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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 3.7 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。
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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 : 2024-10-23 DOI: 10.1016/j.xphs.2024.10.029
Tomohito Tsukamoto, Haruna Mizuta, Eiko Sakai, Fuminori Sakurai, Hiroyuki Mizugchi

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 in vitro situations differed from that in 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 : 2024-10-23 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
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, 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
Microscope-enabled Disc Dissolution System: Concordance between drug and polymer dissolution from an amorphous solid dispersion disc and visual disc degradation. 显微镜驱动的圆片溶解系统:无定形固体分散盘中药物和聚合物的溶解与目视盘降解之间的一致性。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-23 DOI: 10.1016/j.xphs.2024.10.039
Shuaiqian Men, James E Polli

A microscopic erosion time test was recently described to anticipate amorphous solid dispersion (ASD) drug load dispersibility limit, using 0.5ml media volume. Studies here build upon this microscope-enabled method but focus on drug and polymer dissolution from an ASD disc, along with imaging. The objective was 1) to design and build a microscope-enabled disc dissolution system (MeDDiS) with a 900mL dissolution volume and 2) assess the ability of MeDDiS imaging of dissolving discs to provide concordance with measured drug and polymer dissolution profiles. MeDDiS employed a digital microscope to image ASD discs and a one-liter vessel for dissolution. ASD discs containing ritonavir (5-50% drug load) and PVPVA were fabricated and subjected to in vitro dissolution using MeDDiS, where disc diameter was quantified with time. Ritonavir and PVPVA release were also measured. Results indicate concordance between imaging and dissolution. Both found 25% drug load to provide high drug and polymer release, but 30% yielded low release. Quantitatively, MeDDiS images predicted drug and polymer release profile, both above and below the drug load cliff. Overall, studies here describe a MeDDiS which has promised to anticipate drug and polymer dissolution, via imaging of dissolving discs, above and below the ASD drug load cliff.

最近介绍了一种显微侵蚀时间测试方法,用于预测无定形固体分散体(ASD)的药物负载分散极限,使用的介质体积为 0.5 毫升。此处的研究以这种显微镜辅助方法为基础,但重点关注药物和聚合物从 ASD 盘中的溶解以及成像。研究的目的是:1)设计和构建一个溶解容量为 900 毫升的显微镜辅助圆片溶解系统(MeDDiS);2)评估 MeDDiS 对溶解圆片成像的能力,使其与测量的药物和聚合物溶解曲线保持一致。MeDDiS 使用数码显微镜对 ASD 盘和一升容器进行溶解成像。制作了含有利托那韦(5-50% 药物负载)和 PVPVA 的 ASD 圆片,并使用 MeDDiS 对其进行体外溶解,圆片直径随时间变化进行量化。同时还测量了利托那韦和 PVPVA 的释放量。结果表明成像和溶出之间是一致的。两者都发现 25% 的药物负荷可提供较高的药物和聚合物释放量,但 30% 的释放量较低。从定量角度来看,MeDDiS 图像预测了药物和聚合物的释放情况,无论是高于还是低于载药悬崖。总之,本文的研究描述了一种 MeDDiS,它有望通过对溶解盘的成像,预测 ASD 药物载量悬崖上下的药物和聚合物溶解情况。
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引用次数: 0
Delivery of therapeutic RNA by extracellular vesicles derived from Saccharomyces cerevisiae for Medicine Applications. 利用从酿酒酵母中提取的细胞外囊泡输送治疗用 RNA,并将其应用于医药领域。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-23 DOI: 10.1016/j.xphs.2024.10.035
Meng Yuan, Wenyuan Ma, Bingxin Liu, Xue Zou, Bilian Huang, Xiaoyan Tian, Yu Jin, Nan Zheng, Zhiwei Wu, Yongxiang Wang

