WO2023015851A1 - 一种注射用曲安奈德微球植入剂及其制备方法 - Google Patents

一种注射用曲安奈德微球植入剂及其制备方法 Download PDF

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WO2023015851A1
WO2023015851A1 PCT/CN2022/074209 CN2022074209W WO2023015851A1 WO 2023015851 A1 WO2023015851 A1 WO 2023015851A1 CN 2022074209 W CN2022074209 W CN 2022074209W WO 2023015851 A1 WO2023015851 A1 WO 2023015851A1
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triamcinolone acetonide
injection
microsphere
plga
microspheres
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PCT/CN2022/074209
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French (fr)
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李建
张娜
秦昌
孙君娟
牛自芬
袁文博
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山东谷雨春生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention belongs to the technical field of medicine, and relates to a triamcinolone acetonide microsphere implant for injection and a preparation method thereof.
  • Osteoarthritis is a degenerative disease, and many factors can cause degeneration of articular cartilage, joint edge and subchondral bone reactive hyperplasia. Clinical manifestations include slowly developing joint pain, tenderness, stiffness, joint swelling, limited mobility, and joint deformity. The disease mostly occurs in middle-aged and elderly people, and it also occurs in young adults. As our society enters the aging stage, alleviating or even curing osteoarthritis has great social significance.
  • the drugs used to treat osteoarthritis are mainly steroidal anti-inflammatory drugs, but there are side effects such as water and sodium retention, puffiness, risk of infection, and osteoporosis, while non-steroidal drugs have weak anti-inflammatory effects.
  • intra-articular injection of anti-inflammatory drugs has become one of the most effective treatments for osteoarthritis, which can directly deliver drugs to diseased joints site, avoid systemic toxicity, and alter drug distribution in the body.
  • the injection method is efficient, it still has limitations. After administration, the active ingredients of the drug quickly penetrate into the systemic circulation and stay in the joint cavity for a short time, resulting in frequent injections and painful treatment. So the slow-release dosage form of intra-articular injection has become a research hotspot.
  • Triamcinolone acetonide is a kind of adrenal cortex hormone drug, which has anti-inflammatory, anti-pruritic and vasoconstrictive effects, and has a good therapeutic effect on joint pain, joint swelling, stiffness, diffuse arthritis, and water and sodium retention The effect is weak, and the anti-inflammatory effect is strong and lasting.
  • Zilretta triamcinolone acetonide sustained-release injection suspension
  • PLGA lactide-glycolide copolymer
  • Lactide-co-glycolide copolymer (poly(lactic-co-glycolic acid), PLGA) is a degradable functional polymer organic compound, which is formed by disorderly polymerization of two monomers, lactic acid and glycolic acid. , has good biocompatibility, non-toxicity, good capsule-forming and film-forming properties, is widely used in pharmaceuticals, medical engineering materials and modern industrial fields, and has passed FDA certification in the United States PLGA, and can be used as muscle or joint Injection.
  • Patent CN 103260603 B (Application No.: 201180047943.4, Invention Name: Corticosteroids for the Treatment of Arthralgia) discloses the preparation process of Zilretta, the microsphere carrier is PLGA, and the preparation process is: using the molar ratio of lactide and glycolide
  • the PLGA of 75:25 adopts the solvent evaporation method, uses the turntable to atomize the dispersion to form tiny droplets, evaporates the solvent to produce solid particles, uses the cyclone separator to collect the particles, and then sieves them through a 150 ⁇ m sieve.
  • the particles prepared by this method The particle size distribution is relatively wide, the yield is low, and the drug release period is short.
  • the present invention overcomes the above-mentioned deficiencies in the prior art, and provides a triamcinolone acetonide microsphere implant for injection and a preparation method thereof.
  • the present invention adopts PLGA with a molar ratio of lactide and glycolide of 85:15, porous glass Microspheres were prepared by (SPG) membrane emulsification method, and PEG4000 was added to the continuous phase of the preparation process to obtain a narrower particle size distribution, higher yield, improved early burst release, and a longer release period.
