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WO2015196984A1 - Utilisation de microsphères d'acide polylactique pour des maladies hémorragiques - Google Patents

Utilisation de microsphères d'acide polylactique pour des maladies hémorragiques Download PDF

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Publication number
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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English (en)
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

Definitions

  • 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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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une utilisation de microsphères d'acide polylactique pour des maladies hémorragiques. Spécifiquement, la présente invention concerne l'utilisation de microsphères d'acide polylactique dans la préparation d'une composition pharmaceutique pour le traitement de maladies hémorragiques. Dans la présente invention, les microsphères d'acide polylactique sont utilisées directement sous forme d'un suppositoire de blocage hémostatique, et peuvent également servir de support pour un médicament pour la réparation vasculaire locale pour un traitement local.
PCT/CN2015/082133 2014-06-23 2015-06-23 Utilisation de microsphères d'acide polylactique pour des maladies hémorragiques WO2015196984A1 (fr)

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CN109265942B (zh) * 2018-08-16 2021-10-19 张海军 一种聚乳酸微球及其制备方法与应用

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CN1435263A (zh) * 2003-03-05 2003-08-13 成都拓泰医药科技开发有限公司 止血凝胶
CN1870956A (zh) * 2003-06-16 2006-11-29 洛马林达大学医学中心 可展开的止血剂
CN1727013A (zh) * 2005-06-10 2006-02-01 惠州华阳医疗器械有限公司 一种医用止血材料
EP2295480A1 (fr) * 2009-09-10 2011-03-16 Occlugel Polymère implantable biorésorbable

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