11.4  Alternative Approaches to Improve Ocular Therapeutics

Although there are several benefits to using nanotechnology including small-scaled interactions, improved drug permeability, and sustained release, major disadvantages such as rapid elimination by renal systems may counteract the advantages of nanosystems. Kompella et al. compared the release profiles of budesonide PLA nanoparticles and microparticles and found that microparticles had a much more prolonged release profile of 6 weeks of only 23% of the initial drug loading concentration compared to nanoparticle release profile of 2 weeks of 50% initial drug loading concentration (Kompella et al. 2003). Due to the prolonged retention of microparticles, these may be more efficacious in sustaining the delivery ocular therapeutics.

Delivery devices other than nanoparticles such as ocular implants are rapidly entering the ocular pharmaceutical market as they provide several advantages over nanosystems. For example, Retisert®, a nonbiodegradable implant comprised of fluocinolone acetonide (active ingredient) in a silicone/polyvinyl alcohol polymer coating situated on a polyvinyl suture strut can effectively release fluocinolone acetonide for up to 34 months in the treatment of noninfectious uvetis. Currently, no nanotechnology delivery vehicle is capable of sustaining release up to a few years. The disadvantage of the Retisert system is that it must be inserted and removed by a surgeon; however, patients are not subjected to monthly injections or costly doctor visits. Currently, injectable nondegradable systems such as IluvienTM are under development for sustained drug delivery over a few years. The use of biodegradable implants composed of polymer gels or other biologically related compounds may provide for sustained release in years without the need to remove the implant. However, it will be a challenge to control the rate of implant degradation to allow for controlled release of the drug over a long period of time. Ozurdex®, a biodegradable intravitreal implant of dexamethasone, was approved in 2009 for the treatment of macular edema and has shown to persist drug levels for up to 6 months. However, biodegradable implants will degrade over time unlike nonbiodegradable implants and do not provide zero-order drug release, which limits the degree of sustained release. For treatment of certain indications, a 6-month drug profile may be sufficient to fully treat the disease. For other chronic diseases such as diabetic retinopathy or choroidal neovascularization, long-term implants will be more beneficial and will have higher rates of patient compliance.

Implantable, refillable delivery devices are also under investigation as possible alternatives to traditional ocular implants and other particles (Saati et al. 2009). These devices are inherently at an advantage because they can be refilled once every so many years by a relatively noninvasive procedure that can be completed in a doctor’s office. Further, this device may include a mechanical device that can readily calculate the amount of drug that is needed in the nearby tissue by measuring drug levels. The device is then able to dispense the drug at precisely the amount calculated. A possible disadvantage of this system is that mechanical failure may occur and make inaccurate decisions for drug dosage times and levels. The system may be

Fig. 11.5  Ocular routes of administration for delivery of drug to the posterior segment of the eye including topical administration directly on the corneal surface, intravitreal injection (into the vitreous humor), retrobulbar injection (in the orbital space behind the eye globe), suprachoroidal injection (below the sclera and above the choroid), sub-Tenon injection (below Tenon’s capsule), and subconjunctival injection (below the conjunctiva)

engineered such that it can keep a record of the dosing scheme, which can be reviewed by the physician.

Another approach to improve drug penetration, retention time and ultimately, efficacy, is to use alternative sites of injection (see Fig. 11.5 for a schematic depiction of various routes of ocular administration). This will allow for the drug to be directly injected into the target tissue or within close proximity to the target tissue. Suprachoroidal injection has received recent attention due to its ability to deliver drug to the posterior segment of the eye using a technique that is less invasive to the globe than intravitreal injection. However, the safety and efficacy of this approach has yet to be established.

Thus, several alternatives to nanoparticles exist and selection of any delivery system depends on several factors including the disease state, the drug, and patientrelated factors.

11.5  Conclusion

Recent advances in nanotechnology are providing several innovative delivery systems with a nanodimension. Although the rate of drug release is typically more rapid from such systems when compared to larger microparticles and implants, nanosystems offer some unique advantages. Nanosystems can potentially address

some limitations that exist with current ocular therapeutics such as poor residence time, poor permeability across barriers, poor bioavailability, and poor patient compliance. Nanosystems might be particularly beneficial for poorly permeable, poorly soluble, or labile therapeutic agents. They might allow effective noninvasive delivery of drug molecules to the back of the eye. However, alternative approaches to enhance drug efficacy such as microparticles and implants may offer the advantage of more prolonged drug delivery compared to nanoparticles, which might be beneficial for some well-permeable therapeutic agents. The development and design of drug delivery devices will be ultimately dictated by the drug properties, disease properties, and patient convenience.

Acknowledgements This work was supported by the NIH grants R01EY018940, R01EY017533, and RC1EY020361.

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