Venlafaxine Hydrochloride

Aiming to address a significant unmet need for which no other approved treatment option is available for generalized anxiety disorder patients in Japan PITTSBURGH, April 21, 2025 /PRNewswire/ -- Viatris Inc. (Nasdaq: VTRS), a global healthcare company, today announced it has filed applications to the Ministry of Health, Labor and Welfare (MHLW) for approval of Effexor SR Capsules (venlafaxine hydrochloride), a serotonin-noradrenaline reuptake inhibitor (SNRI) to treat adults with generalized anxiety disorder (GAD), an indication for which no other treatment option is currently approved in Japan. As previously announced, our Phase 3 placebo-controlled, randomized, double-blind, multicenter study of venlafaxine in patients with GAD conducted in Japan (Study B2411367) achieved its primary objective of superiority of anxiolytic effects of venlafaxine compared to placebo at 8 weeks, based on the change in the Hamilton Anxiety Rating Scale (HAM-A) total score from baseline (two-sided p-value=0.012). All seven secondary efficacy endpoints as defined by the trial protocol were met. These results and results from a long-term extension study of venlafaxine in Japanese outpatients with GAD were included as part of the applications.1 "The filing of our supplemental New Drug Applications is a key milestone as we move one step closer to bringing the first available treatment option for generalized anxiety disorder to adults in Japan," said Viatris Chief R&D Officer Philippe Martin. "Positive results from our previously announced Phase 3 efficacy and safety studies laid the foundation for our applications with the MHLW. Effexor for GAD is among a number of novel assets we are advancing through our diversified pipeline to address significant unmet needs." Patients with GAD can experience persistent, excessive and uncontrollable anxiety or worry about everyday life activities. Other symptoms include difficulty to get enough sleep, muscle tension/stiffness, feeling restless, irritable, or finding it difficult to concentrate, which may impair patients' social, occupational, or other areas of functioning.2 In Japan, the World Health Organization reports that 2.6% of the population will suffer from GAD in their