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Insights into pharmaceutical co-crystallization using coherent Raman microscopy. 利用相干拉曼显微镜深入了解药物共结晶。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-02 DOI: 10.1016/j.xphs.2024.10.054
Alba M Arbiol Enguita, Elina Harju, Lea Wurr, Teemu Tomberg, Oona Auvinen, Leena Peltonen, Clare Strachan, Jukka Saarinen

Formulating active pharmaceutical ingredients (APIs) as co-crystals requires a thorough understanding of co-crystallization behavior under different process conditions. This study employs two forms of coherent Raman microscopy, narrowband coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS) with spectral focusing, to study co-crystallization via liquid-assisted ball milling. Indomethacin and nicotinamide served as the model API and co-former, and the results were compared with established analytical methods. Narrowband CARS, with univariate peak position analysis, was useful to visualize co-crystal formation, but suffered some degree of signal mixing that affected component identification. Hyperspectral SRS imaging, combined with classical least squares multivariate analysis, separated the different components with high confidence and proved to be a robust and rapid tool to qualitatively and quantitatively image co-crystallization. The coherent Raman imaging results explained divergent co-crystallization endpoints obtained with the conventional solid-state analysis methods. CARS and SRS microscopies also revealed the presence of otherwise undetected trace forms. Finally, we also demonstrated the dramatic reversal of partial co-crystal formation during milling, depending on ethanol content. Overall, the study demonstrates the added value coherent Raman microscopy can provide for analysis of co-crystallization processes.

将活性药物成分(API)配制成共晶需要全面了解不同工艺条件下的共晶行为。本研究采用窄带相干反斯托克斯拉曼散射(CARS)和带光谱聚焦的受激拉曼散射(SRS)这两种相干拉曼显微镜形式来研究通过液体辅助球磨进行的共结晶。吲哚美辛和烟酰胺分别作为模型原料药和共成体,研究结果与已有的分析方法进行了比较。采用单变量峰位分析的窄带 CARS 有助于观察共晶体的形成,但存在一定程度的信号混合,影响了成分的识别。高光谱 SRS 成像与经典的最小二乘法多元分析相结合,以较高的置信度分离出了不同的成分,并证明是定性和定量成像共晶体的可靠而快速的工具。相干拉曼成像结果解释了传统固态分析方法得出的不同共晶终点。CARS 和 SRS 显微镜还揭示了原本未检测到的痕量形式的存在。最后,我们还展示了研磨过程中部分共晶体形成的急剧逆转,这取决于乙醇含量。总之,这项研究证明了相干拉曼显微镜在分析共晶体形成过程中所能提供的附加价值。
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引用次数: 0
A Survey of Solid Form Landscape: Trends in Occurrence and Distribution of Various Solid Forms and Challenges in Solid Form Selection. 固体形式现状调查:各种固体形态的出现和分布趋势以及固体形态选择方面的挑战。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-02 DOI: 10.1016/j.xphs.2024.10.045
Z Jane Li, Yue Lu, Ruiping Wang, Xiaomei Dong, Pengyuan Chen, Jie Duan, Meiting Shi, Liyu Wang, Yuan Liu

This survey provides a comprehensive analysis of solid form screens for 476 new chemical entities (NCEs) conducted at Pharmaron from 2016 to 2023. The findings from this survey reveal notable trends in polymorphism, salt formation, crystallization behavior and molecular weight (MW) distribution of the NCEs evaluated. Most solid form screens were conducted to select the preferred solid form for Investigational New Drug (IND) enabling projects, others were for candidate selection or late-stage development. Comparison to published historical data was made to show changes in occurrence of counterions/co-formers for salts/co-crystals, polymorphs, and the distribution of MWs over time. Increased complexity in the solid-form landscape and selection of the development form are discussed, including challenges in crystallization and selection of lead forms. The distribution of types of crystal forms and the observation of emerging and disappearing polymorphs are presented. These results highlight the evolving challenges and considerations in solid form screening and form selection and offer insights for future pharmaceutical development and crystallization strategies.

