[Inflammatory granuloma after intracanalicular punctal plug migration (a clinical case)]. / Vospalitel'naia granulema pri vnutrikanal'tsevoi migratsii okkliudera sleznoi tochki (sluchai iz praktiki).

At present, installation of punctal plugs (tear duct occluders) draws attention of ophthalmologists, but this method of treating dry eye syndrome (DES) is not without complications. Considering the rise of DES occurrence - the tendency anticipated to continue - as well as expansion of indications for installation of tear duct occluders, their usage can be expected to rise. The article describes a relatively rare clinical case that involved intracanalicular migration of silicone punctal plug. A female patient of 36 years old sought medical help in Research Institute of Eye Diseases (Moscow) to treat a lump in the area of lower lacrimal punctum in the left eye that was growing in size; the lump had appeared around 2 months prior to the visit. Patient's medical history read that around 2 years ago she had a silicone occluder installed in the lower lacrimal punctum of the left eye. On examination, in the area of lower lacrimal punctum, a body with a nutrient vascular pedicle deriving from lower lacrimal duct could be found. The occluder was absent in the opening of the lacrimal punctum. A revision of lower tear duct cavity was performed to remove its contents. The body filling tear duct opening was removed with forceps. Substance was then sent for histological examination. Tear duct was scraped out, the silicone occluder removed and sent to laboratory for scanning electron microscopy. The patient had no complaints 6 months after the procedure. CONCLUSION: The study showed that the forming body was granuloma resulting from aseptic inflammation. Surface of the silicone occluder in retention of lacrimal pathways remained unchanged. Described surgical tactic is suitable for treating patients with intracanalicular punctal plug migration.

Poloxamer 407/TPGS Mixed Micelles as Promising Carriers for Cyclosporine Ocular Delivery.

Cyclosporine is an immunosuppressant agent approved for the treatment of dry eye disease and used off-label for other ocular pathologies. Its formulation and ocular bioavailability present a real challenge due to the large molecular weight (1.2 kDa), high lipophilicity, and low water solubility. The aim of the work was to develop an aqueous micellar formulation for an efficient cyclosporine delivery to the ocular tissues, using a water-soluble derivative of vitamin E (TPGS: d-α-tocopheryl polyethylene glycol 1000 succinate) and poloxamer 407 (Pluronic ®F127) as excipients. The mixed micelles were characterized in terms of particle size, zeta potential, rheology, and stability upon dilution and freeze-drying. Additionally, the enzymatic-triggered release of vitamin E and vitamin E succinate from TPGS was investigated in vitro in the presence of esterase. Compared to the commercially available ophthalmic formulation, the poloxamer 407:TPGS 1:1 molar ratio micellar formulation significantly improved cyclosporine solubility, which increased proportionally to surfactant concentration reaching 0.4% (w/v) for 20 mM surfactant total concentration. Cyclosporine-loaded mixed micelles efficiently retained the drug once diluted in simulated lachrymal fluid and, in the presence of a 20 mM surfactant concentration, were stable upon freeze-drying. The drug-loaded mixed micelles were applied ex vivo on porcine cornea and compared to Ikervis®. Drug accumulation in the cornea resulted proportional to drug concentration (6.4 ± 1.9, 17.6 ± 5.4, and 26.9 ± 7.4 µgdrug/gcornea, after 3 h for 1, 2.5, and 4 mg/mL cyclosporine concentration respectively). The formulation containing cyclosporine 4 mg/mL (20 mM surfactant) was also evaluated on the sclera, with a view to targeting the posterior segment. The results demonstrated the capability of mixed micelles to diffuse into the sclera and sustain cyclosporine delivery (28 ± 7, 38 ± 10, 57 ± 9, 145 ± 27 µg/cm2 cyclosporine accumulated after 3, 6, 24, and 48 h respectively). Reservoir effect experiments demonstrated that the drug accumulated in the sclera can be slowly released into the underlying tissues. Finally, all the formulations developed in this work successfully passed the HET-CAM assay for the evaluation of ocular irritability.

[Prospective evaluation of mouth and eye dryness induced by antimuscarinic drugs used for neurogenic overactive bladder in 35 patients with multiple sclerosis]. / Évaluation prospective de l'impact des anticholinergiques sur la sécheresse buccale et oculaire chez 35 patients atteints de sclérose en plaque avec hyperactivité vésicale neurogène.

