David L. Meadows

Biocide uptake in contact lenses and loss of fungicidal activity during storage of contact lenses.

Purpose. With recent outbreaks of Fusarium keratitis related to contact lens wear, studies were conducted to determine the biocide uptake during lens storage, and the resulting effect on antifungal activity of related products. Methods. ACUVUE 2 (etafilcon A) soft, hydrophilic contact lenses (group IV) were soaked from 1 hour to 7 days in OPTI-FREE Express and OPTI-FREE RepleniSH multipurpose disinfecting solutions with POLYQUAD (polyquaternium-1) and ALDOX (myristamidopropyl dimethylamine) biocides and multipurpose solutions, Bausch & Lomb ReNu with MoistureLoc (Alexidine), ReNu MultiPlus (polyhexamethylene biguanide [PHMB]), and AMO Complete MoisturePLUS (PHMB). Storage solutions were tested to evaluate the effect of preservative uptake on the residual biocide activity against Fusarium solani. Results. Approximately 30% to 60% of the PHMB and Alexidine were depleted by 6 hours, with comparable loss of antimicrobial activity. Decreasing activity was noted with corresponding decreases in active concentration throughout the course of the evaluation. The POLYQUAD systems retained nearly 100% of the biocide and fungicidal activity and maintained their concentration in the solution. Conclusions. OPTI-FREE Express and OPTI-FREE RepleniSH multipurpose disinfecting solutions maintained fungicidal efficacy after storage of lenses. The Alexidine- and PHMB-based multipurpose solutions tested showed significant uptake of preservative into group IV lenses, resulting in a decrease in the residual activity of the storage solution. The POLYQUAD systems showed a low uptake of biocide and maintained fungicidal efficacy against F. solani.

Clinical evaluation of an HP-guar gellable lubricant eye drop for the relief of dryness of the eye

Purpose. To evaluate the efficacy of a new lubricant eye drop containing polyethylene glycol 400 and propylene glycol demulcents with hydroxypropyl-guar as a gelling agent (Test Product) to a system with carboxymethylcellulose (Control Product) for reducing dry eye signs and symptoms. Methods. Eighty-seven dry eye volunteers were enrolled at seven sites for this six-week, concurrently controlled, double-masked clinical study. Results. The Test Product significantly reduced conjunctival staining (p = 0.025) and temporal corneal staining (p = 0.024) compared to the Control. The Test Product also significantly reduced symptoms of dryness in the morning and evening, compared to the Control (p = 0.015 and p = 0.023, respectively). Subjects in the Test treatment group reported lower frequencies of foreign body sensation and felt their eyes were “refreshed longer” compared to those in the Control group (p = 0.033 and p = 0.037, respectively). Conclusions. The Test Product was more effective at reducing both the signs and symptoms of dry eye compared to the carboxymethylcellulose containing Control.

Precorneal residence time of artificial tears measured in dry eye subjects.

Purpose. The purpose of this investigation was to measure the precorneal residence time of saline and five marketed artificial tears in dry eye subjects using fluorometry. Methods. FITC-dextran, 70 kDa molecular weight, was admixed under sterile conditions (0.1% wt/vol) into buffered saline and the marketed artificial tear formulations of varying viscosity. Precorneal residence time (RT) was measured directly in 16 mild to moderate dry eye subjects, classified by sub-type, in a six-way cross-over, masked and randomized study. FITC-dextran tracer decay with a scanning fluorometer was used to estimate the gross RT (i.e., the time in minutes for the signal to return to baseline). Results. All subjects were classified as having non-inflammatory meibomian gland dysfunction except one, who had a mixture of aqueous deficiency and meibomian gland dysfunction. In two separate determinations, the saline RTs were 19.1 ± 7.4 and 17.6 ± 8.2 min. The RTs for the formulations varied to some degree by viscosity, with two higher viscosity formulations demonstrating the longest RTs of 36 to 41 min, approximately twice that of saline (p < 0.001 for both 0.4% polyethylene glycol/0.3% propylene glycol, and 1.0% carboxymethylcellulose). An oil emulsion, low viscosity carboxymethylcellulose and moderate viscosity hydroxypropylmethylcellulose-containing formulation were not statistically different from saline (RTs of 18, 22 and 24 min, p values = 0.983, 0.818 and 0.099, respectively). Conclusions. More than two-fold RT differences were found for the higher viscosity, more muco-adhesive formulations compared to saline. However, other formulations provided RTs close to saline, suggesting that RT is influenced by factors other than simple viscosity. Future studies should examine the interplay of spreading characteristics, pseudoplasticity and muco-adhesion relative to RT to determine the individual and cumulative effects on formulation retention.

