Artificial Tear Formulations Research Articles

Extending the Duration of Tear Film Protection in Dry Eye Syndrome: Review and Retrospective Case Series Study of the Hydroxypropyl Cellulose Ophthalmic Insert

options for extending the duration of tear film protection in dry eyes include artificial tear formulations with enhanced viscosity/polymeric systems, ocular ointments and gels, and, recently, the hydroxypropyl cellulose ophthalmic insert (Lacrisert®; distributed by Aton Pharma, inc., Lawrenceville, NJ, USA). The goal in using these agents is to achieve a balance between maximizing tear film stability and ocular surface retention, while simultaneously maintaining or improving vision, comfort, and convenience. In this article, various agents are reviewed, and findings are presented from a retrospective study of patients who used hydroxypropyl cellulose ophthalmic inserts within the previous 2 years. The median length of therapy with the insert was 5.3 years, and nearly 65% of patients had used it for more than 2 years. Findings suggest that the hydroxypropyl cellulose ophthalmic insert is a relatively safe, tolerable, and effective therapy for dry eye, either alone or in conjunction with other therapies.

Comparison of two artificial tear formulations using aberrometry

Background: This study investigates the effect of artificial tears of different viscosities on aberrations of healthy eyes.Methods: We recruited subjects from the student population of the Northeastern State University Oklahoma College of Optometry. Using the Complete Ophthalmic Analysis System (COAS), aberrometry measurements were taken every second for 60-seconds with a blink every 10-seconds. We made measurements of the naked eye, then after instillation of TheraTears non‐preserved drops, and after instillation of SystanePF, a more viscous formulation. Zernike coefficients up to the sixth order were recorded and analysed. We evaluated changes in spherical and astigmatic dioptric powers and coma‐like, spherical aberration‐like and total higher‐order aberration (HOA) RMS values as a function of time.Results: Both drops yielded significantly higher values than the naked eye for HOA RMS and cylindrical power as well as a hyperopic shift in spherical equivalent (p < 0.001, paired t‐test). SystanePF, the more viscous tear, showed significantly higher values than TheraTears in HOA RMS and cylinder in all inter‐blink periods (p < 0.001, paired t‐test).Conclusions: This study shows artificial tears can have a measurable and significant impact on aberrations of healthy eyes. This effect is sustained for at least one minute and its magnitude appears to be related to the viscosity of the tear formulation.

Retention and Retention of Effect of Topical Formulations in Dry Eye Subjects

It was the purpose of this investigation to examine both retention time (RT) and retention of effect of two ophthalmic formulations in the same dry eye subjects. This was a randomized, subject-masked cross-over study. Dry eye subjects, characterized by sub-type, were recruited. For direct RT measurement, fluorescein isothiocyanate (FITC)-dextran, 70 kDa molecular weight, was admixed at 0.1% wt/vol concentration into buffered saline (active control) and a viscous marketed artificial tear formulations (test formulation). RT in minutes was estimated directly as the return to baseline intrinsic fluorescence with an objective scanning fluorometer. Retention of effect was measured with a xeroscope as non-invasive breakup time (NIBUT) and by use of a numerical rating scale for comfort. Eleven subjects, with most being classified as having non-inflammatory meibomian gland dysfunction, completed the study. The RTs averaged 17.7 (+/-10.0) and 26.8 (+/-16.5) minutes for the saline and test formulations, respectively. The averages for NIBUT were 8.73 (+/-6.1) and 19.5 (+/-4.9) minutes, for saline and the test formulations, respectively. Return to baseline for the numerical rating scale comfort averages were 9.91 (+/-4.1) and 20.21 (+/-6.4) minutes for the saline and test formulations, respectively. When residence time was subtracted from the retention of effect measures, no statistical significance was found for the polymeric solution (vs. comfort, p = 0.153; vs. NIBUT, p = 0.109). However, statistical differences were found for direct retention compared against comfort (p = 0.01) and NIBUT (p = 0.004) for buffered saline. It seems that these two retention of effect measures are much shorter than RT measured directly. Future work should aim to confirm these findings in additional dry eye sub-types and in those with more severe disease manifestations.

