Proparacaine Hydrochloride

Patients reported approximately 58% less discomfort overall in the IHEEZO-treated eye, with the largest absolute differences in the immediate post-injection period, when discomfort is highest NASHVILLE, Tenn., Aug. 20, 2026 (GLOBE NEWSWIRE) -- Harrow (Nasdaq: HROW), a leading provider of ophthalmic disease management solutions in North America, today announced positive results from a prospective, randomized, contralateral-eye study evaluating IHEEZO ® (chloroprocaine hydrochloride ophthalmic gel) 3%, an ophthalmic gel indicated for ocular surface anesthesia, in patients undergoing same-day bilateral intravitreal injections. The single-center, investigator-initiated study demonstrated statistically significant differences favoring IHEEZO at every measured time point. Patients reported approximately 58% less discomfort overall in the IHEEZO-treated eye than in the fellow eye treated with proparacaine ophthalmic solution 0.5%, a statistically significant difference at all four post-injection assessments (all p≤0.048). The largest absolute treatment differences were observed immediately after injection, when discomfort is highest: 1.44 versus 3.06 at two minutes and 1.26 versus 2.82 at one hour, while lower discomfort scores with IHEEZO remained evident through the 24-hour assessment. Millions i of intravitreal injections are performed in the United States each year — making them among the most frequently performed procedures in ophthalmology — and they are often administered repeatedly over months or years to patients with retinal diseases. As a result, the injection experience, including patient discomfort, can become an important consideration for both patients and retina specialists, particularly in practices managing a high volume of patients who return regularly for treatment. Study Results IHEEZO was associated with lower patient-reported discomfort at all four post-injection assessments, measured using a standard 0-to-10 numeric rating scale: The results showed a consistent benefit with IHEEZO throughout the 24-hour assessment period, with lower patient-reported discomfort at every time point. The largest absolute differences occurred shortly after injection, when discomfort is highest. Absolute treatment differences were 1.62 points at two minutes and 1.56 points at one hour, and lower discomfort scores with IHEEZO remained evident through the 24-hour assessment. “Patient comfort is a larger part of the intravitreal injection experience than it is sometimes given credit for,” said Travis