Bexagliflozin

NDA序号 214373 申请人 Theracos Sub LLC  药物名 Brenzavvy (bexagliflozin) 片 剂型 片剂 规格 20mg 给药途径 口服 Rx/OTC分类 Rx 适应症 成人2型糖尿病控制 制剂性状 蓝色、胶囊形、双凸、斜边、薄膜包衣片，一侧印有有“2”和倒置的“2”，另一侧没有印字。片剂包装在30ct或90ct高密度聚乙烯（HDPE）瓶中，带有（b）（4）封口（b）（4）。 存储条件 在20°C至25 °C下储存，允许在15°C至30°C之间短暂储存。 生物药剂学 Theracos Sub, LLC申请拟定的Bexagliflozin片，20毫克。为蓝色薄膜涂层速释片，在拟定的溶出方法中具有延长的体外药物释放特征。FDA重点审评了拟定的质量控制溶出方法和标准的可接受性。 溶解方法和验收标准： 根据所提供的信息，拟定溶出方法和溶解验收标准是可以接受。 BCS定义 溶解度 申请人确定了原料药Bexagliflozin在KCl/HCl缓冲液（pH 1.0）、NaOAc/HOAc缓冲液（pH 4.5）和NaOH/KH2PO4缓冲液（pH 7.6）中的饱和浓度。没有观察到溶解度随pH变化而显著变化。溶解度的平均值在37°C下16小时后为0.44、0.46和0.46mg/ml，在37°C条件下，24小时后为0.45、0.51和0.43mg/ml，pH值分别为1.0、4.5和7.6。 拟定的商业化规格为20毫克，在上述任何缓冲液中很容易溶解在250ml中，因此申请人认为，根据BCS标准，Bexagliflozin原料药是一种高溶解性化合物。 FDA同意申请人对原料药的溶解度定性，其渗透性为低至中。 制剂溶出方法 区分力 申请人使用拟定的溶出方法评估了Bexagliflozin片的溶出速率：20毫克规格含不同比例和等级的辅料。 增加片剂重量  申请人进行了一系列实验，以确定增加片剂总重量对溶出曲线的影响。片剂总重量的变化涉及添加影响片剂释放的辅料。具体见下表： 申请人观察到，片剂重量增加，溶出会变慢，如下图。 SUPAC级别的辅料变化 申请人进行了一系列研究，以确定SUPAC I级和II级变化对处方的影响（表4）。 申请人观察到了辅料的比例变化，会影响到Bexagliflozin片的溶出速率，如下图。 申请人对拟定商业化处方中的辅料数量变化进行了额外的确认性研究。处方中心点（表5中3、4和11代表商业化处方。其他（1、2、5、6、7、8、9和10）使用表5第一行所示的可变辅料用量。 如表5和图5所示： 申请人观察到XX辅料数量变化，与中心点处方对比，没有显著影响溶出曲线。同样，XX辅料数量的一致增加或减少（6和9），对中心点处方对比，没有显著影响溶出曲线。然而，XX辅料量的变化显著影响溶出速率（2、5、7和8）。溶出方法可以用于区分这些辅料比例变化得到的制剂。 辅料PSD变化 申请人使用不同PSD大小的辅料制备得到的制剂溶出如下，发现使用大PSD的辅料得到的制剂溶出速率更快。 申请人同时使用不同级别辅料生产的制剂，溶出曲线结果表明，不同级别辅料得到的制剂溶出没有明显区别。 原料药粒度大小变化 申请人使用不同PSD原料药批次制备得到的制剂，发现溶出速率的系统性变化很小。 FDA评估：申请人充分证明了拟定溶出方法对商业化Bexagliflozin片的批次释放和稳定性测试的适用性。拟定溶出方法显示了对制剂中辅料比例和不同粒度辅料变化的区分能力。 拟定溶出方法（900毫升0.1 N HCl，USP方法I，50转/分）可以满足用于商业化制剂的质量控制。 解读： 虽原料药在不同pH值溶液中的溶解度不高，但基于商业化规格20mg，在250ml的缓冲液中很易溶解，因此原料药被定义为高溶化合物。 Bexagliflozin制剂溶出方法开发，考察了不同辅料比例的制剂，不同粒度辅料的制剂，拟定溶出方法具有一定区分能力。对于不同级别辅料，不同粒度原料药的制剂，拟定溶出方法不具有区分力。FDA认可了申请人拟定的溶出方法。 作者精彩原创集锦 1、创新药研发中原料药工艺与沟通交流常见难点 2、创新药研发中「制剂工」常见难点 3、创新药研发中「变更」相关难点 4、创新药研发中「质量分析控制」相关难点（1） 5、创新药研发中「质量分析控制」相关难点（2） 6、创新药研发难点分析与CMC研究策略探讨 7、《已上市化学药品药学变更研究技术指导原则（试行）原料药变更的问答》浅析 8、FDA：原料药中亚硝胺风险评估的最新观点 9、亚硝胺「传奇」：5年来监管和制药界的反思 10、【学习笔记】2023年度CDE审评报告 11、FDA审评：吡托布鲁替尼的药学变更桥接(完) 12、CDE：ICH指南在国内的实施概况 13、「解读」FDA审评：repotrectinib胶囊5次CMC会议内容 14、FDA：IND阶段CMC关注点 15、药品注册检验难点与建议 16、最新 FDA 人用药物亚硝胺杂质指南更新的「底层」参考 17、不同国家地区注册检验差异对比 曾文亮 博士   近20年药物研发经验，擅长新药研发与注册申报，近5年积累了近十个小分子新药中美IND申报成功和两个1类抗肿瘤新药上市申报成功经验。先后任职于某大型CRO医药研发公司、USP大中华区研发中心和港资原料药厂等，主导过MNC质量研究项目、USP各论更新和药厂QC实验室通过国家GMP检查和WHO审计。   受中国医药保健品进出口商会邀请在二十二届世界制药原料药中国展（CPHI）主导策划了“小分子创新药质量研究和注册策略”沙龙并发表主题演讲；同时受专业药学论坛邀请发表了《创新药质量研究要点和案例分析》、《中美新药申报沟通交流常见问题和案例分析》、《亚硝胺杂质的FDA和EMA控制策略》、《分析方法开发，验证和转移的统计学评价》和《FDA483中清洁验证的典型案例分析》等十余次主题演讲。   更多精彩内容可关注： ▲ 关注文亮频道，探索未知世界

MARLBOROUGH, Mass.--( BUSINESS WIRE )--A new study published in JAMA Network Open titled “ Income-Related Disparities in Mortality Among Young Adults With Type 2 Diabetes ” underscores the need for addressing disparities in care and improving access to important therapies for type 2 diabetes. This study further underscores recent data compiled by the American Diabetes Association which states that diabetes is the most expensive chronic condition in the United States, and millions of Americans struggle to afford effective treatment of their type 2 diabetes and associated complications. Seeking to address this critical health issue, BRENZAVVY ® (bexagliflozin) is a safe, effective and affordable option for adults with type 2 diabetes. In the United States, BRENZAVVY is sold at around $50 per month through a network of online and independent pharmacies. BRENZAVVY's low price point makes sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy a more affordable option for uninsured, underinsured, and Medicare patients. This increased affordability can help ensure that patients can initiate and maintain a safe and effective therapy, improving their ability to manage their type 2 diabetes. Adults with type 2 diabetes can easily determine if BRENZAVVY is right for them by visiting