  • the technical scheme of the present invention is: a kind of triamcinolone acetonide microsphere implant for injection, it is characterized in that, it is the sustained release microsphere comprising triamcinolone acetonide (TCA) and polymer carrier, wherein the content of triamcinolone acetonide is 20-28%, the polymer is lactide-co-glycolide (PLGA), its molecular weight is 10KDa-55KDa, the molar ratio of lactide and glycolide is 90:10-81:19; porous glass ( SPG) membrane emulsification method.
  • TCA triamcinolone acetonide
  • PLGA lactide-co-glycolide
  • SPG porous glass
  • polyethylene glycol is added in the continuous phase (in the PVA solution) of the preparation process.
  • the PEG is PEG4000.
  • the molar ratio of lactide to glycolide is 85:15.
  • the present invention also discloses a preparation method of the above-mentioned triamcinolone acetonide microsphere implant for injection, which is characterized in that triamcinolone acetonide, PLGA and dichloromethane are uniformly mixed, passed through the SPG membrane emulsified membrane tube at a certain pressure, and dispersed to the In the PVA solution (continuous phase) of PEG4000, magnetically stir to volatilize the solvent, solidify the microspheres, wash off the triamcinolone acetonide that was not completely wrapped and precipitated during the solidification of PLGA, and dry to obtain the finished microspheres.
  • the pressure of 8-15 psi passes through the emulsified membrane tube of SPG membrane with a pore size of 30 ⁇ m.
  • the mass concentration of the PVA solution is 1%, and the mass concentration of PEG4000 in the PVA solution is 0.05-0.1%.
  • the cleaning of the triamcinolone acetonide that is not completely encapsulated and precipitated by PLGA during solidification is as follows: washing with ethanol water (volume concentration of ethanol: 40%-80%), 0.05-0.1% PEG4000 and pure water.
  • the beneficial effect of the present invention is: compared with CN 103260603 B, obtained narrower particle size distribution (Span is 1.23), yield is higher (more than 80% of yield), early stage burst release is improved (2 hours burst release 4.6%), the in vitro release of the prepared microspheres was greater than 40 days.
  • Fig. 1 is the influence of different molecular weight PLGA (embodiment 4,9 and 10) on the cumulative release of microsphere;
  • Fig. 2 is the cumulative release figure of the microspheres that same PLGA obtains with two kinds of preparation methods (embodiment 1 and 11);
  • Figure 3 is a cumulative release graph of microspheres obtained with PLGA (Examples 4, 11 and 12) with different ratios of lactide and glycolide, where Example 12 is the uppermost curve and Example 4 is the lowermost curve curve.
  • Drug loading determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition general rule 0512). Take a sample, accurately weigh it, put it in a 100ml measuring bottle, add DMSO to dissolve, add water to dilute to the mark, shake well, filter, accurately measure 1ml of the subsequent filtrate, put it in a 10ml measuring bottle, dilute to the mark with mobile phase, shake well .
  • Reference substance solution take about 10 mg of triamcinolone acetonide reference substance, accurately weigh it, put it in a 100ml measuring bottle, add DMSO to dissolve and dilute to the mark, which is the reference substance stock solution.
  • Particle size distribution Weigh this product, add about 20ml of dispersant (aqueous solution containing phosphate and Tween 80), shake for 30 seconds to mix evenly, disperse in ultrasonic for 3 minutes, shake for another 30 seconds, and pour all the particles into the particle size distribution.
  • dispersant aqueous solution containing phosphate and Tween 80
  • the measuring instrument add 5ml of water three times to rinse the triangular flask, pour it into a laser particle size analyzer, and measure according to the particle size and particle size distribution method (the third method of the general rule 0982 of the Chinese Pharmacopoeia 2020 edition).
  • the optical concentration of the instrument should be between 8% and 20%. Otherwise, reconstitute the sample at the appropriate concentration.
  • Cumulative release in vitro Suspend 4 mg of TCA-containing microspheres in 20 ml of phosphate buffered saline solution containing 0.5% sodium dodecyl sulfate (SDS) at 37 ° C, periodically take 0.5 ml of medium and replace it with fresh medium, and pass HPLC Determination of cumulative release in vitro.
