WO2015196984A1 - Use of polylactic acid microsphere for hemorrhagic diseases - Google Patents

Use of polylactic acid microsphere for hemorrhagic diseases Download PDF

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WO2015196984A1
WO2015196984A1 PCT/CN2015/082133 CN2015082133W WO2015196984A1 WO 2015196984 A1 WO2015196984 A1 WO 2015196984A1 CN 2015082133 W CN2015082133 W CN 2015082133W WO 2015196984 A1 WO2015196984 A1 WO 2015196984A1
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polylactic acid
microspheres
drug
bleeding
use according
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PCT/CN2015/082133
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French (fr)
Chinese (zh)
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李茂全
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李茂全
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds

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  • the invention belongs to the field of chemical medicine, and in particular relates to the application of polylactic acid microspheres in hemorrhagic diseases.
  • Transcatheter arterial embolization is a controlled infusion of an embolic agent into the blood supply artery through an intra-arterial catheter to cause occlusion, thereby changing the hemodynamic state of the target organ and reducing the bleeding artery. Quantity, reaching target tissues and target organs to reduce or stop bleeding medical technology.
  • the purpose of embolization is to block the reduction of blood supply to the target area, thereby reducing or stopping the bleeding state of the target tissue and the target organ.
  • the present invention provides a new use of polylactic acid microspheres in the treatment of bleeding disorders.
  • a polylactic acid microsphere for the preparation of a pharmaceutical composition for treating a bleeding disorder.
  • the bleeding disorder includes a bleeding disorder treatable by embolization.
  • the hemorrhagic disease comprises an acute or chronic non-diffuse hemorrhagic disease.
  • the hemorrhagic disease includes gastrointestinal bleeding, hepatic hemorrhage, postpartum hemorrhage, and intracranial hemorrhage.
  • the hemorrhagic disease includes acute gastrointestinal bleeding, acute liver bleeding.
  • the pharmaceutical composition comprises polylactic acid microspheres, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises a procoagulant.
  • the polylactic acid microspheres comprise homopolymers, and/or copolymers of polylactic acid microspheres.
  • the copolymer is a copolymer composed of polylactic acid microspheres and tripropylene and glycolic acid.
  • the microspheres have a particle diameter of 10 to 200 ⁇ m, preferably 30 to 150 ⁇ m, more preferably 50 to 80 ⁇ m.
  • the polylactic acid microspheres have a particle diameter of 50 to 200 ⁇ m, preferably 70 to 150. ⁇ m, more preferably, 80-100 ⁇ m.
  • the pharmaceutical composition comprises an injection, a powder, an emulsion, a pellet, a lyophilizate, a suppository.
  • the pharmaceutical composition is a suppository.
  • the concentration of the polylactic acid microspheres is from 1 to 99% by weight.
  • the preparation method of the polylactic acid microspheres comprises: emulsification-solvent evaporation method, phase separation method, spray drying method, supercritical fluid method, membrane emulsification method, microchannel emulsification method, electrostatic droplet law.
  • a suppository for treating a bleeding disorder comprising polylactic acid microspheres, and a pharmaceutically acceptable carrier.
  • the suppository further comprises a polylactic acid-tripropylene copolymer, a polylactic acid-polyglycolic acid copolymer, sodium alginate or a combination thereof.
  • a method of treating a bleeding disorder the polylactic acid microspheres or the suppository of the second aspect of the invention being administered to a subject in need thereof.
  • the desired subject is a mammal having a bleeding disorder, such as a human, a mouse, or a rabbit.
  • the administering comprises injecting the polylactic acid microspheres into the aorta (or secondary aorta) upstream of the bleeding site (or bleeding site).
  • Figure 1A shows the PLGA before lyophilization observed under direct view
  • Figure 1B shows the microsphere morphology of the microspheres observed under electron microscope (100 x).
  • Figure 2a shows that at the same PLGA solution concentration, when the stirring rate is small, the emulsion is not sufficiently stirred, and the particle size distribution of the microspheres is wide;
  • Figure 2b-c shows that when the emulsion is sufficiently stirred, the particle size distribution is relatively narrow. At this time, if the stirring rate is increased, the average particle size and distribution of the microspheres are not greatly affected.
  • Figure 3A shows an optical micrograph (20x) of a 100-200 [mu]m PLGA drug-loaded plug microsphere.
  • Figure 3B shows an electron microscopic observation of the surface of the microspheres after gold plating.
  • the present inventors have conducted extensive and intensive research, and for the first time, unexpectedly discovered that the commonly used polylactic acid or microspheres formed thereof with other degradable carriers can be directly used for embolization treatment of hemorrhagic diseases.
  • the present inventors utilize the characteristics of slow degradation of polylactic acid microspheres in the human body, and use them as temporary embolic preparations, so that they can achieve rapid hemostasis purposes and facilitate recanalization of late blood vessels.
  • polylactic acid microspheres can also be used.
  • the active ingredient of a therapeutic drug such as a blood coagulation agent or a vascular repair-promoting agent
  • the present invention has been completed.
  • embolic formulation As used herein, the terms “embolic formulation”, “suppository” are used interchangeably and refer to an embolic preparation for treating a bleeding disorder comprising the polylactic acid microspheres of the present invention.
  • hemorrhagic disease includes various acute, chronic non-diffuse hemorrhagic diseases due to trauma or pathology, and generally the hemorrhagic disease described can be hemostasis treated by embolization.
  • the hemorrhagic diseases include hemorrhage of the digestive tract, such as esophageal variceal bleeding; intracranial hemorrhage, such as aneurysm rupture; postpartum hemorrhage, such as uterine artery hemorrhage caused by placental retention; liver hemorrhage; intratumoral hemorrhage, Such as tumor rupture and so on.
  • the hemorrhagic disease includes acute gastrointestinal bleeding, acute liver bleeding.
  • Polylactic acid is one of the most versatile biodegradable synthetic polymer materials. It has the advantages of toxicity, biodegradability, easy availability of raw materials, good biocompatibility, etc. It is enzymatically decomposed in the living body, eventually forming carbon dioxide and water, and does not accumulate in important organs. Its degradation rate and polymerization The molecular weight of the substance is closely related.
  • polylactic acid microspheres includes polylactic acid microspheres and copolymers of polylactic acid microspheres with other carriers.
  • the other carriers may include degradable carriers commonly used in the art.
  • the copolymer but not limited to, comprises a polylactic acid-tripropylene copolymer, a polylactic acid-polyglycolic acid copolymer (PLGA), or a combination thereof.
  • the ratio of polylactic acid to other carriers can be formulated or prepared according to the water solubility or fat solubility requirements of the finished preparation.
  • the present invention utilizes the sustained release effect of polylactic acid microspheres in vivo to prepare a new embolic preparation for treating hemorrhagic diseases, that is, an embolic preparation containing only polylactic acid microspheres can be used as a temporary thrombus inhibitor, and polylactic acid can also be used.
  • the microspheres encapsulate other procoagulant drugs as carriers of the active ingredient, while embolizing the bleeding vessels The drug is slowly released at the target vessel.
  • the embolic preparation using the polylactic acid microsphere of the present invention can effectively block the bleeding blood vessel to immediately stop bleeding, and can also locally release the procoagulant or the endothelium repairing drug, and is beneficial for long-term blood vessel recanalization.
  • the preparation method of the polylactic acid microspheres which can be used in the present invention is not particularly limited, and there are three kinds of emulsification-solvent evaporation method, phase separation method and spray drying method, and the following seven kinds are known:
  • the solvent evaporation method is a method in which the immiscible two phases are made into an emulsion by mechanical stirring or ultrasonic emulsification, and the solvent in the inner phase is diffused into the outer phase and then volatilized and removed, thereby depositing a spherical material and finally solidifying to form microspheres.
  • the method is simple in operation, and the prepared microspheres have high sphericity, round spherical shape and smooth surface. It is the most commonly used method for preparing PLA and PLGA microspheres, and is suitable for preparing small batches of microspheres. This method can be divided into a variety of systems depending on the solvent system.
  • O/W (oil-in-water) and O/O (oil-in-oil) methods are suitable for embedding water-insoluble drugs
  • W/O/W water-in-oil-in-water
  • W/O/W water-in-oil-in-water
  • W/O/W water-in-oil-in-water
  • the phase separation method is to first disperse the drug as a solid or emulsion in a solution of PLA as a coacervate, and then add a coagulant to the solution to reduce the solubility of the PLA, precipitate and deposit on the surface of the agglomerated core, and generate a new phase ( Condensed phase), the deposition, dissolution, and deposition processes are continuously carried out under stirring to form good spherical particles.
