Ocular Drug Delivery Systems Research Articles

Medical Management of Uveitis - Current Trends

Uveitis is a challenging disease to treat. Corticosteroids have been used in the treatment of uveitis for many years. Immunosuppressives are gaining momentum in recent years in the treatment of uveitis. In this article we present an overview of current treatment of uveitis and the major breakthroughs and advances in drugs and ocular drug delivery systems in the treatment of uveitis.

Ocular drug delivery systems: An overview.

The major challenge faced by today's pharmacologist and formulation scientist is ocular drug delivery. Topical eye drop is the most convenient and patient compliant route of drug administration, especially for the treatment of anterior segment diseases. Delivery of drugs to the targeted ocular tissues is restricted by various precorneal, dynamic and static ocular barriers. Also, therapeutic drug levels are not maintained for longer duration in target tissues. In the past two decades, ocular drug delivery research acceleratedly advanced towards developing a novel, safe and patient compliant formulation and drug delivery devices/techniques, which may surpass these barriers and maintain drug levels in tissues. Anterior segment drug delivery advances are witnessed by modulation of conventional topical solutions with permeation and viscosity enhancers. Also, it includes development of conventional topical formulations such as suspensions, emulsions and ointments. Various nanoformulations have also been introduced for anterior segment ocular drug delivery. On the other hand, for posterior ocular delivery, research has been immensely focused towards development of drug releasing devices and nanoformulations for treating chronic vitreoretinal diseases. These novel devices and/or formulations may help to surpass ocular barriers and associated side effects with conventional topical drops. Also, these novel devices and/or formulations are easy to formulate, no/negligibly irritating, possess high precorneal residence time, sustain the drug release, and enhance ocular bioavailability of therapeutics. An update of current research advancement in ocular drug delivery necessitates and helps drug delivery scientists to modulate their think process and develop novel and safe drug delivery strategies. Current review intends to summarize the existing conventional formulations for ocular delivery and their advancements followed by current nanotechnology based formulation developments. Also, recent developments with other ocular drug delivery strategies employing in situ gels, implants, contact lens and microneedles have been discussed.

Liposomes and nanotechnology in drug development: focus on ocular targets

Poor drug delivery to lesions in patients’ eyes is a major obstacle to the treatment of ocular diseases. The accessibility of these areas to drugs is highly restricted by the presence of barriers, including the corneal barrier, aqueous barrier, and the inner and outer blood–retinal barriers. In particular, the posterior segment is difficult to reach for drugs because of its structural peculiarities. This review discusses various barriers to drug delivery and provides comprehensive information for designing nanoparticle-mediated drug delivery systems for the treatment of ocular diseases. Nanoparticles can be designed to improve penetration, controlled release, and drug targeting. As highlighted in this review, the therapeutic efficacy of drugs in ocular diseases has been reported to be enhanced by the use of nanoparticles such as liposomes, micro/nanospheres, microemulsions, and dendrimers. Our recent data show that intravitreal injection of targeted liposomes encapsulating an angiogenesis inhibitor caused significantly greater suppression of choroidal neovascularization than did the injection of free drug. Recent progress in ocular drug delivery systems research has provided new insights into drug development, and the use of nanoparticles for drug delivery is thus a promising approach for advanced therapy of ocular diseases.

Nanoparticles laden in situ gelling system for ocular drug targeting

Designing an ophthalmic drug delivery system is one of the most difficult challenges for the researchers. The anatomy and physiology of eye create barriers like blinking which leads to the poor retention time and penetration of drug moiety. Some conventional ocular drug delivery systems show shortcomings such as enhanced pre-corneal elimination, high variability in efficiency, and blurred vision. To overcome these problems, several novel drug delivery systems such as liposomes, nanoparticles, hydrogels, and in situ gels have been developed. In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the ocular cul-de-sac to form viscoelastic gel and this provides a response to environmental changes. In the past few years, an impressive number of novel temperature, pH, and ion-induced in situ-forming systems have been reported for sustain ophthalmic drug delivery. Each system has its own advantages and drawbacks. Thus, a combination of two drug delivery systems, i.e., nanoparticles and in situ gel, has been developed which is known as nanoparticle laden in situ gel. This review describes every aspects of this novel formulation, which present the readers an exhaustive detail and might contribute to research and development.