www.brenzavvydirect.com and speaking to a doctor quickly and affordably. For healthcare providers, BRENZAVVY can easily be prescribed without insurance plan headaches, such as prior authorizations or step therapy hurdles, that the SGLT2 inhibitor class traditionally faces. “ The findings of this study reinforce that many adults living with type 2 diabetes simply cannot afford to start and stay on their therapy ,” said the TheracosBio CEO, Brian Connelly. “ With BRENZAVVY, TheracosBio is fulfilling our mission to address financial barriers to care. By unlocking wider access to an important class of therapy, more and more people with type 2 diabetes have better access to a safe, affordable and effective treatment option,” Mr. Connelly added. BRENZAVVY is available as 20 mg oral tablets to be taken once daily, in the morning, with or without food. Phase 3 clinical studies have shown BRENZAVVY significantly reduces hemoglobin A1c and fasting blood sugar after 24 weeks, either as a monotherapy, in combination with metformin, or as an add-on to standard-of-care treatment consisting of a variety of regimens, including metformin, sulfonylureas, insulin, DPP4 inhibitors or combinations of these agents. Although BRENZAVVY is not approved for weight loss or blood pressure reduction, modest decreases in both weight and blood pressure have been observed in the clinical program. To learn more about BRENZAVVY , please visit https://www.brenzavvy.com . To learn more about TheracosBio, please visit https://theracosbio.com . BRENZAVVY Important Safety Information BRENZAVVY ® (bexagliflozin) is a prescription medicine used along with diet and exercise to improve blood sugar in adults with type 2 diabetes. BRENZAVVY is not recommended to decrease blood sugar in people with type 1 diabetes. Do not take BRENZAVVY if you are allergic to bexagliflozin or any of the ingredients in BRENZAVVY. BRENZAVVY can cause serious side effects including diabetic ketoacidosis that may be fatal. Signs and symptoms of ketoacidosis include nausea, vomiting, stomach pains, tiredness, trouble breathing, and ketones in urine or blood. Ketoacidosis can happen even if your blood sugar is less than 250 mg/dL. BRENZAVVY may increase the risk of lower limb amputations. Call your doctor if you notice signs or symptoms. Amputations mainly involve removal of the toe or part of the foot, however, amputations involving the leg, below and above the knee, have also occurred. Some people had more than one amputation. BRENZAVVY may cause dehydration, urinary tract or genital yeast infections, and low blood sugar. Symptoms of dehydration include feeling dizzy, faint, lightheaded, or weak upon standing. Yeast infections can occur in women and men. Signs of low blood sugar may include headache, confusion, drowsiness, dizziness, sweating, irritability, hunger, shaking, fast heartbeat, or weakness. A rare life-threatening bacterial infection in the skin of the perineum could occur. Stop taking BRENZAVVY and call your doctor right away if you have symptoms of this infection The perineum is the area between the anus and genitals. Symptoms of this infection include fever, weakness and pain tenderness, redness, or swelling of the genital area. The most common side effects of BRENZAVVY are vaginal yeast infections, urinary tract infections, and changes in urination, including an urgent need to urinate more often, in large amounts, and at night. For additional important safety information about BRENZAVVY, visit www.brenzavvy.com . About TheracosBio TheracosBio was founded in 2000 and develops affordably priced novel therapeutics for diseases with significant societal impact. The mission of TheracosBio is to expand access to new medications for patients with common diseases. COM-23118-01