Ocular drug delivery system: a reference to natural polymers

INTRODUCTION: Ocular drug delivery is a very challenging endeavor due to the unique anatomical and physiological barriers. The low ocular bioavailability (<10%) obtained from conventional formulations has forced the scientists to develop new formulations to deliver drugs to ocular tissues at a controlled rate to reduce frequent instillations. The natural polymers have represented the potential to deliver drugs topically through the limited precorneal area and release over a prolonged time period. AREAS COVERED: The important points to be considered during the fabrication of ophthalmic formulations for example, properties of drug molecule and polymer which affect the release rate are discussed. Novel polymers, like arabinogalactan, xyloglucan, gum cordia, locust bean gum, carrageenan and Bletilla striata polysaccharide, besides the conventional polymers like chitosan, starch, sodium alginate, sodium hyaluronate, xanthan gum, gelatin, gellan gum, guar gum, collagen and albumin, have demonstrated the potential to safely deliver drugs at a controlled rate in different ophthalmic formulations. EXPERT OPINION: The limitations of topical delivery of genes and chemotherapeutic drugs can be overcome by using natural polymers with characteristic properties. Despite the wide applicability, tremendous efforts are required to establish natural polymers in novel formulations on a commercial scale.     

In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery

Introduction: In situ gel systems refer to a class of novel delivery vehicles, composed of natural, semisynthetic or synthetic polymers, which present the unique property of sol–gel conversion on receipt of biological stimulus.

Areas covered: The present review summarizes the latest developments in in situ gel technology, with regard to ophthalmic drug delivery. Starting with the mechanism of ocular absorption, the review expands on the fabrication of various polymeric in situ gel systems, made up of two or more polymers presenting multi-stimuli sensitivity, coupled with other interesting features, such as bio-adhesion, enhanced penetration or sustained release. Various key issues and challenges in this area have been addressed and critically analyzed.

Expert opinion: The advent of in situ gel systems has inaugurated a new transom for ‘smart’ ocular delivery. By virtue of possessing stimuli-responsive phase transition properties, these systems can easily be administered into the eye, similar to normal eye drops. Their unique gelling properties endow them with special features, such as prolonged retention at the site of administration, followed by sustained drug release. Despite the superiority of these systems as compared with conventional ophthalmic formulations, further investigations are necessary to address the toxicity issues, so as to minimize regulatory hurdles during commercialization.     

Applications of poloxamers in ophthalmic pharmaceutical formulations: an overview

Introduction: An ideal ophthalmic formulation is one that not only prolongs the contact time of the vehicle on the ocular surface but also slows down the drug elimination. The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of the drug may be overcome by the use of in situ gel forming systems. In situ gelling systems increase the viscosity by changing the pH or temperature in the pre-corneal region and lead to an increase of drug bioavailability by slowing drainage. Poloxamers are polyols with thermal gelling properties which are frequently included in ophthalmic formulations to improve the ocular bioavailability of drugs by increasing vehicle viscosity.

Areas covered: An overview on the unique physiological characteristics of ocular globe and the limitations and disadvantages of the conventional ophthalmic pharmaceutical formulations. Readers will appreciate the different strategies to improve the absorption of drugs in the ocular globe, especially the incorporation of poloxamers in ophthalmic formulations, understanding the main advantages of the poloxamers and also learning about the different examples of applications of these polymers in ophthalmic pharmaceutical formulations.

Expert opinion: Poloxamers offers a new strategy to improve bioavailability and decrease the side effects induced by the systemic absorption of topically applied ophthalmic drugs.     

Chitosan: a potential polymer for colon-specific drug delivery system

Introduction: There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties.

Areas covered: CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug.

Expert opinion: The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability).     

