Minimally invasive microneedles for ocular drug delivery

Introduction: Anterior and posterior segment eye diseases are highly challenging to treat, due to the barrier properties and relative inaccessibility of the ocular tissues. Topical eye drops and systemically delivered treatments result in low bioavailability. Alternatively, direct injection of medication into the ocular tissues is clinically employed to overcome the barrier properties, but injections cause significant tissue damage and are associated with a number of untoward side effects and poor patient compliance. Microneedles (MNs) has been recently introduced as a minimally invasive means for localizing drug formulation within the target ocular tissues with greater precision and accuracy than the hypodermic needles.

Areas covered: This review article seeks to provide an overview of a range of challenges that are often faced to achieve efficient ocular drug levels within targeted tissue(s) of the eye. It also describes the problems encountered using conventional hypodermic needle-based ocular injections for anterior and posterior segment drug delivery. It discusses research carried out in the field of MNs, to date.

Expert opinion: MNs can aid in localization of drug delivery systems within the selected ocular tissue. And, hold the potential to revolutionize the way drug formulations are administered to the eye. However, the current limitations and challenges of MNs application warrant further research in this field to enable its widespread clinical application.     

How are we improving the delivery to back of the eye? Advances and challenges of novel therapeutic approaches

Introduction: Drug delivery to the back of the eye requires strategic approaches that guarantee the long-term therapeutic effect with patient compliance. Current treatments for posterior eye diseases suffer from significant challenges including frequent intraocular injections of anti-VEGF agents and related adverse effects in addition to the high cost of the therapy.

Areas covered: Treatment challenges and promising drug delivery approaches for posterior segment eye diseases, such as age-related macular degeneration (AMD) are summarized. Advances in the development of several nanotechnology-based systems, including stimuli-responsive approaches to enhance drug bioavailability and overcome existing barriers for effective ocular delivery are discussed. Stem cell transplantation and encapsulated cell technology (ECT) approaches to treat posterior eye diseases are elaborated.

Expert opinion: There are several drug delivery systems demonstrating promising results. However, a better understanding of ocular barriers, disease pathophysiology, and drug clearance mechanisms is required for better therapeutic outcomes. The stem cell transplantation strategy and ECT approach provide positive results in AMD therapy, but there are a number of challenges that must be overcome for long-term efficiency. Ultimately, there are numerous multidimensional challenges to cure vision problems and a collaborative approach among scientists is required.     

Recent advance of nanoparticle-based topical drug delivery to the posterior segment of the eye

Introduction: Considering that the number of patients afflicted by posterior eye diseases is increasing, effective drug delivery is currently in high clinical demand. Topical administration has been identified as the preferred option, while sufferingfrom multiple barriers. The development of nanoparticle-based drug delivery system provides an option, which would enhance the drug permeability across the barriers and achieve the desired drug level in the targeted tissue.

Areas covered: This review highlights the barrier to the posterior segment of the eye via topical administration. The up-to-date development of lipid nanoparticles, liposomes, emulsions, spanlastics, micelles, polymeric nanoparticles, layered double hydroxides (LDH), dendrimers, cyclodextrins(CDs), and prodrugs are summarized. Moreover, nanocarriers currently in clinical trials for posterior segment diseases have been discussed.

Expert opinion: Topical nanoparticle-based drug delivery systems have demonstrated significant progress. An ideal formulation should prolong retention time on the surface, enhance drug permeability through the ocular tissues, and efficiently deliver drugs to the targeted site. To design the rational targeting nanoparticle-based drug delivery system, a better understanding of the distribution of transporters and receptors on the eye is required. Ultimately, there is an urgent need to develop targeting hybrid drug delivery systems with the combination of the advantages of several nanocarriers.     

Extended ocular drug delivery systems for the anterior and posterior segments: biomaterial options and applications

Introduction: The development of new therapies for treating various eye conditions has led to a demand for extended release delivery systems, which would lessen the need for frequent application while still achieving therapeutic drug levels in the target tissues.

