Below, find all the information on articles and publications from the ORBITAL Early Stage Researchers.

  • Ocular Disorders and Associated Drug Development Challenges: The Current Scenario
    D. Mishra, S. Gade, T. R. R. Singh, Ocular Disorders and Associated Drug Development Challenges: The Current Scenario (2020).

    • Vision is one of the most important human sense and hence eye diseases leading to impairment of vision have been the hot topic for drug delivery research lately. Diseases like glaucoma, cataract, age-related macular degeneration, diabetic retinopathy and trachomatous trichiasis have been known for their potential of visual impairment as well as blindness. A vast amount of research has been done in understanding the pathophysiology, risk factors and drug development and drug delivery challenges associated with these diseases, but the clinical success achieved so far is very sparse. This leading to the requirements for the better understanding of the ocular diseases which can be translated to better drug delivery systems. The current review is formulated with the aims to provide a concise summary of these ocular disorders and to address the challenges in their drug development research.
  • Therapeutic Ophthalmic Lenses: A Review
    Toffoletto, N.; Saramago, B.; Serro, A.P. Therapeutic Ophthalmic Lenses: A Review. Pharmaceutics 2021, 13, 36.

    • An increasing incidence of eye diseases has been registered in the last decades in developed countries due to the ageing of population, changes in lifestyle, environmental factors, and the presence of concomitant medical conditions. The increase of public awareness on ocular conditions leads to an early diagnosis and treatment, as well as an increased demand for more effective and minimally invasive solutions for the treatment of both the anterior and posterior segments of the eye. Despite being the most common route of ophthalmic drug administration, eye drops are associated with compliance issues, drug wastage by lacrimation, and low bioavailability due to the ocular barriers. In order to overcome these problems, the design of drug-eluting ophthalmic lenses constitutes a non-invasive and patient-friendly approach for the sustained drug delivery to the eye. Several examples of therapeutic contact lenses and intraocular lenses have been developed, by means of different strategies of drug loading, leading to promising results. This review aims to report the recent advances in the development of therapeutic ophthalmic lenses for the treatment and/or prophylaxis of eye pathologies (i.e., glaucoma, cataract, corneal diseases, or posterior segment diseases) and it gives an overview of the future perspectives and challenges in the field.
  • Penetration Enhancers for Topical Drug Delivery to the Ocular Posterior Segment—A Systematic Review
    Thareja, A.; Hughes, H.; Alvarez-Lorenzo, C.; Hakkarainen, J.J.; Ahmed, Z. Penetration Enhancers for Topical Drug Delivery to the Ocular Posterior Segment—A Systematic Review. Pharmaceutics 2021, 13, 276.

    • There is an unmet clinical need for eye drop formulations to efficiently treat the diseases of the posterior ocular segment by non-invasive topical administration. Here, we systematically reviewed the literature on ocular penetration enhancers and their ability to transfer drugs to the posterior segment of the eye in experimental studies. Our aim was to assess which penetration enhancer is the most efficient at delivering drugs to the posterior segment of the eye, when topically applied. We conducted a comprehensive search in three electronic databases (Ovid Embase, Ovid MEDLINE, and PubMed) to identify all the relevant manuscripts reported on ocular penetration enhancers based on the PRISMA guidelines. We identified 6540 records from our primary database search and filtered them per our inclusion/exclusion criteria to select a final list of 14 articles for qualitative synthesis. Of these, 11 studies used cell penetrating peptides (CPPs), 2 used chitosan, and 1 used benzalkonium chloride (BAC) as the penetration enhancer. Cationic and amphipathic CPPs, transactivator of transcription (TAT), and penetratin can be inferred to be the best among all the identified penetration enhancers for drug delivery to the fundus oculi via topical eye drop instillation. Further high-quality experimental studies are required to ascertain their quantitative efficacy.
  • Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation
    González-Fernández, F.M.; Bianchera, A.; Gasco, P.; Nicoli, S.; Pescina, S. Lipid-Based Nanocarriers for Ophthalmic Administration: Towards Experimental Design Implementation. Pharmaceutics 2021, 13, 447.

    • Nanotherapeutics based on biocompatible lipid matrices allow for enhanced solubility of poorly soluble compounds in the treatment of ophthalmic diseases, overcoming the anatomical and physiological barriers present in the eye, which, despite the ease of access, remains strongly protected. Micro-/nanoemulsions, solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC) combine liquid and/or solid lipids with surfactants, improving drug stability and ocular bioavailability. Current research and development approaches based on try-and-error methodologies are unable to easily fine-tune nanoparticle populations in order to overcome the numerous constraints of ocular administration routes, which is believed to hamper easy approval from regulatory agencies for these systems. The predictable quality and specifications of the product can be achieved through quality-by-design (QbD) implementation in both research and industrial environments, in contrast to the current quality-by-testing (QbT) framework. Mathematical modelling of the expected final nanoparticle characteristics by variation of operator-controllable variables of the process can be achieved through adequate statistical design-of-experiments (DoE) application. This multivariate approach allows for optimisation of drug delivery platforms, reducing research costs and time, while maximising the understanding of the production process. This review aims to highlight the latest efforts in implementing the design of experiments to produce optimised lipid-based nanocarriers intended for ophthalmic administration. A useful background and an overview of the different possible approaches are presented, serving as a starting point to introduce the design of experiments in current nanoparticle research.
  • Microneedle array systems for long-acting drug delivery
    Lalit K. Vora, Kurtis Moffatt, Ismaiel A. Tekko, Alejandro J. Paredes, Fabiana Volpe-Zanutto, Deepakkumar Mishra, Ke Peng, Raghu Raj Singh Thakur, Ryan F. Donnelly, Microneedle array systems for long-acting drug delivery, European Journal of Pharmaceutics and Biopharmaceutics, Volume 159, 2021, Pages 44-76, ISSN 0939-6411,

