含速释成分的曲马多新型缓释双层片剂的开发、理化特性和药代动力学研究,供每日两次服用

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Naoki Ishitsubo, Shinji Oguro, Hirotoshi Shimahashi, Masato Kawanishi, Takeshi Adachi, Kenji Mitsuda, Nobuyuki Ishibashi
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引用次数: 0

摘要

背景和目的目前市场上销售的曲马多口服固体制剂存在一些潜在的问题,包括由于每天服用的剂量较多,服用速释(IR)制剂的依从性降低,以及服用缓释(SR)制剂后血中曲马多浓度上升缓慢,可能无法达到快速镇痛效果。为了克服这些潜在的问题,我们开发了一种由IR层和SR层组成的曲马多每日两次双层片剂。方法对五种双层片剂(指定为片剂 A-E)进行了溶解试验,并对片剂 A 和 B 进行了药代动力学研究,以探讨双层片剂中 IR 层/SR 层的适当比例。结果调整片剂 A-E 的 IR 层和 SR 层中的赋形剂和曲马多含量后,其溶解曲线发生了变化,而这种变化是可以根据其成分预测到的。在药代动力学研究中,服用 A 片(IR:SR:20:80 毫克)和 B 片(40:60 毫克)后曲马多达到最大血浆浓度(tmax)的时间短于市售的 SR 片,半衰期(t1/2)长于市售的 IR 片。对于 C-E 片剂,进食后给药不会影响曲马多的浓度曲线下面积(AUC)或最大药物浓度(Cmax),但与空腹给药相比,tmax 延长了约 1 小时。D 片(IR:SR:35:65 毫克)在空腹状态下的 tmax 和 t1/2 平均值(± 标准偏差)分别为 1.09 ± 0.56 小时和 7.82 ± 0.85 小时。结论为了解决现有曲马多制剂可能存在的问题,我们开发了一种曲马多的日服两次缓释双层制剂,由IR层和SR层组成。药代动力学研究证实,给药后血浆中曲马多的浓度会迅速升高并长期保持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Development, Physicochemical Characteristics and Pharmacokinetics of a New Sustained-Release Bilayer Tablet Formulation of Tramadol with an Immediate-Release Component for Twice-Daily Administration

Development, Physicochemical Characteristics and Pharmacokinetics of a New Sustained-Release Bilayer Tablet Formulation of Tramadol with an Immediate-Release Component for Twice-Daily Administration

Background and Objective

There are some potential concerns about the currently marketed solid oral dosage forms of tramadol, including decreased adherence to immediate-release (IR) formulations due to the high number of doses taken each day and the slow rise in the blood tramadol concentration after administration of sustained-release (SR) formulations, which may not achieve a rapid analgesic effect. To overcome these potential concerns, a twice-daily double-layered tablet formulation of tramadol comprising IR and SR layers was developed. This article reports studies that assessed its physicochemical and pharmacokinetic properties.

Methods

Dissolution tests of five bilayer tablet formulations (designated tablets A–E) and pharmacokinetic studies of tablets A and B were conducted to investigate the appropriate ratio of the IR/SR layers in the double-layered tablet. Additionally, pharmacokinetic studies of three finished dosage formulations (tablets C–E) were performed in healthy adult males to investigate the effect of food intake on drug absorption.

Results

Adjusting the excipients and tramadol content in the IR and SR layers of tablets A–E altered their dissolution profiles in a manner that could be predicted based on their compositions. The IR layer was released within 15 min, and the SR layer was slowly released over 10 h. In the pharmacokinetic study, the time to maximum plasma concentration (tmax) of tramadol after administration of tablets A (IR:SR: 20:80 mg) and B (40:60 mg) was shorter than that of a commercially available SR tablet, and the half-life (t1/2) was longer than that of a commercially available IR tablet. For tablets C–E, administration after food did not affect the area under the concentration-time curve (AUC) or maximum drug concentration (Cmax) of tramadol, but the tmax was prolonged by about 1 h compared with administration in fasting conditions. The mean ± standard deviation tmax and t1/2 for tablet D (IR:SR: 35:65 mg) in the fasting condition was 1.09 ± 0.56 h and 7.82 ± 0.85 h, respectively. The respective values in the fed condition were 2.47 ± 1.06 h and 7.12 ± 0.85 h, respectively.

Conclusions

To address the potential concerns regarding existing formulations of tramadol, a twice-daily, extended-release bilayer formulation of tramadol consisting of an IR and SR layer was developed. Pharmacokinetic studies confirmed that the plasma tramadol concentration increased quickly after administration and was maintained over a long period of time.

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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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