综述：依折麦布及其复方制剂的配方策略：提升生物制药与治疗潜力

本综述系统阐述了依折麦布（Ezetimibe）及其固定剂量复方（FDC）的先进制剂策略，重点聚焦于通过固态改性（如共晶、固体分散体）、纳米化技术及脂质/表面活性剂递送系统（如SNEDDS、NLCs、SLNs）解决其低溶解性（BCS II类）和口服生物利用度低（约35%）的瓶颈。研究表明，优化制剂可显著提升体外溶出（达98.11%/30min）和体内相对生物利用度（120%-800%），协同他汀（如阿托伐他汀、辛伐他汀）或贝派酸（Bempedoic acid）增强降脂疗效（LDL-C降幅14-25%），为改善心血管疾病（CVD）患者依从性和治疗结局提供强有力证据。

　　

Abstract

依折麦布是一种广泛用于治疗血脂异常的胆固醇吸收抑制剂，但其临床疗效受限于低水溶性和口服生物利用度。本综述总结了近年来依折麦布制剂的最新进展，包括单药和复方系统，并讨论了其对溶解度、药代动力学和治疗效果的影响。分析基于2015–2025年间来自知名科学数据库的文献。先进策略如固态改性、粒径减小和脂质或表面活性剂递送系统显著增强了药物溶出。体内研究报告显示，相对于纯药悬浮液/市售产品，相对生物利用度提高了约120%至800%，转化为有利的药效学特征。除了单药系统，与辛伐他汀、阿托伐他汀、瑞舒伐他汀和洛伐他汀等他汀的创新共递送已证明额外的药理协同作用，并支持固定剂量复方产品的开发。总之，这些进展提供了强有力的证据，表明优化后的依折麦布制剂在单药或复方系统中具有改善生物药剂学特性和未来在血脂异常管理中治疗应用的强大潜力。

Introduction

心血管疾病（CVDs）仍然是全球死亡的主要原因，2019年据世界卫生组织（WHO）统计，其导致1790万死亡，占全球总死亡人数的32%。在各种风险因素中，血脂异常——以低密度脂蛋白胆固醇（LDL-C）和其他致动脉粥样硬化脂蛋白水平升高为特征——在动脉粥样硬化性心血管疾病（ASCVD）的发展中起核心作用。含载脂蛋白B（ApoB）的脂蛋白（如LDL）在动脉壁内的积累加速动脉粥样硬化，强化了LDL-C降低作为心血管风险管理的首要目标。当前临床指南推荐他汀作为一线治疗，因其通过抑制肝脏胆固醇生物合成和上调LDL受体在降低LDL-C方面具有明确疗效。尽管他汀具有已证实的疗效和广泛使用，并非所有患者都能耐受他汀或通过他汀单药治疗达到LDL-C目标。在此类情况下，非他汀治疗作为他汀治疗的重要替代或辅助。

在非他汀药物中，依折麦布具有独特而关键的作用。它是唯一FDA批准的胆固醇吸收抑制剂（CAI），选择性阻断小肠中的Niemann-Pick C1-Like 1（NPC1L1）转运蛋白，从而抑制胆固醇吸收。依折麦布可降低LDL-C 15–25%，且耐受性良好，安全性 profile 有利。ESC（欧洲心脏病学会）和EAS（欧洲动脉粥样硬化学会）指南（2019年）推荐依折麦布作为联合治疗或在他汀不耐受个体中作为单药治疗的首选非他汀选项。类似地，2018年美国心脏病学院（ACC）和美国心脏协会（AHA）指南推荐在他汀单药治疗未达到LDL-C目标的ASCVD患者中添加依折麦布。依折麦布的使用近年来显著增加。例如，德国数据显示，2012年至2021年间，依折麦布单药治疗处方量增加了五倍。与其他非他汀治疗（如PCSK9抑制剂和贝派酸）相比，依折麦布具有显著的经济和实用优势。