Precorneal Residence Time of Artificial Tears Measured in Dry Eye Subjects

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. 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). 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). 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.

Carboxymethylcellulose Binds to Human Corneal Epithelial Cells and Is a Modulator of Corneal Epithelial Wound Healing

In this study, the ability of carboxymethylcellulose (CMC), used in artificial tear formulations, to interact with corneal-epithelial-cells (HCECs) and facilitate corneal epithelial wound healing was investigated. HCECs were incubated with fluorescein-labeled CMC (F-CMC). CMC-epithelial binding was measured by spectrophotometry. The effect on F-CMC binding by hyaluronic acid (HA) or glucose was measured after preincubation in HA, mAb to CD44, or glucose, or mAb to GluT-1. F-CMC binding to fibronectin or collagen was measured by incubating proteins with F-CMC. The wound widths were measured 18 hours after confluent HCECs were scratch wounded. The ability of CMC to induce cell chemotaxis, proliferation, or migration was measured by quantitative assay. The efficacy of CMC in promoting epithelial wound healing was also tested in a rabbit epithelial scrape-wound model. CMC remained bound to the HCECs for 2 hours. Preincubation of HCECs with glucose or mAb to GluT-1, but not with HA or mAb to CD44, reduced the binding of CMC to HCECs from 43.7% to 67.2% or 10.9% to 25.3%, respectively. CMC bound significantly to fibronectin (3.1-fold) or collagen (9.3-fold) compared with the control (BSA), and such binding enhanced cell adhesion. CMC stimulated re-epithelialization of HCECs scratched in vitro and in vivo rabbit cornea epithelial scrape wounds. CMC stimulated cell migration but not proliferation. CMC probably binds to HCECs through interaction of its glucopyranose subunits with glucose transporters. CMC binding to the matrix proteins stimulated HCEC attachment, migration, and re-epithelialization of corneal wounds.

A Comparison of the Effect of Carbomer-, Cellulose-, and Mineral Oil-Based Artificial Tear Formulations

To compare the efficacy, safety, and local tolerance between carbomer-based artificial tears, cellulose-, and mineral oil-based artificial tears. A randomized, open-label, parallel-group comparative 28-day study was designed for 67 patients who were randomized into three treatment groups. Measurements included the scoring of total subjective symptoms and objective signs, Schirmer-Jones test values, and tear break-up time (BUT) at baseline, and after 2 and 4 weeks of treatment. Safety of study treatment was also assessed. Outcomes measured at baseline and 2 and 4 weeks follow-up included the scoring of total subjective symptoms and objective signs, Schirmer-Jones test values, and tear BUT, subjective assessments, and safety. There were no differences regarding total scores, Schirmer-Jones test, or tear BUT at baseline among these three groups at 2 and 4 weeks. Patients in all three treatment groups experienced a significant improvement from baseline in total scores and Schirmer-Jones test values after treatment. Subjective assessment was better with carbomer-based treatment. Each artificial tear formulation successfully relieved symptoms and signs of keratoconjunctivitis sicca. The tolerance of carbomer-based artificial tears was comparable to that of cellulose- and mineral oil-based artificial tears.

Phosphate concentration in artificial tears

Irrigating solutions and eye drops may contain phosphates as part of their buffer system. In the presence of epithelial keratopathy, a high concentration of phosphate favours corneal calcification. Knowledge of the phosphate concentration in artificial tear products helps to prevent this sight-threatening complication. This study gives an overview on the amount of phosphate contained in artificial tears. Fifty-nine samples of commercially available artificial tear preparations were tested. The quantification of phosphate was performed using the molybdate method on a Modular P autoanalyzer. Twenty-six of 59 (44%) artificial tear products had a phosphate concentration above physiological levels (>1.45 mmol/l). A phosphate concentration above 25 mmol/l was found in nine products (15%), a concentration higher than 50 mmol/l in three (5%). Many artificial tear formulations contain unphysiological levels of phosphate, but very high concentrations are found only in a few products. These preparations have the potential to favour the formation of insoluble crystalline calcium phosphate deposits when used on a damaged corneal surface, and should therefore be used cautiously.

