Topical ophthalmic delivery of active ingredients can be achieved using cationic nanoemulsions. In the last decade, Novagali Pharma has successfully developed and marketed Novasorb, an advanced pharmaceutical technology for the treatment of ophthalmic diseases. This paper describes the main steps in the development of cationic nanoemulsions from formulation to evaluation in clinical trials. A major challenge of the formulation work was the selection of a cationic agent with an acceptable safety profile that would ensure a sufficient ocular surface retention time. Then, toxicity and pharmacokinetic studies were performed showing that the cationic emulsions were safe and well tolerated. Even in the absence of an active ingredient, cationic emulsions were observed in preclinical studies to have an inherent benefit on the ocular surface. Moreover, clinical trials demonstrated the efficacy and safety of cationic emulsions loaded with cyclosporine A in patients with dry eye disease. Ongoing studies evaluating latanoprost emulsion in patients with ocular surface disease and glaucoma suggest that the beneficial effects on reducing ocular surface damage may also extend to this patient population. The culmination of these efforts has been the marketing of Cationorm, a preservative-free cationic emulsion indicated for the symptomatic treatment of dry eye.

ObjectivesTopical ocular administration is the most convenient route of administration of drugs for the treatment of eye diseases. However, the bioavailability of drugs following eye instillations of eye drops is very low. Over the past 20 years, extensive efforts have been put into research to improve drug bioavailability without compromising treatment compliance and patients' quality of life.Key findingsOne of the most efficient ways to improve drug bioavailability is to increase the precorneal residence time of the eye drop formulations. As a result, new eye drops, with bioadhesive properties, have been developed based on the cationic oil-in-water (o/w) nanoemulsion technology. These low viscosity eye drop nanoemulsions have improved precorneal residence time through the electrostatic interactions between the positively charged oil nanodroplets and the negatively charged ocular surface epithelium.SummaryThis review is the first to present the benefits of this new strategy used to improve ocular drug bioavailability. The roles of the cationic agent in the stabilization of a safe cationic o/w nanoemulsion have been discussed, as well as the unexpected benefits of the cationic o/w nanoemulsion for the protection and restoration of a healthy tear film and corneal epithelium.

Both models effectively evaluated the cytotoxicity and dynamic recovery of corneal wound healing, and their correlation supports the potential of the in vitro model as a reliable alternative to in vivo ocular toxicity tests. Both models demonstrated that in the face of corneal injury, CEs favored corneal healing, whereas BAK was deleterious.

These data demonstrate that the CsA cationic emulsions were more effective than Restasis at delivering CsA to target tissues, thus confirming the potential advantage of cationic emulsions over anionic emulsions as vehicle for ocular drug delivery for the treatment of ocular surface diseases.

Cardiovascular diseases (CDs) are among the most encountered pathologies in western countries; with obesity reaching pandemic proportions, they are soon to become a worldwide problem. High blood pressure is the main risk factor for CDs, and its tight control is an imperative for the treatment of complications such as renal diseases, heart failure, and atherosclerosis. Blood homeostasis and vascular tone are regulated through at least 3 major closely interrelated pathways in which zinc metallopeptidases modulate the concentration of vasoactive mediators. Those extensively studied vasopeptidases were therefore rapidly targeted with specific inhibitors in order to control the levels of vasoconstrictors [angiotensin II (AII) and endothelin-1 (ET-1)] and vasodilators [bradykinin (BK) and atrial natriuretic peptide (ANP)], thereby controlling blood pressure. The first class of inhibitors to be developed were against angiotensin-converting enzyme (ACE), recently followed by dual inhibitors of ACE/neprylisin (NEP), NEP/endothelin-converting enzyme (ECE), and finally triple ACE/NEP/ECE inhibitors. The dual and triple inhibitors are defined as vasopeptidase inhibitors (VPI). In addition to their ability to effectively lower blood pressure in hypertensive patients, drugs targeting these enzymes also displayed antiinflammatory and antifibrotic activities. The major point emerging from recent studies undertaken to improve the management of CDs is that the combined action of different therapeutic strategies (ie, simultaneous modulation of several neurohumoral mediators) shows better results than conservative therapeutic approaches. In this review, we historically present the advances made in the comprehension of the different mechanisms of blood pressure regulation and some of the drugs that arose from this understanding.

Cationorm® (CN) cationic nanoemulsion was demonstrated to enhance tear film (TF) stability in vivo possibly via effects on tear film lipid layer (TFLL). Therefore the interactions of CN with human meibum (MGS) and TFLL in vitro and in vivo deserve special study. MGS and CN were spread at the air/water interface of a Langmuir surface balance to ensure a range of MGS/CN oil phase ratios: 20/1, 10/1, 5/1, 3/1, 2/1 and 1/1. The films capability to reorganize during dynamic area changes was evaluated via the surface pressure-area compression isotherms and step/relaxation dilatational rheology studies. Films structure was monitored with Brewster angle microscopy. CN/TFLL interactions at the ocular surface were monitored with non-contact specular microscopy. The in vitro studies of MGS/CN layers showed that (i) CN inclusion (at fixed MGS content) increased film elasticity and thickness and that (ii) CN can compensate for moderate meibum deficiency in MGS/CN films. In vivo CN mixed with TFLL in a manner similar to CN/MGS interactions in vitro, and resulted in enhanced thickness of TFLL. In vitro and in vivo data complement each other and facilitated the study of the composition-structure-function relationship that determines the impact of cationic nanoemulsions on TF.

Dry eye disease (DED) is a complex, multifactorial pathology characterized by corneal epithelium lesions and inflammation. The aim of the present study was to evaluate the efficacy of a cationic emulsion of cyclosporine A (CsA) in a mouse model that mimics severe dry eye. Eight to 12-week-old female C57BL/6N mice with tail patches of scopolamine were housed in controlled environment chambers to induce dry eye. At day three, following dry eye confirmation by corneal fluorescein staining (CFS, score 0-15) and phenol red thread (PRT) lacrimation test, the mice (n = 10/gp) were either treated 3 times a day in both eyes with drug-free cationic emulsion, a 0.1% CsA cationic emulsion, or 1% methylprednisolone (positive control), or non-treated. Aqueous tear production and CFS scores were evaluated at baseline and throughout the treatment period. The lacrimation test confirmed the scopolamine-induced decrease in aqueous production by the lacrimal gland. A reduction of 59% in induced-CFS was observed following topical treatment with 0.1% CsA. The beneficial effect of the cationic emulsion vehicle itself on keratitis was also clearly evidenced by its better performance over 1% methylprednisolone, -36%, vs. -28% on the CFS scores, respectively. This study indicates that the cationic emulsion of CsA (0.1%) was a very effective formulation for the management of corneal epithelium lesions in a severe DED mouse model. In addition, it performed better than a potent glucocorticosteroid (1% methylprednisolone). This cationic emulsion of CsA (0.1%), combining CsA and a tear film oriented therapy (TFOT), i.e. with vehicle properties that mechanically stabilize the tear film, represents a promising new treatment strategy for the management of the signs of dry eye.

IVT injections of DXP emulsions were well tolerated and shown to be efficacious for the sustained release of the drug, with the potential to control vascular leakage up to 9 months following a single IVT injection. These data suggest that IVT injections of DXP emulsions could be a safe and effective alternative IVT drug delivery vehicle for corticosteroid to treat back of the eye diseases complicated by macular edema.