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Structure, Morphology and Surface Properties of α-Lactose Monohydrate in Relation to its Powder Properties. 一水 α-乳糖的结构、形态和表面特性与其粉末特性的关系。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-29 DOI: 10.1016/j.xphs.2024.10.031
Thai T H Nguyen, Cai Y Ma, Ioanna D Styliari, Parmesh Gajjar, Robert B Hammond, Philip J Withers, Darragh Murnane, Kevin J Roberts

The particulate properties of α-lactose monohydrate (αLMH), an excipient and carrier for pharmaceuticals, is important for the design, formulation and performance of a wide range of drug products. Here an integrated multi-scale workflow provides a detailed molecular and inter-molecular (synthonic) analysis of its crystal morphology, surface chemistry and surface energy. Predicted morphologies are validated in 3D through X-ray diffraction contrast tomography. Interestingly, from aqueous solution fastest growth is found to lie along the b-axis, i.e. the longest unit cell dimension of the αLMH crystal structure reflecting the greater opportunities for solvation on the prism compared to the capping faces leading to their slower relative growth rates. The tomahawk morphology reflects the presence of β-lactose which asymmetrically binds to the capping surfaces creating a polar morphology. The crystal lattice energy is dominated by van der Waals interactions (between lactose molecules) with electrostatic interactions contributing the remainder. Predicted total surface energies are in good agreement with those measured at high surface coverage by inverse gas chromatography, albeit their dispersive contributions are found to be higher than those measured. The calculated surface energies of crystal habit surfaces are not found to be significantly different between different crystal surfaces, consistent with αLMH's known homogeneous binding to drug molecules when formulated. Surface energies for different morphologies reveals crystals with the elongated crystal morphologies have lower surface energies compared to those with a triangular or tomahawk morphologies, correlating well with literature data that the surface energies of the lactose carriers are inversely proportional to their aerosol dispersion performance.

一水α-乳糖(αLMH)是一种药用辅料和载体,其微粒特性对多种药物产品的设计、配制和性能非常重要。这里的多尺度综合工作流程对其晶体形态、表面化学和表面能进行了详细的分子和分子间(合成)分析。预测的形态通过 X 射线衍射对比断层扫描进行三维验证。有趣的是,从水溶液中发现沿着 b 轴(即 αLMH 晶体结构的最长单胞尺寸)生长最快,这反映出棱柱上的溶解机会比盖面更多,导致其相对生长速度较慢。战斧状形态反映了 β-乳糖的存在,它不对称地与封盖面结合,形成了极性形态。范德华相互作用(乳糖分子之间)在晶格能中占主导地位,静电作用占其余部分。预测的总表面能与反气相色谱法在高表面覆盖率下测得的总表面能十分吻合,但发现它们的分散贡献比测得的要高。不同晶型表面的计算表面能差异不大,这与已知的 αLMH 在配制时与药物分子的均匀结合是一致的。不同形态的表面能显示,与三角形或战斧形形态的晶体相比,细长晶体形态的晶体表面能较低,这与乳糖载体的表面能与其气溶胶分散性能成反比的文献数据十分吻合。
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引用次数: 0
Cocrystal screening in minutes by solution-mediated phase transformation (SMPT): Preparation and characterization of ketoconazole cocrystals with nine aliphatic dicarboxylic acids. 通过溶液介导相变 (SMPT) 在几分钟内完成共晶体筛选:酮康唑与九种脂肪族二羧酸共晶体的制备与表征。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-28 DOI: 10.1016/j.xphs.2024.10.046
Junguang Yu, Rodger F Henry, Geoff G Z Zhang

The rapid and efficient cocrystal screening, based on solution-mediated phase transformation (SMPT), was applied to the screening of cocrystals between ketoconazole (KTZ) and nine aliphatic dicarboxylic acids. Cocrystals formed successfully, in minutes, with a change of suspension characteristics, either a cake formation or the formation of large particles. Bulk cocrystals were characterized by powder X-ray diffraction, thermal analysis, and Raman spectroscopy. Single crystals were grown, and molecular structures were determined. Three previously reported cocrystals were reproduced, and six new cocrystals were discovered, including one that was reported as a failure in literature by solution or grinding method. Two hydrogen-bonded motifs are observed in these nine cocrystals: Most cocrystals form hydrogen bonded discrete tetramer with two KTZ and two acids molecules; while two cocrystals form infinite chain. This study demonstrated the high efficacy of cocrystal generation using the slurry screening method. It should be fully utilized in future cocrystal screening.