Peck, MD, Retina Consultants of Delmarva, principal investigator of the study. “Because each patient received both anesthetic approaches on the same day, we were able to directly compare the patient experience. Patients consistently reported less discomfort in the IHEEZO-treated eye across all time points we measured. For retina specialists who perform a high volume of injections and care for patients who return repeatedly for treatment, these are practical and clinically relevant findings.” “These results provide new clinical evidence from a real-world practice setting supporting IHEEZO’s differentiated clinical pro commonly administered legacy ophthalmic anesthesia modalities – demonstrating a measurable improvement in patient-reported comfort following intravitreal injections,” said Mark L. Baum, Chief Executive Officer of Harrow. “Retina specialists work to preserve vision in patients who require ongoing treatment over many years, and the experience of each of those visits matters and ideally, should be optimized. The consistency and magnitude of the reduction in patient discomfort should strengthen physician confidence in IHEEZO’s clinical pro support broader utilization of the product across retina practices.” About the Study The investigator-initiated study was a prospective, randomized, contralateral-eye comparison conducted in a private retina practice. The study evaluated 100 eyes from 50 adult patients undergoing same-day bilateral intravitreal injections. Both eyes received 2% lidocaine-soaked pledgets prior to administration of the randomized study anesthetic. In each patient, one randomly assigned eye received IHEEZO prior to injection and the fellow eye received preservative-containing proparacaine ophthalmic solution 0.5%, allowing each patient to serve as his or her own control and reducing between-patient variability. Patient-reported ocular discomfort was assessed using a 0-to-10 numeric rating scale at 2 minutes, 1 hour, 6–12 hours, and 24 hours following injection. IHEEZO ® (chloroprocaine hydrochloride ophthalmic gel) 3%, for topical ophthalmic use INDICATIONS AND USAGE IHEEZO is an ester anesthetic indicated for ocular surface anesthesia. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS IHEEZO is contraindicated in patients with a history of hypersensitivity to any component of this preparation WARNINGS AND PRECAUTIONS Not for Injection or Intraocular Administration Corneal Injury Due to Insensitivity Corneal Opacification For Administration by Healthcare Provider: IHEEZO is not intended for patient self-administration ADVERSE REACTIONS Most common adverse reaction is mydriasis (approximately 25%) Please see full  Prescribing information About Harrow Harrow, Inc. (Nasdaq: HROW) is a leading provider of ophthalmic disease management solutions in North America, offering a comprehensive portfolio of products that address conditions affecting both the front and back of the eye, such as dry eye disease, wet (or neovascular) age-related macular degeneration, cataracts, refractive errors, glaucoma and a range of other ocular surface conditions and diseases of the retina. Harrow was founded with a commitment to deliver safe, effective, accessible, and affordable medications that enhance patient compliance and improve clinical outcomes. For more information about Harrow, please visit harrow.com and connect with us on LinkedIn . Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. Any statements in this release that are not historical facts may be considered such “forward-looking statements.” Forward-looking statements are based on management's current expectations and are subject to risks and uncertainties which may cause results to differ materially and adversely from the statements contained herein. Some of the potential risks and uncertainties that could cause actual results to differ from those predicted include, among others, risks related to: liquidity or results of operations; our ability to successfully implement our business plan, develop and commercialize our products, product candidates and proprietary formulations in a timely manner or at all, identify and acquire additional products, manage our pharmacy operations, service our debt, obtain financing necessary to operate our business, recruit and retain qualified personnel, manage any growth we may experience and successfully realize the benefits of our previous acquisitions and any other acquisitions and collaborative arrangements we may pursue; competition from pharmaceutical companies, outsourcing facilities and pharmacies; general economic and business conditions, including inflation and supply chain challenges; regulatory and legal risks and uncertainties related to our pharmacy operations and the pharmacy and pharmaceutical business in general, including the ongoing communications with the U.S. Food and Drug Administration relating to compliance and quality plans at our outsourcing facility in New Jersey; physician interest in and market acceptance of our current and any future formulations and compounding pharmacies generally. These and additional