Journal of pharmaceutical sciences最新文献_第9页

Efflux and uptake of androgen sulfates using transporter-overexpressing HEK293 cells and membrane vesicles 转运蛋白过表达HEK293细胞和膜泡对硫酸雄激素的外排和摄取

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103705

Arttu Uoti , Erkka Järvinen , Noora Sjöstedt , Jan Koenderink , Moshe Finel , Heidi Kidron

Hydrophilic steroid conjugates require active and facilitated transport mechanisms for their distribution into tissues and excretion from the body. The ATP-binding cassette (ABC) and solute carrier organic anion (SLCO) transporters involved in androgen sulfate (-S) disposition have been poorly characterized. In this study, we investigated the in vitro transport of testosterone-S, epitestosterone-S, dehydroepiandrosterone-S (DHEA-S), androsterone-S, and etiocholanolone-S by the multidrug resistance-associated proteins 2–4 (MRP2–4, ABCC2–4), breast cancer resistance protein (BCRP, ABCG2), and organic anion-transporting polypeptides (OATP) 1B1, 1B3, and 2B1 (SLCO1B1, SLCO1B3, and SLCO2B1) using human transporter-overexpressing HEK293 cells and membrane vesicles. We found testosterone-S, epitestosterone-S, and DHEA-S to be selectively transported by BCRP and/or MRP4, whereas all studied androgen sulfates were substrates of MRP3, OATP1B1, OATP1B3, and OATP2B1. MRP2 did not transport any of the studied compounds. Evaluation of transport kinetics revealed MRP4 to interact with its substrates at high to moderate affinity, whereas the observed affinities towards MRP3, BCRP, and OATPs were mostly moderate. These results help to build a better mechanistic understanding of the disposition of androgen sulfates in the human body. Additionally, this data may be used to assess the feasibility of androgen sulfates as additional biomarkers in doping detection.

亲水性类固醇偶联物需要积极和便利的运输机制来分布到组织和从体内排泄。atp结合盒（ABC）和溶质载体有机阴离子（SLCO）转运体参与硫酸雄激素（-S）处置的表征很差。在这项研究中，我们研究了在体外通过多药耐药相关蛋白2-4 （MRP2-4、ABCC2-4）、乳腺癌耐药蛋白（BCRP、ABCG2）和有机阴离子转运多肽（OATP） 1B1、1B3和2B1 （SLCO1B1、SLCO1B3和SLCO2B1）在人转运蛋白HEK293细胞和膜泡中转运睾酮- s、表甾酮- s、脱氢表雄酮- s （DHEA-S）、雄酮- s和etiochololone - s的情况。我们发现睾酮- s、表甾酮- s和脱氢表雄酮- s可被BCRP和/或MRP4选择性转运，而所有研究的雄激素硫酸盐都是MRP3、OATP1B1、OATP1B3和OATP2B1的底物。MRP2不转运任何被研究的化合物。转运动力学的评估显示，MRP4与底物的相互作用具有高至中等的亲和力，而对MRP3、BCRP和oatp的亲和力大多为中等。这些结果有助于更好地了解硫酸雄激素在人体内的作用机制。此外，该数据可用于评估雄激素硫酸盐作为兴奋剂检测中额外生物标志物的可行性。

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引用次数: 0

Corrigendum to “Understanding the conditions under which drugs are transferred from the stomach through the upper small intestine after a high-calorie, high-fat meal” [Journal of Pharmaceutical Sciences/ Volume 113, Issue 6, June 2024, Pages 1546-1554] 《了解高热量、高脂肪膳食后药物从胃通过上小肠转移的条件》的勘误表《药物科学杂志》/第113卷，第6期，2024年6月，第1546-1554页。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103939

Shirin Dietrich , Jens Ceulemans , Eline Hermans , Theodoros Argyropoulos , Konstantinos Goumas , Maria Vertzoni , Christos Reppas

引用次数: 0

Octenyl succinic anhydride-modified starches as emulsifier agents: A comparative study emphasizing stability, rheology, and emulsion´s microstructure 辛烯基丁二酸酐改性淀粉作为乳化剂：强调稳定性、流变性和乳液微观结构的比较研究。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103902

Carolina P. Mora , Oscar O. Melo Martínez , Rodolfo Pinal , Claudia E. Mora-Huertas

