Recent Patents on Drug Delivery & Formulation - Volume 13, Issue 4, 2019

The structure of the eye is very complex in nature which makes it a challenging task for pharmaceutical researchers to deliver the drug at the desired sites via different routes of administration. The development of the nano-based system helped in delivering the drug in the desired concentration. Improvement in penetration property, bioavailability, and residence time has all been achieved by encapsulating drugs into liposomes, dendrimers, solid lipid nanoparticle, nanostructured lipid carrier, nanoemulsion, and nanosuspension. This review puts emphasis on the need for nanomedicine for ocular drug delivery and recent developments in the field of nanomedicine along with recent patents published in the past few years.

Efficient delivery of ocular therapeutics with improved efficacy, enhanced bioavailability, and acceptable patient compliance presents unique challenges. This can be attributed to the presence of protective mechanisms, physicobiological barriers, and structural obstacles in the eye. Nanotherapeutic interventions have been explored extensively over the past few years to overcome these limitations. The present review focusses on the nanoformulations developed for the diagnosis and treatment of various ocular diseases besides providing an in-depth insight into the patents reported for the same.

Bio-molecules are the most important target to be considered while designing any drug delivery system. The logic lies in using such bio-sensing or bio-mimicking systems in their formulations that can mimic the active site of those receptors to which the drug is going to bind. Polymers mimicking the active site of target enzymes are regarded as bio-inspired polymers and can be used to ameliorate many diseased conditions. Nowadays, this strategy is also being adopted against diabetes and its complications. Under hyperglycemic conditions, many pathways get activated which are responsible for the progression of diabetes-associated secondary complications viz. retinopathy, neuropathy, and nephropathy. The enzymes involved in the progression of these complications can be mimicked for their effective management. For an instance, Aldose Reductase (ALR2), a rate-limiting enzyme of the polyol pathway (downstream pathway) which gets over-activated under hyperglycemic condition is reported to be mimicked by using polymers which are having same functionalities in their structure. This review aims at critically appraising reports in which target mimicking bio-inspired formulations have been envisaged against diabetes and its complications. The information summarized in this review will provide an idea about the bio-sensing approaches utilized to manage blood glucose level and the utility of bio-inspired polymers for the management of diabetic complications (DC). Such type of information may be beneficial to pharmaceutical companies and academia for better development of targeted drug delivery systems with sustained-release property against these diseased conditions.

Age-related Macular Degeneration (AMD) is one of the common diseases affecting the posterior part of the eye, of a large population above 45 years old. Anti-Vascular Endothelial Growth Factor- A (Anti-VEGF-A) agents have been considered and approved as therapeutic agents for the treatment of AMD. Due to the large molecular weight and poor permeability through various eye membranes, VEGF-A inhibitors are given through an intravitreal injection, even though the delivery of small therapeutic molecules by topical application to the posterior part of the eye exhibits challenges in the treatment. To overcome these limitations, nanocarrier based delivery systems have been utilized to a large extent for the delivery of therapeutics. Nanocarriers system offers prodigious benefits for the delivery of therapeutics to the posterior part of the eye in both invasive and non-invasive techniques. The nano size can improve the permeation of therapeutic agent across the biological membranes. They provide protection from enzymes present at the site, targeted delivery or binding with the disease site and extend the release of therapeutic agents with prolonged retention. This leads to improved therapeutic efficacy, patient compliance, and cost effectiveness of therapy with minimum dose associated side-effects. This review has summarized various nanocarriers explored for the treatment of AMD and challenges in translation.