  • SDS sodium dodecyl sulfate
  • Embodiment 1 adopt the method of CN 103260603 B
  • TCA triamcinolone acetonide
  • PLGA molecular weight Mw 39KDa, molar ratio, lactide: glycolide 75:25, intrinsic viscosity 0.34dl/g
  • dichloromethane 15ml mix homogeneously
  • Example 1 Using the method described in CN 103260603 B, the particle size distribution of microspheres is D 10 : 20 ⁇ m, D 50 : 33 ⁇ m, D 90 : 69 ⁇ m, Span (particle size distribution coefficient (D 90 -D 10 )/D 50 ) was 1.48, the yield was 43.41%, the drug loading was 25.25%, and the release rate in vitro was 5.3% in 2 hours. Its release performance is consistent with that described in CN 103260603 B.
  • Embodiment 2 SPG membrane emulsification method
  • microspheres prepared by the SPG membrane emulsification method in Example 2 had a particle size of D 10 : 21 ⁇ m, D 50 : 48 ⁇ m D 90 : 97 ⁇ m, a span of 1.58, a yield of 92.60%, and a drug loading of 24.61%. It can be seen that compared with CN 103260603 B, the yield is significantly improved, but the drug loading is lower. Compared with the 2-hour release data, Example 1 is 5.3%, Example 2 is 10.2%, and there is a more obvious burst release effect.
  • embodiment 2 adopts triamcinolone acetonide-dichloromethane system, with the SPG film emulsification film tube of 30 ⁇ m aperture, can extrude regular, uniform microsphere under the pressure of 10 psi, but the microsphere surface after embodiment 2 drying It is flat, and a small amount of triamcinolone acetonide is not completely wrapped in the microspheres. This should be due to the different properties of triamcinolone acetonide and PLGA. During the volatilization of dichloromethane, the precipitation rate is different to some extent. The above PLGA did not completely wrap the precipitated triamcinolone acetonide during curing, and this part of the drug would cause a burst release.
  • Embodiment 3 increase cleaning step
  • Example 2 On the basis of Example 2, after the solidification of the microspheres is completed, wash with ethanol water and pure water, filter, and dry to obtain the finished microspheres.
  • the microspheres obtained in Example 3 had a particle size D50 of 52 ⁇ m, the drug loading was reduced to 22.53%, and the yield was reduced to 83.1%.
  • the triamcinolone acetonide crystals on the surface of the microspheres were washed away, we noticed that the release also Slower, 2 hours in vitro release is 7.2%, and the burst release effect is obviously smaller than that of Example 2, but there is still some gap compared with Example 1, and the particle size distribution of the microspheres is still not particularly ideal.
  • Embodiment 4 Add 0.05% PEG4000
  • Example 3 On the basis of Example 3, add 0.05% PEG4000 to the 1% PVA solution, and after the microspheres are solidified, wash with ethanol water, 0.05% PEG4000, pure water, filter, and dry to obtain the finished microspheres .
  • the microspheres obtained in Example 4 have a better particle size distribution, a Span of 1.23 (D 10 : 27 ⁇ m; D 50 : 53 ⁇ m; D 90 : 92 ⁇ m), a 2-hour burst release in vitro of 4.6%, a drug loading of 23.06%, and a yield of 85.5%.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Example 4 Example 5
  • Example 6 PEG molecular weight specification 4000 300 1600 Span 1.23 1.57 1.35 2 hours burst release% 4.6 6.9 5.3
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • the addition amount of PEG4000 is 0.1%, all the other steps are with embodiment 4.