Comparative studies for ciprofloxacin hydrochloride pre-formed gels and thermally triggered (in situ) gels: in vitro and in vivo appraisal using a bacterial keratitis model in rabbits

Abstract

This article reports on comparative in vitro characterization and in vivo evaluation of pre-formed cellulose-based gels, methylcellulose (MC) and carboxymethylcellulose sodium (CMC) and in situ gel-forming Pluronic F127 (PL) for ocular delivery of ciprofloxacin hydrochloride (Cipro) by using a bacterial keratitis model and histological corneal examination. Drug–polymer interactions were studied employing thermal analysis. Further, different concentrations (1–3% w/w or 10–30% w/w) of gels depending on the nature of the polymer used were prepared, characterized for clarity, pH, rheology and in vitro release. Selected gel formulations were evaluated for ocular delivery to Staphylococcus aureus-infected rabbit corneas; and ocular toxicity through histological examination of the cornea. The results demonstrated no Cipro-polymers physicochemical interactions and pseudoplastic flow for all gels used at 35?°C. Both polymer concentrations and drug solubility in the gels are dominantly the rate-determining factors for in vitro drug release. The corneal healing rate for all gel-based formulations was significantly faster (p?<?0.05) than that for Cipro solution-treated rabbits. PL-based gel induced significant swelling/edema of the corneal stroma, compared with MC- and CMC-based gels. In conclusion, cellulose-based polymers have superior ocular tolerability/dramatically less irritant; and superior efficacy with more convenient administration compared with PL and Cipro solution, respectively.     

Chick chorioallantoic membrane model for in ovo evaluation of timolol maleate–brimonidine tartrate ocular inserts

Abstract

The main aspire of this study was to develop ocular drug delivery system for dual drug glaucoma therapy by timolol maleate–brimonidine tartrate and endeavor the possibility of biocompatibility studies by in ova studies. Matrix type, both hydrophilic and lipophilic polymers, and reservoir-type ocular inserts of timolol maleate were prepared using hydrophilic polymers like polyvinyl alcohol, hydroxyl propyl methyl cellulose K4M and lipophilic polymers like ethylcellulose and eudragit S100 and were optimized. Based on the optimized formulation, triple-layered ocular inserts (reservoir type) of dual drug were prepared by solvent casting technique with an objective of reducing the frequency of administration, obtaining controlled release and greater therapeutic efficacy, preservative free dosage form for the treatment of glaucoma. FTIR spectral studies revealed no pharmaceutical incompatibility and no drug polymer interactions. Maximum drug release (99.18?±?1.7) was achieved when PVP and HPMC K4M in 1:1 ratio with PEG 400 (0.3?ml) drug reservoir layer was sandwiched between ethyl cellulose as rate control membrane up to 32?h in a controlled fashion. Drug release was by non-Fickian diffusion mechanism for single drug formulation. But in dual drug insert, timolol maleate best fit into zero order and for brimonidine tartrate to Higuchi model and diffusion of drugs from this by non-Fickian diffusion mechanism. In ovo studies suggested that the optimized formulation was found to be sterile, biocompatible and physicochemically stable and support us to claim that the developed formulation was biocompatible.     

Ocular application of chitosan

Introduction: A major problem in ocular therapeutics with classical formulations is the maintenance of an effective drug concentration at the site of action for a long period of time. Enhancement of ocular bioavailability with increased dose penetration and longer retention time at desired sites can be achieved by recent formulations. Chitosan stands out with its unique structural advantageous characteristics for different types of formulations like in situ gelling systems, micro- and nanoparticles, inserts, etc.

Areas covered: In this review, the authors focus on ocular therapeutics and the characteristics that make chitosan more acceptable in ocular applications.

Expert opinion: Chitosan seems to be one of the most promising polymeric carriers for both hydrophilic and lipophilic drugs for ocular application.     

Formulation and evaluation of Cyclosporin A emulgel for ocular delivery

Abstract

Emulgels have been extensively covered as a promising drug delivery system for the administration of lipophilic drugs. This work was conducted to develop an emulgel formulation for Cyclosporin A (CsA) employing polycarbophil as the gelling agent for ocular delivery. The prepared emulgels were evaluated for their physical appearance, rheological behavior, drug release, stability, precorneal clearance and irritation. Results showed that CsA emulgel formulations prepared with polycarbophil exhibited acceptable physical properties and drug release, which remained consistent after storage for 3 months. A prolonged retention time was also observed on the ocular surface with improved ocular bioavailability and no irritation. Therefore, the polycarbophil-based emulgel could be exploited as a potential hydrophobic drug carrier for topical ocular drug delivery.     