Hydrogels are aqueous gels composed of cross-linked networks of hydrophilic polymers. Stimuli-responsive based hydrogels have gained focus over the past 20 years for treating ophthalmic diseases. Different stimuli-responsive mechanisms are involved in forming polymer hydrogel networks, including change in temperature, pH, ions, and others including light, thrombin, pressure, antigen, and glucose-responsive. Incorporation of nanocarriers with these smart stimuli-responsive drug delivery systems that can extend the duration of action by increasing ocular bioavailability and reducing the dosing frequency. This review will focus on the hydrogel drug delivery systems highlighting the gelling mechanisms and emerging stimuli-responsive hydrogels from preformed gels, nanogels, and the role of advanced 3D printed hydrogels in vision-threatening diseases like age-related macular degeneration and retinitis pigmentosa. It also provides insight into the limitations of hydrogels along with the safety and biocompatibility of the hydrogel drug delivery systems.

Background: Non-steroidal anti-inflammatory drugs are most commonly used in the management of ocular inflammations. These drugs have poorly aqueous solubility and weakly acidic nature. They interact with cationic quaternary ammonium compound benzalkonium chloride, used as a preservative in ophthalmic formulations, to form insoluble complexes. To overcome this incompatibility solubilizers like polysorbate 80, lysine salts, tocopheryl polyethylene glycol succinate etc. are used which are quite irritating and affect the corneal integrity. Objective: The objective of the present study is to formulate nonirritating, compatible, microbiologically stable ophthalmic formulation with good corneal permeation characteristics. The interaction between diclofenac sodium or ibuprofen with benzalkonium chloride was optimized using a central composite experimental design to prepare nanosuspensions by nanoprecipitation. Methods: The optimized batches of nanosuspensions were evaluated for ex vivo corneal permeation study, preservative challenge test and physical stability. The optimal concentrations of benzalkonium chloride for diclofenac sodium (0.1%, w/v) and ibuprofen (0.1% w/v) nanosuspensions were determined to be 0.002%(w/v), which had a respective average particle size of 440 nm and 331 nm, respectively. The nanosuspensions of diclofenac sodium and ibuprofen provided 1.6 and 2.1- fold higher ex vivo corneal permeation than their respective conventional aqueous solution dosage forms. Further, the concentration of benzalkonium chloride used in the formulations showed adequate preservative efficacy. Results: The optimized nanosuspension formulations of diclofenac and ibuprofen were found to be physically stable and microbiologically safe with greater corneal penetration than the conventional solution dosage forms.

Background: Excessive blue light light-emitting diode (LED) exposure and consequent oxidative stress causes corneal damage and corneal injuries are the major problem arising these days due to excessive use of mobile phone, TV, environment pollution, etc. Objective: In the present investigation, the protectiveness of carboxymethyl Terminalia catappa (CTC) from blue light LED-induced corneal damage was explored. Methods: For this purpose, Terminalia catappa (TC) was functionalized by carboxymethylation and its structural modification was confirmed by spectral attributes. Further, the CTC protective eye drop formulations (0.025-1%, w/v) were prepared and evaluated for their capability of protection from blue light LEDinduced corneal damage as compared to CTC protective eye gel (1.25-7%, w/v). The findings pointed towards excellent protection of CTC gel formulations as compared to CTC eye drop formulations. In addition, the prepared optimized CTC gel had thixotropic behavior as evident from percentage structural recovery which was 1.75 fold higher than marketed formulation (I-Comfort, HPMC 2%, w/v). The safety and non-toxicity of CTC protective eye drop and gel were confirmed by HET-CAM test. Further, a rat eye model was implemented that mimic blue light light-emitting diode induced corneal damage in day to day life to assess the protective effect of CTC protective eye drop and gel. Results: The order of protectiveness of CTC formulations was found to be CTC protective eye gel (4%, w/v) (no corneal damage)>marketed eye gel (12.34% corneal damage)=CTC protective eye drop (0.75%, w/v) (17.48% corneal damage)> marketed eye drop (51% corneal damage). The mechanism behind the protective effect of CTC eye drop and gel was associated with good free radical scavenging activity and corneal adhesive property of CTC. It is established from the present work that, carboxymethyl Terminalia catappa has protective action against blue light light-emitting diode induced corneal damage.