CN101912366B - Degradable gel microspheres interposed in bronchus and application thereof - Google Patents
Degradable gel microspheres interposed in bronchus and application thereof Download PDFInfo
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Abstract
The invention relates to degradable gel microspheres interposed in a bronchus and application thereof. The degradable gel microspheres comprise hyaluronic acid-calcium alginate gel microspheres and medicament-loaded chitosan-calcium alginate gel microspheres, wherein the hyaluronic acid-calcium alginate gel microspheres and the medicament-loaded chitosan-calcium alginate gel microspheres are mixed together uniformly according to proportion, and the volume ratio is 2:1-9. The degradable gel microspheres can be used for preparing sustained-release and controlled-release medicaments for treating lung cancer, lung tumor, tuberculosis, pneumonia and bronchitis and a tissue engineering scaffold material. The degradable gel microspheres interposed in the bronchus do not block up a lung bronchus and also do not initiate ischemic necrosis of surrounding tissues of the bronchus, so the degradable gel microspheres can be used as the tissue engineering scaffold material and a medicament sustained-release scaffold. Two types of microspheres with different functions have complementary advantages, overcome the technical difficulties of microsphere blockage and pulmonary ventilation in the bronchus, and can significantly reduce toxic or side effect of medicaments and improve therapeutic indexes of the medicaments.
Description
Technical field
The present invention relates to the intrabronchial degradable gel microspheres of a kind of intervention and application thereof, be particularly for the hyaluronic acid-calcium alginate gel bead and the medicine carrying chitin-alginic acid calcium gel micro-ball that mix in proportion, and for the preparation of the application in treatment pulmonary carcinoma, lung tumor, pulmonary tuberculosis, pneumonia and bronchitic sustained-release and controlled release medicine and the tissue engineering bracket material.
Background technology
As everyone knows, lung is the respiratory apparatus that one-period relaxes and contracts, and gas moves back and forth in trachea and bronchus.Air flue bore and the volume of respiratory tract change fast with breath rhythm, all size pulmonary branches trachea and alveolar consist of the low-impedance gas channel of high flow rate in the respiratory, in case it is smooth or block that small airway occurs, must cause anoxia, respiratory failure and suffocate.On the other hand, lung be one extremely sensitive to foreign body, have than the organ of forced-ventilated except foreign body in the air flue or medicine the medicine of throwing in through trachea or bronchus, that powder or liquid all can be very fast by expectoration, otherwise the generation pulmonary consolidation, forfeiture respiratory function, death by suffocation.For the patient of pulmonary disease, dyspnea to a certain degree appears in or obstruction smooth with small airway mostly, if this moment medicinal liquid or miniature solid are rendered in the pulmonary branches trachea, not only can not cure the disease, and increases the weight of on the contrary the state of an illness.In addition, lung or drug absorption and transhipment be organ very rapidly, especially absorbs very fast to fat-soluble medicine.Existing chemotherapeutic agents is implanted in the pulmonary branches trachea, and is larger to lung injury, greatly more than in 1-3 days with the sputum expectoration, be difficult to reach safety and effective therapeutic purposes.This shows that be applied to the interior long-acting slow-release controlled release preparation of lung and should be different from existing common sustained-release and controlled release preparation, the safety of preparation in lung has much room for improvement.
The biodegradable polymers material is widely used in medical treatment and drug delivery device in 30 years in the past.Most biological degradation polyalcohols exist with solid-state under room temperature or body temperature condition, therefore these system and devices need to implant by large syringe or surgical operation, only have the smooth microsphere of these biodegradable polymer preparations just can use normal injection pin or fine duct administration.Inject the sustained-release gel administration through bronchus on the clinical medicine at present, only only limit to only a few pulmonary carcinoma and Tuberculous pulmonary cavity patient, in the hope of realizing the target of local sustained release Drug therapy disease.There is no at present the dosage form listing for local sustained release administration in the pulmonary branches trachea both at home and abroad, thus bronchus to be implanted into local sustained release controlled release drug treatment lung disease be thorny problem medically always.
Pulmonary branches trachea controlled release slow releasing pharmaceutical technology remains many problems at present.Because people's alveolar membrane gross area is large, medicine administration in the pulmonary branches trachea, infiltration rate is fast, can be suitable with the onset speed of intravenous injection.The conventional dosage forms of administration is aerosol always in the pulmonary branches trachea.Foradil Aerolizer formoterol fumarate is the research " focus " of in recent years pulmonary delivery system, said preparation has not only been got rid of the propellant such as freon, and carry and use more conveniently, its key technology is effectively to control the diameter of aspirin particle diameter of particle of pulmonary administration (be fit to be about 5 μ m) and optimization suction apparatus.People once attempted the medicine carrying gel is implanted in bronchus or the pulmonary cavity soon, and drug slow control releasing effect is not good.One of them reason, lungs retraction during expiration, bronchoconstriction is implanted into gel to bronchus and produces compressing and destruction, and gel pieces is fled in bronchus, bronchioles with the air-flow of respiratory tract, can form one-way cock, disturbs the normal lung ventilation.Less gel pieces can excrete with the scavenging action of expiration or tunica mucosa tracheae, but larger gel pieces obstructing airway causes extremely dyspnea.In addition, pulmonary branches trachea and segmental bronchus foreign body is implanted or block very responsive, but reflexive ground causes emphysema, pulmonary edema or the pulmonary collapse, causes body death by suffocation, sustained-release administration is one and waits the drug delivery platform researching and developing and innovate in the visible bronchus.
