Application of lipid nanoparticles to ocular drug delivery

ABSTRACT

Introduction: Although eye drops are widely used as drug delivery systems for the anterior segment of the eye, they are also associated with poor drug bioavailability due to transient contact time and rapid washout by tearing. Moreover, effective drug delivery to the posterior segment of the eye is challenging, and alternative routes of administration (periocular and intravitreal) are generally needed, the blood–retinal barrier being the major obstacle to systemic drug delivery.

Areas covered: Nanotechnology, and especially lipid nanoparticles, can improve the therapeutic efficiency, compliance and safety of ocular drugs, administered via different routes, to both the anterior and posterior segment of the eye. This review highlights the main ocular barriers to drug delivery, as well as the most common eye diseases suitable for pharmacological treatment in which lipid nanoparticles have proved efficacious as alternative delivery systems.

Expert opinion: Lipid-based nanocarriers are among the most biocompatible and versatile means for ocular delivery. Mucoadhesion with consequent increase in pre-corneal retention time, and enhanced permeation due to cellular uptake by corneal epithelial cells, are the essential goals for topical lipid nanoparticle delivery. Gene delivery to the retina has shown very promising results after intravitreal administration of lipid nanoparticles as non-viral vectors.     

A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases

Intravitreal implantable device technology utilizes engineered materials or devices that could revolutionize the treatment of posterior segment eye diseases by affording localized drug delivery, responding to and interacting with target sites to induce physiological responses while minimizing side‐effects. Conventional ophthalmic drug delivery systems such as topical eye‐drops, systemic drug administration or direct intravitreal injections do not provide adequate therapeutic drug concentrations that are essential for efficient recovery in posterior segment eye disease, due to limitations posed by the restrictive blood‐ocular barriers. This review focuses on various aspects of intravitreal drug delivery such as the impediment of the blood‐ocular barriers, the potential sites or intraocular drug delivery device implantation, the various approaches employed for ophthalmic drug delivery and includes a concise critical incursion into specialized intravitreal implantable technologies for the treatment of anterior and posterior segment eye disease. In addition, pertinent future challenges and opportunities in the development of intravitreal implantable devices is discussed and explores their application in clinical ophthalmic science to develop innovative therapeutic modalities for the treatment of various posterior segment eye diseases. The inherent structural and functional properties, the potential for providing rate‐modulated drug delivery to the posterior segment of the eye and specific development issues relating to various intravitreal implantable drug delivery devices are also expressed in this review. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2219–2239, 2010     

Dexamethasone distribution characteristic following controllable continuous sub-tenon drug delivery in rabbit

Drug delivery systems are required to be safe, minimally invasive and effectively delivery drug to the target tissues. But delivery drugs to the eye has not yet satisfied this need. Here, we focused on examining the distribution of dexamethasone (DEX) in ocular and plasmic samples following controllable continuous sub-Tenon drug delivery (CCSDD) of dexamethasone disodium phosphate (DEXP) in rabbit, and to compare that with two traditional routes: subconjunctival injection and intravenous injection. The DEX concentration was analyzed by Shimadzu LC–MS 2010 system. In CCSDD group, during observed 24?h, the mean DEX level in collected samples from highest to lowest following in order: sclera, cornea, retina/choroid, iris, plasma, aqueous humor, lens and vitreous body. In ocular solid tissue, the DEX level in posterior segment is higher than in anatomic corresponding anterior segment, but it is opposite in ocular fluid tissue. High levels of DEX were maintained at 12?h in the ocular tissue immediately after the administration. Even at 24?h, the mean DEX concentration was 31.72?ng/ml and 22.40?ng/ml in aqueous and vitreous, respectively. In CCSDD group, the ocular DEX exposure (AUC_0-24) is much higher and plasma exposure is much less than IV group, and it is also similar in SC group except iris. The amount of DEX levels are markedly increased in ocular tissues but it yield lower plasma levels indicating reduction of systemic absorption by CCSDD. Thus, CCSDD is an effective method of delivering DEX into anterior and posterior segment of the eye.     

