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Regulatory Issues in Drug Delivery to the Eye
Published in Glenn J. Jaffe, Paul Ashton, P. Andrew Pearson, Intraocular Drug Delivery, 2006
Lewis J. Gryziewicz, Scott M. Whitcup
There has been debate on whether placebo implants should be mandated in clinical trials. Sham procedures for coronary artery bypass surgery have been employed in clinical trials as the appropriate control group. It is known that preparation for surgery, pre- and postoperative evaluation, and the psychological effects of surgery may introduce bias into a treatment group. Currently, the FDA has required at least two doses of drugs in intravitreal implants for initial clinical trials. A placebo implant has not been required. Sham procedures have been used in clinical trials using ocular drug delivery. A study arm with a low dose of drug in the delivery device may be accepted as an alternative control in some studies.
Futuristic Approaches in Vitreoretinal Surgery
Published in Pradeep Venkatesh, Handbook of Vitreoretinal Surgery, 2023
Intravitreal pharmacotherapy has become the mainstay for management of complications secondary to ARMD, diabetic retinopathy, and retinal vascular occlusions. Owing to the universal short half-life of all currently available anti–vascular endothelial growth factor agents and their inability to eradicate the basic pathology, they have to be administered into the vitreous cavity every 4–8 weeks. Almost 8–12 injections are needed in the first year, followed by continued monitoring and reinjection in the following years over an indefinite time frame. This approach is not time efficient for both the surgeon and the patient. In addition, there is a theoretical cumulative increase of the associated risks, following each additional injection. Alternate drug delivery systems [DDS], which minimize the need for repeated intravitreal injections, are being explored to enable sustained drug delivery. Some of these approaches include sustained-release intravitreal implants, refillable implants, injectable particulate systems, encapsulated cell delivery, iontophoresis, and nanotechnology. Alternate delivery routes like transscleral and suprachoroidal delivery have also been suggested. Of these, the most studied device clinically and currently undergoing phase 3 evaluation is the port delivery system (PDS). This is a refillable device for long-term delivery of drugs into the posterior segment and has to be placed surgically through a 3.2-mm scleral incision. A large incision is necessary to accommodate the diameter of the rigid drug reservoir. Insertion of this device requires prior surgical training to minimize complication rates. [Initial rates of complications were found to be very high, as more than 50% cases developed vitreous haemorrhage]. To reduce the risks, the procedure was then modified. Modification of the procedure involves partial dissection followed by laser and cauterization of the pars plana. Despite the modification, risk of serious adverse events, though diminished, continues to persist. Following recent results of phase 3 studies, the FDA has approved the PDS device [which is being marketed as Susvimo]. It is said to have the ability to maintain the stability of patients with wet ARMD with just two treatments annually. However, a major concern remains a nearly threefold higher risk of endophthalmitis [2%] in the Archway trial. The long-term safety and efficacy of Susvimo in wet ARMD are being further evaluated in the PORTAL study. Other ongoing trials with this device include VELODROME [to study efficacy with 9 month refill in wet ARMD], PAGODA [in diabetic macular edema], and PAVILION [in diabetic retinopathy without macular edema].
Hyaluronic acid-based nanoparticles to deliver drugs to the ocular posterior segment
Published in Drug Delivery, 2023
Posterior segment illness is a leading cause of irreversible visual loss that must be addressed (Meza-Rios et al., 2020; Varela-Fernández et al., 2020). Although the eye is an easy-to-reach body part, drug administration to the posterior portion remains a challenge (Alshaikh et al., 2022). Topical application is a convenient and safe method for delivering ocular medications to the surface of the eye (Wei et al., 2023). Due to the various eye barriers, it is still challenging for topical administration to efficiently transfer drugs to the posterior of the eye. Intravitreal administration, compared with systemically and topically delivered agents, can directly reach intraocular lesions without systemic toxicity. Frequent injection to maintain the concentration of the drugs in the vitreous may lead to an increased risk of complications, such as increased intraocular pressure, endophthalmitis, vitreous hemorrhage, and cataract (Patel et al., 2022). The research and development of continuous-release formulations and intravitreal implants are two critical topics for reducing the quantity and frequency of vitreous cavity injections (Cabrera et al., 2019). To insert vitreous implants, invasive surgical operations are needed, and nonbiodegradable materials may require a second operation for removal. Nanocontrolled delivery technology can improve pharmacokinetics to prolong and monitor the release of medicines by increasing their solubility, bioavailability, and stability (Nayak & Misra, 2018; Cabrera et al., 2019).
Cow ghee fortified ocular topical microemulsion; in vitro, ex vivo, and in vivo evaluation
Published in Journal of Microencapsulation, 2019
Aashu Gupta, Kritika Nayak, Manju Misra
The route of drug administration chosen is non-invasive topical delivery, due to the benefits offered by it in terms of the patient compliance. Thus, the basic idea over here is to develop a topical ocular formulation using ME for diabetic macular oedema, as presently the only mode of delivery known for such ailments is intravitreal implants, which are invasive. Fluocinolone acetonide (FA) is one of important corticosteroids indicated for diabetic macular oedema and is commercially available as non-biodegradable intravitreal implant marketed under the brand name, Illuvien®, which releases drug at an average rate of 0.2 µg/day for almost 36 months. However, the present therapy suffers from serious side effects like retinal detachment, haemorrhage and bleeding (Schwartz et al.2013) and needs redressal. Thus, FA was selected as model drug for the present project.
Polyester-based microdisc systems for sustained release of neuroprotective phosphine-borane complexes
Published in Pharmaceutical Development and Technology, 2018
David A. Janus, Christopher J. Lieven, Megan E. Crowe, Leonard A. Levin
It is also possible that a chronic dose lower than 100 nm would be effective for ganglion cell neuroprotection. PB1 was highly effective against acute axotomy in short-term primary RGC cultures at concentrations down to 1 nm, so it is possible that with continuous dosing the required drug levels, and consequent implant size, could be significantly scaled back. The full release of the drug reservoir at the calculated rate for AP002:PB1 copolymer would be 370–1370 weeks, or 7–26 years. While such long windows for treatment are attractive, studies will be needed to test the linearity of the release rate, polymer toxicity, and the chemical stability of the drug within the polymer complex in vitreous fluid over long periods of time, all features relevant to the design of intravitreal implants (Kuno & Fujii 2010). Although our own data demonstrates the excellent stability of PB1, even at elevated temperatures (Niemuth et al. 2016), there is no benefit to a formulation which remains intact for years if the drug it delivers has degraded.