Topical Insulin Eye Drops: Stability and Safety of Two Compounded Formulations for Treating Persistent Corneal Epithelial Defects.

Compounded insulin eye drops were prepared at 1 IU/mL from commercially available subcutaneous insulin by dilution in saline solution or artificial tears. Physicochemical characterization and in vitro tolerance testing in human and conjunctival cells were followed by a 28-day short-term stability study under various conditions. The formulations were isotonic (280-300 mOsm/L), had a pH close to neutral (7-8), medium surface-tension values (<56 MN/m-1), and low (≈1 mPa·s) and medium (≈5 mPa·s) viscosities (compounded normal saline solution and artificial tear-based preparation, respectively). These values remained stable for 28 days under refrigeration. Microbiological stability was also excellent. Insulin potency remained in the 90-110% range in the compounded formulations containing normal saline solution when stored at 2-8 °C for 28 days, while it decreased in those based on artificial tears. Although both formulations were well tolerated in vitro, the compounded insulin diluted in a normal saline solution exhibited better cell tolerance. Preliminary data in humans showed that insulin in saline solution was an effective and safe treatment for persistent corneal epithelial defects. Compounded insulin eye drops diluted in normal saline solution could, therefore, constitute an emergent therapy for the treatment of persistent corneal epithelial defects.

Enhancing the hypotensive effect of latanoprost by combining synthetic phosphatidylcholine liposomes with hyaluronic acid and osmoprotective agents.

The first line of glaucoma treatment focuses on reducing intraocular pressure (IOP) through the prescription of topical prostaglandin analogues, such as latanoprost (LAT). Topical ophthalmic medicines have low bioavailability due to their rapid elimination from the ocular surface. Nanotechnology offers innovative ways of enhancing the ocular bioavailability of antiglaucoma agents while reducing administration frequency. This study aims to combine LAT-loaded synthetic phosphatidylcholine liposomes with hyaluronic acid (0.2% w/v) and the osmoprotectants betaine (0.40% w/v) and leucine (0.90% w/v) (LAT-HA-LIP) to extend the hypotensive effect of LAT while protecting the ocular surface. LAT-HA-LIP was prepared as a mixture of 1,2-dioleoyl-sn-glycero-3-phosphocholine and 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol and α-tocopherol acetate. LAT-HA-LIP exhibited high drug-loading capacity (104.52 ± 4.10%), unimodal vesicle sizes (195.14 ± 14.34 nm) and a zeta potential of -13.96 ± 0.78 mV. LAT-HA-LIP was isotonic (284.00 ± 1.41 mOsm L-1), had neutral pH (7.63 ± 0.01) and had suitable surface tension (44.07 ± 2.70 mN m-1) and viscosity (2.69 ± 0.15 mPa s-1) for topical ophthalmic administration. LAT-HA-LIP exhibited optimal in vitro tolerance in human corneal and conjunctival epithelial cells. No signs of ocular alteration or discomfort were observed when LAT-HA-LIP was instilled in albino male New Zealand rabbits. Hypotensive studies revealed that, after a single eye drop, the effect of LAT-HA-LIP lasted 24 h longer than that of a marketed formulation and that relative ocular bioavailability was almost three times higher (p < 0.001). These findings indicate the potential ocular protection and hypotensive effect LAT-HA-LIP offers in glaucoma treatment.

A novel osmoprotective liposomal formulation from synthetic phospholipids to reduce in vitro hyperosmolar stress in dry eye treatments.

Dry eye disease (DED) is a worldwide, multifactorial disease mainly caused by a deficit in tear production or increased tear evaporation with an increase in tear osmolarity and inflammation. This causes discomfort and there is a therapeutic need to restore the homeostasis of the ocular surface. The aim of the present work was to develop a biodegradable and biocompatible liposomal formulation from the synthetic phospholipids 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) that is able to reduce the effects of hypertonic stress by helping to restore the lipid layer of the tear film. Liposomes were made using the lipid film hydration method with synthetic phospholipids (10 mg/mL) with and without 0.2% HPMC. They were characterised in terms of size, osmolarity, pH, surface tension, and viscosity. Additionally, the in vitro toxicity of the formulation at 1 and 4 h in human corneal epithelial cells (hTERT-HCECs) and human conjunctival cells (IM-HConEpiC) was determined. Furthermore, osmoprotective activity was tested in a corneal model of hyperosmolar stress. In vivo acute tolerance testing was also carried out in albino New Zealand rabbits by topical application of the ophthalmic formulations every 30 min for 6 h. All the assayed formulations showed suitable physicochemical characteristics for ocular surface administration. The liposomal formulations were well-tolerated in cell cultures and showed osmoprotective activity in a hyperosmolar model. No alterations or discomfort were reported when they were topically administered in rabbits. According to the results, the osmoprotective liposomal formulations developed in this work are promising candidates for the treatment of DED.

Novel Osmoprotective DOPC-DMPC Liposomes Loaded with Antihypertensive Drugs as Potential Strategy for Glaucoma Treatment.

Glaucoma is a group of chronic irreversible neuropathies that affect the retina and the optic nerve. It is considered one of the leading causes of blindness in the world. Although it can be due to various causes, the most important modifiable risk factor is the elevated intraocular pressure (IOP). In this case, the treatment of choice consists of instilling antihypertensive formulations on the ocular surface. The chronicity of the pathology, together with the low bioavailability of the drugs that are applied on the ocular surface, make it necessary to instill the formulations very frequently, which is associated, in many cases, with the appearance of dry eye disease (DED). The objective of this work is the design of topical ocular formulations capable of treating glaucoma and, at the same time, preventing DED. For this, two liposome formulations, loaded with brimonidine or with travoprost, were Tadeveloped using synthetic phospholipids and enriched by the addition of compounds with osmoprotective activity. The proposed formulations not only presented physicochemical characteristics (size, pH, osmolarity, surface tension, and viscosity) and encapsulation efficiency values (EE% of 24.78% and ≥99.01% for brimonidine and travoprost, respectively) suitable for ocular surface administration, but also showed good tolerance in human corneal and conjunctival cell cultures, as well as an in vitro osmoprotective activity. The hypotensive effect of both liposomal formulations was evaluated in normotensive albino New Zealand rabbits, showing a faster and longer lasting reduction of intraocular pressure in comparison to the corresponding commercialized products used as control. According to these results, the hypotensive liposomal formulations combined with osmoprotective agents would result in a very promising platform for the treatment of glaucoma and the simultaneous protection of the ocular surface.

Liposomes as vehicles for topical ophthalmic drug delivery and ocular surface protection.

Introduction: The development of ophthalmic formulations able to deliver hydrophilic and hydrophobic drugs to the inner structures of the eye and restore the preocular tear film has been a leading topic of discussion over the last few years. In this sense, liposomes represent a suitable strategy to achieve these objectives in ocular drug delivery.Areas covered: Knowledge of the different physiological and anatomical eye structures, and specially the ocular surface are critical to better understanding and comprehending the characteristics required for the development of topical ophthalmic liposomal formulations. In this review, several features of liposomes are discussed such as the main materials used for their fabrication, basic structure and preparation methods, from already established to novel techniques, allowing the control and design of special characteristics. Besides, physicochemical properties, purification processes and strategies to overcome delivery or encapsulation challenges are also presented. Expert opinion: Regarding ocular drug delivery of liposomes, there are some features that can be redesigned. Specific biocompatible and biodegradable materials presenting therapeutic properties, such as lipidic compounds or polymers significantly change the way of tackling ophthalmic diseases. Besides, liposomes entail an effective, safe and versatile strategy for the treatment of diseases in the clinical practice.