Hydrogels in ophthalmic applications

More and more people worldwide are affected by severe eye diseases eventually leading to visual impairment or blindness. In most cases, the treatment involves the application of ophthalmic dosage forms such as eye drops, suspensions or ointments. Unfortunately, some of the therapeutic approaches have major shortcomings, especially in the treatment of the posterior segment of the eye, where many vision-threatening diseases originate. Therefore, research focuses on the development of new materials (e.g., for vitreous substitution) and more advanced drug delivery systems. Hydrogels are an extremely versatile class of materials with many potential applications in ophthalmology. They found widespread application as soft contact lenses, foldable intraocular lenses, in situ gelling formulations for ophthalmic drug delivery and ocular adhesives for wound repair; their use as vitreous substitutes and intravitreal drug delivery systems is currently under investigation. In this article, we review the different applications of hydrogels in ophthalmology with special emphasis placed on the used polymers and their suitability as ocular drug delivery systems.     

Potential of liposomes for the intravitreal injection of therapeutic molecules

Intravitreal administration has been widely used since 20 years and has been shown to improve the treatment of diseases of the posterior segment of the eye with infectious origin or in edematous maculopathies. This route of administration allows to achieve high concentration of drug in the vitreous and avoids the problems resulting from systemic administration. However, two basic problems limit the use of intravitreal therapy. Many drugs are rapidly cleared from the vitreous humor; therefore, to reach and to maintain effective therapy repeated injections are necessary. Repeated intravitreal injections increase the risk of endophthalmitis, damage to lens, retinal detachment. Moreover, some drugs provoke a local toxicity at their effective dose inducing side-effects and possible retinal lesions. In this context, the development and the use of new drug delivery systems for intravitreal administration are necessary to treat chronic ocular diseases. Among them, particulate systems such as liposomes have been widely studied. Liposomes are easily injectable and permit to reduce the toxicity and to increase the residence time of several drugs in the eye. They are also able to protect in vivo poorly-stable molecules from degradation such as peptides and nucleic acids. Some promising results have been obtained for the treatment of retinitis induced by cytomegalovirus in human and more recently for the treatment of uveitis in animal. Finally, the fate of liposomes in ocular tissues and fluids after their injection into the vitreous and their elimination routes begin to be more known.     

New Techniques for Drug Delivery to the Posterior Eye Segment

Ocular drug delivery has become an increasingly important field of research especially when treating posterior segment diseases of the eye, such as age-related macular degeneration, diabetic retinopathy, posterior uveitis and retinitis. These diseases are the leading causes of vision loss in developed countries which require repeated long-term administration of therapeutic agents. New drugs for the medication of the posterior ocular segment have emerged, but most drugs are delivered by repeated intravitreal injections associated with ocular complications. Advances in ocular drug delivery system research are expected to provide new tools for the treatment of the posterior segment diseases, providing improved drug penetration, prolonged action, higher efficacy, improved safety and less invasive administration, resulting in higher patient compliance. This review provides an insight into the recent progress and trends in ocular drug delivery systems for treating posterior eye segment diseases, with an emphasis on transscleral iontophoresis.     

Intraocular delivery of oligonucleotides

Anti-mRNA and particularly antisense oligonucleotides are molecules able to inhibit gene expression after intracellular penetration being potentially very interesting for the treatment of ocular diseases where growth factors are involved such as ocular scarring diseases or for the inhibition of viral multiplication. In most cases, the site of action of oligonucleotides has shown to be the posterior segment of the eye and these molecules are injected mainly by the intravitreal route. However, oligonucleotides are poorly stable in biological fluids, have a low intracellular penetration and are quickly eliminated form the vitreous. These issues request repeated administration of oligonucleotides which are able to induce severe damages to the retina. This is the reason why drug delivery systems were developed to improve the stability and intracellular penetration of oligonucleotides and, by sustained release, to increase their long term activity in the treatment of ocular diseases.     

