WO2012003704A1 - 海藻酸钠交联莫西沙星缓释微球、其制备方法和用途以及含有所述微球的血管靶向栓塞剂 - Google Patents
海藻酸钠交联莫西沙星缓释微球、其制备方法和用途以及含有所述微球的血管靶向栓塞剂 Download PDFInfo
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- WO2012003704A1 WO2012003704A1 PCT/CN2010/080549 CN2010080549W WO2012003704A1 WO 2012003704 A1 WO2012003704 A1 WO 2012003704A1 CN 2010080549 W CN2010080549 W CN 2010080549W WO 2012003704 A1 WO2012003704 A1 WO 2012003704A1
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- tuberculosis
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- microsphere
- moxifloxacin
- microspheres
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1658—Proteins, e.g. albumin, gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a microsphere containing an anti-tuberculosis drug and a vascular targeted embolic agent containing the microsphere, in particular to a sustained release of moxifloxacin containing as an active ingredient against tuberculosis by using sodium alginate as a carrier.
- Microspheres and their vascular targeting embolic agents are particularly useful as a carrier.
- the invention also relates to a preparation method of the sustained release microspheres, and the microspheres in the preparation of interventional embolization for treating tuberculosis, pulmonary tuberculosis, massive hemoptysis, tuberculosis, renal tuberculosis, thyroid tuberculosis, cervical lymphatic tuberculosis, genital tuberculosis (fallopian tube, uterus)
- Tuberculosis is one of the major infectious diseases that seriously endanger human health. It has also become the number one killer of infectious diseases and the leading cause of death in adults. In the late 1990s, tuberculosis that had disappeared from the world due to problems such as drug-resistant bacteria has made a worldwide comeback, making it difficult to control tuberculosis.
- the World Health Organization has preliminary statistics that 1.9 billion people worldwide are infected with tuberculosis, and tuberculosis patients have More than 20 million people, the annual incidence of 8 million, the annual average of 3 million people lost their lives. The number of people infected with tuberculosis in China is also increasing. Tuberculosis is on the rise.
- tuberculosis patients ranks second in the world.
- the number of tuberculosis deaths is about 150,000 per year.
- the prevention and treatment of tuberculosis is a major issue that needs to be solved urgently. New tuberculosis drugs and new dosage forms are imminent.
- Mycobacterium tuberculosis mainly inhabits normal cells and has certain drug resistance.
- a certain concentration of anti-tuberculosis drugs must be reached in the cells.
- Oral preparations of anti-tuberculosis drugs are often affected by the first-pass effect and undergo protein binding, metabolism, excretion and decomposition in the systemic circulation. Only a small amount of drugs can reach the target tissues, target organs, target cells, and the target area should be improved.
- the concentration of the drug must increase the dose, which also increases the systemic side effects of the drug.
- the targeted preparation has the targeted release drug, increases the lesion site and intracellular drug concentration, improves the drug effect, reduces the side effects and the like, and therefore considers that the anti-tuberculosis drug targeted preparation has clinical application value and development prospect.
- Moxifloxacin is a fourth-generation fluoroquinolone chemically synthesized antibiotic drug produced by Bayer AG in 1999. Moxifloxacin inhibits bacterial DNA helicase A subunit and topoisomerase IV activity. It blocks the replication of DNA and exerts a bactericidal action. It mainly inhibits DNA helicase against Gram-negative bacteria, and the main target of Gram-positive bacteria is topoisomerase IV.
- the chemical structure of moxifloxacin is characterized by the introduction of a methoxy gene at the 8-position carbon atom, which increases the drug's ability to bind bacteria and penetrate the cell membrane, and the post-antibacterial effect (PAE) is strong and long-lasting.
- Moxifloxacin not only retains the antibacterial activity and antibacterial spectrum of quinolone drugs against Gram-negative bacteria. Moreover, the 8-methoxy gene increases its antibacterial activity and antibacterial spectrum against Gram-positive bacteria. It is very effective against atypical pathogens such as Mycoplasma pneumoniae, Chlamydia, Legionella, and has strong antibacterial activity, including significant antibacterial activity against spore- and bud-free anaerobic bacteria. Moxifloxacin pair SS-lactams, macrolides, aminoglycosides and tetracycline antibiotic-resistant bacteria Effective.
- Moxifloxacin and these antibacterial agents are not cross-resistant, not hepatic cytochrome P-450 isoenzyme inhibitors, thus avoiding many potential drug interactions.
- Moxifloxacin has early bactericidal activity similar to isoniazid (INH) or rifampicin. It has bactericidal activity in early and prolonged stages of tuberculosis patients, indicating good infiltration of tuberculosis lesions and rapid killing of patients with severe cavitary tuberculosis. The fast growing flora in the middle.
- moxifloxacin Since its listing, moxifloxacin has a broad spectrum of antibacterial activity, strong antibacterial activity, wide distribution in the body, high drug concentration in the body, long half-life, good curative effect, small side effects, no cross-resistance with other antibacterial drugs, almost no photosensitivity reaction, etc.
- the advantages are widely used in clinical practice.
- the drug resistance rate of Mycobacterium tuberculosis has become more and more high, especially the problem of multi-drug resistance, which has become a topic of concern in the prevention and control industry, and is also the main factor affecting the efficacy of chemotherapy for tuberculosis. factor. Therefore, the selection of a suitable anti-tuberculosis dosage form is an important part of the current treatment and control of tuberculosis.
- Tuberculosis recurrence and tuberculosis drug resistance are becoming more and more serious. Although the cause is complicated, one of the most important factors is the long course of treatment. The patient can not take regular medication to the end of the treatment. This is a common problem in tuberculosis treatment in all countries of the world. Under the premise of ensuring the therapeutic effect, reducing the dose of the drug and prolonging the interval between drugs, the problem of drug compliance will be effectively solved.
