Bupivacaine

“ 点击蓝字 关注我们 吕万良 北京大学长聘教授、博士生导师、分子药剂学与新释药系统北京市重点实验室常务副主任。担任中国药学会药剂专业委员会主任委员，中国颗粒学会常务理事，《北京大学学报（医学版）》等国内外学术期刊编委、副主编等职务。历任新加坡国立大学/国大医院研究员，约翰-霍普金斯大学国际医学中心研究员，日本富山医科药科大学访问学者，北京大学药学院党委副书记等职务。主要从事生物药剂学研究，在肿瘤和炎症等重大疾病的基因重组制剂、脂质体递药系统研究领域取得了重要进展。在学术期刊上发表论文 190 余篇，主编北京大学长学制教材《现代药剂学》和《先进药剂学》、主编 Springer Nature 专著Liposomes-Based Drug Delivery Systems，入选 Elsevier 高被引中国学者名单，分别获得 2009 年、2012 年教育部自然科学一等奖，2019 年教育部自然科学二等奖等奖项。 脂质体的研究与应用进展 PPS  冯赫宣，李佩珊，刘懿萱，李建伟，吕万良 * （天然药物及仿生药物全国重点实验室 分子药剂学与新释药系统北京市重点实验室 北京大学药学院，北京 100191） [摘要] 脂质体是由脂质材料制备的可用作药物载体的双分子层脂质囊泡。脂质体是近年来发展的一种新型药物载体。脂质体可改变药物在体内的递释性能及由此引起的药效提升和毒副作用降低，其特点包括靶向性和淋巴定向性、延长药物血液循环时间、降低药物毒性、提高稳定性。脂质体的主要制备方法包括薄膜分散法、逆向蒸发法、溶剂注入法、pH 梯度法、硫酸铵梯度法、醋酸钙梯度法、离子载体法、钙融合法及改进的适合规模化生产的其他方法。目前，经过欧美药品管理部门批准上市的原研脂质体药物共有 16 个品种，而进入临床试验不同阶段的脂质体药物品种总计有千余个品种。已批准的脂质体药物主要适应证有肿瘤、真菌感染、术后疼痛等。综述脂质体的研究与应用进展，旨在为脂质体新药的研发及其医药产业技术升级提供参考。 1 脂质体 1.1 脂质体的发展 脂质体（liposome）是一种由脂质材料制备的可用作药物载体的双分子层脂质囊泡。当两亲性脂质分子分散于水相时，其分子的疏水尾部倾向于聚集在一起避开水相，而其分子的亲水头部暴露在水相，自发形成具有脂质双分子层结构的封闭囊泡。 1965 年，英国科学家 Bangham 等 [1] 发现，当磷脂分散在水中时形成多层囊泡，且每一层均为脂质双分子层，各层之间被水相隔开，形成囊泡结构。1968 年，Sessa 等 [2] 采用磷脂材料与各种阴离子、阳离子长链类脂材料，制备多种类型脂质体，并对其理化特性和结构进行了分析。随后，有关脂质体研究的文献数量逐年递增。1970 年，Korn 等 [3] 对脂质体物理结构和生物性质进行了深入研究。 1976年，Gregoriadis 等 [4] 和 Dapergolas 等 [5]的研究显示，脂质体在癌症化疗、糖尿病治疗领域显示出良好的应用前景。1988 年，瑞士 Cilag 公司开发了益康唑脂质体凝胶，该脂质体药物率先在欧洲上市 [6]。1990 年，美国 Gilead 公司开发了两性霉素 B 脂质体注射剂，该产品在美国上市，用于深部真菌感染治疗。1995 年，美国 Sequus 公司开发了阿霉素脂质体（Doxil），该产品在美国上市，用于癌症治疗。1996 年，美国 NeXstar 公司开发了柔红霉素脂质体（DaunoXome），该产品先后在美国、欧洲上市，用于癌症治疗。随后，美国 Pacira 公司开发的阿糖胞苷脂质体（DepoCyt）、美国 Berna Biotech 公司开发的甲肝疫苗脂质体（Epaxal）等以脂质体为载体的治疗药物。此外，在我国也有多种脂质体药物陆续进入临床研究和应用阶段。 1.2 脂质体的特点 脂质体的明显特征是该载体改变了药物在体内的递释性能及由此引起的药效提升和毒副作用降低，其特点包括：靶向性和淋巴定向性、延长药物血液循环时间、降低药物毒性、提高药物稳定性等。 1.2.1 靶向性和淋巴定向性  脂质体对肝、脾等存在网状内皮系统表达丰富的脏器组织具有被动靶向性。例如，锑酸葡胺脂质体可用于治疗肝利什曼寄生虫，其在肝中浓度比普通制剂提高了 200 倍以上。研究显示，经过表面功能修饰的脂质体药物，在动物体内可显著提高作用部位的药物浓度，表现出一定的主动靶向性效应，例如，叶酸受体在乳腺癌、肺癌、肾癌、卵巢癌、结直肠癌等均有高水平表达，叶酸配体修饰的多西紫杉醇脂质体表现出明显的乳腺癌靶向性治疗效应 [7]。 1.2.2 延长药物血液循环时间  脂质体可延长药物的血液循环时间，有利于脂质体荷载药物在实体肿瘤部位的滞留和聚集。例如，Doxil 是一种血液长循环（blood long-circulation）或隐型（stealth）脂质体药物，可用于治疗人体免疫缺陷病毒引起的难治性卡波西肉瘤（Kaposi's sarcoma）。在该脂质体组成中，含有亲水性聚合物聚乙二醇（polyethylene glycol，PEG）修饰的二硬脂酰磷脂酰乙醇胺（1，2-distearoylsn-glycero-3-phosphoethanolamine，DSPE）衍生物（PEG-DSPE），其作用是阻止血浆蛋白吸附，避免脂质体药物在血液循环过程中被单核巨噬细胞系统快速清除，延长脂质体在血液循环中暴露时间，使得脂质体可有效达到病变部位，因为在实体肿瘤、感染、炎症部位，病变可引起毛细血管的通透性增加，长循环脂质体可有效增加在这些部位的聚集量，这种现象被称为高通透性和滞留效应（enhancedpermeability and retention effect，EPR）。 1.2.3 降低药物毒性  脂质体载体降低药物毒性原因可能与脂质体膜包封掩蔽、靶向性分布、尺寸效应与组织密度等因素有关。动物实验研究显示，同游离型阿霉素注射剂相比，Doxil 减少了药物在心肌组织中的聚集量，降低了其心脏毒性。此外，同游离型两性霉素 B 脱氧胆酸盐注射剂相比，两性霉素 B脂质体明显降低了药物的肾脏毒性 [8]。 1.2.4 提高药物稳定性  脂质体提高药物的稳定性与脂质体包封掩蔽及其表面修饰成分有关。将游离药物封装于脂质双分子层中，可保护药物免受体内酶促降解、化学灭活以及被网状内皮系统快速清除。因此，脂质体可防止药物在到达目标组织之前被代谢，同时可最大限度地减少药物血液循环过程和在健康组织中药物毒性 [9]。 1.3 脂质体的主要材料 脂质体膜材料组成成分主要包括磷脂和类脂及其衍生物。磷脂是脂质体最常见的成分，磷脂由 1个亲水性头部和 2 条疏水性脂肪烃链尾部组成。头部的磷酸分子可与其他有机分子（胆碱、丝氨酸）发生酯化反应，生成不同的极性基团，这种特殊的结构使磷脂具有良好的油水两亲性质（见图 1）。 根据来源不同，磷脂可分为天然甘油磷脂和合成甘油磷脂。天然甘油磷脂主要有磷脂酸（phosphatidicacid，PA）、磷脂酰胆碱（phosphatidylcholine，PC）、磷脂酰乙醇胺（phosphatidylethanolamine，PE）、磷脂酰肌 醇（phosphatidylinositol，PI）、磷脂酰甘油（phosphatidylglycerols，PG）和磷脂酰丝氨酸（phosphatidylserine，PS）。合成甘油磷脂主要有 1，2-二硬脂酰基-sn-丙三基-3-磷酸胆碱（1，2-distearoyl-sn-glycero-3-phosphatidylcholine，DSPC）、1，2- 二 棕 榈 酰 磷 脂 酰 胆 碱（1，2-dihexadecanoyl-rac-glycero-3 phosphocholine，DPPC）、1，2-二油酰-sn-甘油-3-磷酰胆碱（1，2-dioleoyl-sn-glycero-3-phosphocholine，DOPC）等 [10]。  按照荷电性不同，磷脂可分为中性磷脂、负电荷磷脂与正电荷磷脂。最为常见的中性磷脂为磷脂酰胆碱，在自然界中磷脂酰胆碱是多数细胞膜的组成成分。由于其易获取、价格低廉、电中性和理化稳定性，磷脂酰胆碱也是制备脂质体的主要脂质材料。除从天然来源的磷脂酰胆碱外，尚有人工合成 磷 脂，如 DPPC、DSPC、DOPC 等。鞘 磷 脂（sphingomyelin，SM）与PE也是常见的中性磷脂材料。  常见的负电荷磷脂有 PA、PG 和 PI，而常见的正电荷磷脂有硬脂酰胺（stearamide，SA）、三氟乙酸二甲基-2，3-二油烯氧基丙基-2-(2-精胺甲酰氨基 ) 乙基铵 [N-(2-((S)-2，5-bis(3-aminopropylamino)pentanamido)ethyl)-N，N-dimethyl-2，3-bis((Z)-octadec9-enyloxy)propan-1-aminiumpentahydrochloride，DOSPA] 和二油酰基三甲基氯化铵（1，2-dioleoyl-3-trimethyl ammonium-propane，DOTAP）等。  