WO2024119375A1 - 一种jak抑制剂长效微球及其制备方法与应用 - Google Patents

一种jak抑制剂长效微球及其制备方法与应用 Download PDF

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WO2024119375A1
WO2024119375A1 PCT/CN2022/136978 CN2022136978W WO2024119375A1 WO 2024119375 A1 WO2024119375 A1 WO 2024119375A1 CN 2022136978 W CN2022136978 W CN 2022136978W WO 2024119375 A1 WO2024119375 A1 WO 2024119375A1
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microspheres
jak inhibitor
acting
long
solution
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曹青日
吴欣虹
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Suzhou University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the technical field of pharmaceutical preparations, and in particular to a method for preparing long-acting microspheres of a JAK inhibitor.
  • JAK is a non-receptor tyrosine protein kinase that mediates the signals produced by cytokines and transmits them through the JAK-STAT signaling pathway.
  • JAK1 has become a target for diseases such as inflammation, cancer, and immunity
  • JAK2 is a target for blood system-related diseases
  • JAK3 is mainly a hot target for autoimmune diseases.
  • JAK inhibitors have been approved for marketing in China, namely Novartis's ruxolitinib, Eli Lilly's baricitinib, Pfizer's tofacitinib, AbbVie's upadacitinib, and Pfizer's abrocitinib.
  • the indications mainly cover rheumatoid arthritis, myelofibrosis, atopic dermatitis, etc.
  • Tofacitinib, ruxolitinib, baricitinib, upadacitinib and abrocitinib are JAK inhibitors for the treatment of rheumatoid diseases. They can effectively inhibit the activity of JAK1 and JKA3, thereby blocking the signal transduction of multiple inflammatory cytokines and effectively inhibiting the occurrence of inflammation. Compared with traditional anti-rheumatic drugs, JAK inhibitors can not only alleviate symptoms, but can even stop the damage of the disease to the body. They can be used for the treatment of organ transplantation, rheumatoid arthritis, ulcerative colitis, psoriasis and other inflammatory-related diseases.
  • the dosage form of existing JAK inhibitors is mainly tablets.
  • tofacitinib citrate tablets have been approved in the United States.
  • Each tablet contains 8 mg tofacitinib citrate, twice a day, for the treatment of rheumatoid arthritis, etc.
  • patients have poor compliance with medication, and considering that it has certain toxicity to the liver, it is of great significance to develop long-acting microspheres of JAK inhibitors.
  • the dosage form of JAK inhibitors listed in China is mainly tablets, and the development of sustained-release preparations is relatively small.
  • ethyl cellulose is used as a sustained-release coating material in CN113384544A, and a variety of excipients such as penetration enhancers, suspending agents, adhesives and lubricants are added to make tofacitinib sustained-release tablets.
  • the sustained-release effect can only reach 8 hours. Because a variety of excipients are added during its preparation process, the content of tofacitinib is 6% to 12%, and the drug content is low. Therefore, the development of a new type of sustained-release preparation with a longer sustained-release time and high drug content-long-acting microspheres of JAK inhibitors has a wider range of application scenarios.
  • microsphere preparations of JAK inhibitors have not been developed in the market.
  • microspheres as a new type of drug carrier, have great development advantages. Therefore, in order to further prepare drugs that can more effectively inhibit non-receptor tyrosine protein kinases, it is necessary to develop a longer-acting sustained-release preparation.
  • the purpose of the present invention is to provide a method for preparing long-acting sustained-release microspheres of JAK inhibitors, which is simple, efficient, has a high encapsulation rate, and can effectively solve the problems of instability of free drugs and short sustained-release time of traditional sustained-release preparations.
  • the present invention provides the following technical solutions.
  • a method for preparing long-acting microspheres of a JAK inhibitor comprises the following steps: mixing a JAK inhibitor solution with a solution containing a surfactant and a biocompatible polymer to obtain an oil phase; then dropping the oil phase into a first aqueous phase, stirring and pouring the mixture into a second aqueous phase, and then stirring, washing, and drying to obtain the long-acting microspheres of the JAK inhibitor.
