Topical Ophthalmic Drug Research Articles

Oxidative stress-induced degradation of Brinzolamide: Isolation and in-depth characterization of unique hydroxylamine and oxime degradation products

Since the safety and efficacy of therapeutic products are strongly related to their stability and purity, impurities including the unavoidable degradation products may affect the pharmacological effect. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines Q3A requires the identification of process impurities and as well as degradation products in any drug substance to assess the inherent stability of the drug. The present work involves an ICH-guided degradation study for the Brinzolamide (BRZ), a topical ophthalmic drug which is generally used to lower the intraocular pressure (IOP) during glaucoma. Under oxidative stress at room temperature for 20 h, four degradation products (namely BRZ-Pk1, BRZ-PK2, BRZ-Pk3, and BRZ-Pk4) are isolated using advanced chromatographic techniques. Upon confirming the masses of the compounds using High-resolution mass spectrometry (HRMS), functional groups are identified with the help of Fourier-transform infrared spectroscopy (FT-IR). Extensive 1-dimensional (1D) and 2-dimensional (2D) Nuclear Magnetic Resonance spectroscopic (NMR) experiments especially 1D nOe, 1H-13C-HSQC and 1H-13C-HMBC unequivocally confirm the structures. Among the four compounds analyzed, three (BRZ-Pk1, BRZ-Pk2, and BRZ-Pk4) are novel, while BRZ-Pk3 was previously reported solely with mass spectrometric data. Nitrogen-based 2D NMR experiments are crucial for determining the oxidation state of hydroxylamine and oxime products within the molecules, and 1D nOe measurements help confirming E/Z isomerism (geometrical isomerism) for BRZ-Pk2 and BRZ-Pk4. All the proposed structures are justified with appropriate analytical data. The proposed mechanisms are expected to help in identifying the possible degradation pathways for similar pharmaceutical candidates.

OphthalMimic: A new alternative apparatus without animal tissue for the evaluation of topical ophthalmic drug products

The necessity of animal-free performance tests for novel ophthalmic formulation screening is challenging. For this, we developed and validated a new device to simulate the dynamics and physical–chemical barriers of the eye for in vitro performance tests of topic ophthalmic formulations. The OphthalMimic is a 3D-printed device with an artificial lacrimal flow, a cul-de-sac area, a support base, and a simulated cornea comprised of a polymeric membrane containing poly-vinyl alcohol 10 % (w/v), gelatin 2.5 % (w/v), and different proportions of mucin and poloxamer, i.e., 1:1 (M1), 1:2 (M2), and 2:1 (M3) w/v, respectively. The support base is designed to move between 0° and 50° to replicate the movement of an eyelid. We challenged the model by testing the residence performance of poloxamer®407 16 % and poloxamer®407 16 % + chitosan 1 % (PLX16CS10) gels containing fluconazole. The test was conducted with a simulated tear flow of 1.0 mL.min−1 for 5 min. The OphthalMimic successfully distinguished PLX16 and PLX16C10 formulations based on their fluconazole drainage (M1: 65 ± 14 % and 27 ± 10 %; M2: 58 ± 6 % and 38 ± 9 %; M3: 56 ± 5 % and 38 ± 18 %). In conclusion, the OphthalMimic is a promising tool for comparing the animal-free performance of ophthalmic formulations.

A review on topical ophthalmic drug delivery system: Reference to viscosity enhancer.