本调查全面分析了Pharmaron从2016年到2023年对476种新化学实体(NCE)进行的固型筛选。调查结果揭示了所评估的新化学实体在多态性、成盐性、结晶行为和分子量(MW)分布方面的显著趋势。大多数固态筛选是为新药研究 (IND) 启动项目选择首选固态,其他则用于候选药物选择或后期开发。通过与已公布的历史数据进行比较,可以看出随着时间的推移,盐类/共晶体、多晶型的反离子/共形物发生的变化以及截留分子量的分布。讨论了固态形式的复杂性增加和开发形式的选择,包括结晶和铅形式选择方面的挑战。介绍了晶体形态类型的分布以及对新出现和消失的多晶型的观察。这些结果突显了在固态形式筛选和形式选择方面不断变化的挑战和考虑因素,并为未来的药物开发和结晶策略提供了启示。
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引用次数: 0
β-Cyclodextrin Derivatives Bind Aromatic Side Chains of the Cyclic Peptide Lanreotide. β-环糊精衍生物结合环肽兰瑞奥肽的芳香族侧链
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-02 DOI: 10.1016/j.xphs.2024.10.042
Negar Jafari, Justin T Douglas, Sarah A Neuenswander, Payam Kelich, Michael J Hageman

Cyclodextrin complexation has a potential to modulate the physicochemical properties of peptide drugs. The ability of peptides to form an inclusion complex can be influenced by factors such as size, amino acid sequence of peptide and the size and charge of the cyclodextrin cavity. In this study, the inclusion complexes of cyclic peptide drug lanreotide acetate with two common β-cyclodextrin derivatives, Sulfobutyl ether β-CD (SBEβ-CD) and hydroxypropyl β-CD (HPβ-CD) were investigated. NMR spectroscopy was used to examine the interaction between β-cyclodextrin derivatives and specific residues of lanreotide. It was observed that the hydrophobic side chain of aromatic residues in the lanreotide sequence can be fit into the cavity of both β-cyclodextrin derivatives. Additionally, NMR revealed a lower diffusion coefficient and higher hydrodynamic radius of complex, indicative of binding to the cavities. Each aromatic residue was individually studied by substituting alanine in lanreotide to measure its association binding with both β-cyclodextrin derivatives. The alanine-substitute study indicated a stronger binding of SBEβ-CD to Lanreotide compared to HPβ-CD. Docking studies suggested that the 1:1 inclusion complex is more favorable than higher order complexes due to the steric hindrance and size considerations. The docking analysis indicated the stable conformation of all three aromatic side chains with both β-cyclodextrin derivatives, SBEβ-CDand HPβ-CD.

环糊精复合物具有调节多肽药物理化性质的潜力。肽形成包合物的能力受多种因素的影响,如肽的大小、氨基酸序列以及环糊精空腔的大小和电荷。本研究考察了环肽药物醋酸兰瑞奥肽与两种常见的β-环糊精衍生物--磺丁醚β-CD(SBEβ-CD)和羟丙基β-CD(HPβ-CD)的包合复合物。核磁共振光谱用于研究β-环糊精衍生物与兰瑞奥肽特定残基之间的相互作用。结果表明,兰瑞奥肽序列中芳香残基的疏水侧链可与两种 β-环糊精衍生物的空腔相匹配。此外,核磁共振显示,复合物的扩散系数较低,流体力学半径较大,表明与空腔结合。通过取代兰瑞奥肽中的丙氨酸,对每个芳香族残基进行了单独研究,以测量其与β-环糊精衍生物的结合情况。丙氨酸替代物研究表明,与 HPβ-CD 相比,SBEβ-CD 与兰瑞奥肽的结合力更强。对接研究表明,由于立体阻碍和尺寸因素,1:1 包合复合物比高阶复合物更有利。对接分析表明,所有三个芳香族侧链都与β-环糊精衍生物 SBEβ-CD 和 HPβ-CD 形成了稳定的构象。
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引用次数: 0
Impact of Surfactants on Solution Behavior and Membrane Transport of Amorphous Solid Dispersions. 表面活性剂对无定形固体分散体的溶液行为和膜传输的影响
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-02 DOI: 10.1016/j.xphs.2024.10.023
Amjad Alhalaweh, Mira El Sayed, Lucia Kovac, Christel A S Bergström

