Cheng-Chun Peng

Extended delivery of hydrophilic drugs from silicone-hydrogel contact lenses containing Vitamin E diffusion barriers

This paper proposes an approach for increasing drug release durations from contact lenses and other biomedical devices by in situ creation of transport barriers of Vitamin E that force drug molecules to diffuse through long tortuous path. Results show that the increase in release duration is quadratic in Vitamin E loading, which is consistent with proposed mathematical models. Loadings of 10 and 40% Vitamin E increase release time of timolol by a factor of about 5 and 400, respectively for NIGHT&DAY lens. Similar results have been obtained for other hydrophilic drugs including fluconazole and dexamethasone 21-disodium phosphate (DXP). Vitamin E loading in the NIGHT&DAY lens leads to slight increase in lens sizes (6.5% increase for 30% loading), a slight reduction in oxygen diffusion (about 40% reduction for 75% loading), and a more significant reduction in the ion permeability (50% reduction for 10% loading). Additionally, Vitamin E loading has a beneficial effect of blocking UV radiation which will reduce the corneal damage due to UV light.

Extended cyclosporine delivery by silicone-hydrogel contact lenses.

Cyclosporine A (CyA) is effective in treating chronic dry eyes and contact lens mediated dry eyes. CyA is delivered through eye drops of an oil-in-water emulsion, which has a small residence time in the eyes, leading to low bioavailability. Here we explore delivery of CyA from contact lenses to provide controlled and extended drug delivery with an increased bioavailability due to enhanced ocular residence time. Loading and release profiles of CyA from commercial contact lenses are presented to show that 1-DAY ACUVUE® releases CyA for about a day and extended wear silicone hydrogel (SiH) lenses release CyA for about 2-weeks. The longer duration from SiH lenses compared to the 1-DAY ACUVUE®lens is due to larger partition coefficients in the gel. A novel approach is presented for increasing release duration from the SiH lenses to the desired 1-month through incorporation of Vitamin E. The results show that Vitamin E loaded lenses can provide CyA release within the therapeutic window for a period of about a month. This pilot study demonstrates the promising potential of delivering CyA from contact lens for treatment of chromic dry eyes and contact lens mediated dry eyes.

Extended release of dexamethasone from silicone-hydrogel contact lenses containing vitamin E

Ophthalmic drug delivery by contact lenses is expected to be more efficient due to continuous extended release of drug and increased residence time in the tear film. However, commercial contact lenses release ophthalmic drugs for a short period of about an hour and are thus not suitable for extended delivery use. Here we explore a novel approach of increasing the release duration of dexamethasone (DX) from commercial contact lenses by loading Vitamin E into the lenses. The Vitamin E was loaded into the lenses by soaking the lenses in Vitamin E-ethanol solution followed by ethanol removal through evaporation. The results show that with about 30% of Vitamin E loading in the contact lens, the DX release time can be increased to 7 to 9 days for ACUVUE(®) OASYS™, NIGHT&DAY™, and O(2)OPTIX™, which is a 9 to 16 fold increase compared to the DX release duration by pure contact lens without Vitamin E loading. The DX delivery by contact lens can be viewed as a one-dimensional transport by a flat thin film, and a mathematical model based on the drug diffusivity difference between Vitamin E and silicone hydrogel was also proposed to explain the DX release time increase by Vitamin E loaded contact lens.

Extended drug delivery by contact lenses for glaucoma therapy.

We combine laboratory-based timolol release studies and in vivo pharmacodynamics studies in beagle dogs to evaluate the efficacy of glaucoma therapy through extended wear contact lenses. Commercial contact lenses cannot provide extended delivery of ophthalmic drugs and so the studies here focused on increasing the release duration of timolol from ACUVUE TruEye contact lenses by incorporating vitamin E diffusion barriers. The efficacy of timolol delivered via extended wear contact lenses was then compared to eye drops in beagle dogs that suffer from spontaneous glaucoma. The lenses were either replaced every 24h or continuously worn for 4 days, and the pharmacodynamics effect of changes in the intraocular pressure (IOP) of timolol from the ACUVUE TruEye contact lenses can be significantly increased by incorporation of vitamin E. The in vivo studies showed that IOP reduction from baseline by pure contact lens on daily basis was comparable with that by eye drops but with only 20% of drug dose, which suggested higher drug bioavailability for contact lenses. In addition, by inclusion of vitamin E into the lenses, the IOP was reduced significantly during the 4-day treatment with continuous wear of lens.

