CN104382858B - Preparation method of oxymatrine/polylactic acid microspheres - Google Patents
Preparation method of oxymatrine/polylactic acid microspheres Download PDFInfo
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- CN104382858B CN104382858B CN201410590100.4A CN201410590100A CN104382858B CN 104382858 B CN104382858 B CN 104382858B CN 201410590100 A CN201410590100 A CN 201410590100A CN 104382858 B CN104382858 B CN 104382858B
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- oxymatrine
- polylactic acid
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Abstract
The invention discloses a preparation method of oxymatrine/polylactic acid microspheres. The preparation method of the oxymatrine/polylactic acid microspheres comprises the following steps: 1) dissolving gelatin in water to obtain a gelatin solution; 2) dissolving oxymatrine and polylactic acid with dichloromethane; 3) slowly adding the solution obtained in the step 2) into the gelatine solution while stirring, and continuously stirring to obtain a microsphere solution; 4) centrifuging, washing the obtained precipitate with water to obtain solid precipitate; and 5) carrying out freeze drying on the solid precipitate obtained in the step 4), thus obtaining the oxymatrine/polylactic acid microspheres. The oxymatrine/polylactic acid microspheres prepared by adopting the method disclosed by the invention have the advantages that average particle size is 8-11 microns, the oxymatrine/polylactic acid microspheres can be retained by blood capillaries of the lungs and concentrated in the lungs, and oxymatrine loaded inside the oxymatrine/polylactic acid microspheres is gradually released to the blood capillaries of the lungs along with decomposition of polylactic acid, so that concentration of oxymatrine in the lungs is always high, a short effective concentration holding time caused by a short half-life period of oxymatrine is avoided, and an effect of continuous and targeted treatment on diseases of the lungs can be realized.
Description
Technical field
The present invention relates to target therapeutic agent field, more particularly to a kind of preparation side of oxymatrine polylactic acid microsphere
Method.
Background technology
Oxymatrine (Oxymatrine) is the main component of alkaloid in the cassia leguminous plants such as Radix Sophorae Flavescentiss.Substantial amounts of medicine
Reason and clinical research find that oxymatrine has various medicines such as antiviral, anti-hepatic fibrosis, heart tonifying, blood pressure lowering, calmness, analgesia
Reason is acted on, inhibited to the vascular endothelial cell proliferation of pulmonary carcinoma, stomach cancer cell induction, and research in recent years is disclosed, oxidation
Matrine is respectively provided with good therapeutic effect for the development of asthma, injury of lung, pulmonary fibrosiss, chronic obstructive pulmonary disease, tool
There is mitigation pneumonia, suppress fibroblast proliferation, reduce the multiple efficacies such as free radical generation, it is shown that this kind of medicine is being controlled
Treat the application prospect in terms of various pulmonary disease.
But found according to available data, oxymatrine there are following pharmacokineticss not enough：
1. half-life short：After oxymatrine drug administration by injection, the elimination half-life about 5min of rat, the elimination half of Healthy People
The phase of declining is only 130.4min, causes oxymatrine valid density to be held time short, it is difficult to long duration of action pulmonary.
2. there is no targeting：After administration, oxymatrine is in vivo with the distribution of blood whole body, proto-drug and its metabolism
Thing is mainly distributed on kidney, and very small amount enters lungs, and useful effect is too small in the dosage of lungs.And it is asthma, pulmonary fibrosiss, chronic
Obstructive pulmonary disease etc. is chronic disease, and life-time service may increase medicine to other organ toxicity's reaction incidence rates, reduce
Patient compliance.
Microsphere (Microsphere) refers to that drug molecule disperses or is attracted in high molecular polymer carrier and formed
Microgranule disperse system, its mean particle dia can be used for arterial thrombosiss, oral and drug administration by injection at 1～300 μm.Medicine makes microsphere
Afterwards, it is mainly characterized by：
1. targeting：Microsphere distribution situation in vivo depends primarily on the size of microsphere, microspherulite diameter 2.5～
10 μm of nanoparticle can be concentrated on Mononuclear phagocyte system；Microsphere more than 7 μm will be concentrated on by the retention of the blood capillary of pulmonary
Lung；More than 40 μm of particle diameter is concentrated on arterial thrombosiss.
2. slow-releasing：Drug release in microsphere need to rely on the degraded of carrier material, and release has a moistening, dissolving, expands
Scattered process, makes drug release slow, reaches the purpose that medicine plays for a long time effect.
