in WR-2721 in the Biodegradable polymer material, is prepared into the WR-2721 microcapsule, experimental results show that and can reach obviously raising mice survival rate by the prolong drug drug release time from external release and 30 days survival rates.
(1) Biodegradable high-molecular is dissolved in the organic solvent, is made into concentration and is 2～4% solution, add concentration and be 0.5～2% surfactant, form organic solvent solution oil phase O;
(2) WR-2721 is dissolved in the deionized water, makes the WR-2721 aqueous solution of 20～100mg/ml, form the first water W
1
(3) agar is dissolved in the hot water, makes 0.1～0.5% aqueous solution, form the second water W
2
(4) glycerol is dissolved in the deionized water, makes 0.4～1% solution, form the 3rd water W
3
(5) with (2) (3) (4) solution mix homogeneously, mixed liquor slowly is added drop-wise among (1) oil phase O, stirs at the condition of ice bath lower magnetic force, and mixing speed is 500～800rpm, and emulsifying forms water-in-oil type emulsion w/o; Continue to stir 1h and get uniform emulsion;
(6) emulsion (5) is used spray drying technology, 60～75 ℃ of intake air temperatures, 60～80 ℃ of outlet temperatures, air inducing amount 80～95% is carried out spray drying, gets the WR-2721 microcapsule;
Described Biodegradable polymer material is the mixture of acrylic resin II, III or two kinds;
Described organic solvent is dehydrated alcohol or acetone;
Described surfactant is Arlacel-80 or Arlacel-60;
1. according to the preparation method of the described WR-2721 microcapsule of claim 1, it is characterized in that: the volume ratio of described water-in-oil type emulsion w/o is w: o=1: 25～1: 5;
2. according to the preparation method of the described WR-2721 microcapsule of claim 1, it is characterized in that: the particle diameter of described microcapsule is for greatly between 0.7 μ m～10 μ m.
The present invention has the following advantages:
1, invents WR-2721 oral enteric microcapsule, changed intravenous injection in the past, taking convenience.
2, certain slow releasing function is arranged, and make the microcapsule rear stability and improve a lot.
3, preparation time is short, and simple.
3, WR-2721 oral enteric microcapsule can improve
60C
0The current deposit rate of gamma-rays 6Gy total irradiation BALB/c mouse, these characteristics help it is developed to radioprotector, are used for prevention and treatment radiation damage, improve patient's life quality.
Description of drawings
The outward appearance and the measuring diameter of Fig. 1 WR-2721 microcapsule
Fig. 2 macromolecular material thermodynamics is identified figure
Fig. 3 WR-2721 crude drug thermodynamics is identified figure
Fig. 4 microcapsule thermodynamics is identified figure
The prevention administration of Fig. 5 WR-2721 microcapsule is right
60C
0The influence of gamma-rays 6Gy one subtotal body irradiation BALB/c mouse current deposit rate.
The curve chart during medicine of Fig. 6 WR-2721 microcapsule and WR-2721
The specific embodiment
Embodiment 1: get Eudragit E udragitL100-50 1g, be dissolved in the 50ml dehydrated alcohol, form oil phase o, stir at the condition of ice bath lower magnetic force, mixing speed is 500～800rpm, slowly adds W to this oil phase
1W
2W
3Mixed aqueous solution makes its emulsifying, continues to stir 1h and gets uniform emulsion; With the emulsion spray drying technology, 60～75 ℃ of intake air temperatures, 60～80 ℃ of outlet temperatures, air inducing amount 80～95% is carried out spray drying, gets the WR-2721 microcapsule; The envelop rate of gained microcapsule is 20%, and the particle diameter of microcapsule is 0.7 μ m～10 μ m, and cumulative release 70～80% in 24 hours, and external release reaches 60h.
Embodiment 2: method for making is with embodiment 1, and wherein the organic solvent dehydrated alcohol changes acetone into;
Embodiment 3: get EudragitS100 1g, be dissolved in the 50ml dehydrated alcohol, form oil phase o, stir at the condition of ice bath lower magnetic force, mixing speed is 500～800rpm, slowly adds W to this oil phase
1W
2W
3Mixed aqueous solution makes its emulsifying, continues to stir 1h and gets uniform emulsion; With the emulsion spray drying technology, 60～75 ℃ of intake air temperatures, 60～80 ℃ of outlet temperatures, air inducing amount 80～95% is carried out spray drying, gets the WR-2721 microcapsule; The envelop rate of gained microcapsule is 19%, and the particle diameter of microcapsule is 0.9 μ m～10 μ m, and cumulative release 75～80% in 24 hours, and external release reaches 65h.
