CN101653420A - Ultrasonically controlled-release target medicinal preparation and production method thereof - Google Patents
Ultrasonically controlled-release target medicinal preparation and production method thereof Download PDFInfo
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Abstract
The invention discloses a biologically degradable ultrasonically controlled target granular medicinal preparation and a production method thereof. The ultrasonically controlled target granular medicinal preparations are 0.5-0.8 microns wide granules made from biologically degradable macromolecules and medicines; the granules are a) porous particulates with pore diameters of 10-1000nm or b) a hollow capsule. The ultrasonically controlled (passively guided) target medicinal release preparation can be transported into human blood cycle system or the diseased part of a human body through injectionor venous perfusion; ultrasonic transmission characteristic on part of a human body with preparation can be changed through the physical theory of ultrasonic waves to generate featured ultrasonic image, thereby increasing the contrasts degree between diseased part and normal tissue as well as between movable part and static part, and carrying out ultrasonic development; simultaneously, the irradiating energy of the ultrasonic waves can promote the release of medicine so as to control the release of medicine by ultrasonic waves.
Description
Technical field
The present invention relates to a kind of ultrasonically controlled-release target pharmaceutical preparation and preparation method thereof, be specifically related to a kind of biodegradable ultrasonically controlled-release microgranule targeted drug preparation and preparation method thereof.
Background technology
The aggregation that pharmaceutical preparation is made up of medicine and adjuvant, its Chinese medicine is the real composition that plays therapeutical effect in the pharmaceutical preparation, adjuvant then is that medicine is stable in order to make, solubilising, hydrotropy, slow release, controlled release, perhaps is convenient to taking and processing etc. and the general name of other various compositions except that medicine of adding of preparation; Just because of the combination of medicine and adjuvant, just make pharmaceutical preparation can be used and reach certain curative effect.
Yet, have only a small part to be transported to patient part after generally medicine is taken and produce curative effect by blood circulation, therefore most medicine then has been transported to each position of whole body by blood circulation and finally has been excreted by liver, kidney metabolism, must be much higher than patient's actual dosage to arrive patient part, really be used for the required dose of disease treatment.Because all medicines all have certain drug toxicity or to the issuable side effect of body, that part of no show patient part and the medicine that is transported to other position of health not only may cause the injury to body normal structure and organ, to their metabolism also will increase Liver and kidney burden, cause the disease of Liver and kidney, such pharmaceutical dosage form also caused simultaneously medicine waste, increased patient's spending.Therefore; development can be delivered directly to medicine patient part, can reach the injected volume that as far as possible reduces medicine under the prerequisite of curative effect, can reduce poisonous side effect of medicine to greatest extent, can take easily and allow the patient be easy to accept, and the scientists that can keep the ideal medicament preparation of certain physics and chemical stability to become under the environment usually direction of making great efforts.
Pharmaceutical carrier plays carrying medicament in pharmaceutical preparation, to the stripping of medicine with spread and regulate and control action, so it is to play regulating medicine dissolving and diffusion rate, the prolong drug most important adjuvant of deenergized period in pharmaceutical preparation.When further pharmaceutical preparation is made certain dosage form and by certain route of administration medication after can bring into play the curative effect of medicine to greatest extent, and reduce the toxic and side effects of medicine.Therefore along with the appearance of the development of neoplasm material and exploitation, novel drugs carrier, make the development of new pharmaceutical formulation and exploitation also become possibility; Thus, (Drug Delivery System, DDS) the conventional medicament preparation of also repeatedly taking from initial a day develops into sustained release pharmaceutical formulation, controlled-release pharmaceutical formulation to drug delivery system, so that the targeting release pharmaceutical formulations of new development over past ten years.
The targeting release pharmaceutical formulations also claims guided missile pharmaceutical preparation, is meant medicine to be delivered directly to the pharmaceutical preparation of target agents area as launching a guided missile.The targeted drug preparation has following advantage: the distribution of (1) limit drug reaches after the target medicine and discharges at a predetermined velocity; (2) be easy to enter parenchyma; (3) in the target position capillary tube, be evenly distributed; (4) the medicine leakage is few before reaching target position; (5) pharmaceutical carrier has biocompatibility and biodegradability, can be by organism metabolism or absorption after drug release is intact.Therefore the targeted drug preparation can overcome that the other medicines preparation is existing only can be with the part drug conveying to the target agents area and most of medicine is dispersed to the disadvantage of whole body normal organ and tissue; Therefore under identical dosage, the targeted drug preparation can improve the drug level of target site greatly, brings into play the curative effect of medicine to greatest extent.Because the targeted drug preparation defines medicine-feeding part, avoided medicine dispersion in vivo, therefore also can reach simultaneously and avoid medicine to the influence of normal organ and tissue, reduce the effect of poisonous side effect of medicine to greatest extent.