lifetime.3 A recent study using a screening tool (GAD-7 ≧ 10) reported the prevalence of probable GAD in Japan is 7.6%.4 This data suggests that GAD may be significantly underdiagnosed in Japan. Outside of Japan, selective serotonin reuptake inhibitors (SSRIs) and SNRIs are recommended as first-line drug therapies for patients diagnosed with GAD. EFFEXOR® is currently approved in Japan for the indication of major depressive disorder in adults. EFFEXOR® has also been approved for the indication of GAD in more than 80 countries outside of Japan. References 1 Viatris Announces Positive Top-line Results from Phase 3 Study of EFFEXOR® in Japanese Adults with Generalized Anxiety Disorder (GAD) 2 Takahashi, Saburo et al., supervisor of translation; II. Diagnostic Criteria and Code 5 Anxiety Disorders/Generalized Anxiety Disorder (p242-246): DSM-5-TR Diagnostic and Statistical Manual of Mental Disorders, Igaku-Shoin 3 Stein DJ, Kazdin AE, Ruscio AM, et al. Perceived helpfulness of treatment for generalized anxiety disorder: a World Mental Health Surveys report. BMC Psychiatry. 2021;21(1):392. 4 Matsuyama S, Otsubo T, Nomoto K, Higa S, Takashio O. Prevalence of Generalized Anxiety Disorder in Japan: A General Population Survey. Neuropsychiatr Dis Treat. 2024 Jun 26;20:1355-1366. doi: 10.2147/NDT.S456272. PMID: 38947368; PMCID: PMC11214750. About Generalized Anxiety Disorder (GAD) Generalized Anxiety Disorder (GAD) is a mental health disorder whose central symptom is chronic and uncontrollable "anxiety" or "worry" about everyday life events or activities. Other symptoms include difficulty to get enough sleep, muscle tension/stiffness, feeling restless, irritable, or finding it difficult to concentrate, which may cause impairment in social, occupational, or other areas of functioning. In Japan, the World Health Organization reports that 2.6% of the population will suffer from GAD in their lifetime. A recent study using a screening tool (GAD-7 ≧ 10) reported the prevalence of probable GAD in Japan is 7.6%. About Viatris Viatris Inc. (Nasdaq: VTRS) is a global healthcare company uniquely positioned to bridge the traditional divide between generics and brands, combining the best of both to more holistically address healthcare needs