    • The development of microneedles (MNs) assisted drug delivery technologies have been highly active for more than two decades. The minimally invasive and self-administered MN technology bypasses many challenges associated with injectable drug delivery systems, by delivering the therapeutic materials directly into the dermal and ocular space and allowing the release of the active ingredient in a sustained or controlled manner. Different types of MNs (biodegradable solid/dissolving MNs and nanoparticle loaded/coated polymeric MNs or delivery by hollow MNs) have been envisioned for long-acting sustained delivery of therapeutic payloads, with the aim of reducing the side effects and administration frequency to improve the patient compliance. In this review, we covered the different types of MNs loaded with different nano/biotherapeutics for long-acting delivery for a wide range of potential clinical applications. We also outlined the future development scenario of such long-acting MN delivery systems for different disease conditions to achieve improved clinical benefit. Finally, we discussed the challenges lie ahead to realize the full potential of sustained-release long-acting MNs in the clinic.
  • Atorvastatin-Eluting Contact Lenses: Effects of Molecular Imprinting and Sterilization on Drug Loading and Release
    Pereira-da-Mota, A.F.; Vivero-Lopez, M.; Topete, A.; Serro, A.P.; Concheiro, A.; Alvarez-Lorenzo, C. Atorvastatin-Eluting Contact Lenses: Effects of Molecular Imprinting and Sterilization on Drug Loading and Release. Pharmaceutics 2021, 13, 606.

    • Statins are receiving increasing attention in the ophthalmic field. Their activity as 3-hydroxy-3-methylglutaryl–CoA (HMG–CoA) reductase inhibitors is clinically used to regulate cholesterol levels and leads to pleiotropic effects, which may help in the management of diabetes-related ocular pathologies. This work aims to design bioinspired contact lenses (CLs) with an affinity for atorvastatin by mimicking the active site of HMG–CoA reductase. Sets of imprinted and nonimprinted 2-hydroxyethyl methacrylate (HEMA) hydrogels were synthesized, varying the contents in functional monomers that bear chemical groups that resemble those present in HMG–CoA reductase, namely, ethylene glycol phenyl ether methacrylate (EGPEM), 2-aminoethyl methacrylate hydrochloride (AEMA), and N-(3-aminopropyl) methacrylamide hydrochloride (APMA). The hydrogels were characterized in terms of suitability as CLs (solvent uptake, light transmission, mechanical properties, and biocompatibility) and capability to load and release atorvastatin. Three sterilization protocols (steam heat, gamma radiation, and high hydrostatic pressure) were implemented and their effects on hydrogel properties were evaluated. Copolymerization of AEMA and, particularly, APMA endowed the hydrogels with a high affinity for atorvastatin (up to 11 mg/g; KN/W > 200). Only high hydrostatic pressure sterilization preserved atorvastatin stability and hydrogel performance. Permeability studies through the porcine cornea and sclera tissues revealed that the amount of atorvastatin accumulated in the cornea and sclera could be effective to treat ocular surface diseases.
  • Asymmetry in Drug Permeability through the Cornea
    Toffoletto, N.; Chauhan, A.; Alvarez-Lorenzo, C.; Saramago, B.; Serro, A.P. Asymmetry in Drug Permeability through the Cornea. Pharmaceutics 2021, 13, 694.

    • The permeability through the cornea determines the ability of a drug or any topically applied compound to cross the tissue and reach the intraocular area. Most of the permeability values found in the literature are obtained considering topical drug formulations, and therefore, refer to the drug permeability inward the eye. However, due to the asymmetry of the corneal tissue, outward drug permeability constitutes a more meaningful parameter when dealing with intraocular drug-delivery systems (i.e., drug-loaded intraocular lenses, intraocular implants or injections). Herein, the permeability coefficients of two commonly administered anti-inflammatory drugs (i.e., bromfenac sodium and dexamethasone sodium) were determined ex vivo using Franz diffusion cells and porcine corneas in both inward and outward configurations. A significantly higher drug accumulation in the cornea was detected in the outward direction, which is consistent with the different characteristics of the corneal layers. Coherently, a higher permeability coefficient was obtained for bromfenac sodium in the outward direction, but no differences were detected for dexamethasone sodium in the two directions. Drug accumulation in the cornea can prolong the therapeutic effect of intraocular drug-release systems.
  • Dexamethasone-Loaded Nanostructured Lipid Carriers for the Treatment of Dry Eye Disease
    Kumari, S.; Dandamudi, M.; Rani, S.; Behaeghel, E.; Behl, G.; Kent, D.; O’Reilly, N.J.; O’Donovan, O.; McLoughlin, P.; Fitzhenry, L. Dexamethasone-Loaded Nanostructured Lipid Carriers for the Treatment of Dry Eye Disease. Pharmaceutics 2021, 13, 905.