Areas covered: Following an overview of the different ocular drug delivery modalities, this article surveys the biomaterials used to develop sustained release drug delivery systems. Microspheres, nanospheres, liposomes, hydrogels, and composite systems are discussed in terms of their primary materials. The advantages and disadvantages of each drug delivery system are discussed for various applications. Recommendations for modifications and strategies for improvements to these basic systems are also discussed.

Expert opinion: An ideal sustained release drug delivery system should be able to encapsulate and deliver the necessary drug to the target tissues at a therapeutic level without any detriment to the drug. Drug encapsulation should be as high as possible to minimize loss and unless it is specifically desired, the initial burst of drug release should be kept to a minimum. By modifying various biomaterials, it is possible to achieve sustained drug delivery to both the anterior and posterior segments of the eye.     

Strategies for modifying drug residence time and ocular bioavailability to decrease treatment frequency for back of the eye diseases

Introduction: Treating posterior eye diseases has become a major area of focus for pharmaceutical and biotechnology companies. Current standard of care for treating posterior eye diseases relies on administration via intravitreal injection. Although effective, this is not without complications and there is great incentive to develop longer-acting therapeutics and/or sustained release delivery systems. Here, we present an overview of emerging technologies for delivery of biologics to the back of the eye.

Areas covered: Posterior eye diseases, intravitreal injection, age-related macular degeneration, anti-VEGF, ocular pharmacokinetics, novel technologies to extend half-life, in vivo models, translation to the clinic, and hurdles to effective patient care.

Expert opinion: Posterior eye diseases are a worldwide public health issue. Although anti-VEGF molecules represent a major advance for treating diseases involving choroidal neovascularization, frequent injection can be burdensome for patients and clinicians. There is a need for effective and patient-friendly treatments for posterior eye diseases. Many technologies that enable long-acting delivery to the back of the eye are being evaluated. However, successful development of novel therapies and delivery technologies is hampered by a multitude of factors, including patient education, translatability of in vitro/in vivo preclinical data to the clinic, and regulatory challenges associated with novel technologies.     

Recent advances in oral delivery of biologics: nanomedicine and physical modes of delivery

Introduction: Research into oral delivery of biologics has a long and rich history but has not produced technologies used in the clinic. The area has evolved in terms of strategies to promote oral biologics delivery from early chemical absorption enhancers to nanomedicine to devices. Continued activity in this area is justifiable considering the remarkable proliferation of biologics.

Areas covered: The article discusses some physiological barriers to oral delivery of biologics, with a special focus on less characterized barriers such as the basement membrane. Recent progress in oral delivery of biologics via nanomedicine is subsequently covered. Finally, the emerging field of device-mediated gastrointestinal delivery of biotherapeutics is discussed.

Expert opinion: Oral delivery of biologics is considered a ‘panacea’ in drug delivery. Almost century-old approaches of utilizing chemical absorption enhancers have not produced clinically translated technologies. Nanomedicine for oral biologics delivery has demonstrated potential, but the field is relatively new, and technologies have not progressed to the clinic. Device-mediated oral biologics delivery (e.g. ultrasound or microneedles) is in its infancy. However, this space is likely to intensify owing to advances in electronics and materials, as well as the challenges and history related to clinical translation of alternative approaches.     

Advances in the use of prodrugs for drug delivery to the eye

Introduction: Ocular drug delivery is presented with many challenges, taking into account the distinctive structure of the eye. The prodrug approach has been, and is being, employed to overcome such barriers for some drug molecules, utilizing a chemical modification approach rather than a formulation-based approach. A prodrug strategy involves modification of the active moiety into various derivatives in a fashion that imparts some advantage, such as membrane permeability, site specificity, transporter targeting and improved aqueous solubility, over the parent compound.