Drug Delivery by Contact Lens in Spontaneously Glaucomatous Dogs

Purpose: The efficacy of ophthalmic drug delivery through contact lenses in animal model was explored to evaluate its potential for serving as an alternative to eye drops, which are inefficient vehicles for delivering ophthalmic drugs. Methods: The efficacy of timolol delivered via contact lenses was compared to eye drops in beagle dogs that suffer from spontaneous glaucoma. Experiments were conducted with NIGHT & DAY™ silicone hydrogel contact lenses and NIGHT & DAY™ loaded with vitamin E, which was included in the lens to extend the release duration of the drug. Timolol was loaded into contact lenses by soaking in drug/phosphate buffered saline solution, and the drug-loaded lenses were subsequently inserted in one of the eyes, with the other eye serving as control. The lenses were replaced every 24 hours, and the pharmacodynamics of intraocular pressure (IOP) and pupil size were monitored in both eyes. Results: The IOP reduction from baseline by NIGHT & DAY™ (5.02 ± 0.83 mmHg) was comparable with that by eye drops with similar drug dosing (4.64 ± 0.41 mmHg). In addition, lenses with one-third of the drug loading as eye drops resulted in the similar IOP reduction, suggesting higher bioavailability for contact lenses compared to eye drops. Inclusion of vitamin E into the lenses did not improve the IOP reduction. The IOP in the untreated eye also decreased from baseline for eye drops (3.17 ± 0.42 mmHg) but it remained relatively unchanged with treatments based on lenses, suggesting reduction in systemic absorption for delivery of drugs by contact lenses. Conclusions: Ophthalmic drug delivery through contact lenses increases bioavailability and reduces systemic drug uptake.

Transport of Topical Anesthetics in Vitamin E Loaded Silicone Hydrogel Contact Lenses

Transport of surface active anesthetic drugs through silicone hydrogel contact lenses containing nanosized vitamin E aggregates is explored for achieving extended anesthetics delivery. Commercial silicone hydrogel contact lenses release most ophthalmic drugs including local anesthetics for only a few hours, which is not adequate. Here we focus on creating dispersion of highly hydrophobic vitamin E aggregates in the lenses as barriers for drug diffusion for increasing the release durations. This approach has been shown previously to be successful in extending the release durations for some common hydrophilic ophthalmic drugs. The topical anesthetic drugs considered here (lidocaine, bupivacaine, and tetracaine) are hydrophilic at physiologic pH due to the charge, and so these cannot partition into the vitamin E barriers. However, these surface active drug molecules adsorb on the surface of the vitamin E barriers and diffuse along the surface, leading to only a small decrease in the effective diffusivity compared to non-surface-active hydrophilic drugs. The drug adsorption can be described by the Langmuir isotherm, and measurements of surface coverage of the drugs on the vitamin E provide an estimate of the available surface area of vitamin E, which can then be utilized to estimate the size of the aggregates. A diffusion controlled transport model that includes surface diffusion along the vitamin E aggregates and diffusion in the gel fit the transport data well. In conclusion, the vitamin E loaded silicone contact lens can provide continuous anesthetics release for about 1-7 days, depending on the method of drug loading in the lenses, and thus could be very useful for postoperative pain control after corneal surgery such as the photorefractive keratectomy (PRK) procedure for vision correction.