INTRODUCTION: Mouth and eye dryness are frequently reported by patients with multiple sclerosis (MS) as side effects of antimuscarinic drugs used for neurogenic overactive bladder. We evaluated the impact of antimuscarinic drugs prescription on these symptoms. METHODS: MS patients consulting for overactive bladder were included. Xerostomia were evaluated at baseline and thirty days after treatment by self-reporting questionnaires (Xerostomia Quality of Life [X-Qol] and Xerostomia Questionnaire [XQ]), by salivary flow rate and sugar test. Xerophtalmia were evaluated by a self-reporting questionnaire (Ocular Surface Disease Index [OSDI]) and Schirmer test. Iatrogenic anticholinergic impregnation was evaluated by the Anticholinergic Drug Scale. RESULTS: From January to December 2014, 35 patients were included. Mean age was 50.1±10.2 years, mean EDSS=4.9. Mean anticholinergic impregnation was 0.6±1.0. Before treatment, none correlation was found between anticholinergic impregnation and other parameters. Twenty-two patients were evaluated after treatment. At baseline and thirty days after treatment, mean scores were respectively: 0.78±0.51 and 0.73±0.43 (P=0.67) for X-Qol, 9.22±11.8 and 7.03±11.4 (P=0.32) for XQ, 18.8±14.9 and 13.9±11.6 (P=0.06) for OSDI. Mean salivary flow rates were respectively 1.54±1.11 and 1.22±1.3 (P=0.53), positive sugar tests concerned respectively 68% and 55% of patients (P=0.53), and positive Schirmer test concerned 50% before and after treatment. CONCLUSION: Eye and mouth dryness exist in our MS population, even before prescription of antimuscarinic treatment, and is not getting worse after prescription. Those symptoms should not be the reason to stop an efficient treatment, but should be the reason to find and treat their aetiology. LEVEL OF EVIDENCE: 4.

Cationorm shows good tolerability on human HCE-2 corneal epithelial cell cultures.

Preservatives have been for a long time known to cause detrimental effects on ocular surface. Cationorm, a preservative-free compound with electrostatic properties is a novel way to solve the problems encountered with traditional benzalkonium chloride (BAK)-containing eye drops. The aim of this study was to evaluate tolerability of the preservative-free cationic emulsion Cationorm in vitro on corneal epithelial cells. The human corneal epithelial cell (HCE-2) culture line was used to study cellular morphology, cytotoxicity and inflammatory responses after Cationorm diluted 1/10 exposure for 5, 15 and 30 min. Exposures to Systane diluted 1/10 with polyquaternium-1/polidronium chloride 0.001% as preservative, BAK 0.001% or C16 (0.0002%) and normal cell culture medium served as positive and negative references. Cell viability was determined by measuring the release of lactate dehydrogenase (LDH) and mitochondrial dehydrogenase activity was evaluated using 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The possible induction of apoptosis was analyzed by measuring the activity of caspase-3, and Cell Counting Kit-8 (CCK-8) was used to evaluate the number of viable cells after the exposure to test compounds. Furthermore, the tendency of the test compounds to produce inflammatory reaction was determined by analyzing the production of proinflammatory cytokines IL-6 and IL-8, and DNA binding of the p65 subunit of transcription factor NF-κB was measured from cell lysates. HCE-2 cells showed no morphological changes after the exposure to Cationorm, but in cells exposed to BAK, clear cytoplasm vacuolization and loose cell-cell contacts were observed in transmission (TEM) or scanning (SEM) electron microscopic analyses. Cell viability, as measured with the release of LDH, indicated a time dependent increase in LDH expression after exposure to all test compounds but especially with BAK. Moreover, Cationorm and BAK time-dependently decreased the mitochondrial metabolism to 73% with Cationorm and 53% with BAK from that of the control cells after 30 min exposure in MTT assay. BAK was the only test compound having clear adverse effects on the cell number and metabolism in CCK-8 assay. The activity of caspase-3 did not show significant differences between the groups. Inflammatory response after exposure to Cationorm was significantly lower than after exposure to BAK. There were no significant differences in NF-κB activity between the groups. Diluted Cationorm and Systane with polyquaternium-1/polidronium chloride 0.001% showed good tolerability on HCE-2 cells and thereby provide a clear improvement when compared to BAK-containing eye drop formulations.

Nanomicellar eye drops: a review of recent advances.

