Esomeprazole Magnesium

Strong Use of Composition-of-Matter Coverage: Patent protects the molecular structure of RHB-107, providing market exclusivity beyond method-of-use claims COVID-19 Therapeutic Use: Includes coverage for treatment of SARS-CoV-2, including wild-type and emerging variants This patent grant enhances RedHill's strategic positioning in the global COVID-19 therapeutic space, a market still expected to be worth more than $3 billion in 2025[1], and expands its patent footprint in Asia, a key pharmaceutical market RHB-107 successfully met the primary endpoint of safety and tolerability, delivering promising reduction in hospitalization efficacy results in a U.S. Phase 2 COVID-19 study[2]. Additional clinical data expected from the externally non-dilutive funded PROTECT study, supported by the U.S. Department of Defense RHB-107 is a novel, patient-friendly oral, once-daily, host-directed potential broad-acting antiviral expected to act independently of viral spike protein mutations[3] RALEIGH, N.C. and TEL-AVIV, Israel, April 28, 2025 /PRNewswire/ -- RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, today announced that the China National Intellectual Property Administration ("CNIPA") has formally allowed a critical use of composition-of-matter patent for RedHill's proprietary investigational compound RHB-107 (upamostat), a potential oral treatment for COVID-19 (patent application No. 202311591091.6). "This newly allowed Chinese patent application is a significant success, enhancing RedHill's strategic positioning in the global COVID-19 therapeutic space – a market still expected to be worth more than three billion dollars in 2025. It provides broad and robust protection of the use of RHB-107, including its structure in oral formulations targeting SARS-CoV-2 infections, including both wild-type and naturally occurring variants and expanding its patent footprint in Asia, a key pharmaceutical market," said Guy Goldberg, RedHill's Chief Business Officer. "It underscores the uniqueness of our antiviral candidate and further strengthens our global intellectual property portfolio as we advance development of a much-needed oral candidate for early, community-based (non-hospitalized) treatment of COVID-19, which still represents a considerable threat to vulnerable patients. As a novel, potentially broad-acting, host-directed antiviral that is expected to act independently of viral spike protein mutations, RHB-107, if approved, could provide a much-needed additional option for use in the early COVID-19 treatment space, alongside Pfizer's Paxlovid." Data from RHB-107's U.S. Phase 2 study, published in