- a biocompatible, natural polymer material sodium alginate as a carrier
- moxifloxacin as a model drug and an adsorbent for cross-linking. Screening, in vitro release experiments and in vivo studies yielded long-acting release biodegradable microsphere vascular embolization formulations.
- the main anti-tuberculosis drugs are oral and injectable, and the efficacy of the injection is not ideal.
- the use of anti-tuberculosis drugs is greatly limited by the inability to obtain effective drug concentrations at the site of the lesion and the apparent systemic toxicity and drug resistance during application.
- a small number of embolization plus drug perfusion therapies also have the following drawbacks: the drug cannot be released relatively uniformly, and when the local perfusion drug concentration is too high, the shock wave effect of the drug may cause local tissue necrosis or damage.
- the anti-tuberculosis drug microsphere vascular embolization agent is a new dosage form.
- the deposition of microspheres in the lungs can delay the release of the drug, and can protect the drug from enzymatic hydrolysis, prolong the residence time of the drug in the lungs, and the incidence of side reactions. Low, well tolerated and safe.
- there is no cross-linking of sodium alginate and adsorbent to moxifloxacin to make anti-tuberculosis vascular embolization agent there is no cross-linking of sodium alginate and adsorbent to moxifloxacin to make anti-tuberculosis vascular embolization agent, and it is applied to tuberculosis, tuberculosis, massive hemoptysis, tuberculosis, tuberculous bronchoconstriction, multidrug-resistant cavitation.
- Renal tuberculosis Renal tuberculosis, thyroid tuberculosis, genital tuberculosis (fallopian tubes, endometrium, testis, epididymis), cervical lymphatic tuberculosis, pericardial tuberculosis, chest tuberculosis, other parts of the body, tuberculosis and other patients with embolization treatment reports.
- Moxifloxacin is a fourth-generation fluoroquinolone chemical antibiotic that is less soluble in water and organic solvents. Oral and injection preparations are often used clinically, and there are defects of small oral absorption and low injection dose. The lesion site cannot obtain an effective drug concentration, and can not be released relatively uniformly, and is also likely to cause adverse reactions.
- the present invention provides a sodium alginate cross-linked moxifloxacin sustained-release microsphere, characterized in that the microsphere comprises a drug carrier, an adsorbent, an anti-tuberculosis drug active ingredient, a reinforcing agent and a curing agent, the carrier
- the adsorbent is human albumin or bovine serum albumin
- the active ingredient of the antituberculosis drug is moxifloxacin
- the reinforcing agent is gelatin or hyaluronic acid
- the divalent metal cation calcium salt or strontium salt is a curing agent.
- the sustained release microspheres are stored in a vegetable oil or liquid paraffin as a preservation solution, and the microspheres have a particle size of 50 to 100 ⁇ m, 50 to 150 ⁇ m, 50 to 200 ⁇ m, 100 to 300 ⁇ m, and 150 to 450 ⁇ m. 300 to 500 ⁇ m, 500 to 700 ⁇ m, 700 to 900 ⁇ m or 900 to 1250 ⁇ m.
- the above sustained release microspheres are formed into dried powdery particles having a particle size ranging from 10 to 50 ⁇ m. 25 to 50 ⁇ m, 50 to 100 ⁇ m, 100 to 350 ⁇ m, 300 to 550 ⁇ m or 500 to 750 ⁇ m.
- the weight ratio of sodium alginate to moxifloxacin in the sustained release microsphere of the present invention is preferably from 1 to 75:0.25 to 12.5.
- the invention also provides a method for preparing the above sustained release microspheres, comprising the following steps:
- the moxifloxacin is prepared by dissolving and adsorbing the adsorbent prepared in the step 2), and obtaining a moxifloxacin solution, that is, a drug solution, wherein the mass percentage of the moxifloxacin and the adsorbent is 1.6 to 4%;
- the divalent metal cation calcium salt or strontium salt is formulated into an aqueous solution having a concentration by volume of 1 to 15% by mass to obtain a solidified liquid; wherein the cationic calcium salt is preferably selected from the group consisting of calcium chloride and calcium lactate, and the cerium salt is preferably chlorine.
- microspheres or microgel beads prepared above are placed in a reinforcing solution, stirred, and the supernatant is discarded to obtain microspheres or microgel beads, that is, slow release of moxifloxacin crosslinked by sodium alginate. Microspheres.
- the sodium alginate cross-linked moxifloxacin sustained-release microspheres obtained in the above step 9) are stored in a vegetable oil or liquid paraffin oil as a preservation solution.
- the vegetable oil may be selected from soybean oil for injection, tea oil, corn oil, rapeseed oil, cottonseed oil, and the like.
- the sodium alginate cross-linked moxifloxacin sustained-release microspheres obtained in the above step 9) are dried to obtain powdery particles, that is, dry balls.
- powdery particles that is, dry balls.
- freeze drying or oven drying is used.
- the high-voltage electrostatic multi-head microsphere generating device used in the step 8) of the above method comprises: a high-voltage static electricity generating device; a propelling pump; a spray head; a sterile container; positive and negative electrodes; ; lifting device.
- the high-voltage static electricity generating device has a plurality of positive and negative electrodes; the propelling pump is connected to the sterile syringe and the spray head; the positive electrode is connected to the spray head; and the negative electrode is connected with the stainless steel wire immersed in the solidified liquid
- the stainless steel wire is connected to the aseptic container; the stainless steel wire has a lifting device at a distance below the sterile container.
- the present invention employs a gelatin solution to add a film to the microbeads; in order to prevent the water-soluble drug from being released from the microspheres during storage (leakage), the present invention employs vegetable oil (or liquid). Paraffin wax saves and acts as a water-in-oil, thus avoiding the loss of the drug before application; the invention adopts high-voltage electrostatic ball-forming technology to avoid the use of organic solvent, is beneficial to improve the stability of the drug, and can adjust the voltage
- the microsphere (capsule) particle size is controlled, the operation is simple, the condition is mild, and the toxic organic solvent and glutaraldehyde used in the prior art can be avoided, and the product is environmentally friendly.