电中性磷脂常用作包载化学药物的脂质体材料，其生物相容性较好。正电荷磷脂常用于制备包载基因药物的脂质体材料，如正电荷磷脂常用于核酸大分子递送。这是因为 DOTAP 可与 DNA 或RNA 通过静电作用结合，形成稳定的磷脂核酸复合物，进而将遗传物质有效地转染入细胞内部。此外，阳离子脂质体也可用作抗原、多肽或小分子药物的高效递送载体，阳离子脂质体有一定的毒副作用。  胆固醇（cholesterol）是一种类脂材料，存在于自然界生物膜中，具有电中性、两亲性等特点，其亲油性比磷脂酰胆碱更强。胆固醇自身不能形成脂质双分子结构，但当胆固醇嵌入双分子层磷脂膜时，可改变脂质体膜的相变温度、流动性和通透性。胆固醇也具有阻止磷脂凝集的功能，从而改变或调节脂质体膜的理化性质。 2 脂质体的制备方法 2.1 薄膜分散法 薄膜分散法（film dispersion）是将脂质体膜材料通过适宜溶剂溶解，去除溶剂后形成脂质薄膜，然后再水化处理形成脂质体的一种制备方法。在药物包封过程中，脂溶性药物可随薄膜材料一起添加，水溶性药物随水化溶液一起添加，最终制备成载药脂质体。薄膜分散法具体步骤：可用有机溶剂溶解脂质体膜材料，通过减压蒸发去除有机溶剂，脂质体膜材料在器壁上形成多层堆积的脂双层，当体系内加入水化剂并进行振摇后，多层脂双层从器壁脱落，自发产生粒径为 0.5 ~ 5 μm 的多层脂质体（multilamellar vesicle，MLV）[11]。  为了制备粒径较小、尺寸均一的 20 ~ 100 nm小单层脂质体（small unilamellar vesicle，SUV）与 200 ~ 500 nm 大 单 层 脂 质 体（large unilamellar vesicle，LUV），薄膜分散后需要联用脂质体匀化技术，以制备粒径适宜且均一的 SUV 与 LUV。常用的脂质体匀化技术有超声法和挤压法。  超声法（ultrasonic method）是将薄膜分散法制得的 MLV 进行超声处理，可得到粒径约 250 nm 的LUV。超声时间长短及所选用的超声方式对最终脂质体粒径产生明显影响。水浴型超声适用于量大或浓度低的脂质体样品，由于超声过程中产生热量，因此还需要对于水温进行监控，以避免对包封药物稳定性产生影响。探针型超声适用于黏稠或浓度较高的脂质体样品，一般探针型超声会产生较高的能量，其超声效果优于水浴超声。  挤压法（extrusion）是将薄膜分散法和超声处理后制得的脂质体混悬液，在挤压的作用下通过孔径不同的激光打孔的聚碳酸酯膜，得到大量粒径较小且均一的 LUV 或 SUV。在实际操作中，选取适当孔径的碳酸酯膜进行梯度挤出至关重要。一般应采取先挤压通过大孔径膜，后多次挤压通过小孔径膜，以利于得到均一的 SUV。 2.2 逆相蒸发法  逆相蒸发法（reverse-phase evaporation）是将脂质体膜材料溶于有机溶剂，然后将溶解原料药物的水溶剂混合，进行水浴超声后可形成油包水型乳剂（W/O）样脂质体混悬液，将得到的混悬液进行减压蒸发，去掉有机溶剂即可得到脂质体混悬液。通过此方法得到的脂质体，可用于包载核酸药物，也可用于包封小分子化学药物，辅以挤出法可得到粒径均匀的 SUV。  改进后的逆向蒸发法可将脂质体膜材料溶解于有机溶剂，通过减压蒸发去除有机溶剂形成薄膜后，加入异丙醚等有机溶剂重新溶解，加入水相溶剂得到 W/O 样脂质体混悬液，再经超声、挤压法对粒径均化处理，可形成单层脂质体，再通过减压蒸发去除有机溶剂，可得到可载药物的 SUV 脂质体混悬液。  同薄膜分散法相比，逆相蒸发法制备脂质体的药物包封率高。然而，在制备过程中需要将药物与脂质体暴露在超声环境和有机溶剂中，可能影响了载药脂质体的完整度及药物稳定性，且逆相蒸发法也较为耗时，不利于脂质体的规模化生产 [12]。以制备布比卡因（bupivacaine）LUV 为例，利用逆相蒸发法可高效制备载药 LUV，相较于传统的薄膜水合法具有更高的药物包封能力。同时，用乙醇替代乙醚可降低残留溶剂的毒副作用，利用超声处理使脂质体形成均匀的分散体。为获得稳定性更高的脂质体，利用等渗缓冲溶液进行渗透压平衡处理。制剂实验结果表明，经渗透平衡处理后脂质体稳定性大幅提高，布比卡因渗漏减小，可保持药物稳定释放，并具备缓释作用 [13] 。 2.3 溶剂注入法   溶剂注入法（solvent injection）是将溶有脂质体膜材料的有机相（如乙醇、乙醚等）快速注入到溶有药物的大量水相中，再经超声等方法制备载药脂质体。当少量的有机相注入大量水相中被快速稀释，而有机相中脂质体膜材料快速形成载药SUV脂质体。  同薄膜分散法或逆相蒸发法相比，溶剂注入法具有以下优点：1）溶剂注入法操作步骤简便；2）溶剂注入法采用的有机溶剂一般为乙醇等，残留有机溶剂毒性相对小；3）溶剂注入法制备环境温和，对于敏感性脂质体膜材料或药物成分影响小，适合于工业化量产。  由于脂质体膜材料在乙醇中溶解度较低，且对于混合相中乙醇浓度还有明确的限定，因此也会导致成品脂质体浓度较低，并且在水相体系中残留乙醇难以有效去除，以上均是溶剂注入法存在的不足之处 [14]。为应对以上溶剂注入法的缺点，需要利用复合溶剂增溶处理以帮助溶解脂质体膜材料。以制备严重急性呼吸综合征冠状病毒 2（severe acute respiratory syndrome coronavirus 2，SARS-CoV-2）免疫原性脂质体为例，利用乙醇注射法制备空白脂 质 体， 并 在 高 温 磷 酸 缓 冲 盐 溶 液（phosphate buffered saline，PBS）下进行加压挤出处理，最后利用 PBS 多次透析去除残留乙醇可制备得到均一的脂质体 [15]。 2.4 pH 梯度法   pH 梯度法（pH gradient）是利用 pH 梯度差异以实现药物离子型、分子型状态转化，使得药物被包封于脂质体的高效包封方法，pH 梯度法也称为主动包封方法。pH 梯度法主要原理是利用制造脂质体膜内外水相酸碱度差异（pH 梯度），使得处于外水相中性环境中药物以分子型跨膜进入脂质体囊泡，随后药物在囊泡内部的酸性环境作用下被质子化后变为离子型，而离子型药物难以再次跨膜回到外水相中，从而可制备高包封率的载药脂质体。 pH 梯度法制备载药脂质体的主要步骤包括，在pH 值较低（如 pH 4）的水相体系中水化制备空白脂质体，并利用弱碱性溶剂将外水相体系 pH 值调至中性或弱碱性，而此时脂质体内水相仍保持弱酸性环境，将药物溶解于与脂质体外水相相同 pH 值的缓冲溶液体系中，随后加入到空白脂质体混悬液中混合、孵育，即可得到高包封率的载药脂质体（见图 2）。研究显示，采用 pH 梯度法制备的阿糖胞苷/柔红霉素脂质体，可同时实现 2 种药物的高效包封 [16]。 2.5 硫酸铵梯度法  硫酸铵梯度法（ammonium sulfate gradient）是利用硫酸铵梯度差异以实现药物离子型、分子型状态转化或在脂质体囊内形成药物沉淀，使得药物被包封于脂质体的高效包封方法，该法也是一种主动包封方法。硫酸铵梯度法的主要原理是制造脂质体膜内外水相硫酸铵梯度差异，使处于外水相环境中药物以分子型跨膜进入脂质体囊泡，随后药物在囊泡内部的硫酸铵环境中被离子化或形成胶状沉淀，从而使离子型药物或沉淀药物难以再次跨膜回到外水相中，从而可制备高包封率的载药脂质体。 硫酸铵梯度法制备载药脂质体的主要步骤包括，通过薄膜分散法制备脂膜，采用一定浓度的硫酸铵溶液水化脂膜制备空白脂质体，再通过透析除去外水相中的硫酸铵后，形成脂质体膜内外的硫酸铵梯度差，与溶有药物的水溶液共孵育，即可得到载药脂质体。以盐酸阿霉素脂质体为例，先采用薄膜分散法制备脂质膜，以硫酸铵溶液（如 250 mmol · L-1） 水化脂膜制备空白脂质体，将脂质体通过超声、挤压匀化处理，得到直径约为 100 nm 的空白脂质体，透析去除脂质体膜外部环境的硫酸铵；另将盐酸阿霉素溶于水中，盐酸阿霉素在近中性水中存在 2 种形式，分子型（DOX-2NH2）与离子型（DOX-2NH3+）动态平衡，分子型碱基可以跨越脂质体膜，进入脂质体膜内部，并在脂质体膜内部与硫酸根结合，产生硫酸阿霉素凝胶样沉淀，实现高包封率的阿霉素脂质体（见图 3）。此外，硫酸铵梯度法也为脂质体内水相提供了 pH 梯度，其包封原理类似于前述 pH 梯度法。然而，盐酸阿霉素包封后药物的沉淀现象与聚集原理较 pH 梯度法有较大的差异性。 2.6 醋酸钙梯度法 醋酸钙梯度法（calcium acetate gradient loading）是一种利用醋酸钙浓度梯度以实现药物离子型、分子型状态转化，使得药物被包封于脂质体的高效包封方法，该法也是一种主动包封方法。  