the International Journal of Infectious Diseases, showed a 100% reduction in hospitalization due to COVID-19, with zero patients (0/41) on the RHB-107 arms versus 15% (3/20) hospitalized for COVID-19 on the placebo-controlled arm (nominal p-value=0.0317). The study also showed an approximately 88% reduction in reported new severe COVID-19 symptoms after treatment initiation, with new severe COVID-19 symptoms reported by only 2.4% of the RHB-107 treated group (1/41) compared to 20% (4/20) of patients in the placebo-controlled arm (nominal p-value=0.036). Further post-hoc analysis showed faster recovery periods from severe COVID-19 symptoms with a median of 3 days to recovery with RHB-107 compared to 8 days with placebo. Additional clinical data is expected from the externally non-dilutive funded PROTECT study, supported by the U.S. Department of Defense. About RHB-107 (upamostat) RHB-107 is a proprietary, first-in-class, once-daily orally administered investigational antiviral, that targets human serine proteases involved in preparing the spike protein for viral entry into target cells. Because it is host-cell targeted, RHB-107 is expected to also be effective against emerging viral variants with mutations in the spike protein. RHB-107 is well tolerated; in the initial COVID-19 study, among 41 patients only one reported a drug-related adverse reaction (a mild, self-limited, rash). In addition, RHB-107 inhibits several proteases targeting cancer and inflammatory gastrointestinal disease. RHB-107 has undergone several Phase 1 studies and two Phase 2 studies, demonstrating its clinical safety profile in approximately 200 patients[4]. RedHill acquired the exclusive worldwide rights to RHB-107, excluding China, Hong Kong, Taiwan and Macao, from Germany's Heidelberg Pharma AG (FSE: HPHA) (formerly WILEX AG) for all indications. About RedHill Biopharma RedHill Biopharma Ltd. (Nasdaq: RDHL) is a specialty biopharmaceutical company primarily focused on U.S. development and commercialization of drugs for gastrointestinal diseases, infectious diseases and oncology. RedHill promotes the FDA-approved gastrointestinal drug Talicia, for the treatment of Helicobacter pylori (H. pylori) infection in adults[5], with submission planned for marketing authorization in other territories. RedHill's key clinical late-stage development programs include: (i) opaganib (ABC294640), a first-in-class, orally administered sphingosine kinase-2 (SPHK2) selective inhibitor with anticancer, anti-inflammatory and antiviral activity, targeting multiple indications with U.S. Government and academic collaborations for development for radiation and