The purpose of the study was to develop an amorphous solid dispersion (ASD) of a poorly soluble compound (AK100) and investigate the impact of different surfactants on its dissolution, supersaturation and membrane transport. The solubility of the AK100 was determined in crystalline and amorphous form in the absence and presence of three surfactants at different concentrations: sodium dodecyl sulphate (SDS), polysorbate 80 (PS80) and D-α-tocopherol polyethylene glycol succinate (TPGS). The relation between solubility and surfactant solubilization was evaluated using a computational model. The ASD powder was prepared by solvent evaporation for non-sink dissolution experiments with and without the pre-dissolved surfactants. A transport study with Caco-2 cells was conducted to evaluate the impact of surfactants-based formulation on membrane transport. Both the corresponding crystalline and amorphous solubility of AK100 increased linearly as a function of the surfactant concentrations. The supersaturation was maintained for at least three hours in absence of surfactant and in presence of TPGS, whereas supersaturation declined with SDS and PS80. As expected, the membrane flux of the AK100 was higher for the ASD than for the crystalline powder, and further increased with increased concentration of TPGS. The supersaturation ratio based on the activity-based calculation from Caco-2 cells study was always higher than that of the concentration-based one for the amorphous and crystalline forms of AK100. This study shows how additional solubilizing excipients during formulation development can improve the resulting dissolution and phase behavior of supersaturated drug solution.

本研究的目的是开发一种难溶性化合物(AK100)的无定形固体分散体(ASD),并研究不同表面活性剂对其溶解、过饱和及膜传输的影响。在没有和有三种不同浓度的表面活性剂(十二烷基硫酸钠(SDS)、聚山梨醇酯 80(PS80)和 D-α-生育酚聚乙二醇琥珀酸酯(TPGS))的情况下,测定了 AK100 的晶体和无定形溶解度。利用计算模型评估了溶解度与表面活性剂溶解度之间的关系。通过溶剂蒸发法制备了 ASD 粉末,进行了含有和不含预溶解表面活性剂的非沉降溶解实验。用 Caco-2 细胞进行了运输研究,以评估基于表面活性剂的配方对膜运输的影响。随着表面活性剂浓度的增加,AK100 的相应结晶溶解度和无定形溶解度均呈线性增加。在无表面活性剂和有 TPGS 的情况下,过饱和度至少能维持三小时,而在有 SDS 和 PS80 的情况下,过饱和度会下降。正如预期的那样,ASD 的 AK100 膜通量高于结晶粉末,并且随着 TPGS 浓度的增加而进一步提高。对于无定形和结晶形式的 AK100,根据 Caco-2 细胞研究中基于活性的计算得出的过饱和度比始终高于基于浓度的计算得出的过饱和度比。这项研究表明,在制剂开发过程中添加增溶辅料可以改善过饱和药物溶液的溶解和相行为。
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引用次数: 0
Progressive Amyloid-β Accumulation in the Brain leads to Altered Protein Expressions in the Liver and Kidneys of APP knock-in Mice. 大脑中淀粉样蛋白-β的逐渐积累导致 APP 基因敲入小鼠肝脏和肾脏中蛋白质表达的改变
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.10.051
Shingo Ito, Yumi Iwata, Mitsumi Otsuka, Yui Kaneko, Seiryo Ogata, Ryotaro Yagi, Tatsuki Uemura, Takeshi Masuda, Takashi Saito, Takaomi Saido, Sumio Ohtsuki