Areas covered: The following review is a comprehensive summary of various novel methodologies and strategies reported over the past few years in the area of ocular drug delivery. Some of the strategies discussed involve polymer and lipid conjugation with the drug moiety to impart hydrophilicity or lipophilicity, or to target nutrient transporters by conjugation with transporter-specific moieties and retrometabolic drug design.

Expert opinion: The application of prodrug strategies provides an option for enhancing drug penetration into the ocular tissues, and overall ocular bioavailability, with minimum disruption of the ocular diffusion barriers. Although success of the prodrug strategy is contingent on various factors, such as the chemical structure of the parent molecule, aqueous solubility and solution stability, capacity of targeted transporters and bioreversion characteristics, this approach has been successfully utilized, commercially and therapeutically, in several cases.     

Solid lipid nanocarriers in drug delivery: characterization and design

Introduction: Solid lipid nanoparticles are promising drug carriers for systemic circulations as well as local applications. One of the major challenges for drug delivery is designing nanocarriers for efficient delivery of active substances to the target site and facilitating drug absorption.

Areas covered: In this article, the effects of excipients and particle preparation methods on the properties of solid lipid nanocarriers (SLNCs) and their impact on drug absorption and efficacies related to different administration routes are reviewed and discussed.

Expert opinion: SLNCs have special characteristics, making them attractive as drug delivery systems, for parenteral and oral delivery for systemic effects, or ocular, pulmonary and topical delivery to enhance local treatment efficacy and reducing systemic side effects. Both excipients and fabrication methods are crucial for the function and size of nanoparticles and should be considered simultaneously in designing particles to obtain the optimal drug absorption and efficacy, especially for local treatments. Despite the demonstrated advantages by the preclinical studies, further studies on improved understanding of the interactions of SLNCs with biological tissues of the target site is necessary for efficient designing functional nanoparticles for clinical applications.

Abbreviations: DG: diglycerides; FFA: free fatty acids; GMS: glyceryl monostearate; MG: monoglycerides; NLC: nanostructured lipid carriers; PL: phospholipids; SLM: solid lipid microparticles; SLN: solid lipid nanoparticles; SLNC: solid lipid nanocarriers; TG: triglycerides.     

The development of biological therapies for neurological diseases: moving on from previous failures

Introduction: Although years of research have expanded the use of biologics for several clinical conditions, such development has not yet occurred in the treatment of neurological diseases. With the advancement of biologic technologies, there is promise for these therapeutics as novel therapeutic approaches for neurological diseases.

Areas covered: In this article, the authors review the therapeutic potential of different types of biologics for the treatment of neurological diseases. Preclinical and clinical studies that investigate the efficacy and safety of biologics in the treatment of neurological diseases, namely Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, and stroke, were reviewed. Moreover, the authors describe the key challenges in the development of therapeutically safe and effective biologics for the treatment of neurological diseases.

Expert opinion: Several biologics have shown promise in the treatment of neurological diseases. However, the complexity of the CNS, as well as a limited understanding of disease progression, and restricted access of biologics to the CNS has limited successful development. Therefore, more research needs to be conducted to overcome these hurdles before developing effective and safe biologics for neurological diseases. The emergence of new technologies for the design, production and delivery of biologics will accelerate translating biologics to the clinic.     

Treatment patterns of rheumatoid arthritis in Japanese hospitals and predictors of the initiation of biologic agents

Objective: To describe the usage of different biologic agents for rheumatoid arthritis (RA) in Japan over time and to identify factors that affects the decision to initiate treatment with biologic agents. Determinants of a switch to another biologic agent for patients who are already on biologic treatment were also analyzed.

Research design and methods: We utilized a hospital claims database containing 36,504 Japanese patients with a confirmed RA diagnosis. To analyze the determinants of treatment choices, we applied logistic regression analysis taking into account socio-demographic and medical factors.

