CN1903365A - Drug-carried nanometer particles, and its preparing process for preparing medicien prepn. for anti-restenosis of blood-vessel - Google Patents
Drug-carried nanometer particles, and its preparing process for preparing medicien prepn. for anti-restenosis of blood-vessel Download PDFInfo
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Abstract
A medicine carrying nanoparticle is composed of a biodegradable high-molecular material chosen from PCL, PLA and PLGA, and the medicine chosen from the medicine for suppressing vascular endothelial hyperplasy, the medicine for suppressing cell reproduction, the thrombus dissolving medicine, anticoagulation medicine, and anti-inflammatory medicine. Its preparing process and its application in preparing the medicine for suppressing reangiostenosis are also disclosed.
Description
Technical field
The invention belongs to a kind of new application of medicine being made the method and formulation of special physical form that is exclusively used in, be specifically related to a kind of drug-carried nanometer and preparation method thereof and the application of this microgranule in the anti-angiogenic restenosis preparation of preparation
Background technology
Nanoparticle comprises Nano microsphere and nano-microcapsule, and they are diameter solid colloid particles between 1-1000nm, and active component (medicine, bioactive materials etc.) can be wrapped in particle inside, also can be attached to particle surface.Nanoparticle is a kind of novel form that has future, as pharmaceutical carrier, nanoparticle distributes in the body that can change medicine, has the targeting, also has advantages such as the drug release rate of adjusting, raising bioavailability, thereby becomes the focus of people's Recent study.Had with multiple material preparation the nano controlled release system that differs from one another now.The method for preparing the nano controlled release system has polyreaction method and polymeric material dispersion method, emulsion polymerisation and interfacial polymerization technology that the former is prepared by polyreaction as the use different monomers; The method of the latter as utilizing high molecular polymer to adopt emulsifying-solvent evaporation method to be prepared.Medicine in the nano controlled release system can discharge by diffusion into the surface, also can by substrate itself gradually corrosion degraded drug release is wherein come out.The slow release of the polymer matrix may command medicine of nanoparticle, thus reach the permanently effective purpose of a drug.
Vascular restenosis be blood vessel at interventional therapy (as angioplasty, tremulous pulse rotary-cut art, implantable intravascular inner support etc.) afterwards, process narrow, that block takes place once more.The approach of medical treatment restenosis concentrates on usually intervenes its early process, as platelet deposition, thrombosis etc., perhaps blocks its intermediary and later stages process, i.e. smooth muscle cell proliferation or substrate forming process.These medicated bags are drawn together thrombolytic, anti-inflammatory agent and the antiplatelet drug of blocking-up early process.And antiproliferative pharmaceutical has the effect of growth factor receptor inhibitors and cytostatics, can suppress the later stage process of restenosis.Therefore the drug release of same-action does not act on the different phase that causes the restenosis process in the vascular lesion position, comes to prevent and treat more effectively restenosis.
Chinese patent 1561987A discloses application and the preparation method of Biodegradable high-molecular Nano microsphere aspect the treatment cancer that is loaded with paclitaxel, contains polylactone-polyethyleneglycol block copolymer of 80-90% in its Nano microsphere, the paclitaxel of 10-20%.Aqueous solution with polyvinyl alcohol or gelatin is a disperse medium, and the organic solvent that contains polylactone-ethylene glycol copolymer and paclitaxel is added wherein, carries out ultrasonic emulsification, and decompression volatilization organic solvent obtains the Nano microsphere that particle diameter is the 300-800 nanometer then.And do not appear in the newspapers as yet with the application of nanoparticle in treatment vascular restenosis pharmaceutical preparation of artificial synthesizing biological degradable macromolecular material preparation, also process finishing.
Chinese patent 1507928A discloses a kind of support that can be used for the preventing/treating vascular restenosis with medication coat, and it has the effect of anti-angiogenic restenosis.It is coated on the support by the medication coat that will have multiple mechanism of action, prevents/treat postoperative restenosis effectively.But the place in that some privileged sites such as blood vessel intersection, thinner blood vessel etc. can not placing racks just can't utilize support to prevent hemostatic tube generation restenosis.
