Esomeprazole Magnesium

RedHill has been selected to provide a presentation to further elaborate on opaganib's potential to U.S. government representatives at the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense's (JPEO-CBRND) "Host Directed Therapeutics Industry Day" -- Based on reviews, feedback, and discussion, the judges selected for presentation those therapeutics that demonstrated capability in the prophylaxis, post-exposure prophylaxis, and the treatment of exposure to viruses, bacteria and toxins. The meeting is scheduled to take place October 29-30, 2024, at the United States Patent and Trademark Office in Alexandria, VA -- The JPEO-CBRND manages U.S. government investments in chemical, biological, radiological, and nuclear (CBRN) defense equipment and medical countermeasures (MCMs). The JPEO-CBRND's mission is to provide integrated, layered, chemical, biological, radiological, and nuclear defense capabilities to the Joint Force across combined Joint all-domain operations -- With multiple U.S. government collaborations for chemical and MCMs and pandemic preparedness, opaganib is a novel, host-directed, potentially broad-acting, orally administered small molecule, clinical-stage drug with demonstrated safety and efficacy profiles, being developed for various oncology, viral infections, inflammatory diseases, and chemical and nuclear/radioprotection indications TEL-AVIV, Israel and RALEIGH, N.C., Oct. 28, 2024 /PRNewswire/ -- RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, today announced that the Company has been selected to further elaborate on opaganib's[1] potential in a presentation to U.S. government representatives at the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense's (JPEO-CBRND) "Host Directed Therapeutics Industry Day". The meeting is scheduled to take place October 29-30, 2024, at the United States Patent and Trademark Office in Alexandria, VA. The JPEO-CBRND manages U.S. government investments in chemical, biological, radiological, and nuclear (CBRN) defense equipment and medical countermeasures (MCMs). The JPEO-CBRND mission is to provide integrated, layered, chemical, biological, radiological, and nuclear defense capabilities to the Joint Force across combined Joint all-domain operations. Based on reviews, feedback, and discussion, the judges selected for presentation those therapeutics that demonstrated capability in the prophylaxis, post-exposure prophylaxis, and treatment of exposure to viruses, bacteria and toxins. "Opaganib is already the subject of multiple ongoing collaborations with several U.S. government agencies. However, selection for presentation at this important governmental investment event provides a significant opportunity to highlight the growing body of evidence in support of opaganib's potential as an oral, host-directed, broad-acting viral, chemical and nuclear countermeasure ," said Guy