In vitro and in vivo consideration of novel environmentally responsive ophthalmic drug delivery system

In the present study, novel environmentally responsive ophthalmic drug delivery system composed of two gelling polymers with different phase transition mechanisms was developed in order to obtain sustained drug release in ocular cavity. Combination of polyacrylic acid (carbopol 934P) and xanthan gum was investigated as ophthalmic vehicle and assessed for its in vitro and in vivo performance. Different ratios of these polymers were used to prepare environmentally responsive ophthalmic drug delivery system by simple mixing procedure. Developed formulation was assessed for physical tests such as appearance/clarity, pH, gelation; and performance characteristics such as drug content, rheological measurement, in vitro release, antimicrobial efficiency, in vivo studies for eye irritation, residence time estimation. Prepared formulation showed agreeable appearance/clarity, acceptable pH and good gelation property. In vitro and in vivo studies demonstrated adequate drug content, desired rheological behavior and reasonable in vitro and in vivo drug release property. In conclusion, the optimum concentration of polymers results in increased residence time and sustained drug release. On the basis of these findings, environmentally responsive system based on combination of carbopol and xanthan gum may be considered as a promising tool for ophthalmic delivery.     

Nanocarriers for ocular delivery for possible benefits in the treatment of anterior uveitis: focus on current paradigms and future directions

Introduction: Many therapeutic strategies have been adopted in the treatment of anterior uveitis, and it includes corticosteroids and NSAIDs. But, the successful delivery of these drugs is restricted due to limitations of conventional formulation. This review emphasizes on the possible benefits and strategies for development of various novel nanocarriers.

Areas covered: The article explores the various polymers involved in the preparation of novel nanocarriers like polymeric nanoparticles, micelles, microemulsion, liposomes and cubosomes. Reported clinical experimental findings are screened and also discussed in this review.

Expert opinion: The principle behind the development of different nanocarriers is to overcome the limitations imposed by conventional formulations. Several efforts have been made by the researchers in achieving these objectives, but the major challenge with nanosystems remains the requirement of excipients that have unknown or objectionable toxicity profile and are not approved by regulatory authorities. This review is an attempt to provide comprehensive information for the scientists working in the concerned research area.     

Guar gum as platform for the oral controlled release of therapeutics

Introduction: The past decade of research has witnessed a huge advancement in research efforts on guar gum (GG)-based polymers as controlled release (CR) formulations for the delivery of therapeutics.

Areas covered: The unique structure and beneficial properties of GG makes it an attractive biomaterial in CR applications. Current status on GG-based polymers has been addressed as a CR formulation in the form of microspheres, nanoparticles, hydrogels and matrix tablets for the delivery of various types of therapeutics having a wide range of physicochemical properties. Majority of literature on GG as a platform technology has dealt with oral route of drug administration as it is the most convenient, patient-compliant and preferred approach. Recent reports on GG-based polymers are summarized and critically discussed to narrate their usefulness as oral delivery systems.

Expert opinion: The research on GG-based formulations has been focused on optimization of the therapy by designing CR dosage forms with a minimum number of excipients. In this context, GG-based polymers are quite attractive. The present review summarizes published reports on these systems and offers expert opinion relevant to oral delivery of therapeutics.     

Influence of Preparation Conditions on Acyclovir-Loaded Poly-d,l-Lactic Acid Nanospheres and Effect of PEG Coating on Ocular Drug Bioavailability

Purpose. The evaluation of nanosphere colloidal suspensions containing acyclovir as potential ophthalmic drug delivery systems was carried out. The influence of polymer molecular weight and type and concentration of various surfactants on nanosphere properties was studied. The ocular pharmacokinetics of acyclovir-loaded nanoparticles was evaluated in vivo and compared with an aqueous suspension of the free drug. Methods. Nanospheres were made up of poly-d,l-lactic acid (PLA). The colloidal suspension was obtained by a nanoprecipitation process. The surface properties of PLA nanospheres were changed by the incorporation of pegylated 1,2-distearoyl-3-phosphatidylethanol- amine. The mean size and zeta potential of the nanospheres were determined by light scattering analysis. The acyclovir loading capacity and release were also determined. In vivo experiments were carried out on male New Zealand rabbits. The ocular tolerability of PLA nanospheres was evaluated by a modified Draize test. The aqueous humor acyclovir levels were monitored for 6 h to determine the drug's ocular bioavailability for the various formulations. Results. A reduction of the mean size and a decrease of the absolute zeta potential of PLA nanospheres resulted from increasing the surfactant concentration. The higher the polymer molecular weight, the smaller the nanosphere mean size. PEG-coated and uncoated PLA nanospheres showed a sustained acyclovir release and were highly tolerated by the eye. Both types of PLA nanospheres were able to increase the aqueous levels of acyclovir and to improve the pharmacokinetics profile, but the efficacy of the PEG-coated nanospheres was significantly higher than that of the simple PLA ones. Conclusions. PEG-coated PLA nanospheres can be proposed as a potential ophthalmic delivery system for the treatment of ocular viral infections.     