Hybrid Dendrimer Hydrogel/Poly(Lactic-Co-Glycolic Acid) Nanoparticle Platform: An Advanced Vehicle for Topical Delivery of Antiglaucoma Drugs and a Likely Solution to Improving Compliance and Adherence in Glaucoma Management

Glaucoma therapy typically begins with topical medications, of which there are 4 major classes in common use in the United States: beta-adrenergic antagonists, alpha-agonists, carbonic anhydrase inhibitors, and prostaglandin analogs. Unfortunately, all 4 classes require at least daily dosing, and 3 of the 4 classes are approved to be administered 2 or 3 times daily. This need for frequent dosing with multiple medications makes compliance difficult. Longer-acting formulations and combinations that require less frequent administration might improve compliance and therefore medication effectiveness. Recently, we developed an ocular drug delivery system, a hybrid dendrimer hydrogel/poly(lactic-co-glycolic acid) nanoparticle platform for delivering glaucoma therapeutics topically. This platform is designed to deliver glaucoma drugs to the eye efficiently and release the drug in a slow fashion. Furthermore, this delivery platform is designed to be compatible with many of the glaucoma drugs that are currently approved for use. In this article, we review this new delivery system with in-depth discussion of its structural features, properties, and preclinical application in glaucoma treatment. In addition, future directions and translational efforts for marketing this technology are elaborated.

The Vitreous Humor As a Barrier to Nanoparticle Distribution

The vitreous humor represents a significant barrier to the penetration of nanoparticulate-based ocular drug delivery systems. The gel structure and biochemical components of the vitreous will impact the rate of nanoparticle movement through the tissue to reach the retinal tissue. Also the structure of the vitreous, flow systems operating within it, age-related structural changes, and the presence of inflammation will also have a potential effect on movement. To effectively target the posterior retina, the physical properties of the nanoparticle formulation are a key element in the design of a system that will penetrate through the vitreous barrier.

Controlled and Continuous Release Ocular Drug Delivery Systems: Pros and Cons

Topical ocular drug administration is the most preferred route for treating conditions affecting the surface of the eye as well as anterior segment diseases; this is mainly due to the rapid and localised drug action and patient acceptability. However, the ocular bioavailability is typically less than 5% from conventional ophthalmic dosage forms such as eye drops. This is mainly due to the unique anatomical and physiological features of the eye. One of the effective pharmaceutical approaches is to provide a controlled and continuous drug release to the surface of the eye to compensate drug loss by nasolacrimal drainage and non-productive absorption of the topically applied drug. This review provides a critical appraisal (advantages and drawbacks) of the different drug delivery strategies that provides controlled and continuous drug supply to the surface of the eye; it covers research conducted over the past three decades.

Nanomaterials for Ocular Drug Delivery

Efficient drug delivery to the eye remains a challenging task for pharmaceutical scientists. Due to the various anatomical barriers and the clearance mechanisms prevailing in the eye, conventional drug delivery systems, such as eye drop solutions, suffer from low bioavailability. More invasive methods, such as intravitreal injections and implants, cause adverse effects in the eye. Recently, an increasing number of scientists have turned to nanomaterial-based drug delivery systems to address the challenges faced by conventional methods. This paper highlights recent applications of various nanomaterials, such as polymeric micelles, hydrogels, liposomes, niosomes, dendrimers, and cyclodextrins as ocular drug delivery systems to enhance the bioavailability of ocular therapeutic agents.

