Novel lipid-based vesicles for sustained buccal delivery of a local anaesthetic for oral pain relief

Abstract

There is a clinical need for a long acting topical anaesthetic formulation that could be applied by patients themselves, dentists, or health care professionals, therefore the project aim was to develop and prepare a mucoadhesive carrier for the buccal delivery of local anaesthetic (LA), embedded into fast disintegrating film to achieve sustained local pain relief. Novel transfersomes loaded with LA such as lidocaine could be a superior approach to improve patient compliance and achieve the required level of anaesthesia. Lidocaine-loaded transfersomes were optimised and formulated using a Taguchi design of experiment (DOE) in terms of phospholipid type, type of edge activator (EA) and ratio of phospholipid to EA. Transfersomes were characterised for size, polydispersity index (PDI), charge, and entrapment efficiency (%EE). The obtained transfersomes were 200 nm in size and with a good PDI around 0.3. A new HPLC method for lidocaine quantification was optimised and validated using a mobile phase of 30 % v/v PBS (0.01 M) and 70 % v/v Acetonitrile at a flow rate of 1 mL/min. Detection was carried out at 255 nm at 30 ˚C and the retention time was 2.84 minutes. Linearity was obtained over the range 0.1-2 mg/mL (R2 0.9999). The proposed method was shown to be valid for linearity, accuracy, sensitivity, intermediate precision and repeatability according to ICH guidelines. The %EE was dependent on the formulation parameters and was between 44-56%. Analysing the data by Taguchi DOE showed the effect of factors on both size and %EE were in the following rank order: lipid: EA ratio ˃EA type ˃lipid type. The type of lipid (natural or synthetic) showed no significant effect on transfersome size. Increasing the EA concentration reduced transfersome size, however, further increments of EA had an opposite effect, and transfersome size increased. Six transfersome samples were selected based on the analysis of the optimisation results, and their release profiles were assessed. All 6 samples proved that the optimised transfersomes can be used as a sustained release delivery system of LA as they released lidocaine slowly over 24h. It was believed that incorporation of mucoadhesive polymers into the delivery system would prolong their residence time at the buccal cavity. Thus, three different polymers (HPMC K4M, HPMC K15M, and chitosan HCl) were screened for forming a continuous coating layer, aiming to preserve the uniform nanosize of transfersomes as well as enhancing the %EE. There was a clear indication of coating layer formation as all formulations showed an increased size afterwards. However, transfersomes coated with HPMC K4M and K15M failed to keep the nanosize or homogenous distribution obtained with the uncoated ones. Although chitosan HCl coated transfersomes showed a slight increment in the size as well, except formulation F5 at low chitosan HCl concentrations (i.e. 0.1 and 0.2 % w/v). Not only did formulation F5 show a non-significant difference in size after coating with chitosan HCl but it also had a higher drug entrapment (84%) compared to the uncoated sample (49%). Therefore, the chitosan-coated formulation (F5-CH) was selected and tested for mucoadhesion and drug release properties. F5-CH exhibited a sustained release profile over 24 h with an immediate release of 23.4% during the first hour, which could guarantee the immediate effect of LA. These findings proposed a novel buccal drug delivery system utilising chitosan HCl coated transfersomes. Three different cell lines (NOK, MRC5, MRC5-SV2) were employed to confirm the safety of coated transfersomes. Which proved to be completely safe and non-toxic at the intended concentration to be delivered. The ex vivo model proved the successful formation of a sustained delivery system, as the drug released from the chitosan coated transfersomes slowly with 80% drug accumulation after 24 h. Single layer films loaded with the coated transfersomes were successfully developed using a mixture of mucoadhesive polymers (HPC and PVA). A simple casting method was used and the produced films disintegrated on average at 2.75 min. They showed good mechanical properties and flexibility, in addition to have a pH of 7.9 that is well tolerated in the buccal mucosa. The content uniformity was confirmed and the drug release from transfersomes was not affected by their loading into polymeric film.