At present, be used for the targeting release pharmaceutical formulations and realize that the guiding technique of medicine " targeting " release function mainly contains " initiatively guiding " and " by action-oriented " two kinds of technology." initiatively guiding " technology mainly be pharmaceutical preparation with the combination that produces by chemical action, biological agent or electrostatic interaction between the target medicine-feeding part, make preparation be fixed on this target medicine-feeding part, thereby realize the purpose of drug targeting administration.Thus, realize that initiatively the target administration of guiding just must at first carry out surface treatment to pharmaceutical carrier, make dosage surface be loaded with certain group or electric charge, though therefore initiatively the targeted drug preparation targeting of guiding is higher, but the difficulty of preparation technology of preparation is big, preparation technology is also more complicated, and can be used to make initiatively the lead kind of the medicine of targeted drug preparation and adjuvant and also be subjected to the restriction of this specification requirement.
" by action-oriented " technology then mainly is to utilize certain physical characteristic of pharmaceutical preparation itself to realize leading, reaching the pharmaceutical preparation of target administration purpose.Reported and can be utilized to realize that the passive guiding physical characteristic that drug targeting discharges has granular size and magnetic, promptly utilize target administration that the different in vivo penetrance of different size particles type pharmaceutical preparation realize and realize the paramagnetic pharmaceutical preparation target administration of running orbit in vivo by guiding at external magnetic field.
Yet, more than those " initiatively guiding " and " by action-oriented " though targeting drug administration preparation medicine can both be delivered directly to the target agents area, play limit drug step by step purpose in vivo, but they can not control the release of medicine, can not control when administration, can not control the dosage of administration.
Summary of the invention
The purpose of this invention is to provide a kind of biodegradable ultrasonically controlled-release microgranule targeted drug preparation and preparation method thereof.This microparticle formulation is the targeted drug delivery formulations of the novel acoustic control of a class " by action-oriented ", and it can develop under ultrasonic irradiation, can discharge medicine under ultrasonication again.
Biodegradable ultrasonically controlled-release microgranule targeted drug preparation provided by the present invention, be to be the microgranule of 0.5-8 μ m by the particle diameter that the raw material that comprises biodegradability macromolecule and medicine is made, described microgranule be following a) or b), described a) is the foraminous microsome of tool, and the aperture in described hole is 10-1000nm; Described b) is the hollow microcapsule.
Described a) outward appearance is open porous structure (see figure 1), and the medicine dissolution in the described MC pharmaceutical preparation is in making described MC biodegradability macromolecule; Described b) it is the hollow microcapsule with compact outer shell that shell is the compact texture (see figure 2), and the pharmaceutical pack in the pharmaceutical preparation of described hollow microcapsule is contained in the inwall of the biodegradability polymer shell of making the hollow microcapsule.
Described biodegradability macromolecule is aliphatic poly lactone or natural polymer; The molecular weight of described aliphatic poly lactone is 5000-50000, the homopolymer that described aliphatic poly lactone is the aliphatic lactone, the binary between the aliphatic lactone ternary is random or block copolymer or aliphatic lactone and polyethers between binary or ternary is random or block copolymer.
The homopolymer of described aliphatic lactone specifically can be polylactide (PLA) or polycaprolactone (PCL); Binary between described aliphatic lactone or ternary is random or block copolymer specifically can be poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) copolymer (PLGA), poly-(lactide-caprolactone) copolymer (PLC), poly-(Acetic acid, hydroxy-, bimol. cyclic ester-caprolactone) copolymer (PGC) or poly-(Acetic acid, hydroxy-, bimol. cyclic ester-lactide-caprolactone) copolymer (PGLC); Binary between described aliphatic lactone and polyethers or ternary is random or block copolymer specifically can be poly-(lactide-polyglycol ether) copolymer (PLE), poly-(caprolactone-polyglycol ether) copolymer (PCE), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester-polyglycol ether) copolymer (PLGE), poly-(lactide-caprolactone-polyglycol ether) copolymer (PCLE) or poly-(Acetic acid, hydroxy-, bimol. cyclic ester-caprolactone-polyglycol ether) copolymer (PGCE); Described natural polymer specifically can be chitosan, gelatin, collagen protein, hyaluronic acid or alginate.
The degradability macromolecule of making described small porous particle body specifically can be the binary between natural polymer or aliphatic lactone and polyethers or ternary is random or block copolymer; The degradability macromolecule of making described hollow microcapsule specifically can be the binary between the homopolymer of natural polymer or aliphatic lactone, aliphatic lactone or ternary is random or block copolymer.
In the above-mentioned bipolymer, two monomeric mol ratios are 1-99: 99-1; In the above-mentioned terpolymer, three monomeric mol ratios are for being followed successively by 96-10: 3-60: 1-30;
Binary between described aliphatic lactone and polyethers or ternary is random or block copolymer in the molecular weight of polyglycol ether be 200～20000, the molecular weight of preferred polyglycol ether is 800～8000; Binary between described aliphatic lactone and polyethers or ternary is random or block copolymer in the molal weight of polyglycol ether be 1～50%, be preferably 10～40%.