Development of solid lipid nanoparticles and nanostructured lipid carriers for improving ocular delivery of acyclovir

The objective of the present investigation was to improve the ocular bioavailability of acyclovir by incorporating it into solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). This required optimization of the process parameters, such as type of lipid, drug to lipid ratios, type and concentration of surfactants, and type and amount of liquid lipids used in the formulations. SLNs and NLCs were prepared by the modified hot oil in water microemuslion method. The prepared nanoparticles were evaluated for their particle size, zeta potential, entrapment efficiency, solid state characteristics, surface morphology, in vitro drug release, and permeation through excised cornea. The prepared nanoparticles were spherical and within the size range suitable for ocular drug delivery (400–777.56 nm). Incorporation of liquid oil in the structure of SLNs resulted in the formation of NLCs with high entrapment efficiency (25–91.64%) compared to SLNs (11.14%). The drug release from SLNs and NLCs was rather a surface-based phenomenon. In comparison to free drug solution, NLCs were capable of having faster permeation through the excised cornea indicating their potential enhanced corneal penetration properties. However, SLNs have reduced the permeation rate significantly. The results of the study suggest that SLNs can be successfully converted to physically superior NLCs, which have the potential to be developed further as ocular drug delivery systems for ACV.

New Mucoadhesive Chitosan Film for Ophthalmic Drug Delivery of Timolol Maleate: In Vivo Evaluation

Chitosan, a cationic polysaccharide biopolymer with mucoadhesive properties, presents a promising future in the prolonged ocular delivery of drugs. The present study compared the efficacy and safety of chitosan-coated timolol maleate (TM) mucoadhesive film, using a 0.5% TM commercial ophthalmic solution in a rabbit model. In addition, this study investigates the maximum release time of these implants in vivo. The mucoadhesive films were prepared by means of a casting and solvent evaporation technique performed in a 2 wt% acetic acid solution and distilled water. Physical properties were characterized by release and swelling studies, differential scanning calorimetry, and attenuated total reflectance fourier transformed infrared spectroscopy (ATR-FTIR). The developed formulations were evaluated for their pharmacodynamics in ocular normotensive albino rabbits, in which the intraocular pressure (IOP) was measured by means of applanation tonometer on alternative days (13 h) for 11 weeks. For 15 days, 0.5% TM commercial ophthalmic solution was administered twice a day (n=5) and compared to chitosan-coated TM (n=5). In the control group (n=5), saline was used twice a day. The maximum TM release time from chitosan films were also recorded. After euthanasia, the right eyes were removed from the 3 groups for histological analyses. In an in vitro study, TM was released over a 4-week period, in which 85% of the drug was released over the first 2 weeks. However, the film's release of TM lowered the in vivo IOP levels over a 10-week period. No significant difference in the lowering of IOP in rabbits treated with 0.5% TM commercial ophthalmic solution, as compared to those that received the films (P<0.05), could be observed. No signs of ocular discomfort or irritations could be identified upon ophthalmic examination by slit-lamp biomicroscopy. Ophthalmic structures that came in direct contact with the films revealed no alterations within the histopathological studies. Moreover, the animals showed no signs of ocular discomfort during the experimental assays. These findings suggest that the TM-loaded chitosan film is safe and efficient and presents a promising future as an ocular drug delivery system in the treatment and prevention of glaucoma.

Nanostructured Lipid Carriers as the Most Promising Approach in Ocular Drug Delivery System

Nanostructured Lipid Carriers as the Most Promising Approach in Ocular Drug Delivery System