The eye is the most accessible site for topical drug delivery. Drug's ocular bioavailability is quite low when administered topically as eye drops. Viscosity enhancers are used to increase ocular bioavailability by extending the precorneal residence time of the drug at the ocular site. Cellulose, polyalcohol and polyacrylic acid are examples of hydrophilic viscosity enhancers. The addition of viscosity modifiers increases the amount of time the drug is in contact with the ocular surface. Several polysaccharides have been studied as excipients and viscosity boosters for ocular formulations, including cellulose derivatives such as chitosan (CS), xyloglucan and arabinogalactan (methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose). Viscosity-increasing substances reduce the surface tension, extend the corneal contact time, slow the drainage, and improve the bioavailability. Chitosan is a viscosity enhancer that was originally thought to open tight junction barrier cells in the epithelium. Chitosan thickens the medication solution and allows it to penetrate deeper. Alginate is an anionic polymer with carboxyl end groups that has the highest mucoadhesive strength and is used to improve penetration. Carboxymethylcellulose (CMC), a polysaccharide with a high molecular weight, is one of the most common viscous polymers used in artificial tears to achieve their longer ocular surface residence period. Hyaluronic acid (HA) is biocompatible and biodegradable in nature, and it is available in ocular sustained-release dose forms. A polymer known as xanthan gum is used to increase viscosity. At 0.2% concentration, carbomer forms a highly viscous gel.

New ophthalmic drug delivery systems

For decades, topical ophthalmic drug administration through the use of eye drops has been the most widely used technique for the treatment of eye diseases. The development of galenic formulation has led to the use and commercialization of new formulations, such as suspensions, emulsions, and ophthalmic ointments that increase residence time in the site of action. Recently, new administration systems have been developed, such as devices and inserts that provide the sustained release of active substance. Some of these systems are already available on the market, whereas others are still undergoing clinical trials, such as promising systems based on nanostructures (nanocapsules, cyclodextrins, nanoemulsions, etc.). Similarly, various formulations and devices have been developed in the field of intravitreal administration, with different implants available on the European market for the treatment of age-related macular degeneration (AMD), diabetic macular edema, or infections that affect the posterior segment. This review includes current developments in ophthalmic topical and intravitreal drug administration routes as well as those under investigation.

Fill levels, cost comparisons, and expulsion force requirements of commonly used topical ophthalmic nonsteroidal anti-inflammatory drugs.

To determine volume fill levels, estimated costs, and force expulsion requirements per bottle of topical ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) commonly perioperatively in the United States. Tertiary care academic medical center. Prospective laboratory investigation. 8 commercially available NSAIDs (3 branded, 5 generic) were tested: branded bromfenac 0.07%, generic bromfenac 0.09%, diclofenac 0.1%, flurbiprofen 0.03%, generic ketorolac 0.5%, branded ketorolac 0.5%, ketorolac 0.47%, and branded nepafenac 0.3%. 10 bottles of each medication were tested, with an additional bottle tested for expulsion force requirements. A double-blinded method was used to measure the actual bottle fill volume and number of drops per bottle. The total cost per drop was calculated using published cash prices. Force requirements were measured using a customized force gauge apparatus. Formulations were compared using the Kruskal-Wallis test, followed by pairwise comparisons with the Dwass, Steel, Critchlow-Fligner Method. 2 branded NSAIDs (bromfenac and nepafenac) had slightly lower-than-sticker volumes while generics other than ketorolac had higher-than-sticker volumes. Diclofenac and branded bromfenac had the highest and lowest adjusted number of drops respectively. Generic bromfenac and generic ketorolac had the highest and lowest adjusted volume compared with sticker volume respectively. Branded bromfenac was the most expensive medication, while generic diclofenac was the least expensive. Force expulsion requirements varied significantly among generic and branded NSAIDs. Volume fill levels, patient-incurred costs, and expulsion force requirements per bottle of topical NSAID medications vary significantly. Surgeons may wish to consider these factors when deciding how best to use these medications perioperatively.

Computational Model of In Vivo Corneal Pharmacokinetics and Pharmacodynamics of Topically Administered Ophthalmic Drug Products.

Although the eye is directly accessible on the surface of the human body, drug delivery can be extremely challenging due to the presence of multiple protective barriers in eye tissues. Researchers have developed complex formulation strategies to overcome these barriers to ophthalmic drug delivery. Current development strategies rely heavily on in vitro experiments and animal testing to predict human pharmacokinetics (PK) and pharmacodynamics (PD). The primary objective of the study was to develop a high-fidelity PK/PD model of the anterior eye for topical application of ophthalmic drug products. Here, we present a physiologically-based in silico approach to predicting PK and PD in rabbits after topical administration of ophthalmic products. A first-principles based approach was used to describe timolol dissolution, transport, and distribution, including consideration of ionized transport, following topical instillation of a timolol suspension. Using literature transport and response parameters, the computational model described well the concentration-time and response-time profiles in rabbit. Comparison of validated rabbit model results and extrapolated human model results demonstrate observable differences in the distribution of timolol at multiple time points. This modeling framework provides a tool for model-based prediction of PK in eye tissues and PD after topical ophthalmic drug administration to the eyes.