Recent developments with biosensing technology and applications in the pharmaceutical industry

Abstract This article reviews recent sensor literature and identifies systems that may be uniquely suited for use in pharmaceutical research and development. Overviews are given for invasive sensor designs based on electrochemical, thermal, mass and photometric detection methods. Eliminating trauma caused by invasive monitoring with biosensors has several very important advantages for clinical, pharmacokinetic and toxicological studies. For this reason, particular emphasis is given to advances made in non-invasive photometric systems. Optical and electrical instrumentation tools are becoming available for tremendous miniaturization of non-invasive sensors which will pave the way for broader areas of application in the future.

Molecular Structure of Interfacial Human Meibum Films

Meibum is the primary component of the tear film lipid layer. Thought to play a role in tear film stabilization, understanding the physical properties of meibum and how they change with disease will be valuable in identifying dry eye treatment targets. Grazing incidence X-ray diffraction and X-ray reflectivity were applied to meibum films at an air-water interface to identify molecular organization. At room temperature, interfacial meibum films formed two coexisting scattering phases with rectangular lattices and next-nearest neighbor tilts, similar to the Ov phase previously identified in fatty acids. The intensity of the diffraction peaks increased with compression, although the lattice spacing and molecular tilt angle remained constant. Reflectivity measurements at surface pressures of 18 mN/m and above revealed multilayers with d-spacings of 50 Å, suggesting that vertical organization rather than lateral was predominantly affected by meibum-film compression.

Biophysical and Morphological Evaluation of Human Normal and Dry Eye Meibum Using Hot Stage Polarized Light Microscopy

PURPOSE To study melting characteristics and the morphology of human and mouse meibum. METHODS Hot stage cross-polarized light microscopy (HSPM) and immunohistochemical approaches were used. RESULTS Isolated human meibum, and meibum of mice (either isolated or within the meibomian ducts of mice), were found to be in liquid-crystal state at physiological temperatures. Melting of both types of meibum started at approximately 10°C and was completed at approximately 40°C. Melting curves of isolated meibum and meibum inside the meibomian ducts were multiphasic with at least two or three clearly defined phase transition temperatures, typically at approximately 12 ± 2°C (minor transition), 21 ± 3°C, and 32 ± 3°C, regardless the source of meibum. Melting was highly cooperative in nature. Samples of abnormal human meibum collected from dry eye patients with meibomian gland dysfunction often showed an increased presence of nonlipid, nonmelting, nonbirefringent, chloroform-insoluble inclusions of a protein nature. The inclusions were positively stained for cytokeratins. The presence of these inclusions was semiquantitatively characterized using a newly proposed 0 to 4 scale. In the presence of large amounts of these inclusions, melting characteristics of meibum and its structural integrity were altered. CONCLUSIONS HSPM is an effective tool that is suitable for biophysical and morphological evaluation of meibum. Morphological properties and melting characteristics of human meibum were found to be similar to those of mice. Abnormal meibum of many dry eye patients contained large quantities of nonlipid, protein-like inclusions, which were routinely absent in meibum of normal controls.

Lens parameter changes under in vitro and ex vivo conditions and their effect on the conjunctiva

PURPOSE To quantify changes in contact lens parameters induced by lens wear and determine whether these changes are associated with contact lens-induced conjunctival staining (CLICS). METHODS In vitro: Lens diameter, sag, edge shape, base curve of six contact lens brands (balafilcon, comfilcon, etafilcon, lotrafilcon B, omafilcon and senofilcon) measured at 21°C and 35°C (eye temperature). Ex vivo: Diameter of lenses collected from a prospective, randomised, contra-lateral, cross-over clinical trial from 36 subjects wearing all lens types for 1 week daily wear, measured in 35°C PBS after removal. Ocular surface was examined for lens-induced conjunctival staining by masked examiner. RESULTS In vitro: Changes in diameter and base curve outside ISO tolerance were found with etafilcon A and omafilcon A. Ex vivo: Comfilcon A and etafilcon A had greatest shrinkage in diameter (0.18mm) and base curve (0.11mm steeper) with temperature increase from 21°C to 35°C. Senofilcon A, lotrafilcon B and balafilcon A maintained most stable parameters between 21°C and 35°C. Changes in diameter and base curve from lens wear were not correlated with CLICS (p>0.49). Multivariate analysis showed significantly greater levels of lens induced staining were associated with lens modulus (p<0.001) and knife (p<0.001) and chisel (p<0.001) edge shapes. CONCLUSIONS Parameter changes induced by lens wear were associated with increasing temperature, but these changes in lens diameter and base curve did not induce CLICS. Modulus and edge shape were associated with increased CLICS. The susceptibility of etafilcon A and omafilcon A lenses to parameter changes might be related to their high water content.