risks and uncertainties are more fully described in Harrow’s filings with the Securities and Exchange Commission (SEC), including its Annual Report on Form 10-K for the year ended December 31, 2025, and other filings with the SEC. Such documents may be read free of charge on the SEC's web site at sec.gov. Undue reliance should not be placed on forward-looking statements, which speak only as of the date they are made. Except as required by law, Harrow undertakes no obligation to update any forward-looking statements to reflect new information, events, or circumstances after the date they are made, or to reflect the occurrence of unanticipated events. Contacts : Mike Biega Vice President of Investor Relations and Communications mbiega@harrowinc.com 617-913-8890 i Comparative incidence of endophthalmitis after intravitreal dexamethasone implant versus anti-VEGF injections: a retrospective study. International Journal of Retina and Vitreous. 2026 A photo accompanying this announcement is available at

肝微粒体稳定性和血浆稳定性是两个关键的临床前ADME参数，共同回答了药物发现阶段一个核心问题：母体化合物在体内的清除机制及其存留时间。微粒体稳定性主要关注肝脏I相氧化代谢，而血浆稳定性则关注全血/血浆环境中的水解等非CYP酶降解。 01 肝微粒体稳定性（Liver Microsome Stability） 药物代谢是药物在体内吸收分布后，在药物代谢酶的催化下发生结构转化的过程。这是大多数药物从体内清除的主要途径。药物代谢反应可分为Ⅰ相和Ⅱ相代谢。Ⅰ相代谢会添加功能基团或暴露分子中的功能基团，如氧化和还原反应。Ⅱ相代谢涉及如葡萄糖醛酸化和磺化等的结合反应。 1.为什么要测试代谢稳定性 由于大多数口服药物主要通过肝脏CYP介导的代谢清除，准确预测肝代谢和首过清除在早期药物发现中至关重要。代谢稳定性作为化合物重要的ADME性质，其影响着化合物在机体内的清除率、半衰期和口服生物利用度。在先导化合物优化阶段，代谢稳定性研究意义在于筛选优势化合物、指导结构修饰，避免将代谢不稳定的化合物推入昂贵的体内研究。代谢稳定性实验是用一系列体外实验评估酶代谢的候选化合物的消除速率。代谢稳定性主要回答这一核心问题："How long will my parent compound remain circulating in plasma within the body?"（受试原型化合物在体内的循环留存时长为多久？） 2.实验方法学分类，制备流程 目前常用于代谢稳定性研究的高通量方法主要包括肝微粒体、肝细胞和肝S9等，其中肝微粒体代谢稳定性（LMS）和肝细胞代谢稳定性（HMS）研究最为常见。肝微粒体（Microsomes）是肝细胞匀浆超速离心后获得的亚细胞组分，主要包含内质网碎片，富含药物代谢酶，不包含胞浆中的酶（如醇脱氢酶、醛氧化酶、黄嘌呤氧化酶）和线粒体酶，如下图所示。 从动物肝脏组织中制备三种核心体外代谢模型——肝微粒体（Microsomes）、S9组分（S9 fraction）和肝细胞（Hepatocytes）的完整实验流程： 肝微粒体（Microsomes）、S9组分（S9 fraction）、肝细胞（Hepatocytes）和3D肝球体比较 3. 代谢稳定性实验设计与标准方案 根据NIH Assay Guidance Manual的标准化方案： 蛋白浓度：0.5 mg/mL（人肝微粒体或其他种属） 底物浓度：通常10 μM（低于Km，确保一级动力学） 时间点：基础筛选采用 t=0 和 t=60 min；优化阶段可扩展为多个时间点（0, 5, 15, 30, 60 min） 辅因子：NADPH再生系统（用于CYP450）；UDPGA + alamethicin（用于UGT） 对照设置： 阳性对照：已知底物（如CYP3A4底物睾酮） 阴性对照：不含NADPH的体系（排除非酶降解） 药代谢稳定性实验流程：将药物与微粒体置于 100 mM 磷酸钾缓冲液中孵育；加入 1 mM NADPH 溶液，在 37 ℃条件下启动代谢反应。采用分析检测技术在不同时间点监测药物底物的剩余量。以峰面积比的自然对数对时间作图，可得一条直线；直线斜率即为消除速率常数，可用于推算固有清除率。通过换算比例因子，可将体外固有清除率与体内清除率建立关联。 关键操作要点：微粒体蛋白浓度建议 <0.5 mg/mL 以减少药物与蛋白的非特异性结合；有机溶剂终浓度需 <1% 以避免抑制CYP450活性。 4. 关键数据解读，理想数值与局限 肝微粒体稳定性是预测肝清除率和首过效应最核心的体外指标。若化合物在微粒体中快速降解，其在体内的半衰期通常较短，口服生物利用度可能较低。 