Summary of the invention
The objective of the invention is also can control vascular restenosis in advance in the place that support can not arrive, and a kind of drug-carried nanometer and preparation method thereof and the application of this microgranule in the anti-angiogenic restenosis preparation of preparation are provided in order to solve in the prior art
The invention technical conceive:
Drug-carried nanometer and can be by cellular uptake because its ultra micro small size makes it be very easy to enter interstice, it can also be safely blood capillary (4 μ m) by the human body minimum enter target organ, therefore, can be used as the carrier of target administration.The present invention adopts emulsifying-solvent evaporation method to prepare nanoparticle.Nanoparticle is modified can to increase itself and the adhering material of vascular tissue, can select methods such as suitable physics or chemical method such as physical blending, surface adsorption and chemical coupling that it is incorporated into nano-particle surface, thereby improve the content of nanoparticle in vascular tissue.During use according to the different state of an illness, the medicine carrying microgranule of different pharmaceutical effect can be pressed the mixed of dosage, be made into and mix the use of suspension preparation, adopt the known interventional therapy of those skilled in the art to be loaded with the nanoparticle of different drugs with function with the foley's tube handle, be discharged into the vascular lesion position, act on the different phase that causes the restenosis process, come to prevent and treat more effectively restenosis.The nano controlled release technology combines with interventional therapy and can realize the blood vessel generation restenosis that the topical control can not arrive at support in the blood vessel.
The invention technical scheme:
A kind of drug-carried nanometer, it is made up of biodegradable polymer and medicine, its biodegradable polymer comprises a kind of in polycaprolactone (PCL), polylactic acid (PLA) and polylactic acid-polyglycolic acid copolymer (PLGA), its medicine is respectively to suppress blood vessel endothelium hypertrophy medicine, cell proliferation medicine, thrombolytic agent, anticoagulation medicine and anti-inflammatory agent, its macromolecular material percentage by weight is 70-95%, the medicine overall weight percent is than being 5-30%, and the mean particle dia scope is the 50-500 nanometer.Nano-particle surface is modified through trim.
Described nanoparticle, it suppresses blood vessel endothelium hypertrophy medicine is paclitaxel; The cell proliferation medicine is a cytochalasin B; Thrombolytic agent comprises urokinase, streptokinase or sense of organization plasminogen activator etc.; Anticoagulation medicine is a heparin; Anti-inflammatory agent is a dexamethasone.
Described nanoparticle, it promotes the trim of nanoparticle intravasation wall tissue to comprise: a kind of in bromination pair dodecyl dimethyls (DMAB), poly-l-lysine and the protamine sulfate, the percentage by weight of trim is 2-10%, and the percentage by weight of nanoparticle is 90-98%.
A kind of preparation method of drug-carried nanometer, the present invention adopts emulsifying-solvent evaporation method to prepare nanoparticle, and it modifies the nanoparticle for preparing, and comprises the following steps:
(1) a kind of with in the two dodecyl dimethyl ammoniums (DMAB) of bromination, poly-l-lysine and the protamine sulfate is dissolved in the water, and compound concentration is the trim aqueous solution of 0.5-4mg/ml;
(2) nanoparticle is added above-mentioned trim aqueous solution, be made into the suspension of concentration 9.5-76mg/ml, high-speed stirred or supersound process 10-120s evenly suspend nanoparticle;
(3) lyophilization.
The application of nanoparticle in the anti-angiogenic restenosis preparation of preparation.
In order to understand essence of the present invention better, below the effectiveness of drug-carried nanometer in the treatment of vascular restenosis is described with the absorbtivity of nanoparticle in the blood vessel and the test of bone tremulous pulse histopathology form and result thereof.