  • the organic solvent is one or more of benzyl alcohol, dichloromethane, ethyl acetate, dimethyl sulfoxide, tetrahydrofuran or methanol, preferably, the organic solvent is benzyl alcohol, dichloromethane and ethyl acetate;
  • the biocompatible polymer is one or more of polylactic acid-co-glycolic acid (PLGA), polylactic acid (PLA), polylactic acid-polyethylene glycol (PLA-PEG) and polycaprolactone (PCL); preferably, the biocompatible polymer is polylactic acid-co-glycolic acid, and its relative molecular mass is 12000-150000 g/mol, wherein the molar ratio of lactide to glycolide is 85:15-50:50.
  • the molar ratio of PLGA lactide to glycolide is 75:25-50:50, more preferably 75:25.
  • the surfactant is one or more of poloxamer, polyethylene glycol, polyoxyethylene sorbitan monooleate, castor oil polyoxyethylene ether or sodium dodecylbenzene sulfonate.
  • the weight ratio of the JAK inhibitor, the biocompatible polymer and the surfactant is 1: (1-50): (0.05-5), preferably 1: (2-5): (0.1-1);
  • the concentration of the JAK inhibitor solution is 1%-20% (w/v), preferably 1%-10%, and the solvent is one or more of ethyl acetate, dichloromethane or benzyl alcohol;
  • the concentration of the biocompatible polymer is 1%-50% (w/v), preferably 1%-25% (w/v), and the solvent is one or more of ethyl acetate, dichloromethane or benzyl alcohol.
  • the volume ratio of the oil phase to the first aqueous phase is 1:1-50, preferably 1:2-15, and more preferably 1:3-10; the volume ratio of the second aqueous phase to the first aqueous phase is 2-20:1, preferably 2-15:1, and more preferably 3-10:1; preferably, the aqueous phase is a polyvinyl alcohol aqueous solution.
  • the present invention drips the oil phase into the first aqueous phase, stirs conventionally for 0.5 to 2 hours, then pours into the second aqueous phase, continues stirring for 0.5 to 1 hour, then washes and freeze-dries for 20 to 100 hours to obtain JAK inhibitor long-acting microspheres.
  • the present invention drips the oil phase into the first aqueous phase, stirs for 0.5 to 1 hour, then pours into the second aqueous phase, then stirs for 0.5 to 1 hour, then washes and freeze-dries for 30 to 60 hours to obtain JAK inhibitor long-acting microspheres.
  • the invention discloses the application of the JAK inhibitor long-acting microspheres in the preparation of sustained-release drugs.
  • the present invention forms an O/W emulsion by dissolving a JAK inhibitor and a biocompatible polymer in an organic solvent as a dispersant and a polyvinyl alcohol aqueous solution as a continuous phase, and then injects the organic solvent into the polyvinyl alcohol aqueous solution for a certain period of time to obtain a JAK inhibitor long-acting microsphere.
  • the JAK inhibitor and the biocompatible polymer are co-dissolved in an organic solvent, which can reduce drug loss and increase drug loading and encapsulation efficiency; the microspheres can be controlled to have a suitable particle size by adopting a reasonable process; in addition, further treatment with a polyvinyl alcohol aqueous solution can make the microspheres harder, avoid deformation during the collection process of the microspheres, and the microspheres have a good morphology.
  • the present invention has the following advantages.
  • the present invention uses JAK inhibitors, biocompatible polymers, and surfactants as raw materials to prepare drug-containing polymer solutions, adjusts the release rate of JAK inhibitor long-acting microspheres, and achieves long-acting release of JAK inhibitor microspheres.
  • the present invention selects the raw material ratio and preparation process, and the prepared JAK inhibitor long-acting microspheres have a high encapsulation rate, a suitable particle size, a round shape, a 4h release rate of 8%, no burst release phenomenon, and a subsequent long-term release, which can be slowly released for two weeks to one month, effectively improving patient compliance.