Goldberg, RedHill's Chief Business Officer. About Opaganib (ABC294640) Opaganib, a proprietary investigational host-directed and potentially broad-acting drug, is a first-in-class, orally administered sphingosine kinase-2 (SPHK2) selective inhibitor with anticancer, anti-inflammatory and antiviral activity, targeting multiple potential indications, including several cancers, diabetes and obesity-related disorders, gastrointestinal acute radiation syndrome (GI-ARS), Sulfur Mustard exposure, COVID-19, Ebola and other viruses as part of pandemic preparedness. Opaganib's host-directed action is thought to work through the inhibition of multiple pathways, the induction of autophagy and apoptosis, and disruption of viral replication, through simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SPHK2, DES1 and GCS). Several U.S. government countermeasures and pandemic preparedness programs have selected opaganib for evaluation for multiple indications, including Acute Radiation Syndrome (ARS), Ebola virus disease and others. Funding bodies include the Radiation and Nuclear Countermeasures Program (RNCP), led by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. government Department of Health & Human Services' National Institutes of Health and the Administration for Strategic Preparedness and Response's (ASPR) Center for Biomedical Advanced Research and Development Authority (BARDA). Opaganib has demonstrated antiviral activity against SARS-CoV-2, multiple variants, and several other viruses, such as Influenza A and Ebola. Opaganib delivered a statistically significant increase in survival time when given at 150 mg/kg twice a day (BID) in a United States Army Medical Research Institute of Infectious Diseases (USAMRIID) in vivo Ebola virus study, making it the first host-directed molecule to show activity in Ebola virus disease. Opaganib also recently demonstrated a distinct synergistic effect when combined individually with remdesivir (Veklury®, Gilead Sciences Inc.), significantly improving potency while maintaining cell viability, in a U.S. Army-funded and conducted in vitro Ebola virus study. Being host-targeted, and based on data accumulated to date, opaganib is expected to maintain effect against emerging viral variants. In prespecified analyses of Phase 2/3 clinical data in hospitalized patients with moderate to severe COVID-19, oral opaganib demonstrated improved viral RNA clearance, faster time to recovery and significant mortality reduction in key patient subpopulations versus placebo on top of standard of care. Opaganib has demonstrated its safety and tolerability profile in more than 470 people in multiple clinical studies and expanded access use. Data from the opaganib global Phase 2/3 study was published in Microorganisms. Opaganib has received several orphan-drug designations from the FDA in oncology and other diseases and has undergone studies in advanced