Diclofenac/biodegradable polymer micelles for ocular applications

In this paper, methoxypoly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelle formulations as promising nano-carriers for poorly water soluble drugs were investigated for the delivery of diclofenac to the eye. Diclofenac loaded MPEG-PCL micelles were prepared by a simple solvent-diffusion method and characterized by dynamic light scattering (DLS), atomic force microscopy (AFM), Fourier transform infra-red (FTIR), X-ray diffraction (XRD), differential scanning calorimetery (DSC), etc. With the analysis of XRD and DSC, the diclofenac was present as an amorphous state in the formulation. The in vitro release profile indicated a sustained release manner of diclofenac from the micelles. Meanwhile, in vivo studies on eye irritation were performed with blank MPEG-PCL micelles (200 mg ml(-1)). The results showed that the developed MPEG-PCL micelles were non-irritants to the eyes of rabbits. In vitro penetration studies across the rabbit cornea demonstrated that the micelle formulations exhibited a 17-fold increase in penetration compared with that of diclofenac phosphate buffered saline (PBS) solution. The in vivo pharmacokinetics profile of the micelle parent drug in the aqueous humor of the rabbit was evaluated and the data showed that the diclofenac loaded MPEG-PCL micelles exhibited a 2-fold increase in AUC(0-24 h) than that of the diclofenac PBS solution eye drops. These results suggest a great potential of our micelle formulations as a novel ocular drug delivery system to improve the bioavailability of the drugs.

Novel intraocular and systemic absorption drug delivery and efficacy of N‐acetylcarnosine lubricant eye drops or carcinine biologics in pharmaceutical usage and therapeutic vision care

The latest estimates of the World Health Organization indicate that there are 161 million visually impaired individuals worldwide, 37 million of whom are blind, with a yearly increase of 1-2 million. The scientists developed and patented the lubricant eye drops formulated as 1%N-acetylcarnosine prodrug of l-carnosine containing a mucoadhesive cellulose-based compound combined with corneal absorption promoters in an ocular drug delivery system. Carcinine is suitable for the systemic administration (per oral) for ophthalmic therapeutic indications. The HPLC analysis was developed to search the pathways of ocular metabolic activities of 1%N-acetylcarnosine and the bioactivation of this drug molecule promoting transcorneal uptake of l-carnosine in the aqueous humor. A meta-analysis of phase 2 randomized double-blind placebo-controlled clinical trial data was conducted. The intraocular absorbed l-carnosine demonstrated a number of pharmacological mechanisms of prevention and reversal of cataracts. Results of systemic absorption of l-carnosine provide tuberomammillary activation that regulates neuronal functions such as hypothalamic control promoting sensory input in the primary vision perceptual pathway. The parabulbar, subconjunctival, and intravitreal injection of carcinine with most of the vehicle removed is not toxic to intraocular structures, reduces postoperative intraocular inflammation, is a potentially useful tool in the treatment of proliferative vitreoretinopathy as well as considered as the antiapoptotic drug for the protection of photoreceptor cells from oxidative light-induced stress. The discovery of naturally occurring carnosine derivatives introduces N-acetylcarnosine and carcinine as effective medical treatment for sight-threatening eye disorders.

Chitosan-based thermosensitive hydrogel as a promising ocular drug delivery system: Preparation, characterization, and in vivo evaluation

The purpose of this study was to evaluate the feasibility of in situ thermosensitive hydrogel based on chitosan in combination with disodium α-d-Glucose 1-phosphate (DGP) for ocular drug delivery system. Aqueous solution of chitosan/DGP underwent sol-gel transition as temperature increased which was flowing sol at room temperature and then turned into non-flowing hydrogel at physiological temperature. The properties of gels were characterized regarding gelation time, gelation temperature, and morphology. The sol-to-gel phase transition behaviors were affected by the concentrations of chitosan, DGP and the model drug levocetirizine dihydrochloride (LD). The developed hydrogel presented a characteristic of a rapid release at the initial period followed by a sustained release and remarkably enhanced the cornea penetration of LD. The results of ocular irritation demonstrated the excellent ocular tolerance of the hydrogel. The ocular residence time for the hydrogel was significantly prolonged compared with eye drops. The drug-loaded hydrogel produced more effective anti-allergic conjunctivitis effects compared with LD aqueous solution. These results showed that the chitosan/DGP thermosensitive hydrogel could be used as an ideal ocular drug delivery system in terms of the suitable sol-gel transition temperature, mild pH environment in the hydrogel as well as the organic solvent free.

