AIM: Eyedroppers deliver medication volumes exceeding conjunctival absorptive capacity, causing spillage and risking ocular/systemic complications. We evaluated piezoelectric microdosing. Results/methodology: Subjects (n = 102) received precision microdroplet delivery of phenylephrine (2.5%) and tropicamide (1.0%): 1 × 1.5 μl, 1 × 6 μl or 2 × 3 μl of each (randomized 1:1:1), into one eye. Contralateral eyes received eyedropper doses of both drugs. Outcomes were pupil dilation (0-60 min) and patient satisfaction. Six-microliter microdosing achieved comparable, and 2 × 3 μl met/exceeded dilation speed and magnitude versus eyedropper. Separately, participants preferred piezoelectric saline self-delivery to eyedroppers, reporting better head-positioning comfort, reduced tearing/overflow and increased likelihood of adhering to ocular medication regimens. CONCLUSION: Piezoelectric microdosing achieves comparable effects as eyedroppers delivering 4-17-fold larger doses. Microdosing may enhance patient adherence to ocular medication regimens while minimizing side effects.
The purpose of this research was to determine the potential use of water-soluble anionic and cationic carbosilane dendrimers (generations 1-3) as mucoadhesive polymers in eyedrop formulations. Cationic carbosilane dendrimers decorated with ammonium -NH3(+) groups were prepared by hydrosylilation of Boc-protected allylamine and followed by deprotection with HCl. Anionic carbosilane dendrimers with terminal carboxylate groups were also employed in this study. In vitro and in vivo tolerance studies were performed in human ocular epithelial cell lines and rabbit eyes respectively. The interaction of dendrimers with transmembrane ocular mucins was evaluated with a surface biosensor. As proof of concept, the hypotensive effect of a carbosilane dendrimer eyedrop formulation containing acetazolamide (ACZ), a poorly water-soluble drug with limited ocular penetration, was tested after instillation in normotensive rabbits. The methodology used to synthesize cationic dendrimers avoids the difficulty of obtaining neutral -NH2 dendrimers that require harsher reaction conditions and also present high aggregation tendency. Tolerance studies demonstrated that both prototypes of water-soluble anionic and cationic carbosilane dendrimers were well tolerated in a range of concentrations between 5 and 10 μM. Permanent interactions between cationic carbosilane dendrimers and ocular mucins were observed using biosensor assays, predominantly for the generation-three (G3) dendrimer. An eyedrop formulation containing G3 cationic carbosilane dendrimers (5 μM) and ACZ (0.07%) (289.4 mOsm; 5.6 pH; 41.7 mN/m) induced a rapid (onset time 1 h) and extended (up to 7 h) hypotensive effect, and led to a significant increment in the efficacy determined by AUC0(8h) and maximal intraocular pressure reduction. This work takes advantage of the high-affinity interaction between cationic carbosilane dendrimers and ocular transmembrane mucins, as well as the tensioactive behavior observed for these polymers. Our results indicate that low amounts of cationic carbosilane dendrimers are well tolerated and able to improve the hypotensive effect of an acetazolamide solution. Our results suggest that carbosilane dendrimers can be used in a safe range of concentrations to enhance the bioavailability of drugs topically administered in the eye.
PURPOSE: To assess the ability of latanoprost-eluting contact lenses to lower the intraocular pressure (IOP) of glaucomatous eyes of cynomolgus monkeys. DESIGN: Preclinical efficacy study of 3 treatment arms in a crossover design. PARTICIPANTS: Female cynomolgus monkeys with glaucoma induced in 1 eye by repeated argon laser trabeculoplasty. METHODS: Latanoprost-eluting low-dose contact lenses (CLLO) and high-dose contact lenses (CLHI) were produced by encapsulating a thin latanoprost-polymer film within the periphery of a methafilcon hydrogel, which was lathed into a contact lens. We assessed the IOP-lowering effect of CLLO, CLHI, or daily latanoprost ophthalmic solution in the same monkeys. Each monkey consecutively received 1 week of continuous-wear CLLO, 3 weeks without treatment, 5 days of latanoprost drops, 3 weeks without treatment, and 1 week of continuous-wear CLHI. On 2 consecutive days before initiation of each study arm, the IOP was measured hourly over 7 consecutive hours to establish the baseline IOP. Two-tailed Student t tests and repeated-measures analysis of variance were used for statistical analysis. MAIN OUTCOME MEASURES: Intraocular pressure. RESULTS: Latanoprost ophthalmic solution resulted in IOP reduction of 5.4±1.0 mmHg on day 3 and peak IOP reduction of 6.6±1.3 mmHg on day 5. The CLLO reduced IOP by 6.3±1.0, 6.7±0.3, and 6.7±0.3 mmHg on days 3, 5, and 8, respectively. The CLHI lowered IOP by 10.5±1.4, 11.1±4.0, and 10.0±2.5 mmHg on days 3, 5, and 8, respectively. For the CLLO and CLHI, the IOP was statistically significantly reduced compared with the untreated baseline at most time points measured. The CLHI demonstrated greater IOP reduction than latanoprost ophthalmic solution on day 3 (P = 0.001) and day 5 (P = 0.015), and at several time points on day 8 (P < 0.05). CONCLUSIONS: Sustained delivery of latanoprost by contact lenses is at least as effective as delivery with daily latanoprost ophthalmic solution. More research is needed to determine the optimal continuous-release dose that would be well tolerated and maximally effective. Contact lens drug delivery may become an option for the treatment of glaucoma and a platform for ocular drug delivery.