Influence of BAKs on tear film lipid layer: In vitro and in silico models

Benzalkonium chloride (BAK) compounds are commonly used in topical ophthalmic products as preservatives and stabilizers. BAK mixtures containing several compounds with different alkyl chain lengths are typically used. However, in chronic eye conditions, such as dry eye disease and glaucoma, the accumulation of adverse effects of BAKs was observed. Hence, preservative-free eye drops formulations are preferred. On the other hand, selected long-chain BAKs, particularly cetalkonium chloride, exhibit therapeutic functions, promoting epithelium wound healing and tear film stability. Nevertheless, the mechanism of BAKs influence on the tear film is not fully understood. By employing in vitro experimental and in silico simulation techniques, we elucidate the action of BAKs and demonstrate that long-chain BAKs accumulate in the lipid layer of the tear film model, stabilizing it in a concentration-dependent fashion. In contrast, short-chain BAKs interacting with the lipid layer compromise the tear film model stability. These findings are relevant for topical ophthalmic drug formulation and delivery in the context of selecting proper BAK species and understanding the dose dependency for tear film stability.

Bacterial contamination of multi-use antibiotic steroid eye ointments and drops.

This comprehensive prospective study aimed to investigate the bacterial contamination of antibiotic steroid eye ointments and drops frequently used by eye patients. In this comprehensive prospective study, a total of 410 multi-use topical eye medications containing 15 different ingredients from 22 pharmaceutical companies used by 185 patients were analyzed. Four groups were formed as follows: group 1: antibiotic ointments (n: 109); group 2: antibiotic drops (n: 103); group 3: steroid ointments (n: 67); and group 4: steroid drops (n: 131). Topical multi-use eye drops and ointments used by patients at home for at least 1week were randomly collected. The caps and contents were separately bacteriologically examined in a chocolate agar medium. Our study detected bacterial contamination in 23 containers (5.6%) of the total 410 topical drugs. According to the groups, bacterial contamination was detected in 10 of 67 (14.9%) steroid ointments, 6 of 109 (5.5%) antibiotic ointments, 4 of 131(3.1%) steroid drops, and 3 of 103 (2.9%) antibiotic drops. While the bacterial contamination rate in ointments was 9.1%, this rate was 3% in drops. The difference between them was statistically significant (p = 0.015). According to the post-hoc pairwise comparisons, the difference between steroid drops and steroid ointment (p = 0.0023) was statistically significant. Among all drugs, contamination was detected in 12 of the 93 (12.9%) containers used after keratitis, conjunctivitis, and inflammatory conditions. It was determined that preservatives statistically reduced bacterial growth on the cap. The preservatives did not have a statistically significant effect on the bacterial contamination of the contents compared to the caps. While all contaminations were detected in illiterate and primary school graduates, no contamination was seen in the drugs used by any secondary school or university graduate. Our study detected contamination in all topical ophthalmic drug groups. Contamination rates were found to be higher in ointments and steroids. Bacterial contamination was also seen in drugs containing preservatives. We should be careful in the use of topical medications. We do not recommend the bilateral use of ointments and drops in infected eyes, such as those with keratitis, or after intraocular surgeries, such as those for cataracts.