Impaired hepatic and renal function influence Alzheimer's disease (AD) progression; however, whether AD progression affects these important organ functions remains unclear. Here, we investigated the impact of AD progression, characterized by brain amyloid-beta (Aβ) accumulation, on liver and kidney function of AppNL-G-F/NL-G-F (APP-KI) mice using quantitative proteomics. SWATH-based quantitative proteomics revealed changes in mitochondrial, drug metabolism, and pharmacokinetic-related proteins in mouse liver and kidneys during the early (2-month-old) and intermediate (5-month-old) stages of Aβ accumulation. Notably, in 5-month-old APP-KI mouse liver, 25 phase I/II metabolizing enzymes (8 CYPs, 7 UGTs, 7 CESs, and 3 SLCs) and five transporters (2 ABCs and 3 SLCs) were significantly altered; specifically, Ugt1a9 and Slc33a1 protein abundances increased, whereas Ugt1a1 and Abcc3 protein abundances decreased. In the kidneys, 13 phase I/II metabolizing enzymes and 10 ABC-SLC transporters were altered, including Ugt1a6, Ugt1a7, Slc22a7, and Abcb1a. Additionally, plasma proteins, such as albumin and alpha-1-acid glycoprotein, which are critical for drug binding and distribution, were also altered. These results underscore the significant role of progressive brain Aβ accumulation in modifying hepatic and renal protein abundances, potentially influencing drug metabolism and disposition in AD. Our findings provide novel insights into the complex relationship between AD progression and organ dysfunction.

肝脏和肾脏功能受损会影响阿尔茨海默病(AD)的进展;然而,AD进展是否会影响这些重要器官的功能仍不清楚。在这里,我们利用定量蛋白质组学研究了以脑淀粉样蛋白-β(Aβ)积累为特征的阿尔茨海默病进展对 AppNL-G-F/NL-G-F (APP-KI) 小鼠肝肾功能的影响。基于SWATH的定量蛋白质组学发现,在Aβ积累的早期(2月龄)和中期(5月龄)阶段,小鼠肝脏和肾脏中的线粒体、药物代谢和药代动力学相关蛋白质发生了变化。值得注意的是,在5月龄APP-KI小鼠肝脏中,25种I/II期代谢酶(8种CYPs、7种UGTs、7种CESs和3种SLCs)和5种转运体(2种ABCs和3种SLCs)发生了显著变化;具体而言,Ugt1a9和Slc33a1蛋白丰度增加,而Ugt1a1和Abcc3蛋白丰度降低。在肾脏中,13 种 I/II 期代谢酶和 10 种 ABC-SLC 转运体发生了改变,包括 Ugt1a6、Ugt1a7、Slc22a7 和 Abcb1a。此外,白蛋白和α-1-酸性糖蛋白等对药物结合和分布至关重要的血浆蛋白也发生了改变。这些结果表明,大脑中Aβ的逐渐积累在改变肝脏和肾脏蛋白质丰度方面起着重要作用,可能会影响AD患者的药物代谢和处置。我们的研究结果为了解AD进展与器官功能障碍之间的复杂关系提供了新的视角。
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引用次数: 0
Bioavailability Improvement by Atomic Layer Coating: Fenofibrate A Case Study. 通过原子层涂层提高生物利用率:非诺贝特案例研究
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.10.052
Balaji Ganapathy, Vijayendra Redasani, Sujit Debnath, Neha Gupta, Ankur Kadam, Fei Wang, Pravin Narwankar

Biopharmaceutical Classification Systems (BCS) class II drugs show poor solubility and high permeability in the body. Fenofibrate (FF) is a classic example of a BCS class II drug, used to treat high cholesterol and triglyceride (fat-like substances) levels in the blood. Atomic layer coating (ALC) is a surface engineering technology adapted from the semiconductor industry, where metal oxides are coated one atomic layer at a time over the active pharmaceutical ingredients (API) particles. ALC coating was proven to improve the processability, alter the hydrophilicity, improve the stability, and fine-tune the release of drugs. Herein, we report the intervention of ALC coating in enhancing the bioavailability of a poorly water-soluble drug (fenofibrate) in the animal model. The physical properties of uncoated fenofibrate were compared with those of zinc oxide-coated and silicon oxide-coated fenofibrate. Following the application of the coatings, the structural integrity (both chemical stability and solid-state stability) of the active pharmaceutical ingredient (API) remained uncompromised, as corroborated by 1H NMR and powder X-ray diffraction analyses. Notably, zinc oxide-coated fenofibrate exhibited favorable flow characteristics, whereas no discernible enhancement in flow behavior was observed for silicon oxide-coated fenofibrate. The results from contact angle measurements suggest that the silicon oxide-coated fenofibrate exhibits superior wetting behavior, as indicated by a contact angle nearing 0°. The application of ALC demonstrates an enhanced dissolution rate when compared to the uncoated active pharmaceutical ingredient (API) while leaving its equilibrium solubility unaffected. Coating the API with silicon oxide improves particle hydrophilicity and wetting properties, whereas zinc oxide coating aids in particle de-agglomeration, thereby enhancing their interaction with an aqueous medium. In vivo bioavailability studies conducted on rodents and larger animal (dog) models indicate a substantial increase in bioavailability (approximately 2 times) for the silicon oxide-coated API in comparison to the uncoated API, as determined by the area under the curve (AUC). Furthermore, the Cmax values for the silicon oxide-coated API also demonstrate a significant increase (approximately 3 times) over the uncoated API. Notably, an oral subacute toxicity study of ALC silicon-coated fenofibrate revealed no toxic effects attributable to the coating. This study underscores the potential of ALC in augmenting the bioavailability of BCS(II) drugs.