cholangiocarcinoma (Phase 2a) and prostate cancer. Opaganib also has a Phase 1 chemoradiotherapy study protocol ready for FDA-IND submission. Opaganib has also shown positive preclinical results in renal fibrosis, and has the potential to target multiple oncology, radioprotection, viral, inflammatory, and gastrointestinal indications. Disclaimer: The views and opinions of authors expressed herein do not necessarily state or reflect those of the U.S. government and shall not be used for advertising or product endorsement purposes. Reference herein to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, does not constitute or imply its endorsement, recommendation, or favoring by the U.S. government and shall not be used for advertising or product endorsement purposes. About RedHill Biopharma RedHill Biopharma Ltd. (Nasdaq: RDHL) is a specialty biopharmaceutical company primarily focused on gastrointestinal and infectious diseases. RedHill promotes the gastrointestinal drug Talicia®, for the treatment of Helicobacter pylori (H. pylori) infection in adults[2]. RedHill's key clinical late-stage development programs include: (i) opaganib (ABC294640), a first -in -class oral broad-acting, host-directed SPHK2 selective inhibitor with potential for chemical and medical countermeasure and pandemic preparedness use, targeting multiple indications with a U.S. government collaboration for development for Acute Radiation Syndrome (ARS), a Phase 2/3 program for hospitalized COVID-19, and a Phase 2 program in oncology; (ii) 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, with non-dilutive external funding covering the entirety of the RHB-107 arm of the 300-patient Phase 2 adaptive platform trial, and is also targeting multiple other cancer and inflammatory gastrointestinal diseases; (iii) 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; (iv) RHB-104, with positive results from a first Phase 3 study for Crohn's disease; and (v) RHB-204, a Phase 3-stage program for pulmonary nontuberculous mycobacteria (NTM) disease. More information about the Company is available at / X.com/RedHillBio. Forward-Looking Statements 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 and include, among others, statements regarding the potential of opaganib. 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 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 that acceptance onto the RNCP Product Development Pipeline 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 opaganib for any indication; the risk that observations from preclinical studies are not indicative or predictive of results in clinical trials; the risk that the FDA pre-study requirements will not be met and/or that the Phase 3 study of RHB-107 in COVID-19 outpatients will not be approved to commence or if approved, will not be completed or, should that be the case, that we will not be successful in obtaining