Novel drug delivery systems for the treatment of glaucoma

AbstractGlaucoma is a group of chronic irreversible neuropathies in which a progressive death of retinal ganglion cells (RGC) and a glaucomatous optic disc neuropathy occurs leading to an irreversible visual field alteration. Intraocular pressure (IOP) increase is a major risk factor strongly associated with the onset and progression of the disease although a non IOP‐dependent neurodegeneration also occurs. Taking all this into account, the glaucoma therapy is based on two different targets: lowering the IOP and neuroprotection.The treatment of choice in patients with high IOP values is topical administration of hypotensive active agents on the ocular surface. The chronicity of the pathology, together with the low bioavailability of the antiglaucomatous drugs applied topically, make it necessary daily instillations, which are associated, in many cases, with the appearance of surface eye alterations and dry eye disease (DED). For these reasons, the development of therapeutic platforms able to increase the bioavailability of the drug while being soft with the ocular surface is getting special attention. Novel formulations involve pharmaceutical systems such as liposomes, nanoemulsions and microemulsions including also compounds with protective activity on the corneal surface (osmoprotective, antioxidants and/or bioadhesive polymers)(1–3).It is well known that therapies lowering IOP does not address neurodegeneration. Moreover, pathophysiological studies of glaucoma have shown that even in patients presenting IOP values within the normal limits, neuronal degeneration occurs. For this reason, the use of neuroprotective therapy in the treatment of glaucoma alone or simultaneously with the therapy based on the control of IOP results of great interest. Treatments destined to lower IOP, in which the target is the anterior segment of the eye are administered topically. By the contrary, neuroprotective therapies require the administration of the drugs near to the retinal target as well as their maintenance during long term Due to the multifactorial nature of the disease there is special interest in the design of novel drug delivery systems able to include a combination of active agents in the same formulation and provide long term effects with a single administration(4).Acknowledgements: Acknowledgements‐ Grant: Fondo Europeo de Desarrollo Regional (FEDER‐CICYT), grant: FIS‐PI17/00079 and PI17/00466, Research Group UCM 920415 ‘Innovation, Therapy and Pharmaceutical Development in Ophthalmology (InnOftal)’ and the ISCII‐FEDER RETICS (OFTARED) (RD16/0008/0004 and RD16/0008/0009)PID2020‐113281RB‐C21 funded by MCIN/AEI/ 10.13039/501100011033.References.1. López‐Cano J.J, González‐Cela‐Casamayor M.A., Andrés‐Guerrero V.,Herrero‐Vanrell R. Molina‐Martínez I.T. “Liposomes as vehicles for topical ophthalmic drug delivery and ocular surface protection”. Expert Opinion on Drug Delivery. 2021. 18(7):819–847. DOI: 10.1080/17425247.2021.1872542.2. M. Gómez‐Ballesteros; J. López‐Cano; I. Bravo‐Osuna; R. Herrero‐Vanrell; I.T. Molina‐Martínez. “Osmoprotectants in Hybrid Liposome/HPMC Systems as Potential Glaucoma Treatment”. Polymers. 2019; 11(6): 929. DOI: 10.3390/polym110609293. I Bravo‐Osuna; V Andrés‐Guerrero; P Pastoriza Abel; IT Molina‐Martínez; R Herrero‐Vanrell. Pharmaceutical microscale and nanoscale approaches for efficient treatment of ocular diseases. Drug Deliv Translational Research.2016. 6(6):686–707.DOI: 10.1007/s13346‐016‐0336‐5.4. R Herrero‐Vanrell; I. Bravo‐Osuna; V. Andrés‐Guerrero; M. Vicario‐de‐la‐Torre; I.T. Molina‐Martínez. The potential of using biodegradable microspheres in retinal diseases and other intraocular pathologies. Progress in Retinal and Eye Research. 2014. 42; 27–43. DOI: 10.1016/j.preteyeres.2014.04.002.