globally. With a mission to empower people worldwide to live healthier at every stage of life, we provide access at scale, currently supplying high-quality medicines to approximately 1 billion patients around the world annually and touching all of life's moments, from birth to the end of life, acute conditions to chronic diseases. With our exceptionally extensive and diverse portfolio of medicines, a one-of-a-kind global supply chain designed to reach more people when and where they need them, and the scientific expertise to address some of the world's most enduring health challenges, access takes on deep meaning at Viatris. We are headquartered in the U.S., with global centers in Pittsburgh, Shanghai and Hyderabad, India. Learn more at viatris.com and investor.viatris.com, and connect with us on LinkedIn, Instagram, YouTube and X (formerly Twitter). Forward-Looking Statements This press release includes statements that constitute "forward-looking statements." These statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may include statements regarding the receipt or timing of regulatory approvals; the outcome of clinical trials; the filing of our supplemental New Drug Applications is a key milestone as we move one step closer to bringing the first available treatment option for generalized anxiety disorder to adults in Japan; and Effexor for GAD is among a number of novel assets we are advancing through our diversified pipeline to address significant unmet needs. Because forward-looking statements inherently involve risks and uncertainties, actual future results may differ materially from those expressed or implied by such forward-looking statements. 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声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。口腔薄膜（oralthinfilms，OTF）是一种新型的药物传递方式，具有给药灵活高和患者用药顺应性高等优点。将药物负载于口溶膜中，服用后药物在口腔内崩解，药物通过口腔粘膜或胃肠道吸收，可使药物迅速起效，并可减轻或避免药物的首过效应，提高药物的生物利用度。口腔膜剂也没有常规口服制剂堵塞口腔或窒息的风险，提高了特殊患者例如儿童、老人、精神病患者和一些卧床患者的用药安全性，同时保留了传统口服固体制剂的优势，包装轻便易携带、剂量准确，并且给药无需饮水送服和二次容器，适合旅行和一些特殊情况下，如晕车时、过敏性病发作、咳嗽或哮喘时，放入口中可被唾液润湿而迅速崩解溶解起效;口腔膜剂可通过口腔豁膜或舌下组织快速吸收进入血液循环，避免了常规口服制剂的首过效应，提高了生物利用度，适用于需要快速起效的一些急症。膜剂可广泛应用于治疗多种疾病，如治疗疼痛、咳嗽/感冒、过敏性鼻炎、糖尿病等。由于膜剂特殊的单剂量包装，可有效隔绝空气和水分，具备良好的化学稳定性。在企业生产中，膜剂生产成本低，生产效率高，且辅料少。