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Physical Compatibility and Chemical Stability of Bupivacaine, Epinephrine, and Nalbuphine in 0.45% Sodium Chloride, 0.9% Sodium Chloride, or Plasma-Lyte A. 布比卡因、肾上腺素和纳布啡在 0.45%氯化钠、0.9%氯化钠或血浆-Lyte A 中的物理兼容性和化学稳定性。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-17 DOI: 10.1016/j.xphs.2024.10.003
Zachary SengerGladys Uwera Mihigo, Mitchell S Howard, Gabriella Baki, Mariann D Churchwell, Virender Kumar, Justin P Reinert

Purpose: To evaluate the physical compatibility and chemical stability of the combination of bupivacaine, epinephrine, and nalbuphine when in mixed in 0.45% sodium chloride, 0.9% sodium chloride, or Plasma-Lyte A.

Methods: Bupivacaine 0.5% (15 mL), epinephrine 1 mg/mL (0.15 mL), and nalbuphine 10 mg/mL (0.5 mL) were combined to prepare three distinct admixtures with 0.45% sodium chloride, 0.9% sodium chloride, or Plasma-Lyte A. Visual inspection, spectrophotometric analysis, pH evaluation, and high-performance liquid chromatography tests were conducted at hours 0, 1, 5, 8, and 24. Samples were stored in ambient room light at room temperature.

Results: There were no demonstrable changes identified in any of the samples with regards to visual changes, spectrophotometric absorbance, or pH. In each studied fluid, the remaining drug concentrations were an average of 100.92% bupivacaine, 95.8% epinephrine, and 100.02% nalbuphine.

Conclusions: The combination of bupivacaine, epinephrine, and nalbuphine was found to be physically compatibility and chemically stable for a period of 24 hours at room temperature.

目的:评估布比卡因、肾上腺素和纳布啡在 0.45%氯化钠、0.9%氯化钠或 Plasma-Lyte A 中混合时的物理相容性和化学稳定性:将 0.5%布比卡因(15 毫升)、1 毫克/毫升肾上腺素(0.15 毫升)和 10 毫克/毫升纳布啡(0.5 毫升)与 0.45% 氯化钠、0.9% 氯化钠或 Plasma-Lyte A 混合,制备三种不同的混合物。在 0、1、5、8 和 24 小时进行目测、分光光度分析、pH 值评估和高效液相色谱测试。样品在室温、环境光下保存:结果:没有发现任何样品在视觉变化、分光光度吸光度或 pH 值方面发生明显变化。在所研究的每种液体中,剩余药物浓度平均为 100.92% 布比卡因、95.8% 肾上腺素和 100.02% 纳布啡:结论:布比卡因、肾上腺素和纳布啡的组合在室温下 24 小时内具有物理相容性和化学稳定性。
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引用次数: 0
Impact of drug incorporation into micelle on reduced griseofulvin and meloxicam permeation across a hollow fiber membrane. 药物加入胶束对降低格列齐芬和美洛昔康在中空纤维膜上的渗透率的影响
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-17 DOI: 10.1016/j.xphs.2024.10.017
Roshni P Patel, Lynne S Taylor, James E Polli

A hollow fiber membrane (HFM) was previously characterized as a potential permeation component of a dissolution/permeation system. Two objectives were to assess the impact of micellization on drug permeation across HFM and identify a preferred permeation model from three models: permeation from only free drug, permeation from both free drug and micelle-bound drug, and permeation with enhancement from micelle shuttling. HFM studies were conducted under unsaturated drug conditions, using griseofulvin and the more hydrophilic drug meloxicam, with and without surfactant [sodium lauryl sulfate, polysorbate 80, and polyoxyethylene (10) lauryl ether]. Griseofulvin was micelle incorporated to a greater extent than meloxicam, such that griseofulvin flux decreased to a greater extent than for meloxicam. The griseofulvin permeation model from only free drug was rejected, since griseofulvin flux required free drug to be about 5-20 fold higher in HFM flux studies than supported by solubility studies, depending on surfactant. Permeation from both free griseofulvin and micelle-bound griseofulvin successfully accommodated observed flux, where micelle permeability was about 5-fold lower than free drug permeability for HFM with 10KDa MWCO. Permeation with enhancement from micelle shuttling was not the preferred explanation, although the model accommodated flux data and provided aqueous boundary layer thicknesses similar to other setups.

