In recent years, nanotechnology has allowed to formulate different ophthalmic vehicles in order to extend residence time in the eye after topical application, decreasing the number of instillations and improving patient¿s compliance. The goal of this study will be to develop an oil-in-water (O/W) nanoemulsions (NEs), composed of almond oil as the inner oil phase and Hepes or Palitzsch buffer as the outer aqueous phased, stabilized by non-ionic surfactants (Tween 20 or Tween 80). By modifying the oil/surfactant/water ratio, the best nanoemulsion formulations in terms of chemical-physical characteristics useful will be selected. In particular, hydrodynamic diameter, size distribution, ¿-potential, microviscosity and polarity of the internal oil phase, along with pH and osmolarity, stability in simulated tears and rheological properties will be evaluated. Furthermore, cytotoxicity studies using the Alamar Blue reduction assay in Y-79 (Human retinoblastoma cell line) cells will be performed to assure their compatibility for ocular administration. Finally, in order to stabilize the feasibility of formulated NEs for ocular delivery, in vitro both irritation studies and Draize test will be carried out.
According to the World Health Organization's (WHO) 2019 World Report on Vision, at least 2.2 billion people worldwide have some form of visual impairment or blindness, with nearly 1 billion of those conditions noted as preventable [1]. These ocular diseases affect the vision and quality of life patients and for this reason the ocular drug delivery is one of the major challenges in the pharmaceutical field [2]. Generally, the most convenient and comfortable route for ocular drug administration is topical eye drops like solutions or suspensions. However, they often raise several issues like solubility, stability and sterility as well as the short residence time on the eye with the consequent low drug bioavailability [3]. Moreover, it is well known that the drug delivery to targets posterior ocular tissues is very restricted due to the presence of precorneal, dynamic and static ocular barriers [4].
In these years, researchers have focused on developing novel, safe and patient compliant formulations which may overcome these limitations and maintain higher drug levels in ocular tissues. Among the several developed DDS, nanoemulsions are one of finest thanks to their transparency, kinetic stability, enlarged droplet volume fraction and enhanced drug solubility when two immiscible liquid phases are mixed. This type of DDS is extensively used in pharmaceutical dosage forms for delivering drugs to the eye, because they are able to increase the contact time of drugs in the eye and thereby eradicate the problems faced by the patients like frequent administration [5].
In this scenario, increasing interest in nanoformulation study and growing literature in this field bring a great help in the management of eye diseases, allowing to the development of numerous products on the market as well as in the clinical trials. Currently, different formulations based on NEs are commercially available for treating several eye diseases such as glaucoma, dry eye syndrome, etc. [6].
The present study will focus on the development of O/W NEs composed of almond oil, a bioactive compound able to act synergically with loaded active compounds, that can be administered as eye drops avoiding irritation or blurred vision. First of all, all nanoemulsion components will be chosen because they are safe for ophthalmic use and to take advantage of their inner biological activity and less cytotoxicity. The formulated O/W NEs will be prepared and sterilized with a very fast and easy method. Moreover, the goal of our formulations will be to obtain an ideal ophthalmic formulation.
An ocular formulation with suitable adhesion force can ameliorate the retention time and slow drug release providing high therapeutic efficacy and better patient compliance. For this reason, the formulated NEs will have to show a high viscosity in order to increase their retention time on the eye, avoiding the use of additive components to the formulation, like mucoadhesive compounds, which may increase the onset of side effects. The osmolarity of all formulations will be monitored in order to assure their low ocular irritation.
The study of proposed formulations can prompt to obtain an update of the state of art by increasing the stability over time, avoiding the use of preservative in the formulation which can induce adverse systemic reactions. Our group already formulated NEs based on neem oil stable up to 3 months [7]. Similarly, NEs proposed in this project will be stable due to the presence of adsorbed emulsifier layer on the small droplet that will stabilize the emulsions against flocculation and even against coalescence.
The mucosal ocular structure is very sensitive to instillation of drug, for this reason, in order to assure the safety of our formulations, in vitro cytotoxicity tests by using Human retinoblastoma cell line will be performed. These data will be confirmed by in vivo ocular irritation test (Draize¿s test).
In conclusion, various novel DDS have been continuously investigated for safe and improved ocular therapy. Ophthalmic NEs by virtue of their composition may be considered as active, safe with a high bioavailability and they can be used as non-invasive, viable and cost-effective nanosystems to improve ophthalmic drug bioavailability. For this reason, it is predictable that additional research and development about this topic is useful in the future concerning the treatment of ophthalmic diseases.
References
[1] R.S. Dave et al. J Control Release, 336, 71-88, 2021
[2] S.B. Da Silva et al. Intern J Biol Macromol, 84,112¿120, 2016
[3] B. Jurisic Dukovski et al. Acta Pharm, 69, 621¿634, 2019
[4] A. Sosnik et al. Prog Polym Sci, 39, 2030¿2075, 2014
[5] S.A. Chime et al. Appl Nanotechol Drug Delivery Intech Open, 77¿126, 2014
[6] F. Lallemand et al. J Drug Deliv, 2012, 1¿16, 2012
[7] F. Rinaldi et al. Enzyme Inhib Med Chem, 32, 1265-1273, 2017