Pharmacologic and clinical profile of dexamethasone intravitreal implant

The challenge in the treatment of chronic retinal diseases is to deliver effective therapy to the target tissues in the back of the eye while limiting drug exposure in nontarget tissues. Intravitreal placement provides the most targeted drug delivery, but repeated penetration of the globe to deliver intravitreal therapy can pose safety risks. A more effective strategy for the treatment of chronic retinal diseases would be to combine intravitreal placement with sustained drug delivery. The dexamethasone intravitreal (DEX) implant is a biodegradable sustained-release intravitreal drug delivery system that is approved for the treatment of macular edema following branch or central retinal vein occlusion and for noninfectious uveitis affecting the posterior segment of the eye. A single DEX implant has been shown to provide clinical benefits for up to 6 months in eyes with retinal vein occlusion or intermediate or posterior uveitis.     

Controllable continuous sub-tenon drug delivery of dexamethasone disodium phosphate to ocular posterior segment in rabbit

Corticosteroids have been used for treatment of posterior segment eye diseases, but the delivery of drug to the posterior segments is still a problem to resolve. In our study, we explore the feasibility of Sub-tenon’s Controllable Continuous Drug Delivery to ocular posterior segment. Controllable continuous sub-tenon drug delivery (CCSDD) system, intravenous injections (IV) and sub-conjunctival injections (SC) were used to deliver dexamethasone disodium phosphate (DEXP) in rabbits, the dexamethasone concentration was measured in the ocular posterior segment tissue by Shimadzu LC-MS 2010 system at different time points in 24?h after first dose injection. Levels of dexamethasone were significantly higher at 12, 24?h in CCSDD than two other approaches, and at 3, 6?h in CCSDD than IV in vitreous body (p?p?p?0–24 in CCSDD group is higher than two other groups in all ocular posterior segment tissue. Our results demonstrated that dexamethasone concentration could be sustained moderately higher in the posterior segment by CCSDD than SC and IV, indicating that CCSDD might be a therapeutic alternative to treat a variety of intractable posterior segment diseases.     

Recent Perspectives in Ocular Drug Delivery

Anatomy and physiology of the eye makes it a highly protected organ. Designing an effective therapy for ocular diseases, especially for the posterior segment, has been considered as a formidable task. Limitations of topical and intravitreal route of administration have challenged scientists to find alternative mode of administration like periocular routes. Transporter targeted drug delivery has generated a great deal of interest in the field because of its potential to overcome many barriers associated with current therapy. Application of nanotechnology has been very promising in the treatment of a gamut of diseases. In this review, we have briefly discussed several ocular drug delivery systems such as microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers, implants, and hydrogels. Potential for ocular gene therapy has also been described in this article. In near future, a great deal of attention will be paid to develop non-invasive sustained drug release for both anterior and posterior segment eye disorders. A better understanding of nature of ocular diseases, barriers and factors affecting in vivo performance, would greatly drive the development of new delivery systems. Current momentum in the invention of new drug delivery systems hold a promise towards much improved therapies for the treatment of vision threatening disorders. All the authors contributed equally to this work.     

Pharmacokinetic model for in vivo/in vitro correlation of intravitreal drug delivery.

A pharmacokinetic model of intravitreal drug delivery has been developed for describing the elimination and distribution of ocular drugs in the posterior segments of the eye. The model, based on Fick's second law of diffusion, assumes the cylindrical vitreous body with three major pathways for elimination: the posterior aqueous chamber, the retina/choroids/sclera (RCS) membrane and the lens posterior capsule. The model parameters such as the diffusion coefficient and the partition coefficient of the drug in the vitreous body and its surrounding tissues, the posterior lens capsule and the retina/choroids/sclera membrane, can be determined from in vitro membrane penetration experiments using respective rabbit tissues. The time course of in vivo mean concentration of the drug in the rabbit vitreous body following intravitreal drug delivery well agreed with the profile calculated from the present pharmacokinetic model for both membrane-controlled polymeric devices and biodegradable rod-matrix systems. The pharmacokinetic model suggests that the major route of elimination of drug molecules released from the vitreous implant is through the posterior aqueous humor because of the absence of a barrier membrane. However, the elimination through the RCS membrane cannot be overlooked because of the large diffusion area of the RCS membrane. The vitreous body concentration of the drug released from biodegradable vitreous implants can be predicted from the in vivo release rate-time profile by the present pharmacokinetic model.     

