Simultaneousmagnetic resonance imaging and pharmacokinetic analysis of intramuscular depots
Simultaneousmagnetic resonance imaging and pharmacokinetic analysis of intramuscular depots
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DOI：
10.1016/j.jconrel.2016.02.029
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发表时间：
2016-04-10
影响因子：
10.8
通讯作者：
Weitschies, Werner
中科院分区：
文献类型：
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作者：
Probst, Mareike;Kuehn, Jens-Peter;Weitschies, Werner
本初步研究介绍了一种可能对肌肉注射药物吸收过程提供新见解的方法：将油状混悬液或扑热息痛(6 mg/kg体重)、强的松龙或其琥珀酸半琥珀酸钠水溶液(10 mg/kg体重)或双氯芬酸(10 mg/kg体重)注射到雌性Lewis大鼠(n=47)的后腿肌肉组织中。对于油性悬浮液，微粉颗粒悬浮在中链甘油三酯中。将水溶液缓冲至pH为7.4+/-0.5。在含有扑热息痛(对乙酰氨基酚)和双氯芬酸的制剂中加入聚乙二醇作为助溶剂，并将氯化钠加入到强的松龙琥珀酸半酯钠的水溶液中，以获得接近等渗的制剂。通过磁共振成像(MRI)对形成的储存库进行可视化，并对其体积和表面积进行表征。使用7T小型动物扫描仪，进行包括脂肪饱和度的T1加权和T2加权序列。同时采集血样进行药物定量分析，在未使用造影剂的情况下，MRI图像上可见水基溶剂和油性分散剂。由于徒手注射主要导致直接应用于筋膜内，从而导致储罐的快速移除，因此进行了MRI引导注射。将药代动力学数据与核磁共振数据进行比较，观察到最大血药浓度出现在从肌肉组织中去除溶剂和分散剂之前。因此，药物不会与仓库一起被吸收。此外，储存库的形状与吸收速率之间没有发现相关性。因此，储存库的表面积或体积较大并不会导致受试制剂中药物的更快释放或吸收。与扑热息痛和强的松龙制剂不同，含有双氯芬酸的制剂导致注射区域周围的间质液体大量积聚，这是急性局部反应的迹象。对肌肉组织的组织学分析显示，间质液量与淋巴细胞和粒细胞的渗入程度有明显的对应关系，表明组织反应。结论：结合MRI和药代动力学数据是深入了解肌肉内药物吸收过程的一种合适的方法。此外，MRI为检测肌肉注射剂型引起的局部副作用提供了极大的可能性。这可能是非常有用的临床前阶段，在开发新的肌肉制剂。(C)2016爱思唯尔B.V.保留所有权利。
The present pilot study introduces a method that might give novel insights in drug absorption processes from intramuscularly administered depots.An oily suspension or an aqueous solution of paracetamol (6 mg/kg body mass), prednisolone or its hemisuccinate sodium salt for the aqueous solutions (10 mg/kg body mass) or diclofenac (10 mg/kg body mass) was injected into the muscle tissue of the hind leg of female Lewis-rats (n=47). For the oily suspensions the micronized particles were suspended in medium-chain triglycerides. The aqueous solutions were buffered to a pH of 7.4 +/- 0.5. Polyethylene glycol was added as a cosolvent in the formulations containing paracetamol (acetaminophen) and diclofenac and sodium chloride was added to the aqueous solutions of prednisolone hemisuccinate sodium to achieve nearly isotonic formulations. The formed depot was visualized by magnetic resonance imaging (MRI) and characterized with regard to volume and surface area. A 7 T-small animal scanner was used and T1-weighted and T2-weighted sequences including a fat saturation were performed. Simultaneously blood samples were taken and the drugs were quantitatively analyzed.The water based solvent and the oily dispersion agent were visible in the MRI images without the use of contrast agents. Since a free hand injection mostly led to an application directly into the fascia, resulting in a fast removal of the depot, MRI-guided injection was conducted. Comparing pharmacokinetic data with MRI data it was observed that maximal blood levels occurred before the solvent and the dispersion agent were removed from the muscle tissue. Thus, the drug is not absorbed together with the depot. Furthermore, no correlation was found between the shape of the depot and the rate of absorption. Consequently, a higher surface area or volume of the depot did not result in a faster release or absorption of the drugs from the tested formulations. In contrast to the paracetamol and prednisolone formulations the formulations containing diclofenac led to a massive accumulation of interstitial fluid around the injection area being a sign for an acute local reaction. Histological analysis of the muscle tissue revealed a clear correspondence between the amount of interstitial fluid and the extent of infiltrating lymphocytes and granulocytes indicating a tissue response.In conclusion combining MRI with pharmacokinetic data is a suitable method to gain deeper insights into drug absorption processes from intramuscular depots. Furthermore, MRI offers a great possibility detecting local side effects caused by an intramuscularly applied dosage form. This might be very useful in preclinical phases during the development of new intramuscular formulations. (C) 2016 Elsevier B.V. All rights reserved.