Employing small extracellular vesicles (EVs) as drug delivery vehicles presents a plethora of advantages over conventional drug delivery methods, including biological compatibility, engineering versatility for targeted delivery, and biodegradability. Therefore, strategies aimed at amplifying their therapeutic potential involve developing efficient, tissue-specific, and non-immunogenic delivery approaches. Despite rapid advancements in the realm of EVs as drug delivery systems in recent years, the availability of a high-yield, reproducible, and cost-effective source for EVs production and isolation remains a limiting factor for practical application. In this study, we isolated EVs from Saccharomyces cerevisiae (S.c) and loaded them with cargoes such as hsa-miR-143 (an apoptosis-inducing miRNA) or miR-H6 (a miRNA targeting HSV-1). We demonstrated the capability of these EVs to deliver microRNAs or even large mRNA to a variety of cell types. The therapeutic potential of S.c-derived EVs (S.c-EVs) was further evidenced by their ability to inhibit tumor growth in animal models. The S.c-EVs proved to be safe and non-immunogenic in vivo. Our results suggest that Saccharomyces cerevisiae represents a cost-effective source of extracellular vesicles, serving as nanocarriers for functional drug delivery in therapeutic applications.

与传统的给药方法相比,使用小的细胞外囊泡 (EV) 作为给药载体具有诸多优势,包括生物相容性、定向给药的工程多功能性和生物可降解性。因此,旨在扩大其治疗潜力的策略包括开发高效、组织特异性和非免疫原性的给药方法。尽管近年来将 EVs 作为药物递送系统的研究进展迅速,但高产、可重现、高成本效益的 EVs 生产和分离来源仍然是限制其实际应用的因素。在这项研究中,我们从酿酒酵母(S.c)中分离出了EVs,并在其中添加了hsa-miR-143(一种诱导细胞凋亡的miRNA)或miR-H6(一种靶向HSV-1的miRNA)等载体。我们证明了这些 EVs 能够将 microRNA 甚至大型 mRNA 运送到各种类型的细胞中。S.c-EVs在动物模型中抑制肿瘤生长的能力进一步证明了S.c-EVs的治疗潜力。事实证明,S.c-EVs 在体内安全且无免疫原性。我们的研究结果表明,酿酒酵母是一种具有成本效益的细胞外囊泡来源,可作为纳米载体用于治疗领域的功能性药物递送。
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引用次数: 0
Bridging the Gap between in vitro and in vivo Solubility-Permeability Interplay. 弥合体外与体内溶解度-渗透性相互作用之间的差距。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-22 DOI: 10.1016/j.xphs.2024.10.008
Michinori Oikawa, Satoru Matsuura, Takeyuki Okudaira, Ryo Ito, Kanako Arima, Masahiro Fushimi, Takamasa Oda, Kaoru Ohyama, Kohsaku Kawakami

Use of solubilization carriers for poorly soluble drugs may disturb transmembrane absorption by lowering the activity of drug molecules, which is known as the solubility-permeability interplay. However, although many in vitro studies have indicated the negative impacts of use of solubilization carriers for oral absorption, in vivo studies that showed the interplay effect are limited. This study provides systematic in vitro, in situ, and in vivo investigation of the interplay effect of cyclodextrin using dexamethasone as a model drug. The evaluation methods included permeation through polymeric, artificial lipid, cell, and intestinal closed-loop membranes. Then, the results were compared with oral administration studies in mice and dogs. Although the interplay effect was clearly observed in the in vitro studies, no obvious interplay was found in the in vivo studies, suggesting that the interplay effect is more prominent in the in vitro permeation studies. Absence of in vivo interplay was attributed to the dilution effect in the gastrointestinal tract, interaction of the drug with living components, and clearance of the drug after membrane permeation. Overall, this investigation clearly demonstrated the applicability and limitations of in vitro permeation studies for predicting the interplay effects of solubilizers after the oral administration.