- the invention adopts alginic acid as a drug carrier cross-linking agent, the anti-tuberculosis drug moxifloxacin is a medicinal active ingredient, and albumin is used as an adsorbent to link moxifloxacin and sodium alginate in a divalent metal cation (calcium ion or strontium).
- a divalent metal cation calcium ion or strontium
- the microspheres are made into microspheres and then wrapped with gelatin to solve the problem of excessive release of water-soluble drugs.
- the wet gel drugs are preserved by high temperature sterilization of vegetable oil or liquid paraffin.
- the microspheres prevent moxifloxacin from being released when not in use.
- the invention changes the dosage form and the administration route of the moxifloxacin anti-tuberculosis drug, achieves the effect of high efficiency, low toxicity and safe and effective clinical application.
- the invention combines the anti-tuberculosis drug moxifloxacin with the adsorbent human or bovine serum albumin, dissolves them in proportion, adsorbs them together, and crosslinks with the sodium alginate carrier, passes through the high-voltage electrostatic multi-head microsphere generator, in the second price Under the action of metal cations (calcium ions or strontium ions), the anti-tuberculosis drug moxifloxacin is encapsulated in the microspheres. In order to prevent the release of the anti-tuberculosis drug moxifloxacin in the preservation solution, gelatin is further added to the microspheres. The film is then placed in a high temperature sterilized vegetable oil or liquid paraffin to preserve the wet gel drug microspheres to prepare a sodium alginate microsphere vascular targeting embolic agent containing moxifloxacin.
- the present invention also relates to a vascular targeted embolic agent characterized by containing the above-mentioned sodium alginate cross-linked moxifloxacin sustained-release microspheres.
- the invention further relates to the use of the above-described sodium alginate cross-linked moxifloxacin sustained release microspheres for the preparation of a vascular targeting embolic agent.
- the vascular targeted embolic agent can be used for treating tuberculosis, for example, for interventional embolization for tuberculosis, tuberculosis, massive hemoptysis or tuberculosis; for treating renal tuberculosis, thyroid tuberculosis, cervical lymph node tuberculosis, pericardial tuberculosis, chest wall tuberculosis and/or pleura Tuberculosis; used to treat tubal tuberculosis, endometrial tuberculosis, testicular tuberculosis or epididymal tuberculosis.
- the invention has the following advantages: 1. Select high-pressure electrostatic multi-head microsphere generators for industrial production to produce drug microsphere vascular targeting embolic agents with controllable size and suitable for clinical use. 2, the selection of biocompatible, natural polymer material sodium alginate as a drug carrier, to obtain a long-acting release biodegradable microsphere vascular targeting embolic agent; 3. Select human serum albumin or bovine serum albumin as adsorbent to adsorb the anti-tuberculosis drug moxifloxacin.
- the preparation of the invention By using the preparation of the invention, not only can the local drug concentration be greatly increased, the concentration of the drug in the circulatory system can be lowered, the toxicity of the drug to normal tissues can be reduced, the drug application can be greatly facilitated, the course of treatment can be reduced, the treatment time can be shortened, and the treatment time can be reduced. Complications of the drug reduce the cost of the patient and reduce drug tolerance.
- the treatment method uses interventional radiology or bronchoscopy intervention to perform target organ angiography. According to the angiography, it is decided to select the diameter of the embolic microspheres for embolization of the target organ, especially the peripheral arterioles embolized in the target organ.
- peripheral arteriolar vessels may be considered: (1) failure of initial treatment, treatment with retreatment of anti-tuberculosis regimen, smear positive tuberculosis after treatment, and sputum culture of Mycobacterium tuberculosis for HR two or more The anti-tuberculosis drug tolerant, that is, multidrug-resistant tuberculosis. (2) A single wall or cheese cavity with persistent positive tuberculosis, and no obvious active lesions or lesions around the cavity have been stable. (3) Individual fibrous cavity of tuberculosis, long-term treatment of sputum is not negative.
- the microcatheter is subjected to superselective embolization, and the aseptic operation is performed, and the transcatheter is injected slowly or slowly as needed according to the specific condition under the fluoroscopy, until the flow rate of the contrast agent is significantly slowed down, that is, the embolization is completed.
- the angiography was performed again to determine the embolization effect.
- the alginate microsphere vascular embolization agent containing moxifloxacin antituberculosis drug is powdery granules
- the dry ball stored in the closed container is first dissolved in physiological saline to reduce (ie, wet bulb), and then added.
- the appropriate amount or diluted contrast agent is evenly mixed, so that the microspheres are fully suspended in the contrast agent, and then super-selectively embolized by the catheter under the monitoring of the imaging device, slowly or slowly injected into the blood vessel of the lesion site until the contrast agent flow rate is obvious. When slowed down, the embolization is completed. The angiography was performed again to determine the embolization effect.
- the outstanding advantage of the invention is that the human or bovine serum albumin adsorbent is safe and effective, and successfully solves the problem that moxifloxacin cannot be completely dissolved in water or organic solvent, and moxifloxacin combines with albumin and water-soluble seaweed.
- the problem that the sodium solution is mixed and cross-linked is not solved, and the phenomenon that the anti-tuberculosis drug microspheres are ideally controlled under the condition of positive and negative electric field reaction with other reagents is solved, and
- the prepared microsphere vascular embolization agent has the characteristics of large drug loading, long residence time in the body, high bioavailability, adjustable drug release rate, targeted drug delivery, and specificity for targeting, and is used for targeting specificity.
- Processing of glassware Dry the cleaned glassware and bake in a high temperature oven (sterilized to remove heat) for use;
- microsphere preparation instrument The high-pressure electrostatic multi-head microsphere generator which can control the ball, has uniform size, simple operation, high output and easy mass production.
