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WO2015179997A1 - Microsphère embolique de polymère polyhydroxyle et son procédé de préparation - Google Patents

Microsphère embolique de polymère polyhydroxyle et son procédé de préparation Download PDF

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Publication number
WO2015179997A1
WO2015179997A1 PCT/CN2014/000571 CN2014000571W WO2015179997A1 WO 2015179997 A1 WO2015179997 A1 WO 2015179997A1 CN 2014000571 W CN2014000571 W CN 2014000571W WO 2015179997 A1 WO2015179997 A1 WO 2015179997A1
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Prior art keywords
microsphere
polymer
acetal
microspheres
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Chinese (zh)
Inventor
姚飞
王丹雄
丘茹惠
孙小薇
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Nanjing Flaming Biomedical Ltd
Suzhou Callisyn Biomedical Ltd
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Nanjing Flaming Biomedical Ltd
Suzhou Callisyn Biomedical Ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52—Amides or imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • 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
    • 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
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances

Definitions

  • the invention relates to an embolization microsphere for interventional therapy for treating tumor diseases and a preparation process thereof, and belongs to the technical field of medical materials.
  • Minimally invasive interventional therapy is becoming more and more widely used in the field of medical technology, especially in the treatment of cancer-rich cancers such as liver cancer, kidney cancer and uterine fibroids, and has become a tumor that cannot be surgically removed.
  • the preferred alternative. The principle is to use a high-definition medical imager to guide the catheter through the artery to reach the tumor site in the human body, and then inject the anti-tumor drug and the embolic agent through the catheter to block the blood supply of the tumor tissue, thereby causing the tumor to shrink in a short time.
  • the purpose of treatment for necrosis is to choose an appropriate embolic agent for blocking the blood supply of tumor tissue.
  • the physical properties of the embolization agent are essential for the final therapeutic effect of interventional surgery.
  • the size is too large, or the size distribution is too wide, and the shape is irregular.
  • the embolic products can cause the following problems during interventional procedures: (1) occlusion of the catheter; (2) mis-suppression, that is, the embolization point is too far from the tumor tissue to cause damage to normal tissue; (3) drift, that is, embolic agent After the operation, leave the predetermined embolization position and enter other blood vessels; (4) The target blood vessel cannot be completely embolized.
  • micro-catheters to deliver embolic agents to the end of the tumor to supply microvessels for minimally invasive interventional therapy is to further improve the efficacy of minimally invasive interventional therapy and reduce damage to normal tissues caused by mis-plugging and drift.
  • the best way therefore, has stricter requirements on the type of embolic agent, especially the size and shape of the particles.
  • the systemic drug concentration is reduced, the side effects are reduced, and the effect on the tumor is improved.
  • the current clinical use of the chemotherapeutic drug perfusion method cannot completely guarantee the local drug release and release of the chemotherapeutic drug due to the limitation of the embolic agent.
  • embolic microspheres have been widely used as a new type of granular embolic agent.
  • the existing microspheres can be classified into polyvinyl alcohol microspheres, starch microspheres, albumin microspheres, gelatin microspheres, polylactic acid microspheres, sodium alginate microspheres, chitosan microspheres and ethyl fibers according to the materials used. Microspheres, etc.
  • microspheres Although these microspheres have a uniform shape, a smooth surface, a uniform size, and good hydrophilicity and suspensibility, they are easy to follow the blood flow, and can block the entire cross section of the blood vessel without recurrence, but some of the microspheres do not have Flexibility and elasticity, it is difficult to deform smoothly through the micro-catheter and can quickly return to the original state, which will cause incomplete embolization, and some microspheres have too large expansion coefficient. It is difficult to select the microsphere size in application, and there is no X-ray. The visibility of the fluoroscopy is not ideal, and the need for superselective intervention is not met.
  • a preparation process of a polyvinyl alcohol particle embolic agent is proposed, which adopts a polyvinyl formal After adding sterile water for injection, freezing, and then sieving and wet sieving and grading to obtain polyvinyl acetal wet granules, and then the above-mentioned polyvinyl formal dimethyl granules are subjected to a second freezing without water for injection. After treatment, polyvinyl acetal granules are formed, and then subjected to dry sieving and grading to obtain polyvinyl formal granules of various sizes.