中空纤维膜(HFM)是溶解/渗透系统中潜在的渗透元件,以前曾对其进行过表征。研究的两个目的是评估胶束化对药物在中空纤维膜上渗透的影响,并从以下三种模式中确定首选渗透模式:仅从游离药物中渗透、从游离药物和胶束结合药物中渗透,以及通过胶束穿梭增强渗透。在不饱和药物条件下,使用格列齐芬和亲水性较强的药物美洛昔康,在添加或不添加表面活性剂[十二烷基硫酸钠、聚山梨醇酯 80 和聚氧乙烯(10)十二烷基醚]的情况下进行了高频渗透研究。与美洛昔康相比,吉西福林的胶束掺入程度更高,因此吉西福林通量的下降程度也比美洛昔康更大。只从游离药物渗透格列齐芬的模型被否定,因为在高频通量研究中,格列齐芬的通量要求游离药物比溶解度研究支持的高出约 5-20 倍,具体取决于表面活性剂。在截留分子量为 10KDa 的 HFM 中,游离格列齐芬和胶束结合格列齐芬的渗透性比游离药物的渗透性低约 5 倍,因此成功地适应了观察到的通量。尽管该模型能够容纳通量数据,并提供与其他设置相似的水边界层厚度,但胶束穿梭产生的渗透增强效应并不是首选的解释。
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引用次数: 0
Evaluation of the impact of the polymer end groups and molecular weight on in vitro and in vivo performances of PLGA based in situ forming implants for ketoprofen. 评估聚合物端基和分子量对基于 PLGA 的酮洛芬原位成型植入物的体外和体内性能的影响。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-17 DOI: 10.1016/j.xphs.2024.10.019
Sanjib Saha, Xinhao Lin, Liping Zhou, Aixiang Xue, Eric Gosselin, Paresh P Chothe, Mittal Darji, Xiuling Lu, Wenzhan Yang

In situ forming implants are appealing long-acting dosage forms for both preclinical and clinical applications due to their simple manufacturing process and easy delivery. This study aims to develop extended-release in situ forming solid implants for subcutaneous administration using two types of commercially available triblock poly (lactic-co-glycolic acid)-poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PLGA-PEG-PLGA) polymers, with either an acid or ester end group. Both types of polymers instantly form in situ implants when injected directly into an aqueous medium. The performance of these implants, containing a model compound ketoprofen, was evaluated by comparing the in vitro drug release profiles with the in vivo performance following subcutaneous administration in rats. Analytical characterizations of two representative in situ implants were conducted to understand their structural impact on polymer degradation and drug release. All tested in situ forming implants demonstrated prolonged drug release profiles both in vitro and in vivo. This study illustrates the successful preparation of sustained-release in situ forming implant formulations for ketoprofen using commercially available polymers, with the molecular weight and the end group of the polymers affecting their degradation and the drug release from the in situ formed implants.

原位成型植入物因其生产工艺简单、给药方便而成为临床前和临床应用中极具吸引力的长效剂型。本研究旨在开发用于皮下给药的缓释原位成型固体植入物,使用两种市售的三嵌段聚(乳酸-聚乙二醇)-聚(乳酸-聚乙二醇-聚乳酸)(PLGA-PEG-PLGA)聚合物,其端基均为酸或酯。这两种聚合物直接注入水介质后,可立即形成原位植入体。通过比较体外药物释放曲线和大鼠皮下注射后的体内表现,评估了这些含有模型化合物酮洛芬的植入物的性能。对两种具有代表性的原位植入物进行了分析,以了解其结构对聚合物降解和药物释放的影响。所有接受测试的原位成型植入物在体外和体内都表现出较长的药物释放曲线。这项研究表明,使用市售聚合物可以成功制备酮洛芬的原位成型缓释植入剂配方,聚合物的分子量和端基会影响其降解和原位成型植入剂的药物释放。
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引用次数: 0
Mechanisms of drug release from a melt-milled, poorly soluble drug substance. 熔融研磨的难溶性药物释放机制
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-17 DOI: 10.1016/j.xphs.2024.10.016
Dominik Sleziona, David R Ely, Markus Thommes