醋酸钙梯度法制备载药脂质体的主要步骤包括，通过薄膜分散法制备脂膜，采用一定浓度的醋酸钙溶液水化脂膜制备空白脂质体，再通过透析除去外水相中的醋酸钙后，形成脂质体膜内外的醋酸钙梯度差，再将其与药物水溶液共孵育，即可得到载药脂质体。该种包封方法，在脂质体膜内外水相间存在 pH 和醋酸钙双重梯度，其包封载药原理与pH 梯度法均一致，即分子型药物可自由跨越脂膜，离子型药物不能自由跨越脂膜，通过人工调控介质中化学梯度，使得药物以分子型状态进入到脂质体膜内然后离子化，以免其再次返回到脂质体膜外，实现药物的高效包封。醋酸钙梯度法适用于弱酸性药物的主动包载。 2.7 离子载体包封法 离子载体（ionophore）包封法是一种利用离子载体使阳离子向脂质体膜外运动而质子向膜内运动，使得脂质体囊泡内酸化以创建pH梯度的一种方法，从而实现药物离子型、分子型状态转化，进而使得药物被包封于脂质体的高效包封方法，该法也是一种主动包封方法。  例如，利用离子载体 A23187（calcimycin，CAS 号：52665-69-7）和尼日利亚菌素，可实现长春新碱或环丙沙星的高效包封，其 LUV 由二硬脂酰磷脂酰胆碱/胆固醇（DSPC/Chol，55 : 45 mol/mol）组成，将脂质体通过葡聚糖凝胶柱处理，使脂质体膜内外呈现跨膜盐梯度（内部溶液：300 mmol · L-1 MnSO4 或 K2SO4；膜外部溶液：300 mmol · L-1 蔗糖）， 加入药物孵育，随后加入离子载体（溶于乙醇）可 使被捕获的阳离子向外运动、质子向内运动并耦合， 从而使脂质体囊泡内部酸化。膜外部弱碱性分子型 药物跨膜后转化为离子型药物，其原理与 pH 梯度 包封方法相同，药物包封率接近 100%。载药后，离 子载体可通过凝胶排阻色谱、透析或用生物珠处理 去除 [17]。对于涉及二价阳离子的实验，需加入螯合 剂乙二胺四乙酸（ethylene diamine tetraacetic acid，EDTA）（见图 4）。 2.8 钙融合法 钙融合法（Ca2+ induced fusion）是在制备阴离子型脂质体过程中加入一定浓度的 Ca2+，该法可在较为温和的环境包封DNA、RNA和酶等生物大分子。研究显示，在脂质体中添加 Ca2+ 后往往会发生脂膜黏附、破裂和塌陷等现象，最终导致形成粒径较大的多层脂质体 [18]。当加入 Ca2+ 得到多层脂质体后，再向体系中加入 EDTA，可得到 LUV。钙融合法适用于核酸和蛋白质药物的脂质体包封。 2.9 其他方法 为应对脂质体工业生产中批间均匀性问题，研究人员进一步研究发展了交叉注流制备法、超临界CO2 流体制备法和微流控制备法等。如在乙醇注入制备法基础上，发展了交叉流注射技术。研究显示，与乙醇注入法相比，交叉流注射制备法在无菌性、质量控制和大规模生产方面均有长足的进步。对于超临界流体制备法而言，进入超临界流体状态物料具备液体和气体 2 种物态特性，一方面具备低表面张力、低黏度及高扩散性的气体状态性质，另一方面拥有高溶解力、高密度的液态特性。超临界流体制备法还具有廉价、溶剂对环境无害、粒度均匀、易灭菌和适合量产等优点 [19]。  3 脂质体的功能化 3.1 长循环脂质体 长循环脂质体（long circulating liposome）也称隐形脂质体，在普通脂质体表面修饰以 PEG 等亲水性物质可制备长循环脂质体。普通脂质体表面经过PEG 修饰后，PEG 在水相环境中于脂质体表面形成致密水层结构，可有效稳定脂质双层结构并产生空间位阻，从而抑制蛋白质吸附并减少吞噬细胞识别，避免脂质体在血液循环中被单核细胞吞噬系统快速清除，进而延长血循环时间，有利于脂质体有效地到达病变部位。研究显示，在脂质体总脂质中添加5 mol% PEG- 脂质，可显著延长血液循环时间 [20]。然而，PEG 化的长循环脂质体可能也会产生阻碍细胞摄取、脂质体所载药物被溶酶体降解、不能靶向至特定细胞等问题。尽管如此，长循环脂质体对于实体瘤部位药物被动靶向递送是有利的 [21]。 3.2 配体脂质体 配体脂质体（ligand-modified liposome）系将靶向性配体修饰于脂质体表面，可使脂质体识别并结合到特定病变细胞或组织，从而增强所携载药物的治疗效果。通常采用靶向分子、靶向肽等配体对脂质体进行功能化修饰。  以肿瘤细胞线粒体为靶点，将线粒体靶向性探针分子三苯基膦（triphenylphosphine，TPP）与羧基聚乙二醇 1000 维生素 E 琥珀酸酯（D-α-tocopheryl polyethylene glycol 1000 succinate，TPGS1000）连接，合成线粒体靶向性脂质体载体材料 TPGS1000-TPP，以紫杉醇为模型药物，构建线粒体靶向性紫杉醇脂质体，可将药物靶向性递送至线粒体，在线粒体水平诱导耐药性肿瘤细胞的凋亡，杀伤耐药肿瘤细胞，从而克服肿瘤的多药耐药性 [22]。  将蛋白转导肽（PTDHIV-1）靶向性分子修饰脂质体表面，可通过受体介导和吸附介导的方式实现细胞跨膜转运。将该蛋白转导肽修饰于脂质体表面，制备靶向性表阿霉素塞来昔布脂质体，能够通过被动靶向至肿瘤区域，并通过蛋白转导肽将脂质体高效转运进入肿瘤细胞，发挥化疗药表阿霉素和调节剂塞来昔布的药理作用，在杀伤肿瘤细胞的同时，清除肿瘤拟态血管，提高侵袭性肿瘤的治疗效果，防止治疗后复发 [23]。 3.3 抗体脂质体 抗体脂质体（antibody-modified liposome）是将单克隆抗体修饰到脂质体表面，形成具有主动靶向性抗体脂质体。单克隆抗体可选择性地与特定受体进行特异性结合，从而实现靶向性。  将抗碳酸酐酶 IX（carbonic anhydrase IX）单克隆抗体（CA-IX mAb）靶向性分子修饰于载雷公藤内酯脂质体表面，可介导靶向性脂质体与肺癌细胞表面 CA-IX 相互识别结合、增强肿瘤细胞对于脂质体的摄取。通过在脂质体表面修饰靶向性单克隆抗体分子，能够主动靶向到肺癌组织区域，在单克隆抗体与肺癌细胞膜表面 CA-IX 识别结合后转运进入肿瘤细胞，并释放雷公藤内酯，可杀伤肿瘤细胞的同时，降低药物对于患者其他组织的毒性 [24]。  3.4 响应性脂质体 响应性脂质体是指当受到生理和病理信号变化而产生响应性变化的功能化脂质体。常见的生理和病理信号变化有 pH、温度等变化。 pH 响应性脂质体（pH responsive liposome）在正常人体体液环境（pH 7.4）中保持稳定，当脂质体通过主动或被动靶向运载至肿瘤组织处，在肿瘤微环境中酸度增加（pH ＜ 6），触发脂质体膜解聚，而释放出包载药物，从而发挥肿瘤杀伤效应。如以pH 响应性肽 H7K(R2)2 作为配体，构建 pH 响应性阿霉素脂质体，可增强肿瘤细胞内化，并在肿瘤细胞内快速释放药物，可有效杀伤肿瘤细胞 [25]。  温 度 响 应 性 脂 质 体（temperature responsive liposome）可在人体正常体温（37℃）时保持稳定，递送至肿瘤组织中的脂质体，通过局部红外加热，引起温敏脂质体解聚，并快速释放出药物，发挥疗效。例如，采用二棕榈酰磷脂酰胆碱、单棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰乙醇胺-PEG2000 这 3 种脂质体膜材料构建的温敏型阿霉素脂质体，利用红外加热使肿瘤组织的血管升温，可快速释放出其包封的药物 [26]。 3.5 细胞仿生脂质体 细胞仿生脂质体（cell bionic liposome）是指将提取的细胞膜成分融合修饰于脂质体表面，由此在保留脂质体功能的基础上获得细胞的部分功能，如同源靶向功能、抗原呈递功能和免疫激活功能等。 将红细胞膜与甘露糖修饰脂质体得到红细胞仿生脂质体 [27]，将红细胞膜融合修饰到脂质体膜，可赋予脂质体以红细胞的长循环效应、脾脏组织靶向能力，脂质体膜上修饰的甘露糖可与脾脏中抗原呈递细胞上甘露糖受体相互识别结合并激活 T 淋巴细胞，发挥抗肿瘤效应。 提取肿瘤细胞膜成分融合修饰于脂质体表面，用于刺激树突状细胞成熟，模拟内源性免疫激活机制 [28]，提升抗原呈递细胞的抗原呈递能力，进而激活 T 淋巴细胞，发挥抗肿瘤效应。  然而，细胞膜融合仿生尚缺乏统一成熟的制备技术和可控的质量标准，细胞膜成分融合利用程度较低（约为 20%）[29]，限制了细胞仿生脂质体的产业化进程。 4 脂质体的开发与应用 4.1 已上市的脂质体药物 基于对美国食品和药品管理局（Food and Drug Administration，FDA）和欧洲药品管理局（European Medicines Agency，EMA）批准的脂质体药物数据分析，截至 2024 年 6 月，总计有 16 款原研脂质体药物上市，其主要临床适应证有肿瘤、真菌感染、术后疼痛等（见表 1）。 