INTRODUCTION: Research on nanotechnology in medicine has also involved the ocular field and nanomicelles are among the applications developed. This approach is used to increase both the water solubility of hydrophobic drugs and their penetration/permeation within/through the ocular tissues since nanomicelles are able to encapsulate insoluble drug into their core and their small size allows them to penetrate and/or diffuse through the aqueous pores of ocular tissues. AREAS COVERED: The present review reports the most significant and recent literature on the use of nanomicelles, made up of both surfactants and amphiphilic polymers, to overcome limitations imposed by the physiology of the eye in achieving a high bioavailability of drugs intended for the therapeutic areas of greatest commercial interest: dry eye, inflammation, and glaucoma. EXPERT OPINION: The results of the numerous studies in this field are encouraging and demonstrate that nanomicelles may be the answer to some of the challenges of ocular therapy. In the future, new molecules self-assembling into micelles will be able to meet the regulatory requirements for marketing authorization for their use in ophthalmic formulations.

Comparative study of cyclosporine A liposomes and emulsions for ophthalmic drug delivery: Process optimization through response surface methodology (RSM) and biocompatibility evaluation.

Herein, cyclosporine A loaded liposomes (CsA-Lips) were fabricated aimed at improving the biocompatibility of the ophthalmic formulation and getting rid of the direct contact of ocular tissues with irritant excipients. Response surface methodology was exploited in order to investigate the influence of miscellaneous factors on the key characteristics of CsA-Lips. Ratio of EPC:CsA, ratio of EPC:Chol, and stirring speed were selected as the independent variables, while size, drug-loading content (DL), and drug-loading content (DL) loss rate were applied as the response variables. In case of the maximal lack-of-fit p-value and minimum sequential p-value, quadratic model was regarded as the fittest model to analyze the data. The correlation of independent variables with response variables was described by three-dimension surface figures. Optimized formulation for CsA-Lips was obtained with ratio of EPC:CsA set as 15, ratio of EPC:Chol set as 2, and stirring speed set as 800 rpm. The particle size of CsA-Lips was 129.2 nm after optimalization while their TEM images exhibited spherical unilamellar vesicles with clearly shell-core structure. CsA released more rapidly from CsA-Lips in comparison with self-made emulsion and Restasis®. Besides, minimum cytotoxicity of CsA-Lips was perceived via both MTT method and LDH method, indicating the excellent compatibility of the ophthalmic formulation. Simultaneously, CsA-Lips showed enhanced nonspecific internalization in the cytoplasm with a time-dose-dependent manner. In conclusion, CsA-Lips could be adhibited as the hopeful ophthalmic drug delivery system clinically for dry eye syndrome (DES).

Alleviation of dry eye syndrome with one dose of antioxidant, anti-inflammatory, and mucoadhesive lysine-carbonized nanogels.

Most dry eye syndromes (DES) are caused by oxidative stress and an overactive inflammatory response, leading to tear deficiency and excessive tear evaporation. Conventional eye drops for DES treatment require high doses and frequent administration due to their insufficient precorneal residence time. To overcome these problems, in this study, we have developed carbonized nanogels (CNGs) via the straightforward pyrolysis of lysine hydrochloride (Lys) to provide a long-lasting eye drop formulation for topical DES therapy. This methodology thermally converts Lys-into nitrogen-doped crosslinked polymers with embedded nanographitic structures, which enable efficient free radical scavenging. The cationic and crosslinked polymeric features of the Lys-CNGs also prolong the precorneal retention time and improve ocular bioavailability. These Lys-CNGs exhibit high biocompatibility with corneal epithelial cells both in vitro and in vivo, indicating their safety as eye drops. In a DES rabbit model, a single dose of Lys-CNGs (50 µg mL-1) can effectively alleviate the signs of DES within 4 days, whereas multiple treatments of 10-fold higher concentration of cyclosporine A are needed to achieve similar therapeutic effects (one dose every 12 h; 500 µg mL-1). The topical administration of Lys-CNGs enable a reduced therapeutic dose and extended dosing interval, thereby demonstrating a superior therapeutic efficacy compared to the commercial cyclosporine A eye drops. These Lys-CNGs, which exhibit significant free radical scavenging, anti-inflammatory activity, high biocompatibility, and a remarkable ocular bioadhesive property, hold great potential as a long-lasting eye drop formulation for the treatment of dry eye disease. STATEMENT OF SIGNIFICANCE: Multifunctional nanobiomaterial-based eye drops can render an ideal pharmaceutical formulation for the treatment of a variety of ocular surface diseases. To our knowledge, this is the first report describing the development of carbonized nanogels as topically administered therapeutics for alleviating dry eye syndrome (DES). We present evidence that the thermal transformation of lysine hydrochloride into carbonized nanogels (Lys-CNGs) endows superior antioxidant, anti-inflammatory, and bioadhesive properties. While a single dose of Lys-CNGs (50 µg mL-1) is sufficient to relieve the symptoms of DES for 4 days, multiple treatments of 10-fold higher concentration of commercially available cyclosporine eye drops are needed to achieve similar therapeutic outcomes (one dose every 12 h; 500 µg mL-1), suggesting an effective and long-lasting ocular carbonized nanomedicine.

