Gastroretentive raft liquid delivery system as a new approach to release extension for carrier-mediated drug

Abstract

Gabapentin (GBP), an antiepileptic and anti-neuropathic agent, suffers from short half-life (5-7 h), has narrow absorption window, and is absorbed via carrier-mediated mechanism resulting in frequent dosing, poor compliance, and poor bioavailability (<60%). Moreover, GBP is a freely water-soluble drug, thus it is considered a challenging candidate to be formulated as extended release dosage form. In this study, raft forming systems were investigated as a potential drug delivery system for prolonging gastric residence time of GBP. A 2³ full factorial design was adopted to study the effect of formulation variables (% gellan gum, % GMO, and % LM-pectin 101), on the percent of GBP released at different time intervals (1, 5, and 8 h) as well as the gel strength, and thus was achieved an optimized formula with zero-order release profile suitable for once-daily administration. In vivo assessment was performed in rats to evaluate gastric residence of the gel formed. In addition, the oral bioavailability of GBP relative to commercially available Neurontin^® immediate release oral solution was also investigated. Significant increase was observed for C_max, AUC_(0-t), and AUC_(0-∞). The increase in relative bioavailability of GBP from the optimized formula was 1.7 folds.

Keywords: GMO; Gabapentin; LM-pectin 101; gellan gum; raft forming systems.

Figure 1.

Light photos showing floating behavior of optimized GBP raft formula at different time intervals in 0.1 N HCl.

Figure 2.

Normal plot of GBP raft formulae for screening of the influence of the studied factors.

Figure 3.

In vitro release profile of GBP before and after coating with Eudragit NE 30D.

Figure 4.

In vitro release profile of GBP in 0.1 N HCl (F-1 to F-8).

Figure 5.

3D surface plot of GBP raft floating formulae after 1 h release in 0.1 N HCl.

Figure 6.

3D surface plot of GBP raft floating formulae after 5 h release in 0.1 N HCl.

Figure 7.

3D surface plot of GBP raft floating formulae after 8 h release in 0.1 N HCl.

Figure 8.

In vitro release profile of GBP from the optimized formula in 0.1 N HCl.

Figure 9.

Viscosity of sols of different GBP formulae.

Figure 10.

DSC thermograms of GBP, physical mixtures, and optimized formula.

Figure 11.

XRD diffractograms of GBP, physical mixtures, and optimized formula.

Figure 12.

SEM of GBP pure drug crystals and GBP crystals coated with Eudragit NE 30D.

Figure 13.

Light photos showing presence of gels in rat stomach at different time intervals after oral administration of optimized formula.

Figure 14.

Average plasma concentration time profiles after single oral administration of both GBP raft forming systems and immediate release marketed Neurontin^® oral solution to six human volunteers.