  • Embodiment 9 PLGA of molecular weight 29KDa
  • Embodiment 10 PLGA of molecular weight 55KDa

Abstract

一种注射用曲安奈德微球植入剂及其制备方法。该植入剂包含曲安奈德和聚合物载体的缓释微球，其中曲安奈德的含量为20～28％，聚合物是丙交酯乙交酯共聚物PLGA，其分子量为10KDa～55KDa，丙交酯和乙交酯的摩尔比为90:10～81:19；取曲安奈德、PLGA与二氯甲烷混合均匀，以一定压力通过SPG膜乳化膜管，分散到含有PEG的PVA溶液中，磁力搅拌挥发溶剂，使微球固化，清洗，干燥，即得微球成品。该微球获得了更窄的粒径分布，收率更高，前期突释得到改善，体外释放大于40天。

Description

一种注射用曲安奈德微球植入剂及其制备方法 技术领域
本发明属于医药技术领域，涉及一种注射用曲安奈德微球植入剂及其制备方法。
背景技术
骨关节炎为一种退行性病变，诸多因素可引起关节软骨退化损伤，关节边缘和软骨下骨反应性增生。临床表现为缓慢发展的关节疼痛、压痛、僵硬、关节肿胀、活动受限和关节畸形等。该病多发生于中老龄阶段，青壮年阶段也有发生。随着我国社会步入老龄化阶段，缓解甚至治愈骨关节炎具有极大的社会意义。用于骨关节炎治疗的药物主要为甾体类的抗炎药，但存在水钠潴留，变虚胖，感染危险以及骨质疏松等副作用，而非甾体类药物抗炎作用较弱。因为口服抗炎药物药效一般且对全身毒性大，所以从上世纪50年代，关节腔内注射抗炎药物成为治疗骨关节炎的最有效疗法之一，该疗法可直接将药物输送到病变关节部位，避免全身毒性，改变药物在体内的分布。注射法虽然高效但仍有局限性，给药后药物有效成分迅速渗透到体循环中，在关节腔内停留时间短，导致频繁注射，治疗过程痛苦。于是关节腔内注射的缓释剂型成为了研究热点。
曲安奈德(TCA)是一种肾上腺皮质激素药，具有抗炎、抗瘙痒和收缩血管等作用，对于关节疼痛、关节肿胀、僵直、弥漫性关节炎具有较好的治疗效果，且水钠潴留作用微弱，抗炎作用较强而持久。目前国外上市的Zilretta(曲安奈德缓释注射悬浮液)，为丙交酯乙交酯共聚物(PLGA)载曲安奈德做成的微球，关节内注射治疗关节炎引起的疼痛，能达到三个月的作用时效。丙交酯-乙交酯共聚物(poly(lactic-co-glycolic acid)，PLGA)是由乳酸和羟基乙酸两种单体经无序聚合而成，是一种可降解的功能高分子有机化合物，具有良好的生物相容性、无毒、良好的成囊和成膜性能，被广泛应用于制药、医用工程材料和现代化工业领域，并在美国PLGA通过FDA认证，可被用作肌肉或关节内注射。
专利CN 103260603 B(申请号：201180047943.4，发明名称：用于治疗关节痛的皮质类固醇)公开了Zilretta的制备工艺，其微球载体是PLGA，制备工艺是：采用丙交酯和乙交酯摩尔比75:25的PLGA，采用溶剂蒸发法，利用转盘将分散体雾化形成微小液滴，蒸发溶剂以产生固体微粒，利用旋风分离器收集微粒，随后经由150μm筛来筛滤，该方法制备的微粒粒径分布比较宽，收率较低、药物释放周期短。
发明内容
本发明克服了上述现有技术的不足，提供了一种注射用曲安奈德微球植入剂及其制备方法，本发明采用丙交酯和乙交酯摩尔比85:15的PLGA，多孔玻璃(SPG)膜乳化法制备微球， 制备过程的连续相中添加PEG4000，获得了更窄的粒径分布，收率更高、前期突释得到改善，释放周期更长。
本发明的技术方案是：一种注射用曲安奈德微球植入剂，其特征是，它是包含曲安奈德(TCA)和聚合物载体的缓释微球，其中曲安奈德的含量为20～28％，聚合物是丙交酯乙交酯共聚物(PLGA)，其分子量为10KDa～55KDa，丙交酯和乙交酯的摩尔比为90:10～81:19；采用多孔玻璃(SPG)膜乳化法制备而成。