Potential Risks of Corneal Refractive Surgery in Patients with Ectodermal Dysplasia.

Ectodermal dysplasia (ED) involves the aberrant development of at least two ectodermal derivatives, such as skin, teeth, hair, sweat glands, and ocular tissue. The group of over 200 conditions is commonly classified into two major types: hypohidrotic/anhidrotic ED, in which sweat glands are either absent or significantly reduced, and hidrotic ED, in which sweat glands are normal. Ocular manifestations pertinent to patients undergoing corneal vision correction surgery include multifaceted dry eye syndrome, corneal pathology, such as recurrent erosions, scars, neovascularization, and limbal stem cell deficiency, and early-onset cataracts and glaucoma. In this article we discuss the current understanding of ED and offer factors to consider when these patients are seeking corneal refractive surgery.

Preparation of Nanoparticle-Containing Ring-Implanted Poly(Vinyl Alcohol) Contact Lens for Sustained Release of Hyaluronic Acid.

Here, a novel ring-implanted poly vinyl alcohol (PVA) contact lens (CL) is fabricated and evaluated as a therapeutic CL with potential of sustained release of hyaluronic acid (HA). HA is loaded on chitosan (CS) nanoparticles (NPs) and then the HA-loaded NPs are dispersed in a ring shape PVA hydrogel which is implanted in the final PVA CL. Results show that HA is successfully loaded on NPs (520 ± 18 nm) with loading efficacy of 87% and loading capacity of 50%. The CL hydrogel has a 275% swelling ratio, no degradation during 14 days, 97% light transmittance, and desirable rheological stability under physiological shear force. The release data show a sustained release for HA from the ring implanted CL up to 14 days. The cellular study reveals no corneal epithelial cell cytotoxicity and cell attachment on the CL. The study demonstrates the successful application of the ring-implanted CL to sustain the delivery of HA for treating the dry eye syndrome.

Dry Eye Syndrome and Sicca Complex are Commonly Found in Patients with Postural Orthostatic Tachycardia Syndrome.

PURPOSE: Patients with postural orthostatic tachycardia syndrome (POTS) present to outpatient dysautonomia clinics endorsing a wide range of symptoms. Dry eyes and mouth, or sicca complex are frequently reported. This retrospective study investigates the incidence and quantifies the severity of dry eye syndrome (DES) in patients with POTS. PATIENTS AND METHODS: This retrospective study compiles survey results, and dry eye clinical data from twenty-three POTS patients (22 females, average age 34.9 and st dev 14.0 years) surveyed during their initial or follow-up appointments. Patient's medication lists were documented to account for anticholinergics, antihistamines, and anticholinesterase use. Patients endorsing dry eye symptoms were tested with Schirmer's test strips to identify clinically dry eyes and stratified for severity. RESULTS: Sixty-five percent of patients endorsed dry eye symptoms (15/23). Seventy-four percent of patients endorsed dry mouth symptoms (17/23). Among patients endorsing dry eyes, 81% of eyes had decreased tear production with Schirmer's strip wetting less than 10 mm/5 min (13/16). CONCLUSION: DES is an additional and significant disease burden for the POTS patient population. Dry eye and exocrine gland function should be evaluated as part of the dysautonomia work up with referral to ophthalmology as appropriate. Patients with clinically dry eyes who report additional autonomic dysfunction should be further evaluated for widespread autonomic dysfunction.

Cationized hyaluronic acid coated spanlastics for cyclosporine A ocular delivery: Prolonged ocular retention, enhanced corneal permeation and improved tear production.