口膜分类口溶膜剂，又称为口腔溶解膜剂、口腔分散膜剂、口腔速溶薄膜剂、口腔速解溶膜，2020版《中国药典》对膜剂的定义为药物与适宜的成膜材料经加工制成的膜状制剂，供口服或粘膜使用。目前，药典已收载复方炔诺酮膜和克霉唑口腔药膜。由吸收途径，口腔薄膜剂可分为两类，一种为口腔粘膜，另一种为口腔分散膜。口腔粘膜薄膜可置于舌上、舌下或面颊内侧。通过粘膜粘附剂，它们可粘附在口腔内部，并通过粘膜（即舌下或脸颊）将药物缓慢释放到体循环中。所以，口腔粘膜薄膜的起效时间特别快，还可以减轻或避免药物的首过代谢或在胃酸环境中降解。口腔分散薄膜是非粘膜粘附性的，通常在与唾液接触后分解。具体可分为两种：“口腔崩解薄膜”和“口腔溶解膜”，这两种均会即刻在口中分解。口腔崩解膜一般载难溶性药物，在口腔中崩解，在胃肠道（GI）中溶解和吸收；口腔溶解膜通常是载水溶性药物，在口腔中崩解和溶解。口腔溶解膜中药物部分可在口腔吸收，但大部分还是在胃肠道中进行吸收。口膜优势及特点（1）降低/避免首过效应常规剂型药物主要是通过胃肠道进入体循环，在此过程中，药物易受胃酸、胆汁、消化酶及其他首过效应的影响而解离或降解，从而影响药物的起效时间、用药剂量或生物利用度。（2）提高患者用药顺应性口腔膜剂具有比其他给药方式更大的表面积，这使制剂的润湿、崩解和溶解更快，无需用水、咀嚼或吞咽即可服药，这对儿科、老年、吞咽障碍及精神病患者用药顺应性和舒适性具有极大优势。（3）剂量灵活可控与液体制剂相比，口溶膜剂能够提高给药剂量精度。每片膜都被赋予精准的药物剂量，以确保患者用药的安全性。通过分切，可获得可变的剂量，非常适合儿科用药。（4）延长产品生命周期从商业角度来看，口溶膜药物传递技术能为专利即将到期的制药公司提供延长药物生命周期的机会。将专利到期或即将到期的药物开发成OTF，可使它们获得额外的市场独占期。已上市品种1970年至今，口腔薄膜作为新型药物递送系统被广泛研究，随着载药能力和稳定性的提高，以及吞咽困难患者需求的持续增长，口腔薄膜给药方式受到了欢迎。目前，已有10余种OTF药物全球市场上市，尽管数量不多，但这些OTF可用于治疗广泛的疾病，如：偏头痛、精神分裂症、阿片类药物依赖、疼痛、恶心和呕吐等。膜剂的生产过程中耗能少、粉尘少、辅料少且成本低、生产效率高，能够替代部分传统制剂，可发挥高效速释的作用。近年来，口腔膜剂作为患者依从性好、方便携带、剂量精准的新剂型，引起越来越多的医药企业和研究机构的重视，而广泛见于各类处方和非处方药物中。口腔膜剂提高了给药的方便性和患者顺应性，尤其在有咀嚼和吞咽困难的儿童、老人和一些卧床患者中正在成为主流药品。统计显示，80%的患者相比于传统固体口服剂型更喜欢口服崩解剂型。目前口腔膜剂上市品种主要集中在北美市场，从2003年起，已有超过80多种产品在北美上市，如Novartis公司治疗儿童感冒的右美沙芬膜和苯海拉明膜，美国MonosolRx公司的昂丹司琼膜等。我国目前上市产品整理如下。表1.目前国内上市的口腔速溶膜信息汇总从目前的过评情况看口溶膜领域齐鲁制药布局品种最多已获批的品种多达5个，恒瑞和豪森同样有产品布局。口服制剂给药方式简便、剂量准确、易携带，在现代医学实践中有着最普遍、最广泛的应用。据不完全统计，在现有的主要药物中，口服制剂占比已经达到60%。但常用的口服制剂片剂、胶囊、丸剂会给部分特殊患者带来吞咽困难甚至窒息休克，而口腔膜剂可很好解决这类问题，提高患者顺应性。口腔膜剂的处方组成膜剂一般由活性药物成分、成膜剂、增塑剂、甜味剂、唾液刺激剂、表面活性剂和香精色素等组成。用于膜剂的所有辅料应是普遍认为安全的(即GRAS列出的)，并且应该被批准用于口服药物剂型，应充分考虑到辅料种类和量的不同，对膜的外观和性能的影响。成膜材料是膜剂处方中最主要最重要的成分，包括天然材料、合成类聚合物等。理想的成膜剂应具备以下特征:无毒、无刺激性、口感好、能保持长期稳定性、不改变处方中API和其他辅料的性质、有良好的润湿性和延展性、不会延长膜的溶化时间且具有最佳剥离强度和拉伸强度。增塑剂是口溶膜处方中的重要成分，它通过降低膜的玻璃转化温度，来增强膜的断裂和拉伸强度及提高拉伸率增加塑性和韧性。常用的增塑剂有:丙三醇、丙二醇、低分子量聚乙二醇等。若其用量不当也会导致膜的开裂和剥离，甚至一些增塑剂会影响药物的吸收速率。另外膜剂中辅料成分还可选择性地添加包括甜味剂、唾液刺激剂、表面活性剂以及着色剂等辅料。甜味剂在膜剂中起矫味作用回，有天然和人工合成2类，包括蔗糖、葡萄糖、糖精钠、阿斯巴甜等。常见的唾液刺激剂有柠檬酸、苹果酸、乳酸等，柠檬酸是其中效果最好、应用最广泛的一类。表面活性剂可提高药物的溶解性，能够使药物在口腔中快速被润湿和溶化，常用的表面活性剂有聚山梨酚、十二烷基硫酸钠和泊洛沙姆等。另外为了提高儿童患者用药的依从性，部分膜剂中添加极少量氧化铁、二氧化硅和氧化锌等着色剂或天然着色剂。口腔膜剂的制备工艺自口腔速溶膜应用开始以来，溶剂浇铸法便是最经典的制备方法。近年来，很多新技术也逐渐出现并发展成熟，包括热熔挤出法、静电纺丝法、和打印法等。这些新技术不仅可以改善溶剂浇铸法的局限性以提高口腔薄膜的性能，同时能制备多层的口腔薄膜以实现药物的缓释。（1）溶剂浇铸法(solventcasting)是制备膜剂较为普遍的方法，且适用于制备含有热敏API处方的口腔膜剂，即成膜材料、API和其他药用辅料溶解或分散于水中，高速搅拌混匀并除去气泡后，将得到豁稠的溶液铺于模具上或涂布成膜剂，干燥后起膜切割成目标规格并分装于指定包装中。