Buprenorphine

SUBLOCADE use during pregnancy showed no increased risk of birth defects, miscarriage, or maternal complications compared to general population rates RICHMOND, Va., May 1, 2025 /PRNewswire/ -- Indivior PLC (Nasdaq/LSE: INDV) today announced the publication of a study "Monthly Buprenorphine Depot Injection (SUBLOCADE) for Opioid Use Disorder During Pregnancy" in the American Journal on Addictions, evaluating the use of SUBLOCADE for the treatment of opioid use disorder (OUD) during pregnancy and postpartum. Three sources of data evaluated in this retrospective study illustrated that the use of monthly SUBLOCADE during pregnancy demonstrated no increased risk and is consistent with the established buprenorphine safety profile.1 This retrospective study includes clinical case studies from four pregnant patients treated with monthly SUBLOCADE, postmarketing surveillance data covering more than five years, and a targeted literature review. In total, 322 reports of pregnancy exposures to SUBLOCADE were identified. Of the four patients included in the clinical practice case studies, all delivered full-term infants with normal birthweight, no fetal anomalies, and no need for treatment for neonatal opioid withdrawal syndrome (NOWS). "The findings shared in this manuscript support perinatal, patient-centered decision-making," said Melinda Ramage, FNP-BC, CARN-AP, LCAS, Director of the North Carolina Perinatal Substance Use Disorder Network and lead author of the publication. "Treatment is not one-size-fits-all, and it is important to explore safe and effective options for the mother–baby dyad." Between 2010 and 2017, opioid use during pregnancy dramatically increased, with a 131% increase in opioid use-related diagnoses at delivery in the U.S.2 The U.S. national maternal morbidity and mortality data reveal mental health and substance use disorders are the leading underlying cause of pregnancy-related deaths in 36 states. While pregnancy-associated overdose deaths have been steadily rising since 2007, those involving fentanyl and other synthetic opioids markedly increased from 5.73 to 9.47 deaths per 100,000 in a span of just 3 years (2017–2020), with most deaths occurring post-delivery.3 This study helps address the current knowledge gap with relevant experience from patients and prescribers who used monthly SUBLOCADE during pregnancy and/or postpartum. In addition to the case studies, the postmarketing surveillance data showed live births with no reported birth defects in the majority of known cases and rates of spontaneous abortion and other outcomes consistent with or lower than general population rates. Review of relevant literature also aligned with the findings from postmarketing and clinical data sources. These data highlight buprenorphine's established safety profile and offers practical insights into clinical care. "OUD patients who are pregnant run the risk of experiencing a number of negative health consequences, such as infection, overdose, severe maternal morbidity, postpartum readmission, and even death, and using opioids during pregnancy