Embodiment 4: get EudragitRS100 and EudragitRL 100 molecule ratios are 1: 4, be total to 1g, be dissolved in the 50ml acetone,, form oil phase o, stir at the condition of ice bath lower magnetic force, mixing speed is 500～800rpm, slowly add the W1W2W3 mixed aqueous solution to this oil phase, make its emulsifying, continue to stir 1h and get uniform emulsion; With the emulsion spray drying technology, 60～75 ℃ of intake air temperatures, 60～80 ℃ of outlet temperatures, air inducing amount 80～95% is carried out spray drying, gets the WR-2721 microcapsule; The envelop rate of gained microcapsule is 20%, and the particle diameter of microcapsule is 0.9 μ m～10 μ m, and cumulative release 70～80% in 24 hours, and external release reaches 72h.
Embodiment 5:WR-2721 microcapsule is right
60C
0The influence of gamma-rays 6Gy one subtotal body irradiation BALB/c mouse current deposit rate
Materials and methods
1.BALB/c mice is raised
Select 60 of the male BALB/c mouse of 18～22g for use, buy by Military Medical Science Institute zoopery center.21 ℃ ± 2 ℃ of mice feeding environment temperature, relative humidity 50% ± 10%, 12 hours dark of 12 hours light, 1 week of precuring.
2.WR-2721 microcapsule is right
60C
0The influence of gamma-rays 6Gy one subtotal body irradiation BALB/c mouse current deposit rate
Medication preparation: precision takes by weighing WR-2721 crude drug 10mg, adds normal saline 5ml, is configured to 2mg/ml solution; WR-2721 microcapsule powder an amount of (containing the about 25mg of WR-2721,50mg, 100mg), it is standby to add appropriate amount of deionized water formation suspension respectively.
Animal grouping and processing: 60 of BALB/c mouse are divided into six groups at random, every group 10, model group is irritated stomach equal-volume normal saline, positive drug WR-2721 group is pressed the 50mg/kg lumbar injection, WR-2721 presses the 50mg/kg gastric infusion for oral group, WR-2721 microcapsule low dose group is pressed 25mg/kg dosage and is irritated stomach, and the dosage group is pressed 50mg/kg dosage and irritated stomach in the WR-2721 microcapsule, and WR-2721 microcapsule high dose group is pressed 100mg/kg dosage and irritated stomach.Positive drug WR-2721 organizes irradiation
60C
030min lumbar injection before the gamma-rays 6Gy, all the other each groups are all at 1 hour gastric infusion of pre-irradiation.
Work in 30 days is deposited situation and is observed:
60C
0Gamma-rays 6Gy irradiation back BALB/c mouse loses weight, dry skin and hair, and lethargy is slow in action, and rolls into a ball the hogback that contracts, visual disorder.Each administration group is compared with model group, and the above-mentioned sign of mice all makes moderate progress.
3.WR-2721 the processing of microcapsule exercising result and statistics
WR-2721 microcapsule prevention administration is right
60C
0The influence of gamma-rays 6Gy one subtotal body irradiation BALB/c mouse current deposit rate.The result carries out statistical analysis with Origin Pro 7.5.
30 days current deposit rates of BALB/c mouse of the 6Gy irradiation handled of different pharmaceutical various dose as a result the results are shown in Table 1 Fig. 5.WR-2721 microcapsule preventive administration can improve
60C
0The current deposit rate of gamma-rays 6Gy one subtotal body irradiation BALB/c mouse.
Table 1WR-2721 microcapsule preventive administration is right
60C
0The influence of the BALB/c mouse current deposit rate of gamma-rays 6Gy irradiation
Compare with model group: *, P＜0.05; *, P＜0.01.
Embodiment 6: scanning electron microscope example preparation and microcapsule shape, measuring diameter
With conductive silver glue or two-sided conducting resinl sample is pasted on the object stage, sightingpiston should make progress, and carries out the ion sputtering plated film 3～5 minutes with the vacuum evaporating instrument then, last machine microscopy.Metal commonly used has gold, copper, aluminum, gold-platinum (6: 4) etc., vacuum 10
-6～10
-5Torr (0.13 * 10
-3～0.13 * 10
-2Pa).Examining under a microscope most of microcapsule is spherical single capsule, smooth surface and scrotiform rounding, disperse better, adhesion, capsule intensity be also better.See Fig. 1
Embodiment 7: the microcapsule thermodynamic analysis
With differential scanning calorimetry (DSC), use calorimeter (TA2920), get microcapsule, WR-2721 crude drug, each about 5mg of macromolecular material, the accurate title, decide, and in the aluminum dish of packing into, is put on the sample holder, with 5 ℃ of min
-1Heating rate is heated to 250 ℃, and high score ascus material is at 140～150 ℃ of no melting peaks as a result, and WR-2721 crude drug and microcapsule have melting peak at 143.7 ℃ and 146.02 ℃ respectively, and three's melting peak is shown in Fig. 2, Fig. 3, Fig. 4.