溶解性差的药物使用增溶载体可能会降低药物分子的活性,从而干扰跨膜吸收,这就是所谓的溶解度-渗透性相互作用。然而,尽管许多体外研究表明使用增溶载体会对口服吸收产生负面影响,但能显示这种相互作用效应的体内研究却很有限。本研究以地塞米松为模型药物,对环糊精的相互作用效应进行了系统的体外、原位和体内研究。评估方法包括通过聚合物膜、人工脂质膜、细胞膜和肠道闭环膜的渗透。然后,将结果与小鼠和狗的口服研究进行比较。虽然在体外研究中明显观察到了相互作用效应,但在体内研究中却没有发现明显的相互作用,这表明相互作用效应在体外渗透研究中更为突出。体内无相互作用的原因包括胃肠道的稀释效应、药物与活体成分的相互作用以及药物在膜渗透后的清除。总之,这项研究清楚地表明了体外渗透研究在预测增溶剂口服后的相互作用效应方面的适用性和局限性。
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引用次数: 0
Scale-up and Clinical Bioavailability Assessment of a 45% Drug Loaded Amorphous Nanoparticle Formulation of a BCS IV Compound for Oral Delivery. 口服给药 BCS IV 化合物的 45% 药物负载无定形纳米粒子制剂的放大和临床生物利用度评估。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-18 DOI: 10.1016/j.xphs.2024.10.014
Mengqi Yu, Deliang Zhou, Hardeep S Oberoi, Ahmed Hamed Salem, Laura A McKee, Jason R Arnholt, Hitesh S Purohit, Devalina Law

A 45% drug loaded (DL) amorphous nanoparticle (ANP) formulation for a BCS IV drug demonstrated promising pharmacokinetics in dogs (Purohit, et al, J. Pharm. Sci. 2023(113)1007-1019). This preclinical data enabled a human proof-of-concept assessment opportunity. The ANP freeze dried powder for oral suspension was prepared using solvent/antisolvent precipitation followed by organic solvent removal and freeze drying (FD). Challenges manifested during scale-up from 50g to 280g. Given the preclinical data, formulation change was restricted, therefore, process modifications were implemented. Cold collection after precipitation prevented particle growth but resulted in 75 nm particles at clinical scale (CS), compared to 150 nm at laboratory scale (LS). This size decrease rendered stabilizer amounts suboptimal for FD operation. Consequently, when FD powder was resuspended in water a smaller fraction of particles was below 450 nm (by filtration), ∼65% for CS compared to ∼85% for LS. Formulation was stable for > 6 months, evaluated by monitoring moisture content, assay, powder X-ray diffraction (PXRD), and redispersion time. Despite ∼65% re-dispersibility, this 45% DL formulation in humans had higher Cmax and AUC ∼73% and ∼46% respectively in fasted-state, and under fed-state it met bioequivalence criteria for AUC but Cmax was 20% lower compared to reference (10% DL ASD tablets) demonstrating advantage of ANP strategy over ASD approach.

一种用于 BCS 静脉注射药物的 45% 药物负载 (DL) 无定形纳米粒子 (ANP) 配方在狗体内显示出良好的药代动力学(Purohit 等人,J. Pharm.Sci.2023(113)1007-1019)。这一临床前数据为人体概念验证评估提供了机会。用于口服混悬液的 ANP 冻干粉采用溶剂/等溶剂沉淀法制备,然后去除有机溶剂并进行冷冻干燥 (FD)。在从 50 克放大到 280 克的过程中遇到了挑战。考虑到临床前数据,改变配方受到限制,因此对工艺进行了修改。沉淀后的冷收集可防止颗粒生长,但在临床规模(CS)下,颗粒的尺寸为 75 nm,而在实验室规模(LS)下,颗粒的尺寸为 150 nm。粒度的减小使稳定剂的用量成为 FD 操作的次优选择。因此,当 FD 粉末重新悬浮于水中时,低于 450 nm 的颗粒比例较小(通过过滤),CS 为 65%,而 LS 为 85%。通过监测含水量、化验、粉末 X 射线衍射(PXRD)和再分散时间,对配方的稳定性进行了评估,结果表明配方的稳定性大于 6 个月。尽管这种 45% DL 的制剂的再分散性为 65%,但在人体空腹状态下,其 Cmax 和 AUC 分别为 73% 和 46%,而在进食状态下,其 AUC 符合生物等效性标准,但 Cmax 比参照物(10% DL ASD 片剂)低 20%,这表明 ANP 策略比 ASD 方法更具优势。
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引用次数: 0
Simultaneous XRD-DSC identifies correct drug-polymer solubility and miscibility for enantiotropic solid forms. 同时 XRD-DSC 确定药物-聚合物的正确溶解度和各向异性固体形式的混溶性。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-18 DOI: 10.1016/j.xphs.2024.10.018
Mustafa Bookwala, Jiawanjun Shi, Ira S Buckner, Simon Bates, Peter L D Wildfong