目前，依折麦布以10 mg口服片剂形式提供， either as a single compound or in fixed-dose combinations with various statins as well as with newer agents, including bempedoic acid。依折麦布是一种生物药剂学分类系统（BCS）II类化合物， characterized by low water solubility, which affects its dissolution and bioavailability。依折麦布的口服生物利用度约为35%， primarily due to its low solubility and P-gp（P-糖蛋白）efflux。这些限制可能导致治疗反应的变异性， some patients requiring combination therapy to achieve recommended LDL-C targets。这推动了各种制剂策略的发展， aimed at enhancing dissolution, reducing P-gp efflux, and improving bioavailability。多种递送方法已被探索用于依折麦布， including solid-state modification, lipid-based delivery systems, and particle size reduction techniques。一个例子是开发依折麦布负载的固体脂质纳米粒（SLNs），其体外溶出比纯药提高六倍，溶出速率比市售制剂提高两倍。体内，该制剂增强了系统暴露，与市售产品相比，C_max和AUC分别增加了2.6倍和3.3倍，与常规悬浮液相比增加了11.6倍和8.7倍。

依折麦布当前的制剂开发 beyond its use as monotherapy and includes its incorporation into combination therapies with other lipid-lowering agents。由于依折麦布主要作为他汀的辅助用药，它 increasingly been developed in the form of fixed-dose combinations。这些制剂旨在增强治疗协同作用，改善患者依从性，并优化药代动力学和药效学特征， especially when designed to overcome their poor solubility and limited bioavailability。

尽管已有超过二十年的临床使用，专注于依折麦布先进制剂策略（单药或复方）的全面综述仍然缺乏。此外，这些创新系统对药物释放、药代动力学和治疗效果的影响尚未完全阐明。本综述旨在通过总结依折麦布及其复方制剂配方的最新进展，评估其生物药剂学性能，并探索其在血脂异常管理中的治疗意义来弥合这些差距。本综述基于过去十年（2015–2025年）发表的文献，选自知名科学数据库，包括PubMed、ScienceDirect、Taylor & Francis、SpringerLink和Scopus。

Biopharmaceutical Basis and Challenges of Ezetimibe

依折麦布被归类为BCS II类药物，因为其结晶水溶性极低（25°C时约0.008 mg/mL）且亲脂性高（log P ≈ 4.5）。即使在生物相关的空腹状态肠液（FaSSIF）中，溶解度也仅升至约11–12 μg/mL，证实溶出限制口服摄取。相反，Caco-2细胞研究报告表观渗透系数在2.7至3.0 × 10^?6 cm/s范围内，这支持将依折麦布归类为高渗透性化合物。尽管其渗透性足够，绝对口服生物利用度仍然中等且可变（35–65%）， mainly due to slow dissolution and extensive pre-systemic metabolism。

口服给药后，依折麦布 undergo rapid and extensive Phase II metabolism, primarily glucuronidation by UGT isoforms (UGT1A1, UGT1A3, and UGT2B15), yielding ezetimibe-glucuronide (EZE-G), the pharmacologically active metabolite。依折麦布及其葡萄糖醛酸苷的峰值血浆浓度通常在2–3小时内观察到。EZE-G约占循环药物相关物质的90%， emphasizing its dominant role in mediating the lipid-lowering effect。依折麦布药代动力学的一个独特特征是其广泛的肠肝循环。一旦在肝脏中葡萄糖醛酸化，EZE-G通过MRP2（ABCC2）转运到胆汁中并储存在胆囊中。进食后，它被释放到肠道中， where intestinal β-glucuronidase enzymes regenerate the parent drug, allowing it to be reabsorbed。这种循环过程导致血浆浓度-时间曲线中出现多个峰值并延长系统暴露。同时，肠道P-糖蛋白（P-gp）可通过促进外流来限制吸收，而肝细胞中的OATP1B1促进EZE-G的肝摄取。这些转运蛋白的遗传多态性已与改变的药代动力学特征和个体间治疗反应变异性相关联。