4.2 临床试验中的脂质体药物 基于美国临床试验注册中心（ClinicalTrials.gov）网站的数据，截至 2024 年 6 月，进入Ⅰ期临床研究有 552 个脂质体品种，其中有 486 项用于治疗晚期或转移期实体瘤或非实体瘤，21 项用于治疗细菌、真菌引起的深部感染，15 项用于手术麻醉、阵痛及其相关药代动力学研究，其余 30 项用于获得性免疫缺陷综合征（acquired immune deficiency syndrome，AIDS）、心血管疾病、干眼症等其他疾病的治疗。如治疗性核素铼（188Re）脂质体，主要用于治疗原发性实体瘤。由于核素具有放射性兼具成像作用，该产品也具有造影功能。然而研究发现，该脂质体的缺点是其在患者肝脏、脾脏中显现出放射性物质积累，这也引起了研究人员的关注。  进入Ⅱ期临床研究的脂质体药物共有 1107 个品种，其中有 976 项用于治疗晚期或转移期实体瘤或非实体瘤，55 项用于治疗细菌、真菌引起的深部感染，33 项用于治疗急性疼痛和术后疼痛，其余 43项用于 AIDS、心血管疾病、干眼症等其他疾病的治疗。如盐酸米托蒽醌脂质体，其在Ⅱ期临床试验中主要考察其治疗晚期实体瘤、T 细胞淋巴瘤的疗效，同时也评估其对患者心脏组织的安全性。  进入Ⅲ期临床研究的脂质体药物共有 518 个品种，旨在对脂质体药物进行多样本、随机、双盲试验，以确证其安全性与治疗效果，其中有 399 项用于治疗晚期或转移期实体瘤或非实体瘤，55 项用于治疗细菌、真菌引起的深部感染，53 项用于治疗急性疼痛和术后疼痛，其余 11 项用于 AIDS、贫血、心力衰竭等其他疾病的治疗。如拓扑替康脂质体（topotecan liposome）治疗小细胞肺癌、卵巢癌和其他晚期实体瘤的研究，利用剂量递增试验直至最大耐受剂量，观察施用不同剂量时受试人群的剂量限制性毒性，以此来确定该脂质体药物的最大耐受剂量、安全性、药代动力学。  进入Ⅳ期临床研究的脂质体药物共有 284 个品种，其中 188 项用于治疗急性疼痛和术后疼痛，64项用于治疗晚期或转移期实体瘤或非实体瘤，其余32 项用于治疗细菌、真菌引起的深部感染及贫血等疾病。目前主要针对已上市的脂质体药物对不同肿瘤类型的有效性研究，如观察紫杉醇脂质体对转移性乳腺癌的疗效，研究伊立替康脂质体对小细胞肺癌的疗效等。 5 结语与展望 经过 60 年的研究和发展，脂质体在开发新型脂质材料、发展新的高效药物包封方法、开发功能性脂质体等领域均取得长足进步。本文仅对目前成熟度较高的脂质体关键技术进行综述，总结了现今脂质体制备的主要方法，包括薄膜分散法、逆向蒸发法、溶剂注入法、pH 梯度法、硫酸铵梯度法、醋酸钙梯度法、离子载体法、钙融合法以及改进的适合规模化生产的其他方法，并且探讨各种制备方法的优势和不足。目前已有 16 种脂质体原研药物经 FDA 或 EMA 批准上市，也有千余项脂质体产品处于临床试验阶段。鉴于脂质体药物载体具有安全性高、全身毒性低、血液循环时间长、病灶部位靶向性强、可进行功能性修饰等优势，脂质体在肿瘤、感染、疼痛、罕见病等重大疾病根治性策略方面展示出广阔的应用前景。相信随着科学技术的不断进步，未来也会有更多新型脂质体药物用于临床治疗，脂质体有望成为用于重大疾病治疗的优质药物载体。 参考文献： [1]  Bangham A D, Standish M M, Watkins J C. 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[29]  Liu L, Bai X, Martikainen M V, et al. Cell membrane coating integrity affects the internalization mechanism of biomimetic nanoparticles[J]. Nat Commun, 2021, 12(1): 5726. DOI: 10.1038/s41467-021-26052-x. 美编排版：朱玲欣 感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2024年第10期。 《药学进展》杂志由中国药科大学和中国药学会共同主办、国家教育部主管，月刊，80页，全彩印刷。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。 《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。 《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。 联系《药学进展》↓↓↓ 编辑部官网：pps.cpu.edu.cn； 邮箱：yxjz@163.com； 电话：025-83271227。 欢迎投稿、订阅！ 往期推荐 聚焦“兴药为民·2023生物医药创新融合发展大会”“兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航 我知道你在看哟

Reported positive YTD 2024 Adjusted EBITDA of $1.4 million Company expects Q4 2024 Net Revenue in the range of $37 million - $43 million ZYNRELEF® (bupivacaine and meloxicam) extended-release solution Vial Access Needle ("VAN") approved in September and on track for Q4 2024 launch CMS Final Rule Non-Opioid Policy for Pain Relief includes ZYNRELEF as a qualifying product for separate payment in both the hospital outpatient department and ambulatory surgical center settings of care SAN DIEGO, Nov. 12, 2024 /PRNewswire/ -- Heron Therapeutics, Inc. (Nasdaq: HRTX) ("Heron" or the "Company"), a commercial-stage biotechnology company, today announced financial results for the three and nine months ended September 30, 2024, and highlighted recent corporate updates. "We are pleased to report that with our prudent financial management and continued revenue growth we were able to achieve positive Adjusted EBITDA for the quarter," said Craig Collard, Chief Executive Officer. "The future looks bright as we continue to grow all product revenue. The CrossLink partnership roll out, FDA approval of the VAN in September, and inclusion in the CMS Final Rule Non-Opioid Policy for Pain Relief, positions ZYNRELEF for significant growth within the surgical setting." "We continue to deliver on our commitment to financial efficiency while growing revenue. The team has made great strides in the transformation of Heron over the past year. We are looking forward to a strong fourth quarter which is off to a great start. As such, we are narrowing guidance