Results: Analyses determined that 11.8% of diagnoses and 25.4% of treated patients in Japan receive a biologic agent. Significant factors associated with biologic treatment initiation include younger age, female sex, and a higher comorbidity index. The route of administration plays a major role when it comes to a switch between different biologic agents.

Conclusions: The lower likelihood of elderly patients to be initiated on biologic treatment might be explained by the risk aversion of Japanese physicians’ and patients who are afraid of the potential side effects of biologics. This finding is also consistent with the notion of an age bias that impedes elderly patients from optimal access to biologic treatment. Because claims data does not contain clinical parameters such as disease activity the results should be validated in a clinical context.     

Basic principles and current status of transcorneal and transscleral iontophoresis

Introduction: Iontophoresis is an active non-invasive drug delivery technique that can increase the transport of charged and neutral molecules into and across biological membranes. Most research to-date has focused on (per)cutaneous iontophoretic drug delivery. However, recent studies illustrate its potential for drug delivery to the eye: corneal iontophoresis may enable targeted topical therapy of intracorneal diseases, whereas transscleral iontophoresis may enable non-invasive intraocular drug delivery.

Areas covered: We describe iontophoretic principles in the context of ocular delivery before providing a summary of recent preclinical studies involving transcorneal and transscleral iontophoresis in vitro and in vivo. Subsequently, an overview of clinical applications with special focus on the transcorneal iontophoresis of riboflavin for corneal cross-linking and transscleral iontophoresis of corticosteroids for the treatment of posterior segment diseases is provided.

Expert opinion: The feasibility of using iontophoresis for ocular drug delivery has been demonstrated. Drug formulation development and the ability to design iontophoretic applicators will now determine its success in the clinic. The specificities of the ocular globe must be taken into account; in particular, its unique morphology, and the smaller surface area available for drug diffusion and the fact that it is more susceptible to irritation and less robust than the skin.     

Delivery of drugs,growth factors,genes and stem cells via intrapericardial,epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease

Introduction: Local myocardial delivery (LMD) of therapeutic agents is a promising strategy that aims to treat various myocardial pathologies. It is designed to deliver agents directly to the myocardium and minimize their extracardiac concentrations and side effects. LMD aims to enhance outcomes of existing therapies by broadening their therapeutic window and to utilize new agents that could not be otherwise be implemented systemically.

Areas covered: This article provides a historical overview of six decades LMD evolution in terms of the approaches, including intrapericardial, epicardial, and intramyocardial delivery, and the wide array of classes of agents used to treat myocardial pathologies. We examines delivery of pharmaceutical compounds, targeted gene transfection and cell implantation techniques to produce therapeutic effects locally. We outline therapeutic indications, successes and failures as well as technical approaches for LMD.

Expert opinion: While LMD is more complicated than conventional oral or intravenous administration, given recent advances in interventional cardiology, it is safe and may provide better therapeutic outcomes. LMD is complex as many factors impact pharmacokinetics and biologic result. The choice between routes of LMD is largely driven not only by the myocardial pathology but also by the nature and physicochemical properties of the therapeutic agents.     

Therapeutic inhibitors for the treatment of dry eye syndrome

Introduction: Dry eye disease (DED), defined as a multifactorial disease of tears and ocular surface, results in symptoms of discomfort, ocular irritation, visual disturbance and tear film instability. This syndrome is accompanied of ocular surface inflammation and it is produced by a deficient activity of the lacrimal functional unit. In addition, it is associated with systemic autoimmune diseases such as Sjögren´s Syndrome, rheumatoid arthritis, systemic lupus erythematosus and some drug administration. The treatment of dry eye disease is based on the typical signs and symptoms of dry eye, which are associated with hyperosmolarity, ocular surface inflammation, discomfort, visual disturbance, and tear film instability.

Areas covered: This review is focused on synthetic drugs currently used in clinical practice, from phase III development onwards to treat the ocular surface signs and symptoms of dry eye disease.