    • Dry eye disease (DED) or keratoconjunctivitis sicca is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction. Symptoms include dryness, irritation, discomfort and visual disturbance, and standard treatment includes the use of lubricants and topical steroids. Secondary inflammation plays a prominent role in the development and propagation of this debilitating condition. To address this we have investigated the pilot scale development of an innovative drug delivery system using a dexamethasone-encapsulated cholesterol-Labrafac™ lipophile nanostructured lipid carrier (NLC)-based ophthalmic formulation, which could be developed as an eye drop to treat DED and any associated acute exacerbations. After rapid screening of a range of laboratory scale pre-formulations, the chosen formulation was prepared at pilot scale with a particle size of 19.51 ± 0.5 nm, an encapsulation efficiency of 99.6 ± 0.5%, a PDI of 0.08, and an extended stability of 6 months at 4 °C. This potential ophthalmic formulation was observed to have high tolerability and internalization capacity for human corneal epithelial cells, with similar behavior demonstrated on ex vivo porcine cornea studies, suggesting suitable distribution on the ocular surface. Further, ELISA was used to study the impact of the pilot scale formulation on a range of inflammatory biomarkers. The most successful dexamethasone-loaded NLC showed a 5-fold reduction of TNF-α production over dexamethasone solution alone, with comparable results for MMP-9 and IL-6. The ease of formulation, scalability, performance and biomarker assays suggest that this NLC formulation could be a viable option for the topical treatment of DED.
  • Drug-Loaded Hydrogels for Intraocular Lenses with Prophylactic Action against Pseudophakic Cystoid Macular Edema
    Toffoletto, N.; Salema-Oom, M.; Anguiano Igea, S.; Alvarez-Lorenzo, C.; Saramago, B.; Serro, A.P. Drug-Loaded Hydrogels for Intraocular Lenses with Prophylactic Action against Pseudophakic Cystoid Macular Edema. Pharmaceutics 2021, 13, 976.

    • Pseudophakic cystoid macular edema (PCME), caused by chronic inflammation, is the most common cause of visual impairment in the medium-term after cataract surgery. Therefore, the prophylactic topical administration of combined steroidal and non-steroidal anti-inflammatory drugs is commonly done. Drug-eluting intraocular lenses (IOLs) gained interest as an efficient way to overcome the compliance issues related to the use of ocular drops without the need for additional surgical steps. The incorporation of functional monomers and molecular imprinting were herein applied to design hydrogels suitable as IOLs and able to co-deliver steroidal (dexamethasone sodium phosphate) and non-steroidal (bromfenac sodium) drugs. The incorporation of N-(2-aminopropyl) methacrylamide (APMA) increased the drug uptake and improved the in vitro release kinetics. Imprinting with bromfenac resulted in a decreased drug release due to permanent drug bonding, while imprinting with dexamethasone increased the amount of dexamethasone released after dual-drug loading. The application of a mathematical model to predict the in vivo drug release behavior suggests the feasibility of achieving therapeutic drug concentrations of bromfenac and dexamethasone in the aqueous humor for about 2 and 8 weeks, respectively, which is compatible with the current topical prophylaxis after cataract surgery.
  • Niosomes-based gene delivery systems for effective transfection of human mesenchymal stem cells
    Natalia Carballo-Pedrares, Axel Kattar, Angel Concheiro, Carmen Alvarez-Lorenzo, Ana Rey-Rico, Niosomes-based gene delivery systems for effective transfection of human mesenchymal stem cells, Materials Science and Engineering: C, Volume 128, 2021, 112307, ISSN 0928-4931,

    • Gene transfer to mesenchymal stem cells (MSCs) has arisen as a powerful approach to increase the therapeutic potential of this effective cell population. Over recent years, niosomes have emerged as self-assembled carriers with promising performance for gene delivery. The aim of our work was to develop effective niosomes-based DNA delivery platforms for targeting MSCs. Niosomes based on 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA; 0, 7 or 15%) as cationic lipid, cholesterol as helper lipid, and polysorbate 60 as non-ionic surfactant, were prepared using a reverse phase evaporation technique. Niosomes dispersions (filtered or not) and their corresponding nioplexes with a lacZ plasmid were characterized in terms of size, charge, protection, and complexation abilities. DOTMA concentration had a large influence on the physicochemical properties of resulting nioplexes. Transfection efficiency and cytotoxic profiles were assessed in two immortalized cell lines of MSCs. Niosomes formulated with 15% DOTMA provided the highest values of β-galactosidase activity, being similar to those achieved with Lipofectamine®, but showed less cytotoxicity. Filtration of niosomes dispersions before adding to the cells resulted in a loss of their biological activities. Storage of niosomes formulations (for 30 days at room temperature) caused minor modification of their physicochemical properties but also attenuated the transfection capability of the nioplexes. Differently, addition of the lysosomotropic agent sucrose into the culture medium during transfection or to the formulation itself improved the transfection performance of non-filtered niosomes. Indeed, steam heat-sterilized niosomes prepared in sucrose medium demonstrated transfection capability.
  • Diabetic eye: associated diseases, drugs in clinic, and role of self-assembled carriers in topical treatment
    Axel Kattar, Angel Concheiro & Carmen Alvarez-Lorenzo (2021) Diabetic eye: associated diseases, drugs in clinic, and role of self-assembled carriers in topical treatment, Expert Opinion on Drug Delivery, DOI: 10.1080/17425247.2021.1953466