for full-year 2024." Financial Guidance for 2024 The Company narrows its full-year 2024 guidance for Product Revenues, Net, Adjusted Operating Expenses and Adjusted EBITDA: Business Highlights The ZYNRELEF VAN will be available for initial use in the fourth quarter following approval by the U.S. Food and Drug Administration ("FDA") on September 24, 2024. The VAN will replace the current vented vial spike and has the potential to simplify aseptic preparation, while also significantly reducing ZYNRELEF's withdrawal time down to between twenty and forty-five seconds. ZYNRELEF will continue to receive separate payment from April 1, 2025, until at least the end of 2027 as the result of inclusion in the "CMS OPPS and ASC Final Rule CY 2025 Non-Opioid Policy for Pain Relief" by the Centers for Medicare & Medicaid Services ("CMS"). The payment limitation for ZYNRELEF is set at $2,267.26, in line with similar products, and it will be granted the status indicator of "K1" – for Non-Opioid Drugs and Biologicals For Post-Surgical Pain Relief. The goal of the policy is to ensure there are no financial incentives to use opioids instead of non-opioid alternatives like ZYNRELEF. To qualify under the new policy, ZYNRELEF needed to meet strict criteria establishing that it does not act upon the body's opioid receptors and that it successfully demonstrated the ability to replace, reduce, or avoid intraoperative or postoperative opioid requirements in clinical trials or peer reviewed literature. These criteria set a strong precedent from CMS that we expect other payors to follow. Cash and Cash Equivalents were $70.9 million as of September 30, 2024 , compared with $80.4 million on December 31, 2023. Acute Care Franchise Acute Care Franchise Net Product Sales: For the three and nine months ended September 30, 2024, acute care franchise Net Product Sales were $7.4 million and $19.7 million, respectively, compared to $4.7 million and $12.9 million, respectively, for the same period in 2023. ZYNRELEF Net Product Sales: Net Product Sales of ZYNRELEF for the three and nine months ended September 30, 2024 were $6.3 million and $17.1 million, respectively, compared to $4.4 million and $12.0 million, respectively, for the same period in 2023. APONVIE® Net Product Sales: Net Product Sales of APONVIE for the three and nine months ended September 30, 2024 were $1.1 million and $2.6 million, respectively, compared to $0.3 million and $0.9 million, respectively, for the same period in 2023. Oncology Care Franchise Oncology Care Franchise Net Product Sales: For the three and nine months ended September 30, 2024, oncology care franchise Net Product Sales were $25.4 million and $83.8 million, respectively, compared to $26.7 million and $79.9 million for the same period in 2023. CINVANTI® Net Product Sales: Net Product Sales of CINVANTI (aprepitant) injectable emulsion for the three and nine months ended September 30, 2024 were $22.6 million and $73.2 million, compared to $23.3 million and $70.6 million for the same period in 2023. SUSTOL® Net Product Sales: Net Product Sales of SUSTOL (granisetron) extended-release injection for the three and nine months ended September 30, 2024 were $2.8 million and $10.6 million, respectively, compared to $3.4 million and $9.3 million, respectively, for the same period in 2023. Conference Call and Webcast Heron will host a conference call and live webcast on Tuesday, November 12, 2024, at 8:00 a.m. ET. The conference call can be accessed by phone by utilizing the following registration link which will provide participants with dial-in details. To avoid delays, we encourage participants to dial into the conference call fifteen minutes ahead of the scheduled