基于溶液介导相变(SMPT)的快速高效共晶体筛选方法被应用于酮康唑(KTZ)与九种脂肪族二羧酸共晶体的筛选。共晶体在几分钟内成功形成,悬浮特性发生了变化,要么形成了饼状,要么形成了大颗粒。粉末 X 射线衍射、热分析和拉曼光谱对块状共晶体进行了表征。对单晶体进行了生长,并确定了分子结构。再现了以前报道过的三种共晶体,并发现了六种新的共晶体,其中包括一种文献报道的溶液法或研磨法失败的共晶体。在这九种共晶体中观察到两种氢键图案:大多数共晶体与两个 KTZ 分子和两个酸分子形成氢键离散四聚体;而两个共晶体则形成无限链。这项研究表明,利用浆料筛选法生成的共晶体具有很高的效率。在今后的共晶体筛选中应充分利用这种方法。
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引用次数: 0
Experimental validation of a parenteral permitted daily exposure value for cleaning-induced degradants from recombinant therapeutic proteins with in vitro immunogenicity assays. 通过体外免疫原性实验验证重组治疗蛋白中清洁诱导降解物的肠外每日允许暴露值。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-28 DOI: 10.1016/j.xphs.2024.10.041
Joseph R Cohen, Marisa K Joubert, Syeda Tabassum, Allyson Capili, Julia Carreon, Cathie Xiang, Siddharth Prabhu, Anthony Merlo, Dan Mytych, David G Dolan, Ram Kouda

Multiproduct manufacturing of biotherapeutic proteins generate cleaning-induced protein degradants because of extreme pH and temperature conditions during the cleaning process. Cleaning Acceptance limits are calculated based on the maximum allowable carryover (MAC) assessment of the previously manufactured active pharmaceutical ingredient (API) - or drug product - based on the permitted daily exposure (PDE) of the previously manufactured API into the dose of subsequent product. In this study, we tested a previously determined PDE value for cleaning-induced protein degradants of 650 µg/dose. A bench-scale cleaning method was used to generate cleaning induced degradants from both a half-life extension (HLE) BiTE® molecule and a mAb product. For this investigation, degradants of HLE BiTE®-A and mAb-1 were characterized alone or after spiking of 650 µg of degradants of HLE BiTE®-A or 650 µg degradants of mAb-1, into mAb-1, respectively. These samples were characterized by endotoxin testing, size exclusion chromatography (SEC), light obscuration by HIAC, and micro-fluidic imaging (MFI). These results suggest that significant degradation of the molecule occurs because of the cleaning procedure, and it is no longer in the intact form or active state. The potential immogenic impact was assessed using a cell line assay to assess immune activation, and a human Peripheral Blood Mononuclear Cell (PBMC) assay to assess T cell activation, T cell proliferation, and cytokine release after 20 h and 7 days. Findings from the various in vitro cell-based immune activation assays suggest that the presence of 650 µg of carryover of degradants either alone or spiked into the same or a cross-product do not increase immunogenicity risk in cell-based assays - suggesting that the current PDE of 650 µg/dose for cleaning-induced degradant carryover does not have a risk of immunogenicity in patients.