Literatur Review: Mata Kering Akibat Obat-Obatan

Dry eye disease is a disease that is often encountered and can occur due to several factors. This disease is more common in women than men. The risk factors that can cause dry eyes are divided based on individual characteristics, environment, chronic disease, autoimmune disease, medications and history of injury. The writing of this article was obtained from various sources in the form of scientific journals and guidelines for related institutions. Source searches were carried out on various online portals such as Medscape, NCBI, Google Scholar and other health websites with the keyword “Dry Eye Disease”, “Dry Eye Syndrome”, “Medications Causes Dry Eyes” Dry eye disease is a disease that is often encountered and occurs because it is multifactorial and can affect the quality of life and interfere with vision, especially when carrying out daily activities. One of the factors that cause dry eyes, namely the use of drugs, both topical drugs and systemic drugs. Concurrent use of five or more medications can increase the occurrence of dry eye. Management of dry eyes can be given artificial tears and stop using medications that trigger dry eyes or replace the drug with another drug. Dry eye disease can be caused by the use of drugs, both topical and systemic drugs. Treatment that can be done, namely by giving artificial tears and avoiding systemic or topical ophthalmic drugs that cause dry eyes.

Mucoadhesive Polymers Enhance Ocular Drug Delivery: Proof of Concept Study with 0.5% Tropicamide in Dogs.

Purpose: To assess the efficacy of 0.5% tropicamide applied after topical administration of 1.4% hydroxyethyl cellulose (HEC) or 1.2% hyaluronic acid (HA) at different time intervals. Methods: Eleven healthy Labrador retriever dogs were used. The study consisted of 7 trials in which pupil diameter (PD) was measured every 30 min for 7 h after drug administration. In trial 1, PD was measured after tropicamide application (control). In trials 2-7, PD was measured after treatment with tropicamide 10 s, 1 and 5 min after application of HEC or HA. Data were analyzed using analysis of variance and post hoc Holm-Sidak tests. Results: Maximal PD (mean ± standard deviation) was significantly greater (P < 0.001) in 5 of 6 experimental trials, with the greatest PD recorded when HEC was applied 1 min (12.2 ± 0.4 mm) and HA 10 s (12.3 ± 0.5 mm) before tropicamide, compared with 11.2 ± 0. 7 mm in control trial 1. PD >10 mm was maintained for 2.75-5 h in trials 2-7 and 2.25 h in trial 1 (P < 0.001). Area under the PD-time curve ranged from 61.9 to 71.3 ± 2.9 mm·hours in trials 2-7, significantly greater than 59.3 ± 1.8 mm·hours in control trial 1 (P ≤ 0.031). Conclusions: Tropicamide efficacy was enhanced by prior administration of a mucoadhesive polymer. Additional studies are needed to determine if HEC and HA of varying concentrations similarly extend and potentiate the effect of other topical ophthalmic drugs in canine eyes.

Eyes on Lipinski's Rule of Five: A New “Rule of Thumb” for Physicochemical Design Space of Ophthalmic Drugs

The study objective was to investigate molecular thermodynamic properties of approved ophthalmic drugs and derive a framework outlining physicochemical design space for product development. Unlike the methodology used to obtain molecular descriptors for assessment of drug-like properties by Lipinski's Rule of 5 (Ro5), this work presents a retrospective approach based on in silico analysis of molecular thermodynamic properties beyond Ro5 parameters (ie, free energy of distribution/partitioning in octanol/water, dynamic polar surface area, distribution coefficient, and solubility at physiological pH) by using 145 marketed ophthalmic drugs. The study's focus was to delineate inherent molecular parameters explicitly important for ocular permeability and absorption from topical eye drops. A comprehensive parameter distribution analysis on ophthalmic drugs’ molecular properties was performed. Frequencies in distribution analyses provided groundwork for physicochemical parameter limits of molecular thermodynamic properties having impact on corneal permeability and topical ophthalmic drug delivery. These parameters included free energy of partitioning (ΔGo/w) calculated based on thermodynamic free energy equation, distribution coefficient at physiological pH (clog DpH7.4), topological polar surface area (TPSA), and aqueous solubility (Sint, SpH7.4) with boundaries of clog DpH7.4 ≤4.0, TPSA ≤250 Å2, ΔGo/w ≤20 kJ/mol (4.8 kcal/mol), and solubility (Sint and SpH7.4) ≥1 μM, respectively. The theoretical free energy of partitioning model streamlined calculation of changes in the free energy of partitioning, Δ(ΔGo/w), as a measure of incremental improvements in corneal permeability for congeneric series. The above parameter limits are proposed as “rules of thumb” for topical ophthalmic drugs to assess risks in developability.

