Multidose Preservative Free Eyedrops by Selective Removal of Benzalkonium Chloride from Ocular Formulations.

PURPOSE: About 70% of eye drops contain benzalkonium chloride (BAK) to maintain sterility. BAK is an effective preservative but it can cause irritation and toxicity. We propose to mitigate ocular toxicity without compromising sterility by incorporating a filter into an eye drop bottle to selectively remove BAK during the process of drop instillation. METHODS: The filter is a packed bed of particles made from poly(2-hydroxyethyl methacrylate) (pHEMA), which is a common ophthalmic material. We showed that pHEMA particle prepared by using ethoxylated trimethylolpropane triacrylate as crosslinker can be incorporated into a modified eyedrop bottle tip to selectively remove the preservative as the formulation is squeezed out of the bottle. Hydraulic permeability of the plug is measured to determine the resistance to eye drop squeezing, and % removal of BAK and drugs are determined. RESULTS: The modified tip has a hydraulic permeability of about 2 Darcy, which allows eyedrops formulations to flow through without excessive resistance. The tip is designed such that the patients can create an eyedrop of solution of 1-10 cP viscosity in 4 s with a nominal pressure. During this short contact time, the packed particles removed nearly 100% of benzalkonium chloride (BAK) from a 15 mL, 0.012% BAK solution but have only minimal impact on the concentration of contained active components. CONCLUSION: Our novel design can eliminate the preservative induced toxicity from eye drops thereby impacting hundreds of millions of patients with chronic ophthalmic diseases like glaucoma and dry eyes.

Hybrid Electrospun Polycaprolactone Mats Consisting of Nanofibers and Microbeads for Extended Release of Dexamethasone.

PURPOSE: We designed electrospun polycaprolactone mats consisting of nanofibers and microbeads for extended delivery of dexamethasone. METHODS: Thin flexible dexamethasone loaded polycaprolactone mats were prepared by electrospinning. The solvents, polymer loading, voltage and tip-to-collector distance were varied to explore the effects on microstructure of the mats. The microstructure was determined by scanning electron microscope imaging; drug transport was measured and modeled, and X-ray diffraction was used to gauge the crystallinity. Drug transport and X-ray diffraction studies were also conducted with a spin cast film for comparison. RESULTS: Thin mats, about 10 µm in thickness, were prepared by electrospinning. By controlling the voltage and tip-to-collector distance, we achieved a hybrid structure comprising of nanorods (nanofibers) and microbeads. The release profiles were fitted to the diffusion equation to obtain the diffusivities in the spheres and the rods. The diffusivity in the electrospun nanofibers was significantly lower compared to the casted films due to increased crystallinity, which was estimated from X-ray diffraction analysis. The electrospun hybrid mats sustained drug release for the desired duration of a month, in spite of the small thickness of about 10 µm. By comparison, a ten-fold thicker cast film sustains release for about the same duration suggesting about 100-fold decrease in diffusivity in the electrospun mats due to increased crystallinity. CONCLUSIONS: Electrospun polycaprolactone mats are optimal for achieving long release durations due to increased crystallinity. Designing a hybrid structure by controlling the electrospinning parameters can be a useful approach to increase the release durations.

Photoprotection and Extended Drug Delivery by UV Blocking Contact Lenses.

PURPOSE: Extended release of photo-unstable drugs from ophthalmic inserts is not useful unless the loaded drug is protected from degradation. Because of the recent interest in extended drug delivery from contact lenses, it is critical to assess whether photo-unstable drugs can be stabilized by loading in lenses. Here, we focus on dexamethasone, which is prone to degradation and has been explored as a candidate for extended release from contact lenses for periods ranging from 10 hours to several days. METHODS: Degradation rates of dexamethasone were measured in phosphate-buffered saline and after loading in contact lenses. The degradation rates were measured in a humidified, constant-temperature (32°C) chamber with controlled UV exposure. Contact lenses with various degrees of UV blocking were used to explore the relationship between degradation rates and UV exposure. It is known that vitamin E absorbs UV radiation; thus, it was loaded into the lenses to explore the feasibility of reducing the degradation rates. RESULTS: About 85% of dexamethasone degraded in 20 hours in non-UV blocking lenses, whereas less than 1% degraded in class 1 UV blocking lenses. Incorporation of vitamin E into the non-UV blocking lenses reduced the fractional degradation to 30%. Degradation rates in phosphate-buffered saline were significantly higher than even in non-UV blocking contact lenses. CONCLUSIONS: The degradation of dexamethasone can be minimized by using a UV blocking contact lens or incorporating vitamin E into a non-UV blocking lens. Vitamin E incorporation has the dual benefits of improving drug stability and release profiles.

