Enhanced Solid-State Nuclear Magnetic Resonance Spectroscopy of Amorphous Solid Dispersions for Pharmaceutical Sciences

用于制药科学的非晶固体分散体的增强型固态核磁共振波谱分析

• 批准号: 2889117
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2889117
• 关键词: Enhanced; Solid; State; Nuclear; Magnetic

One of the greatest challenges faced in drug development is the low aqueous solubility of active pharmaceutical ingredients (APIs), inhibiting their biopharmaceutical performance.1 90% of molecules in drug discovery pipelines display poor water solubility which risks failure due to poor biological performance.2 Formation of amorphous solid dispersions (ASDs) can increase the bioavailability of poorly soluble drugs.3 ASDs consist of APIs in an amorphous state dispersed in an excipient matrix, showing high success in increasing the solubility of APIs.4 Polymers play a critical role in stabilising and inhibiting recrystallisation of the amorphous API in an ASD.5 Specific interactions between the API and polymer are known to aid miscibility in the dispersed systems. Polymer choice is imperative in ASD design to control the drug dissolution rate and stability, therefore an understanding of the interactions present within the dispersion are needed to inform their design.6 Hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) is the most widely used polymer in commercially available ASDs due to its ability to increase the solubility and dissolution of poorly soluble drugs whilst impeding drug recrystallisation.7 The ability to provide structural information of amorphous solids,8 identify drug recrystallisation mechanisms,9 and measure intermolecular interactions between different components of ASDs is why Nuclear Magnetic Resonance (NMR) spectroscopy is an ideal tool to investigate ASDs for increased solubility of APIs.10 General aims of this project include a focus on understanding how HPMC-AS stabilises amorphous APIs on a molecular level. Measurements will be made on ASDs containing HPMC-AS to identify spatial proximities, intermolecular interactions and site-specific interactions between the polymer and different amorphous drugs.11 From this, an understanding on the role HPMC-AS plays in ASDs can be obtained to inform the formulation of successful ASDs, increasing the number of medicines that can be brought to market and the number of diseases that can currently be treated. (1) Schittny, A.; Huwyler, J.; Puchkov, M. Mechanisms of increased bioavailability through amorphous solid dispersions: a review. Drug Delivery 2020, 27 (1), 110-127.(2) Kalepu, S.; Nekkanti, V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B 2015, 5 (5), 442-453.(3) Butar-Butar, M. E. T.; Wathoni, N.; Ratih, H.; Wardhana, Y. W. Solid Dispersion Technology for Improving the Solubility of Antiviral Drugs. Pharmaceutical Sciences and Research 2023, 10 (1), 3.(4) Iyer, R.; Petrovska Jovanovska, V.; Berginc, K.; Jaklic, M.; Fabiani, F.; Harlacher, C.; Huzjak, T.; Sanchez-Felix, M. V. Amorphous solid dispersions (asds): The influence of material properties, manufacturing processes and analytical technologies in drug product development. Pharmaceutics 2021, 13 (10), 1682.(5) Liu, H.; Taylor, L. S.; Edgar, K. J. The role of polymers in oral bioavailability enhancement; a review. Polymer 2015, 77, 399-415.(6) Hiew, T. N.; Zemlyanov, D. Y.; Taylor, L. S. Balancing solid-state stability and dissolution performance of lumefantrine amorphous solid dispersions: the role of polymer choice and drug-polymer interactions. Molecular pharmaceutics 2021, 19 (2), 392-413.(7) Butreddy, A. Hydroxypropyl methylcellulose acetate succinate as an exceptional polymer for amorphous solid dispersion formulations: A review from bench to clinic. European Journal of Pharmaceutics and Biopharmaceutics 2022.(8) Yuan, X.; Sperger, D.; Munson, E. J. Investigating miscibility and molecular mobility of nifedipine-PVP amorphous solid dispersions using solid-state NMR spectroscopy. Molecular pharmaceutics 2014, 11 (1), 329-337.(9) Aso, Y.; Yoshioka, S.; Kojima, S. Relationship between the crystallization rates of amorphous nifedipine, phenobarbital, and flopropione, and their molecular mobility as measured by th