  • the main problem of the phase separation method is that a large amount of organic solvent is required as a coagulant, but these solvents are ultimately difficult to remove from the microsphere product, thereby causing problems such as toxicity, environmental pollution, residual organic solvents, and phase separation methods. Not suitable for the preparation of microspheres of smaller particle size.
  • the spray drying method is to dissolve the polymer in a solvent having a low boiling point, and the drug is preliminarily loaded into the polymer solution by dissolving or dispersing with small particles, and then the solution is sprayed with an atomizer while being dried with upward flowing nitrogen.
  • a method of preparing drug-loaded microspheres is prepared.
  • the method is convenient and rapid to operate, has few processing parameters, is suitable for preparation of various drugs, proteins and polypeptide microspheres, and simplifies the sterilization process, and is most suitable for the industry of microspheres. Production.
  • the fluid whose temperature and pressure are above the critical point is a supercritical fluid.
  • the fluid density in this state is close to that of the liquid and the viscosity is close to that of the gas, so that it has good dissolution and diffusion properties.
  • a supercritical fluid is generally used as an anti-solvent, and a polymer having poor solubility in a supercritical fluid is precipitated from an organic solvent or a solution from a solution by utilizing a property of mutual solubility of a supercritical fluid and an organic solvent. An organic solvent is extracted from the droplets to obtain target particles.
  • the method is widely used in preparing a drug carrier, and can not only refine a poorly soluble drug into nanoparticles, but also embedding the drug in a polymer material to prepare a drug carrier having a core-shell structure and capable of realizing controlled release of the drug. Microspheres. Compared with the traditional method, it has the advantages of low solvent residue, mild conditions and short cycle.
  • Membrane emulsification technology is to use the inorganic membrane micropores to press the dispersed phase into the continuous phase under the action of external pressure to form an emulsion.
  • the monodispersity of the emulsion droplets is achieved to prepare the uniform particle size.
  • the method of the ball Compared with traditional emulsification methods such as mechanical stirring and phacoemulsification, it has the advantages of good particle size uniformity and easy scale production.
  • the preparation of PLA microspheres by SPG membrane emulsification technology can obtain a narrow particle size distribution. However, the size of the microspheres prepared by this method is generally less than 100 ⁇ m.
  • the SPG membrane emulsification method is also not suitable for preparing microspheres of higher hydrophilic monomers, such as methyl methacrylate, ethyl methacrylate, etc., because the SPG membrane is composed of hydrophilic Al2O3-SiO2, capsule.
  • the walls are extremely wetted by hydrophilic monomers resulting in droplet formation of inconsistent sizes.
  • Microfluidic technology is an emerging technology developed in recent years. It can manipulate tiny droplets on microfluidic chips, and has gradually developed microchannel droplet technology based on microfluidic technology. Similar to the droplets produced in the traditional emulsification process, the microfluidic droplets are also divided into O/W, W/O, W/O/W and O/W/O types, but the preparation methods of the two are completely different. .
  • the microfluidic chip two kinds of immiscible liquids are used to generate droplets, one of which is used as the continuous phase, and the other liquid is used as the dispersed phase. With the channel structure and external force of the chip, the continuous phase will be dispersed.
  • the phase is sheared into a uniform micro-volume unit dispersed in the continuous phase, ie, droplets are formed.
  • the two-phase flow rate can be precisely controlled on the microfluidic chip to ensure uniform droplet size, uniform composition and stable properties.
  • the flow rate of the two-phase fluid is changed on the microfluidic chip, that is, the surface tension and shear force of the water/oil two-phase are changed, and the size of the generated droplets will be changed, so that the size can be prepared by using the microfluidic chip. Different droplets.
  • the commonly used microfluidic chip channel types for generating droplets include T-channel, fluid focusing channel, concentric capillary channel, double T-channel, etc., which can successfully prepare O/W, W/O, W/O/W and O. /W/O type droplets. Its application in the preparation of monodisperse microspheres has emerged, and the method has a flow field distribution. Uniform, mild operating conditions, easy control, uniform particle size, and controllable size. The disadvantage is that the microchannel is easy to block when preparing the microspheres.
  • Electrostatic droplet method for preparing microspheres is to apply a high voltage electrostatic field between the orifice and the receiving liquid, and the electrostatic force generated by stretching the polymer solution to make it discontinuous into a filament
  • the droplets are dripped into the receiving liquid against the surface tension of the surface and solidified into a ball, which is characterized by simplicity, high efficiency, and mild conditions.
  • the embolic preparation containing the polylactic acid microsphere can simultaneously achieve the effect of hemostasis and local treatment.
  • the special microsphere structure makes the pressure on the blood vessel less pressure, which is favorable for coagulation.
  • the slow release of the drug does not cause secondary damage to the damaged blood vessel.
  • the degradation cycle of polylactic acid microspheres about 3-8 weeks
  • the degradation after the end of vascular repair can re-open the diseased blood vessels in time to achieve good vascular protection. Reduce blood vessel necrosis.
  • polylactic acid and its derivatives as biodegradable biomaterials have a long history of application in medical engineering and pharmaceuticals, mature preparation processes, reliable experimental basis and good clinical application prospects.
  • a polylactic acid microsphere suppository containing a chemotherapeutic component drug was prepared by an emulsification-solvent evaporation method.
  • a series of sieves with different meshes are stacked from top to bottom according to the number of meshes, and the prepared microsphere suspension is poured into the first sieve and continuously rinsed with distilled water until each No microspheres are screened in the sieve.
  • microspheres of the microspheres were observed under electron microscope (100 ⁇ ), and it was found that the roundness of the 100-200 ⁇ m PLGA microspheres was excellent (Fig. 1B).
  • the microspheres were prepared in a large amount by selecting a formulation and a process having a PLGA concentration of 200-320 mg/ml and a stirring speed of 300 rpm, 500 rpm, 700 rpm, and 900 rpm.
  • the prepared microspheres are collected and sieved together, and the formula is appropriately changed according to the amount of microspheres in each particle size range after sieving.
  • sieving it was found that when the stirring rate was 500 rpm, 700 rpm, and 900 rpm, the particle diameter of the microspheres was mostly 700 ⁇ m or less, and a certain amount of large-sized microspheres was prepared at a stirring rate of 300 rpm.
  • the microsphere sieve is divided into six particle size ranges, which are 0.1-0.22 mm, 0.22-0.34 mm, 0.34-0.5 mm, 0.5-0.68 mm, 0.68-0.8 mm, and 0.8-1 mm, respectively. .
  • the amount of microspheres in the middle four particle size ranges is relatively large, and the number of microspheres in the range of 0.8-1 mm is the least.
  • PLGA concentration, emulsion agitation rate, stir bar size and volatilization stirring rate have an effect on particle size and particle size distribution, that is, the higher the PLGA concentration, the better the roundness of the microspheres;
  • the larger stirring rod can fully stir the emulsion, and the smaller one is not stirred. It is sufficient but can produce a larger particle size; the faster the volatilization rate, the higher the retention of the microsphere morphology.
  • PLGA plug microspheres with narrower particle size and smaller relative standard deviation distribution can be prepared using multi-stage or precision screening equipment.
  • a polylactic acid microsphere suppository containing a procoagulant active ingredient was prepared by an emulsification-solvent evaporation method.
  • a procoagulant drug having a concentration of 0.5 g/mL was dissolved in DMSO.
  • the obtained drug-absorbance standard curve is calculated according to the standard curve formula to calculate the drug loading, the drug loading rate, the drug loading rate and the encapsulation efficiency.
  • the drug encapsulation rate and drug loading in the microspheres can be calculated according to the following formula:
  • Drug encapsulation rate drug quality / dosage in microspheres ⁇ 100%
  • Drug loading mass of drug in microspheres / mass of microspheres weighed ⁇ 100%
  • Figure 3A shows an optical micrograph (20x) of a 100-200 ⁇ m PLGA drug-loaded embolic microsphere.
  • the surface of the microspheres was subjected to gold plating treatment, and subjected to scanning electron microscope observation, and the results are shown in Fig. 3B. Under the scanning electron microscope, the surface morphology of the microspheres is more clear. It can be seen that, due to the addition of DMSO to the system, the roundness of the drug-loaded microspheres is still acceptable, and there are microspheres with better spherical shape.