start time. The conference call will also be available via webcast under the Investor Relations section of Heron's website at . An archive of the teleconference and webcast will also be made available on Heron's website for sixty days following the call. About ZYNRELEF for Postoperative Pain ZYNRELEF is the first and only dual-acting local anesthetic that delivers a fixed-dose combination of the local anesthetic bupivacaine and a low dose of nonsteroidal anti-inflammatory drug meloxicam. ZYNRELEF is the first and only extended-release local anesthetic to demonstrate in Phase 3 studies significantly reduced pain and significantly increased proportion of patients requiring no opioids through the first 72 hours following surgery compared to bupivacaine solution, the current standard-of-care local anesthetic for postoperative pain control. ZYNRELEF was initially approved by the FDA in May 2021 for use in adults for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty. In December 2021, the FDA approved an expansion of ZYNRELEF's indication to include foot and ankle, small-to-medium open abdominal, and lower extremity total joint arthroplasty surgical procedures. On January 23, 2024, the FDA approved ZYNRELEF for soft tissue and orthopedic surgical procedures including foot and ankle, and other procedures in which direct exposure to articular cartilage is avoided. Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large multilevel spinal, and head and neck procedures. Please see full prescribing information, including Boxed Warning, at . About APONVIE for Postoperative Nausea and Vomiting (PONV) APONVIE is a substance NK1 Receptor Antagonist (RA), indicated for the prevention of PONV in adults. Delivered via a 30-second IV push, APONVIE 32 mg was demonstrated to be bioequivalent to oral aprepitant 40 mg with rapid achievement of therapeutic drug levels. APONVIE is the same formulation as Heron's approved drug product CINVANTI. APONVIE is supplied in a single-dose vial that delivers the full 32 mg dose for PONV. APONVIE was approved by the FDA in September 2022 and became commercially available in the U.S. on March 6, 2023. Please see full prescribing information at . About CINVANTI for Chemotherapy Induced Nausea and Vomiting (CINV) Prevention CINVANTI, in combination with other antiemetic agents, is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin as a single-dose regimen, delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) as a single-dose regimen, and nausea and vomiting associated with initial and repeat courses of MEC as a 3-day regimen. CINVANTI is an IV formulation of aprepitant, an NK1 RA. CINVANTI is the first IV formulation to directly deliver aprepitant, the active ingredient in EMEND® capsules. Aprepitant (including its prodrug, fosaprepitant) is a single-agent NK1 RA to significantly reduce nausea and vomiting in both the acute phase (0–24 hours after chemotherapy) and the delayed phase (24–120 hours after chemotherapy). The FDA-approved dosing administration included in the U.S. prescribing information for CINVANTI include 100 mg or 130 mg administered as a 30-minute IV infusion or a 2-minute IV injection. Please see full prescribing information at . About SUSTOL for CINV Prevention SUSTOL is indicated in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens. SUSTOL is an extended-release, injectable 5-hydroxytryptamine type 3 RA that utilizes Heron's Biochronomer® drug delivery technology to maintain therapeutic levels of granisetron for ≥5 days. The SUSTOL global Phase 3 development program was comprised of two, large, guideline-based clinical studies that evaluated SUSTOL's efficacy and safety in more than 2,000 patients