Ocular allergy and dry eye syndrome.

Ocular allergy is a common clinical disorder that includes dry eye syndrome in its differential diagnosis. While ocular allergy treatments have continued to evolve since the early 1990s when the new prescription topical agents became available, there have been no major advances in the treatment of dry eye syndrome other than changes in the chemical structures of various artificial tear formulations. This review is timely and relevant due to the recent FDA approval of several new agents for the treatment of dry eye syndrome. The literature reviewed brings the practicing allergist/clinical immunologist up to date on the recent understanding that T-cell activation plays a key role in dry eye syndrome immunopathophysiology. In addition, the parallel novel treatment developments are discussed, including new formulations for tear substitutes, topical cyclosporine A and purinergic receptor (P2Y2) agonists. The recent developments bode well for patients who are referred for ocular allergy, including dry eye syndrome. A new formulation for a tear substitute that generates a 'soft gel' covering the ocular surface (in situ) is ideal for early forms of dry syndrome, while topical cyclosporine is the first new real prescription treatment for patients with moderate to severe forms of dry eye. Another potential agent to revolutionize the treatment of various disorders is based on the discovery of the purinergic receptor agonists. This is not only relevant for the production of mucin and the change in tear fluid content, but it may also have implications for other sinopulmonary disorders such as cystic fibrosis and chronic sinusitis.

Pre-clinical investigation of the efficacy of an artificial tear solution containing hydroxypropyl-guar as a gelling agent

Purpose. Pre-clinical studies of a new artificial tear product (SystaneTM Lubricating Eye Drops Alcon Laboratories, Inc., Fort Worth, TX) containing the novel gelling agent hydroxypropyl-guar (HP-guar) and two demulcents, polyethylene glycol 400 (PEG) and propylene glycol (PG) were conducted to determine the ability of the product to protect ocular surface epithelial cells from desiccation in vivo and in vitro, and to promote recovery of the damaged corneal epithelial barrier in vivo. Other leading artificial tear products were also evaluated as comparators to determine the relative effectiveness of different polymer systems. Methods. Damage due to desiccation was assessed by measuring corneal uptake of methylene blue compared to untreated corneas. Corneas of anesthetized rabbits were treated with the new artificial tear product and subjected to desiccation by holding the eyelids open for 2 hours with a speculum. Control eyes were subjected to desiccation without application of a tear formulation. To measure recovery of the corneal epithelium from damage, corneas of anethesthetized rabbits were exposed to 0.01% benzalkonium chloride (BAC) for 5 minutes to increase epithelial permeability. The corneas were exposed to the new artificial tear for 1.5 hours followed by measurement of uptake of 5,6 carboxyfluorescein (CF). In the desiccation and CF uptake experiments, the new tear product was also compared to a tear product formulation without HP-guar and to a commercially available artificial tear containing carboxymethyl cellulose (CMC) and Purite®. In a third set of experiments, immortalized human corneal epithelial cells and Chang conjunctival cells in culture were exposed to the PEG/PG/HP-guar tear product, the control formulation without HP-guar, a tear formulation preserved with BAC, or the artificial tear containing CMC/Purite® for 15 min. The tear formulation was removed and the cells were exposed to desiccating conditions in a laboratory safety hood for 10 or 30 min. Cell viability was determined using the MTT assay. Results. The in vivo desiccation model, showed that the new tear product, SystaneTM, offered complete protection of the cornea from desiccation (methylene blue uptake not different than naïve control). Following exposure to 0.01% BAC, the new artificial tear product also provided an environment in which the corneal epithelium recovered completely from damage (CF uptake not different than normal, untreated cornea). This level of protection was not observed when corneas were treated with other formulations. Results from the in vitro desiccation procedure indicated that viability of corneal epithelial and Chang cells treated with the PEG/PG/HP-guar product was significantly greater than viability of cells treated with the tear product without HP-guar or the tear products containing BAC or CMC/Purite®. Conclusions. The tear product containing HP-guar, PEG 400 and propylene glycol satisfies several pre-clinical criteria for an appropriate artificial tear formulation. It gives long-term desiccation protection of the intact cornea and also epithelial cells in culture and has no apparent deleterious affects on cells. It also provides conditions in which a damaged corneal epithelium can recover normal barrier function. The combination of ingredients in the formulation appears to provide an effective mucomimetic artificial tear product. These pre-clinical data suggest that the product will be effective in providing superior relief for the dry eye sufferer.