  • the drug-loaded microspheres like the blank microspheres, have some dents on the surface, which are caused by the volatilization of methylene chloride, and also play a very important role in sustained-release drugs.
  • liver hemorrhage model establishment of animal model of liver injury: 20 healthy New Zealand white rabbits, exposed to the liver after anesthesia, and cut with a scalpel along the ruler at the center of the left lobe of the rabbit liver (avoid the right Leaf gallbladder area) A slit of 20 mm in length and 5 mm in depth was prepared.
  • the treatment group was injected with a catheter at the upstream of the incision to prepare a polylactic acid microsphere containing no procoagulant component having a particle diameter of 50-200 ⁇ m (in which 85% of the particle diameter was in the range of 70 ⁇ m-100 ⁇ m) prepared in Example 2 (non-drug-loaded) Group), and the polylactic acid microsphere suppository (loading group) containing the procoagulant active ingredient in Example 3 as a positive control, and the empty microsphere plus the procoagulant active ingredient suppository as a blank control (control group) until the injection agent is covered incision.
  • Bleeding visual score The hemostasis effect is scored immediately after the completion of the treatment experiment, according to the following grades
  • the hepatic lobe incision in both groups showed obvious bleeding before treatment.
  • the initial bleeding rate was 0.10 ⁇ 0.08ml/s-0.12 ⁇ 0.04ml/s, and there was no significant difference between the two groups (p>0.05).
  • the incision had obvious oozing and hemorrhage after treatment.
  • the visual scores were distributed in grades 2 to 4, while the incision hemorrhage in the drug-loaded group and the non-loaded group basically stopped. No visual acuity was observed for several minutes, and the visual score was distributed in grade 0–1, which was significantly lower than the blank control group (p ⁇ 0.01).
  • the amount of bleeding for 10 minutes including 2 minutes of treatment was (1.83 ⁇ 1.43) ml in the drug-loaded and non-loaded groups, which was also significantly lower than that in the control group (11.02 ⁇ 3.56) ml, which was consistent with the visual score.
  • the amount of bleeding in the drug-loaded group was less than that in the non-drug-loaded group, but there was no significant difference between the two groups.
  • This example demonstrates the safety and efficacy of polylactic acid microspheres for hemostasis in hemorrhagic diseases. Significantly rapid hemostasis can be produced. The efficacy of the treatment was confirmed by hemostatic visual score and 10 min of blood loss. The results showed that no visible bleeding was observed after treatment with the microspheres with or without procoagulant components, and the amount of bleeding at 10 min was much lower than that of the blank control group.

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Abstract

Provided is a use of polylactic acid microsphere for hemorrhagic diseases and a use of polylactic acid microsphere in preparing a composition for treating hemorrhagic diseases. Polylactic acid microsphere is used directly as a hemostatic blocking suppository, and can also serve as a carrier to carry medicine for local vascular repair for local treatment.

Description

聚乳酸微球在出血性疾病中的应用Application of polylactic acid microspheres in hemorrhagic diseases 技术领域Technical field
本发明属于化工医药领域，具体地，涉及聚乳酸微球在出血性疾病中的应用。The invention belongs to the field of chemical medicine, and in particular relates to the application of polylactic acid microspheres in hemorrhagic diseases.
背景技术Background technique
经导管动脉栓塞术(trancatheter arterial embolization,TAE)，是经动脉内导管将栓塞剂有控制地输注到脏器供血动脉内，使之发生闭塞，从而改变靶器官血液动力学状态，减少出血动脉数量，达到靶组织和靶器官减少或停止出血医疗技术。栓塞的目的是阻断减少对靶区的血供，从而减少或停止靶组织和靶器官的出血状态。Transcatheter arterial embolization (TAE) is a controlled infusion of an embolic agent into the blood supply artery through an intra-arterial catheter to cause occlusion, thereby changing the hemodynamic state of the target organ and reducing the bleeding artery. Quantity, reaching target tissues and target organs to reduce or stop bleeding medical technology. The purpose of embolization is to block the reduction of blood supply to the target area, thereby reducing or stopping the bleeding state of the target tissue and the target organ.
然而，不同部位对于栓塞治疗的时间长短要求不同，因此，本领域迫切需要开发一种同时具有栓塞作用和治疗作用的栓塞制剂。However, different sites require different lengths of embolization treatment, and therefore, there is an urgent need in the art to develop an embolic preparation having both embolization and therapeutic effects.
发明内容Summary of the invention
本发明提供了一种聚乳酸微球在治疗出血性疾病中的新用途。The present invention provides a new use of polylactic acid microspheres in the treatment of bleeding disorders.
本发明第一方面，提供了一种聚乳酸微球的用途，用于制备治疗出血性疾病的药物组合物。In a first aspect of the invention, there is provided the use of a polylactic acid microsphere for the preparation of a pharmaceutical composition for treating a bleeding disorder.
在另一优选例中，所述的出血性疾病包括可通过栓塞治疗的出血性疾病。In another preferred embodiment, the bleeding disorder includes a bleeding disorder treatable by embolization.
在另一优选例中，所述的出血性疾病包括急性或慢性的非弥漫性出血性疾病。In another preferred embodiment, the hemorrhagic disease comprises an acute or chronic non-diffuse hemorrhagic disease.
在另一优选例中，所述的出血性疾病包括消化道出血、肝脏出血、产后出血、颅内出血。In another preferred embodiment, the hemorrhagic disease includes gastrointestinal bleeding, hepatic hemorrhage, postpartum hemorrhage, and intracranial hemorrhage.
在另一优选例中，所述的出血性疾病包括急性消化道出血、急性肝脏出血。In another preferred embodiment, the hemorrhagic disease includes acute gastrointestinal bleeding, acute liver bleeding.
在另一优选例中，所述的药物组合物包括聚乳酸微球，和药学上可接受的载体。In another preferred embodiment, the pharmaceutical composition comprises polylactic acid microspheres, and a pharmaceutically acceptable carrier.
在另一优选例中，所述的药物组合物还含有促凝血药。In another preferred embodiment, the pharmaceutical composition further comprises a procoagulant.
在另一优选例中，所述的聚乳酸微球包括聚乳酸微球的均聚物、和/或共聚物。In another preferred embodiment, the polylactic acid microspheres comprise homopolymers, and/or copolymers of polylactic acid microspheres.
在另一优选例中，所述的共聚物是由聚乳酸微球和三丙烯、乙醇酸构成的共聚物。In another preferred embodiment, the copolymer is a copolymer composed of polylactic acid microspheres and tripropylene and glycolic acid.
在另一优选例中，所述的微球粒径为10-200μm，较佳地为30-150μm，更佳地，为50-80μm。In another preferred embodiment, the microspheres have a particle diameter of 10 to 200 μm, preferably 30 to 150 μm, more preferably 50 to 80 μm.
在另一优选例中，所述的聚乳酸微球的粒径为50-200μm，较佳地，为70-150 μm，更佳地，为80-100μm。In another preferred embodiment, the polylactic acid microspheres have a particle diameter of 50 to 200 μm, preferably 70 to 150. Μm, more preferably, 80-100 μm.
在另一优选例中，所述的药物组合物包括注射剂、粉剂、乳剂、微丸剂、冻干剂、栓剂。In another preferred embodiment, the pharmaceutical composition comprises an injection, a powder, an emulsion, a pellet, a lyophilizate, a suppository.
在另一优选例中，所述的药物组合物为栓剂。In another preferred embodiment, the pharmaceutical composition is a suppository.
在另一优选例中，所述的聚乳酸微球的浓度为1-99wt％。In another preferred embodiment, the concentration of the polylactic acid microspheres is from 1 to 99% by weight.
在另一优选例中，所述的聚乳酸微球的制备方法包括：乳化-溶剂挥发法、相分离法、喷雾干燥法、超临界流体法、膜乳化法、微通道乳化法、静电液滴法。In another preferred embodiment, the preparation method of the polylactic acid microspheres comprises: emulsification-solvent evaporation method, phase separation method, spray drying method, supercritical fluid method, membrane emulsification method, microchannel emulsification method, electrostatic droplet law.
本发明第二方面，提供了一种治疗出血性疾病的栓剂，所述的栓塞制剂包括聚乳酸微球，和药学上可接受的载体。In a second aspect of the invention, there is provided a suppository for treating a bleeding disorder, the embolic preparation comprising polylactic acid microspheres, and a pharmaceutically acceptable carrier.