1. the test of nanoparticle absorbtivity in the blood vessel
In order to increase curative effect, need resident more nanoparticle on the blood vessel wall, increase the concentration of nanoparticle in the suspension, can increase the content of nanoparticle in the blood vessel.The pacilitaxel nano granule zoopery shows that after the nanoparticle suspension perfusion with variable concentrations, the content of taxol in the isolated pig carotid artery is measured (use chloroform extraction, detect with high-efficient liquid phase technique then) and be the results are shown in Table 1.Along with the increase of concentration, the content of paclitaxel also increases thereupon in the blood vessel.Show that concentration has very important influence to the absorbtivity of nanoparticle.Theoretically, arterial wall is increased to a certain degree the absorption of nanoparticle and saturated phenomenon can occur.But (5mg/ml-50mg/ml) do not show saturated sign as yet in the concentration range of this experiment.Consider when adopting the conduit system administration, nanoparticle need be passed the micropore of conduit, concentration is high more, the probability of blocking micropore is big more, so when testing in the suggestion body, adopt the nanoparticle suspension of 30mg/ml left and right sides concentration better, can pass through the sacculus micropore smoothly, can reach higher blood vessel absorbtivity again.This high concentration method consumes more medicine, and the surface of nanoparticle process is modified, and the suspension of same concentrations just can increase the absorbtivity of microgranule in the blood vessel.The current potential (Zeta potential) of nano-particle surface electric charge is-3.27mv before modifying, modifying back nano-particle surface mean charge Zeta potential is 20.10mv, because DMAB is a cationic surfactant, it has changed the surface charge of nanoparticle, be rich in electronegative glycosaminoglycan in the vascular wall tissue, thereby interaction by positive and negative charge, promoted the absorption of nanoparticle in blood vessel wall and resident.Pacilitaxel nano granule can make that the absorbtivity of nanoparticle improves nearly 3 times in the blood vessel after DMAB modifies.According to same quadrat method, the pacilitaxel nano granule with three kinds of trim modifieds of same ratio all can improve the absorbtivity of vascular tissue to it, and effect sees Table 2.
The influence that table 1 nanoparticle suspension concentration absorbs its blood vessel
| Blood vessel | The absorbtivity of nanoparticle in the blood vessel wall (μ g/10mg tremulous pulse dry weight) | ||||
| 5mg/ml | 10mg/ml | 20mg/ml | 30mg/ml | 50mg/ml | |
| X±SD | 6.59± 1.12 | 12.94± 1.39 | 21.90± 3.87 | 35.73± 4.99 | 50.37± 4.96 |
Annotate: compare P＜0.001 between each group
Table 2 nano-particle surface is modified the influence that its vascular tissue is absorbed
| The absorbtivity of nanoparticle in the blood vessel wall (μ g/10mg tremulous pulse dry weight) | |||
| Do not modify | DMAB | Poly-D-lysine | Protamine |
| 6.20±1.56 | 19.12±6.34 | 10.0±1.62 | 10.97±1.7 |
Can find out in three kinds of trims preferably by table 2, can make that the absorbtivity of nanoparticle improves nearly 3 times in the blood vessel with the DMAB effect.
2. bone tremulous pulse histopathology form test
The mechanism of prevention and reduction restenosis is to suppress neointimal hyperplasia, and the present invention has obvious effects to this.This experiment is to carry out on the model of excessively pulling the bone tremulous pulse of rabbit, totally 10 examples.Compare with each contrast groups, after 28 days, show that regional perfusion's dexamethasone nanoparticle is obvious to the inhibitory action of vascular restenosis in the blood vessel in the perfusion nanoparticle, the result is as shown in table 3.The available Fig. 1 of result, Fig. 2 of three groups represent more intuitively after in the table 3.The result shows, perfusion dexamethasone nanoparticle (DEX-NP) group is compared with intravenous injection DEX-NP group and regional perfusion's blank nanoparticle group in the local vascular, media area is similar (P＞0.05), and the tube chamber area increases (P＜0.05), and the inner membrance area reduces (P＜0.05).After the interior perfusion of local vascular dexamethasone nanoparticle was described, neointimal hyperplasia was subjected to obvious inhibition, thereby is maintained bigger tube chamber area.Intravenous injection DEX-NP group is compared with regional perfusion blank nanoparticle group, and the formation of new intima is not had obvious influence, and the neointimal hyperplasia unrestraint effect of whole body application DEX-NP to injured blood vessel be described.Compare with the blank nanoparticle group of intravenous injection DEX-NP group and regional perfusion, inner membrance/media area ratio that perfusion DEX-NP organizes in the local vascular has reduced 46.9% and 45.9% respectively.