生物制药分类系统(BCS)II 类药物在体内的溶解性差,渗透性高。非诺贝特(Fenofibrate,FF)是 BCS II 类药物的典型代表,用于治疗血液中胆固醇和甘油三酯(类脂肪物质)水平过高。原子层包衣(ALC)是从半导体工业发展而来的一种表面工程技术,即在活性药物成分(API)颗粒上一次包覆一层金属氧化物。事实证明,ALC 涂层能改善加工性能、改变亲水性、提高稳定性并微调药物的释放。在此,我们报告了 ALC 包衣对提高水溶性差的药物(非诺贝特)在动物模型中的生物利用度的干预。我们比较了未包衣非诺贝特与氧化锌包衣和氧化硅包衣非诺贝特的物理性质。经 1H NMR 和粉末 X 射线衍射分析证实,涂覆涂层后,活性药物成分(API)的结构完整性(化学稳定性和固态稳定性)仍未受到影响。值得注意的是,氧化锌包衣的非诺贝特具有良好的流动特性,而氧化硅包衣的非诺贝特则没有明显的流动性增强。接触角测量结果表明,氧化硅包覆的非诺贝特具有优异的润湿性,接触角接近 0°。与未涂层的活性药物成分(API)相比,ALC 的应用提高了溶解速率,同时其平衡溶解度不受影响。在原料药上涂覆氧化硅可提高颗粒的亲水性和润湿性,而涂覆氧化锌则有助于颗粒的去团聚,从而增强它们与水介质的相互作用。在啮齿动物和大型动物(狗)模型上进行的体内生物利用度研究表明,根据曲线下面积(AUC)测定,与未包衣的原料药相比,包衣氧化硅的原料药的生物利用度大幅提高(约 2 倍)。此外,氧化硅包衣原料药的 Cmax 值也比未包衣原料药显著增加(约 3 倍)。值得注意的是,对 ALC 硅涂层非诺贝特进行的口服亚急性毒性研究表明,涂层不会产生任何毒性反应。这项研究强调了 ALC 在提高 BCS(II)药物生物利用度方面的潜力。
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引用次数: 0
Vehicle Effect on In-Vitro and In-Vivo Performance of Spray Dry Dispersions. 载体对喷雾干燥分散体体外和体内性能的影响
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-30 DOI: 10.1016/j.xphs.2024.10.043
Marika Nespi, Justin Ly, Yuchen Fan, Shu Chen, Liling Liu, Yimin Gu, Steven Castleberry