- Preparation methods of various reagents 1 Preparation of sodium alginate solution: Weigh 8 g of sodium alginate, place it in a glassware, add physiological saline or 500 ml of water for injection while stirring to magnetically stir all sodium alginate to obtain a sodium alginate solution; 2 preparation of adsorbents Human albumin (or bovine serum albumin) in a ratio of 0.1 to 10% (mass by volume), dissolved in water for injection, to obtain an albumin solution, that is, an adsorbent; 3 Preparation of moxifloxacin solution: Weigh 12 grams of commercially available moxifloxacin, placed in the above glassware, and dissolved with 0.1 to 10% (mass by volume) of human albumin or bovine serum albumin solution in 50 ml to obtain a moxifloxacin solution; 4 gelatin fortified solution: Weigh 30 grams of gelatin into a glassware, add 500 ml of normal saline or water for injection while stirring, and stir
- microsphere production The mixture solution is aspirated by a sterile syringe, and dropped into the above solid solution by a high-pressure electrostatic multi-head microsphere droplet generating device, and microspheres or microgels having different particle size ranges are prepared as needed, and the obtained sodium alginate is crosslinked.
- the high-voltage electrostatic multi-head microsphere generator includes: a high-voltage static electricity generating device, a propelling pump, a spray head, a sterile container, positive and negative electrodes, various types of sterile syringes, lifting devices.
- Each of the high-voltage electrostatic multi-head generators has positive and negative poles, and the propulsion pump is connected to a sterile syringe and a spray head, the positive electrode is connected to the spray head, and the negative electrode and the stainless steel wire immersed in the solidified liquid Connected, the stainless steel wire is connected to a sterile container having a lifting device at a distance below the sterile container.
- the particle diameters of the microspheres or microgel beads stored in the preservation solution are 50-100 ⁇ m, 50-150 ⁇ m, 50-200 ⁇ m, 100-300 ⁇ m, 150-450 ⁇ m, 300-500 ⁇ m, 500-700 ⁇ m, 700-. 900 ⁇ m or 900 to 1250 ⁇ m. After decanting the upper layer solution of the above container, rinsing with physiological saline, and using it immediately;
- the upper layer solution of the microspheres obtained above is decanted, and the obtained sodium alginate microspheres containing the moxifloxacin antituberculosis drug are dried (dry balls are obtained by freeze drying or oven drying) to obtain powdery particles; the powdery form
- the particle diameter of the fine particles is in the range of 10 to 50 ⁇ m, 25 to 50 ⁇ m, 50 to 100 ⁇ m, 100 to 350 ⁇ m, 300 to 550 ⁇ m or 500 to 750 ⁇ m; it is stored in a sealed state and then reduced to a wet bulb by soaking in physiological saline for several minutes before use.
- Example 2 Preparation of sodium alginate cross-linked moxifloxacin anti-tubercular microsphere vascular embolization agent:
- Processing of glassware Dry the cleaned glassware and bake in a high temperature oven (sterilized to remove heat) for use;
- microsphere preparation instrument The high-pressure electrostatic multi-head microsphere generator which can control the ball, has uniform size, simple operation, high output and easy mass production.
- Preparation methods of various reagents 1 Preparation of sodium alginate solution: Weigh 10 g of sodium alginate, placed in a glassware, and stir with physiological saline or 500 ml of water for injection to stir all sodium alginate to obtain sodium alginate solution; 2 preparation of adsorbents The human albumin (or bovine serum albumin) is dissolved in water for injection in a ratio of 0.1 to 10% (mass by volume); the adsorbent, that is, the albumin solution; 3 Preparation of anti-tuberculosis drug moxifloxacin solution: Weigh 14 grams of commercially available moxifloxacin, place it in the above glassware, and stir it with 0.1-10% (mass by volume) of human albumin or bovine serum albumin solution to obtain anti-tuberculosis drug moxifloxacin solution.
- microsphere production The mixture solution is aspirated by a sterile syringe, and dropped into the above solid solution by a high-pressure electrostatic multi-head microsphere droplet generating device, and microspheres or microgels having different particle size ranges are prepared as needed, and the obtained sodium alginate is crosslinked.
- the high-voltage electrostatic multi-head microsphere generator includes: a high-voltage static electricity generating device, a propelling pump, a spray head, a sterile container, positive and negative electrodes, various types of sterile syringes, lifting devices.
- Each of the high-voltage electrostatic multi-head generators has positive and negative poles, and the propulsion pump is connected to a sterile syringe and a spray head, the positive electrode is connected to the spray head, and the negative electrode and the stainless steel wire immersed in the solidified liquid Connected, the stainless steel wire is connected to a sterile container having a lifting device at a distance below the sterile container.
- the particle diameters of the microspheres or microgel beads stored in the preservation solution are 50-100 ⁇ m, 50-150 ⁇ m, 50-200 ⁇ m, 100-300 ⁇ m, 150-450 ⁇ m, 300-500 ⁇ m, 500-700 ⁇ m, 700-. 900 ⁇ m or 900 to 1250 ⁇ m. After decanting the upper layer solution of the above container, rinsing with physiological saline, and using it immediately;
- the upper layer solution of the microspheres obtained above is decanted, and the obtained sodium alginate microspheres containing the moxifloxacin antituberculosis drug are dried (dry balls are obtained by freeze drying or oven drying) to obtain powdery particles; the powdery form Particle size range from 10 to 50 ⁇ m 25 to 50 ⁇ m or 50 to 100 ⁇ m; 100 to 350 ⁇ m, 300 to 550 ⁇ m or 500 to 750 ⁇ m; sealed and stored in a physiological saline solution for several minutes before use to reduce to a wet bulb.
- Example 3 Preparation of sodium alginate cross-linked moxifloxacin anti-tubercular microsphere vascular embolization agent:
- Processing of glassware Dry the cleaned glassware and bake in a high temperature oven (sterilized to remove heat) for use;
- microsphere preparation instrument The high-pressure electrostatic multi-head microsphere generator which can control the ball, has uniform size, simple operation, high output and easy mass production.