In vitro pharmaceutical characterization and statistical optimization of a novel topically applied instantly-soluble solid eye drop matrix

Abstract

Ocular diseases of the anterior segment of the eye are increasing and the development of novel drug delivery systems for improved treatment is necessary. The aim of this study was therefore to design and evaluate an instantly-soluble solid eye drop (ISED) for topical ophthalmic drug delivery of the model drug timolol maleate. The porous nature of the lyophilized ISED resulted in rapid fluid ingression, immediate hydration, and dissolution of the ocular matrix. The ISED was lyophilized employing hydroxypropylcellulose and pluronic® F68 as the matrix forming polymers. Polyacrylic acid sodium enhanced the solubility of the ISED, di-glycine, an anti-collapsing agent, while maltodextrin improved the matrix resilience. A statistical design was employed for optimizing the texture, disintegration, and the mean dissolution time (MDT_50%) of the ISED. Results revealed that a robust rapidly disintegrating ISED was produced with the fastest disintegration time recorded at 0.20?s and drug release between 79 and 96%. In addition, improved corneal drug permeation was observed compared to pure timolol dispersion. The maltodextrin concentration significantly affected the ISED matrix resilience (p?=?0.007) and pluronic F68 had a greater impact on disintegration time (p?=?0.000) and MDT (p?=?0.000). The ISED formulation may be a promising alternative to the use of liquid eye drops for topical ophthalmic drug delivery.     

Castor oil and mineral oil nanoemulsion: development and compatibility with a soft contact lens

Abstract

Context: The non-invasive ophthalmic therapy has a drawback: low residence time in the eye socket. Nanoparticles and contact lenses have been studied as promising ocular drug delivery systems.

Objective: To develop a nanoemulsion and evaluate its compatibility with a soft contact lens as a potential strategy for ocular delivery.

Materials and methods: The formulations were developed by spontaneous emulsification and fully characterized. Two drops of nanoemulsion were instilled on the surface of a commercial contact lens and its transparency was measured using a UV-Vis spectrophotometer. Before and after the instillation of the drops, the morphology (scanning electron microscopy – SEM) and ion permeability of the lenses were analyzed.

Results: The formulations had a mean particle size of 234?nm, polydispersity below 0.16, zeta potential of ?8.56?±?3.49?mV, slightly acid pH, viscosity ≈1.2?mPa?s^?1 and spherical-shaped particles. Nanoemulsion was non-irritant (hen’s egg test-chorioallantoic membrane), which was confirmed by the cytotoxicity studies in the SIRC cell cultures. After instillation, SEM analysis showed nanodroplets inside and on the surface of the lenses, although their transparency remained near 100%. No significant differences were found between lens ion permeability coefficients before and after instillation.

Conclusions: Formulations presented appropriate physicochemical characteristics and suitability for ocular application. The contact lens remained transparent and ion-permeable after association with the formulation.     

pH- and ion-sensitive polymers for drug delivery

Introduction: Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body.

Areas covered: Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations.

Expert opinion: Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients.     

Cubosomes and other potential ocular drug delivery vehicles for macromolecular therapeutics

Introduction: Many macromolecular therapeutics designed to treat posterior segment eye diseases (PSEDs) are administered through frequent ocular injection, which can further deteriorate eye health. Due to the high frequency of injection and the high cost of the therapeutics, there is a need to develop new ways in which to deliver these therapeutics: ways which are both safer and more cost effective.

Areas covered: Using the most common PSED, age-related macular degeneration, as an example of a debilitating ocular disease, this review examines the key barriers limiting the delivery of macromolecular therapeutics to the posterior segment of the eye and defines the key requirements placed on particulate drug delivery vehicles (DDVs) to be suitable for this application. Recent developments in macromolecular drug delivery to treat this disease as well as the remaining shortcomings in its treatment are surveyed. Lastly, an emerging class of DDVs potentially suited to this application, called cubosomes, is introduced.