Embodiment 8: measure the bioavailability experiment
Get the beasle dog 12h that goes on a hunger strike, irritate stomach WR-2721 and WR-2721 microcapsule 100mg respectively, 0,15min, 30min, 45min, 1h, 1.5h, 2.0h, 3.0h, 4.0h, 6.0h, 8.0h, 10h, 12h time point in the past the hind leg vein get blood 1ml, add cold perchloric acid-EDTA (1M/2.7mM) solution 1ml at once, shake 5 times, protein precipitation gently, and at hypervelocity refrigerated centrifuge 12000rpmmin
-1(4 ℃) centrifugal 10min draws supernatant and filters with needle-based filter membrane (0.22 μ m), with high effective liquid chromatography for measuring (or be kept at-70 ℃ to be measured).Chromatographic condition
[5]: detached dowel C
18(Angilent 150mm * 3.9mm, 5 μ m); Mobile phase is acetonitrile-water (perfluorooctane sulfonate of 0.1M monoxone and 5mM is transferred pH to 3.0 with triethylamine) (15: 85), flow velocity 1.0mlmin
-1Detector is electrochemical detector (a Hg/Au electrode), and oxidizing potential is set at+0.2V; Injection volume is 20 μ L.Curve such as Fig. 6 during the medicine of two groups of medicines.The AUC that can find out the WR-2721 microcapsule is greater than WR-2721, and peak time is more or less the same, but the WR-2721 microcapsule all keeps higher release level from 45min～3h, has improved bioavailability, and slow releasing function is arranged.
Claims (3)
1. the preparation method of a WR-2721 enteric-coated microcapsule is characterized in that may further comprise the steps:
(1) Biodegradable high-molecular is dissolved in the organic solvent, is made into concentration and is 2～4% solution, add concentration and be 0.5～2% surfactant, form organic solvent solution oil phase O;
(2) WR-2721 is dissolved in the deionized water, makes the WR-2721 aqueous solution of 30～50mg/ml, form the first water W
1
(3) agar is dissolved in the hot water, makes 0.1～0.5% aqueous solution, form the second water W
2
(4) glycerol is dissolved in the deionized water, makes 0.4～1% solution, form the 3rd water W
3
(5) with (2) (3) (4) solution mix homogeneously, mixed liquor slowly is added drop-wise among (1) oil phase O, stirs at the condition of ice bath lower magnetic force, and mixing speed is 500～800rpm, and emulsifying forms water-in-oil type emulsion w/o; Continue to stir 1h and get uniform emulsion;
(6) emulsion (5) is used spray drying technology, 60～75 ℃ of intake air temperatures, 60～80 ℃ of outlet temperatures, air inducing amount 80～95% is carried out spray drying, charging rate 2～4mlmin
-1, compressor flow 400～600Lh
-1, air pump 12～15Pa gets the WR-2721 microcapsule;
Described Biodegradable polymer material is the mixture of acrylic resin II, III or two kinds;
Described organic solvent is dehydrated alcohol or acetone;
Described surfactant is an Arlacel-80, or Arlacel-60.
2. according to the preparation method of the described WR-2721 microcapsule of claim 1, it is characterized in that: the volume ratio of described water-in-oil type emulsion w/o is w: o=1: 25～1: 5.
3. according to the preparation method of the described WR-2721 microcapsule of claim 1, it is characterized in that: the particle diameter of described microcapsule is 0.7 μ m～10 μ m.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110200941A (en) * | 2019-06-24 | 2019-09-06 | 苏州大学 | Act on the radiation protection Nano medication and preparation method thereof of small intestine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101347412A (en) * | 2008-09-02 | 2009-01-21 | 大连美罗药业股份有限公司 | Amifostine trihydrate crystal lyophilized preparation and method of preparing the same |
| CN101637453A (en) * | 2009-08-14 | 2010-02-03 | 西北工业大学 | Method for preparing amifostine microspheres |
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2010
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101347412A (en) * | 2008-09-02 | 2009-01-21 | 大连美罗药业股份有限公司 | Amifostine trihydrate crystal lyophilized preparation and method of preparing the same |
| CN101637453A (en) * | 2009-08-14 | 2010-02-03 | 西北工业大学 | Method for preparing amifostine microspheres |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110200941A (en) * | 2019-06-24 | 2019-09-06 | 苏州大学 | Act on the radiation protection Nano medication and preparation method thereof of small intestine |
| CN110200941B (en) * | 2019-06-24 | 2020-05-15 | 苏州大学 | Radiation protection nano-medicine acting on small intestine and preparation method thereof |
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Application publication date: 20110330 |