Treatment for pulmonary disease (pulmonary tuberculosis, pulmonary carcinoma and pulmonary infection etc.), if can adopt sustained-release and controlled release preparation or lung targeted drug preparation in the lung, the bio distribution of medicine is mainly concentrated on the focus part, reducing drug dose and whole body thereof distributes, can significantly reduce poisonous side effect of medicine, improve the Drug therapy index.A kind of by way of being to pour into colloid or solid drugs by air flue in lung, this is that one on the therapeutic treatment avoided greatly.Another kind of by way of being in lung, to carry sustained release pharmaceutical formulation by blood vessel.In view of the microcirculatory characteristic of lung, pulmonary capillary has crown_interception to particle diameter greater than 7 microns microgranule, can design the microsphere of a kind of 7 μ m-50 μ m through intravenous injection, arrive lung with blood flow, contact lung first and be retained in the pulmonary capillary greater than 7 microns microspheres, medicine constantly discharges with microsphere corrosion or degraded, produces pharmacological action in pulmonary.Develop this class lung target slow-release controlled release drug microsphere, attempted being used for the treatment of pulmonary carcinoma.Because lung target slow-release controlled release drug microsphere causes the change of many pneumonopathy and respiratory failure in lung, this microsphere fails to be applied to clinical treatment always.
Summary of the invention
One of purpose of the present invention is to provide the intrabronchial degradable medicine carrying of a kind of intervention gel micro-ball, by bronchial catheter, operation or suitable syringe the microsphere of specified particle diameter is implanted safely pulmonary branches trachea and intralesional on every side thereof, medicine can be realized preferably local sustained release controlled-release effect.It has solved a technical barrier of current pulmonary branches trachea medicine interventional therapy.
For achieving the above object, the present invention takes following technical scheme:
The intrabronchial degradable gel microspheres of a kind of intervention, it is characterized in that: comprise hyaluronic acid-calcium alginate gel bead and medicine carrying chitin-alginic acid calcium gel micro-ball, described hyaluronic acid-calcium alginate gel bead and medicine carrying chitin-alginic acid calcium gel micro-ball evenly mix in proportion, and volume ratio is 2: 1-9.
A kind of preferred technical scheme is characterized in that: the volume ratio that described hyaluronic acid-calcium alginate gel bead and medicine carrying chitin-alginic acid calcium gel micro-ball mix is 1: 2.
A kind of preferred technical scheme is characterized in that: described hyaluronic acid-calcium alginate gel bead is comprised of hyaluronate sodium, calcium alginate, osmotic pressure regulator and water, and the gel micro-ball diameter is 100-280 μ m, and described osmotic pressure regulator is glycerol.
A kind of preferred technical scheme is characterized in that: in described hyaluronic acid-calcium alginate gel bead, in mass fraction, hyaluronate sodium is 0.5%-3.5%, and calcium alginate is 3%-8%, and glycerol is 0.05-1.5%, and water is 89%-93%.
A kind of preferred technical scheme is characterized in that: in described hyaluronic acid-calcium alginate gel bead, in mass fraction, hyaluronate sodium is 1%, and calcium alginate 5.4%, glycerol are 1%, and water is 92.6%.
A kind of preferred technical scheme is characterized in that: described medicine carrying chitin-alginic acid calcium gel micro-ball is comprised of chitosan, calcium alginate, medicine and water, and the gel micro-ball surface is coated by chitosan, and diameter is 100-300 μ m.
A kind of preferred technical scheme is characterized in that: in the described medicine carrying chitin-alginic acid calcium gel micro-ball, in mass fraction, chitosan is 0.05-0.2%, and calcium alginate is 3.0%-9.0%, and medicine is 0.5-6%, and water is 89.95%-95.45%.。
A kind of preferred technical scheme is characterized in that: in the described medicine carrying chitin-alginic acid calcium gel micro-ball, in mass fraction, chitosan is 0.05%, and calcium alginate is 4%.
A kind of preferred technical scheme, it is characterized in that: described medicine carrying chitin-alginic acid calcium gel micro-ball Chinese medicine is one or more in antibiotic, hormone, anti-tumor chemotherapeutic medicine and/or the polypeptide drug etc., such as Mycobutin, rifapentine, doxorubicin, dexamethasone and/or gamma interferon etc.