Interfacial polymerization of a thin film on contact lenses for improving lubricity.

HYPOTHESIS: A large number of contact lens wearers drop out each year due to end of day discomfort, which could possibly be reduced by designing lenses with highly lubricious surfaces. We hypothesize that polymerizing a thin film of dimethyl acrylamide (DMA) on the surface of the lenses will improve lubricity. EXPERIMENTS: The thin film is polymerized by loading a commercial contact lens (1-DAY ACUVUE® TruEye®) with N,N,N',N'-Tetramethylethane-1,2-diamine (TEMED) and soaking it in a solution of DMA and ammonium per sulfate (APS). The two components of the redox couple (APS and TEMED) mix near the surface of the lens due to diffusion and react rapidly to form free radicals. The free radicals lead the polymerization of the DMA monomer near the surface resulting in the formation of the thin hydrogel layer that is attached to the lens matrix through activation of unreacted vinyl groups or possibly through formation of entanglements with the lens polymer. FINDINGS: The thickness of the layer is controlled by the polymerization time which is limited to 30 s to create a layer of DMA only at the surface. The presence of the DMA layer is confirmed through measurements of Fourier-transform infrared spectroscopy (FTIR) spectra in total internal reflection mode. The layer is determined to be about 3-5 µm thick with a water content of about 285%. The presence of the layer significantly improves lubricity as is evident through the qualitative rubbing test and quantitative measurement of the friction coefficient. A preliminary one-week safety study in rabbits show that lens wear does not cause any toxicity.

Mechanistic modeling of ophthalmic drug delivery to the anterior chamber by eye drops and contact lenses.

Ophthalmic drug for the anterior chamber diseases are delivered into tears by either eye drops or by extended release devices placed in the eyes. The instilled drug exits the eye through various routes including tear drainage into the nose through the canaliculi and transport across various ocular membranes. Understanding the mechanisms relevant to each route can be useful in predicting the dependency of ocular bioavailability on various formulation parameters, such as drug concentration, salinity, viscosity, etc. Mathematical modeling has been developed for each of the routes and validated by comparison with experiments. The individual models can be combined into a system model to predict the fraction of the instilled drug that reaches the target. This review summarizes the individual models for the transport of drugs across the cornea and conjunctiva and the canaliculi tear drainage. It also summarizes the combined tear dynamics model that can predict the ocular bioavailability of drugs instilled as eye drops. The predictions from the individual models and the combined model are in good agreement with experimental data. Both experiments and models predict that the corneal bioavailability for drugs delivered through eye drops is less than 5% due to the small area of the cornea in comparison to the conjunctiva, and the rapid clearance of the instilled solution by tear drainage. A contact lens is a natural choice for delivering drugs to the cornea due to the placement of the contact in the immediate vicinity of the cornea. The drug released by the contact towards the cornea surface is trapped in the post lens tear film for extended duration of at least 30min allowing transport of a large portion into the cornea. The model predictions backed by in vivo animal and clinical data show that the bioavailability increases to about 50% with contact lenses. This realization has encouraged considerable research towards delivering ocular drugs by contact lenses. Commercial contacts are, however, not ideal for drug delivery due to the short release durations which may necessitate wearing multiple lenses each day, reducing the viability of this approach. Recent research has focused on designing contacts that retain all critical properties while increasing the release durations to a few hours or a few days. Beagle dog studies with contact lenses containing vitamin E nanobarriers to attenuate drug transport have shown promising results. Human studies using contacts for drug delivery have also been conducted for allergy therapy but drug eluting contacts are not available in the market for any therapy.