  • the preparation method of the present invention is simple, efficient and suitable for industrial production.
  • FIG1 is a chemical structural formula of a conventional JAK inhibitor.
  • FIG2 is a scanning electron micrograph of the JAK inhibitor long-acting microspheres prepared in Example 2 (400 ⁇ ).
  • FIG3 is an in vitro release curve of the JAK inhibitor long-acting microspheres of Example 2 and Comparative Examples 1-3 at 37° C. (0.02% TW20-PBS solution).
  • FIG4 shows the release curves of the JAK inhibitor long-acting microspheres of Example 2 and Comparative Examples 1-3 at 37° C. (0.02% TW20-PBS solution) in the first three days.
  • Microspheres are skeleton-type solid spheres formed by dissolving or dispersing drugs in biocompatible polymers, and their particle size ranges from 1 to 250 ⁇ m. After the drugs are made into microspheres, they have the following characteristics: masking the bad smell of the drugs, improving the stability of the drugs, reducing irritation to the stomach or reducing the inactivation of the drugs in the stomach, solidifying the liquid drugs for easy storage or re-formation into other dosage forms, controlling the drug release rate, etc.
  • the method for preparing JAK inhibitor long-acting microspheres of the present invention is as follows.
  • a JAK inhibitor is mixed with a biocompatible polymer (including a surfactant) and an organic solvent as a dispersed phase, and a polyvinyl alcohol aqueous solution is used as a continuous phase.
  • the dispersed phase is added dropwise into the continuous phase under conventional magnetic stirring to form an oil-in-water emulsion.
  • JAK inhibitors are tofacitinib, ruxolitinib, baricitinib, upadacitinib, and abrocitinib, and the chemical structure is shown in Figure 1.
  • the specific embodiments of the present invention are further described in detail below in conjunction with the accompanying drawings and examples.
  • the raw materials used in the present invention are existing products, and the specific preparation operations and tests are conventional techniques, such as stirring is a conventional technique, stirring the volatile organic solvent, and the oil phase is continuously dripped into the polyvinyl alcohol aqueous solution, and filtered using a 0.22 ⁇ m filter membrane.
  • stirring is a conventional technique, stirring the volatile organic solvent, and the oil phase is continuously dripped into the polyvinyl alcohol aqueous solution, and filtered using a 0.22 ⁇ m filter membrane.
  • the following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.
  • w/v represents the mass of the solute contained in every 100 ml of solution (expressed in g), for example, 40 mg tofacitinib is dissolved in 1.5 ml of benzyl alcohol, and the concentration of the solution is 2.7%.
  • poloxamer 407 were dissolved in 2.5 ml of ethyl acetate to obtain a polymer solution; the drug solution and the polymer solution were mixed and vortexed to disperse as the oil phase.
  • the oil phase was then added dropwise to 20 ml of polyvinyl alcohol aqueous solution (1wt%), stirred for 40 min, and then the dispersed system was poured into 100 ml of polyvinyl alcohol aqueous solution (1wt%), stirred for 2 h, filtered, washed with water 3 times, pre-frozen in a -80°C refrigerator for 8 h, and freeze-dried for 48 h to obtain microsphere powder.
  • poloxamer 407 in 2.5 ml of ethyl acetate
  • Microsphere morphology The microspheres prepared in Example 2 were taken and the microsphere morphology was measured by scanning electron microscopy. The results are shown in Figure 2. It can be seen that the tofacitinib long-acting microspheres have an appropriate particle size, are round, and have a good morphology.
  • Microsphere particle size Take the microspheres prepared above, suspend them in water, and measure the particle size of the microspheres with a laser particle size distribution analyzer. The results are shown in Table 1. The obtained microsphere particle size (specifically the median diameter) is less than 100 ⁇ m, which is suitable for injection.