The invention provides two kinds of methods that prepare described ultrasonically controlled-release microgranule targeted drug preparation.
Wherein a kind of method adopts water/oil/aqueous emulsion-solvent evaporation technology to be prepared, and by Chinese invention patent ZL 981005772 and ZL 98101117.9 open reports, its main preparation process is this technology:
1) described biodegradability macromolecule and medicine are dissolved in the solvent together, making concentration is the solution of 1-200 mg/ml (is better with 20～100 mg/ml), claims solution A;
2) get 0.5-10ml water adding 1-4 and drip emulsifying agent, mix homogeneously is made solution B;
3) solution B is injected solution A, the volume ratio of described solution A and solution B is 40: 1-2: 1 (with 20: 1-5: 1 for better), then ultrasonic emulsification 30-120 second (with 45-90 second for better), make water-in-oil emulsion;
4) water-in-oil emulsion with step 3) preparation is 1 by volume: 5-1: the ratio of 50 (with 1: 10-1: 20 for better) adds in the stabilizing agent aqueous solution that quality volume (being g/100ml) concentration is 0.5-10% (with 1-5% for better) and stirs, mixing speed 2000-20000 rev/min (with 10000-15000 rev/min for better), mixing time 0.5～5 minute (with 1～3 minute for better) makes water-in-oil-in-water compositions;
5) water-in-oil-in-water compositions of step 4) preparation is continued to stir 2-10 hour (with 3～6 hours for better), mixing speed is 500～2000 rev/mins (with 1000～1500 rev/mins for better), adopt centrifugal separation method separating particles body, the reuse distilled water washs, washing times is 1～5 time (with 2～4 times for better), at last described microsome is carried out lyophilization, obtain the biodegradability microsome of final purpose product of the present invention-pulverous ultrasonically controlled-release;
More than each step operation all under the temperature conditions of 0-37 ℃ (with 4～20 ℃ for better), carry out.
Wherein, solvent described in the step 1) is selected from following at least a: dichloromethane, chloroform, benzene, dichloroethanes, acetone, dioxane, oxolane and water;
Step 2) emulsifying agent described in is a surfactant, specifically can be selected from following at least a: sorbester p17, sorbester p18, polysorbate60 and Tween 80;
Stabilizing agent described in the step 4) is natural or synthetic polymer substance, specifically can be selected from following at least a: polyvinyl alcohol, gelatin and polyvinylpyrrolidone.
Another kind method adopts emulsion-solvent evaporated method to be prepared, and this method is reported openly by Chinese invention patent ZL02124389.1 that its main preparation process is:
1) under 4～37 ℃ and stirring condition, described biodegradability macromolecule and medicine are dissolved in the solvent together, are mixed with concentration and are the solution a of 1-200 mg/ml (with 20-100mg/ml for better);
2) low whipping speed is under the stirring condition of 100-10000 rev/min (is better with 500-3000 rev/min), described solution a added contain quality volumetric concentration (with 0.5～3%w/v for the better) emulsifying agent that is 0.3～5%, and among the aqueous solution b of 0.5～10% (w/v) (is better with 1～5% (w/v)) stabilizing agent, make O/w emulsion; The volume ratio of described solution a and solution b is 1: 10-1: 1000;
3) with step 2) O/w emulsion of preparation continues stirring and (got final product in general 2～10 hours under 50-5000 rev/min of (with 300-2000 rev/min for better) mixing speed, with 3～6 hours for better), solvent is evaporated fully, the separating particles body, the reuse distilled water washs, again resulting microsome is carried out lyophilization at last, obtain the biodegradability microsome of ultrasonically controlled-release;
Wherein, solvent described in the step 1) is selected from following at least a: dichloromethane, chloroform, benzene, dichloroethanes, acetone, dioxane, oxolane and water;
Step 2) emulsifying agent described in is a surfactant, specifically can be selected from following at least a: sorbester p17, sorbester p18, polysorbate60 and Tween 80;
Stabilizing agent described in the step 4) is natural or synthetic polymer substance, specifically can be selected from following at least a: polyvinyl alcohol, gelatin and polyvinylpyrrolidone.
Another object of the present invention provides a kind of ultrasonically controlled-release doser, and this device is made up of ultrasonically controlled-release microgranule targeted drug preparation provided by the present invention and medical ultrasonic equipment.
Acoustic control of the present invention " by action-oriented " targeted drug delivery formulations can be sent into the patient part of blood of human body blood circulation or body by the approach of injection, venous perfusion, can change the transonic characteristic at position, preparation place by hyperacoustic physical principle, make it to produce the ultrasonoscopy of feature, thereby increase between pathological tissues and the normal structure, contrast between motion parts and the stationary part, play the ultrasonic development effect, utilize hyperacoustic irradiation energy to promote the release of medicine simultaneously, play effect with the ultrasound wave control drug release.