在另一优选例中，所述的栓剂还包括聚乳酸-三丙烯共聚物、聚乳酸-聚乙醇酸的共聚物、海藻酸钠或其组合。In another preferred embodiment, the suppository further comprises a polylactic acid-tripropylene copolymer, a polylactic acid-polyglycolic acid copolymer, sodium alginate or a combination thereof.
本发明第三方面，提供了一种治疗出血性疾病的方法，对所需要的对象施用聚乳酸微球或本发明第二方面所述的栓剂。In a third aspect of the invention, there is provided a method of treating a bleeding disorder, the polylactic acid microspheres or the suppository of the second aspect of the invention being administered to a subject in need thereof.
在另一优选例中，所述所需要的对象为患有出血性疾病的哺乳动物，例如人、鼠、兔。In another preferred embodiment, the desired subject is a mammal having a bleeding disorder, such as a human, a mouse, or a rabbit.
在另一优选例中，所述的施用包括将所述的聚乳酸微球注射入出血部位(或出血点)上游的主动脉(或次主动脉)中。In another preferred embodiment, the administering comprises injecting the polylactic acid microspheres into the aorta (or secondary aorta) upstream of the bleeding site (or bleeding site).
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
附图说明DRAWINGS
图1A显示了直视下观察的冻干前的PLGA；图1B显示了电镜下(100×)观察微球微球形貌。Figure 1A shows the PLGA before lyophilization observed under direct view; Figure 1B shows the microsphere morphology of the microspheres observed under electron microscope (100 x).
图2a显示了在相同PLGA溶液浓度下，搅拌速率较小时，乳液搅拌不充分，微球的粒径分布较宽；图2b-c显示了而当乳液搅拌充分时，粒径的分布相对较窄，此时若再加大搅拌速率对产生微球的平均粒径和分布影响不大。Figure 2a shows that at the same PLGA solution concentration, when the stirring rate is small, the emulsion is not sufficiently stirred, and the particle size distribution of the microspheres is wide; Figure 2b-c shows that when the emulsion is sufficiently stirred, the particle size distribution is relatively narrow. At this time, if the stirring rate is increased, the average particle size and distribution of the microspheres are not greatly affected.
图3A显示了直径100-200μm PLGA载药栓塞微球的光学显微镜照片(20×)。图3B显示了将微球表面镀金处理后的电镜观察。Figure 3A shows an optical micrograph (20x) of a 100-200 [mu]m PLGA drug-loaded plug microsphere. Figure 3B shows an electron microscopic observation of the surface of the microspheres after gold plating.
具体实施方式 detailed description
本发明人经过了广泛而深入的研究，首次意外地发现，将常用的聚乳酸或其与其他可降解载体形成的微球可直接用于出血性疾病的栓塞治疗。本发明人利用了聚乳酸微球在人体内缓慢降解的特性，采用其作为临时栓塞制剂，使其能够达到快速的止血目的，并有利于后期血管的再通，此外，聚乳酸微球还可基于其药物缓释载体的特性，将治疗药物(如凝血剂或促进血管修复的)的活性成分带至靶部位，从而达到止血、局部治疗的双重效果。在此基础上，完成了本发明。The present inventors have conducted extensive and intensive research, and for the first time, unexpectedly discovered that the commonly used polylactic acid or microspheres formed thereof with other degradable carriers can be directly used for embolization treatment of hemorrhagic diseases. The present inventors utilize the characteristics of slow degradation of polylactic acid microspheres in the human body, and use them as temporary embolic preparations, so that they can achieve rapid hemostasis purposes and facilitate recanalization of late blood vessels. In addition, polylactic acid microspheres can also be used. Based on the characteristics of the drug sustained-release carrier, the active ingredient of a therapeutic drug (such as a blood coagulation agent or a vascular repair-promoting agent) is brought to the target site, thereby achieving the dual effects of hemostasis and local treatment. On the basis of this, the present invention has been completed.
栓塞制剂Embolization preparation
如本文所用，术语“栓塞制剂”、“栓剂”可互换使用，均指含有本发明聚乳酸微球的、用于治疗出血性疾病的栓塞制剂。As used herein, the terms "embolic formulation", "suppository" are used interchangeably and refer to an embolic preparation for treating a bleeding disorder comprising the polylactic acid microspheres of the present invention.
出血性疾病Hemorrhagic disease
如本文所用，术语“出血性疾病”包括各种急性、慢性的由于外伤或病变引起的非弥漫性出血性疾病，且通常所述的出血性疾病可以通过栓塞进行止血治疗。优选地，所述的出血性疾病包括消化道的出血，如食管静脉曲张破裂出血；颅内出血，如动脉瘤破裂出血；产后出血，如胎盘滞留引起的子宫动脉出血等；肝脏出血；肿瘤内出血，如肿瘤破裂出血等。As used herein, the term "hemorrhagic disease" includes various acute, chronic non-diffuse hemorrhagic diseases due to trauma or pathology, and generally the hemorrhagic disease described can be hemostasis treated by embolization. Preferably, the hemorrhagic diseases include hemorrhage of the digestive tract, such as esophageal variceal bleeding; intracranial hemorrhage, such as aneurysm rupture; postpartum hemorrhage, such as uterine artery hemorrhage caused by placental retention; liver hemorrhage; intratumoral hemorrhage, Such as tumor rupture and so on.
在另一优选例中，所述的出血性疾病包括急性消化道出血、急性肝脏出血。In another preferred embodiment, the hemorrhagic disease includes acute gastrointestinal bleeding, acute liver bleeding.
聚乳酸及聚乳酸微球Polylactic acid and polylactic acid microspheres
聚乳酸是一种用途最广的生物可降解合成高分子材料。具有有无毒性、可控制生物降解、原料易得、生物相容性较好等优点，它在生物体内经过酶分解，最终形成二氧化碳和水，不会在重要器官内聚集，其降解速率与聚合物的分子量密切相关。Polylactic acid is one of the most versatile biodegradable synthetic polymer materials. It has the advantages of toxicity, biodegradability, easy availability of raw materials, good biocompatibility, etc. It is enzymatically decomposed in the living body, eventually forming carbon dioxide and water, and does not accumulate in important organs. Its degradation rate and polymerization The molecular weight of the substance is closely related.
如本文所用，术语“聚乳酸微球”包括聚乳酸微球以及聚乳酸微球与其他载体的共聚物。其中，所述的其他载体可包括本领域常用的可降解载体。优选地，所述的共聚物(但不限于)包括聚乳酸-三丙烯共聚物，聚乳酸-聚乙醇酸共聚物(PLGA)，或其组合。所述的共聚物中，聚乳酸与其他载体的比例可根据成品制剂的水溶性或脂溶性要求进行调配或制备。As used herein, the term "polylactic acid microspheres" includes polylactic acid microspheres and copolymers of polylactic acid microspheres with other carriers. Wherein, the other carriers may include degradable carriers commonly used in the art. Preferably, the copolymer, but not limited to, comprises a polylactic acid-tripropylene copolymer, a polylactic acid-polyglycolic acid copolymer (PLGA), or a combination thereof. In the copolymer, the ratio of polylactic acid to other carriers can be formulated or prepared according to the water solubility or fat solubility requirements of the finished preparation.
因此，本发明利用聚乳酸微球在体内的缓释效应，制备为新的治疗出血性疾病的栓塞制剂，即可采用仅含有聚乳酸微球的栓塞制剂作为临时止血栓剂，也可采用聚乳酸微球包裹其他促凝血药作为活性成分的载体，在栓塞出血血管的同时使 药物在目标血管处缓慢释放。Therefore, the present invention utilizes the sustained release effect of polylactic acid microspheres in vivo to prepare a new embolic preparation for treating hemorrhagic diseases, that is, an embolic preparation containing only polylactic acid microspheres can be used as a temporary thrombus inhibitor, and polylactic acid can also be used. The microspheres encapsulate other procoagulant drugs as carriers of the active ingredient, while embolizing the bleeding vessels The drug is slowly released at the target vessel.
采用本发明聚乳酸微球的栓塞制剂能够有效地堵塞出血血管从而起到立即止血，也能够在局部释放促凝药或血管内皮修复的药物，并有利于长期的血管再通。The embolic preparation using the polylactic acid microsphere of the present invention can effectively block the bleeding blood vessel to immediately stop bleeding, and can also locally release the procoagulant or the endothelium repairing drug, and is beneficial for long-term blood vessel recanalization.