Nanotechnology in Ophthalmic Drug Delivery: A Survey of Recent Developments and Patenting Activity

Controlled release of drugs to the eye tissues is still an important, though challenging topic of research in the area of pharmaceutical technology. The eye is an organ highly protected from extraneous compounds by anatomical, functional and biochemical mechanisms. Such defences often limit the time of contact of the formulation with the eye surface and lead to an insufficient bioavailability of the applied drugs, especially at the level of eye posterior segment. Many nanotechnology strategies have been exploited for the diagnosis and cure of ocular diseases. They range from medical application of nanomaterials, including controlled drug and gene delivery systems, to nanoelectronic biosensors, to nanodevices for in vivo imaging and diagnosis, to implantable biomaterials for tissue regeneration and prolonged targeted therapy. Nanosized ocular drug delivery systems have shown important results in ocular drug delivery in the last years, both as topical applications on the eye surface or after intraocular administration. These colloidal carriers can be suitably engineered to overcome corneal and retinal barriers to drug penetration, protect the encapsulated drug, and prolong its activity by a controlled and/or prolonged site-specific release profile. Although the basic research on ophthalmic delivery systems supplies many technological approaches, very few of them have been able to reach a clinical relevance or to be translated into pre-industrial or industrial applications. The main reason lies in the complexity and specificity of the formulation parameters that ophthalmic products always require to tackle the high sensitivity of ocular tissues. This review surveys some of the more recent patents regarding nanotechnology applications to ophthalmic controlled and targeted drug delivery. Keywords: Nanotechnology, Ophthalmic Drug Delivery, Controlled drug delivery, dendrimers, intraocular release, intravitreal delivery, iontophoresis, liposomes, microparticles, nanocarriers, nanoemulsions, nano-eye drops, nanoparticles, ocular therapy, SLN

Nanotechnology in Ophthalmic Drug Delivery: A Survey of Recent Developments and Patenting Activity

Controlled release of drugs to the eye tissues is still an important, though challenging topic of research in the area of pharmaceutical technology. The eye is an organ highly protected from extraneous compounds by anatomical, functional and biochemical mechanisms. Such defences often limit the time of contact of the formulation with the eye surface and lead to an insufficient bioavailability of the applied drugs, especially at the level of eye posterior segment. Many nanotechnology strategies have been exploited for the diagnosis and cure of ocular diseases. They range from medical application of nanomaterials, including controlled drug and gene delivery systems, to nanoelectronic biosensors, to nanodevices for in vivo imaging and diagnosis, to implantable biomaterials for tissue regeneration and prolonged targeted therapy. Nanosized ocular drug delivery systems have shown important results in ocular drug delivery in the last years, both as topical applications on the eye surface or after intraocular administration. These colloidal carriers can be suitably engineered to overcome corneal and retinal barriers to drug penetration, protect the encapsulated drug, and prolong its activity by a controlled and/or prolonged site-specific release profile. Although the basic research on ophthalmic delivery systems supplies many technological approaches, very few of them have been able to reach a clinical relevance or to be translated into pre-industrial or industrial applications. The main reason lies in the complexity and specificity of the formulation parameters that ophthalmic products always require to tackle the high sensitivity of ocular tissues. This review surveys some of the more recent patents regarding nanotechnology applications to ophthalmic controlled and targeted drug delivery.

An Updated Patent Review on Ocular Drug Delivery Systems with Potential for Commercial Viability

The eye due to its special attributes is an effortlessly accessible location for topical drug administration. Topical administration not only provides local targeting of drugs but also offers a better control over the systemic delivery. Bioavailability of drugs from ocular dosage forms is dependent to the precorneal loss factors (physiological and anatomical constraints of eye) thus, very small fraction of the drug is absorbed through ocular route. The effective dose of medication administered ophthalmically may be altered by changing the formulation. Various research reports have been documented for ocular drug delivery, both on academic level as well as commercial level resulting in augmented increase in the numbers of patents in this field. The primary objective of the present review is to provide an overview of the ocular drug delivery systems with special emphasis on the intellectual aspects of these systems. This paper also attempts to extend the information on ocular drug delivery systems already existing in the literature by focusing on the update on the patents granted as well as applications published for these systems during the last decade.

