CN102670611A - Vascular targeting embolism sustained release agent of triple compound microsphere for antituberculosis drug, preparation method and applications thereof - Google Patents

Vascular targeting embolism sustained release agent of triple compound microsphere for antituberculosis drug, preparation method and applications thereof Download PDF

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CN102670611A
CN102670611A CN2011100537075A CN201110053707A CN102670611A CN 102670611 A CN102670611 A CN 102670611A CN 2011100537075 A CN2011100537075 A CN 2011100537075A CN 201110053707 A CN201110053707 A CN 201110053707A CN 102670611 A CN102670611 A CN 102670611A
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solution
microsphere
tuberculosis
antituberculotics
drug
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CN102670611B (en
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敖国昆
李新建
张光宇
洪宏
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Beijing Shengyiyao Science & Technology Development Co Ltd
309th Hospital of PLA
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Beijing Shengyiyao Science & Technology Development Co Ltd
309th Hospital of PLA
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Abstract

The invention relates to a vascular targeting embolism sustained release agent of a triple compound microsphere for an antituberculosis drug, a preparation method and applications thereof. The sustained release agent comprises a carrier and a drug, wherein the drug is encapsulated by the carrier, the carrier is selected from sodium alginate or chitosan, and the drug is a triple compound antituberculosis drug which comprises rifampin, isoniazide and pyrazinamide or moxifloxacin. Three antituberculosis drugs are employed as matrixes of a drug solution, sodium alginate or chitosan is used as a carrier solution, and a prepared solution is obtained by mixing the drug solution and the carrier solution. A polymer solution having the drug is enabled to be dispersed into droplets with certain particle sizes and to be sprayed into a curing liquid through a method of high voltage electrostatic droplets, and thus the microsphere for the antituberculosis drug are prepared in the presence of calcium ions. The embolism sustained release agent can be used in the drug for treating pulmonary tuberculosis, pulmonary tuberculosis massive hemoptysis, cavitary pulmonary tuberculosis, renal tuberculosis, osteoarticular tuberculosis, genital tubercolosis, thyroid tuberculosis, tuberculosis of cervical lymph nodes, pericardial tuberculosis, chest-wall tuberculosis and other in-vivo tuberculosises.

Description

Antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents
Technical field
The present invention relates to a kind of three compound recipe microsphere vascular targeting thromboembolism slow releasing agents that contain antituberculotics; Being specifically related to a kind of is crosslinked microsphere vascular targeting thromboembolism slow releasing agent of the multiple tuberculosis effective ingredient of carrier and preparation method thereof and in the application of aspects such as intervention embolization with the sodium alginate, belongs to medical embolization equipment field.
Background technology
Tuberculosis is one of healthy main infectious disease of serious harm human life; And China is that 22 tuberculosis height are born one of country in the world; The tuberculosis number occupies the 2nd in the world, and existing lunger accounts for 1/4 of global patient's sum, and annual number because of tuberculosis death has 150,000 approximately; Although treatment lungy and immunoprophylaxis have been obtained very big progress, tuberculosis remains one of major disease of China's emphasis control.Tuberculosis is in rising trend in recent years, and especially resistant tuberculosis and tulase and increasing to control lungy of HIV double infection case have increased difficulty.Along with antituberculotics in clinical extensive use, the resistant rate of mycobacterium tuberculosis is more and more high, multi-drug resistant problem has especially become the problem that anti-consumptive disease circle is paid close attention to.Chemicals is present treatment main means lungy, and irregular treatment or drug withdrawal too early cause the chemotherapy failure but patient regular meeting is because of a variety of causes causes.For overcoming this a great problem of tuberculosis control work, improve compliance and the curative effect of patient to chemotherapy, World Health Organization (WHO) and international anti-tuberculosis association and pulmonary disease community recommend to replace the first-selected medicine of single medicine as tuberculosis patient with the fixed amount complexing agent.Therefore, selecting suitable antituberculotics and exploitation antituberculosis drug and novel form is the pith of current treatment and controlling tuberculosis.
For improving the tuberculosis epidemic situation, WHO, international anti-tuberculosis association (IUAT) and many clinical health care units have carried out a large amount of explorations from aspects such as drug combination, the course of treatment, administration number of times, adverse effect, effective percentage and relapse rates.So-called compound formulation is meant that several different antituberculotics by certain dosage formulation, are mixed and made into a kind of compound preparation form, and its dosage form can be capsule or tablet.What complexing agent was the most frequently used is by rifampicin, isoniazid, and proportionings such as pyrazinamide or ethambutol are formed.The tuberculosis effect is better than contained effect with dosage list medicine in the body of compound preparation, and therefore, pharmacodynamic experiment shows, significantly is superior to the effect that each prescription is used with the effect of Tuberculosis in vitro nuclear in the body of compound preparation.
Rimactazid and pyrazinamide are the choice drug of anti-mycobacterium tuberculosis infection; Rifampicin is that a line medicine of treatment tuberculosis is again necessity composition medicine in the treatment leprosy conjoint therapy; Has a broad antifungal spectrum; The several diseases pathogenic microorganism is all had antibacterial activity, and wherein the tulase to poor growth and intermittently growth has good antibacterial action.To idiophase tubercule bacillus have bactericidal action, use rifampicin treatment tuberculosis separately, tubercule bacillus very easily produces drug resistance in the human body, its natural resistant rate is about 1.7%.Isoniazid has the high degree of specificity antibacterial action to tubercule bacillus, during higher concentration propagation phase tubercule bacillus is had very strong bactericidal action.Tubercule bacillus also has killing action in the pair cell, and its effect is stronger 500 times than streptomycin.Tubercule bacillus also is easy to produce drug resistance to isoniazid, share other antituberculotics after, can delay or prevent the appearance of fastbacteria significantly.No crossing drug resistant such as Rimactazid, streptomycin.Pyrazinamide mainly acts in the cell flora in the macrophage sour environment particularly, and when pyrazinamide joined in the combination of Rimactazid, whole chemotherapy cycles can be reduced to 6 months.
The exploitation of new technique and use and people lay a good foundation to progressively understanding in depth to the exploitation of new antitubercular agent of mycobacteria.The new comparatively ideal condition of antitubercular agent, few or do not have the toxicity except that having required significant usefulness and toxicity, preferably drain slow; Blood level can be kept high level within a certain period of time; Medicine can penetrate cell, particularly phagocyte, can be diffused into cheesy focus and reach or wear in the input cerebrospinal fluid; Human body is better to the toleration of medicine, merges to use to postpone antibacterial to develop immunity to drugs.The treatment phase is shortened in the different drug coupling, replenishes or strengthen the curative effect of existing medicine, develops new slow release delivery system, to reduce administration number of times and to reach the needed dose of expected effect, research molecule target position.Purpose is to find and can shorten treatment time, reduces the toxicity relevant with medicine, and the stock of drugs when drug resistance takes place is provided.Mainly be by a line medicament benemicin to treatment lungy at present; Isoniazid; The therapy of couplings such as pyrazinamide, with rifampicin, isoniazid; Pyrazinamide is that the tuberculosis SCC scheme of core has become a lot of national conventional schemes, and coupling treatment tuberculosis has the unique effect of remarkable shortening chemotherapy time.
The mycobacterium tuberculosis main parasitic is in normal cell and certain drug resistance is arranged, and kill intracellular tulase and must in cell, reach certain antitubercular agent substrate concentration.And the oral formulations of antituberculotics often receives the influence of first pass effect earlier and processes such as process protein binding, metabolism, drainage and decomposition in systemic circulation; Have only small amount of drug just can reach target tissue, target organ, target cell; The drug level that improves the target area just must increase dosage, thereby has also increased the whole body toxic and side effects of medicine.And targeting preparation has the directed medicine that discharges, and increases drug level in diseased region and the cell, improves drug effect, reduces characteristics such as toxic and side effects, thinks that therefore the antituberculotics targeting preparation has Clinical Application to be worth and development prospect.
Medicine carrying microballoons is a kind of spherical or type spherical particle that suitable macromolecular material wraps up as carrier or the absorption medicine is processed that uses.Drug release in the microsphere controlled release system can pass through the cyst wall leaching; Infiltration and diffusing out also can be the corrosion of substrate itself and drug release is wherein come out, and microsphere has many superioritys aspect drug conveying; 1. can slow releasing pharmaceutical, thus prolong drug action time; 2. can reach the purpose of tissue or organ targeted; 3. can guarantee to reduce dosage under the pharmaceutically-active prerequisite, thereby alleviate or reduce or remit poisonous side effect of medicine; 4. can improve stability of drug, help storing.If the above characteristics of microsphere can be applied to antituberculotics, then the problem of tuberculosis patient drug compliance will be solved preferably.Implant with the depot drug product of Biodegradable high molecular as carrier, after drug release was intact, the taking-up of need not performing the operation can reduce patient's misery.When generally macromolecule was as pharmaceutical carrier, along with the minimizing of carrier Chinese medicine content, the rate of release of medicine was slack-off; Can't keep the constant of medicine to discharge, when discovering, along with macromolecule continuous degraded in vivo with the Biodegradable high molecular pharmaceutical carrier; It is loose that the structure of pharmaceutical carrier becomes gradually; The inside contained medicine resistance that therefrom dissolves and spread is reduced, the drug releasing rate quickening, when the quickening of drug releasing rate just in time slack-off when consistent with the caused drug release rate of the minimizing of content of dispersion; The long time constant of just having realized medicine discharges, till carrier has been degraded.
Just there is the scholar to adopt tremie method that single medicine is injected empty internal therapy cavernous pulmonary tuberculosis as far back as the fifties; Or instillation treatment drug resistance pulmonary tuberculosis in the employing bronchus, but because complex operation, the pastille medium is a liquid; Mobile big; Cause that the patient frequently coughs, the patient suffering is big and causes the bronchogenic spread of tubercule bacillus easily, fails popularization and application.The past route of administration is mainly oral; Advocate escalated dose and once a day for the instructions of taking of this medicine in recent years, but still can not reduce its untoward reaction, take especially for a long time and be prone to cause blood system; Hormonal system, the infringement of aspects such as neural psychiatric system and liver.Over year, the clinical practice of branchofiberoscope is day by day ripe and universal, has the scholar to carry out the interventional therapy of cavernous pulmonary tuberculosis under the branchofiberoscope surplus in the of nearly 10; The misery when though the method has alleviated patient treatment greatly; But the medium of interventional therapy still is liquid, and the time that in the focus cavity, stops is shorter, and medicine still is 1～2 kind of water solublity antituberculotics in addition; Curative effect is limited, and is easy to cause bronchogenic spread.For this reason,, it can be concentrated in target site after administration, slowly discharge, reach and improve the purpose that curative effect reduces untoward reaction through microsphere supported from the suitable drug-supplying system of galenic pharmacy angle Selection.To above-mentioned situation, through screening, the present invention adopts a kind of novel antituberculotics three compound recipe microball prepns to be used for lung target vascular therapy thromboembolism slow-released system.The embolic microsphere can be arrested in the tuberculosis blood capillary on every side with blood, can make the small artery temporary embolization, both can cut off the nutrition supply of tuberculosis, also can make the microsphere of medicine carrying be trapped in diseased region, improves local concentration, prolongs action time.