制备方法Preparation
可用于本发明聚乳酸微球的制备方法没有特殊限制，常用的有乳化-溶剂挥发法、相分离法和喷雾干燥法三种，目前已知的有以下七种：The preparation method of the polylactic acid microspheres which can be used in the present invention is not particularly limited, and there are three kinds of emulsification-solvent evaporation method, phase separation method and spray drying method, and the following seven kinds are known:
乳化-溶剂挥发法Emulsification-solvent evaporation
溶剂挥发法是将不相混溶的两相通过机械搅拌或超声乳化制成乳液，内相里的溶剂扩散进入外相然后挥发除去，从而析出成球材料，最后固化形成微球的方法。该方法操作简单，所制微球成球率高、球形圆整、表面光滑，是目前制备PLA、PLGA微球最常用的方法，比较适合制备小批量的微球。该法是根据溶剂***的不同，可分为多种体系。其中，O/W(水包油)和O/O(油包油)法适用于包埋水不溶性药物，W/O(油包水)、W/O/O(油包油包水)和W/O/W(水包油包水)3种方法都适用于包埋水溶性药物，而W/O/O法可获得很高的包封率，W/O/W可用于包埋在有机溶剂中易被破坏的物质(如蛋白和多肽类)。此外，随着药物微粉化技术的普及，目前已发展出使用S/O/O(油包油包固)和S/O/W(水包油包固)两种新方法。前者能避免油水界面和超声乳化，较好地保留药物活性；后者不仅有S/O/O法的优点，还能避免复乳法制备的微球累积释放不完全的缺点，而且收集洗涤操作简单，分散相容易洗净，适合大规模制备多肽、蛋白类微球。The solvent evaporation method is a method in which the immiscible two phases are made into an emulsion by mechanical stirring or ultrasonic emulsification, and the solvent in the inner phase is diffused into the outer phase and then volatilized and removed, thereby depositing a spherical material and finally solidifying to form microspheres. The method is simple in operation, and the prepared microspheres have high sphericity, round spherical shape and smooth surface. It is the most commonly used method for preparing PLA and PLGA microspheres, and is suitable for preparing small batches of microspheres. This method can be divided into a variety of systems depending on the solvent system. Among them, O/W (oil-in-water) and O/O (oil-in-oil) methods are suitable for embedding water-insoluble drugs, W/O (water-in-oil), W/O/O (oil-in-oil-in-water) and W/O/W (water-in-oil-in-water) is suitable for embedding water-soluble drugs, while W/O/O method can achieve high encapsulation efficiency, W/O/W can be used for embedding Substances that are easily destroyed in organic solvents (such as proteins and peptides). In addition, with the popularization of micronization technology for drugs, two new methods of using S/O/O (oil-in-oil encapsulation) and S/O/W (water-in-oil encapsulation) have been developed. The former can avoid the oil-water interface and phacoemulsification, and better retain the drug activity; the latter not only has the advantages of the S/O/O method, but also avoids the disadvantage of incomplete accumulation and release of the microspheres prepared by the double emulsion method, and collects the washing operation. Simple, the dispersed phase is easy to wash, suitable for large-scale preparation of peptides, protein microspheres.
相分离法Phase separation
相分离法是先将药物以固体或乳滴形式分散于PLA的溶液中为凝聚核，再向该溶液中滴加凝聚剂，使PLA溶解度降低而析出、沉积于凝聚核表面，产生新相(凝聚相)，搅拌下使沉积→溶解→沉积过程不断进行，从而形成良好的球形微粒。相分离法主要存在的问题是需要使用大量的有机溶剂作为凝聚剂，但这些溶剂最终较难从微球产品中移除，从而带来毒性、环境污染、有机溶剂残留等问题，且相分离方法不适合制备较小粒径的微球。The phase separation method is to first disperse the drug as a solid or emulsion in a solution of PLA as a coacervate, and then add a coagulant to the solution to reduce the solubility of the PLA, precipitate and deposit on the surface of the agglomerated core, and generate a new phase ( Condensed phase), the deposition, dissolution, and deposition processes are continuously carried out under stirring to form good spherical particles. The main problem of the phase separation method is that a large amount of organic solvent is required as a coagulant, but these solvents are ultimately difficult to remove from the microsphere product, thereby causing problems such as toxicity, environmental pollution, residual organic solvents, and phase separation methods. Not suitable for the preparation of microspheres of smaller particle size.
喷雾干燥法Spray drying
喷雾干燥法是将聚合物溶解在低沸点的溶剂中，药物通过溶解或以小颗粒分散的方法预先载入聚合物溶液中，然后将溶液用雾化器喷雾，同时用向上流动的氮气干燥，从而制备载药微球的方法。该方法操作方便快速，加工参数少，适用于各种药物、蛋白、多肽类微球的制备，并且简化了灭菌工艺，最适合微球的工业 化生产。The spray drying method is to dissolve the polymer in a solvent having a low boiling point, and the drug is preliminarily loaded into the polymer solution by dissolving or dispersing with small particles, and then the solution is sprayed with an atomizer while being dried with upward flowing nitrogen. Thus, a method of preparing drug-loaded microspheres is prepared. The method is convenient and rapid to operate, has few processing parameters, is suitable for preparation of various drugs, proteins and polypeptide microspheres, and simplifies the sterilization process, and is most suitable for the industry of microspheres. Production.
超临界流体法Supercritical fluid method
温度和压力处于临界点之上的流体即为超临界流体，此状态下的流体密度接近于液体而黏度接近于气体，因而具有较好的溶解和扩散性能。在制备载药微球的过程中，通常将超临界流体作为抗溶剂，利用超临界流体与有机溶剂互溶性好的特性，使难溶于超临界流体的聚合物从有机溶剂析出，或从溶液液滴中萃取出有机溶剂，从而得到目标微粒。该法在制备药物载体方面应用较为广泛，既可将难溶性药物微细化成纳米粒子，又可将药物包埋于高分子材料中，制成具有核壳结构且能实现药物缓控释的载药微球。与传统的方法相比，具有溶剂残留量低、条件温和、周期短等优势。The fluid whose temperature and pressure are above the critical point is a supercritical fluid. The fluid density in this state is close to that of the liquid and the viscosity is close to that of the gas, so that it has good dissolution and diffusion properties. In the process of preparing drug-loaded microspheres, a supercritical fluid is generally used as an anti-solvent, and a polymer having poor solubility in a supercritical fluid is precipitated from an organic solvent or a solution from a solution by utilizing a property of mutual solubility of a supercritical fluid and an organic solvent. An organic solvent is extracted from the droplets to obtain target particles. The method is widely used in preparing a drug carrier, and can not only refine a poorly soluble drug into nanoparticles, but also embedding the drug in a polymer material to prepare a drug carrier having a core-shell structure and capable of realizing controlled release of the drug. Microspheres. Compared with the traditional method, it has the advantages of low solvent residue, mild conditions and short cycle.
膜乳化法Membrane emulsification
膜乳化技术是通过无机膜微孔将分散相在外加压力的作用下，压入连续相中形成乳状液，通过控制分散压力和膜孔径，实现乳状液滴的单分散性以制备粒径均一微球的方法。与机械搅拌、超声乳化等传统乳化方法相比，具有微球粒径均一性好和易于规模化生产等优势。用SPG膜乳化技术制备PLA微球能获得较窄的粒径分布。但受膜微孔粒径大小的限制，使用该方法制备的微球粒径一般小于100μm。另外，用SPG膜乳化法也不适于制备更高亲水性单体的微球，比如甲基丙烯酸甲酯、甲基丙烯酸乙酯等，因为SPG膜是由亲水的Al2O3-SiO2组成，囊壁极易被亲水性单体浸湿而导致大小不一致的液滴形成。Membrane emulsification technology is to use the inorganic membrane micropores to press the dispersed phase into the continuous phase under the action of external pressure to form an emulsion. By controlling the dispersion pressure and the membrane pore size, the monodispersity of the emulsion droplets is achieved to prepare the uniform particle size. The method of the ball. Compared with traditional emulsification methods such as mechanical stirring and phacoemulsification, it has the advantages of good particle size uniformity and easy scale production. The preparation of PLA microspheres by SPG membrane emulsification technology can obtain a narrow particle size distribution. However, the size of the microspheres prepared by this method is generally less than 100 μm. In addition, the SPG membrane emulsification method is also not suitable for preparing microspheres of higher hydrophilic monomers, such as methyl methacrylate, ethyl methacrylate, etc., because the SPG membrane is composed of hydrophilic Al2O3-SiO2, capsule. The walls are extremely wetted by hydrophilic monomers resulting in droplet formation of inconsistent sizes.