- Preparation methods of various reagents 1 Preparation of sodium alginate solution: Weigh 15 g of sodium alginate, placed in a glassware, and stirred with physiological saline or 500 ml of water for injection to stir magnetically to dissolve all sodium alginate to obtain a sodium alginate solution; 2 preparation of adsorbents The human albumin (or bovine serum albumin) is dissolved in water for injection in a ratio of 0.1 to 10% (mass by volume); the adsorbent, that is, the albumin solution; 3 Preparation of anti-tuberculosis drug moxifloxacin solution: Weigh 10 g of commercially available moxifloxacin, place it in the above glassware, and dissolve it with 0.1 to 10% (mass by volume) of human albumin or bovine serum albumin solution in 50 ml to obtain anti-tuberculosis drug moxifloxacin solution.
- microsphere production The mixture solution is aspirated by a sterile syringe, and dropped into the above solid solution by a high-pressure electrostatic multi-head microsphere droplet generating device, and microspheres or microgels having different particle size ranges are prepared as needed, and the obtained sodium alginate is crosslinked.
- the high-voltage electrostatic multi-head microsphere generator includes: a high-voltage static electricity generating device, a propelling pump, a spray head, a sterile container, positive and negative electrodes, various types of sterile syringes, lifting devices.
- Each of the high-voltage electrostatic multi-head generators has positive and negative poles, and the propulsion pump is connected to a sterile syringe and a spray head, the positive electrode is connected to the spray head, and the negative electrode and the stainless steel wire immersed in the solidified liquid Connected, the stainless steel wire is connected to a sterile container having a lifting device at a distance below the sterile container.
- the particle diameters of the microspheres or microgel beads stored in the preservation solution are 50-100 ⁇ m, 50-150 ⁇ m, 50-200 ⁇ m, 100-300 ⁇ m, 150-450 ⁇ m, 300-500 ⁇ m, 500-700 ⁇ m, 700-. 900 ⁇ m or 900 to 1250 ⁇ m. After decanting the upper layer solution of the above container, rinsing with physiological saline, and using it immediately;
- the upper layer solution of the microspheres obtained above is decanted, and the obtained sodium alginate microspheres containing the moxifloxacin antituberculosis drug are dried (dry balls are obtained by freeze drying or oven drying) to obtain powdery particles; the powdery form Particle size range from 10 to 50 ⁇ m 25 to 50 ⁇ m or 50 to 100 ⁇ m; 100 to 350 ⁇ m, 300 to 550 ⁇ m or 500 to 750 ⁇ m; sealed and stored in a physiological saline solution for several minutes before use to reduce to a wet bulb.
- the effect of the microspheres is better, and then the appropriate amount of contrast agent is mixed, and the lesion is slowly injected into the lesion through the catheter under fluoroscopy until the flow rate of the contrast agent is significantly slowed down, that is, the embolization is completed.
- the angiography was performed again to determine the embolization effect.
- the results of clinical experiments show that the solvent used in the present invention is safe and effective, and the catheter is inserted into the target blood vessel.
- the drug-loaded microspheres and the contrast agent are mixed by a syringe, and the injection catheter is not condensed and the tube is not blocked.
- the drug microspheres have a suitable particle size (usually 500-700 ⁇ m or 700-900 ⁇ m)
- the microspheres have better effects), have good biocompatibility, are non-toxic and harmless to the human body, have no immunogenicity, and have affinity for the drugs contained therein. The toxic and side effects are small, the drug concentration is large, and the utilization rate is high.
- Example 4 Preparation of sodium alginate cross-linked moxifloxacin anti-tuberculosis microsphere vascular embolization agent:
- Processing of glassware Dry the cleaned glassware and bake in a high temperature oven (sterilized to remove heat) for use;
- microsphere preparation instrument The high-pressure electrostatic multi-head microsphere generator which can control the ball, has uniform size, simple operation, high output and easy mass production.
- Preparation methods of various reagents 1 Preparation of sodium alginate solution: Weigh 20 g of sodium alginate, placed in a glassware, and stir with physiological saline or 500 ml of water for injection to stir magnetically to dissolve all sodium alginate to obtain a sodium alginate solution; 2 preparation of adsorbents The human albumin (or bovine serum albumin) is dissolved in water for injection in a ratio of 0.1 to 10% (mass by volume); the adsorbent, that is, the albumin solution; 3 Preparation of anti-tuberculosis drug moxifloxacin solution: Weigh 22 grams of commercially available moxifloxacin, place it in the above glassware, and stir it with 0.1-10% (mass by volume) of human albumin or bovine serum albumin solution to obtain anti-tuberculosis drug moxifloxacin solution.
- microsphere production The mixture solution is aspirated by a sterile syringe, and dropped into the above solid solution by a high-pressure electrostatic multi-head microsphere droplet generating device, and microspheres or microgels having different particle size ranges are prepared as needed, and the obtained sodium alginate is crosslinked.
- the high-voltage electrostatic multi-head microsphere generator includes: a high-voltage static electricity generating device, a propelling pump, a spray head, a sterile container, positive and negative electrodes, various types of sterile syringes, lifting devices.
- Each of the high-voltage electrostatic multi-head generators has positive and negative poles, and the propulsion pump is connected to a sterile syringe and a spray head, the positive electrode is connected to the spray head, and the negative electrode and the stainless steel wire immersed in the solidified liquid Connected, the stainless steel wire is connected to a sterile container having a lifting device at a distance below the sterile container.
- the particle diameters of the microspheres or microgel beads stored in the preservation solution are 50-100 ⁇ m, 50-150 ⁇ m, 50-200 ⁇ m, 100-300 ⁇ m, 150-450 ⁇ m, 300-500 ⁇ m, 500-700 ⁇ m, 700-. 900 ⁇ m or 900 to 1250 ⁇ m. After decanting the upper layer solution of the above container, rinsing with physiological saline, and using it immediately;
- the upper layer solution of the microspheres obtained above is decanted, and the obtained sodium alginate microspheres containing the moxifloxacin antituberculosis drug are dried (dry balls are obtained by freeze drying or oven drying) to obtain powdery particles; the powdery form Particle size range from 10 to 50 ⁇ m 25 to 50 ⁇ m or 50 to 100 ⁇ m; 100 to 350 ⁇ m, 300 to 550 ⁇ m or 500 to 750 ⁇ m; sealed and stored in a physiological saline solution for several minutes before use to reduce to a wet bulb.