Expert opinion: The multifactorial disease and the lack of correlation between signs and symptoms imply that not all the pharmacological approaches will be successful for dry eye. The correct design of the clinical trials, with appropriate endpoints, and the type of dry eye under study are complicated but mandatory. The anti-inflammatory and secretagogues drugs are both the main compounds to currently treat the dry eye disease.     

Ultrasound-mediated ocular delivery of therapeutic agents: a review

Introduction: Due to numerous anatomical and physiological barriers, ocular drug delivery remains a major limitation in the treatment of diseases such as glaucoma, macular degeneration or inflammatory diseases. To date, only invasive approaches provide clinically effective results. Ultrasound can be defined as the propagation of a high-frequency sound wave exposing the propagation media to mechanical and thermal effects. Ultrasound has been proposed as a non-invasive physical agent for increasing therapeutic agent delivery in various fields of medicine.

Areas covered: An update on recent advances in transscleral and transcorneal ultrasound-mediated drug delivery is presented. Efficient drug delivery is achieved in vitro, ex vivo and in vivo for various types of materials. Numerous studies indicate that efficacy is related to cavitation. Although slight reversible effects can be observed on the corneal epithelium, efficient drug delivery can be performed without causing damage to the cornea.

Expert opinion: Recent developments prove the potential of ultrasound-mediated ocular drug delivery. Cavitation appears to be a preponderant mechanism, opening a way to treatment monitoring by cavitation measurement. Even if no clinical studies have yet been performed, the promising results summarized here are promoting developments toward clinical applications, particularly in assessing the safety of the technique.     

Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy

Introduction: Chemotherapeutic drugs are used in combination to target multiple mechanisms involved in cancer cell survival and proliferation. Carriers are developed to deliver drug combinations to common target tissues in optimal ratios and desirable sequences. Nanoparticles (NP) have been a popular choice for this purpose due to their ability to increase the circulation half-life and tumor accumulation of a drug.

Areas covered: We review organic NP carriers based on polymers, proteins, peptides, and lipids for simultaneous delivery of multiple anticancer drugs, drug/sensitizer combinations, drug/photodynamic therapy or drug/photothermal therapy combinations, and drug/gene therapeutics with examples in the past three years. Sequential delivery of drug combinations, based on either sequential administration or built-in release control, is introduced with an emphasis on the mechanistic understanding of such control.

Expert opinion: Recent studies demonstrate how a drug carrier can contribute to co-localizing drug combinations in optimal ratios and dosing sequences to maximize the synergistic effects. We identify several areas for improvement in future research, including the choice of drug combinations, circulation stability of carriers, spatiotemporal control of drug release, and the evaluation and clinical translation of combination delivery.     

Ocular ketoconazole-loaded proniosomal gels: formulation,ex vivo corneal permeation and in vivo studies

Context: Vesicular drug carriers for ocular delivery have gained a real potential. Proniosomal gels as ocular drug carriers have been proven to be an effective way to improve bioavailability and patient compliance.

Objective: Formulation and in vitro/ex vivo/in vivo characterization of ketoconazole (KET)-loaded proniosomal gels for the treatment of ocular keratitis.

Materials and methods: The effect of formulation variables; HLB value, type and concentration of non-ionic surfactants (Tweens, Spans, Brijs and Pluronics) with or without lecithin on the entrapment efficiency (EE%), vesicle size and in vitro KET release was evaluated. An ex vivo corneal permeation study to determine the level of KET in the external eye tissue of albino rabbits and an in vivo assessment of the level of KET in the aqueous humors were performed.

Results and discussion: In vivo evaluation showed an increase in bioavailability up to 20-folds from the optimum KET proniosomal gel formula in the aqueous humor compared to drug suspension (KET-SP). The selected formulae were composed of spans being hydrophobic suggesting the potential use of a more hydrophobic surfactant as Span during the formulation of formulae. Factors that stabilize the vesicle membrane and increase the entrapment efficiency of KET (namely low HLB, long alkyl chain, high phase transition temperature) slowed down the release profile.