  • the preparation process is relatively simple, but the prepared embolic agent has different particle diameters and is difficult to separate. At the same time, the embolic agent is not biocompatible, has a hard texture, and is difficult to recognize and manipulate inside and outside the body, which may cause incomplete embolization.
  • the shape of the microcapsule-like embolic particles produced by the patent in addition to the spherical shape, may also have irregular shapes, and the three-dimensional size of the irregularly shaped microcapsule-shaped embolic particles will not Uniformity, which results in a large size distribution of the microcapsule embolic particles of the calibration specification, which adversely affects the superselection type using the microcatheter for interventional treatment, and can block the catheter.
  • the pre-loading and sustained-release functions of the microcapsule-embedded microparticles mentioned have no practical application significance because the loading step of the drug is collected in the synthetic preparation process of the micro-capsular embolic particles.
  • the invention provides a pharmaceutical composition for embolization treatment and a preparation method thereof, the pharmaceutical composition comprising a hydroxyl group-containing biocompatibility A polymer produced by a radically initiated polymerization of a molecular material with a monomer containing an unsaturated double bond and an anionic group, and a unilateral vinyl monomer.
  • the obtained embolic agent can carry the drug, the actual operation step is cumbersome. It needs to absorb the surface moisture of the microsphere beforehand, and then soak the microsphere at a temperature of 4 ° C for 2 hours in the solution of the chemotherapeutic drug. The surface is not washed with deionized water and can be used. Summary of the invention
  • a first object of the present invention is to provide a polyhydroxy polymer-embedded microsphere (preferably polyvinyl alcohol-embedded microspheres) which has good biocompatibility and stability, large elastic stretchability and recovery property. Uniform and controllable particle size, good dispersibility, targeted, easy to use, its network structure design and internal negative charge functional group make it have good adsorption capacity for bioactive substances, and can be completely adsorbed within 30 minutes. A defined dose of bioactive material and a controlled release can be used for a variety of minimally invasive interventional procedures.
  • a second object of the present invention is to provide a process for preparing the polyhydroxy polymer-embedded microspheres (preferably polyvinyl alcohol-embedded microspheres), which has a wide range of raw materials and has no toxic side effects on the human body, and is prepared by the preparation.
  • the embedding microspheres have a perfect spherical shape and uniform size, and have an acrylic derivative group (preferred acrylamide group) containing a negatively charged structure, which has good adsorption and release-release ability to biologically active substances, and the entire preparation process Simple and easy to manufacture.
  • Polyhydroxyl polymer embolic microspheres (preferably polyvinyl alcohol-embedded microspheres), which are formed by cross-linking polymerization of biocompatible functionalized macromolecules, characterized in that: the functionalized macromolecule comprises a linkage on the main chain An acetal structure containing at least two groups containing acrylic acid or a derivative thereof or a polymer having at least two crosslinkable small molecules having a structure of acrylic acid or a derivative thereof linked by a covalent bond, and the acetal The structure or crosslinkable small molecule can be crosslinked by free radical polymerization to form a hydrogel unsaturated functional group.
  • the small molecule organic compound comprises a derivative group of acrylic acid including an acrylate, an ester or an amide, preferably an amide.
  • the functionalized macromolecule further comprises a polyhydroxy polymer having a 1,2-diol or 1, 3-diol structural functional group in the main chain.
  • the polyhydroxy polymer comprises polyvinyl alcohol, polyethylene glycol or polysaccharide macromolecule, preferably polyvinyl alcohol; the polysaccharide macromolecule comprises amylose, chitosan or Injection of methyl cellulose.
  • the embolic microspheres internally contain a functional group having an organic acid radical as a negative electrode.
  • the embedding microspheres have a particle size ranging from 1 to 1500 ⁇ m, a compression deformation rate of more than 50%, and can be quickly restored to the original state without any damage after depressurization.
  • the functionalized macromolecular hydrogel intermediate accounts for 70% of the total mass of the polymer monomer.