Increasing the dissolution kinetics of low aqueous soluble drugs is one of the main priorities in drug formulation. New strategies must be developed, which should consider the two main dissolution mechanisms: surface reaction and diffusion. One promising tool is the so-called solid crystal suspension, a solid dispersion consisting of purely crystalline substances. In this concept, reducing the drug particle size and embedding the particles in a hydrophilic excipient increases the dissolution kinetics. Therefore, a solid crystal suspension containing submicron drug particles was produced via a modified stirred media milling process. A geometrical phase-field approach was used to model the dissolution behavior of the drug particles. A carrier material, xylitol, and the model drug substance, griseofulvin, were ground in a pearl mill. The in-vitro dissolution profile of the product was modeled to gain a deep physical understanding of the dissolution process. The used numerical tool has the potential to be a valuable approach for predicting the dissolution behavior of newly developed formulation strategies.

提高低水溶性药物的溶解动力学是药物制剂的主要优先事项之一。必须开发新的策略,其中应考虑到两种主要的溶解机制:表面反应和扩散。一种很有前途的工具就是所谓的固体晶体悬浮液,一种由纯晶体物质组成的固体分散体。在这一概念中,减小药物颗粒大小并将颗粒嵌入亲水性赋形剂中可提高溶解动力学。因此,通过改良的搅拌介质研磨工艺生产出了含有亚微米药物颗粒的固体晶体悬浮液。几何相场法被用来模拟药物颗粒的溶解行为。在珠磨机中研磨载体材料木糖醇和模型药物格列齐特。对产品的体外溶解曲线进行建模,以深入了解溶解过程的物理特性。所使用的数值工具有望成为预测新开发制剂溶出行为的重要方法。
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引用次数: 0
Differentiation of puerarin chelate from salt by phase solubility test. 通过相溶性测试区分葛根素螯合物和盐类
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-16 DOI: 10.1016/j.xphs.2024.10.007
Yuanfeng Wei, Xin Chen, Runxue Ding, Jingwen Zhang, Hui Chen, Junxiao Zhu, Jianjun Zhang, Peiya Shen

Different from salt, metal chelate is a novel state of drug constructed by more separate coordinate bonds to form a chelating circle. Due to their composition similarity, it is hard to distinguish them except identifying ionic bond (i.e., salt) or coordinate bond (i.e., chelate) in the single crystal structure. In this study, sodium chelate (CDCC No: 1865670) and lithium salt (CDCC No: 2161617) of puerarin (PUE) was prepared. In addition to difference in single crystal structure, it was found that they showed totally different phase solubility behaviors: lithium salt demonstrated a typical inverse proportion curve as other common salts, while sodium chelate exhibited disordered scatters. However, when incorporating the unit PUE-Na complex in solution state and complexation constant K11 in chemical equation, the scatters in phase solubility diagram of chelate could be well fitted and the value of K11 was dramatically higher with orders of magnitude than the dissociation constant Kc; while processing phase solubility curve of lithium salt by incorporating complex item, it could not well match the curve at all. PUE sodium chelate is more likely to be a weak electrolyte with partial dissociation, while PUE lithium salt acted as a strong electrolyte with complete dissociation. The phase solubility test would be served as a surrogate tool for differentiation of chelates from salts when single crystal was not available.