依折麦布的有效消除半衰期约为22小时，允许方便的每日一次10 mg给药。该药物主要通过粪便排泄（约78%），而较小部分（约11%）通过尿液排泄， predominantly as ezetimibe-glucuronide。尽管具有有利属性，如高渗透性和长半衰期，依折麦布的临床 performance is constrained by poor aqueous solubility, rapid pre-systemic metabolism, and complex transporter interactions, which contribute to variable absorption and therapeutic response。此外，由于肠肝循环，其多峰值药代动力学特征可能掩盖制剂依赖性效应，使生物利用度优化更具挑战性。

Formulation Approaches to Enhance the Solubility of Ezetimibe in Single-Active Formulations

依折麦布是一种BCS II类药物，其口服递送的主要限制在于其极低的水溶性。尽管它表现出高肠道渗透性，但其在胃肠液中的不良溶出显著限制了其吸收速率和程度，导致可变和次优的生物利用度。因此，制剂策略主要专注于改善胃肠道中的溶解度和溶出速率，旨在增强系统暴露和治疗一致性。近期依折麦布在单药系统中的制剂方法可分为三个主要方向：固态改性、纳米化技术和脂质/表面活性剂递送系统。图1提供了为依折麦布开发的制剂策略的全面概述。

Solid State Modifications

固态改性专注于改变依折麦布的结晶性质以改善其溶解度和溶出速率。这包括开发无定形固体分散体、共晶、包含复合物和低共熔混合物。通过降低晶体晶格能或改善与载体的分子相互作用，这些策略降低了药物的热力学稳定性并促进在胃肠道中的更快溶出。图2说明了依折麦布 incorporated in various solid-state modification systems。

Solid Dispersion

固体分散体是药剂学中一种成熟策略，用于改善难溶性药物的溶解度、溶出速率和口服生物利用度。该技术涉及将药物分散到亲水聚合物基质中。 resulting system can transform the crystalline drug into a more soluble amorphous form or create a molecular-level dispersion within the carrier matrix。这些转变增强了胃肠道中的溶出， potentially improving absorption and therapeutic effect。

几项研究报告了成功应用固体分散体系统以增强依折麦布的 biopharmaceutical performance。例如，使用聚乙烯吡咯烷酮K30（PVP K30）通过溶剂蒸发制备的分散体 substantially improved ezetimibe’s dissolution behavior。与纯结晶药物相比，分散体 enabled faster and more complete drug release（在10分钟内达到98%药物释放，而纯药为47%）。这些转化为动物模型中更有效的血清胆固醇水平降低。使用其他载体如Gelucire 50/13，单独或与PVP K30组合，也已通过改良溶剂蒸发方法进行研究。这些系统 exhibited superior drug release profiles, showing 87.54% drug release within 1 hour, significantly higher than the pure drug (24.67%, p < 0.05)。

另一项研究 prepared surface-modified solid dispersions (SMSD) and solvent-evaporated solid dispersions (SESD) by spray-drying using hydroxypropyl cellulose (HPC) and Tween 80。两种分散体 markedly improved aqueous solubility and accelerated early?stage dissolution relative to the crystalline form。药代动力学测试 confirmed a several?fold rise in systemic exposure, with the SESD formulation providing the most significant enhancement。一项伴随研究 employed a similar spray-drying process to generate binary (ezetimibe–HPC) and ternary (ezetimibe–HPC-Tween 80) solid dispersions at higher polymer-to-drug ratios。药物/聚合物比例为1:10和1:20的固体分散体 significantly enhanced the dissolution of ezetimibe compared to the pure drug, achieving nearly 100% release within 120 minutes, representing a 5-fold increase in dissolution rate。该系统 exhibited higher peak plasma concentrations and overall exposure compared to both the pure drug and the binary system。