生物治疗蛋白质的多产品生产过程中会产生清洗诱导的蛋白质降解物,因为在清洗过程中会出现极端的 pH 值和温度条件。清洗验收限值是根据先前生产的活性药物成分 (API) 或药物产品的最大允许带入量 (MAC) 评估计算得出的,其依据是先前生产的 API 与后续产品剂量的允许日接触量 (PDE)。在这项研究中,我们测试了之前确定的 650 微克/剂量的清洁诱导蛋白质降解物 PDE 值。我们采用了一种工作台规模的清洗方法,从半衰期延长 (HLE) BiTE® 分子和 mAb 产品中生成清洗诱导降解物。在这项研究中,对 HLE BiTE®-A 和 mAb-1 的降解物进行了单独表征,或将 HLE BiTE®-A 和 mAb-1 的降解物添加到 650 µg 的 mAb-1 中进行表征。通过内毒素测试、尺寸排阻色谱法(SEC)、HIAC 光遮蔽和微流体成像(MFI)对这些样品进行了表征。这些结果表明,由于清洗过程,分子发生了严重降解,不再是完整的形式或活性状态。在 20 小时和 7 天后,使用细胞系测定法评估免疫活化情况,并使用人类外周血单核细胞(PBMC)测定法评估 T 细胞活化、T 细胞增殖和细胞因子释放情况,从而评估对生物的影响。各种体外细胞检测的结果表明,在细胞检测中,650 微克的降解剂携带量无论是单独存在还是添加到相同或交叉产品中,都不会增加免疫原性风险,这表明目前 650 微克/剂量的清洁诱导降解剂携带量的 PDE 不会对患者产生免疫原性风险。
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引用次数: 0
Quantitation of AAV in a dual-vector system using SV-AUC. 使用 SV-AUC 对双载体系统中的 AAV 进行定量。
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-28 DOI: 10.1016/j.xphs.2024.10.049
Alexander E Yarawsky, Carlo Ciatto, Peter Slade, Natalya I Figueroa, John W Burgner, Michael T DeLion, Lake N Paul

Sedimentation velocity analytical ultracentrifugation (SV-AUC) has become the "gold standard" for characterization of the empty, partial, and full capsids of gene therapy products (e.g., AAV and Adenovirus vectors). Other techniques, such as SEC-MALS, TEM, and mass photometry, are commonly used for capsid quantitation, however, the resolving power of these techniques is lacking. In this body of work, SV-AUC was implemented in the characterization of a dual-vector AAV system where the difference in packaged genomes was ∼400 nucleotides. The instrument parameters and SV-AUC analysis were optimized to accurately quantitate both AAV vectors with less than 8% error and with highly correlated linearity (R2 > 0.99) as compared to ddPCR. The results of this work highlight the resolution and accuracy of dual-vector capsid quantitation by SV-AUC and demonstrate the use of the powerful Bayesian analysis implemented in the SEDFIT analysis software.

沉降速度分析超速离心法(SV-AUC)已成为表征基因治疗产品(如 AAV 和腺病毒载体)空、部分和完整囊壳的 "黄金标准"。其他技术,如 SEC-MALS、TEM 和质量光度法,通常也用于囊体定量,但这些技术的分辨能力不足。在这项工作中,SV-AUC 被用于表征双载体 AAV 系统,该系统的包装基因组相差 400 个核苷酸。对 SV-AUC 仪器参数和分析进行了优化,与 ddPCR 相比,SV-AUC 能准确定量两种 AAV 载体,误差小于 8%,线性相关度高(R2 > 0.99)。这项工作的结果凸显了 SV-AUC 定量双载体包囊的分辨率和准确性,并展示了 SEDFIT 分析软件中强大的贝叶斯分析功能的应用。
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引用次数: 0
Implications of crystal disorder on the solid-state stability of Olanzapine. 晶体紊乱对奥氮平固态稳定性的影响
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-25 DOI: 10.1016/j.xphs.2024.10.047
Jayant Iyer, Matilde Barbosa, João F Pinto, Amrit Paudel

Mechanical perturbations of drug during solid pharmaceutical processing like milling can often generate crystal disorder posing serious implications to drug's stability. While physical changes like amorphization, recrystallization, polymorphism of the disordered drugs are extensively studied and reported in the literature, the propensities and inter-dependencies of recrystallization and degradation propensities of disordered drugs have seldom received deep attention. Previous investigations from our lab have explored some of these interplays, aiming to develop predictive stability models. As a follow-up, the implication of crystal disorder on the oxidative instability of Olanzapine (OLA) during accelerated storage is investigated in this work. Cryo-milling OLA at varied time intervals generated different extents of crystal disorder. The milled samples were characterized using calorimetry and infrared (IR) spectroscopy to examine the physical state, while their degradation was evaluated using ultra-performance liquid chromatographic methods. An X-ray amorphous OLA sample was generated by melt-cooling, and used as an amorphous reference. The crystallinity of the cryo-milled samples was quantified using a partial least square regression model based on ATR-FTIR spectroscopic data. The cryo-milled samples were exposed to different accelerated stability conditions along with crystalline (unmilled) and quench cooled (amorphous) samples, serving as controls. At periodic intervals, samples were removed from the stability storage, and analyzed using ATR-FTIR and UPLC methods to quantify the crystallinity- and degradation extents. A positive relation was witnessed between the initial degree of crystallinity and degradation kinetics of the disordered OLA samples during stability storage indicating a strong dependency of degradation on the disorder contents for such disordered solids. The results obtained in this study can potentially explain consequences of inter-batch variations of drugs during stability storage, in addition to enabling de-risking strategies towards eliminating solid drug instabilities in product development.