The making step of the bronchial degradable gel microspheres of above-mentioned intervention is as follows:
(1) medicine is weighed in proportion, make thin medicated powder, stand-by; Perhaps with medicine dissolution in the volatile organic solvent, get drug solution;
(2) take by weighing sodium alginate, hyaluronate sodium and glycerol and be dissolved in the distilled water, obtain sodium alginate-sodium hyaluronate solution;
(3) take by weighing sodium alginate and be dissolved in distilled water, obtain 2.5% sodium alginate soln;
(4) take by weighing chitosan and be dissolved in 4% acetic acid solution, obtain 0.2% chitosan solution;
(5) calcium chloride is mixed with the solution of mass fraction 1%～2%, gets the calcium chloride solidification liquid;
(6) with sodium alginate-sodium hyaluronate solution, by high-pressure electrostatic bull drop generating device, produce continuously fine droplet, enter in the described calcium chloride solidification liquid, solidify 1h, distilled water rinsing 2 times, vacuum drying gets hyaluronic acid-calcium alginate gel bead;
(7) solid medicated powder or drug solution are mixed or emulsifying in 1: 4～9 ratios with 2.5% sodium alginate soln of step (3) gained, by high-pressure electrostatic bull drop generating device, low discharge produces fine droplet continuously under 10000V voltage, enter in 1%～3% calcium chloride solidification liquid, solidify 20min, get the medicine carrying calcium alginate gel bead;
(8) with the medicine carrying calcium alginate gel bead through normal saline drip washing, be suspended in again 15-30min in described 0.2% chitosan solution, filter microsphere, distilled water rinsing 2 times obtains medicine carrying chitin-alginic acid calcium gel micro-ball, vacuum drying;
(9) hyaluronic acid-calcium alginate gel bead and the medicine carrying chitin-alginic acid calcium gel micro-ball with gained mixes in proportion, and be through the normal saline swelling, stand-by.
Second purpose of the present invention is to provide the application of the intrabronchial degradable gel microspheres of above-mentioned intervention.
The intrabronchial degradable gel microspheres of above-mentioned intervention is for the preparation of the application in treatment pulmonary carcinoma, lung tumor, pulmonary tuberculosis, pneumonia and bronchitic sustained-release and controlled release medicine and the tissue engineering bracket material.
Clinical practice: before use, hyaluronic acid-calcium alginate gel bead and the medicine carrying chitin-alginic acid calcium gel micro-ball of gained are mixed in proportion, add the normal saline swelling, implant the bronchial specific part of lung by bronchial catheter, operation or suitable syringe safe.
First characteristics of the present invention are not by expectoration and safe and reliable, to have solved the Medical Technology difficult problem of the interior microsphere obstruction of bronchus with the pulmonary ventilation obstacle in the hyaluronic acid of particle diameter 100 μ m-280 μ m viscoelasticities-calcium alginate gel bead implantation pulmonary branches trachea.Hyaluronic acid-calcium alginate gel bead of 100-280 μ m is rich in adhesion and distortion speciality, the gel micro-ball of guaranteeing therapeutic dose is not eliminated with gas shock and piles up at the pulmonary branches trachea, and bronchus total blockage, the pulmonary collapse, pulmonary edema and emphysema do not occur yet.Clinical experiment shows, as the fabulous hyaluronic acid-calcium alginate gel bead of a kind of biocompatibility, implants the pulmonary branches trachea and has quite high reliability and safety.Its principle or mechanism is, the gas-flow resistance of human respiratory results from large air flue more than 80%, and namely trachea and diameter are at the above pulmonary branches trachea of 3mm.And the gas-flow resistance of the bronchus below the diameter 3mm and alveolar duct is less than 20%.This is that total cross-sectional area is respectively 600 times of the trachea cross-sectional area and more than thousands of times because the following bronchus of lung interior diameter 3mm and alveolar duct are ventilated.When an amount of hyaluronic acid-calcium alginate gel bead was laid on the mucosa along diameter 3mm pulmonary branches inner surface of trachea single flat, this bronchus air flue internal diameter slightly dwindled, and can not cause that whole pulmonary respiration resistance obviously increases.Simultaneously 100-280 μ m is rich in the hyaluronic acid of viscoelasticity-calcium alginate gel bead speciality, guarantee that gel micro-ball is not shifted with air-flow, foreign body pneumonia does not occur, and is applied to have quite high reliability and safety in the pulmonary branches trachea as a kind of new sustained release controlled release drug carrier.