  • the polysaccharide macromolecule comprises amylose, chitosan or hydroxymethylcellulose; the molecular weight of the polyvinyl alcohol, polyethylene glycol or polysaccharide macromolecule is 2x l0 4 - 5x l0 4 ;
  • the initiator is a persulfate, tetramethylethylenediamine or a composite of the two.
  • the preparation process of the embedding microspheres is as follows:
  • the total concentration of the polymer monomer is 50-100 g/L, wherein the functionalized macromolecular hydrogel intermediate accounts for the total mass of the polymer monomer.
  • the amine concentration is 1-5 g/L
  • the cellulose acetate concentration is 2-4 g/L
  • the oil-water mixed reaction system is further stirred at 55 ° C for 2-4 hours, and after the reaction is finished, the reaction mixture is filtered to collect the microspheres. It was then washed successively with butyl acetate, ethyl acetate and acetone, and dried under vacuum to obtain embolic microspheres.
  • the aminodialkoxyfluorenyl acetal is selected from amino dimethoxy acetal.
  • the acrylamido dialkoxyindenyl acetal is selected from N-acrylamidodimethoxyacetal.
  • microsphere embolic agent is subjected to screening and sorting, and an embedding microsphere coloring operation is used, and it is notified to add a reactive dye for dyeing, and the reactive dye includes reactive blue or active yellow.
  • This procedure is an option, which is designed to help doctors easily observe the embedding microspheres during operation preparation.
  • the dyes used are combined with the functional groups on the embedding microspheres in a covalent bond. Clinical trials have proven No toxic side effects on the human body. Compared with the prior art, the invention has the following advantages:
  • the polyvinyl alcohol-embedded microsphere of the present invention has good biocompatibility and stability, large elastic expansion ratio and recovery property, uniform particle size controllability, and good dispersibility. Easy to use and targeted.
  • the embedding microspheres are designed as a network structure, and introduce a negative charge functional group in the internal design, which not only has a good fast adsorption capacity for the biologically active substance, but also has a slow release and release ability, and solves the shape of the embolic agent product on the existing market.
  • the preparation process of the polyvinyl alcohol-embedded microspheres of the invention has a wide range of raw materials and has no toxic side effects on the human body, and the prepared embedding microspheres have a perfect spherical shape and uniform size, and have a good biological phase. Capacitance and stability, can be stored normally for more than 3 years at room temperature and saline environment; acrylamide group with negatively charged structure inside, has good adsorption and release and release ability to bioactive substances, the whole preparation process is simple, The manufacturing cost is low.
  • Figure 1 is a compression curve of compression deformation of polyvinyl alcohol embolized microspheres.
  • Figure 2 is a graph showing the shape change of the embedding microspheres without compression.
  • Figure 3 is a graph showing the median change in tumor size after interventional surgery at different stages of CT-enhanced scanning.
  • Figure 4 is a graph showing the maximum change in tumor size after interventional surgery at different stages of CT-enhanced scanning.
  • Figure 5 is a graph showing changes in total tumor survival time at different stages after CT-enhanced scanning interventional surgery.
  • Figure 6 is a graph showing changes in blood supply of tumor blood vessels after interventional surgery at different stages of CT-enhanced scanning.
  • Figure 7 is a schematic diagram of the assessment of physical status of multiple patients after different stages of interventional surgery.
  • Figure 8 is a schematic diagram of drug loading of embolic microspheres for three drugs.
  • Figure 9 is a schematic diagram showing the drug loading and speed comparison of the two types of embedding microspheres.
  • Figure 10 is a graph showing the change of the maximum drug release time of doxorubicin-loaded microspheres in vitro.