  • the present invention prepares microspheres by adding an appropriate amount of surfactant to the oil phase, and the encapsulation rate of the prepared tofacitinib microspheres is higher than that of the method of adding sodium hydroxide or sodium chloride to the water phase to form pores, which is greater than 85%. It shows that the surfactant can not only effectively regulate the release of microspheres by forming pores, but also ensure a high encapsulation rate of microspheres.
  • the encapsulation rate of the microspheres prepared by PLGA is higher, which is greater than 85%. It shows that the encapsulation rate of the microspheres prepared by using PLGA macromolecular polymer is higher.
  • the microspheres prepared by the present invention have a high encapsulation rate, and can also effectively regulate the release of tofacitinib microspheres, so that tofacitinib can be slowly released within one month.
  • Example 2 adjusts the release rate by adding a surfactant to the high molecular weight PLGA (90 kDa), and the drug can be slowly released within one month. If an appropriate amount of surfactant is not added to the oil phase, the tofacitinib microspheres prepared by using small molecular weight PLGA (12 kDa) to form pores release 24.78% on the first day (large burst release), while the tofacitinib microspheres prepared by using large molecular weight PLGA (90 kDa) basically do not release in the first two weeks.
  • the preparation of microspheres by adding an appropriate amount of surfactant to the oil phase can not only improve the encapsulation rate but also significantly improve the release of tofacitinib long-acting microspheres compared to the method of adding sodium chloride to the solid phase to form pores in the microspheres. That is, the phenomenon of large burst release or basically no release of tofacitinib long-acting microspheres in the early stage is significantly improved, meeting the clinical drug needs.
  • the present invention adopts a method of combining PLGA macromolecular polymer with adding surfactant in the oil phase, and the prepared microspheres have a high encapsulation rate and the drug can be slowly released within one month, and can also ensure that the prepared tofacitinib microspheres have a high encapsulation rate.