Table 3. iliac artery histopathology morphometric Analysis result (X ± SD)
| Pathomorphism | Normal saline regional perfusion | Nanoparticle regional perfusion | The intravenous injection of dexamethasone nanoparticle | Dexamethasone nanoparticle regional perfusion |
| MIT(mm) LA(mm 2) IEL(mm 2) EEL (mm 2) IA(mm 2) MA (mm 2) Intima/Me dia | 0.225± 0.023 1.217± 0.137 1.844± 0.203 2.376± 0.265 0.630± 0.104 0.536± 0.120 1.178± 0.411 | 0.227± 0.038 1.225± 0.181 * 1.867± 0.252 2.421± 0.229 0.647± 0.190 * 0.559± 0.113 * 1.159± 0.379 * | 0.230± 0.033 1.226± 0.185 1.902± 0.203 2.465± 0.263 0.664± 0.109 0.563± 0.145 1.180± 0.243 | 0.140± 0.038 ** 1.564± 0.176 ** 1.924± 0.154 * 2.527± 0.230 * 0.368± 0.118 ** 0.569± 0.115 * 0.627± 0.238 ** |
Annotate: MIT, maximum neointimal hyperplasia thickness; LA, the tube chamber area; IEL, interior elastic force film inner area; EEL, outer elastic force film inner area; IA, the inner membrance area; MA, media area; Intima/Media, inner membrance and media area ratio, i.e. hypertrophy index.* compare P＞0.05 with each group of its left side; * compares P＜0.05 with each group of its left side
The present invention can increase the content of nanoparticle in the blood vessel by the drug-carried nanometer of modification, produces the little eutherapeutic effect of dosage.And drug-carried nanometer being transported to the vascular injury place that can not put support by foley's tube, the nanoparticle of different drugs with function acts on the different phase that causes the restenosis process, comes to prevent and treat more effectively restenosis.The nano controlled release technology combines with interventional therapy and can realize topical treatment of vascular restenosis in the blood vessel.Thereby prevent the blood vessel generation restenosis that support can not arrive effectively.
Description of drawings
Fig. 1: different modes of administration is for the inhibitory action of vascular restenosis
Fig. 2: different modes of administration is for the influence of neointimal hyperplasia
Fig. 3: the preparation flow of the drug-carried nanometer of fat-soluble medicine
Fig. 4: the preparation flow of the drug-carried nanometer of water soluble drug
The specific embodiment
The preparation method of the Biodegradable high-molecular nanoparticle that is loaded with anti-angiogenic restenosis medicaments of the present invention is as follows:
One, the preparation method of the drug-carried nanometer of fat-soluble medicine
Fat-soluble medicine such as paclitaxel and dexamethasone adopts oil-in-water (O/W) emulsifying-solvent evaporation method to prepare (see figure 3), and method is as follows:
1. the certain volume dichloromethane dissolves an amount of Biodegradable high-molecular concentration 0.5-4%, and certain volume acetone solution appropriate amount of drug concentration is 0.02-4%, mixes dichloromethane/acetone (ratio is 9: 1 or 8: 2) organic solution then.
2. mixed organic solvents joins (organic solution/aqueous solution=1: 3 to 1: 4) in certain volume (polyvinyl alcohol) the PVA aqueous solution (0.5-2.5%), supersound process 30s-10min under the condition of ice bath.
3. normal pressure stirs volatilization 2-18h down, and the volatilization 1-6h that reduces pressure again is to remove organic solvent.
4. ultracentrifugation 30min under low temperature (4 ℃-15 ℃), the 15000-25000rpm collects solidified nanoparticle, reuse distilled water wash, the centrifugal polyvinyl alcohol of removing in the nanoparticle suspension for 1-3 time.