Chitosan/sulfobutylether-β-cyclodextrin nanoparticles as a potential approach for ocular drug delivery

Development of efficient ocular delivery nanosystems remains a major challenge to achieve sustained therapeutic effect. The purpose of this work was to develop chitosan nanoparticles using sulfobutylether-β-cyclodextrin (SBE-β-CD) as polyanionic crosslinker and to investigate the potential of using those nanostructures as ocular drug delivery systems. Econazole nitrate (ECO) was chosen as model drug molecule. The influence of different process variables (chitosan molecular weight and the concentration of the two ionic agents) on particle size, polydispersity index, zeta potential, drug content, in vitro release and mucoadhesive properties was investigated. The results showed that the prepared nanoparticles were predominant spherical in shape having average particle diameter from 90 to 673 nm with positive zeta potential values from 22 to 33 mV and drug content values ranging from 13 to 45%. Drug release from optimized nanoparticles was controlled with approximately 50% of the original amount released over a 8 h period. The release profile of nanoparticles followed a zero-order release kinetics. The optimized nanoparticles were tested for their use as ocular drug delivery systems on albino rabbits. The in vivo studies revealed that the prepared mucoadhesive nanoparticles had better ability in sustaining the antifungal effect of ECO than the ECO solution. Therefore, chitosan/SBE-β-CD nanoparticles developed showed a promising carrier for controlled delivery of drug to the eye.

Bacterial Ghosts as antigen and drug delivery system for ocular surface diseases: Effective internalization of Bacterial Ghosts by human conjunctival epithelial cells

The purpose of the presented investigation was to examine the efficiency of the novel carrier system Bacterial Ghosts (BGs), which are empty bacterial cell envelopes of Gram-negative bacteria to target human conjunctival epithelial cells, as well as to test the endocytic capacity of conjunctival cells after co-incubation with BGs generated from different bacterial species, and to foreclose potential cytotoxic effects caused by BGs. The efficiency of conjunctival cells to internalize BGs was investigated using the Chang conjunctival epithelial cell line and primary human conjunctiva-derived epithelial cells (HCDECs) as in vitro model. A high capacity of HCDECs to functionally internalize BGs was detected with the level of internalization depending on the type of species used for BGs generation. Detailed analysis showed no cytotoxic effect of BGs on HCDECs independently of the used bacterial species. Moreover, co-incubation with BGs did not enhance expression of both MHC class I and class II molecules by HCDECs, but increased expression of ICAM-1. The high rates of BG's internalization by HCDECs with no BG-mediated cytotoxic impact designate this carrier system to be a promising candidate for an ocular surface drug delivery system. BGs could be useful for future therapeutic ocular surface applications and eye-specific disease vaccine development including DNA transfer.

Comparison of ion-activated in situ gelling systems for ocular drug delivery. Part 1: Physicochemical characterisation and in vitro release

Conventional eye drops can result in poor drug bioavailability due to the unique ocular anatomy and physiology. Ion-activated in situ gelling systems are able to crosslink with cations present in the tear fluid, therefore forming a gel on the ocular surface, which results in prolonged corneal contact time. The present study compared a number of anionic polysaccharides (gellan gum, xanthan gum, carrageenan and alginate) to an uncharged (HPMC) and a positively charged (chitosan) polymer system with emphasis on the gelling behaviour, rheological and textural properties, gel microstructure, contact angle and in vitro release characteristics. All systems exhibited physically entangled polymer networks that were able to disentangle upon shear stress and significantly prolonged the in vitro release of a model hydrophilic drug compared to a solution. While systems based on HPMC and chitosan showed no structural changes upon addition of cations, formulations based on gellan gum and carrageenan demonstrated a remarkable increase in viscosity, pseudoplasticity and hardness upon addition of Ca 2+ and K + respectively. This renders them favourable for ocular use as they would gel once in contact with the cations of the tear fluid, thus reducing nasolacrimal drainage, but would thin upon shearing, preventing ocular irritation and therefore induced lacrimation.