进一步的，在制备过程的连续相(PVA溶液中)中添加聚乙二醇(PEG)。优选的，所述PEG为PEG4000。
优选的，所述丙交酯和乙交酯的摩尔比为85:15。
本发明还公开了上述注射用曲安奈德微球植入剂的制备方法，其特征是，取曲安奈德、PLGA与二氯甲烷混合均匀，以一定压力通过SPG膜乳化膜管，分散到含有PEG4000的PVA溶液(连续相)中，磁力搅拌挥发溶剂，使微球固化，清洗掉PLGA在固化时没有完全包裹析出的曲安奈德，干燥，即得微球成品。
优选的，所述以8-15psi的压力通过孔径为30μm的SPG膜乳化膜管。
优选的，PVA溶液的质量浓度为1％，PVA溶液中PEG4000的质量浓度为0.05～0.1％。
优选的，所述清洗掉PLGA在固化时没有完全包裹析出的曲安奈德为：依次经乙醇水(乙醇的体积浓度40％～80％)、0.05～0.1％的PEG4000和纯水清洗。
本发明的有益效果是：与CN 103260603 B相比，获得了更窄的粒径分布(Span为1.23)，收率更高(收率80％以上)、前期突释得到改善(2小时突释4.6％)，制备的微球体外释放大于40天。
附图说明
图1为不同分子量PLGA(实施例4、9和10)对微球的累积释放的影响；
图2为同样的PLGA用两种制法(实施例1和11)得到的微球的累积释放图；
图3为采用不同比例丙交酯和乙交酯的PLGA(实施例4、11和12)得到的微球的累积释放图，其中实施例12是最上面的曲线，实施例4是最下面的曲线。
具体实施方式
以下结合实施例及附图对本发明进一步说明。按照以下的方法测定微球的载药量、粒径分布和体外累积释放。
载药量：照高效液相色谱法(中国药典2020年版通则0512)测定。取样品，精密称定，置100ml量瓶中，加DMSO溶解，加水稀释至刻度，摇匀，滤过，精密量取续滤液1ml，置10ml量瓶中，用流动相稀释至刻度，摇匀。对照品溶液：取曲安奈德对照品约10mg，精密 称定，置100ml量瓶中，加DMSO溶解并稀释至刻度，为对照品贮备溶液。精密量取对照品贮备溶液3ml，置10ml量瓶中，加流动相稀释至刻度，摇匀。用C18色谱柱，以甲醇∶水(525∶475)为流动相；检测波长为240nm；进样体积20μl。精密量取供试品溶液与对照品溶液20μl分别注入液相色谱仪，记录色谱图；按外标法以峰面积计算。
粒径分布：称取本品，加入约20ml分散剂(含磷酸盐与吐温80的水溶液)，振摇30秒混合均匀，置于超声中分散3min，再振摇30秒，全部倒入粒度测定仪中，分三次各加水5ml冲洗三角瓶，倒入激光粒度仪，照粒度和粒度分布测定法(中国药典2020年版通则0982第三法)测定，仪器的光学浓度应在8～20％之间，否则重新配制适当浓度的样品。以每分钟3000转的转速搅拌，并同时超声1min(超声频率40KHz，功率60W)，依法检查，连续测定，取两次测定平均值即得D 10、D 50、D 90的值。
体外累积释放：将4mg含有TCA的微球悬浮于37℃的20ml含0.5％的十二烷基硫酸钠(SDS)的磷酸盐缓冲溶液中，定期地取0.5ml介质并用新鲜介质替换，通过HPLC测定体外累积释放。
实施例1：采用CN 103260603 B的方法
取250mg的曲安奈德(TCA)、750mg的PLGA(分子量Mw 39KDa，按摩尔比，丙交酯：乙交酯75:25，特性黏度0.34dl/g)与15ml的二氯甲烷混合均匀，将上述分散体置于38～45℃的腔体，以约3300rpm的速度旋转转盘的给料孔，使分散体雾化成微小液滴。蒸发溶剂以产生固体微粒，收集微粒，筛滤。
实施例1采用CN 103260603 B介绍的方法，得微球的粒径分布为D 10：20μm，D 50：33μm，D 90：69μm，Span(粒径分布系数(D 90-D 10)/D 50)为1.48，收率为43.41％，载药量为25.25％，体外2小时释放率为5.3％。其释放性能与CN 103260603 B中描述的比较一致。