has been linked to poor results for both the fetus and the newborn," said Christian Heidbreder, Chief Scientific Officer at Indivior. "As public health professionals and policymakers look for ways to reduce maternal overdose deaths, this study offers important new information about how long-acting medications like SUBLOCADE might be incorporated into a broader strategy to increase access and enhance outcomes for families affected by OUD." Treatment decisions during pregnancy and postpartum should reflect a shared decision-making approach between providers and patients, aligning with clinical guidance and product labeling. The patient-centered model is especially critical when managing chronic conditions, like OUD, in the perinatal period. These data support consideration of using SUBLOCADE as part of evidence-based treatment options, which include offering or continuing perinatal medications for OUD, prioritizing patient stability when considering a change of existing pharmacotherapy in pregnancy and postpartum, and assessing the benefits and risks in a patient-centered framework. This is the largest amount of data available regarding the experience of pregnant patients on SUBLOCADE. Limitations of the study include limited descriptive data for case studies obtained from a small patient cohort and 21% of pregnancies reported outcomes for postmarketing surveillance. Disclosure: This work was funded by Indivior Inc., with the exception of the case studies and the time and contributions of Melinda Ramage, which were not supported by Indivior. About SUBLOCADE® SUBLOCADE ® (buprenorphine extended-release) injection, for subcutaneous use, CIII INDICATION AND HIGHLIGHTED SAFETY INFORMATION INDICATION SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support. HIGHLIGHTED SAFETY INFORMATION WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION; SUBLOCADE RISK EVALUATION AND MITIGATION STRATEGY Serious harm or death could result if administered intravenously. SUBLOCADE forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life-threatening pulmonary emboli, if administered intravenously. Because of the risk of serious harm or death that could result from intravenous self-administration, SUBLOCADE is only available through a restricted program call the SUBLOCADE REMS Program. Healthcare settings and pharmacies that order and dispense SUBLOCADE must be certified in this program and comply with the REMS requirements. CONTRAINDICATIONS Hypersensitivity to buprenorphine or any other ingredients in SUBLOCADE. WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse: SUBLOCADE contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors. Respiratory Depression: Life threatening respiratory depression and death have occurred in association with buprenorphine. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with SUBLOCADE. Risk of Serious Injection Site Reactions: Likelihood of may increase with inadvertent intramuscular or intradermal administration. Evaluate and treat as appropriate. The most common injection site reactions are pain, erythema and pruritus with some involving abscess, ulceration and necrosis. Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. Risk of Opioid Withdrawal with Abrupt Discontinuation: If treatment with SUBLOCADE is discontinued, monitor patients for several months for withdrawal and treat appropriately. Risk of Hepatitis, Hepatic Events: Monitor liver function tests prior to and during treatment. Risk of Withdrawal in Patients Dependent on Full Agonist Opioids: Verify that patients have tolerated transmucosal buprenorphine before injecting SUBLOCADE. Treatment of Emergent Acute Pain: Treat pain with a non-opioid analgesic whenever possible. If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect. ADVERSE REACTIONS Adverse reactions commonly associated with SUBLOCADE (in ≥5% of subjects) were constipation, headache, nausea, injection site pruritus, vomiting, increased hepatic enzymes, fatigue, and injection site pain. For more information about SUBLOCADE, the full Prescribing information including BOXED WARNING, and Medication Guide, visit . About Opioid Use Disorder (OUD) Opioid Use Disorder (OUD) is a chronic disease in which people develop a pattern of using opioids that can lead to negative consequences. OUD may affect the parts of the brain that are necessary for life-sustaining functions. About Indivior Indivior is a global pharmaceutical company working to help change patients' lives by developing medicines to treat opioid use disorder (OUD). Our vision is that all patients around the world will have access to evidence-based treatment for OUD and we are dedicated to transforming OUD from a global human crisis to a recognized and treated chronic disease. Building on its global portfolio of OUD treatments, Indivior has a pipeline of product candidates designed to expand on its heritage in this category. Headquartered in the United States in Richmond, VA, Indivior employs over 1,000 individuals globally and its portfolio of products is available in over 30 countries worldwide. Visit to learn more. Connect with Indivior on LinkedIn by visiting . References: Ramage M, Bishop B, Mangano V, Mankabady B. Monthly Buprenorphine Depot Injection (SUBLOCADE®) for Opioid Use Disorder During Pregnancy. Am J Addict. 2025. Hirai AH, Ko JY, Owens PL, Stocks C, Patrick SW. Neonatal abstinence syndrome and maternal opioid-related diagnoses in the US, 2010–2017. JAMA. 2021; 325(2): 146-155. doi:10.1001/jama.2020.24991 Bruzelius E, Martins SS. US trends in drug overdose mortality among pregnant and postpartum persons, 2017–2020. JAMA. 2022; 328(21): 2159-2161. doi:10.1001/jama.2022.17045 SOURCE Indivior PLC WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