与盐不同,金属螯合物是由多个独立的配位键构成螯合圈的一种新型药物状态。由于它们的成分相似,除了在单晶结构中识别离子键(即盐)或坐标键(即螯合物)外,很难将它们区分开来。本研究制备了葛根素的钠螯合物(CDCC 编号:1865670)和锂盐(CDCC 编号:2161617)。除了单晶结构的差异外,研究还发现它们表现出完全不同的相溶解行为:锂盐与其他常见盐类一样表现出典型的反比例曲线,而螯合钠则表现出无序的散射。然而,当在溶液状态下加入单位 PUE-Na 复合物并在化学方程式中加入络合常数 K11 时,螯合物相溶解度图中的散点可以很好地拟合,且 K11 的值显著高于解离常数 Kc 的数量级;而通过加入络合物项处理锂盐的相溶解度曲线,则完全不能很好地匹配曲线。PUE 钠螯合物更可能是部分解离的弱电解质,而 PUE 锂盐则是完全解离的强电解质。在没有单晶的情况下,相溶解度测试可作为区分螯合物和盐的替代工具。
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引用次数: 0
An integrated approach combining experimental, informatics and energetic methods for solid form derisking of PF-06282999. 结合实验、信息学和能量学方法的综合方法用于 PF-06282999 的固态脱脂。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-16 DOI: 10.1016/j.xphs.2024.10.013
Ghazala Sadiq, Shubham Sharma, Joanna S Stevens, Pablo Martinez-Bulit, Lily M Hunnisett, Christopher Cameron, Brian Samas, Emma Hawking, Nicholas Francia, Jeff Lengyel, Elna Pidcock, Sadia Rahman, Matthew Nisbet, Kevin Back, Cheryl Doherty, Patricia Basford, Timothy G Cooper, Garry O'Connor, Rajni M Bhardwaj

The landscapes of observed and predicted three-dimensional crystal packing arrangements of small-molecule drug candidates can be complex. The possible appearance of a more thermodynamically stable solid form during drug development has led to the digital workflow of informatics-based risk assessments, named a Solid Form Health Check. Herein, we describe the use of a combined approach consisting of experiments, informatics together with energetic calculations in analysis of four competing polymorphs of PF-06282999, a myeloperoxidase (MPO) inhibitor with conformational flexibility and multiple plausible hydrogen bond networks. This combined approach offered a comprehensive understanding of the solid form structure, properties, and performance, ensuring robust solid form derisking and selection.

小分子候选药物观察到的和预测的三维晶体堆积排列情况可能非常复杂。在药物开发过程中,可能会出现热力学上更稳定的固体形式,这就促成了基于信息学的风险评估数字化工作流程,并将其命名为 "固体形式健康检查"。在本文中,我们介绍了在分析 PF-06282999 的四种竞争多晶型时使用的实验、信息学和能量计算相结合的方法,PF-06282999 是一种髓过氧化物酶 (MPO) 抑制剂,具有构象灵活性和多种可信的氢键网络。这种综合方法提供了对固态结构、特性和性能的全面了解,确保了稳健的固态去风险和选择。
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引用次数: 0
Dissolution, phase behavior and mass transport of amorphous solid dispersions in aspirated human intestinal fluids. 无定形固体分散体在吸入人体肠液中的溶解、相态行为和质量传输。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-16 DOI: 10.1016/j.xphs.2024.10.005
Ahmed Elkhabaz, Dana E Moseson, Joachim Brouwers, Patrick Augustijns, Lynne S Taylor

Amorphous solid dispersions (ASDs) typically show improved dissolution and generate supersaturated solutions, enhancing the oral bioavailability of poorly soluble drugs. To gain insights into intraluminal ASD behavior, we utilized two poorly soluble drugs with different crystallization tendencies, atazanavir and posaconazole, prepared as ASDs at a 10% drug loading with hydroxypropyl methylcellulose acetyl succinate (HPMCAS). We evaluated their release in aspirated fasted-state human intestinal fluid (FaHIF), and multi-component fasted-state simulated intestinal fluid (composite-FaSSIF), characterizing the supersaturation profiles and drug-rich nanodroplets that formed. Complete release was observed for atazanavir ASDs over a 90 min period. Flux for dissolved atazanavir ASDs remained high over the experimental time period of 3 h. In contrast, posaconazole solution concentrations were initially high and then decreased. Likewise, flux was initially high and then decreased where these changes are attributed to crystallization of the drug. Generation of spherical nano-sized amorphous droplets of ∼100-150 nm was found to occur in ex vivo FaHIF media for both ASDs, maximizing the diffusive flux during the supersaturation window. Moreover, buffer capacity differences were postulated to influence release rates of ASDs in simulated vs aspirated fluids. Importantly, the solution phase phenomena observed during ASD release in simulated fluids, namely amorphous nanodroplet formation and drug crystallization, were also found to occur in aspirated luminal fluids.