    • Introduction: Diabetes is a pandemic disease that causes relevant ocular pathologies. Diabetic retinopathy, macular edema, cataracts, glaucoma, or keratopathy strongly impact the quality of life of the patients. In addition to glycemic control, intense research is devoted to finding more efficient ocular drugs and improved delivery systems that can overcome eye barriers. Areas covered: The aim of this review is to revisit first the role of diabetes in the development of chronic eye diseases. Then, commercially available drugs and new candidates in clinical trials are tackled together with the pros and cons of their administration routes. Subsequent sections deal with self-assembled drug carriers suitable for eye instillation combining patient-friendly administration with high ocular bioavailability. Performance of topically administered polymeric micelles, liposomes, and niosomes for the management of diabetic eye diseases is analyzed in the light of ex vivo and in vivo results and outcomes of clinical trials. Expert opinion: Self-assembled carriers are being shown useful for efficient delivery of not only a variety of small drugs but also macromolecules (e.g. antibodies) and genes. Successful design of drug carriers may offer alternatives to intraocular injections and improve the treatment of both anterior and posterior segments diabetic eye diseases.
  • From Oxidative Stress to Inflammation in the Posterior Ocular Diseases: Diagnosis and Treatment
    Dammak, Azza, Fernando Huete-Toral, Carlos Carpena-Torres, Alba Martin-Gil, Cristina Pastrana, and Gonzalo Carracedo. 2021. “From Oxidative Stress to Inflammation in the Posterior Ocular Diseases: Diagnosis and Treatment” Pharmaceutics 13, no. 9: 1376.

    • Most irreversible blindness observed with glaucoma and retina-related ocular diseases, including age-related macular degeneration and diabetic retinopathy, have their origin in the posterior segment of the eye, making their physiopathology both complex and interconnected. In addition to the age factor, these diseases share the same mechanism disorder based essentially on oxidative stress. In this context, the imbalance between the production of reactive oxygen species (ROS) mainly by mitochondria and their elimination by protective mechanisms leads to chronic inflammation. Oxidative stress and inflammation share a close pathophysiological process, appearing simultaneously and suggesting a relationship between both mechanisms. The biochemical end point of these two biological alarming systems is the release of different biomarkers that can be used in the diagnosis. Furthermore, oxidative stress, initiating in the vulnerable tissue of the posterior segment, is closely related to mitochondrial dysfunction, apoptosis, autophagy dysfunction, and inflammation, which are involved in each disease progression. In this review, we have analyzed (1) the oxidative stress and inflammatory processes in the back of the eye, (2) the importance of biomarkers, detected in systemic or ocular fluids, for the diagnosis of eye diseases based on recent studies, and (3) the treatment of posterior ocular diseases, based on long-term clinical studies.
  • Overview of the clinical current needs and potential applications for long-acting and implantable delivery systems
    Eneko Larrañeta, Thakur Raghu Raj Singh, Ryan F. Donnelly, 1 – Overview of the clinical current needs and potential applications for long-acting and implantable delivery systems, Editor(s): Eneko Larrañeta, Thakur Raghu Raj Singh, Ryan F. Donnelly, In Woodhead Publishing Series in Biomaterials, Long-Acting Drug Delivery Systems, Woodhead Publishing, 2022, Pages 1-16, ISBN 9780128217498,

    • Over the last couple of decades, the popularity of long-acting drug delivery systems (LADDSs) has increased significantly. This type of drug delivery system presents several advantages over conventional routes such as oral route. LADDSs can be injected/implanted into the body of the patient for providing prolonged unattended drug release. This type of system is an ideal candidate for the treatment of chronic conditions that require constant drug uptake. Moreover, this type of device can be used for the local delivery of drugs. This chapter provides an overview of the current clinical needs and applications of LADDS. Moreover, the potential future applications of this type of technology are discussed.
  • Long-acting drug delivery systems for ocular therapies
    David Waite, Faris M Adrianto, Febri Annuyanti, Yin So, Wenrui Zhang, Sangdi Wang, Yu Wu, Yujing Wang, Thakur Raghu Raj Singh, 3 – Long-acting drug delivery systems for ocular therapies, Editor(s): Eneko Larrañeta, Thakur Raghu Raj Singh, Ryan F. Donnelly, In Woodhead Publishing Series in Biomaterials, Long-Acting Drug Delivery Systems, Woodhead Publishing, 2022, Pages 61-81, ISBN 9780128217498,

    • With an ever-increasing life expectancy in the modern day, chronic ocular diseases are becoming more common. At present, many of these have to be treated with repeated administrations of pharmacological agents, which bring issues ranging from a lack of compliance, due to difficulty in remembering to administer a dose, to more significant problems, such as endophthalmitis and retinal detachment, often associated with the multiple intravitreal injections required to treat some diseases of the posterior segment. In response to this, research into the development of long-acting ocular drug delivery systems has stepped up in recent years, with various types of sustained-release formulations being developed, which have positives and negatives, depending on the target site and the conditions being treated. This chapter aims to explain the increasing need for such systems and to highlight some of the key approaches being taken in the current research to produce them.
  • Safety, biodegradability, and biocompatibility considerations of long-acting drug delivery systems
    Deepakkumar Mishra, Katie Glover, Shilpa Gade, Rahul Sonawane, Thakur Raghu Raj Singh, 10 – Safety, biodegradability, and biocompatibility considerations of long-acting drug delivery systems, Editor(s): Eneko Larrañeta, Thakur Raghu Raj Singh, Ryan F. Donnelly, In Woodhead Publishing Series in Biomaterials, Long-Acting Drug Delivery Systems, Woodhead Publishing, 2022, Pages 289-317, ISBN 9780128217498,