Reversible flocculation with hydroxypropyl guar-borate, a labile anionic polyelectrolyte.

Cationic polystyrene latex was flocculated with mixtures of hydroxypropyl guar (HPG) and boric acid, which form an anionic polyelectrolyte HPG-borate. Flocculation could be reversed by either lowering pH or by adding fructoseboth procedures remove labile borate ions weakly bound to the HPG chains. Mixtures of phenyl boronic acid (PBA) and HPG also flocculate latex although the range of HPG-PBA concentrations, giving flocculation was much narrower than HPG-borate. The differences were explained by the tendency of borate ion to cross-link HPG chains, whereas PBA is monofunctional and cannot cross-link HPG.

Not all anionic polyelectrolytes complex with DTAB.

The influence of hydroxypropyl guar (HPG), with and without boric acid, on dodecyltrimethyl ammonium bromide (DTAB) micellization was characterized by surface tension measurements, isothermal titration calorimetry, and small-angle neutron scattering. Although HPG is a nonionic water-soluble polymer, borate ions form weak bonds with HPG, transforming it into an anionic polyelectrolyte, HPG-borate. Surprisingly, the three independent measurements showed that HPG-borate does not promote DTAB micellization or phase separation normally seen when mixing oppositely charged polyelectrolytes and surfactants. However, the neutron scattering results suggested that HPG-borate binds to and flocculates existing DTAB micelles. The unusual behavior of HPG-borate with DTAB was underscored by showing that carboxymethyl guar (CMG) formed precipitates with DTAB.

Poster 16 - Correlating Biocide Uptake and Release Profiles with Corneal Staining and Subjective Symptoms

Purpose: To determine if the interactions of lens care preservatives with contact lenses is an important factor in clinical signs and symptoms. Methods: This study evaluated uptake and release profiles of two preservatives used in MPS products, alexidine contained in ReNu® with MoistureLocTM and POLYQUAD® (polyquaternium-1) contained in OPTI-FREE® Express®. Three lens materials were used in a cross over study design: SofLensTM 66 (alphafilcon A), Acuvue® 2 (etafilcon A) and Acuvue® AdvanceTM (galyfilcon A, with HYDRACLEARTM). Asymptomatic, adapted daily wear soft lens users wore groups I and IV soft hydrophilic or silicone hydrogel lenses for a maximum of 2, 4 and 6 hrs each day. New lenses were dispensed for each wear period. The worn lenses were analyzed for preservative content using HPLC and release profiles calculated. Short-term changes in corneal staining and ocular symptoms were assessed at defined time intervals following lens insertion in order to compare these ocular findings with laboratory uptake and release properties. Results: All three lens types uptake alexidine during an overnight soaking period. The rate of preservative release during wear depended on the lens type. After 2 hours, Acuvue® 2 and SofLensTM 66 released 46% and 77% of alexidine, respectively. Acuvue® AdvanceTM released 27% of the preservative in two hours. Clinically significant corneal staining was observed at 2 and 4 hours when subjects wore Acuvue® 2 and Acuvue® AdvanceTM lenses soaked in the alexidine-based system. At the 2 hour interval, extent of corneal staining increased in all subjects with Acuvue® 2 lenses, and 50% of the subjects with Acuvue® AdvanceTM lenses. Only minimal staining was observed for SofLensTM 66 at 2, 4 and 6 hours. Symptoms were not correlated with the extent of staining. Lenses cycled in the POLYQUAD® based product showed minimal uptake into lenses and corneal staining was low with all lens materials tested. Conclusions: The study demonstrated the difference in uptake/release profiles for MPS products preserved with alexidine or POLYQUAD ® using 3 soft lens materials. For some lens materials these differences in biocide uptake/release appear to be correlated with corneal staining patterns but not symptoms.