在研磨等固体药物加工过程中,药物的机械扰动往往会产生晶体紊乱,严重影响药物的稳定性。虽然文献中对无序药物的非晶化、再结晶、多态性等物理变化进行了广泛的研究和报道,但无序药物的再结晶倾向和降解倾向及其相互依存关系却很少得到深入的关注。我们实验室以前的研究探索了其中的一些相互作用,旨在开发预测稳定性模型。作为后续研究,我们在本研究中探讨了晶体无序对奥氮平(OLA)在加速储存过程中氧化不稳定性的影响。以不同的时间间隔对奥氮平进行低温研磨,会产生不同程度的晶体紊乱。使用量热法和红外光谱法对研磨样品的物理状态进行了表征,同时使用超高效液相色谱法对其降解情况进行了评估。通过熔融冷却生成了 X 射线无定形 OLA 样品,并将其作为无定形参考。根据 ATR-FTIR 光谱数据,使用偏最小二乘法回归模型对冷冻研磨样品的结晶度进行量化。冷冻研磨样品与结晶(未研磨)和骤冷(无定形)样品一起作为对照,暴露在不同的加速稳定性条件下。每隔一段时间,将样品从稳定性储存库中取出,并使用 ATR-FTIR 和 UPLC 方法进行分析,以量化结晶和降解程度。无序 OLA 样品在稳定贮存期间的初始结晶度与降解动力学之间呈正相关,这表明此类无序固体的降解与无序含量密切相关。本研究获得的结果可以解释药物在稳定贮存过程中的批间差异后果,还可以帮助制定消除产品开发中固体药物不稳定性的风险策略。
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引用次数: 0
Evaluation of the correlation between nuclear localization levels and genome editing efficiencies of Cas12a fused with nuclear localization signals. 评估与核定位信号融合的 Cas12a 的核定位水平与基因组编辑效率之间的相关性。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-24 DOI: 10.1016/j.xphs.2024.10.029
Tomohito Tsukamoto, Haruna Mizuta, Eiko Sakai, Fuminori Sakurai, Hiroyuki Mizuguchi

Genome editing technology using the CRISPR-Cas system is attracting much attention not only as a promising experimental tool for analysis of genome functions, but also as a novel therapeutic approach for genetic disorders. Among the various types of Cas proteins, Cas12a is expected to be a promising gene editing tool due to its unique properties, including low off-target effects. As Cas proteins are of prokaryotic origin, they need to be fused with appropriate localization signals to perform their function in eukaryotic cells. Cas12a proteins fused with a nuclear localization signal (NLS) have been developed so far, but the relation between the nuclear localization activity and the genome editing efficiency has not been fully elucidated. Here, utilizing two Cas12a orthologs, AsCas12a and LbCas12a, with various number of NLSs derived from various origins, we revealed that the improved nuclear localization resulted in increased genome editing efficiencies when expressed using adenovirus (Ad) vector in cultured cells. However, when they were expressed in mouse liver, the improvement of the nuclear localization activity was not necessarily required to achieve the maximum genome editing efficiency four weeks after Ad vector administration. These data indicated that the optimized NLS modification of Cas12a proteins in vitro situations differed from that in vivo.