Second characteristic of the present invention are to utilize the good biocompatibility of hyaluronic acid-calcium alginate gel bead and Growth of Cells cradling function; this gel micro-ball is implanted the pulmonary cavity focus through bronchus; can between the damage lung tissue, form barrier at the air flue air-flow; gel micro-ball as a kind of adhesion by force, distortion and flowable net grid support can be protected lung tissue, auxiliary lung tissue reparation and structural remodeling easily.This is unprecedented in a pneumotherapy treatment means.In calcium alginate gel, the synthetic progressively increase of the maintenance of the phenotype of chondrocyte and glycoprotein is external new chondrogenetic favorable factor, and hyaluronic acid plays a crucial role to maintenance glycoprotein configuration in cartilage matrix.Alginic acid-hyaluronic acid derivatives shows through histology and biochemical research, contains hyaluronic calcium alginate network, and the control environment of implanting the synthetic glycoprotein of cell and collagen protein can be provided, and is conducive to the diffusion of nutrient substance.
The 3rd characteristics of the present invention are the medicine carrying chitin-alginic acid calcium microsphere of diameter 100-300 μ m is introduced in the pulmonary tuberculosis treatment, the pulmonary tuberculosis focus head of district is in the higher concentration medicine phase, be conducive to kill tubercule bacillus, greatly improve the Drug therapy index, reduce patient take medicine frequency and dosage, greatly reduced chemotherapeutics consumption and whole body thereof and distributed, avoided the first pass effect of hepar of oral medicine, can significantly reduce medicine to the liver toxic and side effects, shorten the tuberculosis treatment time.Find by long-term animal experiment study, particle diameter less than the chitin-alginic acid calcium gel micro-ball of 300 μ m in trachea is expelled to bronchus or bronchioles, can not cause animal cough, dyspnea, can not cause local pulmonary edema due to disorder of QI, the pulmonary collapse or foreign body pneumonia yet.In addition, chitin-alginic acid calcium gel micro-ball has very strong adhesive force to bronchial mucosa, is difficult for being got rid of external by the respiratory tract cilium.Utilize the characteristics of chitin-alginic acid calcium gel micro-ball self, namely ion-sensitive gel micro-ball processing technology is simple, and high to the envelop rate of fat-soluble medicine, drug carrying ability is better, has good medicament slow release effect.Especially the present invention designs the coated calcium alginate medicine carrying microballoons of chitosan, can improve the medicament slow release ability of this microsphere, and to the resistance enhancing of phosphate, citrate and monovalent cation corrosion, degraded and the corrosion of microsphere in lung delays.
The invention has the advantages that the medicine carrying chitin-alginic acid calcium microsphere of diameter 100-300 μ m and hyaluronic acid-calcium alginate gel bead of diameter 100-280 μ m are mixed in proportion the implantation lung, two kinds of different microspheres of function are had complementary advantages, solved the technical barrier of the interior microsphere obstruction of bronchus with pulmonary ventilation, and can significantly reduce poisonous side effect of medicine, improve the Drug therapy index.
Hyaluronic acid-calcium alginate gel bead is semisolid, smooth surface, diameter 100-280 μ m, be rich in the semi-transparent spheres of viscoelasticity.Medicine carrying chitin-alginic acid calcium gel micro-ball is semi-solid, surperficial more smooth, diameter 100-300 μ m, the circle that adhesion is arranged or similar round spheroid, the medicine that bag carries comprises antibiotic, hormone, anti-tumor chemotherapeutic medicine, polypeptide drug and/or biological cell, can be one or more.When being used, evenly mix in proportion these two kinds of gel micro-balls, insert in the pulmonary branches trachea, these two kinds of gel micro-balls are with different rates generation corrosion and degraded, the catabolite major part is got rid of external with pulmonary branches trachea mucus, fraction is absorbed by lung, external through the kidney eliminating, have the effect that slowly discharges more than 24 hours.
Conventional medicine comprises that aerosol and dry powder doses are generally the whole body administration, effective drug duration is short, can be implemented in the focus topical and can get involved intrabronchial degradable gel microspheres among the present invention, sustained release, effective drug duration is long, distribute thereby reduce drug dose and whole body thereof, can significantly reduce poisonous side effect of medicine, improve the Drug therapy index.
The bronchial degradable gel microspheres of intervention of the present invention does not block the pulmonary branches trachea, has not caused bronchus surrounding tissue ischemic necrosis yet, can be used as tissue engineering bracket material and medicament slow release skeleton.Hyaluronate sodium, calcium alginate and chitosan have good mucosa adhesion characteristic, with hyaluronic acid derivatives, the calcium alginate gel high resilience of their preparations, can be degradable in 3 time-of-weeks, and to the lung tissue not damaged, do not hinder pulmonary ventilation.
The present invention will be further described below by the specific embodiment, but and do not mean that limiting the scope of the invention.