New alternatives for emulsification are a relevant topic of pharmaceutical research due to the safety concerns of certain materials and the interest in achieving environmentally friendly products. In this sense, this work investigates the performance of five waxy corn starches modified with octenyl succinic anhydride (Hi-Cap® 100, Purity Gum® 2000, Capsul®, N-Creamer® 46, and Purity Gum® Ultra) as emulsifiers, employing caprylic/capric triglyceride as the oily phase and water as the aqueous phase. The type of modified starch influences the droplet size and rheological behavior of emulsions. The systems prepared with N-Creamer® 46 and Purity Gum® Ultra allow the most stable emulsions for 180 days at ∼20 and 40°C ± 0.1°C. The other starches evaluated do not favor the emulsions´ stability, probably due to their lower values of molecular weight, z-average radius of gyration, and dispersed molecular density. Interestingly, the study of the emulsions´ microstructure provides evidence of a three-dimensional starch network around the oil droplets, suggesting the steric effect as the primary mechanism of stabilization when these biopolymers are used. ζ-Potential measurements and the test of electrolyte-induced aggregation corroborate this. These findings contribute to the understanding of how emulsions are stabilized by hydrophobically modified starches, a subject of paramount importance for developing innovative pharmaceutical products.

由于某些材料的安全性问题和对实现环境友好产品的兴趣，乳化的新替代品是制药研究的一个相关主题。在这个意义上，本工作研究了用辛烯基琥珀酸酐（Hi-Cap®100,Purity Gum®2000,Capsul®，N-Creamer®46和Purity Gum®Ultra）作为乳化剂的五种糯玉米淀粉的性能，以癸酸/癸酸甘油三酯为油相，水为水相。变性淀粉的种类影响乳液的液滴大小和流变行为。用N-Creamer®46和Purity Gum®Ultra制备的体系在~ 20和40°C±0.1°C下可保持最稳定的乳剂180天。其他淀粉对乳剂的稳定性不利，可能是由于它们的分子量、z平均旋转半径和分散的分子密度较低。有趣的是，对乳剂微观结构的研究提供了油滴周围三维淀粉网络的证据，表明当使用这些生物聚合物时，立体效应是稳定的主要机制。ζ-电位测量和电解质诱导聚集的测试证实了这一点。这些发现有助于理解疏水改性淀粉如何稳定乳剂，这是开发创新药品的一个至关重要的主题。

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引用次数: 0

Revealing slip behavior in organic molecular crystals: AFM nanoindentation of acetaminophen 揭示有机分子晶体中的滑移行为：对乙酰氨基酚的AFM纳米压痕。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103972

Yuanyuan Jing , John E. Blendell , M. Teresa Carvajal

Molecular crystals are subjected to mechanical stress that can alter their slip planes which are structural features that play a critical role in governing mechanical behaviors such as milling, that requires fundamental insight for the successful manufacturing and performance of solid oral dosage forms. Milling is a critical unit operation in the manufacturing of pharmaceutical dosage forms. During this process, slip planes may become disrupted and dislocations can form, potentially inducing plastic deformation and significantly altering the physicochemical properties of active pharmaceutical ingredients (API). While slip, a dominant mechanism of plasticity, is well characterized in inorganic crystals, its behavior in organic molecular crystals remains poorly understood due to their low symmetry and anisotropic nature. In this study, we investigate plastic deformation in a model organic crystal, acetaminophen, using atomic force microscopy (AFM) nanoindentation. Distinct pile-up patterns forming parallel facets around indentation sites were observed and systematically analyzed. These pile-ups were experimentally confirmed to align with specific crystallographic slip planes. Based on this, a geometry-based strategy was developed to automatically identify, and index slip planes from indentation pile-up features. This method may offer new insights into the deformation behavior of organic crystals and serves as a broadly applicable tool for investigating slip systems across a wide range of pharmaceutical and molecular materials.