尹莉芳中国药科大学药剂学教授，博士生导师，中国药学会药剂专业委员会副主任委员、国家药品监督管理局药品审评中心咨询专家委员会委员、国家药典委员会委员、中国药学会工业药剂学专业委员会委员、中国药学会科普工作委员会委员、国家科学技术奖励办评审专家、科技部国际合作同行专家、江苏省缓释智能制剂及关键功能性辅料开发与评价工程研究中心主任、江苏省药物研究与开发协会化学药物专委会副主任委员、江苏省药品监督管理局药品审评专家等。获得江苏省科学技术奖一等奖、二等奖各一项。尹莉芳教授长期专注缓控释给药系统的研究及产业化，药物新剂型、仿创药物研发及产业化，基因药物成药性研究等领域，主持国家“重大新药创制”科技重大专项，以及国家自然科学基金委、教育部、江苏省科技厅等机构的项目共 30 余项。在缓控释制剂、固体制剂方向产业化经验丰富，与国内外数十家企业合作，近年来主持企业项目近 100 项，完成一类创新药西达本胺片、改良型新药甘草酸二胺肠溶片等数十个品种申报，获得硝苯地平控释片、二甲双胍缓释片等 30 余款药物的新药证书或生产批件。以第一发明人申请发明专利 40 余项，获得授权 20 项，专利权转让 3 项。主编、参编生物药剂学与药物动力学、药剂学、工业药剂学等学科相关教材 8 部，以第一作者或通信作者在 ACS Nano、Adv Sci 等期刊上发表高水平论文 80 余篇。长效注射剂的改良与创新：现状与未来 PPS 张汶彦 1, 2，胡鑫蕾 1, 2，刘莉莎 1, 2，杨磊 1, 2，尹莉芳 1, 2*（1. 中国药科大学药学院，江苏 南京 210009；2. 江苏省缓释智能制剂及关键功能性辅料开发与评价工程研究中心，江苏 南京210009） [ 摘要 ] 目前，药品研发领域日益多元化，改良型新药作为重要分支，在提升药物疗效、缩短研发周期及提升市场竞争力方面展现出显著优势。综述了长效注射剂在改良型新药研发领域的现状和发展趋势。文章系统探讨了长效注射剂的制剂开发策略，涵盖油基长效注射液、注射用混悬液、微球、脂质体及原位凝胶等多种剂型，旨在为长效注射剂的改良与创新提供科学依据和参考。1引言随着医药科技的不断发展，新药研发领域呈现多元化趋势。相较于探索全新靶点与结构的创新药，改良型新药能够依托已知研究数据，有效缩短临床研发周期，延长药物的生命周期，并激发新的市场竞争活力，正逐步成为医药企业研发的新热点 [1]。当下国家产业政策环境鼓励发展改良型新药，力争实现改良和创新并举。国内正处于从仿制药向创新药、改良型新药转型的过渡期。各类注射剂、缓控释固体口服制剂和口腔速溶膜剂等高端复杂制剂已成为国内改良型新药突破的热点方向 [2-3]。其中，长效注射剂（ long-acting injection， LAI）因其独特的临床优势和较高的研究壁垒，正逐渐成为企业改良型新药立项与研发的核心重点。LAI 是指可以在注射给药后较长或指定时间内实现药物持续或受控释放的药物递送系统。此类制剂通常采用皮下或肌肉注射等全身给药方式，也可用于关节内及眼内等局部区域，在单剂量给药后能够提供数周至数月的稳定治疗药物浓度，进而减少给药频次并提高患者依从性。因此， LAI 在慢性及重大疾病的治疗中颇具优势，已广泛用于激素类、精神类和戒毒类药物的制剂改良 [4]。随着制剂技术的迅速发展， LAI 经历了从油溶液到微球（microsphere）、脂质体（liposome）和原位凝胶的变化，体现了从无到有、从简至精的演变过程。例如，利培酮通过多次剂型优化，从普通片剂转化为微球 LAI、原位凝胶 LAI，既满足了临床需求，又延长了产品的生命周期，展现出巨大的市场价值，成为国际市场上改良型新药的典范。 LAI作为仿制药向改良型新药转型必须跨越的技术门槛，将成为我国制药行业构筑核心竞争力的战略工具，并为我国制药行业的国际化铺设了一条高效且富有前瞻性的加速通道。本文综述了 LAI 的制剂策略，旨在为 LAI 的深度开发提供参考与启示。2长效注射剂的研发策略 LAI 的设计旨在通过不同的制剂策略延长药物在体内的停留时间，从而实现持续的药物释放。这些策略包括但不限于油基 LAI、注射用混悬液、微球、脂质体以及原位凝胶。每种制剂策略都有其独特的药物释放机制（见图 1），能够满足不同的临床需求。以下将详细介绍这些 LAI 的制剂策略，分析其原理、制备方法以及在临床应用中的表现，并探讨各类 LAI 在药物递送中的应用前景和研发难点。2.1油基长效注射剂油基 LAI 是将药物溶解或分散在油性溶剂中得到的制剂。传统上用于治疗需要长期用药的慢性疾病，如精神分裂症等。油基 LAI 通常通过肌肉或皮下注射给药，并在注射部位形成药物贮库，将药物缓慢释放到周围血液中 [5]。其缓释机制主要依赖于油性载体在注射部位的缓慢分解和药物在油水之间的分配。油基 LAI 通常由亲脂性药物、油性载体和共溶剂组成。还可以使用助溶剂降低油系统的黏度，同时增加药物的溶解度，苯甲醇是最常用的共溶剂。此外，可将固体药物颗粒分散在油性载体中以提高载药量 [6]。油基 LAI 是最早使用的 LAI 剂型，目前已批准上市的油基 LAI 见表 1。目前，油基 LAI 的研发难点主要集中在：药物在油相中的溶解度和稳定性、注射部位的不适感和药物释放的调整。油相的合理选择对解决以上问题至关重要。黏度是选择油性载体的关键参数，直接影响制剂的扩散程度和可注射性。具体而言，高黏度油能更好地保持制剂注射后的形状，从而减少扩散并延长药物释放时间；而低黏度油则具有良好的可注射性，可以降低注射过程中的疼痛与不适感 [7]。通常情况下，黏度在 60 mPa·s 以下的牛顿流体油溶液的可注射性较好，上市的注射剂产品黏度一般在 29~60 mPa·s 范围内 [8]。除黏度外，药物在油和组织液之间的分配、注射部位、注射量以及注射部位的制剂形状等因素也会影响药物的整体药代动力学特征 [9]。尽管该系统具有良好的长期稳定性和快速简便的制备工艺与灭菌流程，但其缓释时间通常不超过4 周，且仅能用于递送亲脂性药物，还可能引起注射部位的不适感及不良反应。因此，在探索该缓释系统的潜力时，需充分考虑其特定的药物适应性及安全性问题。2.2 注射用混悬液 注射用混悬液是一种通过减小药物粒径增加表面积，以增加药物溶解度、实现长效递送的制剂。根据粒径大小，注射用混悬液可分为微米晶（ 0.5 ~15 μm）混悬液和纳米晶（ 100 ~ 600 nm）混悬液 [10]。对于同种药物，一般药物颗粒的粒径越大，其缓释作用越强。注射用混悬液通常包含活性药物成分（API）、分散介质和稳定剂三部分，此外，处方中还可加入渗透压调节剂、 pH调节剂等辅料以满足制剂安全性、有效性、稳定性、顺应性的需求。用于注射用混悬液的药物通常是水溶性差、亟需提升溶解度与生物利用度的药物，比如某些难溶性的抗癌药物、抗生素和激素类药物。稳定剂包括助悬剂和润湿剂，常使用表面活性剂和高分子聚合物，用于润湿药物，增加分散介质的黏度，减缓药物微粒的沉降，阻止药物微粒聚集结块。注射用混悬液给药后能够在注射部位沉积，随后药物缓慢溶解并吸收入血。在这一过程中，少量已溶解药物和较小粒径的药物颗粒能被快速吸收而发挥药效，较大粒径的药物颗粒渐进性溶解成较小颗粒，持续不断地被吸收入血。不同粒径的药物协同作用，确保了药物在体内的长期稳定释放。目前已有多种注射用混悬液产品上市（见表 2）。相较于其他 LAI，注射用混悬液因辅料体系简单、工业生产便捷而受到科研界与产业界的广泛关注。然而，注射用混悬剂普遍存在药物释放周期较短、制剂体系稳定性较差等问题。当前针对注射用混悬液的研究主要集中于三大核心领域：一是优化药物释放性能；二是提高制剂体系的稳定性；三是粒度控制。粒度是关键质量属性，精确控制粒径分布范围对于优化药物释放和提高稳定性均有重要作用。增加药物的亲脂性、改变粒径和浓度可以延长药物释放时间。 Kenalog® 的活性成分曲安奈德是曲安西龙的亲脂性衍生物，其低水溶性使得曲安奈德混悬液在体内的作用时间更长 [11]。上市产品中，Invega Sustenna® 和 Invega Trinza® 通过调整粒径和浓度实现了不同缓释时间。注射用混悬液中颗粒有时会发生奥斯特瓦尔德熟化，导致重结晶和沉淀，影响注射和释放行为。使用稳定剂可以防止纳米晶体的聚集和重结晶，保持其粒径尺寸和分散性 [12]。2.3 微球微球是将固体或液体药物分散或溶解在聚合物材料中形成的微小球形颗粒，大多由生物可降解聚合物制成，可以在体内逐渐降解，最终被代谢排出体外 [13]。