SeDeM tool-driven full factorial design for osmotic drug delivery of tramadol HCl: Formulation development, physicochemical evaluation, and in-silico PBPK modeling for predictive pharmacokinetic evaluation using GastroPlus™

Authors: Saleem MT, Shoaib MH, Yousuf RI, Ahmed FR, Ahmed K, Siddiqui F, Mahmood ZA, Imtiaz MS
Publication: Front Pharmacol
Keywords: formulation design, gastroplus, in vitro dissolution, pbbm, PBPK modeling, physiologically based biopharmaceutics
Software: GastroPlus®
Division: Simulations Plus

Introduction

An elementary osmotic pump (EOP) is the simplest form of osmotic drug delivery system that consists of the combination of active pharmaceutical ingredients and excipients present within the core with or without an osmotic agent. The core system is externally covered with a non-extensible semipermeable membrane and a drilled orifice for drug release (Stuti et al., 2011). The gastrointestinal fluid imbibes within the core due to the osmotic pressure difference across the semipermeable membrane. Consequently, the release of the drug through the orifice takes place. Various formulation factors affect drug release from EOP like membrane thickness, orifice diameter, amount of plasticizer, and the concentration of osmotic agents. The EOP is a suitable dosage form for designing controlled release formulation of drugs like tramadol HCl having moderate to high solubility (Verma et al., 2000).

The SeDeM expert tool is diagrammatically used to assess the compressibility of pharmaceutical powder excipients and its suitability for commercial-scale tablet manufacturing by the direct compression method (Pérez et al., 2006). This method uses mathematical transformations on 12 flow and compressibility-related characteristics of the powders to generate a unique numerical and graphical profile on a scale of 0–10. Moreover, it also indicates the inherent deficiencies of active pharmaceutical ingredients (APIs) that could be overcome by adding appropriate excipients in required ratios. This system reduces the number of trials and time needed to develop an optimized formulation for commercial tablet manufacturing by direct compression (Suñé-Negre et al., 2008).

The “Advanced Compartmental and Transit” (ACAT) model in PBPK modeling is an approach for determining the pharmacokinetics of drugs in a mechanistic manner. Various biopharmaceutics parameters such as physicochemical properties of the drug molecules (pKa, Log P, solubility, particles size, etc.), physiological conditions related to absorption (gastrointestinal pH, gut and tissues spaces, perfusion rate, etc.), and drug pharmacokinetics (volume of distribution, clearance, rate constants, etc.) are processed to predict in-vivo pharmacokinetics and performance of formulated drugs (Kuentz et al., 2006).

Tramadol HCl is one of the generally safe opioid analgesics with a low potential for dependence. It is used in the pain management of osteoarthritis alone or combination with other analgesics (Scott and Perry, 2000). Compared to other opioid analgesics, tramadol HCl does not cause respiratory distress and gastrointestinal irritation. There are many drug delivery systems designed and available for tramadol used for different types of delivery. Usually, it is given 50 mg after every 4–6 h to manage chronic pain (Wiffen et al., 2017). The absorption of tramadol is complete and relative bioavailability is about 70% because of first-pass metabolism (Eassa and El-Shazly, 2013; Vazzana et al., 2015). Due to its high dosing frequency, tramadol HCl is a good candidate for controlled release formulation. It is a BCS class-I drug; therefore, designing sustained release formulations requires a higher proportion of matrix-based polymers (Klančar et al., 2015). The elementary osmotic pumps for such highly soluble drugs reduce the polymer concentration and help release the drug at zero order. This can be achieved by the combined effect of osmogen, orifice size on the surface of tablets, and different polymers (Prabakaran et al., 2003).

Though tramadol HCl is available as a controlled release system prepared by different techniques, no single comprehensive study was designed on an osmotic system with precision and accuracy with a robust zero-order release for this drug. The present work is based on using the SeDeM expert system for the first time in designing once-daily controlled-release osmotic tablets by direct compression method taking tramadol HCl as a model drug. The in-silico ACAT (PBPK) simulation, using GastroPlusTM, was also evaluated for estimating plasma drug concentration-time profiles of the optimized formulations.

By Muhammad Talha Saleem, Muhammad Harris Shoaib, Rabia Ismail Yousuf, Farrukh Rafiq Ahmed, Kamran Ahmed, Fahad Siddiqui, Zafar Alam Mahmood, Muhammad Sikandar & Muhammad Suleman Imtiaz