In vitro evaluation of a self-emulsifying drug delivery system (SEDDS) for nasal administration of dimenhydrinate

Abstract

The objective of the study was the development and in vitro characterization of a self-emulsifying drug delivery system (SEDDS) for the nasal application of dimenhydrinate. Final composition of SEDDS was established based on drug solubility and stability studies. Dimenhydrinate was loaded into the SEDDS pre-concentrates to 7.5% (m/v). The droplet size of the final SEDDS formulations was in a range between 60 and 220 nm. Permeability, as well as tissue toxicity, of the formulations was investigated using bovine nasal mucosa. Enhancement in permeation up to 2.8-fold compared to pure dimenhydrinate was confirmed. Furthermore, toxicity studies did not reveal any serious tissue damages related to the SEDDS. Additionally, irritation potential of SEDDS was evaluated in ciliary beat frequency measurements. Incorporation of dimenhydrinate into SEDDS might therefore be considered as a promising approach within the field of nasal delivery of antiemetics by utilizing permeation enhancement strategy.

Keywords: Dimenhydrinate; Emulsion; Nasal administration; Permeation; Self-emulsifying drug delivery systems.

Fig. 1

Pseudo-ternary phase diagrams of formulation F1 (a), F2 (b), and F3 (c). Components are represented in volume percent and the shaded areas depict the regions of emulsion. Diagram a: surfactant phase (Cremophor EL/PEG 200/ PG (1.25/1/1)), oil phase (Transcutol HP/Capmul MCM (1/1.3)); diagram b: surfactant phase (Cremophor EL/PEG 400/PG (1.5/1/1)), oil phase (Transcutol HP/Capmul PG-8 (1/1)); diagram c: surfactant phase (Cremophor EL/PEG 400/ PG (2/1/1)), oil phase (Transcutol HP/Capmul MCM (2/1)). Excipients were mixed at 25 °C. Dark gray area, blank formulation; light gray area, dimenhydrinate loaded formulation

Fig. 2

TEM images of F1 (a), F2 (b), and F3 (c)

Fig. 3

Force-time diagrams of the spreadability investigations of the pre-concentrates. The areas between the graphs and x-axis are filled as follows: light gray (F1), dark gray (F2), and light gray with striped pattern (F3). A₁: work of spreading, F₁: firmness, A₂: work of adhesion, F₂: stickiness

Fig. 4

Assessment of the spreadability. Values are means of at least three experiments ± SD (*P < 0.05, **P < 0.01, ***P < 0.001). Light gray columns display the firmness and the work of spreading is represented by the dark gray columns. a Data of the single components. b Values of the SEDDS pre-concentrates of the formulations F1, F2, and F3

Fig. 5

Mucosal permeation study of SEDDS. Graphs display the percentage of permeated dimenhydrinate across bovine nasal mucosa within 4 h incubation at 37 °C. Values represent data of at least three replications plus standard deviation (*P < 0.05, ***P < 0.001). F1 (○, dashed line), F2 (▽,solid line), F3 (◇, dotted line) and standard (△, solid line)

Fig. 6

Evaluation of the toxicity of SEDDS to bovine nasal tissue. a Percentage of cytotoxicity determined performing LDH assay after the permeation study. b Assessment of cell viability with resazurin after 4 h incubation of bovine nasal mucosa with SEDDS in dilutions 1:2 (light gray) and 1:50 (dark gray). Values are means of at least three experiments ± SD (*P < 0.05, **P < 0.001)

Fig. 7

Ciliary beat frequency (CBF) of the control (initial beating frequency) and the recorded samples after treatment with the formulations and wash-off with Ringer’s solution. Values are means of at least three analyses ± SD (*P < 0.05, **P < 0.001)