Comparison of In Vitro Corneal Permeation and In Vivo Ocular Bioavailability in Rabbits of Three Marketed Latanoprost Formulations.

BACKGROUND AND OBJECTIVE: All latanoprost formulations currently available for the treatment of glaucoma or ocular hypertension contain the same concentration of latanoprost (0.005%) but differ in excipients, which may affect corneal drug permeability or stability. This study aimed at comparing corneal penetration of three marketed latanoprost solutions with different excipient formulations in in vitro and in vivo drug permeability studies. METHODS: Three latanoprost formulations were tested under good laboratory practice conditions: a formulation containing benzalkonium chloride (BAK) but no surfactant (Preserved latanoprost); the same formulation except preservative-free (PF) without BAK or surfactant (SF) (PF SF latanoprost); and a different formulation without BAK but containing a non-ionic surfactant (MGHS 40 at 5%) combined with thickening agents (Carbomer 974P, Macrogol 4000) (PF latanoprost). Corneal permeation of latanoprost acid (LAT) was first determined in vitro using a reconstructed human corneal epithelium tissue. Then, in vivo pharmacokinetic studies were performed on pigmented rabbits, for which LAT concentration was measured in the aqueous humour (AH) and iris-ciliary body (ICB). RESULTS: In vitro, the cumulative transport of LAT was linear between 1 h and 4 h for preserved latanoprost and PF SF latanoprost, and LAT concentrations matched exactly at each timepoint. By contrast, the permeation of PF latanoprost was linear between 2 h and 12 h and was significantly lower than that of preserved latanoprost and PF SF latanoprost at 4 and 8 h (p < 0.001). In rabbits, the concentrations of LAT in AH and ICB were not statistically different between preserved latanoprost and PF SF latanoprost at each timepoint, except at 1 h in ICB (p = 0.005). By comparison, the LAT concentration of PF latanoprost was statistically (p < 0.05) lower than that of preserved latanoprost and PF SF latanoprost in AH and ICB from 0.5 to 3 h. CONCLUSION: BAK did not influence the corneal penetration of latanoprost in in vitro and in vivo studies. The formulation containing a non-ionic surfactant resulted in lower and slower ocular penetration compared with preserved or PF SF formulations. This raises questions about the relevance of BAK and some surfactants in enhancing corneal penetration of ocular formulations.

Impact of Latanoprost Antiglaucoma Eyedrops and Their Excipients on Toxicity and Healing Characteristics in the Ex Vivo Eye Irritation Test System.

INTRODUCTION: Corneal epithelial toxicity and delayed healing process have already been attributed to preservatives or some excipients. We study the effects of galenic components in antiglaucoma drugs such as benzalkonium chloride (BAC) or surfactants like macrogolglycerol hydroxystearate 40 (MGHS 40) on corneal toxicity in an ex vivo system mimicking chronic use. METHODS: Latanoprost-containing eyedrops are available with and without preservatives on the market. Unpreserved, they are available in different formulations with various excipients like MGHS at different concentrations (0%, 2.5%, and 5%). We studied these in the ex vivo bioreactor (EVEIT) on initially injured rabbit corneas. The drugs were applied six times daily for observation periods of 3 or 5 days. BAC, 5% MGHS 40 solution, and 0.18% hyaluronic acid served as controls. Macroscopic photographic, biochemical methods and corneal integrity quantification were used for evaluation. Toxicity was assessed by measuring wound healing and corneal fluorescein sodium permeability and was confirmed by histology studies. RESULTS: The BAC-preserved formulation resulted in high corneal toxicity, which was expected. Interestingly, the preservative-free (PF) formulation containing 5% MGHS 40, carbomer, macrogol 4000, and sorbitol showed the highest corneal toxicity, followed by the control formulation with equal MGHS 40 concentration, which presented significantly less damage. No toxicity was shown by eyedrops containing 2.5% MGHS 40 or salts only. CONCLUSION: Our study demonstrates a significant corneal toxicity of certain formulations of PF antiglaucoma ophthalmic drugs containing 5% MGHS 40 with other excipients compared to other formulations with lower MGHS 40 concentrations (2.5% or 0%), or even compared to the solution containing 5% MGHS alone. This suggests a concentration-dependent toxicity of MGHS 40, especially in interaction with other excipients, which may increase its epithelial toxicity, and that has to be considered in clinical glaucoma therapy. Further single-component formulation trials are needed to support this interpretation.

Comparison of Decontamination Efficacy of Cleaning Solutions on a Biological Safety Cabinet Workbench Contaminated by Cyclophosphamide.

BACKGROUND: Several studies have compared cleaning procedures for decontaminating surfaces exposed to antineoplastic drugs. All of the cleaning products tested were successful in reducing most of the antineoplastic drug quantities spilled on surfaces, but none of them completely removed residual traces. OBJECTIVE: To assess the efficacy of various cleaning solutions for decontaminating a biological safety cabinet workbench exposed to a defined amount of cyclophosphamide. METHODS: In this pilot study, specific areas of 2 biological safety cabinets (class II, type B2) were deliberately contaminated with a defined quantity of cyclophosphamide (10 µg or 107 pg). Three cleaning solutions were tested: quaternary ammonium, sodium hypochlorite 0.02%, and sodium hypochlorite 2%. After cleaning, the cyclophosphamide remaining on the areas was quantified by wipe sampling. Each cleaning solution was tested 3 times, with cleaning and wipe sampling being performed 5 times for each test. RESULTS: A total of 57 wipe samples were collected and analyzed. The average recovery efficiency was 121.690% (standard deviation 5.058%). The decontamination efficacy increased with the number of successive cleaning sessions: from 98.710% after session 1 to 99.997% after session 5 for quaternary ammonium; from 97.027% to 99.997% for sodium hypochlorite 0.02%; and from 98.008% to 100% for sodium hypochlorite 2%. Five additional cleaning sessions performed after the main study (with detergent and sodium hypochlorite 2%) were effective to complete the decontamination, leaving no detectable traces of the drug. CONCLUSIONS: All of the cleaning solutions reduced contamination of biological safety cabinet workbenches exposed to a defined amount of cyclophosphamide. Quaternary ammonium and sodium hypochlorite (0.02% and 2%) had mean efficacy greater than 97% for removal of the initial quantity of the drug (107 pg) after the first cleaning session. When sodium hypochlorite 2% was used, fewer cleaning sessions were required to complete decontamination. Further studies should be conducted to identify optimal cleaning strategies to fully eliminate traces of hazardous drugs.

CONTEXTE: Bon nombre d'études ont comparé les méthodes de nettoyage pour décontaminer les surfaces exposées aux antinéoplasiques. Toutes les solutions de nettoyage évaluées permettaient d'enlever la majeure partie des quantités d'antinéoplasiques renversés sur les surfaces, mais aucune n'arrivait à éliminer les traces résiduelles. OBJECTIF: Évaluer l'efficacité de différentes solutions de nettoyage servant à décontaminer une enceinte de sécurité biologique exposée à une quantité précise de cyclophosphamide. MÉTHODES: Dans la présente étude pilote, des zones déterminées de deux enceintes biologiques (classe II, type B2) ont été délibérément contaminées avec une quantité précise de cyclophosphamide (10 µg ou 107 pg). Trois solutions de nettoyage ont été évaluées : l'ammonium quaternaire, l'hypochlorite de sodium à 0,02 % et l'hypochlorite de sodium à 2 %. Après nettoyage, le cyclophosphamide toujours présent sur les surfaces était quantifié à l'aide de prélèvements par lingette. Chaque solution de nettoyage a été évaluée trois fois, tandis que le nettoyage et le prélèvement par lingette ont été répétés cinq fois pour chaque test. RÉSULTATS: Au total, on a recueilli et analysé 57 lingettes ayant servi à l'échantillonnage. Le taux moyen d'efficacité de récupération était de 121,690 % (écart-type de 5,058 %). L'efficacité de la décontamination augmentait en fonction du nombre de séances successives de nettoyage : de 98,710 % après le premier nettoyage à 99,997 % après le cinquième nettoyage pour l'ammonium quaternaire; de 97,027 % à 99,997 % pour l'hypochlorite de sodium à 0,02 %; et de 98,008 % à 100 % pour l'hypochlorite de sodium à 2 %. Après l'étude principale, cinq séances de nettoyage supplémentaires (avec détergent et hypochlorite de sodium à 2%) ont permis de terminer la décontamination, ne laissant aucune trace détectable du médicament. CONCLUSIONS: Toutes les solutions de nettoyage réduisaient la contamination d'une enceinte de sécurité biologique exposée à une quantité précise de cyclophosphamide. L'efficacité moyenne de l'ammonium quaternaire et de l'hypochlorite de sodium (à 0,02 % et à 2 %) pour éliminer la quantité initiale de 107 pg du médicament s'élevait à plus de 97 % après la première séance de nettoyage. Lorsque l'hypochlorite de sodium à 2 % était employé, un moins grand nombre de séances de nettoyage était nécessaire pour terminer la décontamination. De plus amples études sont nécessaires afin de pouvoir trouver des stratégies de nettoyage optimales permettant d'éliminer entièrement les traces de médicaments dangereux.