The specific embodiment
Embodiment 1
The intrabronchial degradable gel microspheres of a kind of intervention comprises hyaluronic acid-calcium alginate gel bead and Mycobutin chitin-alginic acid calcium gel micro-ball, and its making step is as follows:
(1) the 4g Mycobutin is dissolved in the 40mL ethyl acetate, gets mass fraction 10% Mycobutin solution;
(2) take by weighing 1.5g sodium alginate, 0.3g hyaluronate sodium and 0.5g glycerol, jointly be dissolved in the 100mL distilled water, obtain hyaluronate sodium-sodium alginate soln.
(3) take by weighing the 2.5g sodium alginate and be dissolved in the 100mL distilled water, obtain 2.5% sodium alginate soln;
(4) take by weighing the 0.2g chitosan and be dissolved in 4% acetic acid solution 100mL, obtain 0.2% chitosan solution;
(5) calcium chloride is mixed with 1.5% solution, gets the colloidal sol solidification liquid;
(6) with gained hyaluronic acid-sodium alginate solution, by high-pressure electrostatic bull drop generating device, produce continuously fine droplet, enter in the 1.5% calcium chloride solidification liquid and solidify 1h, distilled water rinsing 2 times, vacuum drying gets hyaluronic acid-calcium alginate gel bead;
(7) with method and the making step of above-mentioned (6), first with 10% Mycobutin solution and 2.5% sodium alginate soln in ratio emulsifying in 1: 4, by high-pressure electrostatic bull drop generating device, low discharge produces fine droplet continuously under 10 000V voltages, enter in the 1.5% calcium chloride solidification liquid and solidify, get the Mycobutin calcium alginate gel bead.
(8) the Mycobutin calcium alginate gel bead is through distilled water drip washing, be suspended in again in above-mentioned 0.2% chitosan solution, chitosan is coated with gel micro-ball 15-30min, filter microsphere, distilled water rinsing 2 times, 40 ℃ of vacuum dryings, the ethyl acetate volatilization disperses, and gets Mycobutin chitin-alginic acid calcium gel micro-ball.
Use: before facing use, 0.2g Mycobutin chitin-alginic acid calcium gel micro-ball and the 0.1g hyaluronic acid-calcium alginate gel bead of gained is mixed in the container adding 20mL normal saline swelling 10min～20min.The gel micro-ball suspension of swelling through the bronchoscope guiding, is slowly injected the bronchial specific part of lunger with 0.2mL/Kg dosage.Repeat bronchus inner gel microsphere after 10 days and inject, continuous 4 times.
Mycobutin chitin-alginic acid calcium and hyaluronic acid-calcium alginate gel bead therapeutic effect:
After injecting above-mentioned gel micro-ball in patient's bronchus, breathing and heart rate are slightly accelerated, and breathe behind the 20min and recover normal.The sensation of patient's apnea difficulty has no gel micro-ball in the sputum.X-line fluoroscopy of chest next day has no lung marking change and lung yin shadow and increases the weight of.The patient feels well after 2 weeks, and body weight increases 0.4Kg.X-line fluoroscopy of chest patient after 6 weeks, the pulmonary tuberculosis focus is obviously dwindled.
Embodiment 2
The intrabronchial degradable gel microspheres of a kind of intervention comprises hyaluronic acid-calcium alginate gel bead and rifapentine chitin-alginic acid calcium gel micro-ball, and its making step is as follows:
(1) an amount of rifapentine medicine dry powder is ground, 200 mesh sieves filter.
(2) take by weighing 1.5g sodium alginate, 0.3g hyaluronate sodium and 0.5g glycerol, jointly be dissolved in the 100mL distilled water, obtain hyaluronate sodium-sodium alginate soln.
(3) take by weighing the 2.5g sodium alginate and be dissolved in the 100mL distilled water, obtain 2.5% sodium alginate soln;
(4) take by weighing the 0.2g chitosan and be dissolved in 4% acetic acid solution 100mL, obtain 0.2% chitosan solution;
(5) calcium chloride is made the solution of mass fraction 2%, got the colloidal sol solidification liquid;
(6) gained hyaluronate sodium-sodium alginate soln is passed through high-pressure electrostatic bull drop generating device, produce continuously fine droplet, enter in the described 2% calcium chloride solidification liquid and solidify 1h, distilled water rinsing 2 times, vacuum drying,, get hyaluronic acid-calcium alginate gel bead.
(7) with above-mentioned (5) method and making step, at first 2g rifapentine medicated powder is mixed with 2% sodium alginate soln 100mL, and by high-pressure electrostatic bull drop generating device, get the rifapentine calcium alginate gel bead.
(8) the rifapentine calcium alginate gel bead is suspended in the above-mentioned chitosan solution through normal saline drip washing 1 time again, and chitosan is coated with 15-30min, gets rifapentine chitin-alginic acid calcium gel micro-ball, distilled water rinsing 2 times, and vacuum drying, stand-by.