In tuberculosis, tulase quantity is the highest in the pulmonary cavity, and empty focus is the root that produces fastbacteria, also is the main cause of tuberculosis chemotherapy failure.Disorganization is serious in the focus of cavity, and fibroplasia receives the influence of local vascular rareness and caseation slough, and medicine is difficult for infiltrating the cavity, is difficult to reach efficacious therapy concentration.In recent years; Fibre bronchus mirror's technology obtains good application in the interventional therapy of anti-multiple medicines cavernous pulmonary tuberculosis, can look at patient's lesions position straight through fibre bronchus mirror, and antituberculotics directly is injected in the cavity through conduit; Cause high local concentrations, help the improvement of patient's focus.
Tuberculosis recurrence and tulase drug resistance phenomenon are serious day by day, although it is complicated to produce reason, one of them crucial factor is that treatment is long the course of treatment; The patient can not finish to the course of treatment in the medication of rule capacity; This is the problem that various countries, whole world tuberculotherapy is generally faced, and under the prerequisite that guarantees therapeutic effect, reduces drug dose; Prolong drug blanking time, the problem of drug compliance can effectively be solved.Domestic have only fragmentary report to the research of carrying the antituberculotics microsphere; How with oral or injecting drug use; The systematic study report that carries the antitubercular agent microsphere is mainly concentrated on the research group of the U.S., Japan and India abroad; Research relates to different carriers, different drug, different microspherulite diameters and different route of administration.Also have the scholar to be devoted to the research of tuberculosis slow-released system, mainly be oral agents, inhalant, injection and subdermal implants before.
Antituberculotics is mainly oral and ejection preparation clinically at present, even injection is also not ideal enough.Because can not obtain active drug concentration in lesions position; Can not continue relatively uniformly to discharge; And significantly general toxicity and drug-fast generation in application process; Greatly limited the application of this medicine, the thromboembolism that minority adopted adds the medicine infusion therapy and also has following defective: medicine can not continue to discharge relatively uniformly; During Where topical dabbling drug excessive concentration, the shock wave curative effect of its medicine possibly produce local tissue necrosis or damage.
Summary of the invention
One of the object of the invention is to overcome the defective of prior art and the untoward reaction that the tuberculosis common drug causes; Overcome oral, the injectable drug effect is slow; Can not directly deliver to lesions position to medicine and obtain effective drug level, can not continue weakness such as release relatively uniformly.Change route of administration and dosage form, for the patient provides a kind of carrier material natural, biological degradability is good, and carrier is single, multiple drug regimen, a kind of tuberculosis microsphere vascular targeting thromboembolism slow release novel form that under high-pressure electrostatic microsphere generator and calcium ion effect, produces.
To achieve these goals, adopt following technical scheme:
Scheme one:
A kind of antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents that contain; Comprise carrier and medicine; It is characterized in that: said carrier wraps up said medicine; Said carrier is sodium alginate or chitosan, and said medicine is tuberculosis three compound mediciness, comprises Rimactazid and pyrazinamide or MOXIFLOXACIN.
A kind of optimal technical scheme is characterized in that: the weight ratio of said carrier and said medicine is 1: 1～50, be preferably 1: 1～and 10.
A kind of optimal technical scheme is characterized in that: in the said medicine, the weight ratio of Rimactazid and pyrazinamide or MOXIFLOXACIN is: rifampicin: isoniazid: pyrazinamide or MOXIFLOXACIN are 1:2:4.
Scheme two:
A kind of antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents that contain; With three kinds of antituberculotics Rimactazids and pyrazinamide or MOXIFLOXACIN is the substrate drug solution, is carrier solution with sodium alginate or chitosan, and said drug solution and carrier solution must prepare solution after mixing; Adopt the mode of high-pressure electrostatic drop; Make and produce high electric field between each both positive and negative polarity, when syringe pump will prepare the solution release with constant speed, electric field force had overcome inherent viscous force of sodium alginate and surface tension; The droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the consolidation liquid, under the effect of calcium ion, makes the antituberculotics microsphere.
Further purpose of the present invention provides the method for preparing of described antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents.
Method for preparing of the present invention adopts following technical scheme to realize:
A kind of method for preparing that contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents comprises the steps:
(1) reagent preparation
(1) carrier solution: accurately take by weighing sodium alginate or chitosan powder,, get carrier solution, i.e. sodium alginate or chitosan solution with normal saline or water for injection dissolving;
(2) drug solution:
1. rifampicin solution:
Claim that adding part water for injection in the rifampicin powder milk ejection alms bowl grinds dissolving, reuse surplus injection washing mortar, after the mixing ultrasonic again 10 minutes, rifampicin solution;
2. isoniazid solution:
Claim the isoniazid powder, add the dissolving of injection water, get isoniazid solution;
3. pyrazinamide or MOXIFLOXACIN solution:
Claim pyrazinamide or MOXIFLOXACIN powder, add the dissolving of injection water, get pyrazinamide or MOXIFLOXACIN solution;
(3) preparation solution:
The pyrazinamide that makes or MOXIFLOXACIN solution and isoniazid solution are combined earlier; And then mix with rifampicin solution, three kinds of mixing obtain drug solution, and drug solution is joined in sodium alginate or the chitosan solution; Magnetic stirrer is even, must prepare solution;
(4) ionic calcium soln:
Accurately take by weighing calcium lactate or calcium chloride, by the concentration of 10～120g/L (1～12 W/V%), with the water for injection dissolving, the preparation ionic calcium soln;
(5) curing solution:
Get ionic calcium soln, water for injection and the dehydrated alcohol of above-mentioned gained, mix homogeneously gets curing solution;
(6) reinforced solution:
Take by weighing gelatin or polylysine,, get gelatin or polylysine solution, i.e. reinforced solution with the water for injection dissolving;
(2) microsphere preparation process:
(1) balling-up process:
Above-mentioned gained is prepared solution suck in the 50ml syringe, connect syringe needle, be added on the micro-injection pump; Connection electrode through high-pressure electrostatic microsphere generator, makes and produces high electric field between each both positive and negative polarity; When syringe pump will prepare the solution release with constant speed; Electric field force has overcome inherent viscous force of sodium alginate and surface tension, and the droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the curing solution, is cross-linked into calcium alginate medicine microspheres or micro gel bead rapidly; Treat to sop up supernatant after deposition fully, must contain antituberculotics compound recipe microsphere or micro gel bead;
(2) strengthening process:
Microsphere that makes or micro gel bead are put into reinforced solution, and promptly in gelatin or the polylysine solution, magnetic agitation is 3～5 minutes at a slow speed, supernatant discarded, antituberculotics three compound recipe microsphere or the micro gel beads after must strengthening.
A kind of optimized technical scheme; It is characterized in that: the concentration of described carrier solution (sodium alginate or chitosan solution) be 10～60g/L (1～6 the gram/100ml); The rifampicin solution concentration is 200g/L; The isoniazid solution concentration is 400g/L, and pyrazinamide or MOXIFLOXACIN solution concentration are 800g/L.
A kind of optimized technical scheme is characterized in that: in the described drug solution, the weight ratio of Rimactazid, pyrazinamide or MOXIFLOXACIN is 1: 2: 4.
A kind of optimized technical scheme is characterized in that: in the described preparation solution, the weight ratio of medicine and sodium alginate is 1: 1～50, and the weight ratio that is preferably medicine and sodium alginate is 1: 1～10.
A kind of optimized technical scheme is characterized in that: described curing solution is that ionic calcium soln, water for injection and dehydrated alcohol obtain according to 3: 1: 1 mix homogeneously of volume ratio.
A kind of optimized technical scheme is characterized in that: described gelatin or polylysine solution concentration are 0.2～20 g/L (0.02～2 W/V%).
A kind of optimized technical scheme is characterized in that: described high-pressure electrostatic microsphere generator comprises the syringe peace scalp acupuncture head of HV generator, a plurality of positive and negative electrode, stainless steel ring, micro-injection pump, different model, aseptic glass container, magnetic stirring apparatus and lowering or hoisting gear.
A kind of optimized technical scheme; It is characterized in that: described microsphere or micro gel bead are stored in the vegetable oil (like soybean oil, Oleum Camelliae) or liquid paraffin of injection; The particle diameter specification of microsphere or micro gel bead is: 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～500 μ m, 500～720 μ m, 700～900 μ m or 900～1250 μ m; Time spent discards vegetable oil or liquid paraffin, with normal saline give a baby a bath on the third day after its birth all over be implantable or injecting body in.
A kind of optimized technical scheme is characterized in that: described microsphere or micro gel bead (make dry bulb with lyophilization or oven method) after drying, get powdery granule; The particle size range of said powdery particles is 30～50 μ m, 50～80 μ m, 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～550 μ m, 500～720 μ m, 700～900 μ m; With cobalt-60 radiation sterilization, airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using.
Further purpose of the present invention provides the medical application of said antituberculotics three compound alginic acid sodium microsphere vascular targeting thromboembolism slow releasing agents.
The inventive method gained antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents are used to treat the application in the medicine of aspects such as other tuberculosis in pulmonary tuberculosis, pulmonary tuberculosis massive hemoptysis, pulmonary tuberculosis cavity, renal tuberculosis, osteoarthrosis (breast, lumbar vertebra) tuberculosis, genital tuberculosis (fallopian tube, endometrium, testis, epididymis), tuberculosis of thyroid gland, the tuberculosis of cervical lymph nodes, tuberculosis of pericardium, thoracic tuberculosis, tuberculous pleuritis and the body in preparation.