The aim of this work was to design and evaluate novel cationized hyaluronic acid coated spanlastics (CHASVs), with the immunosuppressive peptide cyclosporine A (CsA) as the model drug. CHASVs exhibited ideal size, zeta potential, pH, osmolarity and entrapment efficiency. The developed CHASVs provided a surface tension of 34.98 ±â€¯0.19 mN/m, a contact angle of 21.07 ±â€¯3.56° and a viscosity of 9-12 mPa·s, which reflected favorable wetting and bioadhesion properties. From the in vitro release study, the sustain release property could also be seen. These proved the availability of CsA by ocular delivery was improved. With an apparent permeation coefficient of 5.22 × 10-6 cm/s and CsA residual of 312.18 ±â€¯1.34 µg/g, CHASVs proved to enhance corneal permeation and accumulation of CsA compared with commercial emulsions. In vivo Draize test showed no signs of acute and chronic ocular toxicity of CHASVs formulations to the eyes of rabbits. Finally, schirmer tear test, tear ferning test and histologic analysis reflected that CHASVs showed significant therapeutic effect and improved tear production in dry eye. Results revealed that CHASVs could be a promising delivery system for CsA and employed as an ideal alternative to commercial emulsions for the treatment of dry eye syndrome.

A review of the efficacy, safety and tolerability of Lacrycon® eye drops for the treatment of dry eye syndrome.

Lacrycon® is a preservative-free hypotonic artificial tear for the treatment of dry eye syndrome containing hyaluronic acid, carbomer, and glycerol. Lacrycon has been used for many years; this is the first comprehensive review of clinical efficacy and tolerability. Eight clinical studies (1992-2013) were reviewed. Comparators included phosphate-buffered saline (Phase I) and active controls (Phase II: Lacrisol™; Phase III: Gel-larmes™, Lacrisol, Hyalistil®, Vismed®, or the currently prescribed tear substitute). Administration schedules varied from 3 to 8 instillations per day for 7 to 84 days, and evaluation timepoints varied between studies. Pre-corneal retention of Lacrycon was 22% better than phosphate-buffered saline in terms of AUC (P=0.048). Patients' evaluation of efficacy was better for Lacrycon than Gel-larmes on Day 15 and 45 (P<0.05) and similar on Day 90 (P>0.05); there was no difference (P>0.05) versus Hyalistil (Day 30) or Vismed (Day 35 and 85). Functional tests were either in favor of Lacrycon (P<0.05) (fluorescein test [versus Gel-larmes/Lacrisol/Hyalistil], tear break-up time [TBUT] and rose Bengal test, Schirmer I test, and tear meniscus [versus Lacrisol]), or there was no difference between treatments (P>0.05) (fluorescein test [versus Vismed], TBUT and rose Bengal test [versus Gel-larmes], Schirmer I test [versus Gel-larmes/Lacrisol/Hyalistil/VisMed], tear meniscus [versus Lacrisol/Hyalistil], Oxford Grading Score, OSDI, van Bijsterveld score, and conjunctival hyperemia [versus Vismed]). Lacrycon was better tolerated than most comparators and had a similar safety profile to Vismed. No comparison showed favored the comparator over Lacrycon. These good efficacy, tolerability and safety data support the use of Lacrycon in dry eye syndrome.

pH triggered controlled drug delivery from contact lenses: Addressing the challenges of drug leaching during sterilization and storage.

In the present work a novel cyclosporine-loaded Eudragit S100 (pH-sensitive) nanoparticles-laden contact lenses were designed to provide sustained release of cyclosporine at therapeutic rates, without leaching of drug during sterilization and storage period (shelf life). The nanoparticles were prepared by Quasi-emulsion solvent diffusion technique using different weight ratios of cyclosporine to Eudragit S100. The contact lenses with direct drug entrapment were also fabricated (DL-50) for comparison. The percentage swelling and optical transparency of nanoparticles-laden contact lenses were improved in comparison to DL-50 lenses. The nanoparticles-laden contact lenses showed sustained drug release profiles, with inverse relationship to the amount of nanoparticles loaded in the contact lenses. It was interesting to note that nanoparticles form nanochannels/cavities after dissolution of Eudragit S 100 in tear fluid pH=7.4 (in vitro release study). This followed the precipitation of drug in hydrogel matrix of contact lenses. As the amount of nanoparticles loading increased, more number of cavities were formed, which caused the formation of large cavities in contact lens matrix. This in turn precipitated the drug. The nanoparticles-laden contact lenses with 1:1 (drug: Eudragit) weight ratio showed the most promising results of sustaining the drug release up to 156h, without affecting optical and physical properties of contact lenses. Packaging study confirmed that the drug was not leached in packaging solution (buffer, pH=6.5) from nanoparticles-laden lenses during shelf life period. In-vivo study in rabbit tear fluid showed sustained release up to 14days. The study revealed the application of pH-sensitive nanoparticles-laden contact lenses for controlled release of cyclosporine without altering the optical and physical properties of lens material.