alternative non-dilutive development funding for RHB-107; the risk that RHB-107's late-stage development for non-hospitalized COVID-19 will not benefit from the resources redirected from the terminated RHB-204 Phase 3 study, and that the Phase 2/3 COVID-19 study for RHB-107 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 COVID-19 studies for opaganib and RHB-107 are likely to be required; the risk 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 a commercial companion diagnostic for the detection of MAP; (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® and Aemcolo®; (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 8, 2024. 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]Opaganib is an investigational new drug, not available for commercial distribution. [2]Talicia® (omeprazole magnesium, amoxicillin and rifabutin) is indicated for the treatment of H. pylori infection in adults. For full prescribing information see: . Logo: SOURCE RedHill Biopharma Ltd. 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（点击图片 查看详情） 目前有越来越多的药物制备成肠溶制剂，笔者根据以往审评经验，同时参考调研文献，主要以质子泵抑制剂类肠溶制剂为切入点，从肠溶制剂的处方工艺、质量研究、稳定性等方面，提出了药学研究的一般考虑，重点需关注调试制剂的剂量倾泻研究、溶出曲线相似性研究和涉及鼻胃管给药时的体外对比研究等，以期对该类仿制药物的研发和注册申报提供参考。 肠溶制剂指在规定的酸性介质中不释放或几乎不释放药物，而在要求的时间内，于pH 6. 8 磷酸盐缓冲液中大部分或全部释放药物的制剂［1］ 。将药物制成肠溶制剂的目的主要有以下几个方面：① 避免药物受到胃内酶类或胃酸的破坏，如质子泵抑制剂类肠溶制剂。② 避免药物对胃黏膜产生强烈刺激，引起恶心、呕吐等不良反应。③ 将药物传递至局部部位（如肠）发挥作用。④ 提供延迟释放作用。⑤ 将主要由小肠吸收的药物尽可能以最高浓度传递至该部位。 药品出海东南亚、WHO、EU及TGA全流程指导 肠溶制剂在其处方工艺、质量控制等方面有一定的特殊性，本文主要结合质子泵抑制剂类（主要指拉唑类）肠溶仿制制剂的审评经验，并参考前期的文献调研，总结汇总了质子泵抑制剂类肠溶仿制制剂开发中药学研究的一般考虑，以期为该类仿制药物的研发和注册申报提供一定参考。本文内容仅代表个人观点，如与现有的技术要求有出入，请以官方发布的技术指南为准。 1 质子泵抑制剂类肠溶仿制制剂开发中药学研究的一般考虑 下文主要从此类仿制制剂的处方工艺开发、质量研究及稳定性等方面展开，更多研究内容仍需持有人或生产企业根据品种情况具体问题具体分析。 1. 1  处方工艺开发 处方工艺开发主要依据ICH Q8 开展相关研究，以下分2 个方面进行论述，即处方开发和工艺开发。 1.1. 1 处方开发 建议先对参比制剂的处方信息进行充分调研，参考参比制剂说明书及公开的相关文献，确定处方中的辅料种类。以产品的关键质量属性为考察指标对辅料的用量进行筛选，根据研究结果确定处方中的辅料用量。下面重点介绍质子泵抑制剂类肠溶制剂处方研究中的特殊关注点。 如原料药的晶型和粒度对产品的溶出等有影响，需对其晶型和粒度进行研究，根据研究结果制定合理的控制策略。拉唑类活性物质一般情况下遇酸易降解，而常用的肠溶材料呈弱酸性，药物与之接触会降解或变色，一般需要在含药部分与肠溶层之间增加一道隔离层，避免活性成分发生降解。 此外，当涉及该类制剂申请多规格生物等效性豁免时，有一个较关键的问题就是处方相似性判定。 生物药冻干制剂开发：处方与工艺 肠溶制剂处方中包括释药控释性辅料和非释药控释性辅料，其处方变化幅度的计算方式不同，需参照《已上市化学药品变更研究的技术指导原则（试行）》［2］ 执行。释药控释性辅料以辅料占原批准处方中所有释药控释性辅料总重量的百分比进行计算，非释药控释性辅料以辅料占原批准处方总重量的百分比计算。如要进行生物等效性豁免，一般要求不同规格处方等比例变化或与参比制剂处方一致抑或其处方变更幅度在中等变更范围内。肠溶制剂所有辅料（含非释药控释性辅料和释药控释性辅料）变更占原批准处方总重量的和不超过5％，属微小变更；所有辅料变更占原批准处方总重量的和不超过10％，属中等变更；超过中等变更属重大变更［3］ 。一般情况下，包肠溶衣机制的肠溶制剂的比表面积对肠溶制剂的溶出行为影响较大，在变更其辅料用量时，可以考虑肠溶制剂的比表面积［3］ 。 1.1. 2 工艺开发 目前获批的质子泵抑制剂类肠溶片的制备工艺主要有2 种。一种是湿法制粒压片后包隔离衣和肠溶衣，最终靠最外层的肠溶衣膜达到延迟释放的作用，活性成分在素片中。该工艺并不复杂，采用常规的设备和工艺便能制备，建议控制包衣增重在合适范围内，并关注工艺的稳健性和可重复性。 另一种制备工艺较复杂，即采用微丸压片工艺制备的肠溶片，如艾司奥美拉唑镁肠溶片，参考阿斯利康公司艾司奥美拉唑镁肠溶片专利（专利号：95190815. 4，多单元片剂）［4］ ，该制备工艺一般是采用蔗糖丸芯或其他糖丸作为载体，先进行上药层微丸包衣，然后依次是隔离层包衣、肠溶层包衣、保护层包衣、总混、压片等工艺，制备成含多单元药物的口服肠溶片。该工艺较复杂，各工艺参数可能都会对成品质量产生影响，需进行详细的研究和验证，以充分证明工艺的稳健性。 对于采用微丸压片工艺制备的拉唑类肠溶片一般需重点关注以下内容：① 处方中丸芯为关键辅料，不同大小的丸芯可能会影响上药层的厚度，进而影响溶出，需要关注处方中丸芯的粒度。