375144 Combination Glaucoma Therapy By Vitamin E Nanobarrier Loaded Silicone-Hydrogel Contact Lenses
Combination Glaucoma Therapy by Vitamin E Nanobarrier Loaded Silicone-Hydrogel Contact Lenses
Glaucoma affects about 60.5 million people worldwide and causes blindness in about 8.2 million. Glaucoma cannot be cured but it can be managed by medications that reduce the intraocular pressure (IOP). Glaucoma drugs are exclusively delivered through eye drops which have a low patient compliance, particularly when more than one IOP reducing drug is required, which happens for about 50% of patients in the US. In addition to poor compliance, drug delivery via eye drops has low bioavailability and potential for side effects. To overcome all the limitations of eye drops we propose to use extended wear contact lenses for glaucoma therapy. This talk will discuss our latest efforts in managing glaucoma through simultaneous delivery of two different glaucoma drugs from contact lenses. We will show that drug delivery by contact lenses can increase bioavailability, improve drug stability and compliance, and reduce side effects. To our knowledge, this is the first study on extended delivery of multiple ophthalmic drugs from the same delivery device.
Extended wear contact lenses are loaded individually with timolol and dorzolamide to determine the partition coefficient and release profiles. The drugs are then loaded simultaneously such that the mass of drug loaded for each drug matches the therapeutic dose. The release profiles are also measured for simultaneous drug loading. Commercial contact lenses cannot provide extended delivery of drugs. To extend the release duration we loaded the lenses with vitamin E diffusion barriers, which increases the release time due to the increase in path length of the drug molecules. The therapeutic effect and safety of the lenses was also evaluated in beagle dogs.
In vitro release studies show that the release duration of the two drugs from lenses without modification is less than 3 hr. With diffusion barriers, the release duration increases to about 72 hr. The drug release profiles are diffusion-controlled in both cases, with vitamin E incorporation reducing the effective diffusivity due to the barrier-effect, which increases the tortuosity. The relative improvements in drug delivery rates are similar for both drugs, further suggesting that the mechanism for the increase in drug release durations in geometric rather than based on direct interaction of the drugs with vitamin E. Preliminary evidence suggests that the vitamin E forms thin barriers with high aspect ratio of about 50 at the interface between the silicone and the hydrogel phases in the contact lenses. Vitamin E incorporation does not have a significant impact on any critical contact lens property, except ion permeability, but even the reduced ion permeability is adequate for in vivo applications. There are some additional benefits of vitamin E incorporation such as improved ultraviolet blocking, reduced modulus and reduced water loss rates, both of which could improve comfort. The in vivo studies showed that the vitamin E loaded contact lenses are safe as there was no adverse event in the entire study with 10 dogs lasting about 10 days. In vivo studies show that the drug eluding lenses can significantly reduce the IOP comparable to b.i.d. delivery of eye drops, even though the lenses were loaded with only 1/6 of the drug loaded in eye drops. Lenses without vitamin E have to be replaced daily, while vitamin E loaded lenses can be worn continuously for 3 days with constant IOP reduction. The IOP reduction with all contact lens studies was more stable compared to the eye-drops and the magnitude was about twice that for the eye drop studies. The studies with vitamin E loaded lenses showed that the IOP reduction effect was maintained for more than a week after the contact lenses were removed. This was attributed to creation of depots in the eyes during the lens-wear duration with subsequent release from the depots towards the target duration.
Based on our studies, we conclude that vitamin E modified lenses are promising for extended multidrug delivery, which may greatly improve therapeutic effect and patient compliance. With this technique, extended delivery of other multidrug system or even multiple comfort enhancers is also possible.
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