Use: before facing use, above 0.4g rifapentine chitin-alginic acid calcium gel micro-ball and 0.2g hyaluronic acid-calcium alginate gel bead are mixed in the syringe, add 30mL normal saline swelling 10min～20min.The gel micro-ball of above-mentioned swelling guides through bronchoscope, slowly injects in lunger's the pulmonary cavity.Bronchoscope is detected the gel micro-ball variation after 15 days, repeats to inject the rifapentine gel micro-ball after January in the cavity.
Rifapentine chitin-alginic acid calcium and hyaluronic acid-calcium alginate gel bead therapeutic effect: after injecting above-mentioned gel micro-ball in tubercular's pulmonary cavity, breathing and heart rate are not accelerated the sensation of patient's apnea difficulty.Next day, the patient was through the fluoroscopy of chest of X-line, had no lung marking change and lung yin shadow and increased the weight of.The patient feels well after 2 weeks, and bronchoscope is detected the pneumonopathy kitchen range, and visible granulation tissue hyperplasia retains a small amount of gel micro-ball in the cavity, and after January, X-line fluoroscopy of chest demonstration pulmonary cavity focus is dwindled.
Embodiment 3
The intrabronchial degradable gel microspheres of a kind of intervention comprises hyaluronic acid-calcium alginate gel bead and doxorubicin (doxorubicin) chitin-alginic acid calcium gel micro-ball, and its making step is as follows:
(1) the 6g doxorubicin is dissolved in the 40mL ethyl acetate, gets 15% doxorubicin solution;
(2) take by weighing 1.5g sodium alginate, 0.3g hyaluronate sodium and 0.5g glycerol, jointly be dissolved in the 100mL distilled water, obtain hyaluronate sodium-sodium alginate soln.
(3) take by weighing the 2.5g sodium alginate and be dissolved in the 100mL distilled water, obtain 2.5% sodium alginate soln;
(4) take by weighing the 0.2g chitosan and be dissolved in 4% acetic acid solution 100mL, obtain 0.2% chitosan solution;
(5) 5g calcium chloride is dissolved in the 500mL distilled water, is mixed with 1% calcium chloride solution, get the colloidal sol solidification liquid;
(6) with gained hyaluronic acid-sodium alginate solution, by high-pressure electrostatic bull drop generating device, produce continuously fine droplet, enter in the 1% calcium chloride solidification liquid and solidify 1h, distilled water rinsing 2 times, vacuum drying,, get hyaluronic acid-calcium alginate gel bead;
(7) with method and the making step of above-mentioned (6), first with 15% doxorubicin solution and 2.5% sodium alginate soln in ratio emulsifying in 1: 6, by high-pressure electrostatic bull drop generating device, produce continuously fine droplet, enter in the described colloidal sol solidification liquid and solidify, get the doxorubicin calcium alginate gel bead.
(6) the doxorubicin calcium alginate gel bead is through distilled water drip washing, be suspended in again in above-mentioned 0.2% chitosan solution, chitosan is coated with gel micro-ball 15-30min, get doxorubicin chitin-alginic acid calcium gel micro-ball, distilled water rinsing 2 times, 40 ℃ of vacuum dryings are removed ethyl acetate, and are stand-by.
Use: the experiment of doxorubicin chitin-alginic acid calcium gel micro-ball treatment pulmonary carcinoma.Before gel micro-ball faces use, 0.2g doxorubicin chitin-alginic acid calcium gel micro-ball and the 0.1g hyaluronic acid-calcium alginate gel bead of gained is mixed in the container, adds 20mL normal saline swelling 10min～20min.The gel micro-ball suspension of swelling through the bronchoscope guiding, is slowly injected the bronchial lumen near pulmonary carcinoma with 0.2mL/Kg dosage.Repeat to inject the doxorubicin gel micro-ball after 15 days in the bronchus, continuous 4 times.
Doxorubicin chitin-alginic acid calcium and hyaluronic acid-calcium alginate gel bead therapeutic effect:
After injecting above-mentioned gel micro-ball in patient's bronchus, breathe and slightly slightly quickening of heart rate, breathe behind the 20min and recover normal.The sensation of patient's apnea difficulty has no gel micro-ball in the sputum.X-line fluoroscopy of chest after one week has no the pulmonary consolidation district and changes.The patient feels good after 2 weeks.Patient X-line fluoroscopies of chest after 6 weeks see that former pulmonary carcinoma focus obviously dwindles, and the patient has no adnormal respiration.
Embodiment 4
The intrabronchial degradable gel microspheres of a kind of intervention comprises hyaluronic acid-calcium alginate gel bead and dexamethasone chitin-alginic acid calcium gel micro-ball, and its making step is as follows:
(1) the 0.5g dexamethasone is dissolved in the 10mL ethyl acetate, gets 5% dexamethasone solution;
(2) take by weighing 1.5g sodium alginate, 0.3g hyaluronate sodium and 0.5g glycerol, jointly be dissolved in the 100mL distilled water, obtain hyaluronate sodium-sodium alginate soln.