微通道乳化法Microchannel emulsification
微流控技术是近年来发展起来的一门新兴技术，在微流控芯片上可操纵形成微小体积的液滴，因而逐渐发展出了基于微流控技术的微通道液滴技术。与传统的乳化过程中产生的液滴相似，微流控上液滴也分为O/W、W/O、W/O/W和O/W/O型，但是二者的制备方法截然不同。在微流控芯片中利用两种不互溶的液体产生液滴，是以其中一种液体作为连续相，以另外一种液体作为分散相，借助芯片的通道结构和外力操控，连续相会将分散相剪切成均匀的微小体积单元分散于连续相中，即形成液滴。微流控芯片上可精确控制两相流速，确保制备的液滴大小均一、组成均匀、性质稳定。另外，微流控芯片上改变两相流体的流速，即改变了水/油两相表面张力和剪切力的大小，生成液滴的大小将会改变，因此利用微流控芯片还可制备大小不同的液滴。目前常用的生成液滴的微流控芯片通道类型有T型通道、流体聚焦通道、同心毛细管通道、双T型通道等，可成功制备O/W、W/O、W/O/W和O/W/O型液滴。其在制备单分散微球中的应用已崭露头角，该法具有流场分布 均匀、操作条件温和、容易控制、制备微球粒径均一、大小可控等优点。缺点是制备微球时微流道易堵塞。Microfluidic technology is an emerging technology developed in recent years. It can manipulate tiny droplets on microfluidic chips, and has gradually developed microchannel droplet technology based on microfluidic technology. Similar to the droplets produced in the traditional emulsification process, the microfluidic droplets are also divided into O/W, W/O, W/O/W and O/W/O types, but the preparation methods of the two are completely different. . In the microfluidic chip, two kinds of immiscible liquids are used to generate droplets, one of which is used as the continuous phase, and the other liquid is used as the dispersed phase. With the channel structure and external force of the chip, the continuous phase will be dispersed. The phase is sheared into a uniform micro-volume unit dispersed in the continuous phase, ie, droplets are formed. The two-phase flow rate can be precisely controlled on the microfluidic chip to ensure uniform droplet size, uniform composition and stable properties. In addition, the flow rate of the two-phase fluid is changed on the microfluidic chip, that is, the surface tension and shear force of the water/oil two-phase are changed, and the size of the generated droplets will be changed, so that the size can be prepared by using the microfluidic chip. Different droplets. At present, the commonly used microfluidic chip channel types for generating droplets include T-channel, fluid focusing channel, concentric capillary channel, double T-channel, etc., which can successfully prepare O/W, W/O, W/O/W and O. /W/O type droplets. Its application in the preparation of monodisperse microspheres has emerged, and the method has a flow field distribution. Uniform, mild operating conditions, easy control, uniform particle size, and controllable size. The disadvantage is that the microchannel is easy to block when preparing the microspheres.
静电液滴法Electrostatic droplet method
静电液滴法制备微球技术，与静电纺丝技术类似，是在锐孔和接收液之间施加高压静电场，产生的静电作用力拉伸聚合物溶液，使之不连续成丝而成一个个液滴，克服自身表面张力滴入接收液，固化成球，具有简便高效、条件温和等特点。Electrostatic droplet method for preparing microspheres, similar to electrospinning technology, is to apply a high voltage electrostatic field between the orifice and the receiving liquid, and the electrostatic force generated by stretching the polymer solution to make it discontinuous into a filament The droplets are dripped into the receiving liquid against the surface tension of the surface and solidified into a ball, which is characterized by simplicity, high efficiency, and mild conditions.
本发明的有益效果Advantageous effects of the present invention
本发明含有聚乳酸微球的栓塞制剂可同时达到止血以及局部治疗的效果，较现有技术中的出血性疾病栓塞剂来说，特殊的微球状结构使其对血管压迫压力小，利于促凝药物的缓慢释放，不会对破损血管造成二次损伤。更重要的是，由于聚乳酸微球的降解周期(约3-8周)，与血管修复周期吻合，在血管修复结束后的降解能够使病变血管及时再通，从而达到良好的血管保护效果并减少血管的坏死。此外，聚乳酸及其衍生物作为可降解生物材料在医学工程及制药方面有着较长的应用历史，成熟的制备工艺，可靠的实验基础及良好的临床应用前景。The embolic preparation containing the polylactic acid microsphere can simultaneously achieve the effect of hemostasis and local treatment. Compared with the hemorrhagic disease embolic agent in the prior art, the special microsphere structure makes the pressure on the blood vessel less pressure, which is favorable for coagulation. The slow release of the drug does not cause secondary damage to the damaged blood vessel. More importantly, due to the degradation cycle of polylactic acid microspheres (about 3-8 weeks), which coincides with the vascular repair cycle, the degradation after the end of vascular repair can re-open the diseased blood vessels in time to achieve good vascular protection. Reduce blood vessel necrosis. In addition, polylactic acid and its derivatives as biodegradable biomaterials have a long history of application in medical engineering and pharmaceuticals, mature preparation processes, reliable experimental basis and good clinical application prospects.
实施例1聚乳酸微球栓剂的制备Example 1 Preparation of polylactic acid microsphere suppository
采用乳化-溶剂挥发法制备了含有化疗剂成分药物的聚乳酸微球栓剂。A polylactic acid microsphere suppository containing a chemotherapeutic component drug was prepared by an emulsification-solvent evaporation method.
步骤：step:
(1)原料PLGA的核磁共振分析：将原料PLGA溶于氘代试剂，进行核磁共振检测已确定其共聚比，频率400MHz。(1) Nuclear magnetic resonance analysis of raw material PLGA: The raw material PLGA was dissolved in a deuterated reagent, and the copolymerization ratio was determined by nuclear magnetic resonance detection at a frequency of 400 MHz.
(2)称取PLGA固体溶于20ml二氯甲烷，配制成浓度为700mg/mL浓度的PLGA溶液)，让PLGA完全溶解。(2) The PLGA solid was weighed and dissolved in 20 ml of dichloromethane to prepare a PLGA solution having a concentration of 700 mg/mL, and the PLGA was completely dissolved.
(3)按1:1.5的比例加入浓度为1％(wt)的PVA溶液30ml。(3) 30 ml of a PVA solution having a concentration of 1% by weight was added in a ratio of 1:1.5.
(4)在270瓦的功率下超声乳化10分钟。(4) Ultrasonic emulsification for 10 minutes at a power of 270 watts.
(5)将乳化后的乳液导入100ml的0.3％(wt)PVA溶液中，机械搅拌3小时，待二氯甲烷完全挥发。(5) The emulsified emulsion was introduced into 100 ml of a 0.3% (wt) PVA solution, and mechanically stirred for 3 hours until the dichloromethane was completely evaporated.
(6)将目数不同的一系列筛子按目数小到大自上而下叠放，将已制好微球悬浊液倒入第一层筛子，并不断用蒸馏水淋洗，直至每一层筛子都不再有微球被筛查。(6) A series of sieves with different meshes are stacked from top to bottom according to the number of meshes, and the prepared microsphere suspension is poured into the first sieve and continuously rinsed with distilled water until each No microspheres are screened in the sieve.
(7)分别收集各个筛子中的PLGA微球，使用冻干法将微球干燥。(7) The PLGA microspheres in each sieve were separately collected, and the microspheres were dried using a freeze-drying method.
结果：直视下观察冻干前的PLGA，可见白色或乳白色微球，较小粒径的为粉 末状，较大者为光滑晶莹的珍珠状，挤压后可变瘪但不会碾碎(图1A)；RESULTS: The PLGA before lyophilization was observed under direct vision, and white or milky white microspheres were observed. The smaller particle size was powder. The final shape, the larger one is a smooth and crystal-like pearl shape, which can be changed after extrusion but will not be crushed (Fig. 1A);
电镜下(100×)观察微球微球形貌，可见100-200μm PLGA微球的圆整度非常优异(图1B)。The microspheres of the microspheres were observed under electron microscope (100×), and it was found that the roundness of the 100-200 μm PLGA microspheres was excellent (Fig. 1B).