Chitosan as tear substitute: a wetting agent endowed with antimicrobial efficacy.

A cationic biopolymer, chitosan, is proposed for use in artificial tear formulations. It is endowed with good wetting properties as well as an antibacterial effect that are desirable in cases of dry eye, which is often complicated by secondary infections. Solutions containing 0.5% w/v of a low molecular weight (M(w)) chitosan (160 kDa) were assessed for antibacterial efficacy against E. coli and S. aureus by using the usual broth-dilution technique. The in vitro evaluation showed that concentrations of chitosan as low as 0.0375% still exert a bacteriostatic effect against E. coli. Minimal inhibitory concentration (MIC) values of chitosan were calculated to be as low as 0.375 mg/ml for E. coli and 0.15 mg/ml for S. aureus. Gamma scintigraphic studies demonstrated that chitosan formulations remain on the precorneal surface as long as commonly used commercial artificial tears (Protagent collyrium and Protagent-SE unit-dose) having a 5-fold higher viscosity.

Preservative efficacy in cefuroxime and ceftazidime eye drop formulations

The efficacy of various common antimicrobial preservatives was tested in eye drop formulations containing the cephalosporin antibiotics cefuroxime and ceftazidime. The British Pharmacopoeia test for the efficacy of antimicrobial preservatives was used and the formulations were challenged with Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. The survival of organisms was monitored over 14 days. Cefuroxime sodium, 50 mg/ml, was studied in simple aqueous solution, and dissolved in an artificial tear formulation, Sno Tears (Smith and Nephew Pharmaceuticals), which contains benzalkonium chloride 0.004% w/v. Ceftazidime (50 mg/ml) was also studied in these two vehicles and, in addition, in a phenylmercuric acetate solution (0.002% w/v) and chlorhexidine acetate (0.02% w/v). Cefuroxime and ceftazidime contributed little, in the short-term, towards a microbicidal preservative effect in the unpreserved aqueous formulations, even against organisms for which they were active. Cefuroxime was adequately preserved in a vehicle of Sno Tears, which contains benzalkonium chloride as the antimicrobial preservative. Ceftazidime was less well preserved in this vehicle, but it was superior to phenylmercuric acetate (0.002% w/v) or chlorhexidine acetate (0.02% w/v).

Artificial tear issues.

The designing of artificial tear products has been undergoing constant reevaluation for many decades. Currently available artificial tear formulations differ remarkably with regard to their compositions. Today, significant controversies exist among pharmaceutical scientists in this field. Many formulation issues need to be addressed before agreement can be reached on the desirable attributes of truly efficacious artificial tear formulas.