Comparison of the clinical efficacy of preserved and preservative-free hydroxypropyl methylcellulose-dextran-containing eyedrops.

PURPOSE: This study aimed to compare the efficacy of two sustained-release formulation of artificial tear drops. PATIENTS AND METHODS: This is a randomized patient-masked clinical trial, a total 88 patients into two group A (n=41; with single dose of artificial tear, containing dextran 70, 1mg/ml and hypromellose, 3mg/ml hydroxypropyl methylcellulose (HPMC) and group B (n=47; with multidose of artificial tear, containing 0.3g HPMC and 0.1g of dextran 70, with 0.01% benzalkonium chloride (BAK) as preservative) were completed the study. The ocular surface disease index (OSDI) questionnaire, tear break up time (TBUT), corneal and conjunctival staining and Schirmer test, were performed. Repeated measures ANOVA was used to assess the differences among the two products. A p-value less than 0.05 was considered significant. RESULTS: The mean of age of the participants in the Group A and B was 44.08±6.29 (range, 33-58 years) years and 45.83±8.42 (31-60 years), respectively. In comparing two groups before the intervention, the OSDI scores, the TBUT scores, the conjunctival and corneal staining scores and the Schirmer scores did not show statistically significant differences (p=0.339, p=0.640, p=0.334, p=0.807 and p=0.676, respectively). After 4 weeks, the OSDI scores, conjunctival and corneal staining scores showed improvement in compare to those before the intervention (p<0.001). But, the differences for the Schirmer test score and TBUT score was not significant (p=0.115, p=0.013, respectively). CONCLUSION: Our outcomes indicated that improvement occurred with use of both products but there was no statistically significant difference between them.

Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies.

Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiological barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age-related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclinical efficacy results from both in-vitro and in-vivo animal studies have led to their steady progression through clinical trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water soluble, these polymeric micelles generate clear aqueous solutions which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non-toxicity, ease of surface modification and controlled drug release are additional advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of preparation, physicochemical properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclinical studies.

Supercritical fluid-mediated liposomes containing cyclosporin A for the treatment of dry eye syndrome in a rabbit model: comparative study with the conventional cyclosporin A emulsion.

BACKGROUND: The objective of this study was to compare the efficacy of cyclosporin (CsA)-encapsulated liposomes with the commercially available CsA emulsion (Restasis) for the treatment of dry eye syndrome in rabbits. METHODS: Liposomes containing CsA were prepared by the supercritical fluid (SCF) method consisted of phosphatidylcholine from soybean (SCF-S100) and egg lecithins (SCF-EPCS). An in vitro permeation study was carried out using artificial cellulose membrane in Franz diffusion cells. Dry eye syndrome was induced in male albino rabbits and further subdivided into untreated, Restasis-treated, EPCS, and S100-treated groups. Tear formation in the dry-eye-induced rabbits was evaluated using the Schirmer tear test. All formulations were also evaluated by ocular irritation tests using the Draize eye and winking methods with the determination of CsA concentration in rabbit tears. RESULTS: After the treatment, the Schirmer tear test value significantly improved in EPCS-treated (P=0.005) and S100-treated (P=0.018) groups compared to the Restasis-treated group. The AUC0₋24 h for rabbit's tear film after the administration of SCF-S100 was 32.75±9.21 µg·h/mg which was significantly higher than that of 24.59±8.69 µg·h/mg reported with Restasis. Liposomal CsA formulations used in this study showed lower irritation in rabbit eyes compared with Restasis. CONCLUSION: These results demonstrate that the novel SCF-mediated liposomal CsA promises a significant improvement in overcoming the challenges associated with the treatment of dry eyes.

Comparison of in vivo efficacy of different ocular lubricants in dry eye animal models.

