Engineering hydrogel nanoparticles to enhance transdermal local anaesthetic delivery in human eyelid skin

Herein, we focused on developing the feasibility of nano-enabled local anaesthetic (LA) delivery to anaesthetise the full thickness of eyelid skin. For this purpose a temperature-responsive hydrogel poly(N-vinylcaprolactam-co-hyaluronic acid) (p(VCL-co-HA)) was prepared through aqueous emulsion polymerization with a Food and Drug Administration (FDA) approved p(VCL) and hyaluronic acid (HA) showing remarkably high LA drug loading capacity.

Nano-enabled local anaesthetic delivery was achieved using FDA-approved materials with remarkably high loading capacity.

Eyelid surgery is most commonly performed under local anesthesia all over the world. Unfortunately not all patients experience local anesthetic injections in the same way. Many people have needle phobias and feel highly anxious at the prospect of an injection along with the pain associated with it, which adds to the overall trauma. Furthermore during prolonged procedures as the anesthetic effect wears off the pain returns, which adds to the traumatic experience. The aforementioned discomfort not only discourages the needle phobic patients but also other patients who have a low threshold for pain or are undergoing their first surgical procedure in the ophthalmic department. This fear may cause delays in seeking ophthalmic care early for serious conditions such as eyelid cancer and may also increase the amount of local anesthesia required for minor procedures which can have risks of systemic side effects from the anesthetic drugs. Both examples have significant impacts on the economy of national health care.The current method of achieving sufficient dermal anesthesia in the eyelid for surgical procedures is subcutaneous injection of the LA drug lidocaine. An interest in non-invasive (needleless) LA drug delivery is well sought to minimize patient discomfort as well as surgical challenges such as intra-operative tissue distortion associated with the infiltration of anesthesia.^1,2The use of topical anesthetic products as an alternative for dermatological procedures on skin elsewhere in the body is well established.³ The most commonly used LA drug in the commercially available topical preparations is lidocaine which can be found for example in the form of a liposomal preparation of 4% lidocaine (LMX4 cream, Ferndale Laboratories Inc., Ferndale, MI, USA) or as an eutectic mixture of 2.5% lidocaine combined with 2.5% prilocaine (EMLA®, AstraZeneca AB, Södertälje, Sweden).³ Other products may contain tetracaine such as the 4% gel preparation Ametop or betacaine (Betacaine Enhanced Gel 4, Tiberius Inc, Tampa, FL).⁴Though most of these preparations require a long application time and the need for occlusion to enhance deep penetration of the LA drug, the achieved anaesthesia is still insufficient to carry out procedures involving full thickness of eyelid skin.³ Furthermore eyelid dynamics prohibit the use of the aforementioned formulations that may cause ocular surface irritation or chemical injury in severe cases.⁵In recent years, much interest has been given to nanocarriers that show potential for enhanced transdermal anaesthetic delivery via a range of routes (including the intracellular, intercellular and transappendageal) which is due to their small size. The carriers offer several advantages such as increased drug-loading capacity, entrapment efficiency and cumulative drug release.⁶Hydrophilic polymeric networks that are capable of imbibing huge volumes of water and undergoing swelling and shrinkage to suitably facilitate controlled drug-release are called hydrogels. Nanogels are synthesized by the cross-linking of N,N′-methylenebisacrylamide and ammonium persulfate (APS) as an initiator using a radical polymerization technique. Their porosity and compatibility with aqueous environments make them highly attractive bio-compatible drug delivery vehicles. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery systems. New synthetic methods have been used to prepare homo- and co-polymeric hydrogels for a wide range of drugs, peptides, and protein delivery applications. HA is an FDA approved co-polymer and is an important component of the cellular matrix and various tissues that make up the organisms which have high moisture retention and high viscoelasticity. HA is widely used in anticancer drug delivery, since it is biocompatible, biodegradable, non-toxic, and non-immunogenic, it can be chemically modified to become a good drug carrier.^7,8For biomedical applications, poly(N-vinylcaprolactam)-based (p(VCL)) hydrogel nanoparticles are ideal as they have similar water content to natural tissue. In addition they are one of the most popular thermoresponsive polymers used in the cosmetic industry as their phase transition in response to temperature can be utilized to optimise skin application. The polymers are often synthetized as co-polymers with other chemicals to achieve additional benefits such as biotechnological applications due to their tunable size from nanometres to micrometres, a large surface area for multivalent bioconjugation and an internal network useful for incorporation of biomolecules or drugs.^9,10In this work we aim to explore the feasibility of nano-enabled LA delivery to anaesthetise the full thickness of the eyelid skin. For this purpose a temperature-responsive hydrogel poly(N-vinylcaprolactam-co-hyaluronic acid) (p(VCL-co-HA)) was prepared through aqueous emulsion polymerization with p(VCL) and HA for high LA drug loading capacity.