Langmuir Trough Study of the Interactions of Tear Mimetic Eyedrop Formulation with Human Meibum Films

Abstract

Meibomian gland disease is associated with quantitative or qualitative deficiencies of meibum (MGS) that result in tear film instability. Thus, there is great demand for ophthalmic nanoemulsions that can replenish MGS and recover its performance at the air/tear surface. Rohto Dry Aid (RDA) utilizes TEARSHIELD TECHNOLOGYTM implementing a complex oil phase of non-polar and polar lipid-like molecules. Therefore, the interactions of RDA with MGS surface films deserve further study as they may provide valuable insights (i) into the mechanisms behind the nanoemulsion therapeutic action and (ii) for the design of novel ophthalmic formulations. Pseudobinary meibum/RDA films were formed at the air–water surface of the Langmuir trough. Surface pressure-area isocycles and stress relaxations were employed to probe the layer (i) reorganization upon cycling and (ii) dilatational elasticity, respectively. Film morphology was accessed by Brewster angle microscopy and the spreading properties of RDA-supplemented meibum were also probed. The diverse ingredients of the nanoemulsion oil phase complemented the non-polar and polar lipid constituents of the meibomian layers, which resulted in enhanced continuity of the MGS duplex film structure and facilitated the MGS spread and viscoelasticity. Nanoemulsions deserve further study as a potent tool for MGS-oriented therapy for dry eyes.

Surface Chemistry Study of Normal and Diseased Human Meibum Films Prior to and after Supplementation with Tear Mimetic Eyedrop Formulation

“…As shown in a previous study [12], similarly to other oil-in-water ophthalmic nanoemulsions with comparable compositions, RDA films exhibited typical behavior [24,25]. Highly reversible, non-collapsible surface films are formed by nanoemulsion.…”

“…As the continuous structure of the TFLL is an important indication for its ability to stabilize the tear film in vivo, this is an interesting result that hints at the clinical promise of opththalmic nanoemulsion applications to treat lipid-deficiency-related forms of dry eye. BAM visualization (Figure 4) revealed that while nMGS formed continuous films of multilayer thickness (estimated at around 60-100 nm, as explained previously) [9][10][11][12], in contrast dMGS layers were patchy and consisted of darker regions, probably of monolayer thickness, and thick bright regions which cannot enclose to a continuous structure and instead form a sparse bright mesh at the aqueous interface. For such estimations a simple semi-quantitative model relates the intensity, I, of the film regions in the BAM image with its thickness, d (d i /d j = [I i /I j ] 1/2 , where the subscripts i and j denote the different images) [3].…”

“…Rohto Dry Aid ophthalmic nanoemulsion (Table 1) (Rohto Pharmaceutical, Osaka, Japan) was used to supplement the dMGS in pseudobinary films [12]. To prevent dust contamination and PBS subphase evaporation, an acrylic cover was installed over the apparatus.…”

“…Langmuir surface balance measurements have proven to be an effective approach for assessing the interfacial properties of MGS films during blink-like area changes that are relevant to physiological conditions [2]. These measurements have also been successfully applied in the development and characterization of ophthalmic formulations [9][10][11][12]. The reorganization of the layers upon blink-like cycling and their dilatational elasticity were investigated using surface pressure (π)-area (A) isocycles and stress relaxations, respectively.…”

“…Another goal was to see whether the supplementation of dMGS with Rohto Dry Aid (RDA), a novel ophthalmic nanoemulsion that uses TEARSHIELD TECHNOLOGY TM to simulate normal tears and restore moistness, can recover the structure and functionality of the diseased Meibomian films, since the formulation was recently shown to facilitate the performance of "healthy" Meibomian lipids [12]. Sesame oil (SO) is implemented in the RDA oil phase as an NPL substitute, while a mixture of polyoxyethylene castor oil 10 (CO-10), polyoxyl 40 stearate (MYS-40), and menthol was chosen to emulate the PL.…”