The pharmaceutical carrier of acoustic control of the present invention " by action-oriented " targeted drug delivery formulations is a biodegradation high molecular, wherein polylactone class Biodegradable high molecular carrier is that a class has biodegradability, degradation rate can be regulated, and catabolite to body be free from side effects, finally can be in vivo by the synthetic class biodegradable medical material of metabolism or absorption; And used natural polymer also is the biodegradable medical material that has obtained extensive use clinical; They finally all can not retained in vivo in vivo by metabolism or absorption.The contained medicine of this acoustic control " by action-oriented " targeted drug delivery formulations does not have special restriction, can be cardiovascular drugs, anticoagulation medicine, cancer therapy drug or antibiotics; Wherein anticoagulant and antiplatelet drug specifically can be heparin, Clopidogrel Hydrogensulfate or urokinase; Cancer therapy drug specifically can be 5-fluorouracil, paclitaxel, amycin, cisplatin or rapamycin.
Acoustic control of the present invention " by action-oriented " targeted drug delivery formulations has following characteristic:
(1) the ultrasonic development function of utilizing targeting preparation provided by the present invention to possess can adopt general B ultrasonic detection technique that preparation running orbit is in vivo observed and record; (2) stirring that utilizes ultrasonic energy and produced is so that destruction, can quicken the speed of medicine, therefore only need to regulate supersonic source and act in " guiding " that external installation site just can play guidance preparation targeting drug release from preparation medium dissolves and diffusion towards periphery; (3) only need to control hyperacoustic transmitting time and transmitted power just can realize the adjusting and the control of drug release time in the preparation body and release dosage are controlled by external adjusting; (4) by with load medicine of different nature on the Biodegradable high molecular microgranule, just can obtain the medicative acoustic control of heterogeneity disease " by action-oriented " targeted drug delivery formulations; (5) because the particle diameter of preparation has only 0.5～8 micron, can filter by lung fully, so said preparation can be transported to each position of whole body and the danger that can not produce thromboembolism by blood circulation in vivo; (6) because pharmaceutical carrier is the macromolecular material with biological degradability, so the intact back of drug release carrier can be in vivo can not exerted an adverse impact to body by metabolism, absorption.
Acoustic control of the present invention " by action-oriented " targeted drug delivery formulations has high clinical value.For example: when the preparation of the present invention that will be loaded with thrombolytic drug or cardiovascular drugs carries out the release of external supersonic control targeting at the body surface position of heart, the coronary thrombosis of myocardial ischemia or myocardial infarction patient is dissolved, recover supply of blood flow, improve blood supply of cardiac muscle, make myocardial ischemia be eased, save survival myocardium, preserve myocardial function.When the body surface of the preparation of the present invention that will be loaded with cancer therapy drug at the canceration position carries out the release of external supersonic control targeting, bring into play partial antitumaous effect, reduce the side effect of cancer therapy drug to the human body vital tissue.In vivo the distribution of acoustic control of the present invention " by action-oriented " targeted drug delivery formulations controllability medicine, promptly need the position local concentration height for the treatment of at targeting moiety, good effect, and at non-targeting moiety, drug release is few, thereby avoided the toxic and side effects of medicine, improved the toleration of patient treatment to normal structure.
Description of drawings
Fig. 1 is the electromicroscopic photograph of the PLGE small porous particle body that carries 5-fluorouracil of preparation among the embodiment 1.
Fig. 2 is the electromicroscopic photograph that carries Clopidogrel Hydrogensulfate PGLC hollow microcapsule of preparation among the embodiment 5.
The specific embodiment
Experimental technique described in the following embodiment if no special instructions, is conventional method; Described reagent and material if no special instructions, all can obtain from commercial channels.
Embodiment 1, the preparation and the performance of carrying the PLGE small porous particle body of 5-fluorouracil
1) the PLGE small porous particle body of 5-fluorouracil is carried in preparation
Under 15 ℃, be that poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester-polyglycol ether) copolymer (each monomeric mol ratio is followed successively by 60/30/10 among the PLGE, and the PEG molecular weight is 1000) of 10,000 is dissolved in 10ml dichloromethane (CH with the 200mg molecular weight
2Cl
2), get solution A fully after the dissolving.Pour described solution A into aqueous solution that 1ml is dissolved with the 10mg 5-fluorouracil,, form water-in-oil emulsion with 30 seconds (macromolecule that contains the PEG component need not add emulsifying agent) of ultrasonic emulsification.Then this water-in-oil emulsion slowly is added drop-wise to 150ml and contains in the aqueous solution that the quality volumetric concentration is 1% (g/100ml) polyvinyl alcohol (PVA) and form water-in-oil-in-water compositions, continue again to stir and dichloromethane was volatilized and granulating gradually in 2 hours.Pass through centrifugalize, distilled water drip washing and lyophilization at last, to obtain particle diameter be 1～8 micron, be loose structure (micropore size is 10-500nm) carry 5-fluorouracil PLGE small porous particle body.This MC electromicroscopic photograph as shown in Figure 1.