分子晶体受到机械应力，可以改变其滑移面，滑移面是在控制机械行为（如铣削）中起关键作用的结构特征，这需要对固体口服剂型的成功制造和性能有基本的了解。碾磨是制造药物剂型的关键单元操作。在此过程中，滑移面可能会被破坏并形成位错，从而可能引起塑性变形，并显著改变活性药物成分（API）的理化性质。虽然滑移是无机晶体中塑性的主要机制，但由于其低对称性和各向异性的性质，其在有机分子晶体中的行为仍然知之甚少。在这项研究中，我们使用原子力显微镜（AFM）纳米压痕研究了模型有机晶体对乙酰氨基酚的塑性变形。观察并系统分析了在压痕部位周围形成平行面的不同堆积模式。实验证实这些堆积与特定的晶体滑移面对齐。在此基础上，提出了一种基于几何的滑动面自动识别和索引压痕堆积特征的策略。这种方法可以为研究有机晶体的变形行为提供新的见解，并作为一种广泛适用的工具，用于研究各种药物和分子材料的滑移系统。

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引用次数: 0

Crystal defects cause nitrosamine formation in ranitidine under accelerated storage conditions 雷尼替丁在加速贮存条件下晶体缺陷导致亚硝胺生成。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103960

Jianchao Xu , Nicholas John Huls , Amber S. Jannasch , Eric J. Munson

The formation of nitrosamines, a class of potent carcinogen impurities, in pharmaceutical products such as ranitidine hydrochloride (RAN) has raised significant public health concerns and led to widespread product recalls. Previous studies have shown that RAN can degrade to N-nitrosodimethylamine (NDMA) after storage at 60 °C for several days. These studies also suggested a link between the degradation rate and the crystal morphology of the RAN. This study shows that NDMA formation in RAN is primarily driven by solid-state reactive species (SSRS) introduced during pharmaceutical manufacturing processes such as crystallization, milling, and grinding. Using cryogenic milling to introduce SSRS systematically, we assessed the stability of RAN at 60 °C and 0 % RH. Our results show a clear relationship between the amount of SSRS in RAN and the amount of NDMA formed upon stability, with cryoground samples exhibiting degradation rates up to two orders of magnitude higher than unprocessed samples. Furthermore, RAN tablets prepared with increased SSRS also showed accelerated NDMA formation. This study demonstrates the importance of mitigating SSRS in pharmaceutical manufacturing by mitigating the presence of SSRS in drug substances/products.

亚硝胺是一类强致癌物质的杂质，在盐酸雷尼替丁（RAN）等医药产品中形成亚硝胺引起了重大的公共卫生关注，并导致了广泛的产品召回。先前的研究表明，RAN在60℃下储存数天后可降解为n -亚硝基二甲胺（NDMA）。这些研究还表明，降解率与RAN的晶体形态之间存在联系。这项研究表明，在RAN中NDMA的形成主要是由结晶、研磨和研磨等制药制造过程中引入的固态反应物质（SSRS）驱动的。通过低温铣削系统地引入SSRS，我们评估了RAN在60 °C和0% RH下的稳定性。我们的研究结果表明，RAN中SSRS的数量与稳定性形成的NDMA的数量之间存在明确的关系，冷冻样品的降解率比未处理样品高两个数量级。此外，增加SSRS制备的RAN片也加速了NDMA的形成。本研究证明了通过减少原料药/制剂中SSRS的存在来减少SSRS在制药生产中的重要性。

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引用次数: 0

Solubilization of poorly water-soluble drugs through partition/association equilibrium: Thermodynamic insights using isothermal titration calorimetry 通过分配/缔合平衡的水溶性差药物的增溶：使用等温滴定量热法的热力学见解。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103886