微球的尺寸通常在 10 ~ 250 μm 范围内（理想情况下为 10 ~ 125 μm），以便通过传统注射器针头注射，并减少巨噬细胞的吞噬作用和局部组织炎症 [14]。微球的释药机制主要包括扩散、溶解以及聚合物的侵蚀和降解 [15-16]。具体来说，药物释放途径包括表面释放、孔隙释放、聚合物屏障扩散、水溶胀屏障扩散，以及聚合物的侵蚀和降解 5种 [17]。一般而言，基于聚乳酸-羟基乙酸共聚物（ PLGA）的微球药物表现出 3 个释放阶段：突释、缓释和二次突释 [18]。近年来，已有多种微球制剂成功上市或申报新药审批，目前已批准上市的长效注射微球如表 3 所示。目前，关于微球的研究主要集中在制备技术、处方优化、新型材料和药物释放调控等方面。经典的微球制备方法工业化生产难度大、成本高， Nutropin®和Plenaxis®皆因生产成本问题退出市场 [19]。近年来，微流控技术、超临界流体技术等新型制备方法相继出现，研究者们不断研发与优化各类新型技术，以期实现微球制备过程的高精度控制、高效率生产和多功能化集成 [20-21]。在处方优化方面，选用不同种类和比例的辅料，可以显著提高微球的药物稳定性和生物利用度。Park 等 [22] 研究了不同添加剂 [ 碳水化合物、蔗糖、氨基酸、表面活性剂、泊洛沙姆 188、磷脂和二肉豆蔻酰磷脂酰胆碱（ DMPC）等 ] 对 W/O/W- 溶剂蒸发法制备的多肽微球稳定性的影响。结果表明，不同的稳定剂可以从水溶液、水/二氯甲烷界面、PLGA 表面和冻融冻干过程等不同方面调节多肽微球的稳定性。除 PLGA 之外，研究人员开发了其他具有相似生物相容性和药物释放控制能力的聚合物，如聚 [1， 3-双（对羧基苯氧基）丙烷-癸二酸 ]（PCPP-SA）、透明质酸（ HA）、三（乙二醇） -聚（邻酯） （ TEG-POE）等，这些材料可用于装载与 PLGA 不相容的药物 [5]。2.4 脂质体脂质体是基于胆固醇和天然磷脂的球形囊泡，能包裹药物并实现长效释放和定向递送。根据粒径和脂质双层膜数量，脂质体主要可分为单室脂质体（ ULV）、多层脂质体（ MLV）和多囊脂质体（MVL）等。脂质体中药物的缓释效果取决于脂质体的大小、结构、表面电荷和脂质组成。注射后，制剂在给药部位形成贮库或在循环系统中稳定存在，实现药物持续释放。Doxil® 是首个获美国 FDA 批准的注射用脂质体，运用 Stealth 技术实现长循环并缓释盐酸阿霉素 [23]。而 MVL 基于其多隔室结构，为实现更长的药物缓释时间提供了一种有效策略。 DepoFoam® 技术 是 由 Pacira 公 司 开 发 的 MVL 技 术。 MVL 由 数百个非同心、多面体的水室组成，每个室由连续的脂质膜网络隔开 [24]，可通过鞘内、皮下等多途径注射给药，并在给药部位形成贮库，通过最外层囊泡的逐渐降解实现持续药物释放。在囊泡重排过程中， MVL 的结构保持不变 [25]。目前已有 3 个基于DepoFoam® 技术的药品获得 FDA 批准上市。目前已批准上市的长效脂质体注射剂见表 4。目前长效脂质体注射剂仍面临药物装载效率、稳定性、工业化生产和药物释放控制等方面的多重挑战。优化生产方法和工艺步骤，并保证脂质体的均匀性和药物装载效率，是当前研究的重点。 Costa等 [26] 基于乙醇注入法，结合连续混合、流动和过程分析技术（ PAT），通过将溶有脂质的有机溶剂与水溶液分别以特定流速注入混合器形成脂质体，显著提高了脂质体的生产效率和质量一致性，同时证明该方法适用于大规模生产。 Yanar 等 [27] 基于微流控技术，使用毫米级流动反应器在连续流动条件下生产脂质体，并证明优化流体条件可以提高脂质体的尺寸均匀性和分散性，从而提升药物递送的效果。由于脂质体的内部空间受限，保证药物稳定性的同时提高装载效率是另一个难题。通过调整脂质成分和工艺条件，可显著提高药物装载效率和稳定性。 Pereira 等 [28] 研究了不同脂质组成对脂质体包封效率的影响。结果表明，使用流动性较高的不饱和脂质制备的脂质体具有最高的包封效率，而使用刚性饱和脂质制备的脂质体包封效率较低。2.5 原位凝胶原位凝胶是一种能在注射部位自发形成凝胶状药物贮库的可生物降解聚合物基液体或可注射半固体制剂。相较于嵌入体内指定部位的植入物系统，原位凝胶因其生物相容性好、患者依从性高和易于产业化而被青睐。原位凝胶通常由 API、溶剂和能形成贮库的基质材料制成。常用的溶剂包括 N- 甲基吡咯烷酮（ NMP）、二甲基亚砜（ DMSO）和苯甲醇等有机溶剂，基质材料通常为水不溶的生物可降解材料，如 PLGA、 PLA、聚己内酯（PCL）、乙酸异丁酸蔗糖酯（ SAIB）和聚原酸酯（ POE）等。根据制剂组成，原位凝胶可以通过沉淀（由溶剂交换、温度或 pH 诱导所致）、有机凝胶化（涉及溶致液晶形成）或单体 / 聚合物链的交联（由光照射、离子或酶等触发）形成原位贮库。其中，溶剂交换诱导的原位沉淀是目前研究最广、上市品种最多的原位凝胶形成方式。该方法通过将药物溶解或分散在溶有基质材料的有机溶剂中形成制剂。注射后，制剂与周围环境发生溶剂交换，使基质材料沉淀并形成固体或半固体贮库，实现药物缓慢释放 [29]。目前已上市的原位凝胶产品主要依托于以下几项技术：基于 PLGA 和 PLA 的 Atrigel® 技术、基于POE 的 BiochronomerTM 技术、基于 SAIB 的 Saber®技术、基于溶致液晶系统的 FluidCrystal® 技术，以及基于 PEG-PLA 嵌段共聚物的 BEPO® 技术。其中，由 Camurus 公司开发的 FluidCrystal® 是由一定浓度的两亲性分子与适宜溶剂混合形成的低黏度液晶前体，注射后与体液接触发生相变而形成高黏度的以凝胶形态存在的半固体液晶结构——溶致液晶凝胶 [30]。基于该技术的药物 Brixadi® 已被 FDA 和欧盟批准上市。目前已获批准上市的原位凝胶注射剂见表 5。与其他 LAI 相比，原位凝胶的制造过程简单可控，更适合工业化生产。但其开发中仍面临药物突释风险、制剂安全性和贮库形成控制等问题。原位凝胶的释放曲线通常是双相的，包括突释和缓慢释放阶段。突释阶段通常被认为是凝胶贮库形成前药物扩散引起的。影响突释的因素包括基质材料的性质、基质材料和溶剂与药物的相互作用以及药物本身的水溶性与晶型等 [31]。缓慢释放阶段则通过固化或半固化的基质材料释放药物，是药物扩散和基质材料降解作用的结合。 Cao 等 [32] 探索了不同溶剂对溶剂交换原位贮库系统释药速率的影响。结果显示，不同溶剂对突释有显著影响， DMSO （ 24.21%） ＜乙醇（ 36.85%） ＜ NMP（ 42.23%）。这种差异主要归因于药物在不同溶剂中的溶解度和溶剂的扩散速率不同。此外，注射后体内贮库的形态也显著影响药物的释放行为。3长效注射剂发展面临的挑战 3.1 高技术壁垒与市场垄断 LAI 的研发涉及复杂的制剂技术，包括药物与辅料选择、载体设计、工艺优化和质量控制。目前制剂关键技术多被国外企业所掌握，一些跨国制药公司拥有多项 LAI 核心专利，通过专利保护和品牌优势形成市场垄断，影响药物价格并抑制创新，导致新药物和新技术的推出速度减缓，从而限制了国内药企在这一领域的技术进步 [9]。此外， LAI 的生产需要特殊的设施和设备，如无菌生产环境和高级的药物释放检测仪器，增加了小型企业的研发投入成本。