The method that its Therapeutic Method adopts intervention radiation or bronchoscope to get involved is carried out the target organ angiography, according to the radiography finding; The diameter that embolism microball is selected in decision for use carries out the target organ embolotherapy, when the present invention uses; Preferred microtubular surpasses selects thromboembolism, adopts the sterile working, and perspective is looked concrete condition through conduit down and slowly or slowly repeatedly injected; When the contrast agent flow velocity obviously slows down, promptly accomplish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.During use; If contain antituberculotics three compound alginic acid sodium microsphere vascular targeting thromboembolism slow releasing agents are powdery granules; Then will be kept in the hermetic container dry bulb earlier and be dissolved in reduction (being wet bulb) in normal saline; Add the contrast agent mix homogeneously after an amount of or the dilution again, microsphere fully be suspended in the contrast agent, again image documentation equipment keep watch on down through in the blood vessel of conduit super-selective thromboembolism at diseased region slowly or slowly repeatedly injection; When the contrast agent flow velocity obviously slows down, promptly accomplish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization.Especially thromboembolism is in the peripheral arteriole blood vessel of target organ; Can consider having of peripheral arteriole blood vessel to the lunger: failure is just controlled in (1); Again through controlling the treatment of tuberculosis scheme again; It is positive to finish back smear tuberculosis the course of treatment, and expectorant is cultivated mycobacterium tuberculosis to two kinds of HR or the more anti-receptor of antituberculotics, promptly anti-multiple medicines tuberculosis.(2) the single book wall of expectorant tulase lasting masculin or cheese cavity, and cavity does not have the person of stablizing of obvious activeness focus or focus on every side.(3) phthisical single fibrotic cavitys is controlled the not cloudy commentaries on classics person of expectorant bacterium for a long time.(4) endobronchial tuberculosis of obstinate expectorant bacterium lasting masculin.(5) intervention embolization of pulmonary tuberculosis massive hemoptysis.(6) interventional therapy of outer other tuberculosis of lung, as: renal tuberculosis, osteoarthrosis (breast, lumbar vertebra) tuberculosis, genital tuberculosis (fallopian tube, endometrium, testis, epididymis), tuberculosis of thyroid gland, lymphoid tuberculosis, tuberculosis of pericardium, thoracic tuberculosis, tuberculous pleuritis etc.
That adopts that said method processes desirable controllable grain size contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents, and the technology that adopts intervention radiation or bronchoscope to get involved changes original dosage form and route of administration; Realize the targeting transmission of medicine, reach the narrow spectrum characteristics of targeting, conduit is inserted target organ section opening; Under the X line is kept watch on, introduce seal wire, action arteries and veins radiography after conduit embeds lumen of vessels is according to the radiography finding; Take the photograph sheet continuously and confirm that the A/C front end withdraws from seal wire; RC, the suitable particle size range of selecting for use above-mentioned sodium alginate to wrap up described three kinds of antituberculotics (Rimactazid, pyrazinamide or MOXIFLOXACIN) microspheres (micro gel bead) is with antituberculotics three compound recipe microspheres (wet bulb); With normal saline flushing microsphere three times, add an amount of contrast agent again and be mixed, perspective is slowly injected lesions position through conduit down; When the contrast agent flow velocity obviously slows down, promptly accomplish thromboembolism.The arteries and veins radiography of taking action is once more judged effect of embolization; With antituberculotics three compound recipe microspheres (dry bulb), be reduced into wet bulb in several minutes with the normal saline immersion before using; In implantable (injection) body.
Outstanding advantage of the present invention is: antituberculotics three compound alginic acid sodium microsphere vascular targeting thromboembolism slow releasing agents are a kind of novel forms; Used high-pressure electrostatic microsphere generator balling-up advanced technology, output is high, helps industrialization production; Easy and simple to handle; Mild condition can avoid the use of deleterious organic solvent (like glutaraldehyde etc.), is environment-friendly products.Used pharmaceutical carrier sodium alginate is a polysaccharide compound, belongs to the polyanion type, and material is natural, from Brown algae, extracts and gets.Used antitubercular agent is selected a line medicine of the antibiotic effect of three kinds of different specificitys for use, and is antibiotic general wide, stable in properties, and the inside and outside tubercule bacillus of pair cell all has stronger killing action.Compound preparation replaces single medicine preparation to meet the standard that World Health Organization (WHO) and international anti-tuberculosis association and pulmonary disease community are recommended; The inside and outside tuberculosis effect of compound preparation significantly is superior to the effect that each prescription is used; Medicine microspheres and tablet or capsule ratio, medicine microspheres has many superioritys aspect drug conveying.Because the oral anti-tuberculous drug thing can not obtain active drug concentration in lesions position,, medicine is not just directly concentrated in target site through the body circulation through the method that gets involved with back general toxicity and drug-fast generation; Slowly discharge, thereby reduced the concentration of medicine in blood circulation, reduced the toxicity of medicine normal structure; Reach the minimizing dosage; Improve curative effect, reduce untoward reaction, the purpose of prolong drug action time.Adopt preferred advanced technology method in the production process, be bundled together three kinds of antituberculotics simultaneously, performance 1+1 is greater than 2 effect; Solve the phenomenon that can not form ball after preparation liquid sprays simultaneously, solved the too fast phenomenon of water soluble drug diffusion, solved the problem that microsphere (micro gel bead) is preserved; The antituberculotics microspherulite diameter ideal that makes is controlled; And it is big that the microsphere vascular thromboembolism slow releasing agent that makes has a drug loading, in vivo the holdup time long, bioavailability is high; The targeting transmission and the release of medicine have the narrow spectrum characteristics of targeting.
In order to obtain to bring into play in vivo the antituberculotics preparation of long-acting; The present invention has selected biocompatibility good; The natural macromolecular material sodium alginate is a carrier, with rifampicin, and isoniazid; Pyrazinamide (or MOXIFLOXACIN) combination medicine is a substrate, obtains the biodegradable pulmonary of long-acting slow-release targeted microspheres blood vessel embolism slow releasing preparation.The antituberculotics microsphere vascular embolizing agent is a kind of novel form, and microsphere is deposited on the release that pulmonary can delay medicine, and can protect medicine not receive enzyme hydrolysis, but prolong drug in the holdup time of pulmonary, rate of side effects is low, better tolerance is safe.Still does not have at present both at home and abroad about sodium alginate and three antituberculotics being processed tuberculosis disease blood-vessels target suppository under the effect of calcium ion, and be applied to pulmonary tuberculosis, the pulmonary tuberculosis massive hemoptysis with the high-pressure electrostatic sessile drop method; Pulmonary tuberculosis cavity, pulmonary tuberculosis property bronchial stenosis, the cavitary pulmonary tuberculosis of anti-the multiple medicines; Renal tuberculosis, osteoarthrosis (breast, lumbar vertebra) tuberculosis, genital tuberculosis (fallopian tube; Endometrium, testis, epididymis), tuberculosis of thyroid gland, the tuberculosis of cervical lymph nodes; Tuberculosis of pericardium, thoracic tuberculosis, the report of patients' such as other position tuberculosis of whole body intervention embolization.
The specific embodiment
Through embodiment the present invention is described further below, but does not mean that restriction protection domain of the present invention.
Embodiment 1 preparation antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents:
One, reagent preparation:
1,10g/L (1% (W/V)) carrier solution:
Accurately take by weighing sodium alginate (or chitosan) powder 10 grams, the concentration ratio of pressing 10g/L with normal saline or water for injection dissolving, gets carrier solution, i.e. sodium alginate or chitosan solution;
2, drug solution:
1. rifampicin solution:
Claim that adding 20ml water for injection in the rifampicin powder 10 gram milk ejection alms bowls grinds dissolving, reuse 30ml injection washing mortar, after the mixing ultrasonic again 10 minutes, rifampicin solution;
2. isoniazid solution:
Claim the isoniazid powder 20 grams, add injection water 50ml dissolving, get isoniazid solution;
3. pyrazinamide (or MOXIFLOXACIN) solution:
Claim pyrazinamide (or MOXIFLOXACIN) powder 40 grams, add injection water 50ml dissolving, get pyrazinamide (or MOXIFLOXACIN) solution;
3, preparation solution:
3. and 2. the said medicine solution that makes combined earlier, and then with 1. mix, wherein; The weight proportion of Rimactazid, pyrazinamide or MOXIFLOXACIN is 1: 2: 4 (ratio of solute); Three kinds of drug solutions that mix are joined in the sodium alginate soln go, magnetic stirrer is even, must prepare solution; In the preparation solution, the weight ratio of medicine and carrier is 1.5:10;
4, ionic calcium soln:
Accurately take by weighing calcium lactate or calcium chloride 10 grams, the concentration ratio of pressing 10g/L (1% (W/V)) with the water for injection dissolving, gets ionic calcium soln;
5, curing solution:
Get 3 parts of ionic calcium solns, 1 part of water for injection, 1 part of dehydrated alcohol, mix homogeneously gets consolidation liquid; (time spent joins temporarily), described consolidation liquid volume ratio was 3: 1: 1;
6, reinforced solution:
Take by weighing gelatin or polylysine 0.2～20 gram,,, get reinforced solution with the water for injection dissolving by the concentration ratio of 0.2～20 g/L;
7, preserve liquid:
The injection soybean oil that employing is buied or injection Oleum Camelliae or liquid paraffin etc.;
Two, manufacture the instrument of microsphere:
1, high-pressure electrostatic microsphere generator:
Device comprises: HV generator; A plurality of positive and negative electrodes; Stainless steel ring; Micro-injection pump; The syringe peace scalp acupuncture head of different model; Aseptic glass container; Magnetic stirring apparatus; Lowering or hoisting gear;
2, inverted microscope:
Be used for observing and make the microspherulite diameter size;
3, electric suction apparatus:
The sucking-off of liquid when being used to make microsphere;
4, magnetic stirring apparatus:
Be used for the stirring of liquid;
Three, microsphere preparation process:
1, balling-up process:
Above-mentioned gained is prepared solution suck in the 50ml syringe, connect syringe needle, be added on the micro-injection pump; Connection electrode is opened high-pressure electrostatic microsphere generator (high-pressure electrostatic microsphere generating means), makes and produces high electric field between each both positive and negative polarity; When syringe pump will prepare the solution release with constant speed; Electric field force has overcome inherent viscous force of sodium alginate and surface tension, and the droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the consolidation liquid, is cross-linked into calcium alginate antituberculotics microsphere (or micro gel bead) rapidly; Treat centrifugal or deposition sops up supernatant after fully, must contain antituberculotics compound recipe microsphere (or micro gel bead);
2, strengthening process:
For preventing that water soluble drug from discharging too early; The present invention has adopted strengthening process; The band medicine microsphere or the micro gel bead that make are put into reinforced solution, and promptly in gelatin or the polylysine solution, magnetic agitation is 3～5 minutes at a slow speed; Supernatant discarded, the antituberculotics three compound recipe microspheres (micro gel bead) after must strengthening;