chemical exposure indications such as Gastrointestinal-Acute Radiation Syndrome (GI-ARS), a Phase 2 study in prostate cancer in combination with Bayer's darolutamide and a Phase 2/3 program for hospitalized COVID-19 patients; (ii) RHB-204, an all-in-one, fixed-dose, orally administered, combination antibiotic therapy with a planned Phase 2 study for Crohn's disease and Phase 3-stage for pulmonary nontuberculous mycobacterial (NTM) disease; (iii) RHB-104, with positive results from a first Phase 3 study for Crohn's disease; (iv) RHB-107 ( upamostat), an oral broad-acting, host-directed, serine protease inhibitor with potential for pandemic preparedness, is in late-stage development as a treatment for non-hospitalized symptomatic COVID-19 and is also targeting multiple other cancer and inflammatory gastrointestinal diseases; and (v) RHB-102, with potential UK submission for chemotherapy and radiotherapy induced nausea and vomiting, positive results from a Phase 3 study for acute gastroenteritis and gastritis and positive results from a Phase 2 study for IBS-D. RHB-102 is partnered with Hyloris Pharma (EBR: HYL) for worldwide development and commercialization outside North America. More information about the Company is available at: / twitter.com/RedHillBio. Forward Looking Statement This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 and may discuss investment opportunities, stock analysis, financial performance, investor relations, and market trends. Such statements may be preceded by the words "intends," "may," "will," "plans," "expects," "anticipates," "projects," "predicts," "estimates," "aims," "believes," "hopes," "potential" or similar words. Forward-looking statements are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Company's control and cannot be predicted or quantified, and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties include, without limitation: market and other conditions; the Company's ability to regain and maintain compliance with the Nasdaq Capital Market's listing requirements; the risk that the addition of new revenue generating products or out-licensing transactions will not occur; the risk of current uncertainty regarding U.S. government research and development funding and that the U.S. government is under no obligation to continue to support development of our products and can cease such support at any time; the risk that the CNIPA does not grant the patent in a timely manner or at all; the risk that acceptance onto the RNCP Product Development Pipeline or other governmental and non-governmental development programs will not guarantee ongoing development or that any such