无定形固体分散体(ASD)通常能改善溶解度并生成过饱和溶液,从而提高溶解度低的药物的口服生物利用度。为了深入了解无定形固体分散体在肠道内的表现,我们采用了两种具有不同结晶倾向的低溶性药物--阿扎那韦和泊沙康唑,用羟丙基甲基纤维素乙酰琥珀酸酯(HPMCAS)制备成药物载量为 10%的无定形固体分散体。我们评估了这两种药物在吸入的空腹状态人体肠液(FaHIF)和多组分空腹状态模拟肠液(复合-FaSSIF)中的释放情况,分析了过饱和度曲线和形成的富含药物的纳米液滴。观察到阿扎那韦 ASD 在 90 分钟内完全释放。相比之下,泊沙康唑溶液的浓度最初较高,随后有所下降。同样,通量也是先高后低,这些变化归因于药物的结晶。研究发现,两种 ASD 在体内外 FaHIF 培养基中都会产生 100-150 纳米大小的球形无定形液滴,从而在过饱和窗口期使扩散通量最大化。此外,还推测缓冲能力的差异会影响 ASD 在模拟液与吸入液中的释放率。重要的是,在模拟液体中观察到的 ASD 释放过程中的溶液相现象,即无定形纳米液滴的形成和药物结晶,在吸入的管腔液体中也会发生。
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引用次数: 0
Impact of Surface Tension, Viscosity, Pump Settings, and Nozzle Size on Filling Process Capability and Accuracy in High-Concentration Biopharmaceuticals. 表面张力、粘度、泵设置和喷嘴尺寸对高浓度生物制药灌装工艺能力和精度的影响
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-16 DOI: 10.1016/j.xphs.2024.10.020
Qizhou Chen, Chenxi Wang, Tingting Wang, Bin Lei, Jing Wang, Jeremy Guo

Filling is the final critical unit operation in the manufacturing process of liquid biological drug products. This paper thoroughly investigates the influence and mechanisms of peristaltic pump settings, nozzle size, product surface tension and viscosity on the biopharmaceutical filling processes based on the established filling process model of surrogates. Our study highlights the significant role of pump settings in influencing filling process capability indexes, in addition to their primary function of regulating flow rate. Surface tension minimally impacts flow behavior but significantly regulates the final drop's behavior, with lower surface tension increasing dripping tendencies. Viscosity proves crucial; higher viscosity intensifies friction and head loss of filling flow in tube/nozzle, causing pressure and flow rate losses, more pronounced dripping, and worse filling accuracy. Furthermore, nozzle size moderates the impact of pump settings, surface tension, and viscosity on filling performance. Larger nozzles help mitigate these effects, contributing to enhanced stability in filling performance under challenging conditions. For high-concentration biopharmaceuticals with elevated viscosity during filling, utilizing larger nozzles and reducing pump speed could achieve enhanced Cpk values and improved filling accuracy. Understanding the complex interactions among these factors is vital for optimizing the biopharmaceutical industry, promoting cost-effective practices, and enhancing production efficiency.