Studying the ophthalmic toxicity potential of developed ketoconazole loaded nanoemulsion in situ gel formulation for ophthalmic administration

Ocular fungal infections are one of the essential reasons for vision loss, especially in developing countries for tropical regions. Ketoconazole (KZ), a broad-spectrum antifungal drug, is a lipophilic compound and practically insoluble in water. Since topical ophthalmic drug delivery confronts low bioavailability, an in situ gel formulation is designed to improve the residence time and consequently the bioavailability. Safety of the developed formulation as a carrier for ophthalmic drug delivery was measured using three different methods: MTT assay for measuring cell viability in which the human retinal pigmentation epithelial cells (RPE) were used, HET-CAM as a borderline method between in vivo and in vitro techniques for investigating the irritation potential of the chosen formulation which was done by adding formulation directly on the CAM surface and visually monitoring the vessels in terms of irritation reactions, and finally the modified Draize test for evaluating tolerability of the selected formulation on eyes. According to our results from the MTT test, cell viability for KZ-NE in situ gel formulation at 0.1% concentration was acceptable. The results obtained from the HET-CAM investigation didn’t show any sign of vessel injury on the CAM surface for prepared formulation. Additionally, during 24 hours, the developed formulation was tolerable by rabbit eyes. Regarding our results, KZ-NE in situ gel formulation was non-irritant and non-toxic and can be well-tolerated and presented as an applicable vehicle for ophthalmic delivery of the anti-fungal drug.

Preclinical Evaluations of Modified Rice Hydrogel for Topical Ophthalmic Drug Delivery of Praziquantel on Avian Philophalmiasis.

The present study aims to evaluate the efficacy of a novel drug delivery system of the modified rice hydrogel containing praziquantel (PZQ) against Philophthalmus gralli isolated from ostrich eyes and determine the toxicity of the preparation on chicken eye model. The parasiticidal activity of PZQ (0, 1, 10, and 100 µg/mL) was tested on P. gralli. The ophthalmic antiparasitic hydrogel was formulated with appropriate amount of PZQ and chemically modified rice gel. The parasitic morphology after exposure with the preparation was examined under scanning electron microscope (SEM). The anthelminthic efficacy of the preparation on motility and mortality of parasites was performed by visual inspection and vital dye staining. The ocular irritation of the preparation was evaluated for 21 days using standard avian model followed by OECD 405. The results demonstrated that the parasiticidal activity of PZQ against P. gralli appears to be in a concentration- and time-dependent manner. In addition, the concentration of PZQ 10 µg/mL (Chi squared test, p = 0.003) and exposure time for 24 h (log-rank test, p = 0.0004) is sufficient to kill parasites, when statistically compared to negative control group. Rice hydrogel containing a lethal concentration of 10 µg/mL PZQ was successfully prepared. The preparation illustrated good parasitic killing and motile inhibiting effect on P. gralli compared with PZQ 10 µg/mL and its control (p < 0.05). An appearance under SEM of non-viable parasite after being incubated with the preparation, showing parasitic deformity, was observed comparing with the viable parasite in 0.9% normal saline solution (NSS). Moreover, no irritation of chicken eyes was also observed. Our results contribute to understanding the efficacy and the safety of the rice hydrogel of PZQ which have a predictive value for controlling P. gralli on the animal eyes. However, the pharmacological application needs to be further investigated for the best possible therapeutic approach.

Development of an In Vitro Blink Model for Ophthalmic Drug Delivery.