2) performance test
A, be simulated animal with the Canis familiaris L., adopt the intravenous drip method to carry out in the body ultrasonic development to measure, the result shows that the PLGE small porous particle body that carries 5-fluorouracil can develop down ultrasonic, and show: the PLGE small porous particle body that carries 5-fluorouracil has ultrasonic development function in the good body.
B, with this year 5-fluorouracil PLGE small porous particle body be made into certain density suspension after the rat femoral vein injects in the rat body, after carrying out the blood capillary microcirculation of rat mesentery, carry out the heart, kidney, liver, lung, the section of encephalolith wax of rat respectively, observed result shows: in each tissue, all do not have the thromboembolism phenomenon and take place.Show and carry the danger that 5-fluorouracil PLGE small porous particle body can be filtered by lung, can not produce thromboembolism when blood circulation.
C, with this year 5-fluorouracil PLGE small porous particle body add in the buffer of pH7.4, then have under 37 ℃, 5-fluorouracil in-vitro release rate comparison under the no ultrasonic irradiation condition.The result shows: in case apply ultrasonic irradiation (power 5W), the rate of release of its 5-fluorouracil is further accelerated with the raising of ultrasonic irradiation power with regard to the rate of release of obvious quickening and 5-fluorouracil.Show that the PLGE small porous particle body that carries 5-fluorouracil has ultrasonic control drug release function.
D, with this year 5-fluorouracil PLGE small porous particle body be made into the suspension of 5mg/L concentration after the rat femoral vein injects the back suffers from the rat body of skin carcinoma, under power (5W), carry out four times on the one, each 10 minutes ultrasonic irradiation at the body surface of suffering from cancer skin with general B ultrasonic detector then.Observe after one week: the canceration position volume of having injected the PLGE small porous particle body of year 5-fluorouracil and having accepted the trouble cancer rat of four ultrasonic irradiation on the one has had obviously and has dwindled; And injected that same dose carries 5-fluorouracil PLGE small porous particle body but the canceration position volume of not accepting the trouble cancer rat of ultrasonic irradiation not have variation substantially; Though increased nearly 1/3 but inject the trouble cancer rat of carrying 5-fluorouracil PLGE small porous particle body and inject the canceration position volume ratio original volume that carries 5-fluorouracil PLGE small porous particle body but accept the trouble cancer rat of four ultrasonic irradiation on the one.Show: the PLGE small porous particle body that carries 5-fluorouracil has the targeted therapy effect of ultrasonic " by action-oriented " to skin carcinoma.
Embodiment 2, the preparation and the performance of carrying paclitaxel PGCE small porous particle body
Preparation method is substantially with embodiment 1.Difference is: preparation temperature is 23 ℃, the carrier that adopts is that the 200mg molecular weight is 15, (each monomeric mol ratio is followed successively by 30/50/20 to poly-(Acetic acid, hydroxy-, bimol. cyclic ester-caprolactone-polyglycol ether) copolymer of 000 among the PGCE, the PEG molecular weight is 2000), medicine is the 5mg paclitaxel, finally to obtain particle diameter be 1～8 micron, be loose structure (micropore size is 100-1000nm) carry paclitaxel PGCE small porous particle body.
Cultivate human liver cancer cell, add in culture fluid and carry paclitaxel PGCE microsome, the pair cell culture fluid is with ultrasonic sound intensity 0.5W/cm simultaneously
2Irradiation 30s then measures apoptosis with fluorescent staining method.The result shows: the PGCE 30/50/20 small porous particle body that carries paclitaxel suppresses effect to the targeting that human liver cancer cell has ultrasonic " by action-oriented ".
Embodiment 3, the preparation and the performance of carrying the PGCE small porous particle body of heparin
Preparation method is substantially with embodiment 1.Difference is: preparation temperature is 20 ℃, the carrier that adopts is that the 180mg molecular weight is 12, (each monomeric mol ratio is followed successively by 30/60/10 to poly-(Acetic acid, hydroxy-, bimol. cyclic ester-caprolactone-polyglycol ether) copolymer of 000 among the PGCE, the PEG molecular weight is 1000), medicine is the 8mg heparin, finally to obtain particle diameter be 1～8 micron, be loose structure (micropore size is 100-1000nm) carry heparin PGCE microsome.
With embodiment 1 method is that the intravenous drip measurement result of simulated animal shows with the Canis familiaris L.: the PGCE microsome that carries heparin has ultrasonic development function in the good body.
The PGCE microgranule of heparin is made into suspension after the rat femoral vein injects in the rat body with this year, after carrying out the blood capillary microcirculation of rat mesentery, carry out the heart, kidney, liver, the lung of rat, the paraffin section of brain respectively, observed result shows: in each tissue, all do not have the thromboembolism phenomenon and take place.Show the danger that the PGCE microgranule that carries the 5-heparin can be filtered by lung, can not produce thromboembolism when blood circulation.
This year of heparin PGCE microgranule heparin in-vitro release rate comparative result in 37 ℃ pH7.4 buffer shows: under the ultrasonic irradiation, the heparin rate of release of year heparin PGCE microgranule obviously accelerates and the heparin rate of release is accelerated with the raising of ultrasonic irradiation power.Show: the PGCE small porous particle body that carries heparin has ultrasonic control drug release function.