5. the nanoparticle preparation is finished in lyophilization.
6. prepare the trim aqueous solution of 0.5-4mg/ml concentration.
7. nanoparticle is added above-mentioned trim aqueous solution, compound concentration is the suspension of 9.5-76mg/ml, and high-speed stirred or supersound process 10-120s evenly suspend nanoparticle.
8. anti-angiogenic restenosis drug-carried nanometer preparation is finished in lyophilization.
9. adopt the cobalt between the 15-30kGy
60The gamma-rays of emission shines nanoparticle sterilizes.
Two, the preparation method of the drug-carried nanometer of water soluble drug
Water soluble drug such as urokinase and heparin adopts emulsion (W/O/W) change-solvent evaporation method to prepare (see figure 4), and method is as follows:
1. the water soluble drug of certain mass is dissolved in the distilled water, concentration is 20-30%, the dichloromethane of certain volume (DCM) or dichloromethane/acetone (8: 2 or 9: 1) organic solution is dissolved an amount of Biodegradable high-molecular capsule material (concentration is 0.5-10%), and the Pu Luonike F68 (Pluronic F68) that contains certain proportion (0.01%-0.1%) in the organic solution is as emulsifying agent
2. pharmaceutical aqueous solution is joined in the organic solution that (pharmaceutical aqueous solution: organic solvent volume ratio=1: 4-20), ultrasonic or high-speed stirred 30s-10min under condition of ice bath forms W immediately
1/ O solution.
3. under 4 ℃ of conditions, cool off with stabilising colostrum
4. colostrum joins in the PVA aqueous solution that concentration is 0.5-2.5%, carries out ultrasonic or high-speed stirred emulsifying 30s-10min equally under condition of ice bath, promptly forms W
1/ O/W
2Emulsion.
5. normal pressure stirs volatilization 2-18h down, and the volatilization 1-6h that reduces pressure again is to remove organic solvent.
6. low temperature (4 ℃-15 ℃), ultracentrifugation 30min under the 15000-25000rpm collects solidified nanoparticle, reuse distilled water wash, the centrifugal polyvinyl alcohol of removing in the nanoparticle suspension for 1-3 time.
7. the nanoparticle preparation is finished in lyophilization.
8. prepare the trim aqueous solution of 0.5-4mg/ml concentration.
9. nanoparticle is added above-mentioned trim aqueous solution, the suspension of compound concentration 9.5-76mg/ml, high-speed stirred or supersound process 10-120s evenly suspend nanoparticle.
10. anti-angiogenic restenosis nanoparticle preparation is finished in lyophilization
11. adopt the cobalt between the 15-30kGy
60The gamma-rays of emission shines nanoparticle sterilizes.
Specific embodiment
The PLGA dichloromethane solution of 9 milliliter of 2% concentration is contained 85.96 milligrams of paclitaxel acetone solns and mixes with 1 milliliter, join in the PVA water dope of 40 milliliter of 1% concentration ultrasonic under the condition of ice bath (40W) emulsifying 2min again.Room temperature electromagnetic agitation 3h then, decompression volatilization 1h.Low temperature, the centrifugal 30min of 23000rpm collect solidified nanoparticle.With distilled water wash, centrifugal 1 time, lyophilization 36h obtains the pacilitaxel nano granule of drug loading 30.54%, and its envelop rate is 90.75%, and mean diameter is 385nm.The above-mentioned nanoparticle that obtains is added the DMAB aqueous solution that 5 ml concns are 1mg/ml, supersound process 10-30s.Lyophilization obtains the nanoparticle of finishing.Nanoparticle mean diameter after the modification is 462.2nm.