Emulsions and microemulsions for ocular drug delivery

Ocular drug delivery through aqueous eye drops is the most common approach for administering ophthalmic drugs, in spite of the low residence time of a few minutes, which limits the bioavailability to less than 5 %. A number of drug delivery approaches have been explored to overcome the drawbacks of the aqueous eye drops including addition of colloidal particles to the eye drops. Emulsions and microemulsions are particularly appealing for delivering hydrophobic drugs to the cornea because of the possibility of loading the drugs in the oil particles. There are some other potential advantages such as the possibility of increasing the residence time through binding between the surfactant covered oil drops and the cornea, or through designing systems that undergo phase transition to a liquid crystalline system with high viscosity. Additionally, some researchers have dispersed microemulsions in contact lenses to further increase the residence time. The benefits of the emulsions and microemulsions listed above are at least partially offset by potential toxicity issues, and also formulation issues such as shelf life. Furthermore, issues related to the ocular physiology including tear biochemistry, and rapid tear turnover also sometimes limit the potential benefits of using microemulsions and emulsions. This review paper focuses on summarizing recent research on ophthalmic delivery through emulsions and microemulsions, with a particular focus on mechanistic and formulation issues.

Aqueous salt transport through soft contact lenses: An osmotic-withdrawal mechanism for prevention of adherence

In addition to improving oxygen permeability, modern silicone-hydrogel (SiHy) soft contact lenses (SCLs) exceed a limiting diffusive ion permeability to aqueous sodium chloride. Below the ion-permeability threshold, siloxane-based SCLs are prone to bind against the corneal epithelium. Salt permeability is argued to reflect indirectly water hydraulic permeability. However, no quantitative explanation is available to date for a threshold salt permeability. We hypothesize that molecular salt diffusion through a SCL supports the postlens tear film (PoLTF) by enhancing water flow into the PoLTF from the cornea. Higher salt concentrations in the PoLTF raise the osmotic pressure there relative to that in the cornea increasing osmotic water withdrawal from the cornea. The proposed osmotic-withdrawal mechanism successfully predicts a self-consistent threshold lens salt permeability when thin-film attractive binding forces are introduced. For the first time, we present a quantitative picture for the possible origin of a threshold salt permeability in SCL manufacture.

In Vitro Spoilation of Silicone-Hydrogel Soft Contact Lenses in a Model-Blink Cell.

PurposeWe developed an in vitro model-blink cell that reproduces the mechanism of in vivo fouling of soft contact lenses. In the model-blink cell, model tear lipid directly contacts the lens surface after forced aqueous rupture, mirroring the pre–lens tear-film breakup during interblink. MethodsSoft contact lenses are attached to a Teflon holder and immersed in artificial tear solution with protein, salts, and mucins. Artificial tear-lipid solution is spread over the air/tear interface as a duplex lipid layer. The aqueous tear film is periodically ruptured and reformed by withdrawing and reinjecting tear solution into the cell, mimicking the blink-rupture process. Fouled deposits appear on the lenses after cycling, and their compositions and spatial distributions are subsequently analyzed by optical microscopy, laser ablation electrospray ionization mass spectrometry, and two-photon fluorescence confocal scanning laser microscopy. ResultsDiscrete deposit (white) spots with an average size of 20 to 300 &mgr;m are observed on the studied lenses, confirming what is seen in vivo and validating the in vitro model-blink cell. Targeted lipids (cholesterol) and proteins (albumin from bovine serum) are identified in the discrete surface deposits. Both lipid and protein occur simultaneously in the surface deposits and overlap with the white spots observed by optical microscopy. Additionally, lipid and protein penetrate into the bulk of tested silicone-hydrogel lenses, likely attributed to the bicontinuous microstructure of oleophilic silicone and hydrophilic polymer phases of the lens. ConclusionsIn vitro spoilation of soft contact lenses is successfully achieved by the model-blink cell confirming the tear rupture/deposition mechanism of lens fouling. The model-blink cell provides a reliable laboratory tool for screening new antifouling lens materials, surface coatings, and care solutions.