② 如采用流化床上药工艺制备载药层，该工艺对原料药粒径要求较高，建议对原料药的粒径进行研究，根据研究结果制定合理的控制策略。③ 隔离衣厚度不同可能导致对上药层微丸的包裹完整程度不同，进而表现为对上药层微丸的保护作用不同。不同的隔离层衣膜厚度也会对产品的溶出产生一定影响。建议对不同的隔离层包衣增重进行研究，根据研究结果制定合理的隔离层包衣增重范围。④ 肠溶衣膜需要具有一定的柔韧性，防止在后续压片工艺中产生裂纹，从而导致产品耐酸的失败而无法达到肠溶释放的目的。建议对增塑剂的用量进行考察，确定增塑剂的合理用量。增塑剂用量过多可能会导致酸性物质透过隔离层迁移到上药层中与原料药直接接触，产生稳定性问题。同时也需要选择合适的肠溶层厚度，以达到目标肠溶效果。⑤ 一般情况下，在肠溶层外还会选择包保护层，可进一步防止肠溶衣的小丸聚集，进一步保护肠溶包衣层，以防在压制过程中开裂。⑥ 其他可能的关注事项需视具体产品具体分析。 除了肠溶片外，目前按新注册分类4 类获批的剂型中主要还包括肠溶胶囊，其处方工艺开发可参考片剂，不再赘述。其他剂型的申报相对较少，不再进一步讨论。 1. 2 质量研究 肠溶制剂的质量标准及质量研究有其特殊之处，除了常规考察项（如性状、鉴别、有关物质及含量等）外，仍需重点关注以下内容。 1. 2. 1 溶出度 该类制剂一般是先在酸性介质中进行耐酸考察1 ～2 h，然后转移到pH 6. 8 或其他偏碱性的缓冲液介质中进行溶出度考察。如雷贝拉唑钠肠溶片，《中华人民共和国药典》中规定耐酸2 h后，供试片均不得有变色、裂缝或崩解现象，耐酸2 h后转移到偏碱性的缓冲液介质中，并拟定相应的溶出度标准。部分品种需要制定耐酸力考察项。 1.2. 2 剂量倾泻研究 肠溶制剂为调试制剂，需按照现行的技术指导原则开展剂量倾泻研究，以证明自制制剂无剂量倾泻风险或剂量倾泻程度低于参比制剂，如自制制剂倾泻程度高于参比制剂，应评估是否需要通过生物等效性试验证明与参比制剂的一致性［5］ 。 一般情况下，调试制剂的剂量倾泻试验参照我国发布的指导原则开展即可，但也有个别情况存在例外，如右兰索拉唑肠溶口崩片［12］ 。美国FDA 个药指南中除了要求在0. 1 盐酸介质中的剂量倾泻研究，同时还要求缓冲液介质中的剂量倾泻研究，即将完成酸介质中剂量倾泻研究的供试品转移到加入相同浓度乙醇的pH 7. 2 的缓冲液介质中继续考察剂量倾泻情况。关于剂量倾泻试验需要具体品种具体分析。 1.2. 3 溶出曲线相似性研究 一般情况下，溶出曲线相似性研究符合现行的技术指导原则要求即可，当涉及多规格生物等效性豁免时，需重点关注溶出曲线相似性评价。溶出介质和溶出转速应参照《〈已上市化学药品药学变更研究技术指导原则（试行）〉溶出曲线研究的问答》［6］ 进行选择。由于部分肠溶制剂的溶出差异较大，批内批间均一性较差，药物溶出量的相对标准偏差可能不符合非模型依赖的相似因子法（f2 ）的要求，可能需要选用其他溶出相似性评价方法进行评价。 某些产品可能比较特殊，需要具体问题具体分析，如右兰索拉唑肠溶胶囊［10］ 。该产品已在美国上市（商品名：Ｄｅｘｉｌａｎｔ），该胶囊中装填有2 种不同释药行为的微丸，使其能有效地在全天控制胃酸的分泌，减轻不良反应［11］ 。美国FDA 个药指南中涉及该产品的大小规格生物等效性试验豁免时对溶出曲线提出了更高要求，需要提供多种溶出介质中的溶出相似性研究资料，具体溶出条件要求汇总见表1。 对右兰索拉唑肠溶胶囊的溶出曲线提出如此高的要求是因为该产品体现出双相释放机制，该产品中灌装了2 种类型的肠溶微丸，其中一种微丸在小肠的近端（pH 约5.5）释放，另一种微丸在肠道的远端（pH约6.75）释放，为达到较好的血药浓度，这2 种类型的微丸需保持在合适的比例［7］ 。为验证这种双相释放机制，故对溶出曲线相似性提出了较多要求。 1.2. 4 肠内营养管给药的体外试验研究 经肠内营养管给药，即通过肠内营养管（诸如鼻胃管、鼻十二指肠管、胃造口术管等）将药物直接输入胃肠道，这种剂型对无法吞咽口服剂型的患者十分重要。美国FDA已有相关指南供业界参考，如《Oral Drug Products Administered Via Enteral FeedingTube: In Vitro Testing and Labeling Recommendations》［8］ 和《Use of Liquids and/or Soft Foods as Vehicles for Drug Administration: General Considerations for Selection and in vitroMethods for Product Quality Assessments Guidance for Industry》［9］ 。 近几年，有些含有微丸或混悬颗粒的质子泵抑制剂类肠溶制剂说明书中增加了鼻胃管给药方式，对于不能吞咽的患者，可将药品溶于说明书规定的分散介质中，然后通过鼻胃管给药。如艾司奥美拉唑镁肠溶干混悬剂，其说明书中涉及鼻胃管给药，其给药方式如下：将1 包本品倒入带导管头的注射器中，并取水15 mL。迅速摇动注射器并等待2 ～3 min 使其变稠。摇晃注射器，在30 min 内通过连接鼻胃管或胃管注入胃中。将等量水（15 mL）加入注射器。摇晃并将剩余药物经鼻胃管或胃管冲洗至胃中。 美国也有较多个药指南针对肠内营养管给药的体外对比研究试验给出相关参考，关于美国FDA 批准的质子泵抑制剂类肠溶制剂涉及鼻胃管给药的产品体外试验对比研究情况［12 －17］ 汇总见表2。为保证仿制制剂与参比制剂通过鼻胃管给药的质量和疗效一致，需根据风险评估制定合理的研究方案，提供详细的体外对比研究资料。 1. 3 稳定性研究 一般情况下，仿制制剂的贮藏条件可参照参比制剂拟定［18 －21］ 。企业应根据拟定的贮藏条件设置合理的稳定性考察条件对产品的稳定性行为进行考察，稳定性考察中所用样品应至少在中试规模下生产，稳定性研究建议考察在贮藏过程中易发生变化的项目，涵盖物理、化学、微生物学特性等，所用分析方法应经过充分的验证，并能指示制剂的稳定性特征。稳定性 2 小结 本文仅以现有的审评经验及文献调研，对质子泵抑制剂类肠溶制剂的仿制开发提供建议，而在实际研究中仍需具体问题具体分析。 生物制品生产质量体系全流程建立及合规管理 质子泵抑制剂类肠溶制剂的仿制，首先需对参比制剂进行深入解析，在对参比制剂进行深入研究的基础上进行处方工艺开发，仿制制剂的释药机制通常应与参比制剂保持一致。随后结合产品的具体情况进行合理的质量研究，结合肠溶制剂特点增加针对性研究和控制，确保仿制制剂质量不低于参比制剂。 来源：中国新药杂志2024年第33卷第19期 免责声明：文章版权归原作者所有，转载本文仅为交流学习使用。如涉及作品内容、版权和其它问题，请与我们联系删除（yaoyanjun007）！文章内容仅代表作者个人观点，不代表本公众号赞同或支持其观点。 参考文献