使用CRISPR-Cas系统的基因组编辑技术不仅是分析基因组功能的一种有前途的实验工具,而且也是治疗遗传疾病的一种新方法,因此备受关注。在各种类型的 Cas 蛋白中,Cas12a 因其独特的特性,包括低脱靶效应,有望成为一种前景广阔的基因编辑工具。由于 Cas 蛋白来源于原核细胞,因此需要融合适当的定位信号才能在真核细胞中发挥作用。目前已开发出融合了核定位信号(NLS)的 Cas12a 蛋白,但其核定位活性与基因组编辑效率之间的关系尚未完全阐明。在这里,我们利用两种Cas12a直向同源物AsCas12a和LbCas12a,以及来自不同来源的不同数量的NLS,发现当使用腺病毒(Ad)载体在培养细胞中表达时,改进的核定位导致基因组编辑效率的提高。然而,当它们在小鼠肝脏中表达时,核定位活性的改善并不一定要求在使用腺病毒载体四周后达到最高的基因组编辑效率。这些数据表明,Cas12a蛋白在体外的优化NLS修饰与体内不同。
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引用次数: 0
Characterization of macrocyclic peptide drug interactions with bile salts and biorelevant colloids via single amino acid mutations and 1H nuclear magnetic resonance (NMR) spectroscopy. 通过单氨基酸突变和 1H 核磁共振 (NMR) 光谱鉴定大环肽药物与胆汁盐和生物相关胶体的相互作用。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-24 DOI: 10.1016/j.xphs.2024.10.021
Tahnee J Dening, José G Napolitano, Jessica L Ochoa, Justin T Douglas, Michael J Hageman

There is growing interest in the oral delivery of poorly permeable peptide drugs; however, the effect of biorelevant colloids found in the aqueous gastrointestinal environment on peptide drug solution behavior has been largely understudied. In this work, we detail the molecular level interactions between octreotide, a water-soluble macrocyclic peptide drug, and biorelevant colloids, i.e. bile salt micelles and bile salt-phospholipid mixed micelles, via dialysis membrane flux experiments and proton nuclear magnetic resonance (1H NMR) spectroscopy. A modified alanine scan was employed to generate eight mutated octreotide analogs; the impact of individual amino acid mutations on peptide dialysis membrane flux rates in micellar (trihydroxy and dihydroxy) bile salt solutions as well as fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) was evaluated and compared against the parent peptide, octreotide. We show that octreotide interacts more strongly with dihydroxy bile salt micelles than trihydroxy bile salt micelles in solution, and in FaSSIF/FeSSIF media, octreotide mainly interacts with the phospholipid component. These interactions are largely mediated by hydrophobic interactions of octreotide's aromatic residues as well as electrostatic interactions between octreotide's basic Lys residue and terminal amine.

人们对渗透性差的多肽药物的口服给药越来越感兴趣;然而,胃肠道水环境中的生物相关胶体对多肽药物溶液行为的影响在很大程度上还没有得到充分研究。在这项工作中,我们通过透析膜通量实验和质子核磁共振(1H NMR)光谱详细研究了水溶性大环肽药物奥曲肽与生物相关胶体(即胆汁盐胶束和胆汁盐-磷脂混合胶束)之间的分子水平相互作用。我们采用改良丙氨酸扫描法生成了八种突变的奥曲肽类似物;评估了单个氨基酸突变对胶束(三羟基和二羟基)胆汁盐溶液以及空腹状态模拟肠液(FaSSIF)和进食状态模拟肠液(FeSSIF)中肽透析膜通量率的影响,并与母肽奥曲肽进行了比较。我们的研究表明,在溶液中,奥曲肽与二羟基胆盐胶束的相互作用比与三羟基胆盐胶束的相互作用更强;在 FaSSIF/FeSSIF 介质中,奥曲肽主要与磷脂成分相互作用。这些相互作用主要是由奥曲肽芳香族残基的疏水作用以及奥曲肽碱性赖氨酸残基和末端胺之间的静电作用介导的。
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引用次数: 0
Dissolution mechanisms of amorphous solid dispersions: Role of polymer molecular weight and identification of a new failure mode. 无定形固体分散体的溶解机理:聚合物分子量的作用和新失效模式的鉴定。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-24 DOI: 10.1016/j.xphs.2024.10.026
Alexandru Deac, Chailu Que, Michelle L Cousineau, Anura S Indulkar, Yi Gao, Geoff G Z Zhang, Lynne S Taylor

