Development of a liposomal acyclovir mucoadhesive film

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). The efficacy of oral acyclovir is limited as a result of its low bioavailability (15-30%) as it is poorly water soluble and therefore requires a frequent dosing regimen. When orally administered, peak plasma concentration occurs after 1.5–2.5 hours, while its elimination half-life is approximately 2-3 hours. Acyclovir displays poor solubility in water and in lipid bilayers, which leads to poor drug levels at target sites after oral, local, or parenteral administration. In order to improve this lack of solubility, novel amphiphilic derivatives have been designed to form nanoparticles, which allow for the efficient encapsulation of this hydrophobic antiviral agent. Reformulation of drugs in liposomes has provided an opportunity to enhance the therapeutic indices of various agents mainly via alteration of their bio-distribution. Liposomal drug delivery systems have received considerable attention due to their immense advantages which include, effective encapsulation of both small and large molecules that have a wide range of hydrophobicity levels and pKa values, prolonging and targeting release of therapeutic agents by modification of liposomal surface and also minimising clinical drug dose thus reducing toxicity effects. Liposomes exhibit a number of special biological characteristics, including specific interactions with biological membranes and various cells, hence, liposomes are used as biocompatible carriers to improve delivery properties across mucus membranes. Mucoadhesive dosage forms may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. The aim of this study was to develop an acyclovir liposomal mucoadhesive film by actively encapsulating acyclovir into liposomes and preparing a mucoadhesive film to optimise delivery of acyclovir liposomes at target sites. To actively encapsulate acyclovir and prepare the acyclovir-containing liposomes, a comprehensive statistical methodology was used in optimising the liposome formulation to encapsulate acyclovir. Central composite design was used as the response surface methodology statistical tool to design and develop an optimised method for active encapsulation of acyclovir into liposomes. The predicted optimised encapsulation parameters were incubation temperature of 60 °C and incubation time of 45 minutes. The mean percentage encapsulation calculated was 27.72%. The overall average size of the liposomes was 99.5 nm with a narrow distribution polydispersity index of 0.105 and were physically characterised as small unilamellar vesicles which possessed an average zeta potential of -45.6 mV. High Performance Liquid Chromatography (HPLC) was used to analyse and determine acyclovir drug content in the liposomes and drug release pattern from the mucoadhesive film. Polyvinyl-pyrrolidone (PVP) and Polyethylene glycol (PEG) were used in the preparation of mucoadhesive film, in which the acyclovir encapsulated liposomes were incorporated. The average amount of acyclovir drug content quantified to be in 4 cm2 of the mucoadhesive film was 36.8543 μg. The average tensile strength of the mucoadhesive film was determined to be 3.06 N/mm2 with an elongation percentage of 4.54%. The toughness of the film was 71.50 N.mm and the force required to rupture film was 16.49 N. The work and maximum force required to detach the mucoadhesive film from the glass side was 2.58 N.mm and 11615.32 mN, respectively. A Franz diffusion cell was used to perform acyclovir drug release studies from the mucoadhesive film and a commercial brand of acyclovir cream (Acitop®). Percentage acyclovir drug release from the film and cream was plotted against time using Sigmaplot® software version 13 following First order, Peppas, Hixon and Crowell, Higuchi (Square Root Time) and Bakers and Lonsdale mathematical models. The mucoadhesive film acyclovir attained the highest correlation coefficient r2 of 0.9879 following the Baker & Lonsdale mathematical model which describes controlled drug release from spherical matrices hence fits the model as the acyclovir is encapsulated in liposomes which are incorporated in the polymer mucoadhesive film. And the acyclovir cream (Acitop®) attained the highest correlation coefficient r2 of 0.9944 following the Peppas mathematical model. The Peppas model has been used to describe drug release from various release dosage forms when there is more than one type of dosage release or when release mechanism is not well known. One assumption of this model is that drug release occurs in one dimension, which is a suitable release profile for the cream as it is absorbed through the skin in one dimension when applied topically. There was significant difference between the drug release data for the mucoadhesive film and the acyclovir cream (Acitop®). A physically stable mucoadhesive film containing acyclovir-loaded liposomes was developed