功能性辅料的垄断现状进一步加大了 LAI 开发成本和难度，以常用辅料 PLGA 为例，其市场主要由国外供应商如 Evonik 和 Corbion 等占据。这种垄断导致国内企业面临高昂的价格问题和供应链中断的风险。因此，实现辅料供应链的自主可控，开发高质量国产药用辅料，对于提升国内 LAI 的研发能力至关重要。3.2 体外释放方法的复杂性和局限性随着 LAI 制剂形式的多样化，不同的给药途径（如肌肉注射、皮下注射）以及制剂参数（如粒径、表面特性、聚合物降解速率等）都可能会影响药物在体内的释放方式和速率。因此，体外释放方法应根据具体的制剂特性和给药方式进行个性化调整，以确保释放模式的准确性和临床相关性。各国药典和相关指导原则尚未提供广泛适用的标准化评价方法。目前，较多使用的体外释放方法包括桨法和流通池法等 [33]，这些方法虽然适用于特定类型的LAI，但仍存在局限性 [34]。例如，桨法虽然易于操作，但难以有效模拟注射剂在体内复杂环境中的释放行为；而流通池法在一定程度上模拟了体内条件，但在长期研究中可能出现设备组件故障。监管机构批准的其他非药典释放方法如透析袋法、转瓶法、摇床法等受设备参数调整影响大，设备参数偏差可能掩盖药物释放行为的真实差异。理想的体外释放方法应具有良好的区分力和重复性，并与体内释放行为相关 [35]。因此，针对不同制剂形式的特性，开发出能够精确控制和重复模拟LAI 体内贮库形状的释放方法，将有助于提高 LAI的研发效率和临床应用效果。3.3 体内外相关性缺乏LAI 体内外相关性（ IVIVC）的建立在其研发中具有重要意义。基于 LAI 注射后体内行为的复杂性，目前缺乏通过体外释放预测体内过程的可靠模型，需要通过大量动物实验来探索体内释药机制 [35]。这不仅增加了研发难度，也对动物福利提出了挑战。建立合适的体外释放方法，构建可靠的 IVIVC 预测模型，也是 LAI 领域亟待解决的问题之一。近年来，针对 LAI 的 IVIVC 研究已有一定进展。许多新型模型和方法的开发为 IVIVC 的建立提供了新的方向 [36-41]。例如， Bibi 等 [38] 通过生理药代动力学（ PBPK）模型预测了人体内的药物行为，为后续研究提供了新思路。 Gan 等 [39] 利用基于生理的纳米载体生物药剂学模型预测了阿霉素脂质体的临床表现，展示了新模型在提高 IVIVC 方面的巨大潜力。 Malavia 等 [40] 开发了一种新型样品保持适配器，通过模拟 LAI 注射后在体内形成的药物贮库结构，显著提高了体外试验的临床相关性和可重复性。 FDA 也在积极探索这些建模与模拟方法，以支持 LAI 的临床开发和监管决策 [42]。整体来看， IVIVC 在 LAI 药物研发中的指导作用日益增强，未来在药物开发和监管过程中将扮演更加关键的角色。4结语与展望 通过技术创新和工艺优化， LAI 在提升药物稳定性、减少给药频次等方面已取得了显著成效，极大地改善了患者的治疗体验和生活质量，为改良型新药的研发提供了新方向。然而， LAI 的发展也面临着诸多挑战，如工业生产的复杂性、体内外相关性的验证难度大以及研发成本高昂等。因此，需要更加注重跨学科合作，将基础研究、产品开发、工艺优化和临床研究等多领域资源紧密结合，形成协同创新机制，加速 LAI 的研发进程和成果转化。未来，政府的政策引导、资金投入和监管指导将为LAI 的研发提供坚实保障；新型辅料的不断涌现、制造工艺的持续创新、智能化药物递送系统的研发及个性化医疗的深化，也会为 LAI 的改良提供更多可能性。参考文献 ： [1]     Nkanga C I, Fisch A, Rad-Malekshahi M, et al. Clinically established biodegradable long acting injectables: an industry perspective[J]. Adv Drug Deliv Rev, 2020, 167: 19-46.[2] 吕奕 , 张怡萌 , 茅宁莹 . 我国化学药改良型新药申报审批情况分析与思考 [J]. 中国新药杂志, 2023, 32(15): 1523-1530.[3] 由春娜 , 邵亚婷 , 董敏 , 等 . 高端制剂的临床可及性研究 [J].中国食品药品监管, 2022(9): 86-95.[4] Li W, Tang J, Lee D, et al. Clinical translation of long-acting drug delivery formulations[J]. Nat Rev Mater, 2022, 7(5): 406-420.[5] Shi Y, Lu A, Wang X, et al. A review of existing strategies for designing long-acting parenteral formulations: focus on underlying mechanisms, and future perspectives[J]. Acta Pharm Sin B, 2021, 11(8): 2396-2415.[6] Wilkinson J, Ajulo D, Tamburrini V, et al. Lipid based intramuscular long-acting injectables: current state of the art[J]. Eur J Pharm Sci, 2022, 178: 106253.[7] Bauer A, Berben P, Chakravarthi S S, et al. Current state and opportunities with long-acting injectables: industry perspectives from the innovation and quality consortium "long-acting injectables" working group[J]. Pharm Res, 2023, 40(7): 1601- 1631.[8]  Sharma R, Yadav S, Yadav V, et al. Recent advances in lipid-based long-acting injectable depot formulations[J]. Adv Drug Deliv Rev, 2023, 199: 114901. DOI:10.1016/j.addr.2023.114901.[9] O'Brien M N, Jiang W, Wang Y, et al. Challenges and opportunities  in the development of complex generic long-acting injectable drug products[J]. J Control Release, 2021, 336: 144-158.[10] Guan W, Ma Y, Ding S, et al. The technology for improving stability of nanosuspensions in drug delivery[J]. J Nanopart Res, 2022, 24(1): 1-38.