with cancer. SUSTOL's efficacy in preventing nausea and vomiting was evaluated in both the acute phase (0–24 hours after chemotherapy) and delayed phase (24–120 hours after chemotherapy). Please see full prescribing information at . About Heron Therapeutics, Inc. Heron Therapeutics, Inc. is a commercial-stage biotechnology company focused on improving the lives of patients by developing and commercializing therapeutic innovations that improve medical care. Our advanced science, patented technologies, and innovative approach to drug discovery and development have allowed us to create and commercialize a portfolio of products that aim to advance the standard-of-care for acute care and oncology patients. For more information, visit . Non-GAAP Financial Measures To supplement our financial results presented on a GAAP basis, we have included information about certain non-GAAP financial measures. We believe the presentation of these non-GAAP financial measures, when viewed with our results under GAAP, provide analysts, investors, lenders, and other third parties with insights into how we evaluate normal operational activities, including our ability to generate cash from operations, on a comparable year-over-year basis and manage our budgeting and forecasting. In our quarterly and annual reports, earnings press releases and conference calls, we may discuss the following financial measures that are not calculated in accordance with GAAP, to supplement our consolidated financial statements presented on a GAAP basis. Adjusted EBITDA Adjusted EBITDA is a non-GAAP financial measure that represents GAAP net income or loss adjusted to exclude interest expense, interest income, the benefit from or provision for income taxes, depreciation, amortization, stock-based compensation, and other adjustments to reflect changes that occur in our business but do not represent ongoing operations. Adjusted EBITDA, as used by us, may be calculated differently from, and therefore may not be comparable to, similarly titled measures used by other companies. There are several limitations related to the use of adjusted EBITDA rather than net income or loss, which is the nearest GAAP equivalent, such as: adjusted EBITDA excludes depreciation and amortization and, although these are non-cash expenses, the assets being depreciated or amortized may have to be replaced in the future, the cash requirements for which are not reflected in adjusted EBITDA; we exclude stock-based compensation expense from adjusted EBITDA although: (i) it has been, and will continue to be for the foreseeable future, a significant recurring expense for our business and an important part of our compensation strategy; and (ii) if we did not pay out a portion of our compensation in the form of stock-based compensation, the cash salary expense included in operating expenses would be higher, which would affect our cash position; we exclude impairment of long-lived assets, the amount and/or frequency of which are not part of our underlying business. we exclude inventory write-downs (and write-ups should they occur), the amount and/or frequency of which are not part of our underlying business. adjusted EBITDA does not reflect changes in, or cash requirements for, working capital needs; adjusted EBITDA does not reflect the benefit from or provision for income taxes or the cash requirements to pay taxes; adjusted EBITDA does not reflect historical cash expenditures or future requirements for capital expenditures or contractual commitments; and we exclude restructuring expenses from adjusted EBITDA. Restructuring expenses primarily include employee severance and contract termination costs that are not related to acquisitions. The