PURPOSE: To compare the efficacy of three types of ocular lubricants in protecting corneal epithelial cells in dry eye animal models. METHODS: Ocular lubricants containing 0.1% or 0.3% sodium hyaluronate (SH), carboxymethylcellulose (CMC), or hydroxypropyl methylcellulose (HPMC) were tested. First, ocular lubricant containing 0.002% fluorescein was dropped onto the rabbit corneas. The fluorescein intensity as an index of retention was measured. Second, a rabbit dry eye model was made by holding the eye open with a speculum, and 50 µL of each ocular lubricant was dropped onto the cornea. After 3 hours, the corneas were stained with 1% methylene blue (MB), and the absorbance of MB was measured. Third, a rat dry eye model was treated with the ocular lubricants for 4 weeks, and the corneal fluorescein staining was scored. Eyes treated with physiological saline were used as controls. Finally, immunohistochemistry was used to analyze occludin, an epithelial barrier protein, in cultured human corneal epithelial cells pretreated with ocular lubricants and desiccated for 20 or 60 minutes. RESULTS: Our results showed that 0.3% SH had a significantly longer retention time than the other lubricants (all P < 0.01). The absorbance of MB was significantly lower in the 0.3% SH group. The corneas of rats exposed to 0.3% SH had significantly lower fluorescein staining scores. A significantly higher number of occludin-positive cells were found after exposure to 0.3% SH than other lubricants. CONCLUSIONS: Ocular lubricant containing 0.3% SH would be preferable to treat patients with dry eye syndrome.

Contact lenses as drug controlled release systems: a narrative review / As lentes de contacto como sistema de libertação controlada de fármacos: uma revisão narrativa

ABSTRACT Topically applied therapy is the most common way to treat ocular diseases, however given the anatomical and physiological constraints of the eye, frequent dosing is required with possible repercussions in terms of patient compliance. Beyond refractive error correction, contact lenses (CLs) have, in the last few decades emerged as a potential ophthalmic drug controlled release system (DCRS). Extensive research is underway to understand how to best modify CLs to increase residence time and bioavailability of drugs within therapeutic levels on the ocular surface.These devices may simultaneously correct ametropia and have a role in managing ophthalmic disorders that can hinder CL wear such as dry eye, glaucoma, ocular allergy and cornea infection and injury. In this narrative review the authors explain how the ocular surface structures determine drug diffusion in the eye and summarize the strategies to enhance drug residence time and bioavailability. They synthesize findings and clinical applications of drug soaked CLs as DCRS combined with delivery diffusion barriers, incorporation of functional monomers, ion related controlled release, molecular imprinting, nanoparticles and layering. The authors draw conclusions about the impact of these novel ophthalmic agents delivery systems in improving drug transport in the target tissue and patient compliance, in reducing systemic absorption and undesired side effects, and discuss future perspectives.

RESUMO A forma mais frequente de aplicação terapêutica em oftalmologia consiste na instilação de gotas oculares, mas dadas as limitações anatómicas e fisiológicas do olho, é necessária dosagem frequente com possível repercussão na adesão do paciente à terapêutica. Nas últimas décadas, as lentes de contacto (CLs) têm surgido como um potencial sistema de libertação controlada de fármacos na superfície ocular (DCRS) para correção do erro refrativo. Está em curso uma extensa investigação para entender a melhor forma de modificar as CLs, de modo a aumentar o tempo de residência e a biodisponibilidade do medicamento na superfície ocular dentro de níveis terapêuticos. Ao corrigirem a ametropia, estes dispositivos poderão simultaneamente desempenhar um papel na gestão de perturbações oftalmológicas, tais como a síndrome do olho seco, glaucoma, alergia ocular e infecção corneana, que podem comprometer o porte seguro e confortável das CLs. Nesta revisão narrativa, os autores explicam como as estruturas da superfície ocular determinam a difusão de fármacos no olho e sintetizam as estratégias para aumentar a permanência e biodisponibilidade dos mesmos. Em seguida, apresentam os resultados e as aplicações clínicas das CLs embebidas em fármacos, como DCRS, através da incorporação de barreiras de difusão, de monómeros funcionais, da liberação controlada por iões, da impressão molecular, de nanopartículas e pelo processo camada sobre camada. Os autores concluem avaliando o impacto destes novos sistemas de entrega de agentes farmacológicos ao melhorar o seu transporte no tecido alvo, reduzindo a sua absorção sistémica e os seus efeitos colaterais indesejáveis, e discutem perspectivas futuras.