3, store method:
Lose for avoiding the medicine of medicine microspheres before application; The present invention has adopted water in oil method in storage life; Promptly use the soybean oil (or other vegetable oil, or liquid paraffin) of injection to preserve microsphere, the time spent discards soybean oil (or other vegetable oil of injection; Or liquid paraffin), give a baby a bath on the third day after its birth all in i.e. implantable (injection) body with normal saline.Dry bulb is preserved (powdery granule); Above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, with lyophilization or oven method make dry bulb both powdery granule, with cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using; In implantable (injection) body;
4, microsphere characteristic:
1. its a kind of microsphere is characterised in that: the said particle diameter specification that contains antituberculotics compound recipe microsphere or micro gel bead of preserving in the liquid (injection vegetable oil or liquid paraffin) that is stored in is: 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～500 μ m, 500～720 μ m, 700～900 μ m or 900～1250 μ m; Behind the upper solution decant with said vesse; With normal saline flushing three times, the instant use;
2. its another kind of microsphere is characterised in that: above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, gained contain antituberculotics compound recipe microsphere after drying, (make dry bulb) with lyophilization or oven method powdery granule.The particle size range of said powdery particles is 30～50 μ m, 50～80 μ m, 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～550 μ m, 500～720 μ m, 700～900 μ m; Dry bulb (powdery granule); With cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using, the instant use;
Tuberculosis recurrence and tulase drug resistance phenomenon are serious day by day, although it is complicated to produce reason, one of them crucial factor is that treatment is long the course of treatment; The patient can not finish to the course of treatment in the medication of rule capacity; This is the problem that various countries, whole world tuberculotherapy is generally faced, and under the prerequisite that guarantees therapeutic effect, reduces drug dose; Prolong drug blanking time, the problem of drug compliance can effectively be solved.In order to obtain to bring into play in vivo the antituberculotics preparation of long-acting; The present invention has selected good biocompatibility; The natural macromolecular material sodium alginate is as carrier; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents is model drug, and through prescription screening, research obtains long-acting release biodegradable microsphere blood-vessels target thromboembolism preparation in extracorporeal releasing experiment and the body.Adopt the method for bronchoscope intervention or intervention radiation again, the treatment lunger inserts target organ section opening with conduit; Under the X line is kept watch on, introduce seal wire, action arteries and veins radiography after conduit embeds lumen of vessels is according to the radiography finding; Take the photograph sheet continuously and confirm that the A/C front end withdraws from seal wire; RC is selected the suitable particle size range of above-mentioned antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents for use; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents (wet bulb); With normal saline flushing microsphere three times; Add an amount of contrast agent again and be mixed, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down; Promptly accomplish thromboembolism, the arteries and veins radiography of taking action is once more judged effect of embolization.Dry bulb (powdery granule) was reduced into wet bulb in several minutes with the normal saline immersion before using; Same add an amount of contrast agent again and be mixed with normal saline flushing microsphere one time, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down, promptly accomplishes thromboembolism, the arteries and veins radiography of taking action once more judgement effect of embolization.
Embodiment 2: preparation antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents:
One, reagent preparation:
1,60 g/L (6% (W/V)) carrier solution:
Accurately take by weighing sodium alginate (or chitosan) powder 60 grams, the concentration ratio of pressing 60g/L with normal saline or water for injection dissolving, gets carrier solution, i.e. sodium alginate or chitosan solution;
2, drug solution:
1. rifampicin solution:
Claim that adding 20ml water for injection in the rifampicin powder 10 gram milk ejection alms bowls grinds dissolving, reuse 30ml injection washing mortar, after the mixing ultrasonic again 10 minutes, rifampicin solution;
2. isoniazid solution:
Claim the isoniazid powder 20 grams, add injection water 50ml dissolving, get isoniazid solution;
3. pyrazinamide (or MOXIFLOXACIN) solution:
Claim pyrazinamide (or MOXIFLOXACIN) powder 40 grams, add injection water 50ml dissolving, get pyrazinamide (or MOXIFLOXACIN) solution;
3, preparation solution:
3. and 2. the said medicine solution that makes combined earlier, and then with 1. mix, wherein; The weight proportion of Rimactazid, pyrazinamide or MOXIFLOXACIN is 1: 2: 4; Three kinds of drug solutions that mix are joined in the sodium alginate soln go, magnetic stirrer is even, must prepare solution; In the preparation solution, the weight ratio of medicine and carrier is 1.5:10;
4, ionic calcium soln:
Accurately take by weighing calcium lactate or calcium chloride 120 grams, the concentration ratio of pressing 120g/L with the water for injection dissolving, gets ionic calcium soln;
5, curing solution:
Get 3 parts of ionic calcium solns, 1 part of water for injection, 1 part of dehydrated alcohol, mix homogeneously gets consolidation liquid; (time spent joins temporarily), described consolidation liquid volume ratio was 3: 1: 1;
6, reinforced solution:
Take by weighing gelatin or polylysine 0.6～60 gram,,, get reinforced solution with the water for injection dissolving by the concentration ratio of 0.2～20 g/L;
7, preserve liquid:
The injection soybean oil that employing is buied or injection Oleum Camelliae or liquid paraffin etc.;
Two, manufacture the instrument of microsphere:
1, high-pressure electrostatic microsphere generator:
Device comprises: HV generator; A plurality of positive and negative electrodes; Stainless steel ring; Micro-injection pump; The syringe peace scalp acupuncture head of different model; Aseptic glass container; Magnetic stirring apparatus; Lowering or hoisting gear;
2, inverted microscope:
Be used for observing and make the microspherulite diameter size;
3, electric suction apparatus:
The sucking-off of liquid when being used to make microsphere;
4, magnetic stirring apparatus:
Be used for the stirring of liquid;
Three, microsphere preparation process:
1, balling-up process:
Above-mentioned gained is prepared solution suck in the 50ml syringe, connect syringe needle, be added on the micro-injection pump; Connection electrode is opened high-pressure electrostatic microsphere generating means, makes and produces high electric field between each both positive and negative polarity; When syringe pump will prepare the solution release with constant speed; Electric field force has overcome inherent viscous force of sodium alginate and surface tension, and the droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the consolidation liquid, is cross-linked into calcium alginate antituberculotics microsphere (micro gel bead) rapidly; Treat centrifugal or deposition sops up supernatant after fully, must contain antituberculotics compound recipe microsphere (or micro gel bead);
2, strengthening process:
For preventing that water soluble drug from discharging too early; The present invention has adopted strengthening process; The band medicine microsphere or the micro gel bead that make are put into reinforced solution, and promptly in gelatin or the polylysine solution, magnetic agitation is 3～5 minutes at a slow speed; Supernatant discarded, the antituberculotics three compound recipe microspheres (micro gel bead) after must strengthening;
3, store method:
Lose for avoiding the medicine of medicine microspheres before application; The present invention has adopted water in oil method in storage life; Promptly use the soybean oil (or other vegetable oil, or liquid paraffin) of injection to preserve microsphere, the time spent discards soybean oil (or other vegetable oil of injection; Or liquid paraffin), give a baby a bath on the third day after its birth all in i.e. implantable (injection) body with normal saline.Dry bulb is preserved (powdery granule); Above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, with lyophilization or oven method make dry bulb both powdery granule, with cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using; In implantable (injection) body;
4, microsphere characteristic:
1. its a kind of microsphere is characterised in that: the said particle diameter specification that contains antituberculotics compound recipe microsphere or micro gel bead of preserving in the liquid (injection vegetable oil or liquid paraffin) that is stored in is: 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～500 μ m, 500～720 μ m, 700～900 μ m or 900～1250 μ m; Behind the upper solution decant with said vesse; With normal saline flushing three times, the instant use;
2. its another kind of microsphere is characterised in that: above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, gained contain antituberculotics compound recipe microsphere after drying, (make dry bulb) with lyophilization or oven method powdery granule.The particle size range of said powdery particles is 30～50 μ m, 50～80 μ m, 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～550 μ m, 500～720 μ m, 700～900 μ m; Dry bulb (powdery granule); With cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using, the instant use;
In tuberculosis, tulase quantity is the highest in the pulmonary cavity, and empty focus is the root that produces fastbacteria, also is the main cause of tuberculosis chemotherapy failure; Disorganization is serious in the focus of cavity, and fibroplasia receives the influence of local vascular rareness and caseation slough; Medicine is difficult for infiltrating the cavity, is difficult to reach efficacious therapy concentration, adopts fibre bronchus mirror's technology in the interventional therapy of anti-multiple medicines cavernous pulmonary tuberculosis, to be applied; Can look at patient's lesions position straight through fibre bronchus mirror, the antituberculotics microsphere directly is injected in the cavity through conduit, and the medicine microspheres cohesiveness is good; In the cavity, exist the time long, high concentration slowly discharges, and helps the improvement of patient's focus; Simple perfusion solution curative effect is lasting, can reduce administration number of times, evident in efficacyly is superior to simple chemotherapy.The present invention has selected good biocompatibility; The natural macromolecular material sodium alginate is as carrier; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents is model drug; Through prescription screening, research obtains long-acting release biodegradable microsphere blood-vessels target thromboembolism preparation in extracorporeal releasing experiment and the body.The method that adopts intervention radiation or bronchoscope to get involved again, treatment pulmonary tuberculosis cavity type patient inserts target organ section opening with conduit; Under the X line is kept watch on, introduce seal wire, action arteries and veins radiography after conduit embeds lumen of vessels is according to the radiography finding; Take the photograph sheet continuously and confirm that the A/C front end withdraws from seal wire; RC is selected the suitable particle size range of above-mentioned antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents for use; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents (wet bulb); With normal saline flushing microsphere three times; Add an amount of contrast agent again and be mixed, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down; Promptly accomplish thromboembolism, the arteries and veins radiography of taking action is once more judged effect of embolization.Dry bulb (powdery granule) was reduced into wet bulb in several minutes with the normal saline immersion before using; Same add an amount of contrast agent again and be mixed with normal saline flushing microsphere one time, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down, promptly accomplishes thromboembolism, the arteries and veins radiography of taking action once more judgement effect of embolization.