实施例2：SPG膜乳化法
取3.3g的曲安奈德、10g的PLGA(分子量44KDa，按摩尔比，丙交酯：乙交酯85:15，特性黏度0.35dl/g)与30ml的二氯甲烷混合均匀，以10psi的压力通过30μm孔径规格的SPG膜乳化膜管，分散到5L的1％PVA(聚乙烯醇)溶液中，常温常压磁力搅拌挥发溶剂，使微球固化，滤过，干燥，即得微球成品。
采用实施例2的SPG膜乳化法制得微球的粒径为D 10：21μm，D 50：48μm D 90：97μm，Span为1.58，收率为92.60％，载药量为24.61％。可见相比CN 103260603 B，其收率明显提高，但是载药量变低，对比2小时释放数据，实施例1为5.3％，实施例2为10.2％，有较明显突释效应。
虽然实施例2采用曲安奈德-二氯甲烷体系，用30μm孔径的SPG膜乳化膜管，在10psi 的压力下可以挤出规则、均一的微球，但是实施例2干燥后的微球表面不平整，有少量的曲安奈德没有被完全包裹在微球之中，这应该是由于曲安奈德和PLGA的性质不同，在二氯甲烷挥发的过程中，析出的速率不同而导致的某种程度上PLGA在固化时没有完全包裹析出的曲安奈德造成的，此部分的药物会造成突释。
实施例3：增加清洗步骤
在实施例2的基础上，微球固化完成后，增加乙醇水清洗和纯水清洗，滤过，干燥，即得微球成品。
实施例3所得微球，粒径D 50为52μm，载药量减小到22.53％，收率减小到83.1％，随着微球表面的曲安奈德结晶被洗掉，我们注意到释放也变慢，体外2小时释放为7.2％，突释效应比实施例2明显变小，但是比对实施例1还是有些差距，并且微球的粒径分布依然不是特别理想。
实施例4：加入0.05％的PEG4000
在实施例3的基础上，1％PVA溶液中加入0.05％的PEG4000，并且微球固化完成后，乙醇水清洗、0.05％的PEG4000清洗、纯水清洗，滤过，干燥，即得微球成品。实施例4所得微球，粒径分布更好，Span为1.23(D 10：27μm；D 50：53μm；D 90：92μm)，体外2小时突释为4.6％，载药量23.06％，收率85.5％。
实施例5：
采用0.05％的PEG300代替PEG4000，其余步骤同实施例4。
实施例6：
采用0.05％的PEG1600代替PEG4000，其余步骤同实施例4。
实施例4-6的效果对比如表1所示。
表1 不同规格PEG的效果对比
  实施例4 实施例5 实施例6
PEG分子量规格 4000 300 1600
Span 1.23 1.57 1.35
2小时突释％ 4.6 6.9 5.3
可见在连续相中添加不同分子量规格的PEG，随着其分子量的增加，前期突释更小，粒径分布也更好些。
实施例7：
PEG4000的添加量为0.02％，其余步骤同实施例4。
实施例8：
PEG4000的添加量0.1％，其余步骤同实施例4。
同样从微球的粒径和前期突释来看，0.02％的PEG4000效果没有0.05％以及0.1％的效果好。
实施例9：分子量29KDa的PLGA
取3.3g的曲安奈德、10g的PLGA(分子量29KDa，按摩尔比，丙交酯：乙交酯85:15，特性黏度0.28dl/g)与30ml的二氯甲烷混合均匀，以9psi的压力通过30μm孔径规格的SPG膜乳化膜管，分散到5L的含有0.05％的PEG4000的1％PVA溶液中，常温常压磁力搅拌挥发溶剂，使微球固化后，乙醇水清洗、0.05％的PEG4000清洗、纯水清洗，滤过，干燥，即得微球成品。
实施例10：分子量55KDa的PLGA
取3.3g的曲安奈德、10g的PLGA(分子量55KDa，按摩尔比，丙交酯：乙交酯85:15，特性黏度0.44dl/g)与30ml的二氯甲烷混合均匀，以15psi的压力通过30μm孔径规格的SPG膜乳化膜管，分散到5L的含有0.05％的PEG4000的1％PVA溶液中，常温常压磁力搅拌挥发溶剂，使微球固化后，乙醇水清洗、0.05％的PEG4000清洗、纯水清洗，滤过，干燥，即得微球成品。