Morphologic and Physiologic Effects of Artificial Tear Formulations on Corneal Epithelial Derived Cells

The biological effects of four commercially available artificial tear formulations were evaluated using sensitive in vitro techniques. Two of the formulations contained ingredients implicated in cell damage; the other two products were not chemically preserved, and their components have not been reported to damage corneal tissue. We assayed the effects of these formulations on viability, morphology, and physiology in corneal cell (SIRC) cultures. Their effect on the hydration of excised rabbit corneas was also determined. In all formulations, cell viability declined with time relative to control cells, but the time course varied significantly. Viability remained at 100% for 6 h in an unpreserved carboxymethylcellulose-based product (CMC-U), and decreased to 50% after greater than 16 hours. Viability decreased to 50% in 3 h for the other unpreserved, polyvinyl alcohol-based product (PVA-U), and in 1 h for a hydroxypropylmethylcellulose formulation (HPMC-P) that contains edetate disodium (EDTA). Cells in a preserved formulation (PVA-P), using polyvinyl alcohol as the polymer and containing EDTA and benzalkonium chloride (BAK), failed to survive even 15 min of treatment. Overall, cells treated with the unpreserved products were nearly indistinguishable from those in the control solution with respect to morphology, electrophysiology, and corneal hydration. Also, the relative ranking from least to most deleterious (control less than CMC-U less than PVA-U less than HPMC-P less than PVA-P) was consistent across several measures. Of the preserved formulations, HPMC-P, which contains the chelating agent EDTA as an additive, was less damaging than was PVA-P, which contains two chemicals, EDTA and BAK, that reportedly damage cells.

Morphologic and Physiologic Effects of Artificial Tear Formulations on Corneal Epithelial Derived Cells

Morphologic and Physiologic Effects of Artificial Tear Formulations on Corneal Epithelial Derived Cells

Quantitative evaluation of the corneal epithelial barrier: effect of artificial tears and preservatives

The effect of artificial tear solutions on the corneal epithelial barrier was evaluated by measuring corneal uptake of 5, 6 carboxyfluorescein (CF) after exposure of rabbit corneas to various formulations in a conjunctival cup. Four tear solutions containing 0.01% benzalkonium chloride (BAC), a formulation containing 0.001% Polyquad, a contact lens re-wetting solution containing 0.004% thimerosal, and each of the above preservatives in balanced salt solution (BSS) were evaluated. Four non-preserved solutions were also tested. After treatment with the solutions corneas were exposed to the CF, removed from the eyes and dialyzed in balanced salt solution. The CF concentration in the dialysate was measured by fluorometry. Solutions containing 0.01% BAC caused a 9.24 to 99.28 fold increase in CF uptake as compared to control. Solutions preserved with Polyquad or thimerosal caused only a 0 to 4 fold increase in CF uptake while non-preserved solutions caused no change compared to control. Corneas prepared for transmission electron microscopy using fixative containing ruthenium red exhibited damage which correlated well with CF uptake; the ruthenium red penetrated the epithelium to the basal cell layer after corneal exposure to solutions containing BAC while only superficial cell layers were stained after exposure to the other test solutions. The method used in this study allows statistical comparison of artificial tear formulations. The data show that patients with severe dry-eye who use artificial tears frequently should avoid tear solutions containing BAC and that non-preserved solutions are preferable for treatment of these patients.

Ophthalmic Solutions, the Ocular Surface, and a Unique Therapeutic Artificial Tear Formulation

In rabbit studies, we found that extended exposure of the ocular surface to existing ophthalmic solutions resulted in gross surface abnormalities and decreases in conjunctival goblet cell density. We developed an electrolyte solution (solution 15) that preserves normal gross appearance, goblet cell density, corneal epithelial glycogen levels, and ocular surface morphologic characteristics after extended exposure to the rabbit ocular surface. We created an artificial tear formulation by adding a demulcent and a buffering system to solution 15 and reducing its osmolarity to 162 mOsm/l. We then compared our artificial tear formulation to Hypotears in a double-masked, crossover study involving 11 patients with dry-eye disorders. Our artificial tear formulation was more effective than Hypotears in decreasing tear film osmolarity and rose bengal staining, and was preferred subjectively by an eight-to-one margin.