development will not be completed or successful; the risk that the FDA does not agree with the Company's proposed development plans for its programs; the risk that the Company's development programs and studies may not be successful and, even if successful, such studies and results may not be sufficient for regulatory applications, including emergency use or marketing applications, and that additional studies may be required; the risk of market and other conditions and that the Company will not successfully commercialize its products; as well as risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company's research, manufacturing, pre-clinical studies, clinical trials, and other therapeutic candidate development efforts, and the timing of the commercial launch of its commercial products and ones it may acquire or develop in the future; (ii) the Company's ability to advance its therapeutic candidates into clinical trials or to successfully complete its pre-clinical studies or clinical trials or the development of any necessary commercial companion diagnostics; (iii) the extent and number and type of additional studies that the Company may be required to conduct and the Company's receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings, approvals and feedback; (iv) the manufacturing, clinical development, commercialization, and market acceptance of the Company's therapeutic candidates and Talicia®; (v) the Company's ability to successfully commercialize and promote Talicia®; (vi) the Company's ability to establish and maintain corporate collaborations; (vii) the Company's ability to acquire products approved for marketing in the U.S. that achieve commercial success and build its own marketing and commercialization capabilities; (viii) the interpretation of the properties and characteristics of the Company's therapeutic candidates and the results obtained with its therapeutic candidates in research, pre-clinical studies or clinical trials; (ix) the implementation of the Company's business model, strategic plans for its business and therapeutic candidates; (x) the scope of protection the Company is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; (xi) parties from whom the Company licenses its intellectual property defaulting in their obligations to the Company; (xii) estimates of the Company's expenses, future revenues, capital requirements and needs for additional financing; (xiii) the effect of patients suffering adverse experiences using investigative drugs under the Company's Expanded Access Program; (xiv) competition from other companies and technologies within the Company's industry; and (xv) the hiring and employment commencement date of executive managers. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's filings with the Securities and Exchange Commission (SEC), including the Company's Annual Report on Form 20-F filed with the SEC on April 10, 2025. All forward-looking statements included in this press release are made only as of the date of this press release. The Company assumes no obligation to update any written or oral forward-looking statement, whether as a result of new information, future events or otherwise unless required by law. Category: R&D [1] [2] A randomized, placebo-controlled pilot study of upamostat, a host-directed serine protease inhibitor, for outpatient treatment of COVID-19 Plasse, Terry F et al. International Journal of Infectious Diseases, Volume 128, 148 – 156. [3] Preliminary data from a recent in vitro study. [4] (22)00638-5/fulltext. [5] Talicia® (omeprazole magnesium, amoxicillin and rifabutin) is indicated for the treatment of H. pylori infection in adults. For full prescribing information see: . Company contact: Adi Frish Chief Corporate & Business Development Officer RedHill Biopharma +972-54-6543-112 [email protected] Logo: SOURCE RedHill Biopharma Ltd. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

“点击蓝字 关注我们叶英力品药业（厦门）股份有限公司董事长，博士。“国家重大人才计划”特聘专家，福建省省级高层次人才（A 类），厦门大学兼职教授，国家“十三五”重大新药创制科技重大专项课题负责人。日本大阪大学博士，美国加州大学尔湾分校博士后，回国前在美国三家生物医药上市公司从事创新药、505(b)(2) 新药以及缓控释给药系统的开发。专注于创新制剂和复杂制剂的产业化开发。带领团队创建了国际国内领先的口腔黏膜给药系统技术平台、气体微球技术平台，成功开发了多个全球首创和国内独家产品，其中 6 款创新制剂和复杂制剂产品获得美国 FDA 批准上市。朱海健力品药业（厦门）股份有限公司总经理，博士。“国家重大人才计划”特聘专家，福建省省级高层次人才（A 类），厦门大学药学院兼职教授，中国药科大学产业教授，国家“十三五”重大新药创制科技重大专项课题负责人。在美国明尼苏达大学获得药剂学博士学位，曾任职于美国 GSK 和Forest 公司，负责 10 余个重磅级创新药的开发。在创新制剂领域成果卓著，发表论文 20 余篇，拥有 20 多项国际国内专利，参与国际会议报告 60 余次。带领团队创建了多个具有知识产权保护的制剂技术平台，公司膜剂制剂平台、缓控释制剂平台和气体微球制剂平台产出的多款产品已获批生产并在国内外上市销售。微型片剂给药系统研究进展 PPS 林福祥，石添香，曹圣楷，苏斌，余勇，朱海健 *，叶英 **（力品药业（厦门）股份有限公司，福建 厦门 361027）[ 摘要 ] 在国家政策的鼓励下，创新制剂和复杂制剂作为医药创新的主要驱动力得到广泛应用并填补了未被满足的临床需求。然而，儿童和老年患者的个性化治疗研究进展缓慢，面临用药困难的局面，亟需给药系统的创新突破。微型片剂具有易于吞咽、剂量准确、可灵活调整和释放模式多样化等特点，可满足多样化的治疗需求，特别是在儿童和老年患者群体中，已被证明是一种高依从性的剂型，展现出优异的应用前景。介绍了微型片剂的剂型特点、临床优势及国内外研究进展，并重点分析了微型片剂开发技术所面临的挑战，旨在为微型片剂给药系统的研发提供参考。1引言一直以来，口服药物递送被公认为最简单有效的药物递送方法，超 60% 左右的小分子药物采用口服给药途径。然而，传统的普通口服固体制剂如果体积较大，在儿童和老年人使用过程中，可能存在吞咽困难等问题，导致治疗依从性差。此外，某些疾病状况会减弱喉咙肌肉的收缩能力，使吞咽变得困难，这就需要将药物制备成口服混悬液或颗粒剂、分散片、口崩片等，或分割片剂来解决吞咽困难，而这些做法会带来崩解、溶出甚至生物利用度等生物药剂学行为的改变，以及剂量准确性、稳定性、安全性和疗效方面的风险。另外对于需要按体重/体表面积折算剂量的药物，或需要按临床治疗要求递增剂量或逐渐撤药的情形，普通片剂剂量调整不方便。微型片剂（mini-tablet，以下简称微片）的出现与发展，为上述问题的解决提供了一个新的途径。微片是指经特制设备制备而成的片剂，直径通常小于 3 mm[1]，有文献将 4 mm 以内的片剂也归为微片 [2]，该类片剂外观上明显小于普通片剂（见图1）。微片具有尺寸小易吞服、剂量准确、可灵活调整剂量等优点，另外通过组合不同功能微片，可以实现多模态释放和复方组合，满足不同的临床治疗需求，为儿童和老年人的个性化医疗以及定制药物输送系统提供了重大机遇。