amount and/or frequency of these restructuring expenses are not part of our underlying business. Adjusted Operating Expenses Adjusted operating expenses is a non-GAAP financial measure that represents GAAP operating expenses adjusted to exclude stock-based compensation expense, depreciation and amortization, and other adjustments to reflect changes that occur in our business but do not represent ongoing operations. The Company has not provided a reconciliation of its full-year 2024 guidance for adjusted EBITDA or adjusted operating expenses to the most directly comparable forward-looking GAAP measures, in reliance on the unreasonable efforts exception provided under Item 10(e)(1)(i)(B) of Regulation S-K, because the Company is unable to predict, without unreasonable efforts, the timing and amount of items that would be included in such a reconciliation, including, but not limited to, stock-based compensation expense, acquisition related expense and litigation settlements. These items are uncertain and depend on various factors that are outside of the Company's control or cannot be reasonably predicted. While the Company is unable to address the probable significance of these items, they could have a material impact on GAAP net income and operating expenses for the guidance period. Forward-looking Statements This news release contains "forward-looking statements" as defined by the Private Securities Litigation Reform Act of 1995. Heron cautions readers that forward-looking statements are based on management's expectations and assumptions as of the date of this news release and are subject to certain risks and uncertainties that could cause actual results to differ materially. Therefore, you should not place undue reliance on forward-looking statements. Examples of forward-looking statements include, among others, statements we make regarding the potential market opportunities for ZYNRELEF, APONVIE, CINVANTI and SUSTOL; revenue, adjusted EBITDA and other financial guidance provided by the Company; the results of the commercial launch of APONVIE; the potential additional market opportunity for the expanded U.S. label for ZYNRELEF or inclusion of ZYNRELEF under the OPPS and the ASC payment system; the timing of the Company's development of the VAN program and receipt of required regulatory approvals; our ability to establish and maintain successful commercial arrangements like our co-promotion agreement with CrossLink Life Sciences, LLC ("CrossLink"); the outcome of the Company's pending ANDA litigation; whether the Company is required to write-off any additional inventory in the future; the expected future balances of Heron's cash, cash equivalents and short-term investments; the expected duration over which Heron's cash, cash equivalents and short-term investments balances will fund its operations and the risk that future equity financings may be needed; any inability or delay in achieving profitability. Important factors that could cause actual results to differ materially from those in the forward-looking statements are set forth in our most recent Annual Report on Form 10-K and any subsequent Quarterly Reports on Form 10-Q, and in our other reports filed with the Securities and Exchange Commission, including under the caption "Risk Factors." Forward-looking statements reflect our analysis only on their stated date, and Heron takes no obligation to update or revise these statements except as may be required by law. Investor Relations and Media Contact: Ira Duarte Executive Vice President, Chief Financial Officer Heron Therapeutics, Inc. [email protected] 858-251-4400 SOURCE Heron Therapeutics, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED