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Review of dose justifications for antibody-drug conjugate approvals from clinical pharmacology perspective: A focus on exposure-response analyses. 从临床药理学角度审查抗体药物共轭物审批的剂量理由:重点关注暴露-反应分析。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-05 DOI: 10.1016/j.xphs.2024.10.002
Qianqian Hu, Lujing Wang, Yuqing Yang, Jong Bong Lee

Antibody-drug conjugates (ADCs) are revolutionizing cancer treatment by specific targeting of the cancer cells thereby improving the therapeutic window of the drugs. Nevertheless, they are not free from unwanted toxicities mainly resulting from non-specific targeting and release of the payload. Therefore, the dosing regimen must be optimized through integrated analysis of the risk-benefit profile, to maximize the therapeutic potential. Exposure-response (E-R) analysis is one of the most widely used tools for risk-benefit assessment and it plays a pivotal role in dose optimization of ADCs. However, compared to conventional E-R analysis, ADCs pose unique challenges since they feature properties of both small molecules and antibodies. In this article, we review the E-R analyses that have formed the key basis of dose justification for each of the 12 ADCs approved in the USA. We discuss the multiple analytes and exposure metrics that can be utilized for such analysis and their relevance for safety and efficacy of the treatment. For the endpoints used for the E-R analysis, we were able to uncover commonalities across different ADCs for both safety and efficacy. Additionally, we discuss dose optimization strategies for ADCs which are now a critical component in clinical development of oncology drugs.

抗体药物共轭物(ADCs)通过特异性靶向癌细胞从而改善药物的治疗窗口期,为癌症治疗带来了革命性的变化。然而,ADCs 也存在一些不必要的毒性,主要是由于非特异性靶向和有效载荷的释放。因此,必须通过对风险-效益概况的综合分析来优化给药方案,以最大限度地发挥治疗潜力。暴露-反应(E-R)分析是风险-效益评估中使用最广泛的工具之一,在 ADC 的剂量优化中起着举足轻重的作用。然而,与传统的 E-R 分析相比,ADC 具有小分子和抗体的双重特性,因此带来了独特的挑战。在这篇文章中,我们回顾了作为美国批准的 12 种 ADC 中每一种的剂量论证的重要依据的 E-R 分析。我们讨论了可用于此类分析的多种分析物和暴露指标,以及它们与治疗安全性和有效性的相关性。对于用于 E-R 分析的终点,我们能够发现不同 ADC 在安全性和有效性方面的共性。此外,我们还讨论了 ADC 的剂量优化策略,该策略现已成为肿瘤药物临床开发的重要组成部分。
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引用次数: 0
Improving oral absorption of a rapidly crystallizing parent drug using prodrug strategy: Comparison of phosphate versus glycine based prodrugs. 利用原药策略改善快速结晶母药的口服吸收:磷酸盐原药与甘氨酸原药的比较。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-03 DOI: 10.1016/j.xphs.2024.09.012
Anura S Indulkar, Russell Slade, Navendu Jana, Robin R Frey, Thomas D Penning, Albert Lai, Alix F Leblanc

With an increasing number of Biopharmaceutical Classification System (BCS) II/IV pipeline compounds, solubilizing and supersaturating formulation strategies are becoming prevalent. Beyond formulation and solid form strategies, prodrugs are also employed to overcome solubility-limited absorption of poorly water-soluble compounds. Prodrugs can potentially yield supersaturated systems upon conversion to the parent drug intraluminally and thus enhance absorption. However, supersaturation also increases the driving force for crystallization, resulting in low solution concentrations, which can potentially negate the advantage of prodrugs. In this work, two unique solubility-enhancing prodrugs, phosphate and glycine esters, were investigated for a rapidly crystallizing parent drug. Ex vivo absorption studies using rat tissue and in vivo studies in dogs were performed. Conversion rate of the phosphate prodrug to the parent was dependent on the milieu and increased ∼24-fold in the presence of intestinal contents as medium and tissue relative to neat buffer. In contrast, conversion of the glycine prodrug was minimal under any conditions tested, suggesting that the conversion occurs after absorption into the enterocytes. Phosphate prodrug showed a non-linear increase in parent drug absorptive flux across rat intestinal tissue with concentration when intestinal contents were used as donor media. This was attributed to rapid conversion and high supersaturation of the parent drug which subsequently resulted in crystallization at high doses in the donor chamber. Glycine prodrug did not undergo complete conversion at high doses and was absorbed unchanged on the basolateral side, indicating saturation of the converting enzymes in the enterocytes. The combined flux (parent drug and glycine) showed a linear increase with dose and crystallization was not observed. Under physiological conditions, glycine prodrug that is absorbed unchanged from the intestine can potentially undergo complete conversion in hepatocytes after absorption and make the parent drug systemically available. Thus, glycine prodrug provided overall higher absorption compared to phosphate prodrug. The observed flux levels for both the prodrugs were higher compared to the parent drug alone, highlighting an advantage to use of a prodrug strategy to improve absorption of such compounds. Oral dosing in a dog PK study revealed that the bioavailability using the phosphate prodrug was ∼50% whereas, it was ∼100% with glycine prodrug, supporting the in vitro observations.

随着生物制药分类系统(BCS)II/IV 级管线化合物数量的不断增加,增溶和过饱和制剂策略正变得越来越普遍。除了制剂和固体制剂策略外,原药也被用来克服水溶性差的化合物在吸收时受到的溶解度限制。原药在腔内转化为母药后有可能产生过饱和体系,从而促进吸收。然而,过饱和也会增加结晶的驱动力,导致溶液浓度过低,从而可能抵消原药的优势。本研究针对快速结晶的母药研究了磷酸酯和甘氨酸酯这两种独特的溶解度增强原药。利用大鼠组织进行了体内外吸收研究,并在狗身上进行了体内研究。磷酸酯原药向母药的转化率取决于环境,在有肠道内容物作为介质和组织的情况下,转化率比纯缓冲液高出 24 倍。相反,在任何测试条件下,甘氨酸原药的转化率都很小,这表明转化是在吸收进入肠细胞后发生的。当使用肠内容物作为供体介质时,磷酸盐原药在大鼠肠组织中的母药吸收通量随浓度的增加而呈非线性增加。这归因于母药的快速转化和高过饱和,从而导致供体室中的高剂量结晶。甘氨酸原药在高剂量时没有完全转化,在基底侧吸收时没有变化,这表明肠细胞中的转化酶达到饱和。综合通量(母药和甘氨酸)随剂量呈线性增加,未观察到结晶。在生理条件下,从肠道吸收的甘氨酸原药在吸收后可能会在肝细胞中发生完全转化,并使母药成为全身可用的药物。因此,与磷酸原药相比,甘氨酸原药的吸收率更高。与单独使用母药相比,两种原药的通量水平都更高,这凸显了使用原药策略改善此类化合物吸收的优势。在狗的口服 PK 研究中发现,使用磷酸原药的生物利用度为 50%,而使用甘氨酸原药的生物利用度为 100%,这支持了体外观察结果。
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引用次数: 0
Oral Absorption from Surfactant-Based Drug Formulations: The Impact of Molecularly Dissolved Drug on Bioavailability 基于表面活性剂的药物制剂的口服吸收:分子溶解药物对生物利用率的影响。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-01 DOI: 10.1016/j.xphs.2024.07.017
Enabling drug formulations are often required to ensure sufficient absorption after oral administration of poorly soluble drugs. While these formulations typically increase the apparent solubility of the drug, it is widely acknowledged that only molecularly dissolved, i.e., free fraction of the drug, is prone for direct absorption, while colloid-associated drug does not permeate to the same extent.
In the present study, we aimed at comparing the effect of molecularly and apparently (i.e., the sum of molecularly and colloid-associated drug) dissolved drug concentrations on the oral absorption of a poorly water-soluble drug compound, Alectinib. Mixtures of Alectinib and respectively 50 %, 25 %, 12.5 %, and 3 % sodium lauryl sulfate (SLS) relative to the dose were prepared and small-scale dissolution tests were performed under simulated fed and fasted state conditions. Both the molecularly and apparently dissolved drug concentrations were assessed in parallel using microdialysis and centrifugation/filtration sampling, respectively. The data served as the basis for an in vitro-in vivo correlation (IVIVC) and as input for a GastroPlusTM physiologically-based biopharmaceutics model (PBBM).
It was shown that with increasing the content of SLS the apparently dissolved drug in FeSSIF and FaSSIF increased to a linear extent and thus, the predicted in vivo performance of the 50 % SLS formulation, based on apparently dissolved drug, would outperform all other formulations. Against common expectation, however, the free (molecularly dissolved) drug concentrations were found to vary with SLS concentrations as well, yet to a minor extent. A systematic comparison of solubilized and free drug dissolution patterns at different SLS contents of the formulations and prandial states allowed for interesting insights into the complex dissolution-/supersaturation-, micellization-, and precipitation-behavior of the formulations. When comparing the in vitro datasets with human pharmacokinetic data from a bioequivalence study, it was shown that the use of molecularly dissolved drug resulted in an improved IVIVC.
By incorporating the in vitro dissolution datasets into the GastroPlusTM PBBM, the apparently dissolved drug concentrations resulted in both, a remarkable overprediction of plasma concentrations as well as a misprediction of the influence of SLS on systemic exposure. In contrast, by using the molecularly dissolved drug (i.e., free fraction) as the model input, the predicted plasma concentration-time profiles were in excellent agreement with observed data for all formulations under both fed and fasted conditions.
By combining an advanced in vitro assessment with PBBM, the present study confirmed that only the molecularly dissolved drug, and not the colloid-associated drug, is available for direct absorption.
为确保口服溶解性差的药物被充分吸收,通常需要使用药物制剂。虽然这些制剂通常会增加药物的表观溶解度,但人们普遍认为,只有分子溶解的药物(即药物的游离部分)才容易被直接吸收,而胶体相关药物的渗透程度并不相同。在本研究中,我们旨在比较分子溶解的药物浓度和表面溶解的药物浓度(即分子药物和胶体药物的总和)对水溶性较差的药物化合物阿来替尼口服吸收的影响。我们制备了阿来替尼(Alectinib)与相对于剂量分别为50%、25%、12.5%和3%的十二烷基硫酸钠(SLS)的混合物,并在模拟进食和空腹状态下进行了小规模溶出试验。同时分别使用微透析和离心/过滤取样方法评估了药物的分子浓度和表观溶解浓度。这些数据是体外-体内相关性(IVIVC)的基础,也是 GastroPlusTM 生理生物制药模型(PBBM)的输入数据。结果表明,随着 SLS 含量的增加,FeSSIF 和 FaSSIF 中的表观溶解药物呈线性增加,因此,根据表观溶解药物预测,50% SLS 制剂的体内性能将优于所有其他制剂。然而,与一般预期不同的是,游离(分子溶解)药物浓度也随 SLS 浓度的变化而变化,但变化程度较小。通过系统比较配方中不同 SLS 含量和餐前状态下的溶解和游离药物溶解模式,可以深入了解配方的复杂溶解/过饱和、胶束化和沉淀行为。在将体外数据集与生物等效性研究中的人体药代动力学数据进行比较时,结果表明使用分子溶解药物可提高 IVIVC。将体外溶解数据集纳入 GastroPlusTM PBBM 后,表面溶解的药物浓度导致对血浆浓度的预测明显偏高,同时也错误地预测了 SLS 对全身暴露的影响。相反,将分子溶解的药物(即游离部分)作为模型输入,预测的血浆浓度-时间曲线与所有制剂在进食和空腹条件下的观察数据非常吻合。通过将先进的体外评估与 PBBM 结合起来,本研究证实了只有分子溶解的药物而非胶体相关药物可被直接吸收。
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引用次数: 0
Optimization and characterization of a dose-controllable orodispersible dexamethasone film for personalized medicine. 用于个性化医疗的可控制剂量的口服地塞米松薄膜的优化和表征。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-01 DOI: 10.1016/j.xphs.2024.09.023
Motoki Inoue, Moyumi Odate, Toshiro Fukami

Decadron® tablets are commercially available in 0.5 and 4 mg formulations, often requiring the use of multiple tablets or fractional doses when the required dosage is unavailable. This practice can lead to inaccuracies and handling difficulties associated with tablet splitting and crushing tablets into powder. This study aimed to develop an orodispersible dexamethasone film that would allow precise dose control and overcome these challenges. The film formulation was optimized by dissolving varying amounts of hypromellose, glycerol, and dexamethasone in ethanolic solutions. These solutions were cast and dried at different thicknesses. Statistical optimization using the design of experiments was used to determine the ideal film composition. The optimized films met pharmaceutical standards, with a mass variation ≦ 2 %, thickness variation ≦ 2.5 %, and disintegration time ≦ 20 s. The uniform distribution of dexamethasone within the film enabled easy content control based on the film area. Dissolution testing indicated that the dissolution behavior of the film formulation behaved similarly to commercial tablets for up to 90 min. In conclusion, the developed orodispersible film offers precise dexamethasone dose control and addresses the limitations of tablet splitting, positioning it as a promising candidate for personalized medicine applications.

Decadron® 片剂有 0.5 毫克和 4 毫克两种市售配方,在没有所需剂量时,通常需要使用多片或小剂量。这种做法可能会导致不准确性,以及与片剂分割和将片剂粉碎成粉末相关的处理困难。本研究旨在开发一种口服可分散地塞米松薄膜,以实现精确的剂量控制并克服这些难题。通过在乙醇溶液中溶解不同量的聚甲基丙烯酸甲酯、甘油和地塞米松,对薄膜配方进行了优化。这些溶液以不同的厚度进行浇注和干燥。使用实验设计进行统计优化,以确定理想的薄膜成分。优化后的薄膜符合制药标准,质量变化率 ≦ 2%,厚度变化率 ≦ 2.5%,崩解时间 ≦ 20 秒。地塞米松在薄膜中的均匀分布使薄膜面积易于控制含量。溶解测试表明,在长达 90 分钟的时间内,薄膜制剂的溶解行为与商业片剂相似。总之,所开发的口腔分散膜能精确控制地塞米松的剂量,并解决了片剂分割的局限性,是个性化药物应用的理想选择。
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引用次数: 0
Small Molecule Topical Ophthalmic Formulation Development—Data Driven Trends & Perspectives from Commercially Available Products in the US 小分子局部眼科制剂的开发--美国商用产品的数据驱动趋势与前景。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-01 DOI: 10.1016/j.xphs.2024.07.023
Topical ophthalmic drug product development is a niche research domain as the drug formulations need to be designed to perform in the unique ocular physiological conditions. The most common array of small molecule drug formulations intended for topical ophthalmic administration include solutions, suspensions, emulsions, gels, and ointments. The formulation components such as excipients and container closure are unique to serve the needs of topical ophthalmic delivery compared to other parenteral products. The selection of appropriate formulation platform, excipients, and container closure for delivery of drugs by topical ophthalmic route is influenced by a combination of factors like physicochemical properties of the drug molecule, intended dose, pharmacological indication as well as the market trends influenced by the patient population. In this review, data from literature and packaging inserts of 118 reference listed topical ophthalmic medications marketed in the US are collected and analyzed to identify trends that would serve as a guidance for topical ophthalmic formulation development for small molecule drugs. Specifically, the topics reviewed include current landscape of the available small molecule topical ophthalmic drug products in the US, physicochemical properties of the active pharmaceutical ingredients (APIs), formulation platforms, excipients, and container closure systems.
眼科局部用药产品开发是一个利基研究领域,因为药物制剂需要在独特的眼部生理条件下发挥作用。最常见的眼科局部用药小分子药物制剂包括溶液剂、悬浮剂、乳剂、凝胶剂和软膏剂。与其他非肠道用药产品相比,眼科局部给药所需的辅料和容器封口等制剂成分是独一无二的。选择合适的制剂平台、辅料和容器封口来通过眼科局部给药途径给药,会受到多种因素的影响,如药物分子的理化性质、预期剂量、药理适应症以及受患者群体影响的市场趋势。在本综述中,我们收集并分析了在美国上市的 118 种眼科局部用药参考文献和包装插页中的数据,以确定可作为小分子药物眼科局部用药制剂开发指南的趋势。具体而言,审查的主题包括美国现有小分子眼科局部用药产品的现状、活性药物成分 (API) 的理化性质、制剂平台、辅料和容器封闭系统。
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引用次数: 0
Dissolving Microneedles Patch: A Promising Approach for Advancing Transdermal Delivery of Antischizophrenic Drug 溶解微针贴片:推进抗精神分裂症药物透皮给药的可行方法。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-01 DOI: 10.1016/j.xphs.2024.08.011

Objective

Microneedles (MNs) are minimally invasive transdermal drug delivery systems capable of penetrating the stratum corneum to overcome the barrier properties. The primary objective of this research was to prepare dissolving microneedle patches (DMNP) loaded with quetiapine (QTP).

Methods

DMNP were fabricated employing the solvent casting technique, utilizing various polymer feed ratios including polyvinyl alcohol (PVA), polyvinylpyrrolidone K30 (PVP-K30), and polylactide-co-glycolide (PLGA) polymers. The loaded DMNP with QTP underwent a comprehensive characterization process encompassing assessments for compatibility, thickness, insertion potential, morphology, thermal behavior, X-ray diffraction, ex-vivo permeation, skin irritation, and histopathological changes.

Results

FTIR studies confirmed the compatibility of QTP with the microneedle patch composites. The thickness of the drug-loaded DMNP ranged from 0.67 mm to 0.97 mm. These microneedles exhibited an impressive penetration depth of 480 μm, with over 80% of the needles maintaining their original shape after piercing Parafilm-M. SEM analysis of the optimized DMNP-2 revealed the formation of sharp-tipped and uniformly surfaced needles, measuring 570 μm in length. Remarkably, the microneedles did not elicit any signs of irritation upon application of the prepared DMNP. The DMNP-2 showcased an impressive cumulative ex-vivo permeation of QTP, reaching 17.82 µg/cm2/hr. Additionally, histopathological assessment of vital organs in rabbits attested to the safety profile of the formulated microneedle patches.

Conclusions

In conclusion, the developed microneedle patch represents a promising strategy for enhancing the transdermal delivery of QTP. This innovative approach has the potential to increase patient compliance, offering a more efficient and patient-friendly method of administering QTP.
目的:微针(MNs)是一种微创透皮给药系统,能够穿透角质层,克服屏障特性。本研究的主要目的是制备含有喹硫平(QTP)的可溶解微针贴片(DMNP):方法:采用溶剂浇铸技术,利用不同的聚合物进料比(包括聚乙烯醇(PVA)、聚乙烯吡咯烷酮 K30(PVP-K30)和聚乳酸共聚乙二醇(PLGA)聚合物)制备 DMNP。装载了 QTP 的 DMNP 经过了全面的表征过程,包括相容性、厚度、插入潜力、形态、热行为、X 射线衍射、体内外渗透、皮肤刺激性和组织病理学变化等方面的评估:傅立叶变换红外光谱研究证实了 QTP 与微针贴片复合材料的相容性。载药 DMNP 的厚度在 0.67 毫米到 0.97 毫米之间。这些微针的穿透深度达到了 480 μm,穿透 Parafilm-M 后,超过 80% 的微针保持了原来的形状。对优化后的 DMNP-2 进行的扫描电镜分析表明,形成的针尖尖锐、表面均匀,长度为 570 μm。值得注意的是,在使用制备的 DMNP 时,微针不会引起任何刺激症状。DMNP-2 显示出令人印象深刻的 QTP 体内累积渗透率,达到 17.82 µg/cm2/hr。此外,对兔子重要器官的组织病理学评估也证明了配制的微针贴片的安全性:总之,所开发的微针贴片是增强 QTP 透皮给药的一种有前途的策略。这种创新方法有可能提高患者的依从性,提供一种更高效、更方便患者的 QTP 给药方法。
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引用次数: 0
Utility of Cellular Measurements of Non-Specific Endocytosis to Assess the Target-Independent Clearance of Monoclonal Antibodies 细胞对非特异性内吞作用的测量可用于评估单克隆抗体的靶向非依赖性清除。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-01 DOI: 10.1016/j.xphs.2024.07.009
Past studies have demonstrated higher clearance for monoclonal antibodies possessing increased rates of non-specific endocytosis. However, this metric is oftentimes evaluated indirectly using biophysical techniques or cell surface binding studies that may not provide insight into the specific rates of cellular turnover. Furthermore, few examples evaluating non-specific endocytosis have been reported for a therapeutic antibody that reached clinical assessment. In the current report, we evaluated a therapeutic human immunoglobulin G2 monoclonal antibody targeted against the interleukin-4 receptor alpha chain (IL-4Rα) that exhibited elevated target independent clearance in previous Phase 1 and 2 studies. We confirmed high non-specific clearance of the anti-IL-4Rα antibody as compared to a reference antibody during pharmacokinetic assessments in wild type mice where target-mediated disposition was absent. We then developed a cell-based method capable of measuring cellular protein endocytosis and demonstrated the anti-IL-4Rα antibody exhibited marked non-specific uptake relative to the reference compound. Antibody homology modeling identified the anti-IL-4Rα antibody possessed positive charge patches whose removal via targeted mutations substantially reduced its non-specific endocytosis. We then expanded the scope of the study by evaluating panels of both preclinical and clinically relevant monoclonal antibodies and demonstrate those with the highest rates of non-specific uptake in vitro exhibited elevated target independent clearance, low subcutaneous bioavailability, or both. Our results support the observation that high non-specific endocytosis is a negative attribute in monoclonal antibody development and demonstrate the utility of a generic cell-based screen as a quantitative tool to measure non-specific endocytosis of protein therapeutics at the single-cell level.
过去的研究表明,非特异性内吞率增加的单克隆抗体清除率更高。然而,这一指标通常是通过生物物理技术或细胞表面结合研究间接评估的,可能无法深入了解细胞周转的具体速率。此外,对于已进入临床评估的治疗性抗体,很少有评估非特异性内吞作用的实例报道。在本报告中,我们评估了一种针对白细胞介素-4 受体α链(IL-4Rα)的治疗性人类免疫球蛋白 G2 单克隆抗体。我们证实,与参考抗体相比,抗 IL-4Rα 抗体在野生型小鼠体内的药代动力学评估中具有较高的非特异性清除率,而在野生型小鼠体内则不存在靶向介导的处置。然后,我们开发了一种基于细胞的方法,能够测量细胞蛋白质的内吞作用,结果表明,与参考化合物相比,抗IL-4Rα抗体表现出明显的非特异性吸收。抗体同源建模发现抗IL-4Rα抗体具有正电荷斑块,通过靶向突变去除这些正电荷斑块可大大降低其非特异性内吞作用。随后,我们扩大了研究范围,对临床前和临床相关的单克隆抗体进行了评估,结果表明,体外非特异性吸收率最高的抗体表现出较高的靶向清除率、较低的皮下生物利用度或两者兼而有之。我们的研究结果支持高非特异性内吞是单克隆抗体开发中的负面属性这一观点,并证明了基于通用细胞的筛选作为定量工具在单细胞水平上测量蛋白质治疗药物的非特异性内吞的实用性。
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引用次数: 0
Investigation of the State of Hydration of a Non-Stoichiometric Hydrate in a Low Dose Formulation Using 19F Solid-State NMR 利用 19F 固态 NMR 研究低剂量制剂中的非均相水合物的水合状态。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-01 DOI: 10.1016/j.xphs.2024.08.001
A variable or non-stoichiometric hydrate of GDC-4379 was developed into a formulated capsule with a 1% drug loading. The water content of this hydrate varied from 0-0.7 moles over the relative humidity (RH) range of 0-98% (25°C). Since a variable state of hydration coupled with rapid equilibration of lattice water with the environmental RH can lead to challenges in formulation development, an analytical method to directly and accurately determine the state of hydration of the active in such a low dose formulation was deemed necessary. Owing to its high selectivity and fast acquisition times, 19F solid-state NMR was effectively utilized to directly determine the lattice water content of the active in the formulated capsule. By correlating Δδ, the chemical shift difference between the isotropic peaks, with the relative humidity and ultimately the lattice water content, the state of hydration of GDC-4379 in the formulated capsule was experimentally determined as 0.63 moles of water/mole of anhydrate.
GDC-4379 的可变水合物或非化学计量水合物被开发成药物含量为 1%的配方胶囊。在相对湿度(RH)为 0-98% (25°C) 的范围内,这种水合物的含水量在 0-0.7 摩尔之间变化。由于水合状态的变化以及晶格水与环境相对湿度的快速平衡会给制剂开发带来挑战,因此有必要采用一种分析方法来直接准确地测定这种低剂量制剂中活性物质的水合状态。19F 固态核磁共振具有高选择性和快速采集时间的特点,因此被有效地用于直接测定配制胶囊中活性物质的晶格水含量。通过将各向同性峰之间的化学位移差Δδ与相对湿度以及晶格水含量相关联,实验确定了配制胶囊中 GDC-4379 的水合状态为 0.63 摩尔水/摩尔无水物。
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引用次数: 0
Effect of particle size on gastric emptying of enteric-coated granules in fasted beagle dogs: Relationship with interdigestive migrating motor complex 粒度对空腹小猎犬肠溶颗粒胃排空的影响:与消化间移行运动复合体的关系。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-01 DOI: 10.1016/j.xphs.2024.07.018
This study investigates the particle size threshold at which the interdigestive migrating motor complex (IMMC) becomes active in gastric emptying for fasted beagle dogs. Enteric-coated granules containing cetirizine dihydrochloride (CET) were prepared in three particle sizes, 200, 660, and 1,200 µm (D50). To mark IMMC timing and water movement from the stomach, enteric-coated aspirin tablets and acetaminophen solution were used. To six fasted beagle dogs with 50 mL of acetaminophen solution was administered each granule size as a multiple-unit and a single enteric-coated aspirin tablet (3-period crossover study). No significant difference in pharmacokinetic parameters of CET after oral administration of different particle sizes was observed. However, the appearance time of CET in plasma with smaller granules (200 and 660 µm) was significantly faster than that of salicylic acid (a major metabolite of aspirin) in all dogs. In the case of the largest granules (1,200 µm), no significant time difference was observed in the appearance of both compounds in plasma. Furthermore, in two dogs, both compounds appeared at the same time, implying IMMC-regulated gastric emptying for the largest CET granules. These results support a particle size threshold between 660 and 1,200 µm for gastric emptying without IMMC action in fasted beagle dogs.
本研究调查了空腹小猎犬胃排空过程中消化道间移行运动复合体(IMC)开始活跃的粒径阈值。含有盐酸西替利嗪(CET)的肠溶包衣颗粒有三种粒径:200、660 和 1200 微米(D50)。使用阿司匹林肠溶片和对乙酰氨基酚溶液来标记 IMMC 时间和胃中水分的移动。给六只禁食的小猎犬注射 50 毫升对乙酰氨基酚溶液,每种粒径的阿司匹林肠溶片均为多剂量单位(3 期交叉研究)。口服不同粒径的 CET 后,其药代动力学参数无明显差异。不过,在所有狗的血浆中,较小颗粒(200 微米和 660 微米)的 CET 出现时间明显快于水杨酸(阿司匹林的主要代谢物)。在颗粒最大(1,200 微米)的情况下,两种化合物在血浆中出现的时间没有明显差异。此外,在两只狗体内,两种化合物同时出现,这意味着最大的 CET 颗粒的胃排空受 IMMC 调节。这些结果表明,在空腹的小猎犬体内,胃排空的粒径阈值介于 660 至 1,200 微米之间,且无 IMMC 作用。
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引用次数: 0
Candesartan Cilexetil Formulations in Mesoporous Silica: Preparation, Enhanced Dissolution In Vitro, and Oral Bioavailability In Vivo 介孔二氧化硅中的坎地沙坦西来替酯制剂:制备、增强体外溶解度和体内口服生物利用度。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-01 DOI: 10.1016/j.xphs.2024.07.007
Candesartan cilexetil (CC) is one of well-tolerated antihypertensive drugs, while its poor solubility and low bioavailability limit its use. Herein, two mesoporous silica (Syloid XDP 3150 and Syloid AL-1 FP) and the corresponding amino-modified products (N-XDP 3150 and N-AL-1 FP) have been selected as the carriers of Candesartan cilexetil to prepare solid dispersion through solvent immersion, and characterized through using powder X-ray diffraction analysis, infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, and solid-state nuclear magnetic resonance spectroscopy, etc. The state of CC changed from crystalline to amorphous after loading onto the silica carriers, in which no interactions between CC and silica existed. Then, the dissolution behaviors in vitro were studied through using flow-through cell dissolution method. CC-XDP 3150 sample exhibited the most extensive dissolution, and the cumulative release of CC from it was 1.88-fold larger than that of CC. Moreover, the pharmacokinetic results in rats revealed that the relative bioavailability of CC-XDP 3150 and CC-N-XDP 3150 solid dispersions were estimated to be 326 % % and 238 % % in comparison with CC, respectively. Clearly, pore size, pore volume, and surface properties of silica carrier have remarkable effect on loading, dissolution and bioavailability of CC. In brief, this work will provide valuable information in construction of mesoporous silica-based delivery system toward poorly water-soluble drugs.
坎地沙坦西来替酯(Candesartan cilexetil,CC)是一种耐受性良好的降压药,但其溶解性差、生物利用度低等特点限制了它的使用。本文选择了两种介孔二氧化硅(Syloid XDP 3150和Syloid AL-1 FP)和相应的氨基修饰产品(N-XDP 3150和N-AL-1 FP)作为坎地沙坦西来替昔酯的载体,通过溶剂浸泡法制备固体分散体,并利用粉末X射线衍射分析、红外光谱、差示扫描量热法、扫描电子显微镜和固态核磁共振波谱等对其进行表征。结果表明,CC负载到二氧化硅载体上后,其状态由结晶变为无定形,CC与二氧化硅之间不存在相互作用。然后,通过流动细胞溶解法研究了体外溶解行为。结果表明,CC-XDP 3150样品的溶解度最大,CC的累积释放量是CC的1.88倍。此外,大鼠药代动力学结果显示,CC-XDP 3150 和 CC-N-XDP 3150 固体分散体的相对生物利用度分别为 CC 的 326% 和 238%。显然,二氧化硅载体的孔径、孔容和表面特性对 CC 的负载、溶解和生物利用率有显著影响。简而言之,这项研究将为构建基于介孔二氧化硅的低水溶性药物递送系统提供有价值的信息。
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Journal of pharmaceutical sciences
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