实施例2不同因素对聚乳酸微球的影响Example 2 Effect of Different Factors on Polylactic Acid Microspheres
配制100-1000mg/mL浓度区间的PLGA溶液，结果发现，随着PLGA浓度升高，所产生的微球分布会变宽，而在相同PLGA溶液浓度下，搅拌速率较小时，乳液搅拌不充分，会出现粒径很大的微球，微球的粒径分布也会变宽，部分微球的粒径已经超过了激光粒度仪的最大检测粒径—2000μm，见图2a；而当乳液搅拌充分时，粒径的分布相对较窄，此时若再加大搅拌速率对产生微球的平均粒径和分布影响不大，见图2b-c。When the PLGA solution was prepared at a concentration range of 100-1000 mg/mL, it was found that the distribution of the generated microspheres became wider as the concentration of PLGA increased, and the emulsion agitation was insufficient when the stirring rate was small at the same PLGA solution concentration. Microspheres with large particle size will appear, and the particle size distribution of the microspheres will also be broadened. The particle size of some microspheres has exceeded the maximum particle size of the laser particle size analyzer - 2000 μm, as shown in Figure 2a; When the particle size distribution is relatively narrow, if the stirring rate is increased, the average particle size and distribution of the microspheres are not greatly affected, as shown in Fig. 2b-c.
经以上实验筛选，结果发现，选择PLGA浓度200-320mg/ml，搅拌速度为300rpm、500rpm、700rpm和900rpm的配方和工艺，大量制备微球。将制好的微球收集在一起筛分，再根据晒筛分后各个粒径区间微球的量适当更改配方。筛分时发现当搅拌速率在500rpm、700rpm和900rpm时，微球粒径大多在700μm以下，用300rpm的搅拌速率，会制备出一定量的大粒径微球。As a result of the above experiments, it was found that the microspheres were prepared in a large amount by selecting a formulation and a process having a PLGA concentration of 200-320 mg/ml and a stirring speed of 300 rpm, 500 rpm, 700 rpm, and 900 rpm. The prepared microspheres are collected and sieved together, and the formula is appropriately changed according to the amount of microspheres in each particle size range after sieving. When sieving, it was found that when the stirring rate was 500 rpm, 700 rpm, and 900 rpm, the particle diameter of the microspheres was mostly 700 μm or less, and a certain amount of large-sized microspheres was prepared at a stirring rate of 300 rpm.
为了制造粒径大多处于300μm以下的微球，优选使用700-900rpm的搅拌速度。In order to produce microspheres having a particle diameter of usually 300 μm or less, it is preferred to use a stirring speed of 700 to 900 rpm.
根据分样筛的目数大小，把微球筛分成六个粒径范围，分别为0.1-0.22mm、0.22-0.34mm、0.34-0.5mm、0.5-0.68mm、0.68-0.8mm、0.8-1mm。中间四个粒径范围微球量相对较多，0.8-1mm范围内的微球数量最少。According to the mesh size of the sample sieve, the microsphere sieve is divided into six particle size ranges, which are 0.1-0.22 mm, 0.22-0.34 mm, 0.34-0.5 mm, 0.5-0.68 mm, 0.68-0.8 mm, and 0.8-1 mm, respectively. . The amount of microspheres in the middle four particle size ranges is relatively large, and the number of microspheres in the range of 0.8-1 mm is the least.
结论：通过设计与研究乳化发现，PLGA浓度、乳剂搅拌速率、搅拌棒大小和挥发搅拌速率对于粒径和粒径分布的均有影响，即PLGA浓度越高，微球的圆整度越好；乳液搅拌速率早期越快乳液搅拌的越充分，粒径分布越均匀相对，标准差越窄越，相反则导致粒径大，分布不均匀；较大搅拌棒可充分搅拌乳液，较小者搅拌不充分但可产生较大微球粒径；挥发搅拌速率越快，微球形态的保持度越高。此外，采用多级或精密的筛分设备，可制备粒径更窄，相对标准差分布更小的PLGA栓塞微球。Conclusion: Through design and research emulsification, PLGA concentration, emulsion agitation rate, stir bar size and volatilization stirring rate have an effect on particle size and particle size distribution, that is, the higher the PLGA concentration, the better the roundness of the microspheres; The earlier the emulsion stirring rate, the more fully the emulsion is stirred, the more uniform the particle size distribution is, the narrower the standard deviation is, the larger the particle size is, and the uneven distribution is. The larger stirring rod can fully stir the emulsion, and the smaller one is not stirred. It is sufficient but can produce a larger particle size; the faster the volatilization rate, the higher the retention of the microsphere morphology. In addition, PLGA plug microspheres with narrower particle size and smaller relative standard deviation distribution can be prepared using multi-stage or precision screening equipment.
实施例3含药物的聚乳酸微球栓剂的制备Example 3 Preparation of Drug-Containing Polylactic Acid Microsphere Suppositories
采用乳化-溶剂挥发法制备了含有有促凝血活性成分药物的聚乳酸微球栓剂。A polylactic acid microsphere suppository containing a procoagulant active ingredient was prepared by an emulsification-solvent evaporation method.
步骤：step:
(1)将浓度为700mg/mL的PLGA溶于二氯甲烷。 (1) PLGA having a concentration of 700 mg/mL was dissolved in dichloromethane.
(2)将浓度为0.5g/mL的促凝血药物溶于DMSO。(2) A procoagulant drug having a concentration of 0.5 g/mL was dissolved in DMSO.
(3)将PLGA的二氯甲烷溶液与促凝血药物的DMSO溶液按10ml：4ml混合。(3) The dichloromethane solution of PLGA and the DMSO solution of the procoagulant drug were mixed in 10 ml: 4 ml.
(4)将混合溶液倒入0.5％PVA溶液中，搅拌，乳化，水洗，冻干。(4) The mixed solution was poured into a 0.5% PVA solution, stirred, emulsified, washed with water, and lyophilized.
在计算载药微球的载药量时，称取50mg PLGA载药微球，加入1ml二氯甲烷溶液，溶解5h，之后用0.1mol/L HCl溶液多次萃取，吸取萃取液紫外测定其吸光度，获得载药量-吸光度标准曲线根据标准曲线公式计算得到相应的药物浓度，即可计算微球的载药量，载药率和包封率。微球中的药物包封率、载药量都可以按下列公式来计算：When calculating the drug loading of the drug-loaded microspheres, 50 mg of PLGA drug-loaded microspheres were weighed, 1 ml of dichloromethane solution was added, dissolved for 5 hours, and then extracted with 0.1 mol/L HCl solution several times, and the absorbance of the extract was measured by ultraviolet absorption. The obtained drug-absorbance standard curve is calculated according to the standard curve formula to calculate the drug loading, the drug loading rate, the drug loading rate and the encapsulation efficiency. The drug encapsulation rate and drug loading in the microspheres can be calculated according to the following formula:
药物包封率＝微球中的药物质量/投药量×100％Drug encapsulation rate = drug quality / dosage in microspheres × 100%
载药量＝微球中药物质量/称取的微球质量×100％Drug loading = mass of drug in microspheres / mass of microspheres weighed × 100%
通过计算药物包封率在50％，载药量最高为10％，图3A显示了直径100-200μm PLGA载药栓塞微球的光学显微镜照片(20×)。将微球表面镀金处理后，进行扫描电镜观察，结果如图3B所示。扫描电子显微镜下，微球的表面形貌更加清晰。图中可以看到，由于DMSO加入到体系中，造成载药微球的圆整度尚可，存在球形比较好的微球。观察单个微球可以看到，载药微球和空白微球一样，表面都有一些凹痕，都是二氯甲烷挥发造成的，同时也对于缓释药物起到了相当重要的作用。By calculating the drug encapsulation rate at 50% and the drug loading amount up to 10%, Figure 3A shows an optical micrograph (20x) of a 100-200 μm PLGA drug-loaded embolic microsphere. The surface of the microspheres was subjected to gold plating treatment, and subjected to scanning electron microscope observation, and the results are shown in Fig. 3B. Under the scanning electron microscope, the surface morphology of the microspheres is more clear. It can be seen that, due to the addition of DMSO to the system, the roundness of the drug-loaded microspheres is still acceptable, and there are microspheres with better spherical shape. Observing a single microsphere can be seen that the drug-loaded microspheres, like the blank microspheres, have some dents on the surface, which are caused by the volatilization of methylene chloride, and also play a very important role in sustained-release drugs.