灌装是液体生物药品生产过程中的最后一个关键单元操作。本文基于已建立的代用灌装工艺模型,深入研究了蠕动泵设置、喷嘴尺寸、产品表面张力和粘度对生物制药灌装工艺的影响及其机理。我们的研究强调了泵的设置除了具有调节流速的主要功能外,还在影响灌装工艺能力指标方面发挥着重要作用。表面张力对流动行为的影响微乎其微,但对最终液滴行为的影响却很大,较低的表面张力会增加滴落倾向。粘度至关重要;粘度越高,管/喷嘴中充填流的摩擦和水头损失就越大,从而导致压力和流速损失,滴漏越明显,充填精度越差。此外,喷嘴的大小也会减缓泵的设置、表面张力和粘度对灌装性能的影响。较大的喷嘴有助于减轻这些影响,从而提高在苛刻条件下灌装性能的稳定性。对于在灌装过程中粘度较高的高浓度生物制药,使用较大的喷嘴并降低泵速可提高 Cpk 值并改善灌装精度。了解这些因素之间复杂的相互作用对于优化生物制药行业、促进成本效益实践和提高生产效率至关重要。
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引用次数: 0
Letter to Editor: Comments about "Structural studies of a non-stoichiometric channel hydrate using high resolution X-ray powder diffraction, solid-state nuclear magnetic resonance, and moisture sorption methods". 致编辑的信:关于 "利用高分辨率 X 射线粉末衍射、固态核磁共振和吸湿方法对非均匀通道水合物进行结构研究 "的评论。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-16 DOI: 10.1016/j.xphs.2024.10.006
Jean René Authelin
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引用次数: 0
Changes in drug crystallinity in a commercial tacrolimus amorphous formulation result in variable pharmacokinetics. 商用他克莫司无定形制剂中药物结晶度的变化导致不同的药代动力学。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-15 DOI: 10.1016/j.xphs.2024.09.025
Lynne S Taylor, Niraj E Trasi, Hitesh S Purohit, Dajun Sun, Minori Kinjo, Zhanglin Ni, Sanjida Mahjabeen, Kairui Kevin Feng, Wei-Jhe Sun, Murali K Matta, Brian Decker, Raymond E Galinsky

Tacrolimus capsules contain the drug as the amorphous form. It is well known that drug crystallinity is a risk factor for the performance of amorphous formulations. This study investigated the impact of varying levels of crystalline drug on the pharmacokinetics of tacrolimus following oral dosing of a 5 mg capsule under fasting conditions. Two treatments with percent crystallinity of 20% and 50% were achieved by exposing a marketed generic tacrolimus product to open dish storage conditions of 35 °C and 75% relative humidity (RH) for up to 20 days. Crystallinity was monitored with X-ray powder diffraction. Prograf®, the reference listed drug (RLD), an amorphous generic drug product, and generic drug products containing 20% and 50% crystalline tacrolimus were evaluated. All four treatments were administered to healthy participants in a randomized, single-dose, four-treatment, four-period, four-way crossover study. Blood sampling occurred over 24 h. The amorphous generic tacrolimus product was determined not to be bioequivalent to the RLD. The capsules containing both 20% and 50% crystalline tacrolimus also failed the bioequivalence recommendations when compared to the amorphous generic or to the RLD. Both levels of crystalline tacrolimus resulted in BE failure for both Cmax and AUC parameters. The impact of tacrolimus crystallization was greater for maximum blood concentration (Cmax) values relative to the area-under-the-curve (AUC) values. This study demonstrates that crystalline tacrolimus formed in a marketed generic product and these changes resulted in variable pharmacokinetics which could be of significant clinical concern.

他克莫司胶囊含有无定形形式的药物。众所周知,药物结晶是影响无定形制剂性能的一个风险因素。本研究调查了在空腹条件下口服 5 毫克胶囊后,不同程度的药物结晶对他克莫司药代动力学的影响。将市场上销售的普通他克莫司产品置于 35°C 和 75% 相对湿度 (RH) 的开口盘储存条件下长达 20 天,可获得结晶度分别为 20% 和 50% 的两种处理。结晶度通过 X 射线粉末衍射法进行监测。评估了普罗格拉夫®、参比上市药物(RLD)、无定形仿制药产品以及含有20%和50%结晶他克莫司的仿制药产品。在一项随机、单剂量、四疗程、四阶段、四交叉研究中,健康参与者服用了所有四种治疗药物。采血时间为 24 小时。经测定,无定形非专利他克莫司产品与RLD不具有生物等效性。含有 20% 和 50% 结晶他克莫司的胶囊与无定形仿制药或 RLD 相比,也未通过生物等效性建议。两种含量的结晶他克莫司均导致 Cmax 和 AUC 参数的生物等效性失败。相对于曲线下面积(AUC)值,他克莫司结晶对最大血药浓度(Cmax)值的影响更大。这项研究表明,在市场上销售的非专利产品中形成了结晶的他克莫司,这些变化导致了药代动力学的变化,可能会引起重大的临床问题。
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引用次数: 0
期刊
Journal of pharmaceutical sciences
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