Rapid and selective removal of preservative from ophthalmic formulations during eyedrops instillation.

About 70% of eyedrops contain benzalkonium chloride (BAK) as a preservative to prevent the growth of microorganisms. While preservatives are mandated to maintain sterility, many patients exhibit irritation and toxicity to such compounds. We propose to mitigate the ocular toxicity in the ocular formulations without compromising sterility by designing a device that can be incorporated into an eyedrops bottle to selectively remove the preservatives during the process of drop instillation. Here, we specifically focus on macroporous poly(2-hydroxyethyl methacrylate) (pHEMA) gel due to its excellent biocompatibility and high partition coefficient for BAK. In addition to specific selectivity for BAK, the device also requires high hydraulic permeability to allow drop dispensing without excessive pressure drop. The pHEMA monolith can remove nearly 100% of contained BAK from a 25 ml, 0.012% BAK solution with negligible uptake of the hydrophilic drugs such as timolol and dorzolamide. The filter, however, had to be pre-equilibrated with hydrophobic drugs to reach a high separation of BAK without reducing the concentration of the active drug. The average hydraulic permeability of the filter was 0.025 Darcy, which is about 5-fold lower than the ideal value. Incorporation of a pHEMA macroporous gel into an eyedrops bottle can virtually eliminate the exposure of the eyes to the preservatives without compromising the sterility. Our novel design can eliminate the preservative induced toxicity from eyedrops thereby impacting hundreds of millions of patients with chronic ophthalmic diseases such as glaucoma and dry eyes.

Dual drug delivery from vitamin E loaded contact lenses for glaucoma therapy.

Glaucoma patients frequently instill eye drops multiple times each day, which is a cause for reduced compliance. Additionally, eye drops suffer from other limitations including low bioavailability, which can lead to side effects. We propose to develop drug-eluting contact lenses for managing glaucoma with increased bioavailability and improved compliance. Contact lenses are developed for extended simultaneous release of timolol and dorzolamide, both of which are commonly prescribed hydrophilic drugs. The extended release is achieved by loading lenses with vitamin E barriers. In vitro release studies are performed with control and vitamin E loaded lenses for both drugs loaded separately and then together in the same lens. The safety and efficacy of combination therapy by contacts are demonstrated in a Beagle model of glaucoma. Simultaneous loading of timolol and dorzolamide increases the release duration of both drugs. Also vitamin E incorporation is highly effective in increasing the release durations of both drugs to about 2-days. The lenses loaded with both drugs exhibited superior IOP reduction compared to eye drops with about 6-fold lower drug loading. More importantly, combination therapy by continuous wear of vitamin E loaded contact for 2-days, followed by a new set of contacts for another two days, reduced IOP during the 4days of wear time and for another 8days after removal of the contacts. Vitamin E loading is very effective for providing combination therapy by contact lenses due to the increase in release durations of several drugs. The contact lens based therapy reduces IOP with lower drug dose compared to eye drops and may significantly improve the compliance as the effect of the therapy lasts significantly longer than the wear-duration.

Therapeutic contact lenses: a patent review.

INTRODUCTION: Ophthalmic drugs are almost exclusively delivered via eye drops in spite of several deficiencies, including low bioavailability and poor compliance. Contact lenses have the potential to increase bioavailability by an order of magnitude, while also improving compliance. AREAS COVERED: In this review, the authors summarize advances in therapeutic contact lenses. The major focus of the review is on patents on drug-eluting contact lenses, but non-drug-eluting contacts that offer a therapeutic benefit are also included. The content is divided based on the broad technology of the patent, including novel materials, molecular imprinting, diffusion barriers, colloid encapsulation, surface modification, layering, and other novel approaches. In addition to patents, research publications are also included to facilitate the understanding of the mechanisms and challenges. EXPERT OPINION: Among all non-invasive alternatives, contact lenses offer the highest bioavailability to the cornea due to the location of the lens in the immediate vicinity of the cornea. Several approaches have been patented to improve contact lens design for an extended release duration of drugs. Many technologies have successfully integrated suitable drug release profiles into contact lenses, but drug-eluting contacts are not yet commercialized likely due to regulatory challenges, including the high costs of clinical trials.