Thermodynamic properties, including solubility and miscibility, which are highly correlated with amorphous solid dispersion physical stability were identified for the complex solid forms of bromopropamide using simultaneous X-ray diffraction (XRD)-differential scanning calorimetry (DSC). The most stable solid form of bromopropamide was crystallized and its crystal structure was solved. The crystallized material was characterized using simultaneous XRD-DSC measurements, which allowed dual analyses of a single sample. Transitions of bromopropamide during heating resulted in observation of the unique diffraction patterns of its different solid forms. The dissolution endpoint (Tend) was measured for various mixtures of bromopropamide and polyvinylpyrrolidone-vinyl acetate random copolymer (PVPVA). The use of XRD-DSC allowed confident and accurate measurements of the Tend for a large range of compositions, assisting in the estimation of drug-polymer solubility and miscibility. Thermodynamic properties identified using combined XRD-DSC were further compared to those obtained using only DSC data. It was found that DSC data in isolation can lead to ambiguity, misinterpretations, and incorrect conclusions, especially for a solid demonstrating multiple, closely related forms.

利用 X 射线衍射(XRD)-差示扫描量热仪(DSC)同时测定了溴丙酰胺复杂固态的热力学性质,包括溶解度和混溶性,这些性质与无定形固体分散体的物理稳定性高度相关。对最稳定的溴丙酰胺固体形式进行了结晶,并解决了其晶体结构问题。利用同时进行的 XRD-DSC 测量对结晶材料进行了表征,从而实现了对单一样品的双重分析。通过观察溴丙酰胺在加热过程中的转变,可以观察到其不同固体形态的独特衍射图样。对溴丙酰胺和聚乙烯吡咯烷酮-醋酸乙烯无规共聚物的各种混合物的溶解终点(Tend)进行了测量。使用 XRD-DSC 可以对多种成分的 Tend 进行可靠而准确的测量,有助于估算药物-聚合物的溶解度和混溶性。使用 XRD-DSC 组合确定的热力学特性与仅使用 DSC 数据获得的特性进行了进一步比较。研究发现,单独使用 DSC 数据可能会导致模糊、误解和错误结论,尤其是对于表现出多种密切相关形式的固体。
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引用次数: 0
Professor Lynne S. Taylor: Scientist, educator, and adventurer. 林恩-泰勒教授:科学家、教育家和探险家。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-18 DOI: 10.1016/j.xphs.2024.10.015
Dana E Moseson, Na Li, Jukka Rantanen, Keisuke Ueda, Geoff G Z Zhang

This special edition of the Journal of Pharmaceutical Sciences is dedicated to Professor Lynne S. Taylor (Retter Distinguished Professor of Pharmacy, Department of Industrial and Molecular Pharmaceutics, Purdue University), to honor her distinguished career as a pharmaceutical scientist and educator. The goal of this commentary is to provide an overview of Professor Taylor's career path, summarize her key research contributions, and provide some insight into her personal and professional contributions as an educator, mentor, wife, mother, friend, and adventurer.

本期《药学学报》特刊献给琳恩-泰勒教授(普渡大学工业与分子药学系雷特特聘药学教授),以纪念她作为药学科学家、教育家和冒险家的杰出职业生涯。本评论旨在概述泰勒教授的职业道路,总结她的主要研究贡献,并对她作为教育家、导师、妻子、母亲、朋友和冒险家的个人和专业贡献提供一些见解。
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Journal of pharmaceutical sciences
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