Hwee Jing Ong , Fernando Alvarez-Nunez , Rodolfo Pinal

This study investigates the thermodynamics of solubilizing poorly water-soluble drugs using a biodendrimeric solid dispersion (BDSD) platform consisting of an octenylsuccinate-modified dendrimer-like biopolymer (OS-DLB) and poloxamer 338 (PLX). Three model drugs were selected: phenytoin (PHT), griseofulvin (GSF), and ibuprofen (IBU). Isothermal titration calorimetry (ITC), an effective method for characterizing thermodynamic parameters of intermolecular interactions, was utilized. The findings revealed that solubilization of these drugs by OS-DLB is thermodynamically favorable. For IBU, the most hydrophobic model drug, the numerous weak interactions between the solutes and OS-DLB produce an enthalpic effect sufficient to counteract the strong attractive forces among water molecules, significantly enhancing the apparent solubility of IBU. For the semipolar model drugs, PHT and GSF, the interactions between the solutes and the hydrocarbon chains are not sufficient to overcome the hydrogen bonds between water molecules, resulting in minimal to moderate solubility enhancement. The presence of PLX in the formulation was found to influence the solubilizing power of OS-DLB, depending on the compatibility between the PLX-modified OS-DLB microenvironment and the hydrophobicity of the drug. The intrinsic polarity of IBU closely matches that within OS-DLB; consequently, PLX plays only a moderate role in enhancing the solubilizing capacity of OS-DLB. For PHT, the least hydrophobic model drug, the polarity shift within OS-DLB facilitated by PLX is insufficient to effect a significant solubility enhancement. The maximum potentiation effect of PLX is observed with GSF, the model drug with intermediate hydrophobicity. This effect is attributable to the increased interactions between the solutes and the hydrocarbon chains, resulting in greater enthalpic and entropic contributions.

本研究利用由辛烯基琥珀酸修饰的树状生物聚合物（OS-DLB）和poloxam338 （PLX）组成的生物枝状固体分散体（BDSD）平台研究了水溶性差药物的溶解热力学。选择3种模型药物：苯妥英（PHT）、灰黄霉素（GSF）和布洛芬（IBU）。等温滴定量热法（ITC）是表征分子间相互作用热力学参数的有效方法。研究结果表明，OS-DLB对这些药物的增溶在热力学上是有利的。对于最疏水的模型药物IBU来说，溶质与OS-DLB之间的大量弱相互作用产生了足以抵消水分子间强引力的焓效应，显著提高了IBU的表观溶解度。对于半极性模型api、PHT和GSF，溶质与烃链之间的相互作用不足以克服水分子之间的氢键，导致溶解度的增强很小到中等。配方中PLX的存在会影响OS-DLB的增溶能力，这取决于PLX修饰的OS-DLB微环境与API的疏水性之间的相容性。IBU的固有极性与OS-DLB内的极性非常接近；因此，PLX对OS-DLB增溶能力的增强作用较弱。对于PHT，疏水性最低的API模型，PLX促进OS-DLB内的极性转移不足以显著增强溶解度。在具有中等疏水性的模型原料药GSF中，PLX的增强效果最大。这种效应是由于GSF溶质与烃链之间的相互作用增加，导致焓和熵的贡献增大。

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引用次数: 0

High-amylose starch forms complexes with bioactive compounds present in the Amphipterygium adstringent ethanol extract 高直链淀粉形成复合物与生物活性化合物存在于翼翼状胬肉乙醇提取物。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103824

Luis A. Bello-Perez , Edith Agama-Acevedo , Josue Moreno-Zaragoza , Perla Osorio-Diaz , Daniel Arrieta-Baez

Plants have been used for thousands of years to treat health problems. The bioactive compounds in parts of them are associated with cures for some diseases. The protection and release of bioactive compounds (bioaccessibility) are key issues in producing a therapeutic effect. Amylose and amylopectin, starch macromolecules, produce interactions with bioactive compounds, resulting in the formation of complexes. This study aimed to analyze the bioactive compounds in the complex produced between Amphipterygium adstringens (AA, cuachalalate) extract and high-amylose starch. Both the extract and the complex were analyzed by ultra-high-resolution liquid chromatography. AA extract showed compounds associated with antioxidant, anti-inflammatory, antibiotic, and anti-tumoral effects. The complex showed reduced compounds in the extract, and some compounds were not complexed with starch. The bioactive compounds present in the extract of medicinal plants can be complexed with amylose for their protection when ingested orally.

几千年来，植物一直被用来治疗健康问题。其中部分的生物活性化合物与某些疾病的治疗有关。生物活性化合物的保护和释放（生物可及性）是产生治疗效果的关键问题。淀粉大分子直链淀粉和支链淀粉与生物活性化合物相互作用，形成复合物。本研究旨在分析双翅胬肉（AA, cuachalalate）提取物与高直链淀粉复合物的生物活性成分。采用超高分辨率液相色谱法对提取物和配合物进行分析。AA提取物具有抗氧化、抗炎、抗菌和抗肿瘤作用。该配合物在提取物中显示出减少的化合物，并且一些化合物不与淀粉配合。药用植物提取物中存在的生物活性化合物可与直链淀粉络合，以在口服时提供保护。