With 10ml dichloromethane dissolving 200mg PLGA, 1ml acetone solution 42.5mg dexamethasone acetate medicated powder, mix two kinds of organic solutions then, this mixed organic solvents is joined in the PVA aqueous solution of 40ml 2% concentration, ultrasonic under the condition of ice bath (40W) emulsifying 10min, room temperature electromagnetic agitation 12h, decompression volatilization 1.5h removes organic solvent, at low temperature, ultracentrifugation 30min under the 23000rpm, collect solidified nanoparticle, the reuse distilled water wash, the centrifugal PVA that removes nano-particle surface for three times, lyophilization 36h obtains drug loading and is 17.37% dexamethasone nanoparticle, its envelop rate is 98.97%, and mean diameter is 260nm.The above-mentioned nanoparticle that obtains is added the DMAB aqueous solution that 5 ml concns are 1mg/ml, supersound process 10-30s.Lyophilization obtains the nanoparticle of finishing.
Embodiment 3. heparin nanoparticles
6 milliliters of PLGA dichloromethane solutions (concentration is 6%) are joined in the bottle of the aqueous solution (concentration is 26%) that contains 0.6 milliliter of heparin, ultrasonic emulsification 3min (output is 40W) under condition of ice bath immediately, obtain colostrum, this colostrum is joined the PVA aqueous solution of 24 milliliter of 0.5% concentration, under condition of ice bath, carry out ultrasonic emulsification 3min equally, promptly form W
1/ O/W
2Emulsion.Again this emulsion is carried out magnetic agitation, normal pressure is volatilization organic solvent 2h down, and (23000rpm * 20min) collect solidified nanoparticle uses distilled water wash three times, lyophilization 36h to high speed centrifugation.Obtain drug loading and be 5.35% heparin nanoparticles, nanoparticle mean diameter 297nm.
In order to strengthen the effect of the anti-angiogenic restenosis of medicine carrying microgranule, the medicine carrying microgranule of different pharmaceutical effect can be pressed the mixed of dosage according to the state of an illness, the saline mixing suspension preparation that is made into 30mg/ml concentration uses, and adopts the known interventional therapy of those skilled in the art that nanoparticle is delivered to impaired vascular site.
Claims (5)
1. drug-carried nanometer, form by biodegradable polymer and medicine, it is characterized in that biodegradable polymer comprises a kind of in polycaprolactone (PCL), polylactic acid (PLA) and polylactic acid-polyglycolic acid copolymer (PLGA), medicine is respectively to suppress blood vessel endothelium hypertrophy medicine, cell proliferation medicine, thrombolytic agent, anticoagulation medicine and anti-inflammatory agent, its macromolecular material percentage by weight is 70-95%, and the medicine total weight percent is 5-30%; The mean particle dia scope is the 50-500 nanometer, and nano-particle surface is modified through trim.
2. nanoparticle according to claim 1, it is characterized in that suppressing blood vessel endothelium hypertrophy medicine is paclitaxel; The cell proliferation medicine is a cytochalasin B; Thrombolytic agent comprises urokinase, streptokinase or sense of organization plasminogen activator; Anticoagulation medicine is a heparin; Anti-inflammatory agent is a dexamethasone.
3. nanoparticle according to claim 1, it is characterized in that promoting the trim of nanoparticle intravasation wall tissue to comprise: a kind of in the two dodecyl dimethyl ammoniums (DMAB) of bromination, poly-l-lysine and the protamine sulfate, the percentage by weight of trim is 2-10%, and the percentage by weight of nanoparticle is 90-98%.
4. the preparation method of a drug-carried nanometer, the present invention adopts emulsifying-solvent evaporation method to prepare nanoparticle, it is characterized in that the nanoparticle for preparing is modified, and may further comprise the steps:
(1). a kind of with in the two dodecyl dimethyls (DMAB) of bromination, poly-l-lysine and the protamine sulfate, be dissolved in the water, being mixed with concentration is the trim aqueous solution of 0.5-4mg/ml;
(2). nanoparticle is added in the above-mentioned trim aqueous solution, be made into the suspension that concentration is 9.5-76mg/ml,, nanoparticle is evenly suspended through high-speed stirred or supersound process 10-120s;
(3). lyophilization.
5. the application of drug-carried nanometer in the anti-angiogenic restenosis preparation of preparation.
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