不同的分子量PLGA对微球的累积释放和前期的突释影响都比较大(如图1所示)，实施例9(PLGA分子量29KDa)突释明显，实施例4(PLGA分子量44KDa)和实施例10(PLGA分子量55KDa)二者的前期突施无明显差异，实施例4的后期累计释放率较合适，适于制备体外释放大于40天的微球。
实施例11：
取3.3g的曲安奈德、10g的PLGA(分子量39KDa，按摩尔比，丙交酯：乙交酯75:25，特性黏度0.34dl/g)与30ml的二氯甲烷混合均匀，以10psi的压力通过30μm孔径规格的SPG膜乳化膜管，分散到5L的含有0.05％的PEG4000的1％PVA溶液中，常温常压磁力搅拌挥发溶剂，使微球固化后，乙醇水清洗、0.05％的PEG4000清洗、纯水清洗，滤过，干燥，即得微球成品。
如图2所示，与实施例1比较，同样的PLGA用两种制法得到的微球，其释放曲线有差别，SPG膜乳化制得的微球中后期释放更快一些。
实施例12：
取3.3g的曲安奈德、10g的PLGA(分子量40KDa，丙交酯：乙交酯50:50，特性黏度0.32dl/g)与30ml的二氯甲烷混合均匀，以10psi的压力通过30μm孔径规格的SPG膜乳化膜管，分散到5L的含有0.05％的PEG4000的1％PVA溶液中，常温常压磁力搅拌挥发溶剂， 使微球固化后，乙醇水清洗、0.05％的PEG4000清洗、纯水清洗，滤过，干燥，即得微球成品。
如图3所示，不同比例的PLGA(实施例4、11和12)对释放的影响比较大，用SPG膜乳化法制备体外释放大于40天的微球，PLGA采用摩尔比85:15的丙交酯-乙交酯比较适合。

Claims (9)

  1. 一种注射用曲安奈德微球植入剂，其特征是，它是包含曲安奈德和聚合物载体的缓释微球，其中曲安奈德的含量为20～28％，聚合物是丙交酯乙交酯共聚物PLGA，其分子量为10KDa～55KDa，丙交酯和乙交酯的摩尔比为90:10～81:19；采用多孔玻璃膜乳化法制备而成。
  2. 如权利要求1所述的一种注射用曲安奈德微球植入剂，其特征是，所述丙交酯和乙交酯的摩尔比为85:15。
  3. 如权利要求1所述的一种注射用曲安奈德微球植入剂，其特征是，在制备过程的连续相中添加聚乙二醇PEG。
  4. 如权利要求3所述的一种注射用曲安奈德微球植入剂，其特征是，所述PEG为PEG4000。
  5. 如权利要求1-4中任一项所述的一种注射用曲安奈德微球植入剂的制备方法，其特征是，取曲安奈德、PLGA与二氯甲烷混合均匀，以一定压力通过SPG膜乳化膜管，分散到含有PEG的PVA溶液中，磁力搅拌挥发溶剂，使微球固化，清洗掉PLGA在固化时没有完全包裹析出的曲安奈德，干燥，即得微球成品。
  6. 如权利要求5所述的一种注射用曲安奈德微球植入剂的制备方法，其特征是，所述以8-15psi的压力通过孔径为30μm的SPG膜乳化膜管。
  7. 如权利要求5所述的一种注射用曲安奈德微球植入剂的制备方法，其特征是，所述PVA溶液的质量浓度为1％。
  8. 如权利要求5所述的一种注射用曲安奈德微球植入剂的制备方法，其特征是，所述PEG为PEG4000，所述PVA溶液中PEG4000的质量浓度为0.05～0.1％。
  9. 如权利要求8所述的一种注射用曲安奈德微球植入剂的制备方法，其特征是，所述清洗掉PLGA在固化时没有完全包裹析出的曲安奈德为：依次经乙醇水、0.05～0.1％的PEG4000和纯水清洗。
PCT/CN2022/074209 2021-08-10 2022-01-27 一种注射用曲安奈德微球植入剂及其制备方法 WO2023015851A1 (zh)

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