In early drug development, amorphous spray-dried dispersions (SDDs) applied to enhance the bioavailability of poorly water-soluble compounds are typically administered to preclinical species via oral gavage in the form of suspensions. The liquid formulations are usually prepared on the same day of dosing to minimize the exposure of the amorphous material to the aqueous vehicle, thereby reducing the risk of crystallization. Dose-ability (e.g. syringeability) of the suspensions is also a critical factor for the administration, particularly when high doses, thus concentrations, are required for toxicology studies. As a result, it is standard practice during early formulation screening to assess the stability and the maximum feasible concentration of SDDs in various vehicles. In this study, we evaluated the impact of different vehicles on the performance of a model SDD in in-vitro and in-vivo settings, to mitigate the risks associated with its administration in liquid form. A poorly water-soluble compound (GEN-A) was selected to screen various SDDs and generate the SDD model at 30% drug load with HPMCAS-MF polymer carrier. The SDD was suspended in selected aqueous vehicles after a careful vehicle components screening, that included suspending agents (HPC-SL), solubilizers (PEG400, Propylene glycol), surfactants (Vitamin E TPGS, SLS, Tween 80, Poloxamer 188), and complexing agents (HP-ꞵ-CD, SBE-ꞵ-CD). The suspensions were characterized for stability, dose-ability and dissolution in biorelevant media, prior administration in pre-clinical species. The SDD dissolution profile revealed that the drug's supersaturation level was positively impacted by the presence of a surfactant (SLS) and a complexing agent (SBE-ꞵ-CD) with respect to a suspending agents (HPC-SL) in the vehicle. Similarly, the pharmacokinetics profiles of the drug following the administration of the SDD in a vehicle with a complexing agent (SBE-ꞵ-CD) achieved greater exposure compare to the SDD in a vehicle with a suspending agent (HPC-SL). These findings confirm a synergistic effect between the SDD and the vehicles, suggesting that this combination could be leveraged to maximize the advantages of the amorphous approach.

在早期药物开发过程中,用于提高水溶性差的化合物生物利用度的无定形喷雾干燥分散体(SDDs)通常以悬浮液的形式通过口服给临床前物种用药。液体制剂通常在给药当天制备,以尽量减少无定形物质与水性载体的接触,从而降低结晶风险。悬浮液的剂量适应性(如注射器适应性)也是给药的一个关键因素,尤其是在毒理学研究需要高剂量、高浓度的情况下。因此,早期制剂筛选的标准做法是评估 SDD 在各种载体中的稳定性和最大可行浓度。在本研究中,我们评估了不同载体在体外和体内环境中对模型 SDD 性能的影响,以降低以液体形式给药带来的风险。我们选择了一种水溶性较差的化合物(GEN-A)来筛选各种 SDD,并使用 HPMCAS-MF 聚合物载体生成了药物载量为 30% 的 SDD 模型。经过仔细筛选载体成分,包括悬浮剂(HPC-SL)、增溶剂(PEG400、丙二醇)、表面活性剂(维生素 E TPGS、SLS、吐温 80、Poloxamer 188)和络合剂(HP-ꞵ-CD、SBE-ꞵ-CD),将 SDD 悬浮于选定的水性载体中。在临床前物种用药前,对悬浮剂在生物相关介质中的稳定性、剂量适应性和溶解性进行了表征。SDD 溶解曲线显示,相对于载体中的悬浮剂(HPC-SL),表面活性剂(SLS)和络合剂(SBE-ꞵ-CD)的存在对药物的过饱和水平有积极影响。同样,与含有悬浮剂(HPC-SL)的载体中的 SDD 相比,在含有络合剂(SBE-ꞵ-CD)的载体中的 SDD 给药后,药物的药代动力学特征达到了更高的暴露量。这些发现证实了 SDD 与载体之间的协同效应,表明可以利用这种组合来最大限度地发挥非晶体方法的优势。
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引用次数: 0
Dissolution profiles of high-dose salt-form drugs in bicarbonate buffer and phosphate buffer. 高剂量盐形式药物在碳酸氢盐缓冲液和磷酸盐缓冲液中的溶解曲线。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-30 DOI: 10.1016/j.xphs.2024.10.025
Yuki Tarumi, Kiyohiko Sugano