- tuberculosis Patients with other tuberculosis outside the lungs, such as: renal tuberculosis, thyroid tuberculosis, cervical lymphatic tuberculosis, genital tuberculosis (fallopian tube, endometrium, testis, epididymis), pericardial tuberculosis, chest wall tuberculosis, using interventional radiology or bronchoscopy intervention Application of pleural tuberculosis and other tuberculosis in the body.
- tuberculosis such as: renal tuberculosis, thyroid tuberculosis, cervical lymphatic tuberculosis, genital tuberculosis (fallopian tube, endometrium, testis, epididymis), pericardial tuberculosis, chest wall tuberculosis, using interventional radiology or bronchoscopy intervention Application of pleural tuberculosis and other tuberculosis in the body
- the catheter was inserted into the blood supply artery of the target organ, and angiography was performed. According to the angiography, the appropriate particle size range of the above-mentioned alginate microspheres containing moxifloxacin was selected. Cross-linking moxifloxacin microspheres (wet bulbs) with sodium alginate and washing the microspheres three times with physiological saline (usually 300-500 ⁇ m) The effect of the microspheres is better. Then, the appropriate amount of contrast agent is mixed, and the lesion is slowly injected into the lesion through the catheter under fluoroscopy until the flow rate of the contrast agent is significantly slowed down, that is, the embolization is completed.
- the angiography was performed again to determine the embolization effect.
- the results of clinical experiments show that the solvent used in the present invention is safe and effective, and the local drug concentration is increased while reducing the total amount of drugs and reducing the occurrence of systemic side effects; after the biodegradable drug-loaded microspheres are implanted with tuberculosis, the drug release can be close to zero level. The release rate keeps the drug concentration steady, does not produce a burst effect, and the microspheres do not need to be surgically removed.
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Abstract
Description
1、选择产业化生产的高压静电多头微球发生仪,生产出大小可控,适合临床上不同用途的药物微球血管靶向栓塞剂;
2、选择生物相容性好,天然高分子材料海藻酸钠作为药物载体,获得长效释药可生物降解微球血管靶向栓塞剂;
3、选择人血清白蛋白或牛血清白蛋白作为吸附剂,很好地吸附抗结核药莫西沙星。
将清洗干净的玻璃器皿凉干,放在高温烤箱内烘烤(除菌去热源)待用;
选用制球可控,大小均匀,操作简便,产量高,易大量生产的高压静电多头微球发生仪。
①制备海藻酸钠溶液:
称取8克海藻酸钠,置于玻璃器皿内,边搅拌边加入生理盐水或注射用水500ml磁力搅拌至海藻酸钠全部溶解,得海藻酸钠溶液;
②配制吸附剂
将人血白蛋白(或牛血清白蛋白)按比例0.1~10%(质量体积百分比),用注射用水溶解, 得白蛋白溶液,即,吸附剂;
③配制莫西沙星溶液:
称取12克市售莫西沙星,置于上述玻璃器皿内,用0.1~10%(质量体积百分比)的人血白蛋白或牛血清白蛋白溶液50ml搅拌溶解,得莫西沙星溶液;
④明胶强化溶液:
称取30克的明胶置于玻璃器皿内,边搅拌边加入生理盐水或注射用水500ml,磁力搅拌至明胶全部溶解,得明胶强化溶液;
⑤配制含无水乙醇固化溶液:
称取氯化钙或氯化钡或乳酸钙200克置于玻璃器皿内,边搅拌边加入注射用水4000ml,磁力搅拌至钙全部溶解后加入1000ml无水乙醇,得含无水乙醇固化溶液;
⑥保存溶液:
用购置的供注射用的大豆油(或供注射用的茶油、玉米油、花生油、菜籽油、棉籽油等)或液体石蜡为保存溶液;