    • Biodegradation and biocompatibility are crucial for developing long-acting implantable drug delivery systems. Because of the prolonged biological residence of these implants, understanding of in vivo degradation and biocompatibility helps establish the commercial success of these implants. International Organization for Standardization has laid down various guidelines for the development and optimization of in vitro degradation studies. This chapter discusses multiple ISO guidelines and current research to understand the influence of different study parameters on biodegradation study. The chapter also summarizes the immunological consideration in the design and evaluation of long-acting implants.
  • Long-Acting Drug Delivery Systems Pharmaceutical, Clinical, and Regulatory Aspects: A volume in Woodhead Publishing Series in Biomaterials
    Edited by: Eneko Larrañeta, Thakur Raghu Raj Singh, Ryan F. Donnelly

    • Long-Acting Drug Delivery Systems: Pharmaceutical, Clinical, and Regulatory Aspects offers a comprehensive overview of the technical, clinical, regulatory and industrial perspectives on these drug delivery systems. The book follows a sequential order, beginning with the current technical state-of-the-field and moving on to more clinical, industrial and regulatory topics. Opening chapters describe the current needs and potential applications of implantable and long-acting therapeutic approaches. The book goes on to describe established and novel long-acting systems, with a focus on the materials used to prepare these systems and their biocompatibility. Importantly, applied topics such as scale-up manufacturing, products under clinical trials and regulatory aspects are covered, offering the reader a holistic view of this rapidly growing field.
  • Posterior Segment Ophthalmic Drug Delivery: Role of Muco-Adhesion with a Special Focus on Chitosan
    Burhan, A.M.; Klahan, B.; Cummins, W.; Andrés-Guerrero, V.; Byrne, M.E.; O’Reilly, N.J.; Chauhan, A.; Fitzhenry, L.; Hughes, H. Posterior Segment Ophthalmic Drug Delivery: Role of Muco-Adhesion with a Special Focus on Chitosan. Pharmaceutics 2021, 13, 1685.

    • Posterior segment eye diseases (PSEDs) including age macular degeneration (AMD) and diabetic retinopathy (DR) are amongst the major causes of irreversible blindness worldwide. Due to the numerous barriers encountered, highly invasive intravitreal (IVT) injections represent the primary route to deliver drugs to the posterior eye tissues. Thus, the potential of a more patient friendly topical route has been widely investigated. Mucoadhesive formulations can decrease precorneal clearance while prolonging precorneal residence. Thus, they are expected to enhance the chances of adherence to corneal and conjunctival surfaces and as such, enable increased delivery to the posterior eye segment. Among the mucoadhesive polymers available, chitosan is the most widely explored due to its outstanding mucoadhesive characteristics. In this review, the major PSEDs, their treatments, barriers to topical delivery, and routes of topical drug absorption to the posterior eye are presented. To enable the successful design of mucoadhesive ophthalmic drug delivery systems (DDSs), an overview of mucoadhesion, its theory, characterization, and considerations for ocular mucoadhesion is given. Furthermore, chitosan-based DDs that have been explored to promote topical drug delivery to the posterior eye segment are reviewed. Finally, challenges of successful preclinical to clinical translation of these DDSs for posterior eye drug delivery are discussed.
  • Validation of a Rapid and Easy-to-Apply Method to Simultaneously Quantify Co-Loaded Dexamethasone and Melatonin PLGA Microspheres by HPLC-UV: Encapsulation Efficiency and In Vitro Release
    Brugnera, M.; Vicario-de-la-Torre, M.; Andrés-Guerrero, V.; Bravo-Osuna, I.; Molina-Martínez, I.T.; Herrero-Vanrell, R. Validation of a Rapid and Easy-to-Apply Method to Simultaneously Quantify Co-Loaded Dexamethasone and Melatonin PLGA Microspheres by HPLC-UV: Encapsulation Efficiency and In Vitro Release. Pharmaceutics 2022, 14, 288.

    • This paper discusses the development and validation of a rapid method for the reversed phase HPLC-UV quantification of biodegradable poly(D,L-lactic-co-glycolic) acid (PLGA) microspheres co-loaded with two neuroprotective agents (dexamethasone and melatonin) (DX-MEL-MSs) to be intravitreally administered as a promising glaucoma treatment. The study was performed to validate two procedures that quantify the content of the two active substances entrapped into the polymer matrix during an encapsulation efficiency assay and the amount of drugs liberated over time during the in vitro release assay. The reversed-phase method allowed for the simultaneous determination of dexamethasone and melatonin, which were respectively detected at 240.5 and 222.7 nm. Chromatographic separation was performed using an Ascentis® C18 HPLC Column (25 cm × 4.6 mm, 5 µm) with an isocratic mobile phase composed of methanol-water (70:30, v/v) with 1.0 mL min−1 flow rate. The two procedures were validated analytically in terms of system suitability testing, specificity, linearity, precision, accuracy, sensitivity, and robustness. Both the validated procedures were applied to characterize DX-MEL-MSs and were found appropriate to quantify the drug quantities encapsulated and estimate their release profile over 10 days. The validation study designed in this work can be helpful for planning any other protocols that refer to the quantification of PLGA based drug delivery systems.
  • Testing drug release from medicated contact lenses: The missing link to predict in vivo performance
    Ana F. Pereira-da-Mota, Chau-Minh Phan, Angel Concheiro, Lyndon Jones, Carmen Alvarez-Lorenzo, Testing drug release from medicated contact lenses: The missing link to predict in vivo performance, Journal of Controlled Release,Volume 343, 2022, Pages 672-702,ISSN 0168-3659, (