(3) take by weighing the 2.5g sodium alginate and be dissolved in the 100mL distilled water, obtain 2.5% sodium alginate soln;
(4) take by weighing the 0.2g chitosan and be dissolved in 4% acetic acid solution 100mL, obtain 0.2% chitosan solution;
(5) calcium chloride is mixed with 1.5% solution, gets the colloidal sol solidification liquid;
(6) with gained hyaluronic acid-sodium alginate solution, by high-pressure electrostatic bull drop generating device, produce continuously fine droplet, enter in the 1.5% calcium chloride solidification liquid and solidify 1h, distilled water rinsing 2 times, vacuum drying,, get hyaluronic acid-calcium alginate gel bead;
(7) with method and the making step of above-mentioned (6), first with 5% dexamethasone solution and 2.5% sodium alginate soln in ratio emulsifying in 1: 9, by high-pressure electrostatic bull drop generating device, produce continuously fine droplet, enter in the described colloidal sol solidification liquid and solidify, get the dexamethasone solution calcium alginate gel bead.
(8) the dexamethasone solution calcium alginate gel bead is through distilled water drip washing, be suspended in above-mentioned 0.2% chitosan solution, chitosan is coated with gel micro-ball 15-30min again, gets dexamethasone chitin-alginic acid calcium gel micro-ball distilled water rinsing 2 times, 40 ℃ of vacuum dryings are removed ethyl acetate.
(9) get the dry hyaluronic acid-calcium alginate gel bead of 50mg and dexamethasone solution calcium alginate gel bead and immerse 24mL normal saline, swelling 5min～20min.
Use: the gel micro-ball suspension of above-mentioned swelling is pressed 0.5mL/Kg dosage, through slender conduit, slowly inject in 14 rabbit left side bronchus.Respectively dissected 2 rabbits in the 1st, 3,5,7,14,21 and 30 day.
Dexamethasone chitin-alginic acid calcium gel micro-ball is implanted rabbit bronchus experimental result:
Behind the injected gel microsphere, rabbit breathes and heart rate is obviously accelerated, and breathing and heart rate recover normal behind the 60min.Injected gel microsphere the 1st day and 3 days, slight pulmonary venous pleonaemia occurs in rabbit left pulmonary part among a small circle, the transparent beads of visible cluster in the bronchus of left side, rabbit right lung no abnormality seen has no transparent beads in the right lung bronchus.Injected gel microsphere the 7th day, the rabbit right lung is normal, and left pulmonary has no pulmonary venous pleonaemia, the transparent beads of accidental cluster in the bronchus of left side, left side bronchial mucosa no abnormality seen.From the 14th day to the 30th day, it was all normal to remain tested rabbit breathing and heart rate, and the visible bilateral pulmonary of domestic rabbit dissection is normal, noresidue gel micro-ball in the bilateral pulmonary bronchus.
Embodiment 5
The bronchial degradable gel microspheres of a kind of intervention comprises hyaluronic acid-calcium alginate gel bead and gamma interferon chitin-alginic acid calcium gel micro-ball, and its making step is as follows:
(1) the 0.5g gamma interferon is dissolved in the 10mL normal saline, gets 5% gamma interferon solution;
(2) take by weighing 1.5g sodium alginate, 0.3g hyaluronate sodium and 0.5g glycerol, jointly be dissolved in the 100mL distilled water, obtain hyaluronate sodium-sodium alginate soln.
(3) take by weighing the 2.0g sodium alginate and be dissolved in the 100mL distilled water, obtain 2% sodium alginate soln;
(4) take by weighing the 0.2g chitosan and be dissolved in 4% acetic acid solution 100mL, obtain 0.2% chitosan solution;
(5) 5g calcium chloride is dissolved in the 500mL distilled water, is mixed with 1% calcium chloride solution, get the colloidal sol solidification liquid;
(6) with gained hyaluronic acid-sodium alginate solution, by high-pressure electrostatic bull drop generating device, produce continuously fine droplet, enter in the 1% calcium chloride solidification liquid and solidify 1h, distilled water rinsing 2 times, vacuum drying,, get hyaluronic acid-calcium alginate gel bead;
(7) with method and the making step of above-mentioned (6), first 5% gamma interferon solution is mixed in 1: 9 ratio with 2% sodium alginate soln, by high-pressure electrostatic bull drop generating device, produce continuously fine droplet, enter in the described colloidal sol solidification liquid and solidify, get the gamma interferon calcium alginate gel bead.
(8) the gamma interferon calcium alginate gel bead is through normal saline drip washing, be suspended in above-mentioned 0.2% chitosan solution, chitosan is coated with gel micro-ball 15-30min again, gets gamma interferon chitin-alginic acid calcium gel micro-ball, normal saline rinsing 2 times, vacuum lyophilization.