The purpose of the present study was to compare the dissolution profiles of high-dose salt-form drugs in bicarbonate buffer (BCB) and phosphate buffer (PPB) focusing on the pH changes in the bulk phase. The pH titration curves of BCB and PPB (pH 6.5, buffer capacity (β) = 4.4 mmol/L/pH unit) were first theoretically calculated and experimentally validated. For dissolution tests, six drug salts with an acid counterion, one drug salt with a weak base counterion, and one free acid drug were employed (125 to 800 mg clinical dose). The dose/fluid volume ratio (Dose/FV) was aligned with the clinical condition. In the pH titration study, the pH value decreased below pH 6.0 by adding HCl > 2.8 mmol/L (BCB) or > 1.6 mmol/L (PPB) and increased above pH 7.0 by adding NaOH > 2.0 mmol/L (BCB) or > 2.4 mmol/L (PPB). In the dissolution test, even though the initial pH and β values were the same, the pH value at 4 h was lower in PPB than in BCB in all cases. For the drug salts with an acid counterion, the area under the dissolution curve was 1.2 to 2.6-fold lower in BCB than in PPB. A marked precipitation process was observed in BCB, but less pronounced or absent in PPB. The results of this study suggest the use of BCB and a clinically equivalent Dose/FV may be valuable in predicting the oral absorption of high-dose drug salts.

本研究的目的是比较大剂量盐形式药物在碳酸氢盐缓冲液(BCB)和磷酸盐缓冲液(PPB)中的溶出曲线,重点关注体相中的 pH 值变化。首先对 BCB 和 PPB(pH 值为 6.5,缓冲能力 (β) = 4.4 mmol/L/pH 单位)的 pH 滴定曲线进行了理论计算和实验验证。溶解试验采用了六种含酸性反离子的药物盐、一种含弱碱反离子的药物盐和一种游离酸性药物(临床剂量为 125 至 800 毫克)。剂量/液体体积比(Dose/FV)与临床情况一致。在 pH 滴定研究中,加入 HCl > 2.8 mmol/L(BCB)或 > 1.6 mmol/L(PPB)时,pH 值下降至 pH 6.0 以下;加入 NaOH > 2.0 mmol/L(BCB)或 > 2.4 mmol/L(PPB)时,pH 值上升至 pH 7.0 以上。在溶解试验中,尽管初始 pH 值和 β 值相同,但在所有情况下,PPB 在 4 小时后的 pH 值均低于 BCB。对于含有酸性反离子的药物盐,BCB 的溶解曲线下面积比 PPB 低 1.2 至 2.6 倍。在 BCB 中观察到明显的沉淀过程,而在 PPB 中则不明显或没有沉淀。本研究结果表明,使用 BCB 和临床等效剂量/FV 可能对预测大剂量药物盐的口服吸收很有价值。
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引用次数: 0
Impact of sink conditions on drug release behavior of controlled-release formulations. 水槽条件对控释制剂药物释放行为的影响
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-29 DOI: 10.1016/j.xphs.2024.10.032
Siddhi S Hate, Stephen A Thompson, Aditya B Singaraju

Developing a controlled release (CR) formulations is a complex and iterative process, often requiring preclinical or clinical studies to establish in vitro-in vivo correlations. This can be particularly challenging for poorly soluble drugs due to the non-sink conditions encountered in vitro. Although compendial dissolution methods (e.g., USP II, IV) have historically been used to understand the dissolution performance of CR formulations, there is increasing interest in more physiologically relevant experimental techniques to improve the predictive ability. In this study, traditional USP apparatus as well as the biorelevant absorptive dissolution apparatus were employed to understand the impact of apparatus type and sink condition on the release mechanisms of CR formulations and in turn evaluate the application of absorptive dissolution apparatus for dissolution testing of CR formulations. Release mechanisms were further analyzed using the Peppas equations, providing additional mechanistic insights. The release behavior showed a strong dependence on sink conditions for drugs with low intrinsic solubility, while highly soluble drugs were unaffected by dissolution conditions. Interestingly, the dissolution mechanism was found to be independent of the apparatus type. The study clearly underscores the importance of considering the sink conditions in developing more predictive and biorelevant dissolution testing methods for CR formulations. Furthermore, the study highlights the potential impact on the sink and resultant differences in the drug release mechanisms as a function of the dose.