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Abstract

一种JAK抑制剂长效缓释微球及其制备方法与应用。将JAK抑制剂与生物相容性聚合物（含表面活性剂）分别溶于有机溶剂后混合作为分散相，聚乙烯醇的水溶液作为连续相，并在搅拌下将分散相注入连续相中，形成水包油型乳液；然后搅拌使有机溶剂挥发，再将水包油型乳液注入聚乙烯醇水溶液中固化，最后用蒸馏水冲洗并收集微球，冷冻干燥得到JAK抑制剂长效微球。其能有效制备稳定包封高含量的JAK抑制剂微球，实现产业化，且制备所得JAK抑制剂微球可保证体内稳定有效药物浓度，并延长药物作用时间，可满足临床应用的需求。

Description

一种JAK抑制剂长效微球及其制备方法与应用 技术领域
本发明涉及药物制剂技术领域，具体涉及一种JAK抑制剂的长效微球的制备方法。
 背景技术
JAK是一种非受体型酪氨酸蛋白激酶，可介导细胞因子产生的信号，并通过JAK-STAT信号通路传递下去。JAK共有JAK1、JAK2、JAK3、TYK2四种亚型，亚型之间有重叠的结合对象。目前JAK1已成为炎症、癌症、免疫等疾病的靶点；JAK2是血液系统相关疾病的靶点；JAK3主要是自身免疫性疾病的热门靶点。目前，国内已有5款JAK抑制剂获批上市，分别为诺华的芦可替尼、礼来的巴瑞替尼、辉瑞的托法替尼、艾伯维的乌帕替尼、辉瑞的阿布昔替尼，适应症主要覆盖类风湿关节炎、骨髓纤维化、特应性皮炎等。
托法替尼、芦可替尼、巴瑞替尼、乌帕替尼和阿布昔替尼作为JAK抑制剂治疗类风湿性疾病，能有效抑制JAK1和JKA3的活性，从而阻断多种炎症细胞因子的信号转导，有效抑制炎症的发生。与传统的抗风湿药物相比，JAK抑制剂不仅能减轻症状，甚至能停止疾病对机体的损害。可用于器官移植，类风湿关节炎、溃疡性结肠炎、银屑病等多种炎症相关疾病的治疗。
现有JAK类抑制剂的剂型主要以片剂为主。例如，枸橼酸托法替尼片剂目前已在美国获批，每片含8mg枸橼酸托法替尼，每日两次，用以治疗类风湿关节炎等。因其治疗疗程较长，患者服药顺应性较差，同时考虑对肝脏有一定的毒性，因此研制JAK抑制剂的长效微球具有非常重要的意义。目前，国内上市的JAK抑制剂的剂型主要是片剂，缓释制剂的开发较少。其中，CN113384544A中采用乙基纤维素作为缓释包衣材料，加入促渗剂、助悬剂、粘合剂和润滑剂等多种辅料制成托法替尼缓释片剂，其缓释效果只能达到8小时，因其制备过程加入多种辅料成分，托法替尼的含量为6%～12%，含药量偏低。所以研制缓释时间更长、药物含量高的新型缓释制剂—JAK抑制剂的长效微球有更为广泛的应用场景。而且，目前在市场上，关于JAK抑制剂的长效微球制剂并未被开发，同时微球作为药物的新型载体，具有较大的发展优势，因此，为进一步制备出能更加有效地抑制非受体型酪氨酸蛋白激酶类药物，需要研制开发出一种更长效的缓释制剂。
 技术问题
本发明的目的是提供一种JAK抑制剂的长效缓释微球制备方法，简单高效、包封率高，能够有效解决游离药物不稳定、传统缓释制剂缓释时间较短等问题。
 技术解决方案
为实现上述目的，本发明提供了如下的技术方案。
一种JAK抑制剂长效微球的制备方法，包括以下步骤：将JAK抑制剂溶液与含有表面活性剂以及生物相容性聚合物的溶液混合，得到油相；再将油相滴加入第一水相，搅拌倒入第二水相，然后搅拌、洗涤、干燥，得到JAK抑制剂长效微球。
本发明中，油相中，有机溶剂为苯甲醇、二氯甲烷、乙酸乙酯、二甲基亚砜、四氢呋喃或甲醇中的一种或几种，优选的，有机溶剂为苯甲醇、二氯甲烷和乙酸乙酯；所述生物相容性聚合物为聚乳酸-羟基乙酸共聚物（PLGA）、聚乳酸（PLA）、聚乳酸-聚乙二醇（PLA-PEG）和聚己内酯（PCL）中的一种或几种；优选的，所述生物相容性聚合物为聚乳酸-羟基乙酸共聚物，其相对分子质量为12000～150000g/mol，其中，丙交脂与乙交酯的摩尔比为85:15～50:50。优选的，PLGA丙交脂与乙交酯的摩尔比为75:25～50:50，更优选为75:25。所述表面活性剂为泊洛沙姆、聚乙二醇、聚氧乙烯失水山梨醇单油酸酯、蓖麻油聚氧乙烯醚或十二烷基苯磺酸钠的一种或几种。
本发明中，所述JAK抑制剂、生物相容性聚合物、表面活性剂的重量比为1∶（1～50）∶（0.05～5），优选为1∶（2～5）∶（0.1～1）；JAK抑制剂溶液的浓度为1%～20% (w/v)，优选为1%～10%，溶剂为乙酸乙酯、二氯甲烷或苯甲醇的一种或几种；含有表面活性剂以及生物相容性聚合物的溶液中，生物相容性聚合物的浓度为1%～50%（w/v），优选为1%～25%（w/v），溶剂为乙酸乙酯、二氯甲烷或苯甲醇的一种或几种。
本发明中，油相与第一水相的体积比为1∶1～50，优选1∶2～15，进一步优选1∶3～10；所述第二水相与第一水相的体积比为2～20∶1，优选2～15∶1，进一步优选3～10∶1；优选的，水相为聚乙烯醇水溶液。
本发明将油相滴加入第一水相，常规搅拌0.5～2小时，再倒入第二水相，继续搅拌0.5～1小时，再洗涤、冷冻干燥20～100小时，得到JAK抑制剂长效微球。优选的，本发明将油相滴加入第一水相，搅拌0.5～1小时，再倒入第二水相，然后搅拌0.5～1小时，再洗涤、冷冻干燥30～60小时，得到JAK抑制剂长效微球。
