Abstract
Abstract
 The aim of this study was to prepare rebamipide ocular inserts in order to extend its release on the ocular surface for dry eye treatment. Solubility study was applied to the drug with or without l-arginine using different solvents. Solvent casting technique was used to prepare the inserts; l-arginine was used to solubilize the drug, hydroxypropyl methylcellulose grades (E5 and K15M) and poly ethylene glycol 200 were used as excipients. The inserts were evaluated for their physical and mechanical properties, moisture loss% and absorption %, surface pH, and in-vitro drug release. The use l-arginine exhibited an enhancement of rebamipide solubility in both deionized water and phosphate buffer (pH 7.4) by approximately 250 times and 3 times, respectively. The formulations showed uniform weight and thickness except for F1, and all showed uniform drug content. The absence of plasticizer in F1 caused haziness in its appearance and brittleness of the inserts. F3 which contain hydroxypropyl methylcellulose K15M showed good physical and mechanical properties thus was selected for in vitro release and was compared to the marketed brand Mucosta® suspension eye drop; F3 showed significant enhancement in extending the release of rebamipide compared to the reference marketed brand.
 Keywords: Rebamipide, L-arginine, Ocular insert, Solvent casting technique
 
 
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Highlights
Dry eye syndrome is a multifactorial disease that affects the tears and ocular surface, and lead to various symptoms as visual disturbance, discomfort, gritty feeling and burning sensation; it may cause tear film instability and possible defects of ocular surface and inflammation. (1) This disease may occur due to the decreased ability of lacrimal functional unit to produce sufficient amount of tear film components which results in a poor quality or/and low quantity of tear film (2,3,4,1)
Differential scanning calorimetry (DSC) graph showed a peak at 307oC figure (3), which is close to the values stated in the references. (16,17)
Formula F3 which contains hydroxypropyl methyl cellulose (HPMC) E5: K15M (1:0.4) and PEG200 (35%w/w of total polymer weight) showed significantly larger T50% and T80% compared to the Mucosta® ophthalmic suspension (p-values 0.034 and 0.015) respectively; the similarity factor between was (f2 =37.27). These results indicate that the prepared rebamipide ocular insert (F3) release profile was different from that of the reference and had noticeable drug release retarding effect
Summary
Dry eye syndrome is a multifactorial disease that affects the tears and ocular surface, and lead to various symptoms as visual disturbance, discomfort, gritty feeling and burning sensation; it may cause tear film instability and possible defects of ocular surface and inflammation. (1) This disease may occur due to the decreased ability of lacrimal functional unit (lacrimal glands, ocular surface, and lacrimal drainage pathways) to produce sufficient amount of tear film components which results in a poor quality or/and low quantity of tear film (2,3,4,1). Rebamipide is a quinolone compound, its molecular formula is (C19H15ClN2O4) and it has a molecular weight (370.79 g/mole), the structure is illustrated in figure (1). It is classified as class IV according to the biopharmaceutical classification system (BCS).(6). (1,7) The compound was first introduced, in 1990, for gastric ulcer treatment; investigating rebamipide ability to induce mucin secretion from ocular cells, has led to its approval for dry eye treatment in 2011 and it was marketed, in 2012, as (Mucosta® ophthalmic suspension unit dose 2%) in Japan. The most important advantage is to increase the dosage form’s contact time with the conjunctiva and it varies from few hours to days; when compared to solution which has contact time no longer than fifteen minutes (10), the inserts showed a great enhancement in residence time. (11,12)
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