  • Example 3 100 g of polyvinyl alcohol having a molecular weight of 2 ⁇ 10 4 -5 ⁇ 10 4 was added to a flask containing 500 mL of pure water, and the mixture was stirred for 10 minutes to uniformly disperse it; the temperature was raised to 90-100 ° C by heating, and after the polyvinyl alcohol was completely dissolved, it was cooled. After cooling to 25 ° C or lower, 1.5 g of acrylamido-dimethoxyacetal obtained in Example 1 was added thereto, and after stirring for 10 minutes, 70 mL of concentrated hydrochloric acid was added dropwise to the solution, and the reaction was continued after the completion of the dropwise addition. Stir for 6 hours, then collect the crude product, wash, remove water, concentrate to obtain functionalized macromolecular hydrogel The intermediate is stored at room temperature.
  • Example 3 100 g of polyvinyl alcohol having a molecular weight of 2 ⁇ 10 4 -5 ⁇ 10 4 was added to a flask containing 500 mL of pure water, and
  • microsphere embolic agent 4 g of sodium 2-acrylamide-2-methylpropane sulfonate, 3 g of potassium persulfate and 150.00 g of functionalized macromolecular hydrogel intermediate prepared in Example 2 were dissolved in water.
  • the embedding microsphere has a perfect spherical shape, the particle size ranges from 1 to 1500 ⁇ m, the size is uniform, the compression deformation rate is more than 50%, and the pressure can be quickly restored to the original state without any damage.
  • microsphere embolic agent will be stored in physiological saline, dyed
  • the embolized microspheres are easily recognized both in vivo and in vitro, enhancing the manageability of the procedure.
  • microsphere embolic agent 17 g of sodium 2-acrylamide-2-methylpropane sulfonate and 12 g of potassium persulfate and 500.00 g of functionalized macromolecular hydrogel intermediate prepared in Example 6 were dissolved in water.
  • the reaction mixture was filtered to collect 90 g of microspheres, which were then washed successively with butyl acetate, ethyl acetate and acetone, and dried under vacuum to obtain embolic microspheres.
  • the embedding microspheres have a perfect spherical shape, the particle size ranges from 1 to 1500 ⁇ m, the size is uniform, and the compression deformation rate is more than 50%.
  • Example 9 Embedding microsphere performance test:
  • test requirements stainless steel 5mm diameter ⁇ /5 parallel probe, induction force 10g, speed lmm / s, compression control mode, compression 50% and keep 10 seconds, return speed 2mm /s, requires the microsphere to return to its original shape after the compression deformation reaches 50% and remains for ten seconds. No damage was observed under a microscope. The test results are shown in Fig. 1 and Fig. 2. It is observed in this test: The embedding microspheres have a perfect spherical shape with a particle size range of 1-1500 ⁇ , and the compression deformation rate is over 50%. Reverted to its original shape without any damage.
  • Embolization microsphere size screening classification The embedding microspheres prepared in the above Examples 7 and 8 were obtained, and the following five specifications of blue embedding microspheres were obtained by rinsing and sieving: 100-300 ⁇ m, 300-500 ⁇ m, 500-700 ⁇ m, 700 -900 ⁇ and 900-1200 ⁇ .
  • Test method The embolized microsphere samples were randomly taken from the above-mentioned various embedding microspheres, and the microsphere samples were placed on a glass slide and observed under a microscope. Each sample was sampled fifteen times, and the observation results are shown in Table 1.
  • the above-described screening and sorting of the embedding microspheres uses an embedding microsphere coloring operation, which is dyed by the addition of a reactive dye including reactive blue or active yellow.
  • the operation step is an option, and the purpose thereof is to help the doctor to easily observe the embedding microspheres in the operation preparation process, and the dye pair is combined with the functional group on the embedding microsphere in the form of covalent bond, and the clinical experiment has been carried out. Proof of side effects on the human body
  • the polyvinyl alcohol-embedded microspheres prepared by the present invention have a stability performance of at least 36 months in the above test of physical and chemical properties.
  • TACE transcatheter hepatic arterial chemoembolization
  • FIG. 3 shows the median change in tumor size by CT-enhanced scan. The results are as follows:
  • Figure 4 shows the maximum change in tumor size for CT-enhanced scans. The results are as follows:
  • Length X width X height (maximum value): 13.0x18.0x33.0 cm;
  • length X width X height (maximum): 16.1 x19.0x25.0 cm;
  • length X width X height (maximum value): 16.0x16.0x18.0 cm;
  • FIG. 5 shows the changes in total tumor survival time (OS) by CT-enhanced scan. The results are as follows:
  • the 6-month survival rate was 41%.