药物开发面临的最大挑战之一是活性药物成分 (API) 的水溶性较低，从而抑制了其生物制药性能。1 药物发现管道中 90% 的分子水溶性较差，这可能会因生物性能不佳而导致失败。2无定形固体分散体 (ASD) 的形成可以提高难溶性药物的生物利用度。3 ASD 由分散在赋形剂基质中的无定形状态 API 组成，在提高 API 溶解度方面取得了巨大成功。4聚合物在稳定和抑制 ASD 中无定形 API 的重结晶方面发挥着关键作用。5 已知 API 和聚合物之间的特定相互作用有助于分散系统中的混溶性。在 ASD 设计中，聚合物的选择对于控制药物溶出速率和稳定性至关重要，因此需要了解分散体中存在的相互作用来为其设计提供信息。6 羟丙基甲基纤维素乙酰琥珀酸酯 (HPMC-AS) 是商业上使用最广泛的聚合物可用的 ASD，因为它能够增加难溶性药物的溶解度和溶出，同时阻碍药物重结晶。7 能够提供无定形固体的结构信息，8 识别药物重结晶机制，9 和测量 ASD 不同成分之间的分子间相互作用是核磁共振 (NMR) 波谱是研究 ASD 以增加 API 溶解度的理想工具的原因。10 该项目的总体目标包括重点了解 HPMC-AS 如何在非晶态 API 上保持稳定。分子水平。将对含有 HPMC-AS 的 ASD 进行测量，以确定聚合物与不同无定形药物之间的空间邻近性、分子间相互作用和位点特异性相互作用。 11 由此，可以了解 HPMC-AS 在 ASD 中的作用，以提供信息成功制定自闭症谱系障碍（ASD），增加可推向市场的药物数量以及目前可治疗的疾病数量。 (1) 希特尼，A.；休勒，J.； Puchkov, M. 通过无定形固体分散体提高生物利用度的机制：综述。药物输送 2020, 27 (1), 110-127.(2) Kalepu, S.； Nekkanti, V. 不溶性药物输送策略：回顾最新进展和商业前景。药学学报 B 2015, 5 (5), 442-453.(3) Butar-Butar, M. E. T.;沃索尼，N.；拉蒂，H.； Wardhana，Y.W. 提高抗病毒药物溶解度的固体分散技术。药物科学与研究 2023, 10 (1), 3.(4) Iyer, R.；彼得罗夫斯卡·乔瓦诺夫斯卡，V.；伯金克，K.；雅克利克，M.；法比亚尼，F.；哈拉赫，C.；胡兹贾克，T.； Sanchez-Felix，M.V. 非晶固体分散体（asds）：材料特性、制造工艺和分析技术对药品开发的影响。药剂学 2021, 13(10), 1682.(5) 刘红;泰勒，L.S.； Edgar, K. J. 聚合物在增强口服生物利用度中的作用；评论。聚合物 2015, 77, 399-415.(6) Hiew, T. N.;泽姆利亚诺夫，D.Y.； Taylor，L.S.平衡本芴醇无定形固体分散体的固态稳定性和溶出性能：聚合物选择和药物-聚合物相互作用的作用。分子药剂学 2021, 19 (2), 392-413.(7) Butreddy, A. 醋酸羟丙基甲基纤维素琥珀酸酯作为无定形固体分散体制剂的特殊聚合物：从实验室到临床的回顾。欧洲药剂学和生物药剂学杂志 2022.(8) Yuan, X.;斯佩格，D.； Munson, E. J. 使用固态 NMR 光谱研究硝苯地平-PVP 无定形固体分散体的混溶性和分子迁移率。分子药剂学 2014, 11 (1), 329-337.(9) Aso, Y.;吉冈，S.； Kojima, S. 无定形硝苯地平、苯巴比妥和氟丙哌酮的结晶速率与通过 th 测量的分子迁移率之间的关系