Colloidal carriers for ophthalmic drug delivery

To achieve effective drug concentration at the intended site for a sufficient period of time is a requisite desired for many drug formulations. For drugs intended to ocular delivery, its poor bioavailability is due to pre-corneal factors. Most ocular diseases are treated by topical drug application in the form of solution, suspension and ointment. However, such dosage forms are no longer sufficient to combat some ocular diseases. Intravitreal drug injection is the current therapy for disorders in posterior segment. The procedure is associated with a high risk of complications, particularly when frequent, repeated injections are required. Thus, sustained-release technologies are being proposed, and the benefits of using colloidal carriers in intravitreal injections are currently under investigation for posterior drug delivery. This review will discuss recent progress and specific development issues relating to colloidal drug delivery systems, such as liposomes, niosomes, nanoparticles, and microemulsions in ocular drug delivery.     

Nanotechnology in ocular delivery: current and future directions

Our knowledge in the field of ocular drug delivery is rapidly expanding. An increase in the understanding of ocular drug absorption and disposition vis-à-vis developments in nanotechnology has led to the emergence of many of the nanotechnology-based ocular drug delivery systems including nanoparticles, microemulsions, liposomes, solid lipid nanoparticles, light-sensitive nanocarrier systems, etc. The need to develop effective treatments for posterior eye segment diseases is more important than surface delivery. Treatment of blinding diseases of the eye, such as proliferative retinopathy or macular degeneration, requires effective and safe delivery of drugs to posterior eye segment tissues, and recent advances in nanotechnology have demonstrated successful outcomes. Nanoscientists should focus their efforts on nano-ophthalmology. This review describes the current status and progress made so far, and the course that needs to be pursued in the future.     

Topical Drug Delivery to the Posterior Segment of the Eye: Addressing the Challenge of Preclinical to Clinical Translation

Topical delivery of therapeutics to the posterior segment of the eye remains the “holy grail” of ocular drug delivery. As an example, anti–vascular endothelial growth factor biologics, such as ranibizumab, aflibercept, and bevacizumab, are delivered by intravitreal injection to treat neovascular age-related macular degeneration and, although these drugs have revolutionized treatment of the disease, less invasive alternatives to intravitreal injection are desired. Multiple reports in the literature have demonstrated topical delivery of both small and large molecules to the back of the eye in small animal models. Despite this progress, successful translation to larger species, and ultimately humans, has yet to be demonstrated. Selection of animal models with relevant ocular anatomy and physiology, along with appropriate experimental design, is critical to enable more relevant feasibility assessments and increased probability of successful translation.     

Current and future ophthalmic drug delivery systems. A shift to the posterior segment

Topical eye drop administration is useful only for the treatment of anterior segment diseases. The posterior eye segment is an important therapeutic target with unmet medical needs. The leading causes of visual impairment in the industrial countries are related to the disorders in the posterior eye tissues. New drugs for the medication of the posterior ocular segment have emerged, but most drugs are delivered by repeated intravitreal injections. Effective, safe, and comfortable methods of drug delivery are needed. The emerging methods include polymeric-controlled release injections and implants, nanoparticulates, microencapsulated cells, iontophoresis, and gene medicines. The biggest drug delivery challenge is to develop effective methods for posterior segment therapies that would also be applicable for the out-patient use.     

Therapeutic applications of viscous and injectable poly(ortho esters).

