<p>Quality by Design (QbD)-Based Numerical and Graphical Optimization Technique for the Development of Osmotic Pump Controlled-Release Metoclopramide HCl Tablets</p>

Abstract

Purpose: To develop the osmotically controlled-release gastroprokinetic metoclopramide HCl tablets, using quality by design (QbD)-numerical and graphical optimization technique for the treatment of gastroparesis and prophylaxis of delayed nausea and vomiting induced by low-high emetogenic chemotherapy. Methods: Formulations were designed by central composite design using Design Expert version 11.0.0, with osmogen concentration (X 1), orifice size (X 2), and tablet weight gain after coating (X 3) as input and in-vitro drug release at 1hr. (Y 1), 6 hrs. (Y 2), and 12 hrs. (Y 3), and the regression coefficient of drug release data fitted to zero-order, RSQ zero (Y 4) as output variables. Core tablets prepared by direct compression were coated with Opadry ® CA. The experimental design was validated by the polynomial equation. A correlation between predicted and observed values was evaluated by random checkpoint analysis. The optimized formulations were characterized for drug release, pH effect, osmolarity, agitation intensity, surface morphology, and stability study, and were subjected to accelerated studies according to ICH guidelines. Results: The interaction charts and response surface plots deduced a significant simultaneous effect of X variables on in vitro drug release and RSQ zero. The numerical optimization model predicted >90% drug release with X 1 (13.30%), X 2 (0.6 mm), and X 3 (7.96%). Random checkpoint analysis showed a good correlation between predicted and observed values. The optimized formulation followed zero-order kinetics (r 2 =0.9703) drug release. Shelf life calculated was 2.8 years as per ICH guidelines. Conclusion: The QbD-based approach was found successful in developing controlled release osmotic tablets of metoclopramide HCl, for reducing the dosage frequency, better emetic control, and improve patient compliance.

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™

“…On the contrary, formulations (F9-F16) containing a high level (+1) of Methocel ™ K4M released tramadol HCl at a zero-order rate, but the erratic release behavior was observed (see Table 6 and Figure 2B), which may be possibly associated with the excessive swelling of some units within 6-12 h. Lin et al also reported that when the outer coating is non-extensible and could not uphold a high intrinsic osmotic pressure, the osmotic pump suffered a failure which may lead to burst release (Lin et al, 2002). Only two formulations, F3 and F4, followed zero-order release rates, Y4 (0.992 and 0.994) which was observed independent of orifice size (F3 = 0.2 mm, F4 = 0.8 mm), however, Farooqi et al reported that initial burst release from osmotic tablets was due to large orifice size and minimal weight gain after coating (Farooqi et al, 2020). Moreover, in the present work, the maximum release was found to be more than 90%, up to 16 h. This shows that the inclusion of matrix forming polymer effectively controlled the tramadol HCl release rate, especially in the initial hours; however, at the 12th hour, the effect started to decrease (see Figures 3A-D, 4A-D).…”

“…The independent variables were NaCl (X1) as an osmotic agent, Methocel ™ K4M (X2) as a release rate controlling agent, percent weight gain after coating with Opadry ® CA (X3), and orifice diameter (X4), which were set at low and high levels coded as +1 and −1 respectively. The selection of in put variables and their level ranges were based on preliminary reported studies (El-Zahaby et al, 2018;Farooqi et al, 2020), so that their influence on critical response variables, drug release (%) at 2 h (Y1), 12 h (Y2), 16 h (Y3), and RSQ zero (Y4) can be studied (Shah and Prajapati, 2019). A stepwise regression analysis was conducted using a full factorial design to determine the influence of significantly controlling input factors on response variables (Xue et al, 2015).…”

“…The core tablets of trial formulations (F1-F16) containing 190 mg of tramadol HCl were compressed directly, then subjected to coating by Opadry ® CA dispersion as the semipermeable membrane former. Farooqi et al, in 2020 also applied Opadry ® CA as a semipermeable membrane former in developing an osmotically controlled release metoclopramide HCl tablet (Farooqi et al, 2020). The uniform stretching of the coating polymer onto the surface of the core tablet is shown in SEM images alongwith the presence of an evident orifice.…”

Formulation of metoclopramide HCl gastroretentive film and in vitro- in silico prediction using Gastroplus® PBPK software

“…However, MTC was previously prepared in a floating matrix tablet ( Singh et al 2007 ). Retention of MTC in the stomach guarantees the prolonged effect and improves systemic availability, which is considered to overcome nausea or vomiting due to chemotherapy treatment or migraine disease ( Friedman et al, 2008 , Sharif et al, 2019 , Farooqi et al, 2020 ). Also, the MTC’s prolonged effect formulations overcome the rapid systemic or plasma concentration dropping due to MTC’s short half-life of 5 to 6 h ( Zabirowicz,Gan 2019 ).…”

Development, optimization and pharmacokinetic evaluation of biphasic extended-release osmotic drug delivery system of trospium chloride for promising application in treatment of overactive bladder

“…This is achieved by using the technique of controlled release and bioavailability enhancement [3]. Controlled release pharmaceutical dosage forms are superior to conventional dosage forms of the same drugs due to reduced dosing frequency, improved pharmacological activity, and a reduction in the fluctuation of drug concentration in plasma resulting in efficient and prolonged therapeutic effect [4]. Extended-release drug delivery is beneficial to deliver the drug molecules with a short plasma half-life.…”