Embodiment 3: preparation antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents:
One, reagent preparation:
1,20 g/L carrier solutions:
Accurately take by weighing sodium alginate (or chitosan) powder 20 grams,,, get carrier solution, i.e. sodium alginate or chitosan solution with normal saline or water for injection dissolving by the concentration ratio of 20 g/L;
2, drug solution:
1. rifampicin solution:
Claim that adding 40ml water for injection in the rifampicin powder 20 gram milk ejection alms bowls grinds dissolving, reuse 60ml injection washing mortar, after the mixing ultrasonic again 10 minutes, rifampicin solution;
2. isoniazid solution:
Claim the isoniazid powder 40 grams, add injection water 100ml dissolving, get isoniazid solution;
3. pyrazinamide (or MOXIFLOXACIN) solution:
Claim pyrazinamide (or MOXIFLOXACIN) powder 80 grams, add injection water 100ml dissolving, get pyrazinamide (or MOXIFLOXACIN) solution;
3, preparation solution:
3. and 2. the said medicine solution that makes combined earlier, and then with 1. mix, wherein; The weight proportion of Rimactazid, pyrazinamide or MOXIFLOXACIN is 1: 2: 4; Three kinds of drug solutions that mix are joined in the sodium alginate soln go, magnetic stirrer is even, must prepare solution; In the preparation solution, the weight ratio of medicine and carrier is 1:5;
4, ionic calcium soln:
Accurately take by weighing calcium lactate or calcium chloride 180 grams, the concentration ratio of pressing 90g/L with the water for injection dissolving, gets ionic calcium soln;
5, curing solution:
Get 3 parts of ionic calcium solns, 1 part of water for injection, 1 part of dehydrated alcohol, mix homogeneously gets consolidation liquid; (time spent joins temporarily), described consolidation liquid volume ratio was 3: 1: 1;
6, reinforced solution:
Take by weighing gelatin or polylysine 0.4～40 gram,,, get reinforced solution with the water for injection dissolving by the concentration ratio of 0.2～20 g/L;
7, preserve liquid:
The injection soybean oil that employing is buied or injection Oleum Camelliae or liquid paraffin etc.;
Two, manufacture the instrument of microsphere:
1, high-pressure electrostatic microsphere generator:
Device comprises: HV generator; A plurality of positive and negative electrodes; Stainless steel ring; Micro-injection pump; The syringe peace scalp acupuncture head of different model; Aseptic glass container; Magnetic stirring apparatus; Lowering or hoisting gear;
2, inverted microscope:
Be used for observing and make the microspherulite diameter size;
3, electric suction apparatus:
The sucking-off of liquid when being used to make microsphere;
4, magnetic stirring apparatus:
Be used for the stirring of liquid;
Three, microsphere preparation process:
1, balling-up process:
Above-mentioned gained is prepared solution suck in the 50ml syringe, connect syringe needle, be added on the micro-injection pump; Connection electrode is opened high-pressure electrostatic microsphere generating means, makes and produces high electric field between each both positive and negative polarity; When syringe pump will prepare the solution release with constant speed; Electric field force has overcome inherent viscous force of sodium alginate and surface tension, and the droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the consolidation liquid, is cross-linked into calcium alginate antituberculotics microsphere (micro gel bead) rapidly; Treat centrifugal or deposition sops up supernatant after fully, must contain antituberculotics compound recipe microsphere (or micro gel bead);
2, strengthening process:
For preventing that water soluble drug from discharging too early; The present invention has adopted strengthening process; The band medicine microsphere or the micro gel bead that make are put into reinforced solution, and promptly in gelatin or the polylysine solution, magnetic agitation is 3～5 minutes at a slow speed; Supernatant discarded, the antituberculotics three compound recipe microspheres (micro gel bead) after must strengthening;
3, store method:
Lose for avoiding the medicine of medicine microspheres before application; The present invention has adopted water in oil method in storage life; Promptly use the soybean oil (or other vegetable oil, or liquid paraffin) of injection to preserve microsphere, the time spent discards soybean oil (or other vegetable oil of injection; Or liquid paraffin), give a baby a bath on the third day after its birth all in i.e. implantable (injection) body with normal saline.Dry bulb is preserved (powdery granule); Above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, with lyophilization or oven method make dry bulb both powdery granule, with cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using; In implantable (injection) body;
4, microsphere characteristic:
1. its a kind of microsphere is characterised in that: the said particle diameter specification that contains antituberculotics compound recipe microsphere or micro gel bead of preserving in the liquid (injection vegetable oil or liquid paraffin) that is stored in is: 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～500 μ m, 500～720 μ m, 700～900 μ m or 900～1250 μ m; Behind the upper solution decant with said vesse; With normal saline flushing three times, the instant use;
2. its another kind of microsphere is characterised in that: above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, gained contain antituberculotics compound recipe microsphere after drying, (make dry bulb) with lyophilization or oven method powdery granule.The particle size range of said powdery particles is 30～50 μ m, 50～80 μ m, 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～550 μ m, 500～720 μ m, 700～900 μ m; Dry bulb (powdery granule); With cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using, the instant use;
Spitting of blood is the pulmonary tuberculosis common sympton, and the especially chronic fibrotic cavitys type of pulmonary tuberculosis, the Secondary cases bronchiectasis due to the pulmonary tuberculosis; Because arteriae bronchiales increase slightly, blood vessel elasticity is relatively poor, and fragility reaches factors such as pulmonary artery pressure height greatly; When violent cough, be prone to take place life-threatening massive hemoptysis; And the medical treatment haemostatic effect is undesirable, not having operation indication or patient's pulmonary function difference can not tolerate surgery the time, treats comparatively thorny.Spitting of blood can not be controlled and may suffocate; A large amount of spitting of bloods possibly cause hemorrhagic shock to jeopardize patient's life; The immediate cause of spitting of blood is due to the TB focus erosion damage pulmonary vascular, and lungs exist dual blood to supply, and the lesion vessels main source of spitting of blood is arteriae bronchiales.Bronchial arterial embolism is through conduit suppository to be injected a certain (or several) arteriae bronchiales selectively, so as to artery-clogging, and the control massive hemorrhage.Along with antimycobacterial drug plays a role gradually, pulmonary's TB focus absorbs reparation gradually, and sputum mixed with blood finally fades away, and shows that bronchial arterial embolization massive hemoptysis curative effect certainly.The present invention has selected good biocompatibility; The natural macromolecular material sodium alginate is as carrier; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents is model drug; Through prescription screening, research obtains long-acting release biodegradable microsphere blood-vessels target thromboembolism preparation in extracorporeal releasing experiment and the body.Adopt the method for bronchoscope intervention or intervention radiation again, treatment hemoptysis of pulmonary tuberculosis type patient inserts target organ section opening with conduit; Under the X line is kept watch on, introduce seal wire, action arteries and veins radiography after conduit embeds lumen of vessels is according to the radiography finding; Find the bleeding part, take the photograph sheet continuously and confirm the A/C front end; Withdraw from seal wire, RC is selected the suitable particle size range of above-mentioned antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents for use; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents (wet bulb),, add an amount of contrast agent again and be mixed with normal saline flushing microsphere three times; Perspective is slowly injected the far-end of bleeding part down through conduit; When the contrast agent flow velocity obviously slows down, promptly accomplish the thromboembolism hemostasis, the arteries and veins radiography of taking action is once more judged effect of embolization; To confirm that affected area vascular bed obviously is reduced to disappearance, until no hemorrhage tremulous pulse.Dry bulb (powdery granule) was reduced into wet bulb in several minutes with the normal saline immersion before using; Same add an amount of contrast agent again and be mixed with normal saline flushing microsphere one time, perspective is slowly injected the bleeding part through conduit down, when the contrast agent flow velocity obviously slows down, promptly accomplishes thromboembolism, and the arteries and veins radiography of taking action once more judgement effect of embolization is until no hemorrhage tremulous pulse.
Embodiment 4: preparation antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents:
One, reagent preparation:
1,30 g/L carrier solutions:
Accurately take by weighing sodium alginate (or chitosan) powder 30 grams,,, get carrier solution, i.e. sodium alginate or chitosan solution with normal saline or water for injection dissolving by the concentration ratio of 30 g/L;
2, drug solution:
1. rifampicin solution:
Claim that adding 10ml water for injection in the rifampicin powder 5 gram milk ejection alms bowls grinds dissolving, reuse 15ml injection washing mortar, after the mixing ultrasonic again 10 minutes, rifampicin solution;
2. isoniazid solution:
Claim the isoniazid powder 10 grams, add injection water 25ml dissolving, get isoniazid solution;
3. pyrazinamide (or MOXIFLOXACIN) solution:
Claim pyrazinamide (or MOXIFLOXACIN) powder 20 grams, add injection water 25ml dissolving, get pyrazinamide (or MOXIFLOXACIN) solution;
3, preparation solution:
3. and 2. the said medicine solution that makes combined earlier, and then with 1. mix, wherein; The weight proportion of Rimactazid, pyrazinamide or MOXIFLOXACIN is 1: 2: 4; Three kinds of drug solutions that mix are joined in the sodium alginate soln go, magnetic stirrer is even, must prepare solution; In the preparation solution, the weight ratio of medicine and carrier is 1:10;
4, ionic calcium soln:
Accurately take by weighing calcium lactate or calcium chloride 70 grams,,, get ionic calcium soln with the water for injection dissolving by the concentration ratio of 70 g/L;
5, curing solution:
Get 3 parts of ionic calcium solns, 1 part of water for injection, 1 part of dehydrated alcohol, mix homogeneously gets consolidation liquid; (time spent joins temporarily), described consolidation liquid volume ratio was 3: 1: 1;
6, reinforced solution:
Take by weighing gelatin or polylysine 0.4～40 gram,,, get reinforced solution with the water for injection dissolving by the concentration ratio of 0.2～20 g/L;
7, preserve liquid:
The injection soybean oil that employing is buied or injection Oleum Camelliae or liquid paraffin etc.;
Two, manufacture the instrument of microsphere:
1, high-pressure electrostatic microsphere generator:
Device comprises: HV generator; A plurality of positive and negative electrodes; Stainless steel ring; Micro-injection pump; The syringe peace scalp acupuncture head of different model; Aseptic glass container; Magnetic stirring apparatus; Lowering or hoisting gear;
2, inverted microscope:
Be used for observing and make the microspherulite diameter size;
3, electric suction apparatus:
The sucking-off of liquid when being used to make microsphere;
4, magnetic stirring apparatus:
Be used for the stirring of liquid;
Three, microsphere preparation process:
1, balling-up process:
Above-mentioned gained is prepared solution suck in the 50ml syringe, connect syringe needle, be added on the micro-injection pump; Connection electrode is opened high-pressure electrostatic microsphere generating means, makes and produces high electric field between each both positive and negative polarity; When syringe pump will prepare the solution release with constant speed; Electric field force has overcome inherent viscous force of sodium alginate and surface tension, and the droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the consolidation liquid, is cross-linked into calcium alginate antituberculotics microsphere (micro gel bead) rapidly; Treat centrifugal or deposition sops up supernatant after fully, must contain antituberculotics compound recipe microsphere (or micro gel bead).