有关微片的早期文献可追溯到 1984 年，Najemnik 等 [3] 首次设计出一种瓜尔胶微片，但受限于微片冲模技术、制造表征设备、质量研究和临床评价等，微片在当时并未受到广泛的关注。随着制备技术的发展以及微片临床可接受性研究机会的增加，微片研究在过去的 20 多年里迅速增长 [4]（见图 2）。自 1991 年首个微片制剂 Panzytrat 在新西兰上市以来，已有十几款微片药品在全球范围内获批上市。表 1 汇总了国内外上市的部分微片产品。目前欧美国家尚无针对微片的特定指南，普遍认为开发口服固体药物产品的指南同样适用于微片，需关注微片制剂的吞咽性、口感和可接受性的临床测试。在我国，2024 年 2 月国家药品监督管理局（NMPA）药品审评中心（CDE）发布了全球首个关于微片的开发指南——《微型片剂（化学药品）药学研究技术指导原则（试行）》，为微片研究提供了法规依据和支持，受到了制药行业的广泛关注。本文介绍了微片的剂型特点和临床优势，以及分类和应用，并重点分析了微片的制备技术及其质量评价的最新进展和所面临的挑战，旨在为微片给药系统的开发提供参考。2微片的特点和临床优势微片作为一种有前景的患者友好型药物输送系统，特别适用于存在吞咽困难的患者群体（例如儿童与老年患者）。目前已上市和在研的微片产品主要用于治疗帕金森病、癫痫、心律失常、多发性硬化症及高脂血症等疾病。微片的临床特点和优势主要体现在以下几个方面。2.1 用药依从性良好微片尺寸小，能够显著减少吞咽障碍，适用于吞咽困难的老人、儿童。多项临床研究 [5-8] 表明不同年龄段儿童（0.6 个月 ~ 7 岁）对口服微片具有良好的可接受性，大部分可整片吞服，安全性高、依从性好。微片还可以通过包衣等技术，减少在口腔中的药物释放，实现良好的掩味 [9-10]。2.2 剂量准确且可灵活调整微片可以通过增减片数灵活调整剂量，从而提供个体化给药方案。微片很好地解决了儿童分药难问题，减少了传统固体制剂因分剂量而造成的误差，同时降低污染风险，比传统刻痕片更具优势。2.3 灵活组合给药或设计成复方制剂，满足不同临床需求可以根据疾病治疗要求将不同药物进行组合，从而设计成复方制剂，如用大胶囊装填 2 种及以上的药物微片，或将不同微片分别装入小胶囊再装填到大胶囊中。Sarangi 等 [11] 开发了一种可用于治疗肺动脉高压的联合用药胶囊，胶囊中同时包含波生坦缓释微片和枸橼酸西地那非速释微片。微片灵活的组合方式使其在复杂给药方案中展现了独特的临床价值。2.4 可控制药物释放速率通过组合具有不同释放模式的微片，可达到预期的释放曲线，以满足临床上对不同疾病的治疗需求。Ugurlu 等 [12] 开发了一种右旋酮洛芬氨丁三醇的脉冲给药胶囊，胶囊中包含速释微片和结肠释放微片，可实现 1 h 快速释放，并持续 12 h。2.5 稳定性良好虽然液体制剂因适合低龄儿童吞咽且便于控制剂量而受到青睐，但其所含的稳定剂如防腐剂、抗氧化剂等，存在一定的安全隐患。此外，液体制剂运输和储存成本相对较高。微片既有液体制剂灵活给药的特点，又有固体制剂良好的稳定性，易于包装和携带 [13]。3微片的分类和应用目前国内外对微片的研究主要集中于口服用药领域，同时微片在其他领域也逐步展现出应用潜力，如眼科用药和阴道用药等。根据应用领域和功能，口服微片主要有速释微片、缓控释微片、迟释微片、胃滞留微片、双相微片等，而非口服微片有眼用微片与阴道微片等。3.1 速释微片速释微片口服后迅速释放药物成分，达到快速起效的目的。如帕金森病治疗药物 Flexilev[14]，为左旋多巴和苄丝肼的复方微片，易崩解成细颗粒分散在水中或口腔中，适合吞咽困难的患者服用。3.2 缓控释微片缓控释微片在服用后药物缓慢释放，与速释制剂相比可以降低给药频率，减少血药波动，提高患者的依从性和降低药物的毒副作用。缓控释微片主要有膜控型微片、骨架型微片和表面积控制型微片。3.2.1 膜控型微片 膜控型微片选用缓控释包衣材料进行包衣，通过调整包衣材料规格和包衣增重控制缓控释行为。如上市产品丙戊酸钠缓释微片 Orfiril long[15]，采用了水不溶性的季胺基甲基丙烯酸酯共聚物 B 型（非 pH 依赖型）联合致孔剂包衣来达到缓释效果。3.2.2 骨架型微片 该类型微片选择缓释骨架材料发挥缓释作用，通过调节骨架材料类型和用量改变药物的释放行为。李婉斯 [16] 采用羟丙甲纤维素缓释骨架材料，分别制备了牛黄、麝香及乳香没药超临界提取物缓释微片，并将 3 种缓释微片装入胶囊中，结果显示 6 个指标性成分（胆酸、麝香酮、醋酸辛酯、11-羰基-β-乙酰乳香酸、β-乳香酸、β-榄香酮酸）的2 h 释放度均小于 29.03%，6 h 释放度均在 54.82% ~ 60.44% 范围内，10 h 均可达 90.31%，实现了多组分同步均衡释放。3.2.3 表面积控制型微片 该类型微片通过其表面溶蚀和溶解，控制药物释放速度。如上市产品 Rythmol SR[17]，微片处方中原料药（API）占比达90% 以上，处方中没有缓释辅料，通过微片表面溶蚀发挥缓释作用。3.3 迟释微片迟释微片在口服给药后不立即释放药物，而到肠内才开始释放药物。如上市产品 Tecfidera[18]，采用肠溶材料甲基丙烯酸共聚物 A 型包衣，使药物在肠中释放，从而减少了对胃的刺激，降低了不良反应。3.4 胃滞留微片胃滞留微片利用流体动力学平衡原理或选用生物黏附性材料，使药物能长时间漂浮或黏附于胃中，延长药物在胃中的停留、释放时间，从而改善药物的吸收，提高生物利用度，适合在胃肠道上段有吸收窗或在肠中性质不稳定的药物。根据释放机制的不同，胃滞留微片主要有胃漂浮型和生物黏附型。3.4.1 胃漂浮微片 胃漂浮微片采用具有膨胀性质的材料、低密度的材料或组合泡腾剂等，可实现胃内漂浮。盐酸氯他弗林是一种抗痉挛药物，腹泻时在肠内停留时间短，生物利用度差，需频繁给药，Louis 等 [19] 以海藻酸钠和碳酸氢钠制备了盐酸氯他弗林胃漂浮微片，其在兔体内生物利用度显著高于市售产品。3.4.2 黏附型微片 黏附型微片采用具有黏附作用的辅料，使得微片黏附于胃黏膜上，从而延长药物停留与释放时间。Rump 等 [20] 制备了含有黏附材料卡波姆 71G NF 的微片，其在 11 名健康受试者禁食状态下的胃停留时间明显延长。