Release of betaine and dexpanthenol from vitamin E modified silicone-hydrogel contact lenses.

PURPOSE: To develop a contact lens system that will control the release of an osmoprotectant and a moisturizing agent with the aim to reduce symptoms of ocular dryness. MATERIALS AND METHODS: Profiles of the release of osmoprotectant betaine and moisturizing agent dexpanthenol from senofilcon A and narafilcon B contact lenses were determined in vitro under sink conditions. Both types of lenses were also infused with vitamin E to increase the duration of drug release due to the formation of the vitamin E diffusion barriers in the lenses. The release profiles from vitamin E-infused lenses were compared with those from the control lenses. RESULTS: Both dexpanthenol and betaine are released from commercial silicone hydrogel lenses for only about 10 min. Vitamin E loadings into contact lenses at about 20-23% can increase the release times to about 10 h, which is about 60 times larger compared to the control unmodified lenses. CONCLUSIONS: Vitamin E-loaded silicone hydrogel contact lenses released betaine and dexpanthenol in a controlled fashion.

Contact lenses as a platform for ocular drug delivery.

INTRODUCTION: Most ophthalmic drugs are delivered through eye drops even though only about 1 - 5% of the drug reaches the target tissue and the patient compliance is not good. Drug-eluting contact lenses could significantly increase bioavailability, reduce side effects and improve patient compliance. AREAS COVERED: Recent research on drug-eluting contact lenses has focused on increasing the release duration through molecular imprinting, dispersion of barriers or nanoparticles, increasing drug binding to the polymer, sandwiching a PLGA (poly[lactic-co-glycolic acid]) layer in a lens and developing novel materials. This review covers all these studies with a specific focus on the transport mechanisms and advantages and disadvantages of each approach. EXPERT OPINION: The main reason for prior failures was the short duration of release from the lenses. The new technologies can provide extended drug release for hours to days. The in vivo animal and clinical studies have proven the safety and efficacy of drug-eluting contact lenses, while showing considerable improvements compared to eye drops. The future appears to be promising but several challenges remain such as processing and storage issues, regulatory hurdles, high costs of clinical studies, potential lack of acceptance by the elderly, etc.

Feasibility of corneal drug delivery of cysteamine using vitamin E modified silicone hydrogel contact lenses.

Cystinosis is an inherited genetic disease characterized by the accumulation of cystine crystals in several tissues including the cornea. The corneal manifestations of cystinosis are treated by hourly instillation of cysteamine eye drops each day while awake. The high frequency of eye drop instillation along with the long duration of treatment leads to poor compliance in many patients. We have combined in vitro experiments with mathematical modeling to investigate the feasibility of daily use of cysteamine loaded contact lenses to replace the hourly instillation of drops. Our approach was based on incorporation of vitamin E diffusion barriers into commercially available contact lenses to increase the duration of drug release. Contact lenses were first soaked in a solution of vitamin E in ethanol. Subsequently, the lenses were soaked in an aqueous solution of cysteamine to load the drug. The drug release profiles from vitamin E treated lenses were measured under sink conditions. In addition, drug oxidation rates were measured after exposing drug loaded contact lenses to humidified room air. To study further the feasibility of using contact lenses for the delivery of cysteamine, a mass transfer model was used to determine the rates at which the drug loaded in the lens is delivered to the cornea. The results show that vitamin E loading increases the release duration from 10 min to about 3 h in solution, thus allowing the possibility of extended drug delivery. In addition to improving the release profiles, vitamin E loading also improved the drug stability by reducing the oxidation rates. The mathematical modeling of drug transport in the eye suggested that the vitamin E loaded contact lens can provide the daily therapeutic dose without causing toxicity, while significantly increasing the bioavailability compared to eye drops. Based on the in vitro experimental results and the mathematical modeling, it is likely that a single contact lens worn for about 2h could achieve the same therapeutic effects as hourly instillation of eye drops.