一种创新方法 to enhance ezetimibe’s solubility and patient compliance involved incorporating its amorphous solid dispersion into an oral disintegrating film (ODF)。分散体 demonstrated reduced crystallinity and improved dissolution when mannitol was used as the carrier。优化的ODF，通过使用HPMC和羧甲基淀粉钠的因子设计开发， exhibited significantly enhanced drug release compared to the pure drug, supporting its potential as a fast-disintegrating formulation。

总之，这些发现表明，固体分散体系统可以通过在亲水载体中的 amorphization and molecular dispersion 显著改善依折麦布的溶出和口服生物利用度。当进一步整合到患者友好的剂型如口腔崩解膜中时，该策略不仅增强了生物药剂学性能，还提供了改善患者依从性和治疗结局的机会。

Co-Crystal

共晶是由活性药物成分和一个或多个共形物组成的结晶固体，以明确的化学计量比通过非共价相互作用组装。 forming a new crystal lattice distinct from the individual components can lead to modified physicochemical properties, most notably enhanced solubility and improved dissolution behavior, without altering the drug’s molecular structure。共结晶是一种有前景的固态改性方法，用于改善难溶性药物的溶解度和溶出。

特别是，使用二羧酸（如草酸、琥珀酸和马来酸）作为共形物 through solvent evaporation methods 制备依折麦布共晶。这些共晶 demonstrated improved dissolution performance compared to the pure drug, with maleic acid-based cocrystals showing superior characteristics among the dicarboxylic acid series。最优系统 demonstrated an 18.8-fold increase in dissolution efficiency compared to the pure drug, with 95.2% of the drug released within 45 minutes。

在另一项研究中，使用反应结晶方法开发了依折麦布-咪唑共晶并进行了全面评估。该系统 exhibited high solubility and thermodynamic stability in water and simulated intestinal fluid。与纯依折麦布相比，共晶 exhibited significantly enhanced in vitro dissolution, with a C_max of 5.0 μg/mL in water (vs ~3.7 μg/mL for the pure drug) and 40.0 μg/mL in FaSSIF (vs ~12.0 μg/mL), and a higher AUC (2963.62 ± 9.1 μg·min/mL)。重要的是，体内研究 confirmed its hypolipidemic efficacy, showing a significant reduction in lipid levels and an atherogenic index comparable to that of the control (normal) group, indicating its therapeutic relevance and biocompatibility。

总之，共结晶已被证明能显著增强依折麦布的溶出，使其成为改善依折麦布生物药剂学性能的有前景策略。

Inclusion Complex

另一种改善依折麦布溶解度和口服性能的有前景方法是形成包含复合物，特别是与环糊精。包含复合物是分子组装体，其中疏水性药物部分或完全被宿主分子（通常是环糊精）的空腔包裹。这种包裹保护药物免受水环境的影响，增加其表观溶解度和溶出速率而不改变其化学结构。

几种类环糊精衍生物已被研究用于与依折麦布形成包含复合物。一项研究 utilizing β-cyclodextrin in a 1:1 molar ratio, along with solubilizing agents such as polyethylene glycol 1000 succinate (TPGS) and L-ascorbic acid-2-glucoside (AA2G), enhanced dissolution performance。三元包含复合物 E–CD–AA2G significantly enhanced ezetimibe dissolution, achieving 82.5% ± 2.8% drug release at 30 minutes and a 3–3.5-fold increase in dissolution efficiency (DE) compared to the pure drug, which dissolved only 36.2% ± 4.2% over 120 minutes (p < 0.05 for all comparisons), and also demonstrated superior anti-dyslipidemic effects relative to both the pure drug and the control group。

在更近期的研究中，使用各种修饰的β-环糊精制备包含复合物， including RM-β-CD, DM-β-CD, TM-β-CD, HP-β-CD, and SBE-β-CD。所有复合物，除SBE-β-CD外，当使用更高摩尔比时 exhibited significantly improved solubility and dissolution。其中，RM-β-CD and DM-β-CD showed the most notable enhancement。这些发现 underscore the utility of cyclodextrin-based inclusion complexes as an effective formulation strategy for ezetimibe, by improving aqueous solubility and dissolution behavior。