3.5 双相微片将速释和缓释微片进行组合，速释部分可以使血药浓度迅速提高，快速起效；而缓释部分使血药浓度持续平稳，药效持久。Kwon 等 [21] 开发了一种双释药型艾司奥美拉唑镁微片，速释微片 15 min 快速释放完全，缓释微片可持续释放 360 min。3.6 眼用微片滴眼剂是眼部给药的首选剂型，但在眨眼、流泪等因素的影响下，药物停留时间变短，生物利用度低，因而需要频繁给药。眼用微片通过局部给药延长药物与角膜的接触时间，从而延长释药时间，提高生物利用度。此外，微片不含防腐剂，可减少过敏反应的风险。Abd El-Bary 等 [22] 将左氧氟沙星制备成零级缓释黏附微片，可达到 24 h 缓释且无副作用。3.7 阴道微片阴道的自洁作用和普通固体制剂的重力作用，限制了药物在阴道内的停留和吸收。生物黏附型微片质量小，可均匀黏附在阴道中，改善药物的滞留时间，从而延长药效。Hiorth 等 [23] 开发了一种己基氢氯酸铵生物黏附型微片，其具有优良的阴道组织生物黏性及非 pH 依赖的控制释药特性。4微片开发的关键技术和挑战虽然微片具有上述众多的临床优势和应用潜力，但其研究起步较晚，研究成果较少，上市的微片产品并不多。此外，微片技术还未完全成熟固化，研发与产业化面临着诸多技术挑战，例如：需特殊定制冲模，微型冲头直径小，对吻合性与耐用性要求高，使用不当易折断或变形，不利于成本控制；对颗粒粉体特性要求极高，适用范围受限；填充设备需定制计量盘，并具备在线控制功能；微片装入胶囊后贮存或胶囊溶解过程中可能出现微片的黏结，影响整体制剂的质量。这些技术挑战均提高了微片研发准入的技术门槛和成本。笔者所在团队结合自身研发经验，认为微片的开发应特别关注颗粒的粉体特性、微片冲模的设计以及生产过程控制等。4.1 颗粒的粉体特性相比于传统片剂，微片研发更加注重原辅料的粉体特性（粒径分布、流动性等），这些指标影响粉末进入中模内孔的顺畅性，是微片生产的关键因素。药物颗粒/粉末的粒径不宜过大，否则将影响压力的传递和产品的均一性。Shah 等 [24] 认为药物颗粒/粉末大小与模孔直径比值在 1∶30 ~ 1∶20 可以最小化重量差异。另有文献报道当膜孔直径与颗粒/粉末最大粒径（D99）之比大于 3 时，粉末不会造成模孔堵塞 [25]。良好的流动性能确保混合物快速均匀地流入模孔，否则影响填充准确性。Flemming 等 [26] 研究了 11 种直压型辅料的流速，结果显示喷雾干燥乳糖DCL11 型和 FLOW 型最优，这 2 种辅料的 Hausner指数不超过1.25，在孔径1.5 mm的流速大于49 mg·s -1 。微片压片需要的流速与微片体积以及压片停留时间有关，体积越大，停留时间越短，对流速的要求更高。当起始原辅料的粒径、流动性等不能满足生产要求时，可通过制粒手段进行改善。Elezaj 等 [10] 在开发儿童用氯沙坦钾微片时发现，由于原料药占比高，采用直压工艺，总混物的流动性差、易黏冲，通过采用干法制粒和调整处方，成功解决了这些问题。随着现代制药技术的不断发展，一些新兴技术也被逐步应用到微片研发与生产领域，如 3D 打印 [27]、DoD 打印 [28]、静电纺丝 [29] 等，这些技术可以实现高精度、高复杂度的微片结构，为微片的发展带来了新的机遇。4.2 微片冲模的设计冲模是微片制备最关键的部件。冲模设计重点考虑冲针直径、数量、分布、弧度、精度、材质、组合方式等 [1]，具体要求应结合产品设计、生产可行性、产量要求等。微片的冲模尺寸最终影响微片的大小，已上市微片药品的直径多在2~3 mm范围，且以2 mm居多。微片的厚度尽量保持和直径一致，有助于后续的加工和临床使用。微片的冲针数量可以从几个到几十个不等，能够同时压制多个微片，显著提高生产效率。Martin[30] 对比了 7 种不同弧度的冲针，其中平面型（Flat）价格低廉，易于测量和维护，但包衣容易发生黏片。另外平面斜边（FFBE）或平面半径（FFRE），是非包衣微片首选外形。冲针弧度不宜过高，因为中间位置受力小，可能导致裂片。对于微片冲模的尺寸公差目前尚无具体规定，但基于微片压片的特殊性，为了冲针与中模孔的准确对位，避免变形和断裂，微片冲针、中模的孔径尺寸公差须严于普通片剂。微片冲模材质一般应兼具硬度和韧性，根据微片冲模制备厂家的公开资料 [31]，S-7 钢、A-2 钢、440C 钢等材质等均适用于微片冲模的制备。商业化的微片冲模分为组装型和整体型。组装型可以更换受损冲针，更具灵活性和性价比，它又可分为内嵌型、外嵌型和销固定型 3 种，其中又以内嵌型更佳，易拆装，可快速更换冲针。整体型无法拆卸，冲针破损后无法更换，任何一根冲针损坏均会导致整个冲模无法继续使用。4.3 生产过程控制4.3.1 混合 混合均匀度是制剂混合工序的关键考察指标，《微型片剂（化学药品）药学研究技术指导原则（试行）》[1] 建议对混合工序的加料顺序、混合速度和时间等参数进行研究。Hagen 等 [32] 探索了提高微片混合均匀度的手段，重点考察了甘露醇粒径大小、混合设备、混合时间和取样量大小对混合均匀性的影响。4.3.2 压片 压片工序是微片与普通片区别最大的单元操作。压片过程中冲针的完整与否是影响微片质量和生产效率的关键因素。冲针的磨损、变形、断裂等受损情况会直接导致微片的外观不合格，硬度、重量差异超限等。因此在拆、装、使用过程中均需比普通冲模更小心，避免冲针磕碰变形或损坏。另外在压片过程中，应及时监控压片压力、微片外观、硬度、片重等，也可借助金属检测器监测冲针是否断裂和残缺。开始压片时的压力不宜过大，理论上冲头压力等于单冲针的额定压力乘以冲针的数量，考虑到压片机可能出现的轻微移位和磨损，使模具承受额外的压力，建议开始压片时所用压力应小于 70% 额定压力 [33]。微片压制除了需要高质量的冲模，还需要压片机具备较高的精度和稳定性。如果配件间组合不严密，可能导致漏粉和飞粉的情况 [34]，另外在生产过程中因机械振动等原因可能造成冲模移位或堵塞，导致冲头折断或变形。选用有预压功能的压片机更有利于微片成型及保护冲针。4.3.3 包衣 包衣的前提是微片芯具有良好的脆碎度，通常不得高于 0.5%。目前微片包衣技术主要为流化床包衣和锅包衣，两者原理不同，包衣参数和注意事项各有特点。