The mechanisms of drug release from amorphous solid dispersions (ASDs) are complex and not fully explored, making it difficult to optimize for in vivo performance. A recurring behavior has been the limit of congruency (LoC), a drug loading above which the ASD surface forms an amorphous drug-rich barrier in the presence of water, which hinders release, especially in non-sink conditions. Drug-polymer interactions and drug glass transition temperature were reported to affect the LoC. However, the effect of polymer molecular weight has not been explored. ASDs of clotrimazole and different molecular weight grades of poly (vinylpyrrolidone) (PVP) were studied for their release to obtain their LoC drug loadings. Failure modes underpinning the LoC were investigated using fluorescence confocal microscopy to analyze the ASD/solution interface and phase behavior of ASD films at high relative humidity. ASDs with good release formed stable drug-rich nanodroplets at the ASD/solution interface, while ASDs with poor release were limited by one of two failure modes, depending on PVP molecular weight. In Failure Mode I the nanodroplets quickly agglomerated, while in Failure Mode II the system underwent phase inversion. This work highlights the importance of identifying the mechanisms underlying the LoC to improve the release of higher drug loading ASDs.

无定形固体分散体(ASD)的药物释放机制十分复杂,而且尚未得到充分探索,因此很难对其体内性能进行优化。一个经常出现的现象是同质性极限(LoC),即药物负载量超过这一极限时,无定形固体分散体表面在有水存在的情况下会形成富含药物的无定形屏障,从而阻碍药物的释放,尤其是在非沉降条件下。据报道,药物与聚合物的相互作用和药物的玻璃化温度会影响 LoC。然而,聚合物分子量的影响尚未得到探讨。对克霉唑的 ASD 和不同分子量等级的 PVP 进行了释放研究,以获得其 LoC 药物负载量。使用荧光共聚焦显微镜分析了 ASD/溶液界面和 ASD 薄膜在高相对湿度下的相行为,研究了 LoC 的失效模式。释放效果好的 ASD 在 ASD/溶液界面上形成了稳定的富含药物的纳米液滴,而释放效果差的 ASD 则受限于两种失效模式之一,具体取决于 PVP 的分子量。在失效模式 I 中,纳米液滴会迅速团聚,而在失效模式 II 中,系统会发生相反转。这项工作强调了确定 LoC 的基本机制以改善高药物负载 ASD 释放的重要性。
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引用次数: 0
Biowaiver monographs for immediate-release solid oral dosage forms: Lemborexant. 速释口服固体制剂的生物豁免专论:Lemborexant.
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-23 DOI: 10.1016/j.xphs.2024.10.030
Kristian Beran, Bertil Abrahamsson, Naseem Charoo, Rodrigo Cristofoletti, René Holm, Atsushi Kambayashi, Peter Langguth, Mehul Mehta, Alan Parr, James E Polli, Vinod P Shah, Jennifer Dressman

Lemborexant is a dual orexin receptor antagonist assigned to class II of the Biopharmaceutics Classification System (BCS). Thus, the ICH M9 Guideline excludes immediate-release (IR) solid oral dosage forms containing lemborexant from BCS-based biowaivers, irrespective of their in vitro dissolution behavior. By contrast, classification of lemborexant according to the refined Developability Classification System (rDCS) falls into class I, indicating few biopharmaceutics risks. Customized rDCS investigations identify dissolution as the main risk factor, in line with clinical data in humans which suggest that the absorption of lemborexant is limited neither by solubility nor by permeability. Instead, any risks lie in dissolution. Analysis by the rDCS coupled with biorelevant dissolution testing thus provides a way forward for manufacturers to mitigate the risks associated with changes in formulation or introduction of a generic version prior to running clinical bioequivalence (BE) studies. As a way forward regarding biowaivers for lemborexant and similar cases, where justifying BE based on the current BCS-based approach is not possible, a four-step pathway towards establishing BE virtually could be adopted as follows: (i) rDCS analysis to identify critical bioavailability attributes, (ii) comparative (biorelevant) dissolution testing, (iii) Physiologically Based Biopharmaceutics Modeling (PBBM), and (iv) virtual BE assessment.