Eutectic Mixture

低共熔混合物代表了另一种固态改性策略，以增强难溶性药物的溶出行为。这些系统由两种或多种组分紧密组合形成，当以特定比例混合时，其熔点低于单个组分。这种降低的熔点通常与增强的分子流动性和增加的可湿性相关，这可有助于改善溶出速率。

对于依折麦布，使用药学上可接受的共形物如水杨酸、对羟基苯甲酸甲酯和烟酰胺探索了低共熔系统。在测试的配方中，水杨酸和对羟基苯甲酸甲酯的低共熔混合物 significantly enhanced drug dissolution, indicating favorable solid-state interactions that facilitated the more rapid release of the drug。相反，与烟酰胺的低共熔混合物 resulted in a marked reduction in dissolution, suggesting that not all co-formers yield beneficial interactions。这些发现 underscore the significance of co-former selection in eutectic systems and confirm that properly designed eutectic mixtures can serve as a viable and straightforward approach to enhance the biopharmaceutical performance of ezetimibe, without necessitating complex processing or specialized equipment。另一项研究通过机械化学研磨开发了依折麦布-琥珀酰亚胺低共熔系统。该系统 demonstrated approximately a two-fold increase in solubility and dissolution rate, and markedly improved oral bioavailability。这些结果 highlight the potential of eutectic mixtures as a simple yet effective strategy to improve the dissolution and oral bioavailability of ezetimibe, provided that co-former selection is carefully optimized。

Particle Size Reduction Techniques

除了固态改性，粒径减小是另一种广泛采用的策略，以改善依折麦布的溶解度和口服生物利用度。该方法旨在减小药物的粒径，通常到纳米或微米尺度范围，这显著增加了可用于溶出的表面积，如Noyes-Whitney方程所解释。增加的表面积产生更快的溶出速率，改善表观，并促进在胃肠道中更好的吸收。

Nanoparticles

纳米粒子是亚微米胶体载体，可以 encapsulate or adsorb drug molecules, enhancing their solubility, stability, and intestinal absorption through increased surface area and interaction with biological membranes。依折麦布已被 incorporated into nanoparticles to improve oral delivery。一项研究 used polysaccharide fractions from Linum usitatissimum to develop ezetimibe nanoparticles via nanoprecipitation and emulsion solvent evaporation techniques。纳米沉淀方法 yielded better dissolution performance than the emulsion-based method, demonstrating enhanced release characteristics。通过纳米沉淀制备的纳米粒子 exhibited higher ezetimibe dissolution (83.1%) compared to emulsion-based nanoparticles (80.3%) and showed improved drug release compared to the pure drug。

另一项研究 employed ionotropic gelation to formulate chitosan-based ezetimibe nanoparticles, which exhibited significantly improved dissolution compared to the marketed tablet。纳米粒子 showed higher ezetimibe release than the marketed tablet, with 35.2% vs 10.95% at 30 minutes and 66.8% vs 38.2% total release (p < 0.05)。此外，该配方 demonstrated superior antihyperlipidemic effects in vivo, effectively reducing total cholesterol, triglycerides, LDL-C, VLDL-C, and atherogenic index compared to untreated and marketed product groups。这些发现 highlight the potential of nanoparticle systems to improve both the biopharmaceutical and therapeutic performance of ezetimibe。

Nanocrystal

纳米晶体是亚微米大小的结晶颗粒，完全由活性药物组成。它们提供了一种适用于疏水性化合物的无载体方法。通过减小粒径，纳米晶体改善表面积和溶出速率。表面活性剂或稳定剂通常用于稳定结晶分散体。