⑦配制混合溶液:
将上述制备的海藻酸钠溶液和莫西沙星溶液搅拌均匀得混合溶液;
用无菌注射器吸取上述混合液,通过高压静电多头微球液滴发生装置滴入上述固化液溶液中,根据需要制得粒径范围不同大小的微球或微胶珠,所得海藻酸钠交联莫西沙星的微球或微胶珠沉入容器下面。
将清洗干净的玻璃器皿凉干,放在高温烤箱内烘烤(除菌去热源)待用;
选用制球可控,大小均匀,操作简便,产量高,易大量生产的高压静电多头微球发生仪。
①制备海藻酸钠溶液:
称取10克海藻酸钠,置于玻璃器皿内,边搅拌边加入生理盐水或注射用水500ml磁力搅拌至海藻酸钠全部溶解,得海藻酸钠溶液;
②配制吸附剂
将人血白蛋白(或牛血清白蛋白)按比例0.1~10%(质量体积百分比),用注射用水溶解;得吸附剂,即白蛋白溶液;
③配制抗结核药物莫西沙星药液:
称取14克市售莫西沙星,置于上述玻璃器皿内,用0.1~10%(质量体积百分比)的人血白蛋白或牛血清白蛋白溶液50ml搅拌溶解,得抗结核药物莫西沙星溶液;
④配制明胶强化溶液:
称取26克的明胶置于玻璃器皿内,边搅拌边加入生理盐水或注射用水500ml,磁力搅拌至明胶全部溶解,得明胶强化溶液;
⑤配制含无水乙醇固化溶液:
称取氯化钙或氯化钡或乳酸钙200克置于玻璃器皿内,边搅拌边加入注射用水4000ml,磁力搅拌至钙全部溶解后加入1000ml无水乙醇,得含无水乙醇固化溶液;
⑥保存溶液:
用购置的供注射用的大豆油(或供注射用的茶油、玉米油、花生油、菜籽油、棉籽油等)或液体石蜡为保存溶液;
⑦配制混合溶液:
将上述制备的海藻酸钠溶液和配制的抗结核药物莫西沙星溶液搅拌均匀得混合溶液;
用无菌注射器吸取上述混合液,通过高压静电多头微球液滴发生装置滴入上述固化液溶液中,根据需要制得粒径范围不同大小的微球或微胶珠,所得海藻酸钠交联莫西沙星的微球或微胶珠沉入容器下面。
将清洗干净的玻璃器皿凉干,放在高温烤箱内烘烤(除菌去热源)待用;
选用制球可控,大小均匀,操作简便,产量高,易大量生产的高压静电多头微球发生仪。
①制备海藻酸钠溶液:
称取15克海藻酸钠,置于玻璃器皿内,边搅拌边加入生理盐水或注射用水500ml磁力搅拌至海藻酸钠全部溶解,得海藻酸钠溶液;
②配制吸附剂
将人血白蛋白(或牛血清白蛋白)按比例0.1~10%(质量体积百分比),用注射用水溶解;得吸附剂,即白蛋白溶液;
③配制抗结核药物莫西沙星药液:
称取10克市售莫西沙星,置于上述玻璃器皿内,用0.1~10%(质量体积百分比)的人血白蛋白或牛血清白蛋白溶液50ml搅拌溶解,得抗结核药物莫西沙星溶液;
④配制明胶强化溶液:
称取20克的明胶置于玻璃器皿内,边搅拌边加入生理盐水或注射用水500ml,磁力搅拌至明胶全部溶解,得明胶强化溶液;
⑤配制含无水乙醇固化溶液:
称取氯化钙或氯化钡或乳酸钙200克置于玻璃器皿内,边搅拌边加入注射用水4000ml,磁力搅拌至钙全部溶解后加入1000ml无水乙醇,得含无水乙醇固化溶液;
⑥保存溶液:
用购置的供注射用的大豆油(或供注射用的茶油、玉米油、花生油、菜籽油、棉籽油等)或液体石蜡为保存溶液;
⑦配制混合溶液:
将上述制备的海藻酸钠溶液和配制的抗结核药物莫西沙星溶液搅拌均匀得混合溶液;
用无菌注射器吸取上述混合液,通过高压静电多头微球液滴发生装置滴入上述固化液溶液中,根据需要制得粒径范围不同大小的微球或微胶珠,所得海藻酸钠交联莫西沙星的微球或微胶珠沉入容器下面。
将清洗干净的玻璃器皿凉干,放在高温烤箱内烘烤(除菌去热源)待用;
选用制球可控,大小均匀,操作简便,产量高,易大量生产的高压静电多头微球发生仪。
①制备海藻酸钠溶液:
称取20克海藻酸钠,置于玻璃器皿内,边搅拌边加入生理盐水或注射用水500ml磁力搅拌至海藻酸钠全部溶解,得海藻酸钠溶液;
②配制吸附剂
将人血白蛋白(或牛血清白蛋白)按比例0.1~10%(质量体积百分比),用注射用水溶解;得吸附剂,即白蛋白溶液;
③配制抗结核药物莫西沙星药液:
称取22克市售莫西沙星,置于上述玻璃器皿内,用0.1~10%(质量体积百分比)的人血白蛋白或牛血清白蛋白溶液50ml搅拌溶解,得抗结核药物莫西沙星溶液;
④配制明胶强化溶液:
称取22克的明胶置于玻璃器皿内,边搅拌边加入生理盐水或注射用水500ml,磁力搅拌至明胶全部溶解,得明胶强化溶液;
⑤配制含无水乙醇固化溶液:
称取氯化钙或氯化钡或乳酸钙200克置于玻璃器皿内,边搅拌边加入注射用水4000ml,磁力搅拌至钙全部溶解后加入1000ml无水乙醇,得含无水乙醇固化溶液;
⑥保存溶液:
用购置的供注射用的大豆油(或供注射用的茶油、玉米油、花生油、菜籽油、棉籽油等)或液体石蜡为保存溶液;
⑦配制混合溶液:
将上述制备的海藻酸钠溶液和配制的抗结核药物莫西沙星溶液搅拌均匀得混合溶液;
用无菌注射器吸取上述混合液,通过高压静电多头微球液滴发生装置滴入上述固化液溶液中,根据需要制得粒径范围不同大小的微球或微胶珠,所得海藻酸钠交联莫西沙星的微球或微胶珠沉入容器下面。
Claims (14)
- 一种海藻酸钠交联的莫西沙星缓释微球,其特征在于所述的微球包括药物载体、吸附剂、抗结核药物活性成分、加强剂和固化剂,所述载体为海藻酸钠,吸附剂为人血白蛋白或牛血清白蛋白,抗结核药物活性成分为莫西沙星,加强剂为明胶或透明质酸,二价金属阳离子钙盐或钡盐为固化剂。
- 根据权利要求1所述的缓释微球,其特征在于所述微球储存在作为保存液的植物油或液体石蜡中时,微球粒径规格为:50~100µm、50~150µm、50~200µm、100~300µm、150~450µm、300~500µm、500~700µm、700~900µm或900~1250µm。
- 根据权利要求1所述的缓释微球,其特征在于所述微球是干燥的粉末状颗粒,其粒径范围为10~50µm 、25~50µm、50~100µm、100~350µm、300~550µm或500~750µm。
- 根据权利要求1所述的缓释微球,其特征在于海藻酸钠与莫西沙星的重量比为1~75∶0.25~12.5。
- 一种制备根据权利要求1所述缓释微球的方法,其特征是包括下述步骤,1)将海藻酸钠用生理盐水或注射用水按质量体积百分比为0.5~15%比例溶解,得海藻酸钠溶液,即,载体溶液;2)将人血白蛋白或牛血清白蛋白用注射用水按质量体积百分比0.1~10%比例溶解,得白蛋白溶液,即,吸附剂;3)将莫西沙星用步骤2)配制的吸附剂研磨搅拌溶解并吸附,得莫西沙星溶液,即,药物溶液,其中莫西沙星与吸附剂的用量按质量体积百分比为1.6~4%;4)将二价金属阳离子钙盐或钡盐配制成质量体积百分比1~15%浓度的水溶液,得固化液;5)将所得固化液中加入无水乙醇和注射用水,固化液:无水乙醇:注射用水的体积比为:2∶1∶2,得含有无水乙醇的固化液;6)取明胶或透明质酸用注射用水溶解,得质量体积百分比0.1-10%的明胶或透明质酸溶液,即,加强溶液;7)将药物溶液和载体溶液按比例合并,它们的体积比为:1∶1~30,磁力搅拌均匀,得制备溶液;8)将上述所得制备溶液通过高压静电多头微球发生装置,喷雾微滴,分散于固化液中,待沉淀完全后去除上清液,得含莫西沙星的海藻酸钠交联的微球或微胶珠;9)将上述制得的微球或微胶珠放入加强溶液中,搅拌,弃去上清液,得带药微球或微胶珠,即,海藻酸钠交联的莫西沙星缓释微球。