4.3.3.1 流化床包衣 包衣过程需平衡流化状态，使微片处于有序的循环状态。相比于微丸，微片体积、密度更大，需要更大的气体流速才能将其流化。气流分布板是流化床包衣机中的关键部件，分布板开孔率、孔道性状会影响流态状态、包衣效率和质量。不同开孔率的气流分布板适用于不同粒径大小的物料，文献报道采用“C”孔板 [35] 和“D”孔板 [24] 均可满足微片的包衣。4.3.3.2 锅包衣 相比于流化床包衣，锅包衣具有以下优势：1）黏片风险低；2）破碎风险低；3）包衣产量更大；4）包衣时间短 [36-37]。如果采用普通的包衣锅，微片容易从孔径中掉落，因此需要特殊定制的包衣锅。Funaro 等 [36] 在普通侧通风包衣锅中安装 0.8 mm 楔形筛网，成功实现微片（2.5 mm）的包衣，并在批量逐步放大的包衣实验中观察到良好的工艺可扩展性，包衣过程顺利无偏差。4.3.4 包装 目前微片上市产品主流包装形式为胶囊包装、条袋装，也有采用微片分配器。Hejduk 等 [38] 总结了多种类型的微片包装形式，并对每种形式的特点、优缺点以及适用场景进行了详细的描述和评价。该团队认为胶囊包装、袋装为常见的药品包装形式，可以提供良好的给药方法，但微片分配器仍具有广泛的临床需求，它可以帮助患者和护理人员准确地获得基于所需剂量的确切数量微片，同时保障在计数之前片剂不与外界接触，降低污染风险。无论选择哪种包装方式，确保填充数量准确是包装的基本要求。主流计量方式分为非在线控制和在线控制两种。非在线控制通常只采用计量盘进行计数，孔槽开孔数量根据填充数量定制，可能出现缺粒现象；在线控制通常为计量盘结合激光数粒或计量盘结合集成摄像计数，可以在机器上设置允许的误差粒数，达到更严格的数量控制。关于填充的误差，目前尚无明确的标准。Mitra等 [39] 将填充误差和单个制剂单元的含量均匀度可接受标准以及理论填充数量相关联，以含量均匀度可接受标准为 15% 为例，计算出理论允许的误差数量，当计算的数量不是整数时向下取整，从而得到了实际允许的填充误差。5微片的质量研究和质量控制当前，国内外药典中尚未设立针对微片的具体评价标准。微片的评价应关注性状、质量差异、含量、含量均匀度、溶出度等项目 [1, 11]。这些指标除遵循普通片剂的相关要求外，还应特别关注以下几点。1）性状：包括尺寸和口感，会显著影响患者服药的顺应性，特别是儿童用药应关注。2）重量差异：单粒微片的重量差异控制在±15%。但成品通常采用以单次服用的最小剂量的微片数量进行重量差异评估。3）含量、含量均匀度、溶出度：在处方开发和优化阶段，为加深对项目的了解，可以对单个微片进行含量、含量均匀度、溶出度研究，以更好地支持处方开发和优化。到临床试验及商业化生产阶段，预期剂量通常已经确定，应以单次服用的最小剂量微片数作为放行的一个单位进行含量、含量均匀度、溶出度的考察 [40]。4）对于微片的一些中间产品控制指标，如果直接选择常规片剂方法来检测，获得的结果可能具有误导性，需根据实际情况进行改进。例如，对于脆碎度检测，建议增加旋转次数，或在执行测试时在轮内添加玻璃珠；对于硬度检测，建议使用能够准确测定 5 ~ 25 N 断裂力的传感器；对于崩解时限，建议使用 100~140 目的较小筛网。6微片稳定性研究微片稳定性研究通常参考 ICHQ1、《化学药物（原料药和制剂）稳定性研究技术指导原则（修订）》等来开展。开启后需多次使用或多剂量包装的产品，应进行使用期间稳定性考察，如上市产品 Flexilev为多剂量包装产品，根据 Medicin.dk 药品数据库提供的 Flexilev 药品基本信息，其说明书明确规定开启后使用期限为 2 个月。需将微片与软食、饮料等混合使用的，应开展临床辅助给药的软食、饮料相容性研究。7微片国内外研发近况目前已上市的 10 余款微片新药产品均来自国 外 制 药 企 业， 如 Pharmaco (NZ) Ltd.、Desitin、Sensidose AB 等。国内的微片研发还处于起步阶段，但随着业界对微片的关注度不断增加，布局微片的国内药企越来越多，如科信必成、力品药业等。表2 列举了部分国内外正在研发的微片产品，主要聚焦于儿童患者群体。8结语与展望在过去 20 年中，微片因易吞咽、剂量准确且可灵活调整、灵活组合给药等特点为制药行业逐渐认知，且越来越多的临床研究证明了其在儿童和老人等特殊群体中的巨大潜力。但与传统剂型相比，微片的商品化速度还是相对缓慢，上市产品数量有限，笔者认为限制微片医学转化的因素主要有三点： 1）微片冲模设计、生产设备要求苛刻，生产工艺、过程控制复杂，技术壁垒高；2）微片和其他剂型的临床优势比较研究开展较少或不全面；3）国内外法规、指导原则较为缺乏，增加了药品注册的不确定性和风险。微片作为一种创新的剂型，在儿童用药领域临床价值确切，但是依然建议药企在开发微片制剂的早期就与审评机构充分沟通立项依据和临床设计。若是在普通片剂或胶囊剂等基础上开发适用于儿童、吞咽困难者等特殊人群的微片制剂，不影响给药剂量 / 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(2016-07-30)[2024-10-18]. https://www. americanpharmaceuticalreview.com/Featured-Articles/190921-Minitablets-Manufacturing-Characterization-Methods-and-Future Opportunities/.美编排版：史鑫宇感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2025年第 3 期。《药学进展》杂志由国家教育部主管、中国药科大学和中国药学会共同主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。联系《药学进展》↓↓↓编辑部官网：pps.cpu.edu.cn；邮箱：yxjz@163.com；电话：025-83271227。欢迎投稿、订阅！往期推荐聚焦“兴药为民·2023生物医药创新融合发展大会”“兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航我知道你在看哟