The PGCE small porous particle body of heparin is made into the suspension of 7mg/L concentration after the dog femoral vein inject to be suffered from the dog body of myocardial infarction with this year, carries out one day eight time, each 10 minute ultrasonic irradiation with general B ultrasonic detector with 5W power at the heart body surface of dog then.Observe two days later: the cardiovascular of having injected the PGCE microgranule of year heparin and having accepted the myocardial infarction dog of eight ultrasonic irradiation on the one obviously becomes unobstructed; And injected that same dose carries heparin PGCE microgranule but the dog cardiovascular infraction situation of not accepting the trouble myocardial infarction of ultrasonic irradiation remains unchanged substantially; Though but injection carry heparin PGCE microgranule the trouble myocardial infarction dog and injection carry the PGCE microgranule of heparin but the narrow situation of cardiovascular of dog of accepting the trouble myocardial infarction of eight ultrasonic irradiation on the one becomes even more serious significantly, and have dog to cause death because of myocardial infarction.Show: the PGCE small porous particle body that carries heparin has the targeting thromboembolism treatment effect of ultrasonic " by action-oriented " to myocardial infarction.
Embodiment 4, the preparation and the performance of carrying urokinase PLGE small porous particle body
Preparation method is substantially with embodiment 1.Difference is: but at 23 ℃, the carrier that adopts is that the 150mg molecular weight is 12, (each monomeric mol ratio is followed successively by 50/40/10 to poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester-polyglycol ether) copolymer of 000 among the PLGE, the PEG molecular weight is 1500), medicine is the 8mg urokinase, finally to obtain particle diameter be 1～8 micron, be loose structure (micropore size is 50-1000nm) carry urokinase PLGE small porous particle body.
Separate the rabbit femoral artery, sacculus is inserted in puncture, causes offside femoral artery inner film injury, and formation intra-arterial thrombosis, detect proof thrombosis with angiography and Vascular Ultrasonography, inject by the thrombosis arterial proximal and slowly inject above-mentioned ultrasonic microbubble, and simultaneously with sound intensity 0.5W/cm
2Irradiation 30s then measures the patency rate and the blood flow rate of injured blood vessel.Observed the thrombolytic effect of the PGCE microgranule of year urokinase to rabbit femoral artery thrombosis.The result shows: the PGCE microsome that carries urokinase has the targeting thromboembolism treatment effect of ultrasonic " by action-oriented " to arterial thrombus.
Embodiment 5, the preparation and the performance of carrying Clopidogrel Hydrogensulfate PGLC hollow microcapsule
1) Clopidogrel Hydrogensulfate PGLC microcapsule is carried in preparation
5ml is contained the distilled water solution of 5mg Clopidogrel Hydrogensulfate and 5ml, and to contain the 200mg molecular weight be 10, after the dichloromethane solution of 000 poly-(Acetic acid, hydroxy-, bimol. cyclic ester-lactide-caprolactone) copolymer (each monomeric mol ratio is followed successively by 30/60/10 among the PGLC) mixes, it in 100ml concentration ultrasonic emulsification 1 minute in the presence of 0.1% the class of department 80, form water-in-oil emulsion, 15, under 000 rev/min of mixing speed, in the presence of Tween 80, inject the gelatin solution of 100ml 1%, emulsifying 1 minute.The gained water-in-oil-in-water compositions stirred the microcyst centrifugalize that obtains 5 hours at 1000 rev/mins.Clean four times with distilled water, be dispersed at last in the water, lyophilization, what obtain particle diameter and be 3～8 microns, wall thickness and be 80 nanometers carries Clopidogrel Hydrogensulfate PGLC 30/60/10 hollow microcapsule.The electromicroscopic photograph of this hollow microcapsule is seen Fig. 2.
Embodiment 6, the preparation and the performance of carrying Clopidogrel Hydrogensulfate PGLC hollow microcapsule
With embodiment 5 preparation methoies, but adopting molecular weight is 15,000 poly-(Acetic acid, hydroxy-, bimol. cyclic ester-lactide-caprolactone) copolymer (PGLC 30/60/10) and Clopidogrel Hydrogensulfate, what obtain particle diameter and be 3～8 microns, wall thickness and be 80 nanometers carries Clopidogrel Hydrogensulfate PGLC 30/60/10 hollow microcapsule.
Adopt the method for testing of embodiment 3, the result shows: PGLC 30/60/10 microcapsule that carries Clopidogrel Hydrogensulfate has the targeting thromboembolism treatment effect of ultrasonic " by action-oriented " to myocardial infarction.
Embodiment 7, the preparation of carrying amycin PLGA 50/50 hollow microcapsule
The preparation method of medicine carrying microgranule body is substantially with embodiment 5, difference is: adopting the distilled water solution that contains the 5mg amycin and containing the 200mg molecular weight is 8, the dichloromethane solution of poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) copolymer (PLGA 50/50) of 000, obtain be particle diameter be 2～8 microns, wall thickness be 50 nanometers carry amycin PLGA50/50 hollow microcapsule.