本发明公开了上述JAK抑制剂长效微球在制备缓释药物中的应用。
本发明通过将JAK抑制剂与生物相容性聚合物溶于有机溶剂作为分散性，聚乙烯醇水溶液作为连续相，形成O/W乳液，有机溶剂充分挥发，再注入聚乙烯醇水溶液中一定时间，得到JAK抑制剂长效微球。JAK抑制剂与生物相容性聚合物共溶于有机溶剂中，可以降低药物损失，并提高载药量与包封率；采用合理的工艺，可以控制微球具有适宜的粒径；此外，用聚乙烯醇水溶液进一步处理，可使微球更加坚硬，避免微球的收集过程中发生变形，微球形态良好。
 有益效果
本发明具有以下优点。
（1）本发明以JAK抑制剂、生物相容性聚合物、表面活性剂为原料制备含药聚合物溶液，调节了JAK抑制剂长效微球的释放速度，实现JAK抑制剂微球的长效释放。
（2）本发明选择原料比例以及制备工艺，所制备的JAK抑制剂长效微球包封率较高，粒径适宜，形态圆整，4h释放度为8%，没有突释现象，后续长效释放，可缓慢释放二周至一个月，有效提高患者顺应性。
（3）本发明的制备方法简单高效，适合工业生产。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合附图详细说明如后。
 附图说明
图1为常规JAK抑制剂的化学结构式。
图2为实施例2制备的JAK抑制剂长效微球扫描电镜图（400×）。
图3为实施例2和对比例1-3的JAK抑制剂长效微球的37℃（0.02%TW20-PBS溶液）体外释放曲线。
图4为实施例2和对比例1-3的JAK抑制剂长效微球37℃（0.02%TW20-PBS溶液）前三天的释放曲线。
 本发明的实施方式
微球是通过将药物溶解或分散在生物相容性聚合物中形成的骨架型的实体小球，其粒径范围在1～250 μm之间。药物制成微球以后有以下特点：掩盖药物不良气味，提高药物的稳定性，减少对胃的刺激或减少药物在胃内的失活，使液态药物固态化便于贮存或再制成其他剂型，控制药物释放速率等。本发明制备JAK抑制剂长效微球的方法如下。
（1）将JAK抑制剂与生物相容性聚合物（含表面活性剂）、有机溶剂混合作为分散相，聚乙烯醇水溶液作为连续相，在常规磁力搅拌下将分散相滴加入连续相中，形成水包油型乳液。
（2）搅拌挥发乳液中的部分有机溶剂，将所得分散系统注入聚乙烯醇水溶液。
（3）用蒸馏水冲洗并收集微球，冷冻干燥（冷冻干燥机型号：FDU-2110）得到JAK抑制剂长效微球。
JAK抑制剂为托法替尼、芦可替尼、巴瑞替尼、乌帕替尼、阿布昔替尼，化学结构式如图1所示。下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。本发明采用的原料为现有产品，具体制备操作以及测试为常规技术，比如搅拌为常规技术，搅拌挥发有机溶剂，油相连续滴加至聚乙烯醇水溶液中，利用0.22 μm滤膜过滤。以下实施例用于说明本发明，但不用来限制本发明的范围。本发明中，溶液浓度中，w/v表示每100 ml溶液中含溶质的质量（以g表示），比如40 mg托法替尼溶于1.5 ml苯甲醇，溶液的浓度为2.7%。
实施例1。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和86 mg泊洛沙姆407溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min，再将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
实施例2。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和20 mg泊洛沙姆407溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min，再将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
实施例3。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和10 mg泊洛沙姆407溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min，再将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
实施例4。
称取40 mg巴瑞替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和10 mg泊洛沙姆407溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min，再将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
实施例5。
称取40 mg芦可替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和10 mg泊洛沙姆407溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
实施例6。
称取40 mg乌帕替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和10 mg泊洛沙姆407溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