Poly(ortho esters) (POE) are hydrophobic and bioerodible polymers that have been investigated for pharmaceutical use since the early 1970s. Among the four described generations of POE, the third (POE III) and fourth (POE IV) are promising viscous and injectable materials which have been investigated in numerous biomedical applications. POE III has been extensively studied for ophthalmic drug delivery, it presents an excellent biocompatibility and is currently being investigated as a vehicle for sustained drug delivery to treat diseases of the posterior segment of the eye. POE IV is distinguishable by a highly reproducible and controlled synthesis, a higher hydrophobicity, and an excellent biocompatibility. It is currently under development for a variety of applications, such as ocular delivery, periodontal disease treatment and applications in veterinary medicine. This review will also focus on new perspectives for this promising family of polymers, such as guided tissue regeneration, treatment of osteoarthritis, as well as peptide and protein delivery.     

MRI study of subconjunctival and intravitreal injections

Previous magnetic resonance imaging (MRI) studies to investigate the routes of penetration and barriers in ocular delivery have provided insights into the mechanisms of transscleral and intraocular drug delivery. The objective of the present study was to investigate ocular penetration and clearance after subconjunctival and intravitreal injections using a contrast agent at concentrations higher than those in the previous studies. This high concentration approach was hypothesized to allow the visualization of the contrast agent in the eye that could not be achieved previously. Subconjunctival and intravitreal injections of contrast agent Magnevist, a model hydrophililc probe, were performed in rabbits, and the distribution and clearance of the probe after the injections were examined by MRI. After subconjunctival injection in vivo, significant contrast agent penetration into the anterior chamber was observed but not into the vitreous. A clearance pathway of the hydrophilic probe from the subconjunctival depot to the regions near the periocular fat behind the eye was found. After intravitreal injection in vivo, the contrast agent was observed in the anterior chamber, optic nerve, and tissues surrounding the eye during clearance. MRI continues to provide insights into the transport barriers and clearance pathways of hydrophilic molecules in ocular delivery.     

Antimicrobial drug delivery to the eye

A major obstacle in the treatment of ocular infections is the difficulty in obtaining adequate antimicrobial drug concentration at the site of infection. This article reviews the pharmacokinetic principles of ophthalmic drug delivery as it pertains to antimicrobial therapy. The administration of antimicrobials by topical application, subconjunctival injection, intravitreal injection, vitreous replacement fluid, and systemic administration are addressed. Representative data on the intraocular penetration of antimicrobials as well as recommended doses of drugs for ocular infections are presented.     

A study of the dexamethasone sodium phosphate release properties from a periocular capsular drug delivery system

The aim of this study was to investigate whether a periocular capsular drug delivery system (DDS) can release dexamethasone sodium phosphate (DEXP) in vitro and in vivo to the posterior segment of rabbit's eye. In vitro, the periocular capsular DDS containing 2?mg/ml or 5?mg/ml DEXP was immersed in modified Franz diffusion cell. Four-hundred microliters of liquid was aspirated at 0.5, 1, 2, 4, 8, 24 and 48?h for determination. In vivo, the DEXP-filled periocular capsular DDS was implanted into the sub-Tenon's sac of the New Zealand rabbit. DEXP concentration at the serum aqueous humor, cornea, iris, lens, ciliary body, vitreous, retina, choroids and sclera was quantified at 1, 3, 7, 14, 28 and 56?d after implantation. The DEXP concentration was determined by ultra-performance liquid chromatography-tandem mass spectrometry. In vitro, the periocular capsular DDS released the DEXP in time-dependent manner from 1/2 to 48?h. In vivo, the concentrations of the DEXP at the retina, choroids, ciliary body and iris were 123.11 (91.23, 732.61)?ng/g, 362.46?±?330.46?ng/g, 71.64 (71.35, 180.21)?ng/g and 192.50?±?42.66?ng/g, respectively, at 56?d after implantation. Minimal DEXP was found in the aqueous, serum and vitreous. Our results demonstrated that DEXP could be sustained released from the periocular capsular DDS, which indicated that the periocular capsular DDS might be a potential candidate of transscleral drug delivery for the management of posterior segment diseases.