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引用次数: 0

Evaluating the utility of endogenous OCT2 and MATE1/2-K biomarkers for DDI assessment in early clinical settings 评估内源性OCT2和MATE1/2-K生物标志物在早期临床环境中评估DDI的效用。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103776

Rina Nishii , Yongjun Xue , Runlan Huo , Jian Chen , Hong Shen , Yizhe Chen , Ken Ogasawara

With growing interest in a biomarker-based approach for drug-drug interaction (DDI) predictions, creatinine, N1-methylnicotinamide (NMN), and N1-methyladenosine (m¹A) have been identified as endogenous substrates of organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) 1/2-K, though clinical validation remains limited. This study builds on recent advancements by evaluating these biomarkers retrospectively using samples from a clinical pharmacology study that assessed DDI via renal cationic transporters between fedratinib (inhibitor) and metformin (substrate) in healthy participants. Fedratinib reduced renal clearance for all endogenous substrates, with m¹A (38 %) and NMN (36 %) showing reductions comparable to metformin (40 %), while creatinine exhibited slightly lower (29 %), likely reflecting its limited contribution to transporter-mediated renal tubular secretion. Simulations focused on m¹A due to its favorable characteristics over NMN, particularly its minimal diurnal and intra-participant variability, demonstrating that reliable DDI assessments can still be achieved despite sampling constraints typical in oncology settings. Collectively, our study supports the predictive capabilities of endogenous substrates as biomarkers for renal cation transporter inhibition, with m¹A in particular showing promise for early DDI assessments in the Phase 1 studies.

随着人们对基于生物标志物的药物-药物相互作用（DDI）预测方法的兴趣日益浓厚，肌酸酐、n1 -甲基烟酰胺（NMN）和n1 -甲基腺苷（m1A）已被确定为有机阳离子转运体（OCT） 2和多药物和毒素挤出（MATE） 1/2-K的内源性底物，尽管临床验证仍然有限。本研究基于最近的进展，通过回顾性评估这些生物标志物，使用来自临床药理学研究的样本，在健康参与者中评估通过肾脏阳离子转运体在fedratinib（抑制剂）和二甲双胍（底物）之间的DDI。Fedratinib降低了所有内源性底物的肾脏清除率，m1A（38%）和NMN（36%）的降低与二甲双胍（40%）相当，而肌酐的降低略低（29%），可能反映了其对转运蛋白介导的肾小管分泌的有限贡献。模拟集中在m1A上，因为其优于NMN的特性，特别是其最小的日和参与者内部变异性，表明尽管肿瘤环境中典型的采样限制，可靠的DDI评估仍然可以实现。总的来说，我们的研究支持内源性底物作为肾离子转运蛋白抑制的生物标志物的预测能力，特别是m1A在1期研究中显示出早期DDI评估的希望。

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引用次数: 0

Fast-dissolving electrospun cellulose fiber-based matrices as modular oral dosage forms 快速溶解的电纺丝纤维素纤维基基质作为模块化口服剂型。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103908

Mario A. Cano-Vega , Héctor Lozano-Perez , Rodolfo Pinal , Meng Deng

Fast-dissolving oral dosage forms are attractive systems for controlled delivery of poorly water-soluble drugs. This study introduces a novel modular oral dosage platform composed of fast-dissolving drug-loaded electrospun hydroxypropyl methylcellulose (HPMC)/ polyethylene oxide (PEO) fibers. Electrospun fibers were fabricated and optimized using two solvent systems, namely dichloromethane/ethanol and water/ethanol, and loaded with model compounds exhibiting different solubility profiles. Characterization by scanning electron microscopy, differential scanning calorimetry, and X-ray diffraction confirmed the formation of drug-loaded HPMC/PEO-based fibers with drug amorphization. Dissolution studies of as-fabricated fibers demonstrated rapid disintegration and efficient drug release from the fibers. An optimized fabrication process was further developed to form a proof-of-concept integrated bilayer module by enabling the precise deposition of drug-loaded electrospun fibers onto a solvent-cast non-drug-loaded HPMC-based film. The fibrous layer maintained its bead-free morphology, reduced crystallinity, and fast dissolution properties post-integration. Our findings highlight the potential of drug-loaded electrospun HPMC/PEO fibers as an advanced drug delivery system, supporting the development of next-generation modular oral dosage forms for controlled and customizable drug delivery.