(9) take by weighing the gamma interferon chitin-alginic acid calcium gel micro-ball of the dry hyaluronic acid-calcium alginate gel bead of 30mg and 270mg drying, the two mixing, immersion 20mL normal saline
Use: the gel micro-ball suspension of above-mentioned swelling is pressed 0.8mL/Kg dosage, through slender conduit, slowly injects in 12 rabbit left side bronchus.Observe rabbit body temperature, breathing and changes in heart rate, and respectively dissected 2 rabbits in the 3rd, 5,7,14,21 and 28 day.
The gamma interferon calcium alginate gel bead is implanted rabbit bronchus safety experiment result: behind the whole injected gel microsphere, after rabbit left side bronchus is implanted into the gamma interferon calcium alginate gel bead, breathing and heart rate are obviously accelerated, rabbit breathing and heart rate recover normal behind the 60min, occur to cough or dyspnea without 1 routine rabbit.Injected gel microsphere the 3rd day, slight pulmonary venous pleonaemia and edema occur in rabbit left pulmonary part among a small circle, the transparent beads of visible cluster in the bronchus of left side, rabbit right lung no abnormality seen has no transparent beads in the right lung bronchus.Injected gel microsphere the 7th day, the rabbit left pulmonary has no pulmonary edema, the accidental transparent beads that is dispersed in the bronchus of left side.The rabbit right lung is normal.From the 14th day to the 30th day, it was normal to remain tested rabbit breathing and heart rate.It is normal to dissect the visible bilateral pulmonary of rabbit, and the bilateral pulmonary bronchus is interior without transparent beads.Rabbit body temperature is all normal during the whole experimental observation, does not observe fever phenomenon.
Claims (6)
1. get involved intrabronchial degradable gel microspheres for one kind, it is characterized in that: comprise hyaluronic acid-calcium alginate gel bead and medicine carrying chitin-alginic acid calcium gel micro-ball, described hyaluronic acid-calcium alginate gel bead and medicine carrying chitin-alginic acid calcium gel micro-ball evenly mix in proportion, and volume ratio is 2: 1-9; Described hyaluronic acid-calcium alginate gel bead is comprised of hyaluronate sodium, calcium alginate, osmotic pressure regulator and water, the gel micro-ball diameter is 100-280 μ m, described osmotic pressure regulator is glycerol, in mass fraction, hyaluronate sodium is 0.5%-3.5%, calcium alginate is 3%-8%, and glycerol is 0.05-1.5%, and water is 89%-93%; Described medicine carrying chitin-alginic acid calcium gel micro-ball is comprised of chitosan, calcium alginate, medicine and water, and diameter is 100-300 μ m, in mass fraction, chitosan is 0.05-0.2%, calcium alginate is 3.0%-9.0%, and medicine is 0.5-6%, and water is 89.95%-95.45%; Described bronchial diameter is below 3mm.
2. the intrabronchial degradable gel microspheres of intervention as claimed in claim 1 is characterized in that: the volume ratio that described hyaluronic acid-calcium alginate gel bead and medicine carrying chitin-alginic acid calcium gel micro-ball mix is 1: 2.
3. the intrabronchial degradable gel microspheres of intervention as claimed in claim 1, it is characterized in that: in described hyaluronic acid-calcium alginate gel bead, in mass fraction, hyaluronate sodium is 1%, and calcium alginate 5.4%, glycerol are 1%, and water is 92.6%.
4. the intrabronchial degradable gel microspheres of intervention as claimed in claim 1, it is characterized in that: in the described medicine carrying chitin-alginic acid calcium gel micro-ball, in mass fraction, chitosan is 0.05%, and calcium alginate is 4%.
5. the intrabronchial degradable gel microspheres of intervention as claimed in claim 1, it is characterized in that: described medicine is Mycobutin, rifapentine, doxorubicin, dexamethasone and/or gamma interferon.
Such as the intrabronchial degradable gel microspheres of each described intervention among the claim 1-5 for the preparation of the application in treatment lung tumor, pulmonary tuberculosis, pneumonia and bronchitic sustained-release and controlled release medicine and the tissue engineering bracket material.
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| CN112972753A (en) * | 2019-12-02 | 2021-06-18 | 太阳雨林（厦门）生物医药有限公司 | Sustained-release embolism microsphere for treating bronchiectasis hemoptysis caused by chronic inflammation |
| CN114748635A (en) * | 2020-12-25 | 2022-07-15 | 姜秉均 | Nano composition containing hydrophobic substance and preparation method and application thereof |
| CN116570617A (en) * | 2023-06-16 | 2023-08-11 | 华熙生物科技股份有限公司 | Coated hyaluronic acid or salt thereof for oral administration, and preparation method and application thereof |
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