2, strengthening process:
For preventing that water soluble drug from discharging too early; The present invention has adopted strengthening process; The band medicine microsphere or the micro gel bead that make are put into reinforced solution, and promptly in gelatin or the polylysine solution, magnetic agitation is 3～5 minutes at a slow speed; Supernatant discarded, the antituberculotics three compound recipe microspheres (micro gel bead) after must strengthening.
3, store method:
Lose for avoiding the medicine of medicine microspheres before application; The present invention has adopted water in oil method in storage life; Promptly use the soybean oil (or other vegetable oil, or liquid paraffin) of injection to preserve microsphere, the time spent discards soybean oil (or other vegetable oil of injection; Or liquid paraffin), give a baby a bath on the third day after its birth all in i.e. implantable (injection) body with normal saline.Dry bulb is preserved (powdery granule); Above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, with lyophilization or oven method make dry bulb both powdery granule, with cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using; In implantable (injection) body.
4, microsphere characteristic:
1. its a kind of microsphere is characterised in that: the said particle diameter specification that contains antituberculotics compound recipe microsphere or micro gel bead of preserving in the liquid (injection vegetable oil or liquid paraffin) that is stored in is: 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～500 μ m, 500～720 μ m, 700～900 μ m or 900～1250 μ m; Behind the upper solution decant with said vesse; With normal saline flushing three times, the instant use;
2. its another kind of microsphere is characterised in that: above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, gained contain antituberculotics compound recipe microsphere after drying, (make dry bulb) with lyophilization or oven method powdery granule.The particle size range of said powdery particles is 30～50 μ m, 50～80 μ m, 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～550 μ m, 500～720 μ m, 700～900 μ m; Dry bulb (powdery granule); With cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using, the instant use;
Renal tuberculosis is a whole body part lungy, and before the tuberculosis chemotherapeutics came out, tuberculosis was considered to the disease do not controlled; Sickness rate is high, and mortality rate is high, and renal tuberculosis is main with the nephrectomy; Because the progress of tuberculosis chemotherapeutic and to the physiological further understanding of renal tuberculosis pathology has changed the surgical intervention scheme of renal tuberculosis in the past, think in the past must the row operation the patient; Might adopt medicine (other method) and cure; The present invention has selected good biocompatibility, and the natural macromolecular material sodium alginate is model drug as carrier with antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents; Through prescription screening, research obtains long-acting release biodegradable microsphere blood-vessels target thromboembolism preparation in extracorporeal releasing experiment and the body.Adopt the method for intervention radiation again, treatment renal tuberculosis patient inserts target organ section opening with conduit; Under the X line is kept watch on, introduce seal wire, action arteries and veins radiography after conduit embeds lumen of vessels is according to the radiography finding; Take the photograph sheet continuously and confirm that the A/C front end withdraws from seal wire; RC is selected the suitable particle size range of above-mentioned antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents for use; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents (wet bulb); With normal saline flushing microsphere three times; Add an amount of contrast agent again and be mixed, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down; Promptly accomplish thromboembolism, the arteries and veins radiography of taking action is once more judged effect of embolization.Dry bulb (powdery granule) was reduced into wet bulb in several minutes with the normal saline immersion before using; Same add an amount of contrast agent again and be mixed with normal saline flushing microsphere one time, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down, promptly accomplishes thromboembolism, the arteries and veins radiography of taking action once more judgement effect of embolization.
Embodiment 5: preparation antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents:
One, reagent preparation:
1,40 g/L carrier solutions:
Accurately take by weighing sodium alginate (or chitosan) powder 400 grams,,, get carrier solution, i.e. sodium alginate or chitosan solution with normal saline or water for injection dissolving by the concentration ratio of 40 g/L;
2, drug solution:
1. rifampicin solution:
Claim that adding 30ml water for injection in the rifampicin powder 15 gram milk ejection alms bowls grinds dissolving, reuse 45ml injection washing mortar mixes getting rifampicin solution after ultrasonic;
2. isoniazid solution:
Claim the isoniazid powder 30 grams, add injection water 75ml dissolving, get isoniazid solution;
3. pyrazinamide (or MOXIFLOXACIN) solution:
Claim pyrazinamide (or MOXIFLOXACIN) powder 45 grams, add injection water 75ml dissolving, get pyrazinamide (or MOXIFLOXACIN) solution;
3, preparation solution:
3. and 2. the said medicine solution that makes combined earlier; And then with 1. mix wherein; The weight proportion of Rimactazid, pyrazinamide or MOXIFLOXACIN is 1: 2: 4, three kinds of drug solutions that mix is joined the demagnetization force agitator stirs in the sodium alginate soln, must prepare solution; In the preparation solution, the weight ratio of medicine and carrier is 1:8;
4, ionic calcium soln:
Accurately take by weighing calcium lactate or calcium chloride 240 grams,,, get ionic calcium soln with the water for injection dissolving by the concentration ratio of 60 g/L;
5, curing solution:
Get 3 parts of ionic calcium solns, 1 part of water for injection, 1 part of dehydrated alcohol, mix homogeneously gets consolidation liquid; (time spent joins temporarily), described consolidation liquid volume ratio was 3: 1: 1;
6, reinforced solution:
Take by weighing gelatin or polylysine 0.6～60 gram,,, get reinforced solution with the water for injection dissolving by the concentration ratio of 0.2～20 g/L;
7, preserve liquid:
The injection soybean oil that employing is buied or injection Oleum Camelliae or liquid paraffin etc.;
Two, manufacture the instrument of microsphere:
1, high-pressure electrostatic microsphere generator:
Device comprises: HV generator; A plurality of positive and negative electrodes; Stainless steel ring; Micro-injection pump; The syringe peace scalp acupuncture head of different model; Aseptic glass container; Magnetic stirring apparatus; Lowering or hoisting gear;
2, inverted microscope:
Be used for observing and make the microspherulite diameter size;
3, electric suction apparatus:
The sucking-off of liquid when being used to make microsphere;
4, magnetic stirring apparatus:
Be used for the stirring of liquid;
Three, microsphere preparation process:
1, balling-up process:
Above-mentioned gained is prepared solution suck in the 50ml syringe, connect syringe needle, be added on the micro-injection pump; Connection electrode is opened high-pressure electrostatic microsphere generating means, makes and produces high electric field between each both positive and negative polarity; When syringe pump will prepare the solution release with constant speed; Electric field force has overcome inherent viscous force of sodium alginate and surface tension, and the droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the consolidation liquid, is cross-linked into calcium alginate antituberculotics microsphere (micro gel bead) rapidly; Treat centrifugal or deposition sops up supernatant after fully, must contain antituberculotics compound recipe microsphere (or micro gel bead).
2, strengthening process:
For preventing that water soluble drug from discharging too early; The present invention has adopted strengthening process; The band medicine microsphere or the micro gel bead that make are put into reinforced solution, and promptly in gelatin or the polylysine solution, magnetic agitation is 3～5 minutes at a slow speed; Supernatant discarded, the antituberculotics three compound recipe microspheres (micro gel bead) after must strengthening.
3, store method:
Lose for avoiding the medicine of medicine microspheres before application; The present invention has adopted water in oil method in storage life; Promptly use the soybean oil (or other vegetable oil, or liquid paraffin) of injection to preserve microsphere, the time spent discards soybean oil (or other vegetable oil of injection; Or liquid paraffin), give a baby a bath on the third day after its birth all in i.e. implantable (injection) body with normal saline.Dry bulb is preserved (powdery granule); Above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, with lyophilization or oven method make dry bulb both powdery granule, with cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using; In implantable (injection) body.
4, microsphere characteristic:
1. its a kind of microsphere is characterised in that: the said particle diameter specification that contains antituberculotics compound recipe microsphere or micro gel bead of preserving in the liquid (injection vegetable oil or liquid paraffin) that is stored in is: 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～500 μ m, 500～720 μ m, 700～900 μ m or 900～1250 μ m; Behind the upper solution decant with said vesse; With normal saline flushing three times, the instant use;
2. its another kind of microsphere is characterised in that: above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, gained contain antituberculotics compound recipe microsphere after drying, (make dry bulb) with lyophilization or oven method powdery granule.The particle size range of said powdery particles is 30～50 μ m, 50～80 μ m, 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～550 μ m, 500～720 μ m, 700～900 μ m; Dry bulb (powdery granule); With cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using, the instant use;
Much more bone tuberculosis is a kind of secondary tuberculosis, to see with vertebra and tuberculosis of sternum, because the confession of tuberculosis of bone and joint affected area blood is poor; Medicine infiltrates slow, for preventing recurrence, adopts the oral or intravenous drip of patient to place a large amount of antitubercular agents and treat with local clinically; Preceding method is as reaching the efficacious therapy drug level at the TB focus position; What accompany with it is that whole body blood drug level also remains on a higher level, tends to cause the untoward reaction of medicine to its hetero-organization, and this just means can reduce patient's daily life quality; Make the patient to the generation negation of taking medicine, influence the therapeutic effect of medicine; Back method drug absorption is very fast, and action time is shorter, thereby effect is not satisfactory.Selection is held time long and the little slow releasing preparation of negative response is that TB focus is removed the ideal local application of postoperative mode.The present invention has selected good biocompatibility; The natural macromolecular material sodium alginate is as carrier; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents is model drug; Through prescription screening, research obtains long-acting release biodegradable microsphere blood-vessels target thromboembolism preparation in extracorporeal releasing experiment and the body.Adopt the intervention radiation method again, treatment bone tuberculosis patient selects TB focus to remove the ideal local application of postoperative mode; Antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents (wet bulb) are slowly injected lesions position, or under the X line is kept watch on, introduce seal wire, action arteries and veins radiography after conduit embeds lumen of vessels; According to the radiography finding; Take the photograph sheet continuously and confirm that the A/C front end withdraws from seal wire; RC is selected the suitable particle size range of above-mentioned antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents for use; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents (wet bulb); With normal saline flushing microsphere three times; Add an amount of contrast agent again and be mixed, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down; Promptly accomplish thromboembolism, the arteries and veins radiography of taking action is once more judged effect of embolization.Dry bulb (powdery granule) was reduced into wet bulb in several minutes with the normal saline immersion before using; Same add an amount of contrast agent again and be mixed with normal saline flushing microsphere one time, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down, promptly accomplishes thromboembolism, the arteries and veins radiography of taking action once more judgement effect of embolization.