开发控释(CR)制剂是一个复杂而反复的过程,通常需要进行临床前或临床研究,以建立体外-体内相关性。由于在体外遇到的非沉降条件,这对于溶解性差的药物来说尤其具有挑战性。虽然药典溶出度方法(如 USP II、IV)历来被用于了解 CR 制剂的溶出性能,但人们对更贴近生理的实验技术越来越感兴趣,以提高预测能力。本研究采用了传统的 USP 仪器和生物相关的吸收性溶出仪,以了解仪器类型和水槽条件对 CR 制剂释放机制的影响,进而评估吸收性溶出仪在 CR 制剂溶出测试中的应用。使用 Peppas 方程进一步分析了释放机理,从而提供了更多的机理见解。对于固有溶解度低的药物,其释放行为显示出对溶沉条件的强烈依赖性,而高溶解度药物则不受溶解条件的影响。有趣的是,研究发现溶解机制与仪器类型无关。这项研究明确强调了在开发更具预测性和生物相关性的 CR 制剂溶出测试方法时考虑沉降条件的重要性。此外,该研究还强调了沉降条件的潜在影响以及由此导致的药物释放机制随剂量变化而产生的差异。
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引用次数: 0
ω-Carboxyl Terminated Cellulose Esters are Effective Crystallization Inhibitors for Challenging Drugs. ω-羧基端基纤维素酯是挑战性药物的有效结晶抑制剂
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-29 DOI: 10.1016/j.xphs.2024.10.034
Stella Petrova, Chengzhe Gao, Tze Ning Hiew, Kevin J Edgar, Lynne S Taylor

Polymeric additives are widely used to delay drug crystallization from supersaturated solutions, which is critical for enhancing oral bioavailability by amorphous solid dispersion (ASD). The efficacy of these polymers relies on their capacity to inhibit nucleation and subsequent crystal growth. Drug nucleation is pivotal to crystallization; therefore, effective polymers are essential for suppressing nucleation from supersaturated solutions. We studied the performance of cellulose ω-carboxyalkanoates designed as crystallization inhibitors by measuring their influence on nucleation induction times of poorly soluble drugs celecoxib, posaconazole, and enzalutamide, from supersaturated solutions. In the absence of polymers, crystallization occurred within 5 to 15 minutes for all three drugs. Polymer hydrophobicity strongly influenced effectiveness in crystallization inhibition. Hydrophobic polymers prolonged induction times for up to 8 hours, while hydrophilic polymers were less effective, except for cellulose acetate glutarate (CA1.18-GA1.21; degrees of substitution acetate 1.18, glutarate 1.21). The cellulose ω-carboxyalkanoates had glass transition temperatures well above 100 °C, outstanding for ASD stability requirements. We investigated the impact of these designed polymers on surface tension and found that it only weakly influenced crystallization inhibition. Among the nine crafted cellulose derivatives, water-soluble CA1.18-GA1.21 emerged as a highly promising ASD polymer, preventing crystallization for 2-8 hours for all fast-crystallizing model compounds.

聚合物添加剂被广泛用于延迟药物从过饱和溶液中结晶,这对于通过无定形固体分散体(ASD)提高口服生物利用度至关重要。这些聚合物的功效取决于其抑制成核和随后晶体生长的能力。药物成核是结晶的关键;因此,有效的聚合物对于抑制过饱和溶液的成核至关重要。我们通过测量纤维素ω-羧基烷酸盐对过饱和溶液中难溶药物塞来昔布、泊沙康唑和恩扎鲁胺成核诱导时间的影响,研究了纤维素ω-羧基烷酸盐作为结晶抑制剂的性能。在没有聚合物的情况下,这三种药物都能在 5 到 15 分钟内结晶。聚合物的疏水性对结晶抑制效果有很大影响。疏水性聚合物可延长诱导时间长达 8 小时,而亲水性聚合物的效果较差,但醋酸纤维素戊二酸盐(CA1.18-GA1.21;取代度醋酸纤维素 1.18,戊二酸纤维素 1.21)除外。ω-羧基烷酸纤维素的玻璃化转变温度远高于 100 °C,非常适合 ASD 的稳定性要求。我们研究了这些设计聚合物对表面张力的影响,发现其对结晶抑制的影响很弱。在九种精心制作的纤维素衍生物中,水溶性 CA1.18-GA1.21 是一种非常有前途的 ASD 聚合物,它能在 2-8 小时内阻止所有快速结晶模型化合物的结晶。
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引用次数: 0
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Journal of pharmaceutical sciences
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