实施例7。
称取40 mg阿布昔替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和10 mg泊洛沙姆407溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
实施例8。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和20 mg泊洛沙姆188溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至25 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min，再将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌0.5 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
实施例9。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和15mg泊洛沙姆338溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌30 min，再将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌45分钟，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
实施例10。
称取50 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（酯封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和10 mg泊洛沙姆407溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至30 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min，再将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌1 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
对比例1。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=12 kDa）溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
对比例2。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
对比例3。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%，含1mg/ml氯化钠）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
对比例4。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%，加入氢氧化钠调节pH至10）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
对比例5。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLA（羧封端, Mw=90 kDa）和10mg泊洛沙姆407溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
对比例6。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPCL（羧封端, Mw=90 kDa）和10mg泊洛沙姆407溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
对比例7。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和10mg氧乙烯（80）失水山梨醇单油酸酯溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
对比例8。
称取40 mg托法替尼溶于1.5 ml苯甲醇，得到药物溶液；取200 mgPLGA（羧封端丙交脂与乙交酯的摩尔比=75:25, Mw=90 kDa）和10 mg蓖麻油聚氧乙烯35醚溶于2.5 ml乙酸乙酯中，得到聚合物溶液；将药物溶液与聚合物溶液相互混合，涡旋分散，作为油相。再将油相滴加至20 ml聚乙烯醇水溶液（1wt%）中，搅拌40 min后，将分散体系倒入100 ml聚乙烯醇水溶液（1wt%）中，搅拌2 h，过滤后用水洗涤3次，放入-80℃冰箱预冻8 h后，冷冻干燥48 h，得到微球粉末。
测试例。
微球形态。取实施例2制备的微球，用扫描电镜测定微球形态，结果见图2，可见托法替尼长效微球粒度适宜，微球圆整，形态良好。