Adopt the method for testing of embodiment 2, the result shows: carry amycin PLGA 50/50 microcapsule the targeting that human liver cancer cell has ultrasonic " by action-oriented " is suppressed effect.
The PLE 60/40 small porous particle body of embodiment 8, year cisplatin
The preparation method of carrying cisplatin small porous particle body is substantially with embodiment 1, difference is: preparation temperature is 20 ℃, adopting the 170mg molecular weight is 20, (PLE 60/40 for poly-(lactide-polyglycol ether) copolymer of 000, the PEG molecular weight is 1000) and the distilled water solution of 7mg cisplatin, what obtain is that the similar Fig. 1 of pattern, particle diameter are 1～8 micron PLE 60/40 small porous particle body that carries cisplatin that is loose structure (micropore size is 500-1000nm).
Employing is with the method for testing of embodiment 2, and the result shows: the PLE 60/40 small porous particle body that carries cisplatin suppresses effect to the targeting that human liver cancer cell has ultrasonic " by action-oriented ".
Claims (10)
1, a kind of biodegradable ultrasonic control targeting release microparticles pharmaceutical preparation, be to be the microgranule of 0.5-8 μ m by the particle diameter that the raw material that comprises biodegradability macromolecule and medicine is made, described microgranule be following a) or b), described a) is the foraminous microsome of tool, and the aperture in described hole is 10-1000nm; Described b) is the hollow microcapsule.
2, ultrasonic control targeting release microparticles according to claim 1 pharmaceutical preparation is characterized in that: described biodegradability macromolecule is aliphatic poly lactone or natural polymer; Described aliphatic poly lactone molecular weight 5000-50000's, the homopolymer that described aliphatic poly lactone is the aliphatic lactone, the binary between the aliphatic lactone ternary is random or block copolymer or aliphatic lactone and polyethers between binary or ternary is random or block copolymer;
Preferred polylactide of the homopolymer of described aliphatic lactone or polycaprolactone; Binary between described aliphatic lactone or ternary is random or preferably poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) copolymer of block copolymer, poly-(lactide-caprolactone) copolymer, poly-(Acetic acid, hydroxy-, bimol. cyclic ester-caprolactone) copolymer or poly-(Acetic acid, hydroxy-, bimol. cyclic ester-lactide-caprolactone) copolymer; Binary between described aliphatic lactone and polyethers or ternary is random or preferably poly-(lactide-polyglycol ether) copolymer of block copolymer, poly-(caprolactone-polyglycol ether) copolymer, poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester-polyglycol ether) copolymer, poly-(lactide-caprolactone-polyglycol ether) copolymer or poly-(Acetic acid, hydroxy-, bimol. cyclic ester-caprolactone-polyglycol ether) copolymer; The preferred chitosan of described natural polymer, gelatin, collagen protein, hyaluronic acid or alginate.
3, ultrasonic control targeting release microparticles according to claim 2 pharmaceutical preparation is characterized in that: the degradability macromolecule of making described small porous particle body is the binary between natural polymer or aliphatic lactone and polyethers or ternary is random or block copolymer; The degradability macromolecule of making described hollow microcapsule is the binary between the homopolymer of natural polymer or aliphatic lactone, aliphatic lactone or ternary is random or block copolymer.
4, according to claim 2 or 3 described ultrasonic control targeting release microparticles pharmaceutical preparatioies, it is characterized in that: in the described bipolymer, two monomeric mol ratios are 1-99: 99-1; In the described terpolymer, three monomeric mol ratios are 6-10: 3-60: 1-30 successively;
Binary between described aliphatic lactone and polyethers or ternary is random or block copolymer in the molecular weight of polyglycol ether be 200～20000, the molecular weight of preferred polyglycol ether is 800～8000; Binary between described aliphatic lactone and polyethers or ternary is random or block copolymer in the molal weight of polyglycol ether be 1～50%, be preferably 10～40%.
5, according to arbitrary described ultrasonic control targeting release microparticles pharmaceutical preparation among the claim 1-4, it is characterized in that: the foraminous microsome of described tool is following 1)-4) in any one:
1) the foraminous microsome particle diameter of described tool is 1-8um, and the aperture is 10-500nm;
2) the foraminous microsome particle diameter of described tool is 1-8um, and the aperture is 100-1000nm;
3) the foraminous microsome particle diameter of described tool is 1-8um, and the aperture is 50-1000nm;
4) the foraminous microsome particle diameter of described tool is 1-8um, and the aperture is 500-1000nm;
The particle diameter of described hollow microcapsule is 3-8um or 2-8um.