PURPOSE: To present cases of endophthalmitis following intravitreal injections where povidone-iodine (PI) was not used as part of the surgical preparation. DESIGN: Retrospective case series. METHODS: All cases of presumed injection-related endophthalmitis presenting to the Massachusetts Eye and Ear Infirmary between June 2008 and November 2014 and Dean McGee Eye Institute between January 2010 and January 2015 were identified. Patients who did not receive PI preparation owing to documented self-reported allergy to iodine, iodine-containing contrast material, or shellfish were identified and their injection histories and clinical courses reviewed. RESULTS: The combined rate of postinjection endophthalmitis at these 2 centers was 0.019%. Among 42 patients with postinjection endophthalmitis, 5 (11.9%) did not receive PI prophylaxis. The mean number of intravitreal injections without PI before the development of endophthalmitis was 10.6 with a 9.4% rate of endophthalmitis (5 cases per 53 injections). All patients underwent tap-and-inject procedures with vancomycin 1 mg and ceftazidime 2 mg. Two patients did not receive PI at the time of tap and inject; 1 of these patients required subsequent pars plana vitrectomy for worsening clinical course. Cultures were positive in 4 of 5 cases; all positive cultures grew coagulase-negative Staphylococcus. All patients who received subsequent intravitreal injections received PI prophylaxis without allergic reactions, thus demonstrating a lack of true PI allergy. CONCLUSIONS: Avoiding PI owing to self-reported iodine "allergy" risks substantial ocular morbidity. Allergy testing can be pursued per patient request or in rare cases of suspected true PI allergy; however, in cases where delayed treatment would adversely affect visual outcome, the clinician should feel confident that minimal allergic risk exists.
PURPOSE: To describe the fabrication, evaluation, and preliminary in vivo safety of a new drug delivery system (DDS) for topical anti-TNF-α antibody administration. METHODS: A DDS was fabricated using inverse template fabrication of a hydrophobic three-dimensional porous scaffold (100-300 μm in diameter porosity) loaded with 10% polyvinyl alcohol hydrogel carrying 5 mg/ml (weight/volume) of anti-TNF-α antibody. Drug-loaded DDS was sterilized with 25 kGy of gamma irradiation. Long-term in vitro antibody affinity and release was evaluated at room temperature or 37°C using enzyme-linked immunosorbent assay (ELISA) and protein fluorescence. In vivo clinical and histolopathological assessment was performed by subcutaneous implantation in BALB/c mice for 3 months. RESULTS: Gamma irradiation, repeated dry/wet cycles, and storage at room temperature for 1 year or 37°C for 1 month had no deleterious effects on antibody affinity. Anti-TNF-α release was high during the first minutes of aqueous exposure, followed by stabilization and gradual, low-dose, antibody release over the next 30 days. Histopathologic evaluation of explanted DDS showed a fibrous pseudocapsule and a myxoid acute/chronic inflammation without granuloma formation surrounding the implants. CONCLUSIONS: Sustained local delivery of anti-TNF-α antibody is feasible using the described DDS, which provides stability of the enclosed antibody for up to 1 year of storage. Preliminary results show good in vivo tolerance following subcutaneous placement for 3 months. The proposed fabrication and sterilization process opens new possibilities for the delivery of biologic agents to the anterior surface of the eye. TRANSLATIONAL RELEVANCE: The described DDS will facilitate the treatment of ocular surface diseases amenable to biologic therapy.
PURPOSE: The present study examined the long-term (3 years) effects of a single (12 min) thermal pulsation system (TPS) treatment on symptomatic patients with evaporative dry eye disease (DED) secondary to meibomian gland dysfunction (MGD). METHODS: In this prospective, cohort, observational, single-center study design, signs (meibomian gland secretion [MGS] scores and tear film breakup time [TBUT]) and symptoms (Ocular Surface Disease Index [OSDI] and Standard Patient Evaluation of Eye Dryness [SPEED] questionnaires) were determined in 20 patients (40 eyes) with MGD and dry eye symptoms at baseline (BL), 1 month, and 3 years post-TPS treatment using LipiFlow. RESULTS: Meibomian gland secretion scores increased from BL (4.5±0.8) to 1 month (12.0±1.1, P≤0.001). Improvement persisted at 3 years (18.4±1.4) relative to BL (P≤0.001). Meibomian gland secretion scores in all regions of the lower eyelid were improved over BL at 1 month (nasal [P≤0.001], central [P≤0.001], temporal [P≤0.01]) and 3 years (nasal [P≤0.001], central [P≤0.001], temporal [P≤0.001]). TBUT increased from BL (4.1±0.4) to 1 month (7.9±1.4, P≤0.05) but was not significantly different than BL at 3 years (4.5±0.6, P>0.05). The OSDI scores decreased from BL (26.0±4.6) to 1 month (14.7±4.3, P≤0.001) but returned to BL levels at 3 years (22.5±5.4, P>0.05). The SPEED scores decreased from BL (13.4±1.0) to 1 month (6.5±1.3, P≤0.001), and this improvement persisted at 3 years (9.5±1.6, P≤0.001). CONCLUSIONS: Thermal pulsation may be a uniquely efficacious treatment option for DED secondary to MGD in that a single 12-min procedure is associated with significant improvement in MGS and SPEED scores for up to 3 years.