Successfully Improving Ocular Drug Delivery Using the Cationic Nanoemulsion, Novasorb

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

Relevance of Lipid-Based Products in the Management of Dry Eye Disease

Components of the ocular surface synergistically contribute to maintaining and protecting a smooth refractive layer to facilitate the optimal transmission of light. At the air-water interface, the tear film lipid layer (TFLL), a mixture of lipids and proteins, plays a key role in tear surface tension and is important for the physiological hydration of the ocular surface and for ocular homeostasis. Alterations in tear fluid rheology, differences in lipid composition, or downregulation of specific tear proteins are found in most types of ocular surface disease, including dry eye disease (DED). Artificial tears have long been a first line of treatment in DED and aim to replace or supplement tears. More recently, lipid-containing eye drops have been developed to more closely mimic the combination of aqueous and lipid layers of the TFLL. Over the last 2 decades, our understanding of the nature and importance of lipids in the tear film in health and disease has increased substantially. The aim of this article is to provide a brief overview of our current understanding of tear film properties and review the effectiveness of lipid-based products in the treatment of DED. Liposome lid sprays, emulsion eye drops, and other lipid-containing formulations are discussed.Peer reviewe

Efficacy and Safety of 0.1% Cyclosporine a Cationic Emulsion in the Treatment of Severe Dry Eye Disease: A Multicenter Randomized Trial:

PurposeThe SANSIKA study was conducted to assess the treatment effect of 0.1% cyclosporine A cationic emulsion (CsA CE) eye drops on signs and symptoms of patients with severe dry eye disease (DED)..

Efficacy and safety of 0.1% ciclosporin A cationic emulsion in dry eye disease: a pooled analysis of two double-masked, randomised, vehicle-controlled phase III clinical studies

Background/aim To assess the treatment effect of 0.1% ciclosporin A cationic emulsion (CsA CE) versus vehicle on signs/symptoms of dry eye disease (DED) in various subgroups (moderate-to-severe DED/severe DED/ Sjogren's syndrome (SS)/SS with severe DED). Methods Pooled data were analysed from two similar phase III studies: SICCANOVE (moderate-to-severe DED) and SANSIKA (severe DED with severe keratitis). In both studies, patients aged >= 18 years received CsA CE 0.1% (n=395) or vehicle (n=339) once daily for 6 months. A composite responder efficacy endpoint (corneal fluorescein staining-Ocular Surface Disease Index (CFSOSDI) at month 6) was used to evaluate the efficacy of CsA CE in alleviating signs/symptoms of DED (response defined as improvement of >= 2 grades in CFS and >= 30% in OSDI (baseline to month 6)). Human leucocyte antigen-DR (HLA-DR) conjunctival expression was used as a biomarker of ocular surface inflammation. Results CsA CE-treated patients were significantly more likely to be CFS-OSDI responders than vehicletreated patients in the overall (OR 1.66, 95% CI 1.11 to 2.50;P=0.015), severe DED (1.80, 1.04 to 3.19;P=0.038) and SS with severe DED (3.37, 1.20 to 11.19;P=0.030) populations. The difference was not significant for CsA CE versus vehicle for the overall Sjogren's population (OR 1.77, CI 0.89 to 3.66;P=0.109). CsA CE also significantly reduced median HLA-DR expression versus vehicle at 6 months (P=0.002). Conclusion Pooled phase III data indicate CsA CE produced significant improvement in signs/symptoms versus vehicle in patients with moderate-to-severe DED (especially in those with severe keratitis), including patients with SS with severe DED

Artificial Tears: Biological Role of Their Ingredients in the Management of Dry Eye Disease

Dry eye disease (DED) is the most common ocular surface disease, characterized by insufficient production and/or instability of the tear film. Tear substitutes are usually the first line of treatment for patients with DED. Despite the large variety of tear substitutes available on the market, few studies have been performed to compare their performance. There is a need to better understand the specific mechanical and pharmacological roles of each ingredient composing the different formulations. In this review, we describe the main categories of ingredients composing tear substitutes (e.g., viscosity-enhancing agents, electrolytes, osmo-protectants, antioxidants, lipids, surfactants and preservatives) as well as their effects on the ocular surface, and we provide insight into how certain components of tear substitutes may promote corneal wound healing, and/or counteract inflammation. Based on these considerations, we propose an approach to select the most appropriate tear substitute formulations according to the predominant etiological causes of DED

Review of Preclinical Outcomes of a Topical Cationic Emulsion of Cyclosporine A for the Treatment of Ocular Surface Diseases