快速溶解的口服剂型是一种有吸引力的系统，用于控制低水溶性药物的递送。本研究介绍了一种新型的模块化口服给药平台，该平台由速溶载药电纺羟丙基甲基纤维素(HPMC)/聚氧聚乙烯（PEO）纤维组成。采用二氯甲烷/乙醇和水/乙醇两种溶剂体系制备并优化了电纺丝纤维，并加载了具有不同溶解度的模型化合物。通过扫描电镜、差示扫描量热法和x射线衍射表征，证实了具有药物非晶化的载药HPMC/ peo基纤维的形成。溶出性研究表明，制备的纤维分解速度快，药物释放效率高。研究人员进一步开发了一种优化的制造工艺，通过将负载药物的电纺丝纤维精确沉积在溶剂铸造的非负载药物的hmc基薄膜上，形成了概念验证的集成双层模块。纤维层在整合后保持其无珠的形态，降低结晶度和快速溶解性能。我们的研究结果强调了载药电纺丝HPMC/PEO纤维作为一种先进的药物输送系统的潜力，支持下一代模块化口服剂型的开发，用于控制和定制药物输送。

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引用次数: 0

Application of mechanochemistry to green, scalable, and continuous manufacturing of pharmaceutically relevant peptides by twin-screw extrusion 机械化学在绿色、可扩展、连续双螺杆挤出制药相关肽生产中的应用。

IF 3.8 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2025-12-01 DOI: 10.1016/j.xphs.2025.103941

Dominick Daurio , Casey S. Jacobsen , Karthik Nagapudi , Robert Saw , Maria Victoria Silva Elipe , Oliver Thiel , Renata Balgley , Sai Prasanth Chamarthy , Fernando Alvarez-Nunez

The industry is developing green methods for producing pharmaceutically relevant compounds through scalable and continuous processes. By utilizing mechanical forces and heat, mechanochemistry facilitates green chemical reactions while notably reducing the need for potentially harmful solvents and reagents. Therapeutic peptides are gaining significant scientific attention, evidenced by the rising interest in glucagon-like peptide-1 (GLP-1) receptor agonists and other agents. Solid-phase peptide synthesis (SPPS) is the state of the art in industrial peptide production; however, it utilizes solvents and reagents that may impact the environment. Mechanochemical peptide synthesis at lab scale using twin-screw extrusion (TSE) was previously achieved under batch processing. Here, we explore the versatility of mechanochemical peptide synthesis using TSE, which is a green, scalable, and continuous process. Solvent-free synthesis of a model dipeptide was demonstrated. Reduction in operating temperatures was achieved using minimal solvent. The process was subsequently scaled up and shown to be compatible with common protecting and leaving groups of amino acids, as well as various commercially available amino acids. The versatility of this methodology was further explored through sequential TSE reactions to produce a model tripeptide. This work positions mechanochemical peptide synthesis using TSE under continuous flow as a sustainable method for industrial therapeutic peptides production.

该行业正在开发绿色方法，通过可扩展和连续的过程生产药学相关化合物。通过利用机械力和热，机械化学促进绿色化学反应，同时显著减少对潜在有害溶剂和试剂的需求。随着对胰高血糖素样肽-1 （GLP-1）受体激动剂和其他药物的兴趣日益浓厚，治疗性肽正在获得重要的科学关注。固相肽合成（SPPS）是工业肽生产的最新技术；但是，它使用的溶剂和试剂可能会影响环境。机械化学多肽合成在实验室规模使用双螺杆挤压（TSE）以前实现了批处理。在这里，我们探索使用TSE的机械化学肽合成的多功能性，这是一个绿色，可扩展和连续的过程。证明了一种模型二肽的无溶剂合成。使用最少的溶剂可以降低操作温度。该过程随后扩大规模，并证明与常见的保护和离开氨基酸基团以及各种市售氨基酸兼容。通过连续的TSE反应产生模型三肽，进一步探索了这种方法的多功能性。本研究将机械性化学多肽合成定位为连续流动下使用TSE作为工业治疗性多肽生产的可持续方法。

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引用次数: 0