伦博雷沙坦是一种双重奥曲肽受体拮抗剂,属于生物制药分类系统(BCS)的第二类。因此,无论其体外溶出行为如何,《ICH M9 指南》都将含有伦博雷生的速释(IR)口服固体制剂排除在基于 BCS 的生物豁免之外。与此相反,根据改进的可显影性分类系统(rDCS)对伦博雷康进行的分类属于 I 类,表明生物制药风险很小。定制的 rDCS 调查发现,溶解是主要的风险因素,这与人体临床数据一致,表明 Lemborexant 的吸收既不受溶解度的限制,也不受渗透性的限制。相反,任何风险都在于溶解。因此,在进行临床生物等效性(BE)研究之前,rDCS 分析与生物相关溶出度测试相结合,为生产商提供了一条降低制剂变化或引入仿制药相关风险的途径。在不可能根据目前基于生物相容性标准的方法证明生物等效性的情况下,可采用以下四步方法来确定生物等效性:(i) rDCS 分析以确定关键的生物利用度属性,(ii) 比较(生物相关)溶出试验,(iii) 基于生理学的生物药剂学建模 (PBBM),(iv) 虚拟生物利用度评估。
{"title":"Biowaiver monographs for immediate-release solid oral dosage forms: Lemborexant.","authors":"Kristian Beran, Bertil Abrahamsson, Naseem Charoo, Rodrigo Cristofoletti, René Holm, Atsushi Kambayashi, Peter Langguth, Mehul Mehta, Alan Parr, James E Polli, Vinod P Shah, Jennifer Dressman","doi":"10.1016/j.xphs.2024.10.030","DOIUrl":"10.1016/j.xphs.2024.10.030","url":null,"abstract":"<p><p>Lemborexant is a dual orexin receptor antagonist assigned to class II of the Biopharmaceutics Classification System (BCS). Thus, the ICH M9 Guideline excludes immediate-release (IR) solid oral dosage forms containing lemborexant from BCS-based biowaivers, irrespective of their in vitro dissolution behavior. By contrast, classification of lemborexant according to the refined Developability Classification System (rDCS) falls into class I, indicating few biopharmaceutics risks. Customized rDCS investigations identify dissolution as the main risk factor, in line with clinical data in humans which suggest that the absorption of lemborexant is limited neither by solubility nor by permeability. Instead, any risks lie in dissolution. Analysis by the rDCS coupled with biorelevant dissolution testing thus provides a way forward for manufacturers to mitigate the risks associated with changes in formulation or introduction of a generic version prior to running clinical bioequivalence (BE) studies. As a way forward regarding biowaivers for lemborexant and similar cases, where justifying BE based on the current BCS-based approach is not possible, a four-step pathway towards establishing BE virtually could be adopted as follows: (i) rDCS analysis to identify critical bioavailability attributes, (ii) comparative (biorelevant) dissolution testing, (iii) Physiologically Based Biopharmaceutics Modeling (PBBM), and (iv) virtual BE assessment.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impact of dissolution medium pH and ionization state of the drug on the release performance of amorphous solid dispersions. 溶解介质 pH 值和药物电离状态对无定形固体分散体释放性能的影响
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-23 DOI: 10.1016/j.xphs.2024.10.028
Anura S Indulkar, Samantha Alex, Geoff G Z Zhang