实施例4聚乳酸微球栓剂的应用Example 4 Application of Polylactic Acid Microsphere Suppositories
实验方法experimental method
4.1肝脏出血模型建立，肝切割伤动物模型的建立：健康新西兰大白兔20只，麻醉后开腹暴露肝脏，用11号手术刀沿尺子切割的方法，在兔肝左叶中心处(避开右叶胆囊区)制备一个长20mm、深5mm的切口。治疗组采用导管在切口处上游注入实施例2中制备的粒径为50-200μm(其中85％的粒径在70μm-100μm的范围)的不含促凝血成分的聚乳酸微球(非载药组)，以及实施例3中含有促凝血活性成分的聚乳酸微球栓剂(载药组)作为阳性对照，而空微球加促凝血活性成分栓剂作为空白对照(对照组)，直至注射药剂覆盖切口。4.1 Establishment of liver hemorrhage model, establishment of animal model of liver injury: 20 healthy New Zealand white rabbits, exposed to the liver after anesthesia, and cut with a scalpel along the ruler at the center of the left lobe of the rabbit liver (avoid the right Leaf gallbladder area) A slit of 20 mm in length and 5 mm in depth was prepared. The treatment group was injected with a catheter at the upstream of the incision to prepare a polylactic acid microsphere containing no procoagulant component having a particle diameter of 50-200 μm (in which 85% of the particle diameter was in the range of 70 μm-100 μm) prepared in Example 2 (non-drug-loaded) Group), and the polylactic acid microsphere suppository (loading group) containing the procoagulant active ingredient in Example 3 as a positive control, and the empty microsphere plus the procoagulant active ingredient suppository as a blank control (control group) until the injection agent is covered incision.
出血视觉评分：治疗实验完成后即刻对止血效果进行评分，根据下列等级标Bleeding visual score: The hemostasis effect is scored immediately after the completion of the treatment experiment, according to the following grades
准判断：Quasi-judgment:
0级—完全止血；Level 0 - complete hemostasis;
1级—只有缓慢渗血；Level 1 - only slow oozing;
2级—缓慢渗出和轻微的活动性出血；Grade 2 - slow exudation and mild active bleeding;
3级—明显的活动性出血； Level 3 - significant active bleeding;
4级—显著的大量出血。Level 4 - significant bleeding.
肝创伤后止血效果比较Comparison of hemostasis after liver trauma
两组实验兔肝叶切口治疗前均有明显的出血，初始出血率分布在0.10±0.08ml/s-0.12±0.04ml/s，组间无统计学差异(p>0.05)。采用不同的处理因素治疗后，对照组治疗后切口还有较明显的渗血和出血，视觉评分分布在2级-4级，而载药组以及非载药组切口出血均基本止住，持续观察数分钟无肉眼活动性出血，视觉评分分布在0级–1级，显著低于空白对照组(p<0.01)。而包括治疗时2min在内的10min出血量在载药组和非载药组为(均值为1.83±1.43)ml，也显著低于对照组(11.02±3.56)ml，与视觉评分结果吻合。而载药组的出血量少于非载药组，但二者没有显著性差别。The hepatic lobe incision in both groups showed obvious bleeding before treatment. The initial bleeding rate was 0.10±0.08ml/s-0.12±0.04ml/s, and there was no significant difference between the two groups (p>0.05). After treatment with different treatment factors, the incision had obvious oozing and hemorrhage after treatment. The visual scores were distributed in grades 2 to 4, while the incision hemorrhage in the drug-loaded group and the non-loaded group basically stopped. No visual acuity was observed for several minutes, and the visual score was distributed in grade 0–1, which was significantly lower than the blank control group (p<0.01). The amount of bleeding for 10 minutes including 2 minutes of treatment was (1.83±1.43) ml in the drug-loaded and non-loaded groups, which was also significantly lower than that in the control group (11.02±3.56) ml, which was consistent with the visual score. The amount of bleeding in the drug-loaded group was less than that in the non-drug-loaded group, but there was no significant difference between the two groups.
4.2采用肝脏出血模型类似方法，模拟消化道出血模型，并进行止血实验，结果显示，与载药组相似，不含促凝血活性成分药物的聚乳酸微球栓剂也能有效止血并促进血管内皮的修复。4.2 Using a similar method of hepatic hemorrhage model, simulating the model of gastrointestinal bleeding and performing hemostasis experiments, the results showed that similar to the drug-loaded group, polylactic acid microsphere suppository containing no procoagulant active ingredient can effectively stop bleeding and promote vascular endothelium. repair.
本实施例展示了聚乳酸微球对出血性疾病止血的安全性和有效性。可产生显著快速的止血效果。治疗有效性通过止血视觉评分和10min出血量得到证实，结果显示无论含有或不含有促凝血成分的微球组治疗后均未见肉眼活动性出血，10min出血量也远远低于空白对照组。This example demonstrates the safety and efficacy of polylactic acid microspheres for hemostasis in hemorrhagic diseases. Significantly rapid hemostasis can be produced. The efficacy of the treatment was confirmed by hemostatic visual score and 10 min of blood loss. The results showed that no visible bleeding was observed after treatment with the microspheres with or without procoagulant components, and the amount of bleeding at 10 min was much lower than that of the blank control group.
此外，在术后6周内对聚乳酸微球的残留进行检测。结果表明，在载药组和非载药组的动物中栓塞部分的动脉已经再通，观察不到聚乳酸微球的残留。这提示，将聚乳酸微球用于治疗出血性疾病，不仅有助于在治疗时减少创收，而且在术后有助于后期血管的再通和再利用。In addition, the residual of polylactic acid microspheres was detected within 6 weeks after surgery. The results showed that the arteries of the embolized part of the animals in the drug-loaded group and the non-drug-loaded group had been recanalized, and the residual of the polylactic acid microspheres was not observed. This suggests that the use of polylactic acid microspheres for the treatment of hemorrhagic diseases not only helps to reduce the rate of infection during treatment, but also facilitates the recanalization and reuse of later blood vessels after surgery.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (10)

  1. 一种聚乳酸微球的用途，其特征在于，用于制备治疗出血性疾病的药物组合物。Use of a polylactic acid microsphere for the preparation of a pharmaceutical composition for treating a bleeding disorder.
  2. 如权利要求1所述的用途，其特征在于，所述的出血性疾病包括消化道出血、肝脏出血、产后出血、或颅内出血。The use according to claim 1, wherein the bleeding disorder comprises gastrointestinal bleeding, hepatic hemorrhage, postpartum hemorrhage, or intracranial hemorrhage.
  3. 如权利要求1所述的用途，其特征在于，所述的药物组合物包括聚乳酸微球，和药学上可接受的载体。The use according to claim 1 wherein said pharmaceutical composition comprises polylactic acid microspheres and a pharmaceutically acceptable carrier.
  4. 如权利要求1所述的用途，其特征在于，所述的聚乳酸微球包括聚乳酸微球的均聚物、和/或共聚物。The use according to claim 1, wherein the polylactic acid microspheres comprise homopolymers and/or copolymers of polylactic acid microspheres.
  5. 如权利要求1所述的用途，其特征在于，所述的微球粒径为50-200μm，较佳地为70-150μm，更佳地，为50-80μm。The use according to claim 1, characterized in that the microspheres have a particle diameter of 50 to 200 μm, preferably 70 to 150 μm, more preferably 50 to 80 μm.
  6. 如权利要求1所述的用途，其特征在于，所述的药物组合物包括注射剂、粉剂、乳剂、微丸剂、冻干剂、栓剂。The use according to claim 1, wherein the pharmaceutical composition comprises an injection, a powder, an emulsion, a pellet, a lyophilizate, and a suppository.
  7. 如权利要求1所述的用途，其特征在于，所述的聚乳酸微球的浓度为1-99％。The use according to claim 1, wherein the polylactic acid microspheres have a concentration of from 1 to 99%.
  8. 如权利要求1所述的用途，其特征在于，所述的聚乳酸微球的制备方法包括：乳化-溶剂挥发法、相分离法、喷雾干燥法、超临界流体法、膜乳化法、微通道乳化法、静电液滴法。The use according to claim 1, wherein the preparation method of the polylactic acid microspheres comprises: emulsification-solvent evaporation method, phase separation method, spray drying method, supercritical fluid method, membrane emulsification method, microchannel Emulsification method, electrostatic droplet method.
  9. 一种治疗出血性疾病的栓剂，其特征在于，所述的栓塞制剂包括聚乳酸微球，和药学上可接受的载体。A suppository for treating a bleeding disorder, characterized in that the embolic preparation comprises polylactic acid microspheres, and a pharmaceutically acceptable carrier.
  10. 一种治疗出血性疾病的方法，其特征在于，对所需要的对象施用聚乳酸微球或权利要求9所述的栓剂。 A method for treating a bleeding disorder, characterized in that a polylactic acid microsphere or the suppository according to claim 9 is administered to a subject in need thereof.
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