  • Figure 6 shows the changes in tumor blood supply after CT-enhanced scanning intervention. The results are as follows: The successful embolization rate after the first operation was 94.8%;
  • the successful embolization rate after the second operation was 100.0%;
  • the successful embolization rate after the third operation was 100.0%.
  • Figure 7 shows the physical status assessment (ECOG) of multiple patients after surgery. The results are as follows: After the first operation, the physical condition is assessed at 1 or 0, and can be fully moved, accounting for 81.8%;
  • the physical condition is assessed at 1 or 0, and can be fully moved, accounting for 96.0%;
  • Drug loading method 10 mg of doxorubicin was dissolved in 2.0 mL of pure water. Take 100-300 ⁇ wet embolization microspheres, squeeze out clear water, accurately weigh 0.25g microspheres, put into 20mL vial, add 2mL of known concentration of doxorubicin solution, soak the microspheres in doxorubicin In the solution, shake gently from time to time. A 50 uL micro syringe was used to sample 20 uL at 5, 10, 20, 60, and 120 min, diluted with 5.0 mL of pure water, and the absorbance was measured at 485 nm.
  • the absorbance is substituted into the standard curve equation to calculate the concentration of the drug contained in the sample:
  • Drug loading (the amount of the drug before the drug is loaded - the drug content of the drug after the drug is loaded) / the weight of the microsphere.
  • the microsphere loaded with doxorubicin was measured to have a drug loading of 19.2 mg per gram of microspheres.
  • the drug loadings of the microspheres loaded with epirubicin and pirarubicin were 19.7 mg and 20.8 mg/g microspheres, respectively.
  • the drug loading results of the above three drugs are shown in Figure 8.
  • the drug loading test results showed that the drug was loaded onto the microspheres in about 20 minutes and basically reached equilibrium.
  • Method for releasing drug-loaded microspheres Take 0.25 g of doxorubicin-loaded microspheres (loaded with 19 mg doxorubicin/g microspheres), blot the surface solution, place in a 250 mL flask, and add 100 mL of pH 7.4 phosphate buffer. The solution (PBS) was placed in a magnetic stir bar and stirred 100 times per minute in a 37 ° C water bath. ImL release solution was taken at 5, 20, 40, 60, 90, 120, 180, 240 min, diluted with 3 mL of pure water, absorbance was measured at 485 nm, and ImL isothermal PBS was immediately added. The measured absorbance was substituted into the doxorubicin standard curve equation to calculate the drug release amount.
  • Maximum drug release % (maximum drug release / microsphere drug loading) xl 00%.

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Abstract

La présente invention concerne une microsphère embolique de polymère polyhydroxyle et son procédé de préparation. La microsphère embolique de polymère polyhydroxyle est formée par polymérisation par réticulation de macromolécules fonctionnelles biocompatibles. La macromolécule fonctionnelle comprend : une structure d'acétal comprenant au moins deux groupes contenant de l'acide acrylique ou un dérivé de celui-ci reliés sur la chaîne principale ou un polymère comprenant au moins deux micromolécules réticulables qui sont reliées dans un mode de liaison covalente et possèdent la structure d'acide acrylique ou un dérivé de celui-ci. Les structures d'acétal ou les micromolécules réticulables peuvent former un groupe fonctionnel insaturé d'hydrogel par réticulation par polymérisation radicalaire, et un groupe fonctionnel utilisant un radical acide organique en tant que porteur de charge négative est contenu à l'intérieur de la microsphère. La microsphère embolique peut être utilisé pour un traitement minimalement invasif.
PCT/CN2014/000571 2014-05-28 2014-06-10 Microsphère embolique de polymère polyhydroxyle et son procédé de préparation Ceased WO2015179997A1 (fr)

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CN201410232150.5A CN103977458B (zh) 2014-05-28 2014-05-28 多羟基聚合体栓塞微球及其制备工艺
CN201410232150.5 2014-05-28

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