    • Contact lenses (CLs) offer a wide variety of advantages as ocular drug-releasing platforms, but the feasibility of medicated CL development is constrained by numerous scientific, technological, and regulatory challenges. One main difficulty is the setting of release rate specifications for each drug, since at present there are no standardized in vitro release models that can appropriately predict the performance of drug-eluting CLs once placed onto the eye. CL-adapted release tests may provide knowledge on how the drug release pattern should perform in vivo to trigger and maintain the therapeutic effects for both anterior and posterior ocular tissues. Moreover, in vitro release tests are valuable tools for quality assessment during production and to investigate the effect of a change in composition or process variables. This review aims to shed light on biorelevant ways of evaluating in vitro drug release from CLs and the feasibility of establishing in vitro-in vivo correlations (IVIVC) to predict in vivo performance. First, general guidelines and Pharmacopeia release tests for topical ophthalmic formulations as well as in vitro release tests implemented for drug-CLs in the last two decades are analyzed. Then, development of an appropriate method to investigate IVIVC is attempted from the few papers simultaneously reporting in vitro release profiles and either in vivo release or therapeutic response. Finally, key points to be considered for in vitro testing drug release from a medicated CL are suggested to pave the way to the clinical arena.
      Keywords: Drug-eluting contact lens; in vitro release tests; in vivo release; Release rate specifications; Therapeutic response; in vitro-in vivo correlations
  • Structure–Function Relationships in the Rodent Streptozotocin-Induced Model for Diabetic Retinopathy: A Systematic Review
    Lelyte, Inesa, et al. “Structure–Function Relationships in the Rodent Streptozotocin-Induced Model for Diabetic Retinopathy: A Systematic Review.” Journal of Ocular Pharmacology and Therapeutics, 22 Mar. 2022, 10.1089/jop.2021.0128. Accessed 12 Apr. 2022.

    • The streptozotocin (STZ)-induced rodent model is one of the most commonly employed models in preclinical drug discovery for diabetic retinopathy (DR). However, standardization and validation of experimental readouts are largely lacking. The aim of this systematic review was to identify and compare the most useful readouts of STZ-induced DR and provide recommendations for future study design based on our findings. We performed a systematic search using 2 major databases, PubMed and EMBASE. Only articles describing STZ-induced DR describing both functional and structural readouts were selected. We also assessed the risk of bias and analyzed qualitative data in the selected studies. We identified 21 studies that met our inclusion/exclusion criteria, using either rats or mice and study periods of 2 to 24 weeks. Glucose level thresholds used to define hyperglycemia were inconsistent between studies, however, most studies used either 250 or 300.6 mg/dL as a defining criterion for hyperglycemia. All included studies performed electroretinography (ERG) and reported a reduction in a-, b-, or c-wave and/or oscillatory potential amplitudes. Spectral-domain optical coherence tomography and fluorescein angiography, as well as immunohistochemical and histopathological analyses showed reductions in retinal thickness, vascular changes, and presence of inflammation. Risk of bias assessment showed that all studies had a high risk of bias due to lack of reporting or correctly following procedures. Our systematic review highlights that ERG represents the most consistent functional readout in the STZ model. However, due to the high risk of bias, caution must be used when interpreting these studies.
  • Nanosuspension-loaded dissolving bilayer microneedles for hydrophobic drug delivery to the posterior segment of the eye
    Yu Wu, Lalitkumar K. Vora, Deepakkumar Mishra, Muhammad Faris Adrianto, Shilpkala Gade, Alejandro J. Paredes, Ryan F. Donnelly, Thakur Raghu Raj Singh,
    Nanosuspension-loaded dissolving bilayer microneedles for hydrophobic drug delivery to the posterior segment of the eye, Biomaterials Advances, 2022, 212767, ISSN 2772-9508,