Amorphous solid dispersions (ASDs) are widely employed as a strategy to improve oral bioavailability of poorly water soluble compounds. Typically, optimal dissolution performance from a polyvinylpyrrolidone vinyl acetate (PVPVA) based ASD is observed at relatively low drug loading limit. Above a certain drug load, termed limit of congruency (LoC), the release from ASDs significantly decreases. So far, the majority of the dissolution behavior has been tested in conditions where the drug primarily exists in unionized form. In this work, the impact of pH of the dissolution environment on the release performance of ASDs of an ionizable drug was studied. Atazanavir (ATZ), a weakly basic drug with a pKa of 4.5 was used as a model compound and PVPVA was used as a non-ionizable matrix polymer. Dissolution rate was measured using Wood's apparatus which normalizes the surface area of the dissolving tablet. The pH of the dissolution media was varied between 1 and 6.8, to cover a range where ATZ exists as >99 % ionized or unionized species. At pH 6.8, near complete release was observed only when the drug load was ≤ 6 %. Unlike typically observed drastic decline in release behavior for PVPVA based ASDs above LoC, ATZ ASDs underwent gradual decline in dissolution behavior when the DL was increased to 8 %. This was attributed to potential formation of an ATZ-PVPVA associated phase with dissolution rate slower than neat PVPVA. However, the 10 % DL ASD showed negligible ATZ release. On another extreme (pH 1) where ATZ is ∼100 % ionized, the dissolution rate of ATZ was faster than that of PVPVA. ASD dissolution rate was found to be slower than that of the neat drug but faster than PVPVA and interestingly, did not change with DL. This can be attributed to formation of an ionized ATZ-PVPVA phase which controls the dissolution rate of the ASD. At pH 3, where the drug is ∼97 % ionized, near complete release was observed for drug loads ≤ 8 %. To observe significant increase in drug loading with near complete release, >98 % ionization of ATZ was required. At pH 2 where ATZ is ∼99.7 % ionized, near complete release was observed for drug loads up to 30 %. Furthermore, the deterioration in dissolution performance with an increase in drug load continued to be gradual at pH 2. The enhancement in dissolution performance did not correlate with solubility enhancement of ATZ due to ionization. We theorize that the enhancement in the dissolution performance due to ionization is the result of formation of an ionized ATZ-PVPVA phase which increases the hydrophilicity and the miscibility of the ASD. This can help resist water induced phase separation during ASD dissolution and therefore, result in continuous, and congruent dissolution of the drug and polymer.

无定形固体分散体(ASD)被广泛用作改善水溶性差的化合物口服生物利用度的一种策略。通常情况下,基于聚乙烯吡咯烷酮-醋酸乙烯酯(PVPVA)的无定形固体分散体在相对较低的药物负载极限下可达到最佳溶解性能。超过一定的药物载量(称为 "一致性极限"(LoC)),ASD 的释放量就会明显降低。迄今为止,大多数溶解行为都是在药物主要以联合形式存在的条件下进行测试的。在这项工作中,研究了溶解环境的 pH 值对可离子化药物的 ASD 释放性能的影响。以 pKa 为 4.5 的弱碱性药物阿扎那韦(ATZ)为模型化合物,以 PVPVA 为非离子化基质聚合物。采用伍德仪器测量溶解速率,该仪器将溶解片剂的表面积归一化。溶解介质的 pH 值在 1 到 6.8 之间变化,在这一范围内,ATZ 以大于 99% 的离子化或联合化形式存在。在 pH 值为 6.8 时,只有当药物载量≤ 6% 时才能观察到接近完全的释放。与通常观察到的 PVPVA 基 ASD 在 LoC 以上的释放行为急剧下降不同,当 DL 增加到 8%时,ATZ ASD 的溶解行为逐渐下降。这是因为可能形成了 ATZ-PVPVA 关联相,其溶解速度比纯 PVPVA 慢。然而,10% DL ASD 的 ATZ 释放量可忽略不计。在另一个极端条件下(pH 值为 1),ATZ 的离子化程度为 100%,ATZ 的溶解速度比 PVPVA 快。研究发现,ASD 的溶解速度比纯药物慢,但比 PVPVA 快,有趣的是,ASD 的溶解速度并不随 DL 的变化而变化。这可能是由于形成了离子化的 ATZ-PVPVA 相,从而控制了 ASD 的溶解速率。在 pH 值为 3 时,药物离子化率为 97%,当药物负载量≤ 8%时,药物几乎完全释放。要观察到药物负载量明显增加并接近完全释放,ATZ 的电离率必须大于 98%。在 pH 值为 2 时,ATZ 的电离度为 99.7%,当药物含量达到 30%时,可观察到接近完全的释放。此外,在 pH 值为 2 时,溶解性能随着药物载量的增加而逐渐下降。我们推测,电离导致的溶解性能提高是电离 ATZ-PVPVA 相形成的结果,电离 ATZ-PVPVA 相增加了 ASD 的亲水性和混溶性。这有助于在 ASD 溶解过程中抵制水引起的相分离,从而实现药物和聚合物的连续一致溶解。
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引用次数: 0
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Journal of pharmaceutical sciences
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