International audienceBackground: Cyclosporine A (CsA) has been used as a topical treatment for various ocular surface diseases including dry eye disease (DED). Several CsA formulations are available as solutions or emulsions. Purpose: This review describes the development and the preclinical testing of a cationic oil-in-water emulsion of CsA (CE-CsA) in terms of pharmacodynamics, pharmacokinetics, and ocular tolerance. Due to the cationic charge, CE electrostatically interacts with the negatively-charged ocular surface, improving its residence time. Compared to other CsA formulations, CE-CsA and CE itself were found to reduce the signs and symptoms of DED, by restoring tear film stability and properties, and inhibiting the expression and secretion of pro-inflammatory factors. No delay in wound healing nor ocular toxicity were observed using CE formulations. Conclusion: these findings indicate that the type of vehicle can significantly affect the performance of eye drops and play an ancillary role in DED treatment. CE appears as a promising strategy to deliver drugs to the ocular surface while maintaining its homeostasis

Cationic Emulsion-Based Artificial Tears as a Mimic of Functional Healthy Tear Film for Restoration of Ocular Surface Homeostasis in Dry Eye Disease

Dry eye disease (DED) is a complex multifactorial disease that affects an increasing number of patients worldwide. Close to 30% of the population has experienced dry eye (DE) symptoms and presented with some signs of the disease during their lifetime. The significant heterogeneity in the medical background of patients with DEs and in their sensitivity to symptoms renders a clear understanding of DED complicated. It has become evident over the past few years that DED results from an impairment of the ocular surface homeostasis. Hence, a holistic treatment approach that concomitantly addresses the different mechanisms that result in the destabilization of the tear film (TF) and the ocular surface would be appropriate. The goal of the present review is to compile the different types of scientific evidence (from in silico modeling to clinical trials) that help explain the mechanism of action of cationic emulsion (CE)-based eye drop technology for the treatment of both the signs and the symptoms of DED. These CE-based artificial tear (AT) eye drops designed to mimic, from a functional point of view, a healthy TF contribute to the restoration of a healthy ocular surface environment and TF that leads to a better management of DE patients. The CE-based AT eye drops help restore the ocular surface homeostasis in patients who have unstable TF or no tears

Time to source control and outcome in community-acquired intra-abdominal infections The multicentre observational PERICOM study

International audienceBACKGROUND Optimal management of community-acquired intra-abdominal infections (IAI) requires timely surgical source control and adequate anti-infective treatment. OBJECTIVE To describe the initial management of community-acquired IAI admitted to the emergency department and assess the association between the length of time to either diagnosis or therapeutic procedures and patient outcomes. DESIGN A prospective, multicentre, observational study. SETTING Thirteen teaching hospitals in France between April 2018 and February 2019. PATIENTS Two hundred and five patients aged at least 18 years diagnosed with community-acquired IAI. MAIN OUTCOME MEASURES The primary outcome was hospital length of stay. The secondary outcome was hospital mortality. RESULTS Patients had a mean age of 56 (+/- 21) years and a median [interquartile] SAPS II of 26 [17 to 34]. Among the study cohort, 18% were postoperatively transferred to intensive care unit and 7% had died by day 28. Median [IQR] time to imaging, antibiotic therapy and surgery were 4 [2 to 6], 7.5 [4 to 12.5] and 9 [5.5 to 17] hours, respectively. The length of time to surgical source control [0.99, 95% confidence interval (CI), 0.98 to 0.99], SOFA greater than 2 [0.36 (95% CI, 0.26 to 0.651)], age greater than 60 years [0.65 (95% CI, 0.45 to 0.94)], generalized peritonitis [0.7 (95% CI, 0.56 to 0.89)] and laparotomy surgery [0.657 (95% CI, 0.42 to 0.78)] were associated with longer hospital length of stay. The duration of time to surgical source control [1.02 (95% CI, 1.01 to 1.04)], generalized peritonitis [2.41 (95% CI, 1.27 to 4.61)], and SOFA score greater than 2 [6.14 (95% CI, 1.40 to 26.88)] were identified as independent risk factors for 28-day mortality. CONCLUSION This multicentre observational study revealed that the time to surgical source control, patient severity and generalized peritonitis were identified as independent risk factors for increased hospital LOS and mortality in community-acquired IAI. Organisational strategies to reduce the time to surgical management of intra-abdominal infections should be further evaluated. STUDY REGISTRATION ClinicalTrials.gov on 1 April 2018, NCT03544203