Conclusions: Proniosomal gels as drug delivery carriers were proven to be a promising approach to increase corneal contact and permeation as well as retention time in the eye resulting in a sustained action and enhanced bioavailability.     

Brimonidine and brinzolamide for treating glaucoma and ocular hypertension; a safety evaluation

Introduction: Brimonidine tartrate and brinzolamide eye drops are often used as third and fourth line treatment options to reduce intraocular pressure (IOP) in the management of glaucoma and ocular hypertension. Better tolerated, more effective topical agents requiring once daily instillation including prostaglandin analogues and beta-blockers usually are preferred as initial therapy, unless there are contraindications. Brimonidine and brinzolamide are often required owing to progressive glaucoma or intolerances to or ineffectiveness of front-line agents.

Areas covered: We review the safety of formulations containing brimonidine tartrate and/or brinzolamide. Safety considerations for these agents in higher risk populations are highlighted.

Expert opinion: Each class of ocular hypotensive eye drop has a unique set of possible side effects. Brimonidine might have neuro-protective capabilities and offer reasonable IOP control, but its use is limited by a relatively high rate of ocular allergy, hyperemia and discomfort. Brinzolamide is generally well tolerated, but often lacks efficacy. The introduction of brimonidine/brinzolamide fixed combination suspension improves adherence (by simplifying the medical regimen) and reduces preservative load on the ocular surface. New drug delivery systems incorporating brimonidine and brinzolamide are in development and promise to improve the safety profiles of both drugs.     

Intranasal delivery of stem cell-based therapies for the treatment of brain malignancies

Introduction: Glioblastoma (GBM) is the most aggressive malignant brain cancer in adults, and its poor prognosis and resistance to the existing standard of care require the development of innovative therapeutic modalities. The local delivery of stem cells as therapeutic carriers against glioma has produced encouraging results, but encounters obstacles with regards to the repeatability and invasiveness of administration. Intranasal delivery of therapeutic stem cells could overcome these obstacles, among others, as a noninvasive and easily repeatable mode of administration.

Areas covered: This review describes nasal anatomy, routes of stem cell migration, and factors affecting stem cell delivery to hard-to-reach tumors. Furthermore, this review discusses the molecular mechanisms underlying stem cell migration following delivery, as well as possible stem cell effector functions to be considered in combination with intranasal delivery.

Expert opinion: Further research is necessary to elucidate the dynamics of stem cell effector functions in the context of intranasal delivery and optimize their therapeutic potency. Nonetheless, the technique represents a promising tool against brain cancer and has the potential to be expanded for use against other brain pathologies.     

Lipid nanoparticles for intranasal administration: application to nose-to-brain delivery

Introduction: The blood brain barrier is a functional barrier allowing the entry into the brain of only essential nutrients, excluding other molecules. Its structure, although essential to keep the harmful entities out, is also a major roadblock for pharmacological treatment of brain diseases. Several alternative invasive drug delivery approaches, such as transcranial drug delivery and disruption of blood brain barrier have been explored, with limited success and several challenges. Intranasal delivery is a non-invasive methodology, which bypasses the systemic circulation, and, through the intra- and extra- neuronal pathways, provides direct brain drug delivery. Colloidal drug delivery systems, particularly lipidic nanoparticles offer several unique advantages for this goal .

Areas covered: This review focuses on key brain diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis, and provide a detailed overview of the current lipid nanoparticle based treatment options explored thus far. The review also delves into basic preparation, challenges and evaluation methods of lipid drug delivery systems.

Expert opinion: Brain diseases present complex pathophysiology, in addition to the practically inaccessible brain tissues, hence according to the authors, a two-pronged approach utilizing new target discovery coupled with new drug delivery systems such as lipid carriers must be adopted.