Transcutaneous nano-enabled anaesthetics for eyelid surgery

Objective:Local Anaesthesia and intravenous sedation are frequently used for patients undergoing upper eyelid surgery, although general anaesthesia may be desirable in some patients. Local anaesthetics (LA) are usually administered as a diffuse superficial slowly subcutaneous injection along the upper lid skin crease. This leads to haemorrhage, hematomas, lid swelling, superficial anaesthesia and anxiety. EMLA cream (eutectic mixture of lidocaine 2.5% and procaine 2.5%) is commonly used for topical anaesthesia but is not suitable for eyelid application due to high pH of the cream being dangerous to applications close to the eye while application needs to take place an hour prior any surgical operation. 
Hypothesis: Enveloping LA within self-nanoemulsifying drug delivery systems (SNEDDS) hydrogels will enable the sustained topical delivery via eyelid skin. Solubility tests in various excipients and tertiary diagrams informed optimal composition of SNEDDS. Lidocaine SNEDDS (LS) 10% w/w, lidocaine SNEDDS hydrogels (LSG) 10% w/w, bupivacaine SNEDDS (BS) 5%w/w and bupivacaine SNEDDS hydrogels (BSG) 2.5% w/w were prepared and characterised in terms of particle size, colloidal stability, morphology and rheology. Their permeation across cellulose acetate membrane, excised mouse skin and excised human eyelid skin (Moorfields Eye Hospital, Dr George Saleh) was tested. Histopathological studies on human eyelid skin were conducted ex vivo. SNEDDS can increase lidocaine and benzocaine solubility in aqueous media in above clinical relevant concentrations (i.e. 750 mg/g and 500 mg/g for lidocaine and bupivacaine respectively which is 188 fold and 1634 fold higher than their aqueous solubility respectively). Hydrogels illustrated similar rheology to EMLA and upon dilution the presence of spherical particle size (100-300 nm) and good colloidal stability (<-20mV). Hydrogels illustrated superior steady state flux across artificial and human eyelid skin compared to EMLA cream (1254.2 and 108.4 μg/cm2/h versus 157.5 and 37.5 μg/cm2/h). Structure of epidermis and dermis is well maintained after exposure to SNEDDS and their hydrogels with no acanthosis or hyperkeratosis). LA SNEDDS enabled hydrogels illustrated high loading, particle size below 300 nm, spherical morphology. Franz cell permeation studies have illustrated a fourfold enhancement in skin permeation compared to clinically used EMLA cream. Developed nano-enabled hydrogels prepared from GRAS excipients can provide a non-invasive transcutaneous alternative for eyelid surgery.