    • Intravitreal injections (IVT) are regarded as the gold standard for effective delivery of hydrophobic drugs to the back of the eye. However, as a highly invasive procedure, the injection itself may lead to poor patient compliance and severe complications. In this research work, a hybrid system of nanosuspensions (NS) and dissolving microneedles (MNs) was developed as an alternative to conventional hypodermic needles used in IVT for minimally invasive transscleral delivery of hydrophobic drugs. NS of a hydrophobic drug, triamcinolone acetonide (TA), were fabricated using a wet milling technique. TA NS optimised by central composite factorial design had a proven diameter of 246.65 ± 8.55 nm. After optimisation, TA NS were incorporated into MN arrays to form a bilayer structure by high-speed centrifugation. TA NS-loaded MNs were robust enough to pierce excised porcine sclera with insertion depth higher than 80% of the needle height and showed rapid dissolution (<3 min). In contrast, the plain TA-loaded MNs exhibited poor mechanical and insertion performances and took more than 8 min to be fully dissolved in the scleral tissue. Importantly, transscleral deposition studies showed that 56.46 ± 7.76 μg/mm2 of TA was deposited into the sclera after 5 min of NS-loaded MN application, which was 4.5-fold higher than plain drug-loaded MNs (12.56 ± 2.59 μg/mm2). An ex vivo distribution study revealed that MN arrays could promote the transscleral penetration of hydrophobic molecules with higher drug concentrations observed in the deep layer of the sclera. Moreover, the developed TA NS-loaded MN array was biocompatible with ocular tissues, as demonstrated using the hens egg-chorioallantoic membrane assay and cytotoxicity test. The results presented here demonstrate that the hybrid system of NS and dissolving MNs can provide a novel and promising technology to alleviate retinal diseases in a therapeutically effective and minimally invasive manner.
  • Melatonin-Eluting Contact Lenses Effect on Tear Volume: In Vitro and In Vivo Experiments
    Serramito, M.; Pereira-da-Mota, A.F.; Carpena-Torres, C.; Huete-Toral, F.; Alvarez-Lorenzo, C.; Carracedo, G. Melatonin-Eluting Contact Lenses Effect on Tear Volume: In Vitro and In Vivo Experiments. Pharmaceutics 2022, 14, 1019.

    • (1) Background: The purpose of this study was to synthesize melatonin-eluting contact lenses (CLs) and evaluate both the ocular kinetics of the released melatonin and its effect on tear volume and intraocular pressure. (2) Methods: In vitro, melatonin-eluting CLs were synthesized by using non-functionalized (HEMA) and functionalized (HEMA/APMA) monomers. In vivo, a short-term prospective and randomized study was performed on 15 rabbits divided into two groups: 12 rabbits wearing functionalized CLs and 3 rabbits without CLs as a control. The melatonin levels in tears, aqueous humor, vitreous body and retina, tear volume, and intraocular pressure were measured for 8 h. (3) Results: In vitro, both monomers did not show differences in terms of melatonin loading and release (p ≥ 0.05). In vivo, the melatonin concentration was elevated in tears and aqueous humor after 2 and 4 h of wearing CLs, respectively (p < 0.05). Additionally, the CLs increased tear volume for 2 h (p < 0.05). (4) Conclusions: The melatonin-eluting CLs released their content over the ocular surface for at least 2 h, which was associated with a secretagogue effect on tear volume. However, the increased amount of melatonin found in the aqueous humor had no effect on intraocular pressure.
      Keywords: melatonin; contact lenses; drug delivery; dry eye; glaucoma
  • Vitreous humor: composition, characteristics and implication on intravitreal drug delivery.
    Deepakkumar Mishra, Shilpkala Gade, Katie Glover, Ravi Sheshala & Thakur Raghu Raj Singh (2022) Vitreous humor: composition, characteristics and implication on intravitreal drug delivery., Current Eye Research, DOI: 10.1080/02713683.2022.2119254

    • Intravitreal administration of drug molecules is one of the most common routes for treating posterior segment eye diseases. However, the properties of vitreous humour changes with the time. A number of ocular complications such as liquefaction of the vitreous humour, solidification of the vitreous humour in the central vitreous cavity and detachment of the limiting membrane due to the shrinking of vitreous humour are some of the factors that can drastically affect the efficacy of therapeutics delivered via intravitreal route. Although significant research has been conducted for studying the properties of vitreous humour and its changes during the ageing process, there have been limited work to understand the effect of these changes on therapeutic efficacy of intravitreal drug delivery systems. In this review, we plan to discuss the biological composition and biomechanical properties of vitreous humour, methods to study the properties of vitreous humour and the changes in these properties and their relevance in ocular drug delivery field. We aim to provide a useful insight into these aspects which can aid the process of development of novel intravitreal drug delivery systems.

Below, find publications from our Associated Partners: 