在依折麦布的情况下，纳米晶体 successfully developed using a bottom-up precipitation method with stabilizers like d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and L-ascorbic acid-2-glucoside (AA2G)。两种稳定剂 enhanced solubility and dissolution。TPGS-stabilized nanocrystals showed superior pharmacodynamic effects in vivo。这种增强部分归因于TPGS的P-gp抑制剂功能。P-gp是一种在肠上皮细胞中表达的外排转运蛋白，可以限制某些药物的口服吸收。通过抑制P-gp，TPGS有助于减少药物外流回肠腔，允许更大的细胞内浓度和系统吸收。因此，TPGS作为稳定剂和P-gp抑制剂的双重作用使其在旨在改善依折麦布口服生物利用度的纳米晶体配方中特别有价值。

Fibrous Microparticle

纤维状微粒是亚微米大小的载药纤维，通常通过诸如电喷雾或电纺丝等技术生产。这些结构增加了药物的表面积，并通过将活性药物成分分散在亲水载体基质中来促进快速溶出。

在一项研究中，由依折麦布、聚乙烯吡咯烷酮（PVP）和Cremophor RH40组成的电喷雾纤维状微粒 significantly enhanced both solubility and dissolution performance compared to the pure drug。在测试的配方中，以1:5:0.1重量比含有依折麦布、PVP和Cremophor RH40的配方 demonstrated the most favorable performance in terms of aqueous solubility and dissolution rate。该系统 showed significantly enhanced solubility and dissolution (~26-fold and ~4.5-fold, respectively) compared to pure drug。药代动力学评估 further confirmed a significant enhancement in oral bioavailability, as evidenced by increased systemic exposure。这些发现 support the potential of fibrous microparticles as a promising delivery platform for poorly water-soluble drugs such as ezetimibe。

Lipid/Surfactant-Based Formulations

另一种制剂策略涉及脂质/表面活性剂系统，旨在改善依折麦布的增溶和肠道吸收。依折麦布是一种BCS II类药物，水溶性有限。这些系统在胃肠道中形成胶体分散体或乳剂， enhancing dissolution and promoting lymphatic uptake。脂质基载体，特别是那些含有特定表面活性剂的载体，可以调节肠道外排机制，如P-糖蛋白（P-gp）， potentially increase intracellular drug concentrations by inhibiting drug efflux。一些脂质系统， employing long-chain triglycerides, may promote lymphatic transport, thereby partially bypassing hepatic first-pass metabolism。 combined ability to increase solubility, sustain supersaturation, promote lymphatic uptake, and inhibit efflux mechanisms makes lipid/surfactant-based delivery particularly effective for enhancing the oral bioavailability of ezetimibe。在脂质基递送系统中，依折麦布已成功开发使用各种平台， including microemulsions, self-nanoemulsifying drug delivery systems (SNEDDS), nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), and micellar systems。图3说明了依折麦布的低水溶性及其 incorporation into various lipid- and surfactant-based delivery systems。

Microemulsion

微乳系统代表了另一种有前景的策略，以增强依折麦布的溶解度和口服生物利用度。微乳是热力学稳定的、各向同性的分散体，由油、表面活性剂、助表面活性剂和水相组成。由于其纳米级液滴尺寸和高界面表面积，它们显著改善药物增溶并促进跨生物膜的扩散。微乳的自发形成和热力学稳定性 facilitate rapid dispersion in gastrointestinal fluids, thereby enhancing the rate and extent of drug dissolution。

一个值得注意的例子是开发来自挥发性o/w微乳系统的纳米依折麦布， which contains ethyl acetate as the oil phase, Brij 35 as the surfactant, and ethanol as the cosurfactant。该配方 demonstrated a markedly enhanced dissolution rate compared to the pure drug, underscoring the potential of microemulsion-based approaches in addressing ezetimibe’s solubility limitations。纳米依折麦布 exhibited a significantly improved dissolution rate, reaching 98.11% in 30 minutes, compared to 5.17% and 7.67% for the pure drug in water and a surfactant medium, respectively。这些发现 suggest that microemulsion-based systems provide a viable approach to enhancing the dissolution and oral bioavailability of ezetimibe, particularly in overcoming its poor aqueous solubility。