- 根据权利要求5所述的方法,其特征在于步骤9)得到的带药微球或微胶珠保存在植物油或液体石蜡油中。
- 根据权利要求5所述的方法,其中所述的阳离子钙盐选自氯化钙和乳酸钙,所述钡盐为氯化钡。
- 根据权利要求5-7任一项所述的方法,其中步骤8)所用的高压静电多头微球发生装置包括:高压静电发生装置;推进泵;喷射头;无菌容器;正负电极;各种型号的无菌注射器;升降装置。所述高压静电发生装置上有多个正负电极;所述推进泵与无菌注射器和喷射头相连;所述正极与喷射头相连;所述负极与浸在所述固化液中的不锈钢钢丝相连接;所述不锈钢钢丝与无菌容器相连;所述不锈钢钢丝与无菌容器下方有调节距离的升降装置。
- 一种血管靶向栓塞剂,其特征在于含有根据权利要求1-4任一项所述的缓释微球。
- 根据权利要求1-4任一项所述的微球在制备血管靶向栓塞剂中的用途。
- 根据权利要求10所述的用途,其中所述血管靶向栓塞剂用于治疗结核病。
- 根据权利要求10所述的用途,其中所述血管靶向栓塞剂用于治疗肾结核、甲状腺结核、颈淋巴结核、心包结核、胸壁结核和/或胸膜结核。
- 根据权利要求10所述的用途,其中所述血管靶向栓塞剂用于治疗输卵管结核、子宫内膜结核、睾丸结核或附睾结核。
- 根据权利要求10所述的用途,其中所述血管靶向栓塞剂用于介入栓塞治疗肺结核、肺结核大咯血或肺结核空洞。
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PCT/CN2010/080549 WO2012003704A1 (zh) | 2010-07-09 | 2010-12-30 | 海藻酸钠交联莫西沙星缓释微球、其制备方法和用途以及含有所述微球的血管靶向栓塞剂 |
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US (1) | US9028847B2 (zh) |
CN (1) | CN102309458B (zh) |
WO (1) | WO2012003704A1 (zh) |
Cited By (1)
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CN105816920A (zh) * | 2016-03-29 | 2016-08-03 | 江南大学 | 一种改性海藻酸钠栓塞微球的制备方法 |
Families Citing this family (9)
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CN111803698B (zh) * | 2014-02-14 | 2022-05-27 | 波士顿科学国际有限公司 | 具有治疗剂释放的快速降解栓塞颗粒 |
CN103977316A (zh) * | 2014-05-28 | 2014-08-13 | 宋秀花 | 一种治疗空洞型肺结核咯血的中药 |
WO2017030876A1 (en) | 2015-08-14 | 2017-02-23 | Clearh2O, Inc. | High throughput process for delivering semi-firm gel for poultry |
CN108727675B (zh) * | 2017-04-14 | 2020-05-19 | 北京化工大学 | 一种防污复合材料及制备方法 |
KR20200125582A (ko) * | 2018-03-02 | 2020-11-04 | 미쯔비시 가스 케미칼 컴파니, 인코포레이티드 | 알루미나의 보호액, 보호방법 및 이것을 이용한 알루미나층을 가지는 반도체 기판의 제조방법 |
CN112791228A (zh) * | 2019-11-13 | 2021-05-14 | 太阳雨林(厦门)生物医药有限公司 | 一种用于肺结核咯血的缓释栓塞微球 |
CN112972753A (zh) * | 2019-12-02 | 2021-06-18 | 太阳雨林(厦门)生物医药有限公司 | 一种用于治疗慢性炎症引起的支气管扩张性咯血的缓释栓塞微球 |
CN113018268B (zh) * | 2019-12-25 | 2024-02-02 | 鲁南制药集团股份有限公司 | 一种注射用德拉沙星葡甲胺冻干制剂及其制备方法 |
CN117815434B (zh) * | 2024-03-05 | 2024-05-24 | 山东第二医科大学 | 一种氧化再生纤维素栓塞微球及其制备方法 |
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- 2010-12-30 WO PCT/CN2010/080549 patent/WO2012003704A1/zh active Application Filing
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CN105816920A (zh) * | 2016-03-29 | 2016-08-03 | 江南大学 | 一种改性海藻酸钠栓塞微球的制备方法 |
CN105816920B (zh) * | 2016-03-29 | 2018-10-23 | 江南大学 | 一种改性海藻酸钠栓塞微球的制备方法 |
Also Published As
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CN102309458B (zh) | 2016-02-03 |
US20130156827A1 (en) | 2013-06-20 |
US9028847B2 (en) | 2015-05-12 |
CN102309458A (zh) | 2012-01-11 |
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