The existing various microball preparation listings of foreign countries, such as triptorelin micro-balloon injection (triptorelin,
Decapeptyl), goserelin micro-balloon injection (goserelin, Zoladex), leuprorelin micro-balloon injection
(leuprorelin, Enantone) etc..Also various Lung targeting tuberculosis or antitumor drug microsphere succeed in developing, such as sharp good fortune
Flat gelatine microsphere, Gelatin Microspheres of Carboplatin, etoposide loaded albumin microspheres etc., it is shown that microball preparation is in lung tumors, pulmonary tuberculosis
And good application prospect in pulmonary infection treatment.But, due to oxymatrine water solublity height, it is difficult to be dissolved in organic molten
Agent, causes in microsphere that content is extremely low in oxymatrine.
The content of the invention
For the deficiencies in the prior art, the present invention provides a kind of oxymatrine polylactic acid microsphere and preparation method thereof, leads to
Cross the selection of specific adjuvant, optimum proportioning, the screening of concentration, oxymatrine polylactic acid microsphere particle diameter, the pastille for preparing
Amount is ideal, and targeting is concentrated on pulmonary, and with good biocompatibility and biodegradability, oxymatrine release
Slowly, effect for the treatment of pulmonary disease can for a long time be played.
The technical scheme is that：A kind of preparation method of oxymatrine polylactic acid microsphere, comprises the following steps：
1) take gelatin and gelatin solution is dissolved to obtain in water；
2) oxymatrine, polylactic acid dichloromethane are dissolved；
3) under agitation by step 2) resulting solution is slowly added in gelatin solution, continues to stir to obtain microspheres solution；
4) it is centrifuged, gained precipitation water cleans to obtain solid precipitation；
5) by step 4) gained solid precipitation lyophilization obtain final product oxymatrine microsphere；
The mass ratio of the oxymatrine, polylactic acid and gelatin is 1：0.8-1.2：0.8-1.2, institute's gelatine solution
Concentration is 0.5g/100ml.
Step 2) oxymatrine concentration be 4g/100ml.
As optimal technical scheme, step 2) for ultrasonic dissolution.
As optimal technical scheme, step 3) in oxymatrine lysate and Gelatin liquid volume ratio be 1：8.
As optimal technical scheme, step 3) concrete operations be：Under 1650-1750rpm/min stirrings, by step 2)
Resulting solution is slowly added in gelatin solution, stirs 10min, and 2-3 hours are stirred under 900rpm/min, obtains microspheres solution.
Used as further preferred, the mass ratio of oxymatrine, polylactic acid and gelatin is 1：1：1.
Using above-mentioned technical proposal, with Biodegradable polymer material polylactic acid as carrier, polylactic acid decomposes in vivo
End-product be water and carbon dioxide, therefore obtained oxymatrine polylactic acid microsphere has good biocompatibility and biology
Degradability；The mean diameter of oxymatrine polylactic acid microsphere is 8～11 μm, is concentrated on by the blood capillary retention of pulmonary
Lung, loads the blood capillary that oxymatrine therein is gradually released to pulmonary with the decomposition of polylactic acid so that the oxidation of pulmonary
Matrine remains higher concentration, it is to avoid because valid density is held time short caused by oxymatrine half-life short, reach
Pulmonary disease is continued, targeted therapy is acted on.Therefore, the present invention also provides a kind of oxymatrine polylactic acid microsphere and is preparing lung
Purposes in portion's disease target treatment medicine.
In agents useful for same of the present invention, oxymatrine be Shaanxi Hui Ke plants development corporation, Ltd. product, polylactic acid Shandong
Jinan Dai Gang biological engineering company limited product, gelatin is purchased from Shandong Zibo Ou Chang gelatin sale company limited, with reference to tool
Body embodiment is further described.