In Vitro Drug Metabolism Studies Using Human Liver Microsomes | IntechOpen，https://www.intechopen.com/chapters/84232 FGI：肠道利用度FH：肝脏利用度 Foral：口服生物利用度 EGI：肠道摄取率 / 肠道抽取率 EH：肝脏摄取率 / 肝脏抽取率 药物进入体循环前，在小肠壁肠上皮细胞、继而在肝脏肝细胞中，经CYP3A4介导首过代谢，和/或经P-糖蛋白（P-gp）转运外排过程示意图。首过代谢决定口服药效强弱、给药剂量、剂型选择、个体药效差异和药物相互作用，是临床选药、调剂量、改给药途径的重要依据。 文献强调通过%剩余或t1/2 进行排序： 专业注释与局限： 批间差问题：商用微粒体（不同批次的人肝样本）活性差异显著。在关键节点，建议储备同批次微粒体，或在换批时进行桥接实验比较标准品数值。 缺失II相代谢：微粒体试验主要反映I相代谢。若化合物主要经葡萄糖醛酸化（UGT酶）或硫酸化清除，微粒体数据会低估真实的肝清除率，需补充肝细胞稳定性实验。 无法预测转运体介导的清除 体外-体内外推存在不确定性（需考虑游离分数、肝血流量等） 5. 肝微粒体稳定性LMS和肝细胞稳定性HMS实验结果差异的主要原因有哪些？ 肝微粒体由肝脏组织匀浆经过差速离心所得，肝微粒体富含各种代谢酶尤其是CYP450酶，易于储存和使用，成本相对较低。肝细胞保持了完整的细胞结构，拥有更完整的代谢酶系统和不同清除途径的辅酶因子。此外，与肝微粒体不同的是，肝细胞还保留了细胞膜和膜上的转运体蛋白。肝微粒体稳定性和肝细胞稳定 性实验结果差异的主要原因如下： 1)当化合物的膜渗透能力较差或为外排转运体底物时，化合物由于在肝细胞体系中无法完全暴露于代谢酶中，会导致化合物在肝细胞中代谢速率较慢。 2)Non-CYP介导的代谢包括PhaseⅠ的AO、MAO和PhaseⅡ的UGT代谢等。这些酶大多不存在于肝微粒体中或肝微粒体中缺少UGT的辅助因子，相比之下，这些Non-CYP代谢酶或相应的辅助因子均存在于肝细胞中。因此，主要经由AO或MAO等Non-CYP酶代谢的化合物在肝微粒体和肝细胞稳定性实验中的结果可能呈现出某些差异。 另有一些经验性的统计研究发现，肝微粒体稳定性与化合物的理化性质、渗透性和酶表型有一定的关系，例如有研究发现主要经CYP3A代谢的化合物在肝微粒体中的固有清除率高于肝细胞稳定性中的固有清除率，但经CYP2D6代谢的化合物在两种基质中的代谢无明显区别。 应对LMS和HMS差异的策略：面对肝微粒体与肝细胞代谢数据差异，需按研发阶段分层决策：早期筛选重视“排序一致性”，开发预测重视“机制理解与模型选择” 1）早期筛选：以体内相关性为唯一准绳，此阶段核心是低成本、高通量地淘汰高风险化合物，策略依差异原因而定：差异源于被动渗透性低，HMS > LMS 稳定性（肝细胞因膜屏障代谢慢），且体内清除率低。 策略是维持LMS筛选。这是保守且高效的做法，LMS虽高估清除率，但可最大限度避免“假阴性”，确保不遗漏代谢不稳定分子。差异源于非CYP酶代谢，HMS < LMS 稳定性（肝细胞含完整非CYP酶系，代谢更快），且体内清除率高。策略是果断放弃LMS，转用肝细胞。 2）开发阶段：基于机制的IVIVE预测人体清除率,此阶段需探明差异机理，选择合适体外模型和缩放因子进行人体清除率预测。差异源于被动渗透性低则无需过度研究机制，依据临床前多种属的体外-体内相关性，直接选择LMS或HMS数据及对应的缩放因子进行预测即可。如果差异源于外排转运体，策略是参考临床前种属IVIVC选择模型，但必须补充转运体动力学实验，结合PBPK模型预测肝清除率，以防范种属间转运体表达差异导致的预测偏差。若临床前种属IVIVC良好，直接用HMS数据及缩放因子预测；若相关性不一致，则用重组酶表征代谢路径，结合PBPK模型预测。 总结：应对差异的核心在于建立筛选排序与体内真实情况的强相关性，开发阶段则需明确机制、选对模型、精准定量。 6. 肝微粒体代谢稳定性认识的常见误区 误区一：体外CLint高 → 体内清除率一定高（忽视体外-体内体系的关键差异）核心差异与修正： 血浆蛋白结合：PPB极高，大量药物与血浆蛋白结合，游离药物浓度低，体内清除率实际不高 渗透性屏障：低渗透性化合物无法有效跨越肝细胞膜接触代谢酶，体内清除受限 酶比例差异：体外孵育体系中酶/底物比例与体内实际不同 动态vs静态：体外是静态强制接触，体内是动态流动，药物可逃离代谢位点 非微粒体酶：体内存在微粒体外的代谢酶（如血浆酯酶、胞质酶），体外LMS无法反映 体外高CLint仅为警示信号，不能单独预测体内清除率，必须结合PPB和渗透性综合判断。 误区二：LMS中等偏慢但体内清除率高 → 一定存在非肝清除途径 三步分析策略： 第一步排查非微粒体代谢：考察化合物在肝细胞和血浆中的稳定性。血浆酯酶、肝细胞质酶等可能参与代谢，这些在LMS中无法检出 第二步排查分布因素：检查全血/血浆分配比。若化合物大量进入红细胞，血浆浓度偏低，则基于血浆计算的CL会偏高，造成“高清除”假象 第三步考虑非肝清除途径：如肾脏排泄或胆汁排泄。这类实验成本高，应放在最后，除非已有明确指向性证据 误区三：LMS消除快 → 体内半衰期一定短（混淆清除率与半衰期的决定因素，忽视分布容积的作用） 体内半衰期由清除率和分布容积共同决定 即使清除率高，若化合物广泛分布于组织，仍可获得可接受的半衰期 体外条件下化合物被强制限在孵育孔中，而体内可大量分布于非代谢器官，延缓消除 结论：不可仅凭LMS速率判断体内消除快慢，需结合分布容积评估半衰期。 误区四：LMS快但体内AUC还行 → 可以接受 错误根源：仅关注总药物浓度（Total AUC），忽视游离药物暴露（unbound AUC） 分两类情况： 类型一：LMS快 + PPB高 总AUC可能不差，但游离AUC（AUC unbound）显著不足 药效通常与游离药物浓度相关，存在药效不足的风险 例外：若PK/PD特征特殊，却与总AUC相关，则可接受 类型二：LMS快 + 渗透性低 给药途径受限，可能仅适用血管内给药 适应症受限，仅适用于血液系统疾病靶点 结论：需同时关注游离暴露量，并根据给药途径和靶点组织分布决定取舍。 