  • S.A. DiPasquale, L.D. Wuchte, R.J. Mosley, R.M. Demarest, M.L. Voyles, M.E. Byrne. One Week Sustained In Vivo Therapeutic Release and Safety of Novel Extended-Wear Silicone Hydrogel Contact Lenses. Advanced Healthcare Materials, 2021.
    • Since the seminal work of Wichterle in 1965 describing the first soft contact lenses and their potential for ocular drug delivery, the field has yet to realize his vision. Maintaining all lens commercial properties combined with a mechanism for controlled drug release of therapeutically relevant concentrations for duration of wear is a major challenge. Here, successful in vivo week-long sustained release of a small molecular weight therapeutic in rabbits from extended-wear silicone hydrogel contact lenses meeting all commercial specifications by utilizing a novel macromolecular memory strategy is reported for the first time. Lens-treated eyes show a continuous, therapeutically relevant bromfenac tear concentration of 256.4 ± 23.1 µg mL−1 for 8 days. Bromday (bromfenac ophthalmic solution, 0.09%, Bausch+Lomb) topical drops exhibit a quick peak concentration of 269.3 ± 85.7 µg mL−1 and 100 min duration. Bioavailability (AUC0-8days) and mean residence time of lenses are 26 and 155 times higher than drops, respectively. Lenses are safe, well tolerated, and no corneal histological differences are observed. This work highlights the enormous potential of drug releasing lenses as a platform strategy, and offers a new dropless clinical strategy for post-cataract, uveitis, post-LASIK, and corneal abrasion treatment.
  • T.A. Finley, J. Sonsino, M.E. Byrne. Wearable Eye Technologies. Cataract & Refractive Surgery Today, 70-77, 2021.
    Featuring the article ‘OcuMedic Freedom Lenses: Drug-Releasing Bandage Contact Lenses for Drop-Free Postoperative Treatment’.
    [One of the cover stories –termed the Disruptors. Link:]
  • S.A. DiPasquale, B. Uricoli, M. DiCerbo, T.L. Brown, M.E. Byrne. Controlled Release of Multiple Therapeutics from Silicone Hydrogel Contact Lenses for Post-Cataract/Post-Refractive Surgery and Uveitis Treatment. Translational Vision Science and Technology, Accepted & In Press, October 2021.
  • L.D. Wuchte, S.A. DiPasquale, M.E. Byrne. In Vivo Drug Delivery via Contact Lenses: The Current State of the Field from Origins to Present. Journal of Drug Delivery Science and Technology, 63, 2021.
    • Over the past half century, contact lenses have been investigated for their potential as drug delivery devices for ocular therapeutics. Hundreds of studies have been published in the pursuit of the most effective and efficient release strategies and methods for contact lens drug delivery. This paper provides a thorough overview of the various contact lens drug delivery strategies, with a specific, comprehensive focus on in vivo studies that have been published since the field began in 1965. Significant accomplishments, current trends, as well as future strategies and directions are highlighted. In vivo study analysis provides a straightforward perspective and assessment of method success and commercialization potential in comparison to benchtop, in vitro studies. Analysis of the majority of published work indicates in vitro and in vivo studies do not correlate with a correlation coefficient of 0.25, with many in vitro studies grossly overestimating drug release duration and not showing appreciable drug release control. However, there has been an increase in activity in the last decade, and some methods have generated promising results exhibiting controlled release with commercialization potential. Clinical translation of drug releasing lenses is on the horizon and has high potential to impact a large number of patients providing efficacious treatment compared to current topical treatments.
  • L. Osorno, J.D.R. Medina, D.E. Maldonado, R.J. Mosley, M.E. Byrne. Extended Release of Doxorubicin-Loaded 3DNA Nanocarriers from In-Situ Forming, Self-assembled HydrogelsJournal of Ocular Pharmacology and Therapeutics, 36(6), 447-457, 2020.
    • Purpose: Cataracts are the leading cause of blindness worldwide, resulting in over 30 million surgeries each year. These cases are expected to double within the next 10 years. About 25% of all patients develop secondary cataracts or posterior capsule opacification (PCO) postsurgery. PCO is a vision impairment disorder that develops from myofibroblasts migration and contraction that deforms the capsule surrounding the lens. Currently, Nd:YAG laser therapy is used to treat PCO; however, laser is not available worldwide and adverse side effects may arise. Thus, there is a considerable unmet need for more efficacious and convenient preventive treatments for PCO. Our work focuses on engineering an innovative, prophylactic sustained release platform for DNA-based nanocarriers to further reduce the incidence of PCO.Methods: Novel, optically clear, self-assembled poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) triblock copolymer hydrogels were used for the sustained release of the DNA-based nanocarriers (3DNA®) loaded with cytotoxic doxorubicin (DOX) and targeted with a monoclonal antibody called G8 (3DNA:DOX:G8), which is specific to cells responsible for PCO.Results: The 29 (w/v)% polymer hydrogels with the 3DNA nanocarriers presented over 80% of light transmittance, soft mechanical properties (<350 Pa), and sustained release for 1 month.Conclusions: In this work, we show for the first time that the hydrophobic PLGA-PEG-PLGA hydrogels can be used as platforms for sustained delivery of nucleic acid-based nanocarriers. This work demonstrates that polymeric formulations can be used for the extended delivery of ocular therapeutics and other macromolecules to treat a variety of ocular conditions.
  • Taylor, M. J., Thompson, A. M., Alhajlah, S., Tuxworth, R. I., & Ahmed, Z. (2022). Inhibition of Chk2 promotes neuroprotection, axon regeneration, and functional recovery after CNS injury. In Science Advances (Vol. 8, Issue 37). American Association for the Advancement of Science (AAAS).
    • DNA double-strand breaks occur in many acute and long-term neurological conditions, including neurodegeneration, neurotrauma, and stroke. Nonrepaired breaks chronically activate the DNA damage response in neurons, leading to neural dysfunction and apoptosis. Here, we show that targeting of the central ATM-Chk2 pathway regulating the response to double-strand breaks slows neural decline in Drosophila models of chronic neurodegeneration. Inhibitors of ATM-Chk2, but not the parallel ATR-Chk1 pathway, also promote marked, functional recovery after acute central nervous system injury in rats, suggesting that inhibiting nonhomologous end-joining rather than homologous recombination is crucial for neuroprotection. We demonstrate that the Chk2 inhibitor, prexasertib, which has been evaluated in phase 2 clinical trials for cancer, has potent neuroprotective effects and represents a new treatment option to promote functional recovery after spinal cord or optic nerve injury.

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