6, a kind of method for preparing arbitrary described ultrasonic control targeting release microparticles pharmaceutical preparation among the claim 1-5, adopt water/oil/aqueous emulsion-solvent evaporation technology to be prepared, to may further comprise the steps:
1) arbitrary described biodegradability macromolecule and medicine among the claim 1-5 are dissolved in the solvent together, make the solution that concentration is the 1-200 mg/ml, claim solution A;
2) get 0.5-10ml water adding 1-4 and drip emulsifying agent, mix homogeneously is made solution B;
3) solution B is injected solution A, the volume ratio of described solution A and solution B is 40: 1-2: 1, then ultrasonic emulsification 30-120 second, make water-in-oil emulsion;
4) water-in-oil emulsion with step 3) preparation is 1 by volume: 5-1: 50 ratio adds in the stabilizing agent aqueous solution that the quality volumetric concentration is 0.5-10% and stirs, mixing speed 2000-20000 rev/min, mixing time 0.5-5 minute, make water-in-oil-in-water compositions;
5) water-in-oil-in-water compositions with the step 4) preparation continues to stir 2-10 hour, mixing speed is 500-2000 rev/min, isolates the microcapsule particle, and the reuse distilled water washs, at last described microcapsule is carried out lyophilization, obtain the biodegradability microcapsule of pulverous ultrasonically controlled-release;
Wherein, described operation is all carried out under 0-37 ℃ temperature conditions,
Solvent described in the step 1) is selected from following at least a: dichloromethane, chloroform, benzene, dichloroethanes, acetone, dioxane, oxolane and water;
Step 2) emulsifying agent described in is a surfactant;
Stabilizing agent described in the step 4) is natural or synthetic polymer substance.
7, method according to claim 6 is characterized in that: described emulsifying agent is selected from following at least a: sorbester p17, sorbester p18, polysorbate60 and Tween 80; Described stabilizing agent is selected from following at least a: polyvinyl alcohol, gelatin and polyvinylpyrrolidone;
The concentration of solution A is the 20-100 mg/ml in the described step 1); The volume ratio of described step 3) solution A and solution B is 20: 1-5: 1, and the time of ultrasonic emulsification is 45-90 second; Be 1 by volume with water-in-oil emulsion in the described step 4): 10-1: 20 ratio adds in the stabilizing agent aqueous solution that mass concentration is 1-5% and stirs, and mixing speed 10000-15000 rev/min, mixing time 1-3 minute, makes water-in-oil-in-water compositions; In the described step 5) water-in-oil-in-water compositions is continued to stir 3-6 hour, mixing speed is 1000-1500 rev/min, isolates the microcapsule particle, and the reuse distilled water washs, and washing times is 1-5 time, preferred 2-4 time; Separate the microcapsule ion in the described step 5) and adopt centrifugal separation;
Described step 1)-5) operation is all carried out under 4-20 ℃ temperature conditions.
8, a kind of method for preparing arbitrary described ultrasonic control targeting release microparticles pharmaceutical preparation among the claim 1-5 adopts emulsion-solvent evaporated method to be prepared, and may further comprise the steps:
1) under 4～37 ℃ and stirring condition with claim 1-4 in arbitrary described biodegradability macromolecule and medicine be dissolved in together in the solvent, being mixed with concentration is the solution a of 1-200 mg/ml;
2) low whipping speed is under 100-10000 rev/min the stirring condition, described solution a is added to contain the quality volumetric concentration be 0.3～5% emulsifying agent, and among the aqueous solution b of 0.5～10% stabilizing agent, makes O/w emulsion; The volume ratio of described solution a and solution b is 1: 10-1: 1000;
3) with step 2) O/w emulsion of preparation continue to stir under 50-5000 rev/min of mixing speed, solvent is evaporated fully, isolate the microcapsule particle, the reuse distilled water washs, again resulting microcapsule is carried out lyophilization at last, obtain the biodegradability microcapsule of ultrasonically controlled-release;
Wherein, solvent described in the step 1) is selected from following at least a: dichloromethane, chloroform, benzene, dichloroethanes, acetone, dioxane, oxolane and water;
Step 2) emulsifying agent described in is a surfactant, and described stabilizing agent is natural or synthetic polymer substance.
9, method according to claim 8 is characterized in that: described emulsifying agent is selected from following at least a: sorbester p17, sorbester p18, polysorbate60 and Tween 80; Described stabilizing agent is selected from following at least a: polyvinyl alcohol, gelatin and polyvinylpyrrolidone;
The concentration of solution a is the 20-100 mg/ml in the described step 1); Described step 2) low whipping speed is under 500-3000 rev/min the stirring condition, described solution a is added to contain the quality volumetric concentration be 0.5～3% emulsifying agent, and among the aqueous solution b of 1～5% stabilizing agent, makes O/w emulsion; In the described step 3) O/w emulsion is continued to stir 2～10 hours under 300-2000 rev/min of mixing speed, preferably stirred 3～6 hours.
10, a kind of ultrasonically controlled-release doser is made up of arbitrary described ultrasonic control targeting release microparticles pharmaceutical preparation and medical ultrasonic equipment among the claim 1-4.
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