Self-Nanoemulsifying Drug Delivery System (SNEDDS)

SNEDDS代表一种有前景的脂质基策略，以增强难溶性药物的口服递送。这些系统是油、表面活性剂和助表面活性剂的各向同性混合物，在胃肠道流体中经温和搅动自发形成细小的水包油纳米乳剂。 resulting nano-sized droplets markedly increase the drug’s surface area, maintain it in a solubilized state, and facilitate its absorption。此外，表面活性剂组分 may inhibit intestinal P-glycoprotein (P-gp) efflux, further enhancing systemic exposure。

近期研究证明了SNEDDS在改善依折麦布生物利用度方面的有效性。一种优化的SNEDDS配方，使用Box–Behnken Design开发， incorporated Peceol as the oil phase, Tween 80 as the surfactant, and Transcutol-P as the co-surfactant。该配方 demonstrated a significant improvement in drug release compared to the pure drug, confirming the benefits of statistical design in achieving optimal performance (49.21% after 5 minutes; 95.27% after 40 minutes)。

另一项研究 developed a solid SNEDDS system containing Capryol 90 and Cremophor EL, demonstrating superior solubility and dissolution behavior in a separate investigation。固体SNEDDS enhanced aqueous solubility (~337 μg/mL vs 1.69 μg/mL) and improved drug dissolution 2–3-fold compared to pure drug (~60% vs ~25% at 30 min)。药代动力学研究 revealed a substantial increase in plasma concentration and overall systemic exposure compared to the pure drug。这些发现 highlight the dual advantage of SNEDDS in enhancing both the solubilization and intestinal absorption of ezetimibe, making it a compelling approach for the oral delivery of this BCS Class II compound。

Solid Lipid Nanoparticles (SLNs)

另一种有前景的脂质基制剂策略是固体脂质纳米粒（SLNs），已被广泛探索以增强难溶性药物的溶解度和口服生物利用度。SLNs由封装药物的固体脂质核心组成，并由表面活性剂稳定，形成在胃肠道环境中保持稳定的纳米级颗粒。该系统 increases the dissolution rate, may prolong gastrointestinal residence time, and protects the drug from enzymatic or chemical degradation。

在一项研究中，使用高压均质化开发了依折麦布负载的SLNs， employing Compritol 88 as the solid lipid and Tween 80 as the surfactant。 resulting formulation exhibited significantly improved drug release compared to conventional suspension and marketed products。SLN系统 showed an 80.2% release in 12 hours, ~6 times higher than the suspension and 2 times higher than the marketed product (p < 0.05)。此外，药代动力学分析 demonstrated a notable increase in peak plasma concentration and overall drug exposure。这些发现 highlight the potential of SLNs as an effective carrier system to enhance ezetimibe’s oral delivery and therapeutic performance。

Nanostructured Lipid Carriers (NLCs)

纳米结构脂质载体（NLCs）是先进的脂质基递送系统，由固体和液体脂质组成，由表面活性剂稳定。与SLNs不同，NLCs将一定比例的液体脂质纳入固体脂质基质中， resulting in a less ordered internal structure。这种结构缺陷提供了额外空间以容纳药物分子， resulting in a higher drug loading capacity and reduced drug expulsion during storage。脂质基质 protects the encapsulated drug from degradation, enhancing its solubility and dissolution rate。此外，通过促进淋巴摄取并 potentially bypassing hepatic first-pass metabolism, NLCs improve the oral bioavailability of poorly water-soluble drugs。

几项研究探索了各种配方方法和加工技术，在依折麦布的溶出和治疗性能方面 yield consistently favorable outcomes。

一种 notable approach employed ultrasonication to develop NLCs of ezetimibe using a lipid blend of oleic acid and stearic acid, stabilized with Tween 80 and poloxamer 188。调整固体与液体脂质的比例 allowed modulation of the drug release profile (drug release ranged from