Specific embodiment
Embodiment 1：It is prepared by oxymatrine microsphere
Prescription：
Oxymatrine：1.0g
Polylactic acid：1.0g
Dichloromethane：25ml
Gelatin：0.5% (g/ml), 200ml
1. weigh gelatin 5.0g to dissolve in 1000ml purified water, obtain 0.5% gelatin solution, it is stand-by；
2. oxymatrine 1.0g, polylactic acid 1.0g are weighed, is dissolved in 25ml dichloromethane, ultrasound 1 hour is stand-by；
3. the gelatin solution of 200ml 0.5% is measured in 500ml beakers, ultrasonic mistake is slowly added under 1700rpm/min
Oxymatrine afterwards and PLA solution, stir 10min, and 2-3 hours are stirred under 900rpm/min, obtain microspheres solution；
4. microspheres solution is centrifuged with 50ml centrifuge tubes：15min is centrifuged under 4000rpm/min, supernatant is abandoned, purified water is used
20ml cleans precipitation solid, and repeated washing totally 3 times obtains solid precipitation；
5. the solid precipitation for cleaning up is put into into freeze dryer lyophilization 48 hours in -80 DEG C of refrigerator freezing 30min,
Obtain final product oxymatrine microsphere.
Embodiment 2：It is prepared by oxymatrine microsphere
Prescription：
Oxymatrine：1.0g
Polylactic acid：0.8g
Dichloromethane：20ml
Gelatin：0.5% (g/ml), 200ml
1. weigh gelatin 5.0g to dissolve in 1000ml purified water, obtain 0.5% gelatin solution, it is stand-by；
2. oxymatrine 1.0g, polylactic acid 0.8g are weighed, is dissolved in 20ml dichloromethane, ultrasound 1 hour is stand-by；
3. the gelatin solution of 200ml 0.5% is measured in 500ml beakers, ultrasonic mistake is slowly added under 1700rpm/min
Oxymatrine afterwards and PLA solution, stir 10min, and 2-3 hours are stirred under 900rpm/min, obtain microspheres solution；
4. microspheres solution is centrifuged with 50ml centrifuge tubes：15min is centrifuged under 4000rpm/min, supernatant is abandoned, purified water is used
20ml cleans precipitation solid, and repeated washing totally 3 times obtains solid precipitation；
5. the solid precipitation for cleaning up is put into into freeze dryer lyophilization 48 hours in -80 DEG C of refrigerator freezing 30min,
Obtain final product oxymatrine microsphere.
Embodiment 3：It is prepared by oxymatrine microsphere
Prescription：
Oxymatrine：1.0g
Polylactic acid：1.2g
Dichloromethane：30ml
Gelatin：0.5% (g/ml), 200ml
1. weigh gelatin 5.0g to dissolve in 1000ml purified water, obtain 0.5% gelatin solution, it is stand-by；
2. oxymatrine 1.0g, polylactic acid 1.2g are weighed, is dissolved in 30ml dichloromethane, ultrasound 1 hour is stand-by；
3. the gelatin solution of 200ml 0.5% is measured in 500ml beakers, ultrasonic mistake is slowly added under 1700rpm/min
Oxymatrine afterwards and PLA solution, stir 10min, and 2-3 hours are stirred under 900rpm/min, obtain microspheres solution；
4. microspheres solution is centrifuged with 50ml centrifuge tubes：15min is centrifuged under 4000rpm/min, supernatant is abandoned, purified water is used
20ml cleans precipitation solid, and repeated washing totally 3 times obtains solid precipitation；
5. the solid precipitation for cleaning up is put into into freeze dryer lyophilization 48 hours in -80 DEG C of refrigerator freezing 30min,
Obtain final product oxymatrine microsphere.
Comparative example 1：
Prescription：
Oxymatrine：1g
Polylactic acid：0.5ml
Dichloromethane：5ml
Polyvinyl alcohol：0.5ml, 1% (g/ml)
1. weigh polyvinyl alcohol 1.0g to dissolve in 100ml purified water, obtain 1% gelatin solution, it is stand-by；
2. oxymatrine 1.0g, polylactic acid 0.5ml are weighed, is dissolved in 5ml dichloromethane, ultrasound 1 hour is stand-by；
3. the poly-vinyl alcohol solution of 0.5ml 1% is measured in 100ml beakers, under 1700rpm/min ultrasound is slowly added to
Later oxymatrine and PLA solution, stir 10min, and 2-3 hours are stirred under 900rpm/min, obtain microspheres solution；
4. microspheres solution is centrifuged with 50ml centrifuge tubes：15min is centrifuged under 4000rpm/min, supernatant is abandoned, purified water is used
20ml cleans precipitation solid, and repeated washing totally 3 times obtains solid precipitation；
5. the solid precipitation for cleaning up is put into into freeze dryer lyophilization 48 hours in -80 DEG C of refrigerator freezing 30min,
Obtain final product oxymatrine microsphere.
The measure of oxymatrine microsphere drug loading
1. chromatographic condition
Mobile phase：Acetonitrile：Ethanol：3% phosphoric acid liquid=85:10:5
Flow velocity：1.0ml/min；
Detection wavelength：220nm；
Sampling volume：20μl.
2. testing result
High performance liquid chromatograph detection sample is used, oxymatrine polylactic acid microsphere drug loading is calculated：Implement
Example 1 is 6.08%；Embodiment 2 is 5.94%；Embodiment 3 is 5.96%；Comparative example 1 is 3.29%.
Microsphere property analysis：Oxymatrine polylactic acid microsphere form and particle diameter distribution are observed
1) oxymatrine polylactic acid microsphere morphologic observation：
The scanning electron microscope diagram of oxymatrine polylactic acid microsphere shows that balling-up is good, uniformly.
2) oxymatrine polylactic acid microsphere droplet measurement：
Using made oxymatrine microspherulite diameter in 10 μm or so (8-11 μm) percentages as inspection target, implement
Example 1-3 is respectively 78%, 75% and 72%, meets Lung targeting requirement, oxymatrine polylactic acid microsphere is obtained and is enriched in pulmonary
Blood capillary；Comparative example 1 is 55%.
3) oxymatrine polylactic acid microsphere stability experiment：
Obtained oxymatrine polylactic acid microsphere is placed in into 4 DEG C of refrigerator, is taken out behind 3 months, 6 months and is seen
Examine, embodiment 1-3 prepares oxymatrine polylactic acid microsphere form as before, has good stability；Microsphere 3 prepared by comparative example 1
Metamorphosis are obvious during the moon.
4. oxymatrine polylactic acid microsphere controlled drug release and targeting are tested
1) experiment of oxymatrine polylactic acid microsphere tablets in vitro
The external Drug Releasing Test of microsphere is carried out using dialysis.Precision takes oxymatrine or oxymatrine polylactic acid is micro-
Ball, after adding 1ml normal saline to make Oxymatrine alkali dissolution or microsphere be suspended, in being respectively charged into bag filter, bag mouth is tightened, and is put
In the stripping rotor for filling 50ml normal saline, in 37 ± 1 DEG C of constant temperature, persistently rotate under the rotating speed of 50r/min, regularly take release
Liquid 1mL, adds immediately the normal saline of equivalent.The release liquid taken out is detected using HPLC, the cumulative release hundred of medicine is calculated
Divide rate (%).
Quickly, medicine is up to 42.9%, 1h releases 92.8% when 15 minutes for not wrapped OM drug releases in vitro.Implement
, with the slow Slow release of more constant speed, cumulative release amount reaches oxymatrine polylactic acid microsphere prepared by example 1-3 during 12h
86.5% or so, 88-89% is substantially remained in later, with obvious slowly releasing effect.Discharge during microsphere 2h prepared by comparative example 1
Medicine 75.2%, slowly releasing effect is not obvious.
2) distribution experiments in polylactic acid microsphere body
6～8 week old SPF level BALB/C mice (20～22g is provided by Third Military Medical University's Experimental Animal Center).Super
FLuor750, SE (cy7-SE, purchased from Beijing Fanbo Biochemicals Co., Ltd.).
(1) cy7-SE- oxymatrines polylactic acid microsphere preparation method：
1. weigh gelatin 0.5g to dissolve in 100ml purified water, obtain 0.5% gelatin solution, it is stand-by；
2. oxymatrine 50mg, polylactic acid (polylactic acid) 50mg, cy7-SE10mg are weighed, it is molten in 1ml dichloromethane
Solution, ultrasound 1 hour is stand-by；
3. measure the gelatin solution of 10ml 0.5% in 20ml beakers, be slowly added to oxymatrine after ultrasound,
Cy7-SE and PLA solution, high-shear emulsion machine 6000rpm/min stirring 5min is then little with magnetic stirrer 2-3
When, obtain microspheres solution；
4. microspheres solution is centrifuged with 10ml centrifuge tubes：15min is centrifuged under 4000rpm/min, supernatant is abandoned, it is pure with 5ml
Water cleans precipitation solid, and repeated washing totally 3 times obtains solid precipitation；
5. the solid precipitation for cleaning up is put into into freeze dryer lyophilization 48 hours in -80 DEG C of refrigerator freezing 30min,
Obtain final product cy7-SE- oxymatrine polylactic acid microspheres.
(2) distribution observation in cy7-SE- oxymatrines polylactic acid microsphere body
9mg cy7-SE- oxymatrine polylactic acid microspheres, plus 1ml physiological saline solution are weighed, 2000rpm centrifugations are gone
Supernatant, precipitation adds 0.4ml physiological saline solution resuspended, tail vein injection, and phase point is lived and kills animal, living imaging system when predetermined
Observation microsphere tissue distribution patterns.
Experimental result shows that cy7-SE- oxymatrines polylactic acid microsphere is distributed mainly on lung tissue after injection, other groups
Nearly no fluorescence is knitted, the fluorescence intensity of lung tissue is gradually lowered from 30min, 2h, 24h, 168h.Illustrate prepared by this method micro-
Ball has lung targeted characteristic, and with slow-releasing.
Conclusion：
1. the oxymatrine polylactic acid microsphere that prepared by the present invention, balling-up is good, and uniformly, its mean diameter is 8-11 μ
M, meets Lung targeting requirement.
2. the microsphere that prepared by the present invention has lung targeted characteristic in rat kidney tissue, and release in vitro has obvious slow-releasing.
The principle and its effect of above-described embodiment only illustrative present invention, it is of the invention not for limiting.It is any ripe
Know the personage of this technology all can carry out modifications and changes under the spirit and the scope without prejudice to the present invention to above-described embodiment.Cause
This, such as those of ordinary skill in the art is complete with institute under technological thought without departing from disclosed spirit
Into all equivalent modifications or change, should by the present invention claim be covered.
Claims (6)
1. a kind of preparation method of oxymatrine polylactic acid microsphere, comprises the following steps：
1) take gelatin and gelatin solution is dissolved to obtain in water；
2) oxymatrine, polylactic acid dichloromethane are dissolved；
3) under agitation by step 2) resulting solution is slowly added in gelatin solution, continues to stir to obtain microspheres solution；
4) it is centrifuged, gained precipitation water cleans to obtain solid precipitation；
5) by step 4) gained solid precipitation lyophilization obtain final product oxymatrine microsphere；
The mass ratio of the oxymatrine, polylactic acid and gelatin is 1：0.8-1.2：0.8-1.2, the concentration of institute's gelatine solution
For 0.5g/100ml.
2. the preparation method of oxymatrine polylactic acid microsphere as claimed in claim 1, it is characterised in that step 2) Oxymatrine
The concentration of alkali is 4g/100ml.
3. the preparation method of oxymatrine polylactic acid microsphere as claimed in claim 1 or 2, it is characterised in that step 2) for ultrasound
Dissolving.
4. the preparation method of oxymatrine polylactic acid microsphere as claimed in claim 1 or 2, it is characterised in that step 3) in oxidation
The volume ratio of matrine lysate and Gelatin liquid is 1：8.
5. the preparation method of oxymatrine polylactic acid microsphere as claimed in claim 1 or 2, it is characterised in that step 3) it is concrete
Operate and be：Under 1650-1750rpm/min stirrings, by step 2) resulting solution is slowly added in gelatin solution, stirs 10min,
2-3 hours are stirred under 900rpm/min, microspheres solution is obtained.
6. as the oxymatrine polylactic acid microsphere that any one of claim 1-5 is prepared is preparing pulmonary disease targeting
Purposes in medicine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1676121A (en) * | 2004-03-29 | 2005-10-05 | 中国人民解放军军事医学科学院毒物药物研究所 | Slow-release micro-ball formulation for tissue, organ local therapy, and its preparing method and use |
| CN101138551A (en) * | 2007-09-24 | 2008-03-12 | 广州呼吸疾病研究所 | Preparation method of lung targeting emodin polylactic acid microsphere and application in anti-mouse pulmonary fibrosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104013582B (en) * | 2014-06-27 | 2016-08-31 | 陶玲 | A kind of preparation method of aspirin PEG-PLGA microsphere |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1676121A (en) * | 2004-03-29 | 2005-10-05 | 中国人民解放军军事医学科学院毒物药物研究所 | Slow-release micro-ball formulation for tissue, organ local therapy, and its preparing method and use |
| CN101138551A (en) * | 2007-09-24 | 2008-03-12 | 广州呼吸疾病研究所 | Preparation method of lung targeting emodin polylactic acid microsphere and application in anti-mouse pulmonary fibrosis |
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