Embodiment 6: preparation antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents:
One, reagent preparation:
1,50 g/L carrier solutions:
Accurately take by weighing sodium alginate (or chitosan) powder 100 grams,,, get carrier solution, i.e. sodium alginate or chitosan solution with normal saline or water for injection dissolving by the concentration ratio of 50 g/L;
2, drug solution:
1. rifampicin solution:
Claim that adding 20ml water for injection in the rifampicin powder 10 gram milk ejection alms bowls grinds dissolving, reuse 30ml injection washing mortar mixes getting rifampicin solution after ultrasonic;
2. isoniazid solution:
Claim the isoniazid powder 20 grams, add injection water 50ml dissolving, get isoniazid solution;
3. pyrazinamide (or MOXIFLOXACIN) solution:
Claim pyrazinamide (or MOXIFLOXACIN) powder 40 grams, add injection water 50ml dissolving, get pyrazinamide (or MOXIFLOXACIN) solution;
3, preparation solution:
3. and 2. the said medicine solution that makes combined earlier; And then with the weight proportion that 1. mixes Rimactazid, pyrazinamide or MOXIFLOXACIN be 1: 2: 4; Three kinds of drug solutions that mix are joined the demagnetization force agitator stirs in the sodium alginate soln; Must prepare solution, in the preparation solution, the weight ratio of medicine and carrier is 1:7; 4, ionic calcium soln:
Accurately take by weighing calcium lactate or calcium chloride 10～120 grams,,, get ionic calcium soln with the water for injection dissolving by the concentration ratio of 10～120 g/L;
5, curing solution:
Get 3 parts of ionic calcium solns, 1 part of water for injection, 1 part of dehydrated alcohol, mix homogeneously gets consolidation liquid; (time spent joins temporarily), described consolidation liquid volume ratio was 3: 1: 1;
6, reinforced solution:
Take by weighing gelatin or polylysine 0.6～6 gram,,, get reinforced solution with the water for injection dissolving by the concentration ratio of 0.2～20 g/L;
7, preserve liquid:
The injection soybean oil that employing is buied or injection Oleum Camelliae or liquid paraffin etc.;
Two, manufacture the instrument of microsphere:
1, high-pressure electrostatic microsphere generator:
Device comprises: HV generator; A plurality of positive and negative electrodes; Stainless steel ring; Micro-injection pump; The syringe peace scalp acupuncture head of different model; Aseptic glass container; Magnetic stirring apparatus; Lowering or hoisting gear;
2, inverted microscope:
Be used for observing and make the microspherulite diameter size;
3, electric suction apparatus:
The sucking-off of liquid when being used to make microsphere;
4, magnetic stirring apparatus:
Be used for the stirring of liquid;
Three, microsphere preparation process:
1, balling-up process:
Above-mentioned gained is prepared solution suck in the 50ml syringe, connect syringe needle, be added on the micro-injection pump; Connection electrode is opened high-pressure electrostatic microsphere generating means, makes and produces high electric field between each both positive and negative polarity; When syringe pump will prepare the solution release with constant speed; Electric field force has overcome inherent viscous force of sodium alginate and surface tension, and the droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the consolidation liquid, is cross-linked into calcium alginate antituberculotics microsphere (micro gel bead) rapidly; Treat centrifugal or deposition sops up supernatant after fully, must contain antituberculotics compound recipe microsphere (or micro gel bead).
2, strengthening process:
For preventing that water soluble drug from discharging too early; The present invention has adopted strengthening process; The band medicine microsphere or the micro gel bead that make are put into reinforced solution, and promptly in gelatin or the polylysine solution, magnetic agitation is 3～5 minutes at a slow speed; Supernatant discarded, the antituberculotics three compound recipe microspheres (micro gel bead) after must strengthening.
3, store method:
Lose for avoiding the medicine of medicine microspheres before application; The present invention has adopted water in oil method in storage life; Promptly use the soybean oil (or other vegetable oil, or liquid paraffin) of injection to preserve microsphere, the time spent discards soybean oil (or other vegetable oil of injection; Or liquid paraffin), give a baby a bath on the third day after its birth all in i.e. implantable (injection) body with normal saline.Dry bulb is preserved (powdery granule); Above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, with lyophilization or oven method make dry bulb both powdery granule, with cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using; In implantable (injection) body.
4, microsphere characteristic:
1. its a kind of microsphere is characterised in that: the said particle diameter specification that contains antituberculotics compound recipe microsphere or micro gel bead of preserving in the liquid (injection vegetable oil or liquid paraffin) that is stored in is: 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～500 μ m, 500～720 μ m, 700～900 μ m or 900～1250 μ m; Behind the upper solution decant with said vesse; With normal saline flushing three times, the instant use;
2. its another kind of microsphere is characterised in that: above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, gained contain antituberculotics compound recipe microsphere after drying, (make dry bulb) with lyophilization or oven method powdery granule.The particle size range of said powdery particles is 30～50 μ m, 50～80 μ m, 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～550 μ m, 500～720 μ m, 700～900 μ m; Dry bulb (powdery granule); With cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using, the instant use;
In recent years; Whole world incidence rate lungy is seen rising again; Phthisical increase means increasing of the outer tuberculosis of lung, can estimate that genital tuberculosis will be more also, but the 26S Proteasome Structure and Function of genital tuberculosis heavy damage reproductive system; Cause the genital tuberculosis barrenness, reproductive function is caused the infringement that to retrieve.The present invention has selected good biocompatibility; The natural macromolecular material sodium alginate is as carrier; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents is model drug; Through prescription screening, research obtains long-acting release biodegradable microsphere blood-vessels target thromboembolism preparation in extracorporeal releasing experiment and the body.Adopt the intervention radiation method again, treatment genital tuberculosis (fallopian tube, endometrium, testis, epididymis) patient; Conduit is inserted target organ section opening, under the X line is kept watch on, introduce seal wire, action arteries and veins radiography after conduit embeds lumen of vessels; According to the radiography finding, take the photograph sheet continuously and confirm the A/C front end; Withdraw from seal wire, RC is selected the suitable particle size range of above-mentioned antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents for use; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents (wet bulb); With normal saline flushing microsphere three times; Add an amount of contrast agent again and be mixed, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down; Promptly accomplish thromboembolism, the arteries and veins radiography of taking action is once more judged effect of embolization.Dry bulb (powdery granule) was reduced into wet bulb in several minutes with the normal saline immersion before using; Same add an amount of contrast agent again and be mixed with normal saline flushing microsphere one time, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down, promptly accomplishes thromboembolism, the arteries and veins radiography of taking action once more judgement effect of embolization.
Embodiment 7: preparation antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents:
One, reagent preparation:
1,40 g/L carrier solutions:
Accurately take by weighing sodium alginate (or chitosan) powder 40 grams,,, get carrier solution, i.e. sodium alginate or chitosan solution with normal saline or water for injection dissolving by the concentration ratio of 40 g/L;
2, drug solution:
1. rifampicin solution:
Claim that adding 20ml water for injection in the rifampicin powder 10 gram milk ejection alms bowls grinds dissolving, reuse 30ml injection washing mortar mixes getting rifampicin solution after ultrasonic;
2. isoniazid solution:
Claim the isoniazid powder 20 grams, add injection water 50ml dissolving, get isoniazid solution;
3. pyrazinamide (or MOXIFLOXACIN) solution:
Claim pyrazinamide (or MOXIFLOXACIN) powder 30 grams, add injection water 50ml dissolving, get pyrazinamide (or MOXIFLOXACIN) solution;
3, preparation solution:
3. and 2. the said medicine solution that makes combined earlier; And then with the weight proportion that 1. mixes Rimactazid, pyrazinamide or MOXIFLOXACIN be 1: 2: 4; Three kinds of drug solutions that mix are joined in the sodium alginate soln go, magnetic stirrer is even, must prepare solution; In the preparation solution, the weight ratio of medicine and carrier is 1:5;
4, ionic calcium soln:
Accurately take by weighing calcium lactate or calcium chloride 60 grams,,, get ionic calcium soln with the water for injection dissolving by the concentration ratio of 50 g/L;
5, curing solution:
Get 3 parts of ionic calcium solns, 1 part of water for injection, 1 part of dehydrated alcohol, mix homogeneously gets consolidation liquid; (time spent joins temporarily), described consolidation liquid volume ratio was 3: 1: 1;
6, reinforced solution:
Take by weighing gelatin or polylysine 0.8～8 gram,,, get reinforced solution with the water for injection dissolving by the concentration ratio of 0.2～20 g/L;
7, preserve liquid:
The injection soybean oil that employing is buied or injection Oleum Camelliae or liquid paraffin etc.;
Two, manufacture the instrument of microsphere:
1, high-pressure electrostatic microsphere generator:
Device comprises: HV generator; A plurality of positive and negative electrodes; Stainless steel ring; Micro-injection pump; The syringe peace scalp acupuncture head of different model; Aseptic glass container; Magnetic stirring apparatus; Lowering or hoisting gear;
2, inverted microscope:
Be used for observing and make the microspherulite diameter size;
3, electric suction apparatus:
The sucking-off of liquid when being used to make microsphere;
4, magnetic stirring apparatus:
Be used for the stirring of liquid;
Three, microsphere preparation process:
1, balling-up process:
Above-mentioned gained is prepared solution suck in the 50ml syringe, connect syringe needle, be added on the micro-injection pump; Connection electrode is opened high-pressure electrostatic microsphere generating means, makes and produces high electric field between each both positive and negative polarity; When syringe pump will prepare the solution release with constant speed; Electric field force has overcome inherent viscous force of sodium alginate and surface tension, and the droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the consolidation liquid, is cross-linked into calcium alginate antituberculotics microsphere (micro gel bead) rapidly; Treat centrifugal or deposition sops up supernatant after fully, must contain antituberculotics compound recipe microsphere (or micro gel bead).