Purpose: The purpose of this study was to develop an advanced in vitro blink model that can be used to examine the release of a wide variety of components (for example, topical ophthalmic drugs, comfort-inducing agents) from soft contact lenses. Methods: The model was designed using computer-aided design software and printed using a stereolithography 3D printer. The eyelid and eyeball were synthesized from polyvinyl alcohol and silicone material, respectively. Simulated tear fluid was infused through tubing attached to the eyelid using a syringe pump. With each blink cycle, the eyelid slides and flexes across the eyeball to create an artificial tear film layer. The flow-through fluid was collected using a specialized trough. Two contact lenses, etafilcon A and senofilcon A, were incubated in 2 mL of a water-soluble red dye for 24 h and then placed on the eye model (n = 3). The release of the dye was measured over 24 h using a tear flow rate of 5 µL/min. Results: Approximately 25% of the fluid that flowed over the eye model was lost due to evaporation, nonspecific absorption, and residual dead volume. Senofilcon A absorbed more dye (47.6 ± 2.7 µL) than etafilcon A (22.3 ± 2.0 µL). For etafilcon A, the release of the dye followed a burst-plateau profile in the vial but was sustained in the eye model. For senofilcon A, the release of the dye was sustained in both the vial and the eye model, though more dye was released in the vial (p < 0.05). Overall, the release of the dye from the contact lenses was higher in the vial compared with the eye model (p < 0.05). Conclusion: The blink model developed in this study could be used to measure the release of topical ophthalmic drugs or comfort agents from contact lenses. Simulation of a blink mechanism, an artificial tear film, and nonspecific absorption in an eye model may provide better results than a simple, static vial incubation model.

Design, Optimization, and Characterization of Lactoferrin-Loaded Chitosan/TPP and Chitosan/Sulfobutylether-β-cyclodextrin Nanoparticles as a Pharmacological Alternative for Keratoconus Treatment.

This research study describes the design, optimization, and characterization of two different types of chitosan-based nanoparticles as novel drug delivery systems of a protein drug, lactoferrin. A preclinical consistent base was obtained for both nanosystems, being considered as the first pharmacological treatment for keratoconus as an alternative to current invasive clinical methods. Both types of nanoparticles were obtained via the ionotropic gelation technique. The size and morphology of the nanoparticles were studied as a function of the preparation conditions. A mean size of 180.73 ± 40.67 nm, a size distribution [polydispersity index (PDI)] of 0.170 ± 0.067, and positive ζ-potential values, ranging from 17.13 to 19.89 mV, were achieved. Lactoferrin was successfully incorporated into both types of nanocarriers. In vitro release profiles showed a lactoferrin enhanced, prolonged, and controlled delivery from the polymeric matrix. These formulations also demonstrated no stability or cytotoxicity problems, as well as appropriate mucoadhesive properties, with a high permanence time in the ocular surface. Thus, both types of nanoparticles may be considered as nanocarriers for the controlled release of lactoferrin as novel topical ophthalmic drug delivery systems.

Power Analysis and Sample Size Determination for Crossover Trials with Application to Bioequivalence Assessment of Topical Ophthalmic Drugs Using Serial Sampling Pharmacokinetic Data

ObjectiveTo develop methods for determining a suitable sample size for bioequivalence assessment of generic topical ophthalmic drugs using crossover design with serial sampling schemes. MethodsThe power functions of the Fieller-type confidence interval and the asymptotic confidence interval in crossover designs with serial-sampling data are here derived. Simulation studies were conducted to evaluate the derived power functions. ResultsSimulation studies show that two power functions can provide precise power estimates when normality assumptions are satisfied and yield conservative estimates of power in cases when data are log-normally distributed. The intra-correlation showed a positive correlation with the power of the bioequivalence test. When the expected ratio of the AUCs was less than or equal to 1, the power of the Fieller-type confidence interval was larger than the asymptotic confidence interval. If the expected ratio of the AUCs was larger than 1, the asymptotic confidence interval had greater power. Sample size can be calculated through numerical iteration with the derived power functions. ConclusionThe Fieller-type power function and the asymptotic power function can be used to determine sample sizes of crossover trials for bioequivalence assessment of topical ophthalmic drugs.