Expert opinion: Based on their excellent colloidal stability and high internal surface area, cubosomes hold great potential for the sustained release of therapeutics. Novel production methods and a better understanding of the mechanisms through which drug release from these particles can be controlled are two major recent developments toward successful application.     

Hybrid thermosensitive-mucoadhesive in situ forming gels for enhanced corneal wound healing effect of L-carnosine

PurposeThermosensitive in situ gels have been around for decades but only a few have been translated into ophthalmic pharmaceuticals. The aim of this study was to combine the thermo-gelling polymer poloxamer 407 and mucoadhesive polymers chitosan (CS) and methyl cellulose (MC) for developing effective and long-acting ophthalmic delivery systems for L-carnosine (a natural dipeptide drug) for corneal wound healing.MethodsThe effect of different polymer combinations on parameters like gelation time and temperature, rheological properties, texture, spreading coefficients, mucoadhesion, conjunctival irritation potential, in vitro release, and ex vivo permeation were studied. Healing of corneal epithelium ulcers was investigated in a rabbit’s eye model.ResultsBoth gelation time and temperature were significantly dependent on the concentrations of poloxamer 407 and additive polymers (chitosan and methyl cellulose), where it ranged from <10 s to several minutes. Mechanical properties investigated through texture analysis (hardness, adhesiveness, and cohesiveness) were dependent on composition. Promising spreading-ability, mucoadhesion, transcorneal permeation of L-carnosine, high ocular tolerability, and enhanced corneal epithelium wound healing were recorded for poloxamer 407/chitosan systems.ConclusionIn situ gelling systems comprising combinations of poloxamer-chitosan exhibited superior gelation time and temperature, mucoadhesion, and rheological characteristics suitable for effective long-acting drug delivery systems for corneal wounds.     

Fabrication and evaluation of lipid nanoparticulates for ocular delivery of a COX-2 inhibitor

Context: The unique physiological limitations of the eye have been assigned as reason of low bioavailability by conventional drug delivery systems. There is need of such drug carriers, which ensure improved bioavailability as well as patient compliance upon instillation into the eye.

Objective: The present investigation deals with development of solid lipid nanoparticles (SLNs) containing celecoxib (CXB) for treatment of ophthalmic inflammations.

Materials and methods: The SLNs were formulated by melt-emulsion sonication and low temperature-solidification process and evaluated for particle size, surface morphology, physicochemical properties, percentage drug incorporation efficiency, in vitro drug release, in vitro trans-corneal permeation, in vivo efficacy in ocular inflammation, stability study and gamma scintigraphy study to assess the residence of solid lipid nanoparticles over ocular surfaces.

Results: The SLNs were spherical and the optimized formulation had particle size of 198.77?±?7.5?nm, which is quite suitable for ocular applications. The maximum entrapment efficiency of 92.46?±?0.07% was achieved for formulation SLN 20. The permeation across the cornea was also significantly better than aqueous suspension (8.21?±?0.67 versus 4.61?±?0.71) at p?<?0.05.

Discussion and conclusion: The SLN formulations demonstrated improved performance of entrapped CXB while mitigating the key parameters of ocular inflammation in rabbits. The particulate formulations have exhibited prolonged retention over ocular surfaces as evident from results of gamma scintigraphy using ^99mTc labeled SLNs.     

Advanced systems for glucocorticoids' dermal delivery

Introduction: Although the skin provides a natural physical barrier against particle penetration, there are opportunities to deliver therapeutic agents through this barrier. With rapid developments in materials science, pharmaceutics, and biotechnology, new systems have emerged for topical glucocorticoids (TG) delivery. Despite being a mature class of drugs, TG are still the most frequently prescribed drugs by dermatologists, explaining the interest on this field.

Areas covered: Over the years, research has focused on strategies to optimize the potency of steroids while minimizing adverse effects. Several attempts have been made to increase the safety of TG treatment, including new application schedules, special vehicles, and new synthesized agents. This paper gives an overview on the conventional and advanced vehicles used to deliver TG, including strategies to improve the delivery and accumulation of TG. The therapeutic advantages of TG delivery to the epidermis are discussed with a special focus on new drug-delivery systems for topical application.

Expert opinion: New technologies have been developed for TG delivery, and studies are currently underway in order to obtain improved benefit/risk ratio. A rationale development approach that integrates simple formulations would help to develop vehicles with these features.