[11] Missel P J, Horner M, Muralikrishnan R. Simulating dissolution of intravitreal triamcinolone acetonide suspensions in an anatomically accurate rabbit eye model[J]. Pharm Res, 2010, 27(8): 1530-1546.[12] Pawar V K, Singh Y, Meher J G, et al. Engineered nanocrystal technology: in-vivo fate, targeting and applications in drug delivery[J]. J Control Release, 2014, 183: 51-66.[13] Su Y, Zhang B, Sun R, et al. PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application[J]. Drug Deliv, 2021, 28(1): 1397-1418.[14] Lee J, Kwon H J, Ji H, et al. Marbofloxacin-encapsulated microparticles provide sustained drug release for treatment of veterinary diseases[J]. Mater Sci Eng C Mater Biol Appl, 2016, 60: 511-517.[15] Wang M, Wang S, Zhang C, et al.Microstructure formation and characterization of long-acting injectable microspheres: the gateway to fully controlled drug release pattern[J]. Int J Nanomedicine, 2024, 19: 1571-1595.[16] Abulateefeh S R. Long-acting injectable PLGA/PLA depots for leuprolide acetate: successful translation from bench to clinic[J]. Drug Deliv Transl Res, 2023, 13(2): 520-530.[17] Tamani F, Bassand C, Hamoudi M C, et al. Mechanistic explanation of the (up to) 3 release phases of PLGA microparticles: monolithic dispersions studied at lower temperatures[J]. Int J Pharm, 2021, 596: 120220. DOI:10.1016/j.ijpharm.2021.120220.[18] Rahmani F, Naderpour S, Nejad B G, et al. The recent insight in the release of anticancer drug loaded into PLGA microspheres[J]. Med Oncol, 2023, 40(8): 229. DOI:10.1007/s12032-023-02103-9.[19] Cai H, Li A, Qi F, et al. Application of biodegradable microsphere injections: an anticancer perspective[J]. Mater Adv, 2024, 5: 3094-3112.[20] Giles M B, Hong J K Y, Liu Y, et al. Efficient aqueous remote loading of peptides in poly(lactic-co-glycolic acid)[J]. Nat Commun, 2022, 13(1): 3282.[21] Deng J, Ye Z, Zheng W, et al. Machine learning in accelerating microsphere formulation development[J]. Drug Deliv Transl Res, 2023, 13(4): 966-982.[22] Park H, Ha D H, Ha E S, et al. Effect of stabilizers on encapsulation efficiency and release behavior of exenatide-loaded PLGA microsphere prepared by the W/O/W solvent evaporation method[J]. Pharmaceutics, 2019, 11(12): 627. DOI:10.3390/ pharmaceutics11120627.[23] Barenholz Y. Doxil®-the first -approved nano-drug: lessons learned[J]. J Control Release, 2012, 160(2): 117-134.[24] Salehi B, Mishra A P, Nigam M, et al. Multivesicular liposome (depofoam) in human diseases[J]. Iran J Pharm Res, 2020, 19(2): 9-21.[25] Breitsamer M, Winter G. Vesicular phospholipid gels as drug delivery systems for small molecular weight drugs, peptides and proteins: state of the art review[J]. Int J Pharm, 2019, 557: 1-8.[26] Costa A, Burgess J D. Systems and methods for continuous manufacturing of liposomal drug formulations: US201615557575[P]. 2020-04-28.[27] Yanar F, Mosayyebi A, Nastruzzi C, et al. Continuous-flow production of liposomes with a millireactor under varying fluidic conditions[J]. Pharmaceutics, 2020, 12(11): 1001. DOI:10.3390/pharmaceutics12111001.