Reduced administration frequency for the treatment of fungal keratitis: a sustained natamycin release from a micellar solution

ABSTRACT Background Natamycin is the only topical ophthalmic antifungal drug approved by the Food and Drug Administration (FDA) of the United States, but has unsatisfactory factors such as high dosing frequency. Methods We report the synthesis and preparation of self-assembled poly(ethylene glycol)-block-poly(glycidyl methacrylate) (PEG-b-PGMA) micelles. These nanoparticles exhibit sustained delivery of a hydrophobic natamycin by topical administration on eye due to the hydrolysable properties of PGMA segments of micelle. Hydrolysis of glycidyl groups within a physiologically relevant environment provides an additional driving force for drug release by generation of hydrophilic hydroxyl groups to ‘push’ the encapsulated hydrophobic drug away from the resultant hydrophilic domains and into surrounding environment. Results In vitro and in vivo results revealed that the self-assembled micelles and the encapsulated natamycin were not cytotoxic and the released drug have strong antifungal ability to Candida albicans. Importantly, sustained natamycin release from micelles leads to the reduced administration frequency of natamycin from 8 times per day to 3 times per day in rabbits suffering from fungal keratitis (FK). Conclusion This study demonstrates a facile method that can greatly reduce dosing frequency of natamycin administration and thus improve long-term patient compliance.

Use of topical bromfenac for treating ocular pain and inflammation beyond cataract surgery: a review of published studies.

Topical ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat postoperative inflammation and pain following cataract surgery and for treatment and prophylaxis of pseudophakic cystoid macular edema (CME). Bromfenac is a brominated NSAID with strong in vitro anti-inflammatory potency. Like other ophthalmic NSAIDs, bromfenac is often used outside of the cataract surgery setting. This paper provides an overview of bromfenac’s preclinical ocular pharmacology and pharmacokinetics, followed by a review of 23 published clinical studies in which various marketed bromfenac formulations were used for conditions other than cataract surgery or pseudophakic CME. These include: post-refractive eye surgery; macular edema associated with diabetes, uveitis, or retinal vein occlusion; inflammation associated with age-related macular degeneration; pain related to intravitreal injections; and other ocular anterior segment and surface disorders with an inflammatory component. The published evidence reviewed supports the safety and effectiveness of bromfenac in these additional ophthalmic indications. Bromfenac was well tolerated when given alone or in combination with intravitreal anti-vascular endothelial growth factor agents, topical corticosteroids, or topical mast-cell stabilizers. The most common adverse event reported was ocular irritation. No serious adverse events (ie, corneal epithelial disorders) were reported, although the majority of studies did not systematically evaluate potential side effects. Corneal complications, such as melts reported with diclofenac and ketorolac, were not observed with bromfenac in the studies. In summary, published study data support the clinical utility of bromfenac in various ocular disorders beyond post-cataract surgery. Additional studies are warranted to further define the potential role of bromfenac ophthalmic solution in clinical practice.

Efficacy and safety of bromfenac 0.075% formulated in DuraSite for pain and inflammation in cataract surgery

ABSTRACTIntroduction: Bromfenac is a topical ophthalmic non-steroidal anti-inflammatory drug (NSAID) used to reduce pain and treat post-operative inflammation after cataract surgery. Bromfenac 0.075% in the DuraSite™ vehicle is a newly-approved formulation which has been shown to be efficacious and safe for use in cataract surgery to reduce pain and treat inflammation. It has been shown to have a slightly better posterior segment ocular bioavailability compared to similar topical ophthalmic NSAIDs. However, there is a paucity of studies investigating its role in the prevention and treatment of post-operative pseudophakic cystoid macular edema.Areas covered: In this review, the authors provide an overview of similar products available, describe the novelty of bromfenac 0.075% in the DuraSite vehicle, and discuss the relevant clinical studies to determine if the formulation is safe and efficacious.Expert opinion: Bromfenac 0.075% in the DuraSite vehicle is a new topical ophthalmic medication which has been approved by the FDA for the prevention of pain and treatment of post-operative inflammation. It provides cataract surgeons with an additional medication for cataract surgery. However, no robust studies have been performed showing the effect that it has on the reduction or prevention of post-operative pseudophakic cystoid macular edema.