误区五：LMS越稳定越好 错误根源：忽视适应症特点、靶点作用机制及PK/PD特征的差异化需求。 许多CNS药物不需要高代谢稳定性——只需短暂脉冲触发靶点，持续高暴露反而导致副作用（如嗜睡、持续亢奋） 机体处于动态平衡，药物需“拨正”而非“过度干预” 目标区间的动态确定原则： LMS是排序工具，非绝对取舍标准。早期目的是对化合物进行ranking，而非基于单一参数做决策 目标区间随研究阶段动态调整，取决于： 化合物体外活性 靶点作用机制 其他ADME性质 PK/PD特征（药效是否依赖持续暴露或Cmax） 如果药效需持续高浓度维持 → 提高LMS稳定性要求 如果药效与Cmax关联更大，不需持续作用 → 可适当放宽LMS要求 结论：代谢稳定性的“理想值”是因项目而异的动态目标，需要过体内外相关性分析和PK/PD研究逐步明确。 02 血浆稳定性（Plasma Stability） 血浆稳定性评估化合物在全血浆环境中的化学和酶学稳定性，反映化合物抵抗血浆中各种降解因素的能力。 回答核心药理学问题：“原型化合物在血液运输途中，是否会被血浆中的酶分解？” 1.血浆稳定性研究意义 血浆稳定性往往是决定化合物全身暴露量、药效及安全性的核心因素之一。药物给药后，会接触血浆中大量酶类及活性组分，这类物质可快速水解断裂酯键、酰胺键或肽键。水解作用会降低化合物体内循环血药浓度，进而导致药代动力学（PK）性质变差或药理活性丧失。在药物研发早期开展血浆稳定性评价，可有效预判化合物代谢薄弱位点，有助于区分化合物不稳定性来源于血浆水解还是肝脏代谢。血浆稳定性不足，往往导致无法达到预期生物利用度；而对部分类似物而言，血浆稳定性过强又可能引发药物蓄积和/或体内暴露时间过长的风险。 血浆是血液的重要组成部分，主要成分包括水、血浆蛋白、葡萄糖、激素、矿质离子及多种水解酶（如胆碱酯酶、醛缩酶、脂肪酶、脱氢肽酶、碱性和酸性磷酸酶等）。血浆中易被降解的化合物官能团主要有酯基、酰胺、氨基甲酸酯、内酰胺、内酯、磺酰胺及肽类结构等。血浆稳定性与全血稳定性不同——后者还包含红细胞内的酶和不同pH/氧气环境。 主次关系：水解酶（尤其酯酶）是血浆中药物降解的绝对主导因素。氧化还原酶活性可忽略；pH和血浆蛋白既可独立发挥作用，也可协同影响酶解速率。 2. 实验设计与操作 · 实验基质：新鲜或商品化的人血浆（或特定种属血浆）。 · 浓度设置：文献建议设两个浓度（如10μM和100μM，或模拟预期的Cmax与10×Cmax）。高浓度检测是为了排除酶饱和带来的假阴性——低浓度降解快，高浓度可能因酶饱和而显得稳定。 · 时间点：t = 0和t = 180 min（3小时），覆盖大多数口服药物的吸收相和分布相。 · 关键对照： o 阳性对照：普鲁卡因（Procaine，极易被酯酶水解，t1/2极短）。 o 阴性对照：普鲁卡因胺（Procainamide，酰胺键替代酯键，极其稳定）。 https://www.creative-bioarray.com/services/plasma-stability-assay.html 3.数据解读与注释 关键参数 · 通常测试孵育3小时后母药剩余百分比。 · 稳定性优良：>80%剩余，化合物在血液环境中化学/酶学稳定，不必担心采血样时或体内循环中快速降解。稳定性较差：<50%剩余，口服入血前或在血中就被破坏，到达靶点的药量不足。 · 血浆不稳定性会直接影响生物分析策略的设计。对于血浆中易降解的化合物，采血时试管内须预加酯酶抑制剂，且样本处理需在冰浴下快速完成。否则血浆中药物继续降解，导致检测到的浓度远低于真实体内浓度，严重误导PK参数计算。 丙美卡因（Propantheline）眼科用药，临床上主要用于眼科表面麻醉等。 4.常见不稳定性及应对策略： 5.前药设计与血浆稳定性 血浆稳定性研究对前药策略至关重要： 03 肝微粒体稳定性VS血浆稳定性两者的关联与在药物发现流程中的定位 1.肝微粒体稳定性与血浆稳定性对比总览 2.两者的关联与在药物发现流程中的定位 关联：共同决定药物的“体内存留时间” 两项研究回答了同一个核心问题：“原型化合物在体内能存在多久？”，但它们针对的是不同阶段和不同器官的清除威胁： ·血浆稳定性 → 评估药物在运输途中（血管内）的“生存能力”，是进入肝脏前的第一道防线。 ·肝微粒体稳定性 → 评估药物通过肝脏时被代谢清除的风险，是最主要的清除壁垒。 只有两者都表现良好，化合物才能在体循环中维持有效浓度并到达靶组织。 任何一个环节失守都会导致体内暴露量不足。 在药物发现流程中的定位：早期并行评估 3.关键联系与区别 总结 在临床前候选化合物筛选阶段，肝微粒体稳定性预测了肝脏代谢的主要壁垒，而血浆稳定性排除了血液中的潜伏陷阱。两者缺一不可，共同构成了评估化合物是否具备足够半衰期以维持有效血药浓度、是否值得投入资源进行体内药效学研究的关键依据。两者缺一不可，共同构成评估化合物是否具备足够半衰期以维持有效血药浓度、是否值得投入资源进行体内药效学研究的关键体外ADME依据。在药物发现流程中，应同步进行、平行评估，为结构优化提供不同方向的指导，并在候选化合物提名时进行联合验证。 参考文献： 1. Drug metabolic stability in early drug discovery to develop potential lead compounds. DRUG METABOLISM REVIEWS. 2021,VOL.53,NO.3,459–477 2. An update on the importance of plasma protein binding in drug discovery and development. EXPERT OPINION ON DRUG DISCOVERY. 2021, VOL. 16, NO. 12, 1453–1465. 免责声明：文章内容均来源于网络及文献，仅供参考，禁止商业用途