API的稳定性及其与辅料、溶剂的相容性是影响该工艺的关键因素，针对不同的API可选择不同型号的成膜材料，或制成固体分散体等形式保证最终膜剂的稳定网。该工艺中水分的量会极大地影响薄膜的稳定性及其机械性能，应采用特殊的措施来制备和包装ODF以控制湿度的影响。图1.溶剂浇铸法制备过程示意图（2）热熔挤出法(Hot-meltExtrusion，HME)是制备含对热不敏感API和辅料的膜剂重要工艺。通过将药物、成膜剂及其他辅料加热并均化，直到它们熔融并混合后受挤压通过模具，压成所需的膜形状，最后将挤出的薄膜冷却，切割和包装成所需膜剂。该法制备过程中不需要溶剂，对难溶性药物的分散机制更好，与溶剂浇铸法相比膜有更好的含量均匀度，并且加入合适的增塑剂可降低膜的延展性，提高产品灵活性和抗伸长率。制备过程有良好的参数控制且达到最小的药物浪费。但该工艺对处方的要求较高，药物适用面较窄。图2.热熔挤出法制备过程示意图（3）静电纺丝法（Electrospinning）是制备纳米纤维（nanofibers）的常用技术。在电场作用下，聚合物溶液的液滴可以从球体向圆锥体转变，并可以进一步延展至纳米级别的纤维丝。随着静电纺丝法的潜力逐渐被挖掘，近年来被广泛应用于基于纳米纤维生产制造口腔薄膜，除了因比表面积大提高载药量外，还能有效地增强药物的溶解度和渗透性。基于纳米纤维制备的口腔薄膜，具有优良的机械强度和柔韧性，可实现对药物的控释。连续采用静电纺丝法，可以制备多层结构的纳米纤维薄膜，内层为含活性成分的聚合物材料，外层为纳米纤维。由于外层材料的疏水特性，多层纳米纤维薄膜表现出优良的缓释效果，这让静电纺丝法用于制备口腔薄膜具有广阔的应用前景。尽管静电纺丝法在某些方面有巨大的优势，但是在实际应用过程还是存在诸多弊端。例如，原辅料必须用有机溶剂溶解，为环保和溶剂残留留下了安全隐患。静电纺丝法涉及高度复杂和高成本的设备，制备过程步骤较多，严重制约其在制药和生物医学领域的产业化和商业化。图3.静电纺丝法制备过程示意图（4）打印法，打印技术是在计算机辅助设计（Computer-aideddesign，CAD）下，将打印材料一层层叠加起来，形成具有所需形态的产品。打印技术能完成连续一步制造，同时能实现多种制药剂量的个性化设计。因其特点，3D打印又被称为增材制造（additivemanufacture）。（5）静电喷雾沉积技术，静电喷雾沉积（Electrostaticspraydeposition，ESD）是一种干粉喷雾沉积技术，以静电喷枪将成膜粉末均匀喷在固定衬底上并形成均匀的沉积物，之后经高温将沉积物固化。未来趋势通过本文对于口腔膜剂的研发状况及市售药物的分析，主要得到了以下几点结论:①口腔膜剂与现有剂型相比，具有崩解快、溶解迅速、快速释药和生物利用度高等许多优点。②口腔膜剂适用于所有年龄患者尤其是儿童和老人以及特殊患者，具有传统口服制剂所无法达到的很高的患者依从性。尤其是儿童对传统口服制剂具有较强的排斥心理，导致许多医院面对儿童患者用药困难。③现今上市的口腔膜剂药物虽然品种不多，但作为新型制剂在患者人群中有着较好的声誉和很好的市场前景，对于该类药物的开发也一直处于热门状态。有研究表明该类药物在糖尿病、偏头痛、过敏免疫疗法、尼古丁依赖及止痛药物依赖上有很强的应用潜力。与传统剂型（如片剂、胶囊和糖浆）相比，OTF具有许多不可替代的优势，随着剂型的发展，将会有更多药物用于口腔薄膜给药。OTF给药途径适合吞咽困难的患者，如：儿童、老人和咽喉不适的人。值得注意的是，随着人口老龄化不断加剧，，对安全无障碍给药方式的需求会日益增加，市场直接推动OTF市场的增长。MarketResearchFuture预测，2018-2023年全球口腔薄膜市场将以10.50%的复合年增长率(CAGR)增加。另一位业内人士预测，包括OTF在内的所有新型药物输送系统的全球市场价值将在同一时间以2.9%的复合年增长率增长。随着越来越多的药物被开发或改为OTF剂型，现有技术限制的解决方案会随即出现。尽管限制是静态的——如：载药量。另一角度，这些并不是限制，而是优先满足特定患者群体的需求。儿童和老人是OTF药物的主要消费者，随着研究的深入，研究者们将扩大OTF的应用范围，使这种新型给药系统成为标准剂型。笔者认为口溶膜在剂型上虽有诸多优势具有剂量准确、携带方便、患者依从性良好等特点，在部分疾病及适应证人群治疗中，口溶膜能很好解决其他剂型所带来的不便，提高患者用药依从性。但是并不是所有药物都适合开发成为口溶膜。企业在立项时需谨慎。特别需要全面评估适应证和剂型特点，充分调研产品国内外上市情况，对于药审中心关注的剂型适用性及临床优势应予以充分说明，20年到22年是口溶膜开发最为火爆的几年，很多研发机构都立项了很多相关品种，但是从获批的情况看能杀出重围的也只有齐鲁、恒瑞、豪森这样的国内制药头部企业。近年来争夺比较激烈的是布瑞哌唑口溶膜，四川科伦身位稍稍领先，齐鲁同样虎视眈眈，且该品种目前已经有10家企业申报，呈现出“大乱斗”的局面。口溶膜要么不立项，一旦发现合适品种多家“打破头”的局面可能是未来的常态。参考文献：[1] 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