[28] Pereira S, Egbu R, Jannati G, et al. Docetaxel-loaded liposomes:the effect of lipid composition and purification on drug encapsulation and in vitro toxicity[J]. Int J Pharm, 2016, 514(1): 150-159.[29] 张晓伟 . 沉淀型原位凝胶植入剂的相转变行为及其对药物缓释机制的影响 [D]. 沈阳 : 中国医科大学, 2021.[30] Rahnfeld L, Luciani P. Injectable lipid-based depot formulations:where do we stand?[J]. Pharmaceutics, 2020, 12(6): 567. DOI: 10. 3390/pharmaceutics12060567.[31] Bhujel R, Maharjan R, Kim N A, et al. Practical quality attributes of polymeric microparticles with current understanding and future perspectives[J]. J Drug Deliv Sci Tec, 2021, 64(6): 102608. DOI:10.1016/j.jddst.2021.102608.[32] Cao Z, Tang X, Zhang Y, et al. Novel injectable progesteroneloaded nanoparticles embedded in SAIB-PLGA in situ depot system for sustained drug release[J]. Int J Pharm, 2021, 607:121021. DOI:10.1016/j.ijpharm.2021.121021.[33] Rudd N D, Reibarkh M, Fang R, et al. Interpreting in vitro release performance from long-acting parenteral nanosuspensions using USP-4 dissolution and spectroscopic techniques[J]. Mol Pharm, 2020, 17(5): 1734-1747.[34] Kim Y, Park E J, Kim T W, et al. Recent progress in drug release testing methods of biopolymeric particulate system[J]. Pharmaceutics, 2021, 13(8): 1313. DOI:10.3390/ pharmaceutics13081313.[35] Siemons M, Schroyen B, Darville N, et al. Role of modeling and simulation in preclinical and clinical long-acting injectable drug development[J]. AAPS J, 2023, 25(6): 99. DOI:10.1208/s12248- 023-00864-9.[36] Bao Q, Wang X, Wan B, et al. Development of in vitro-in vivo correlations for long-acting injectable suspensions[J]. Int J Pharm, 2023, 634: 122642. DOI:10.1016/j.ijpharm.2023.122642.[37] Wang X, Roy M, Wang R, et al. Towards in vitro-in vivo correlation models for in situ forming drug implants[J]. J Control Release, 2024, 372: 648-660.[38] Bibi D, Bilgraer R, Steiner L, et al. Physiologically-based pharmacokinetic modeling and in vitro–in vivo correlation of TV-46000 (risperidone LAI): prediction from dog to human[J]. Pharmaceutics, 2024, 16(7): 896. DOI:10.3390/ pharmaceutics16070896.[39] Gan K, Li Z, Darli P M, et al. Understanding the in vitro-in vivo nexus: advanced correlation models predict clinical performance of liposomal doxorubicin[J]. Int J Pharm, 2024, 654: 123942. DOI: 10.1016/j.ijpharm.2024.123942.[40] Malavia N, Bao Q, Burgess D J. Novel dissolution methods for drug release testing of long-acting injectables[J]. Int J Pharm, 2024, 664: 124634. DOI: 10.1016/j.ijpharm.2024.124634.[41] Dabke A, Ghosh S, Dabke P, et al. Revisiting the in-vitro and invivo considerations for in-silico modelling of complex injectable drug products[J]. J Control Release, 2023, 360: 185-211.[42] Lee J, Gong Y, Bhoopathy S, et al. Public workshop summary report on fiscal year 2021 generic drug regulatory science initiatives: data analysis and model-based bioequivalence[J]. Clin Pharmacol Ther, 2021, 110(5): 1190-1195. 喜欢我们文章的朋友点个“在看”和“赞”吧，不然微信推送规则改变，有可能每天都会错过我们哦~免责声明“汇聚南药”公众号所转载文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请在留言栏及时告知，我们会在24小时内删除相关信息。信息来源：药学进展往期推荐本平台不对转载文章的观点负责，文章所包含内容的准确性、可靠性或完整性提供任何明示暗示的保证。