Gómez-Segura Lidia, Parra Alexander, Calpena Ana C, Gimeno Álvaro, Boix-Montañes Antonio
Department of Medicine and Animal Health, Faculty of Veterinary, Autonomous University of Barcelona, Bellaterra, 08193 Barcelona, Spain.
Department of Veterinary Medicine and Zootechnic, Faculty of Agricultural Sciences, University of Applied and Environmental Sciences, RX22+57 Bogota, Colombia.
Vet Sci. 2020 Oct 10;7(4):152. doi: 10.3390/vetsci7040152.
Carprofen (CP), a non-steroidal anti-inflammatory drug (NSAID), is profusely used in veterinary medicine for its analgesic and anti-inflammatory activity. Some undesirable effects are associated with its systemic administration. Alternative local routes are especially useful to facilitate its administration in animals. The main aim of this paper is to validate the suitability of ex vivo permeation experiments of CP with porcine mucous membranes (buccal, sublingual and vaginal) and ophthalmic tissues (cornea, sclera and conjunctiva) intended to be representative of naïve in vivo conditions. Chromatographic analysis of CP in membrane-permeated samples and drug-retained have been validated following standard bioanalytical guidelines. Then, recovery levels of drugs in tissue samples were assessed with aqueous phosphate buffered saline (PBS) buffer to preserve the histological integrity. Finally, as a proof of concept, a series of CP permeation tests in vertical Franz diffusion cells has been performed to evaluate permeation flux and permeability constants in all tissues, followed by a histological study for critical evaluation. Furthermore, synthetic tissue retention-like samples were prepared to verify the value of this experimental study. Results show linear relationships with good determination coefficient (R > 0.998 and R > 0.999) in the range of 0.78 to 6.25 mg/mL and 3.125 mg/mL to 100 mg/mL, respectively. Low limits of quantification around 0.40 µg/mL were allowed to follow permeation levels until a minimum of 0.40% of the locally-applied dose. This method showed a good accuracy and precision with values lower than 2%. After the recovery technique, reproducible values below 30% were achieved in all tissues, suggesting it is a non-damaging method with low efficiency that requires the use of further solvents to enhance the extraction percentages. After permeation and histology tests, no relevant peak interferences were detected, and no cell or tissue damage was found in any tissue. In conclusion, results demonstrate the suitability of this test to quantify the distribution of CP with good histological tolerability.
卡洛芬（CP）是一种非甾体抗炎药（NSAID），因其镇痛和抗炎活性而在兽医学中被大量使用。其全身给药会产生一些不良影响。替代的局部给药途径对于方便在动物体内给药特别有用。本文的主要目的是验证CP在猪黏膜（颊黏膜、舌下黏膜和阴道黏膜）和眼组织（角膜、巩膜和结膜）上进行的体外渗透实验的适用性，这些组织旨在代表未处理的体内条件。按照标准生物分析指南对膜渗透样品和药物保留样品中的CP进行了色谱分析验证。然后，用磷酸盐缓冲盐水（PBS）缓冲液评估组织样品中的药物回收率，以保持组织学完整性。最后，作为概念验证，在垂直式Franz扩散池中进行了一系列CP渗透试验，以评估所有组织中的渗透通量和渗透常数，随后进行组织学研究以进行关键评估。此外，制备了类似组织保留的合成样品以验证该实验研究的价值。结果表明，在0.78至6.25 mg/mL和3.125 mg/mL至100 mg/mL范围内，分别具有良好的测定系数（R>0.998和R>0.999）的线性关系。允许约0.40 µg/mL的低定量限跟踪渗透水平，直至局部给药剂量的至少0.40%。该方法显示出良好的准确度和精密度，值低于2%。采用回收技术后，所有组织均获得低于30%的可重现值，表明这是一种低效率的非损伤性方法，需要使用其他溶剂来提高提取率。经过渗透和组织学测试后，未检测到相关的峰干扰，且在任何组织中均未发现细胞或组织损伤。总之，结果表明该测试适用于定量CP的分布，且具有良好的组织学耐受性。