2, strengthening process:
For preventing that water soluble drug from discharging too early; The present invention has adopted strengthening process; The band medicine microsphere or the micro gel bead that make are put into reinforced solution, and promptly in gelatin or the polylysine solution, magnetic agitation is 3～5 minutes at a slow speed; Supernatant discarded, the antituberculotics three compound recipe microspheres (micro gel bead) after must strengthening.
3, store method:
Lose for avoiding the medicine of medicine microspheres before application; The present invention has adopted water in oil method in storage life; Promptly use the soybean oil (or other vegetable oil, or liquid paraffin) of injection to preserve microsphere, the time spent discards soybean oil (or other vegetable oil of injection; Or liquid paraffin), give a baby a bath on the third day after its birth all in i.e. implantable (injection) body with normal saline.Dry bulb is preserved (powdery granule); Above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, with lyophilization or oven method make dry bulb both powdery granule, with cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using; In implantable (injection) body.
4, microsphere characteristic:
1. its a kind of microsphere is characterised in that: the said particle diameter specification that contains antituberculotics compound recipe microsphere or micro gel bead of preserving in the liquid (injection vegetable oil or liquid paraffin) that is stored in is: 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～500 μ m, 500～720 μ m, 700～900 μ m or 900～1250 μ m; Behind the upper solution decant with said vesse; With normal saline flushing three times, the instant use;
2. its another kind of microsphere is characterised in that: above-mentioned gained is contained the upper solution decant of antituberculotics compound recipe microsphere, gained contain antituberculotics compound recipe microsphere after drying, (make dry bulb) with lyophilization or oven method powdery granule.The particle size range of said powdery particles is 30～50 μ m, 50～80 μ m, 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～550 μ m, 500～720 μ m, 700～900 μ m; Dry bulb (powdery granule); With cobalt-60 radiation sterilization; Airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using, the instant use;
Extrapulmonary tuberculosis is more common in tuberculosis, is important component part lungy.The outer tuberculosis of lung is because the position concealment, and its atypical clinical manifestations is difficult for diagnosis, easily mistaken diagnosis and failing to pinpoint a disease in diagnosis.M tuberculosis infection can cause sending out to other adjacent organs or tissue through lymphatic system or the capable approach of blood, so in tuberculosis control planning, never come into one's own.Therefore the present invention has selected good biocompatibility; The natural macromolecular material sodium alginate is as carrier; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents is model drug; Through prescription screening, research obtains long-acting release biodegradable microsphere blood-vessels target thromboembolism preparation in extracorporeal releasing experiment and the body.Adopt the intervention radiation method again, outer other tuberculosis of treatment lung, as: the tubercular at other positions in the bodies such as tuberculosis of thyroid gland, lymphoid tuberculosis, tuberculosis of pericardium, thoracic tuberculosis, tuberculous pleuritis; Conduit is inserted target organ section opening, under the X line is kept watch on, introduce seal wire, action arteries and veins radiography after conduit embeds lumen of vessels; According to the radiography finding; Take the photograph sheet continuously and confirm that the A/C front end withdraws from seal wire; RC is selected the suitable particle size range of above-mentioned antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents for use; With antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents (wet bulb); With normal saline flushing microsphere three times; Add an amount of contrast agent again and be mixed, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down; Promptly accomplish thromboembolism, the arteries and veins radiography of taking action is once more judged effect of embolization.Dry bulb (powdery granule) was reduced into wet bulb in several minutes with the normal saline immersion before using; Same add an amount of contrast agent again and be mixed with normal saline flushing microsphere one time, perspective is slowly injected lesions position through conduit down, when the contrast agent flow velocity obviously slows down, promptly accomplishes thromboembolism, the arteries and veins radiography of taking action once more judgement effect of embolization.

Claims (14)

1. one kind contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents; Comprise carrier and medicine; It is characterized in that: said carrier wraps up said medicine; Said carrier is sodium alginate or chitosan, and said medicine is tuberculosis three compound mediciness, comprises Rimactazid and pyrazinamide or MOXIFLOXACIN.
2. the antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents that contain as claimed in claim 1, it is characterized in that: the weight ratio of said carrier and said medicine is 1: 1～50.
3. the antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents that contain as claimed in claim 2, it is characterized in that: in the said medicine, the weight ratio of Rimactazid and pyrazinamide or MOXIFLOXACIN is 1:2:4.
4. one kind contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents; It is characterized in that: with three kinds of antituberculotics Rimactazids and pyrazinamide or MOXIFLOXACIN is the substrate drug solution; With sodium alginate or chitosan is carrier solution; Said drug solution and carrier solution must prepare solution after mixing, and adopt the mode of high-pressure electrostatic drop, make and produce high electric field between each both positive and negative polarity; When syringe pump will prepare the solution release with constant speed; Electric field force has overcome inherent viscous force of sodium alginate and surface tension, and the droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the consolidation liquid, under the effect of calcium ion, makes the antituberculotics microsphere.
5. a method for preparing that contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents comprises the steps:
(1) reagent preparation
(1) carrier solution: accurately take by weighing sodium alginate or chitosan powder,, get carrier solution, i.e. sodium alginate or chitosan solution with normal saline or water for injection dissolving;
(2) drug solution:
1. rifampicin solution:
Claim that adding part water for injection in the rifampicin powder milk ejection alms bowl grinds dissolving, reuse surplus injection washing mortar, after the mixing ultrasonic again 10 minutes, rifampicin solution;
2. isoniazid solution:
Claim the isoniazid powder, add the dissolving of injection water, get isoniazid solution;
3. pyrazinamide or MOXIFLOXACIN solution:
Claim pyrazinamide or MOXIFLOXACIN powder, add the dissolving of injection water, get pyrazinamide or MOXIFLOXACIN solution;
(3) preparation solution:
The pyrazinamide that makes or MOXIFLOXACIN solution and isoniazid solution are combined earlier; And then mix with rifampicin solution, three kinds of mixing obtain drug solution, and drug solution is joined in sodium alginate or the chitosan solution; Magnetic stirrer is even, must prepare solution;
(4) ionic calcium soln:
Accurately take by weighing calcium lactate or calcium chloride, by the concentration of 10～120g/L, with the water for injection dissolving, the preparation ionic calcium soln;
(5) curing solution:
Get ionic calcium soln, water for injection and the dehydrated alcohol of above-mentioned gained, mix homogeneously gets curing solution;
(6) reinforced solution:
Take by weighing gelatin or polylysine,, get gelatin or polylysine solution, i.e. reinforced solution with the water for injection dissolving;
(2) microsphere preparation process:
(1) balling-up process:
Above-mentioned gained is prepared solution suck in the 50ml syringe, connect syringe needle, be added on the micro-injection pump; Connection electrode through high-pressure electrostatic microsphere generator, makes and produces high electric field between each both positive and negative polarity; When syringe pump will prepare the solution release with constant speed; Electric field force has overcome inherent viscous force of sodium alginate and surface tension, and the droplet that makes the polymer solution of its pastille be dispersed into certain grain size is injected in the curing solution, is cross-linked into calcium alginate medicine microspheres or micro gel bead; Treat to sop up supernatant after deposition fully, must contain antituberculotics compound recipe microsphere or micro gel bead;
(2) strengthening process:
Microsphere that makes or micro gel bead are put into reinforced solution, and magnetic agitation is 3～5 minutes at a slow speed, supernatant discarded, antituberculotics three compound recipe microsphere or the micro gel beads after must strengthening.
6. the method for preparing that contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents as claimed in claim 5; It is characterized in that: the concentration of described carrier solution is 10～60g/L; The rifampicin solution concentration is 200g/L; The isoniazid solution concentration is 400g/L, and pyrazinamide or MOXIFLOXACIN solution concentration are 800g/L.
7. the method for preparing that contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents as claimed in claim 5, it is characterized in that: in the described drug solution, the weight ratio of Rimactazid, pyrazinamide or MOXIFLOXACIN is 1: 2: 4.
8. the method for preparing that contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents as claimed in claim 5, it is characterized in that: in the described preparation solution, the weight ratio of medicine and sodium alginate is 1: 1～50.
9. the method for preparing that contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents as claimed in claim 5 is characterized in that: described curing solution is that ionic calcium soln, water for injection and dehydrated alcohol obtain according to 3: 1: 1 mix homogeneously of volume ratio.
10. the method for preparing that contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents as claimed in claim 5, it is characterized in that: described gelatin or polylysine solution concentration are 0.2～20 g/L.
11. the method for preparing that contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents as claimed in claim 5 is characterized in that: described high-pressure electrostatic microsphere generator comprises the syringe peace scalp acupuncture head of HV generator, a plurality of positive and negative electrode, stainless steel ring, micro-injection pump, different model, aseptic glass container, magnetic stirring apparatus and lowering or hoisting gear.
12. the method for preparing that contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents as claimed in claim 5; It is characterized in that: described microsphere or micro gel bead are stored in the vegetable oil or liquid paraffin of injection; The particle diameter specification of microsphere or micro gel bead is: 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～500 μ m, 500～720 μ m, 700～900 μ m or 900～1250 μ m; Time spent discards vegetable oil or liquid paraffin, with normal saline give a baby a bath on the third day after its birth all over be implantable or injecting body in.
13. the method for preparing that contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents as claimed in claim 5 is characterized in that: described microsphere or micro gel bead get powdery granule after drying; The particle size range of said powdery particles is 30～50 μ m, 50～80 μ m, 50～100 μ m, 100～200 μ m, 100～300 μ m, 150～450 μ m, 300～550 μ m, 500～720 μ m, 700～900 μ m; With cobalt-60 radiation sterilization, airtight preservation was reduced into wet bulb in several minutes with the normal saline immersion before using.
14. claim 5～13 gained contains antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agents and is used for treating the application of the medicine of other tuberculosis in pulmonary tuberculosis, pulmonary tuberculosis massive hemoptysis, pulmonary tuberculosis cavity, renal tuberculosis, tuberculosis of bone and joint, genital tuberculosis, tuberculosis of thyroid gland, the tuberculosis of cervical lymph nodes, tuberculosis of pericardium, thoracic tuberculosis, tuberculous pleuritis and the body in preparation.
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CN105288601A (en) * 2014-07-01 2016-02-03 中国人民解放军沈阳军区总医院 Application of hydrogel microspheres embedded with blood coagulation related enzyme
CN112791228A (en) * 2019-11-13 2021-05-14 太阳雨林（厦门）生物医药有限公司 Slow-release embolism microsphere for pulmonary tuberculosis hemoptysis

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