微球粒径：取上述制备的微球，各用水混悬，用激光粒度分布仪测定微球粒径，结果见表1，所得的微球粒径（特指中位径）小于100 μm，适合注射使用。微球载药量与包封率：分别称取10mg上述制备的微球，加入乙腈溶解微球后，加入pH=4.2, 0.02%PBS-TW20定容至50ml，取上清，12500rpm离心，取700μl进行HPLC分析，测得总药物浓度。称取10mg的微球，加入pH=4.2,0.02%PBS-TW20定容至50ml，取上清液，进行HPLC分析，测得游离药物浓度。总药物量-游离药物量为包载药物量，结果见表1。载药量与包封率的计算公式如下。
。
。
本发明通过在油相中添加适量表面活性剂制备微球较于在水相加入氢氧化钠或氯化钠致孔的方法，制备所得的托法替尼微球包封率更高，均大于85%。表明表面活性剂不仅致孔能有效调节微球释放，还能保证微球较高的包封率。另外相较于PLA和PCL而言，采用PLGA制备所得微球包封率更高，均大于85%。说明采用PLGA大分子聚合物制备所得微球包封率更高。综上所述，本发明制备所得微球，包封率较高，而且还能够有效调节托法替尼微球释放，使托法替尼能在一个月之内缓慢释放。
微球的体外释放曲线。
将6.8 g磷酸氢二钾和0.79 g氢氧化钠溶解于1000 mL水中，加入0.5% (w/v)吐温20，得到释放介质PBS-吐温20溶液。
将6.8 g磷酸氢二钾和0.79 g氢氧化钠溶解于1000 mL水中，得到释放介质PBS溶液。
分别称取20mg实施例2和对比例1-2制备的托法替尼缓释微球于50mL 具塞锥形瓶中，加入50ml0.02%TW20-PBS溶液，放入恒温37℃摇床（50 rpm），分别于4 h、1 d、3 d、7 d、14 d等不同时间点取样1ml，离心，取上清0.7ml用于HPLC分析，剩下微球用新鲜介质重新混悬继续放样，计算累积释放百分率，绘制累积释放百分率-时间的释放曲线图，结果见图3、图4。可以看出，托法替尼缓慢从微球中释放出来，释放曲线平缓，可持续释放一个月。其中，实施例2通过在大分子量的PLGA（90 kDa）加入表面活性剂调节释放度，药物能在一个月之内缓慢释放。如果未在油相中添加适量表面活性剂，采用小分子量PLGA（12 kDa）致孔制备所得托法替尼微球第一天释放24.78%（突释较大），而采用大分子量PLGA（90 kDa）制备所得的托法替尼微球前两周基本不释放。还可以看出，通过在油相中添加适量表面活性剂制备微球较于在固化相加入氯化钠使微球致孔的方法，以表面活性剂作为致孔剂，不仅能提高包封率而且还能显著改善托法替尼长效微球的释放度，即明显改善了托法替尼长效微球前期突释较大或者前期基本不释放的现象，满足临床用药需求。
本发明采用PLGA大分子聚合物结合在油相中加入表面活性的方法，制备所得的微球包封率较高且药物能在一个月之内缓慢释放，而且还能保证制备所得托法替尼微球具有较高包封率。
以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。

Claims (10)

  1. 一种JAK抑制剂长效微球的制备方法，其特征在于，包括以下步骤：将JAK抑制剂溶液与含有表面活性剂以及生物相容性聚合物的溶液混合，得到油相；再将油相滴加入第一水相，搅拌后倒入第二水相，然后搅拌、洗涤、干燥，得到JAK抑制剂长效微球。
  2. 如权利要求1所述JAK抑制剂长效微球的制备方法，其特征在于，油相中，有机溶剂为苯甲醇、二氯甲烷、乙酸乙酯、二甲基亚砜、四氢呋喃或甲醇中的一种或几种；所述生物相容性聚合物为聚乳酸-羟基乙酸共聚物、聚乳酸、聚乳酸-聚乙二醇、聚己内酯中的一种或几种；所述表面活性剂为泊洛沙姆、聚乙二醇、氧乙烯失水山梨醇单油酸酯、蓖麻油聚氧乙烯醚或十二烷基苯磺酸钠的一种或几种。
  3. 如权利要求1所述JAK抑制剂长效微球的制备方法，其特征在于，所述JAK抑制剂、生物相容性聚合物、表面活性剂的重量比为1∶（1～50）∶（0.05～5）。
  4. 如权利要求1所述JAK抑制剂长效微球的制备方法，其特征在于，JAK抑制剂溶液的浓度为1%～20%；含有表面活性剂以及生物相容性聚合物的溶液中，生物相容性聚合物的浓度为1%～50%。
  5. 如权利要求1所述JAK抑制剂长效微球的制备方法，其特征在于，油相与第一水相的体积比为1∶1～50；所述第二水相与第一水相的体积比为2～20∶1。
  6. 如权利要求1所述JAK抑制剂长效微球的制备方法，其特征在于，水相为聚乙烯醇水溶液。
  7. 如权利要求1所述JAK抑制剂长效微球的制备方法，其特征在于，将油相滴加入第一水相，搅拌0.5～2小时，再倒入第二水相，然后搅拌0.5～1小时，再洗涤、干燥，得到JAK抑制剂长效微球。
  8. 如权利要求1所述JAK抑制剂长效微球的制备方法，其特征在于，干燥为冷冻干燥。
  9. 如权利要求1所述JAK抑制剂长效微球的制备方法制备的JAK抑制剂长效微球。
  10. 权利要求9所述JAK抑制剂长效微球在制备缓释药物中的应用。
PCT/CN2022/136978 2022-12-06 2022-12-06 一种jak抑制剂长效微球及其制备方法与应用 Ceased WO2024119375A1 (zh)

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