Pharmaceutical, biomedical and ophthalmic applications of biodegradable polymers (BDPs): literature and patent review.

In the last few decades, the interest in biodegradable materials for biomedical applications has increased significantly. Both natural and synthetic biodegradable polymers (BDPs) have been broadly explored for various biomedical applications. These include sutures and wound dressings, screws for bone fracture, scaffolds in tissue engineering, implants, and other carriers for targeted and sustained release drug delivery. Owing to their unique characteristics, including their surface charge variable copolymer block and composition and film-forming properties, BDPs have been widely used as favourable materials for ophthalmic drug delivery. Mucoadhesive BDPs have been used in ophthalmic formulations to prolong drug retention time and improve bioavailability, allowing ophthalmic controlled release systems to design. Furthermore, BDPs-based implants, microneedles, and injectable nano- and micro-particles enabled ocular posterior segment targeting and, most importantly, circumvented the need for removing the delivery systems after application. This review outlines the major advances of BDPs and highlights the latest progress of employing natural and synthetic BDPs for various biomedical applications, emphasising the treatment and management of ophthalmic conditions.

Incorporating Morpholine and Oxetane into Benzimidazolequinone Antitumor Agents: The Discovery of 1,4,6,9-Tetramethoxyphenazine from Hydrogen Peroxide and Hydroiodic Acid-Mediated Oxidative Cyclizations.

The reactivity of hydrogen peroxide and catalytic hydroiodic acid toward 3,6-dimethoxy-2-(cycloamino)anilines is tunable to give ring-fused benzimidazoles or 1,4,6,9-tetramethoxyphenazine in high yield. Mechanisms via a detected nitroso-intermediate are proposed for oxidative cyclization and the unexpected intermolecular displacement of the oxazine. An aqueous solution of molecular iodine is capable of the same transformations. Oxidative demethylation gave targeted benzimidazolequinones, including without cleavage of the incorporated oxetane.

Exploring the Ocular Absorption Pathway of Fasudil Hydrochloride towards Developing a Nanoparticulate Formulation with Improved Performance.

Rho-kinase (ROCK) inhibitors represent a new category of anti-glaucoma medications. Among them, Fasudil hydrochloride, a selective ROCK inhibitor, has demonstrated promising outcomes in glaucoma treatment. It works by inhibiting the ROCK pathway, which plays a crucial role in regulating the trabecular meshwork and canal of Schlemm's aqueous humor outflow. This study aims to investigate the ocular absorption pathway of Fasudil hydrochloride and, subsequently, develop a nanoparticle-based delivery system for enhanced corneal absorption. Employing the ionic gelation method and statistical experimental design, the factors influencing chitosan nanoparticle (Cs NP) characteristics and performance were explored. Fasudil in vitro release and ex vivo permeation studies were performed, and Cs NP ocular tolerability and cytotoxicity on human lens epithelial cells were evaluated. Permeation studies on excised bovine eyes revealed significantly higher Fasudil permeation through the sclera compared to the cornea (370.0 µg/cm2 vs. 96.8 µg/cm2, respectively). The nanoparticle size (144.0 ± 15.6 nm to 835.9 ± 23.4 nm) and entrapment efficiency range achieved (17.2% to 41.4%) were predominantly influenced by chitosan quantity. Cs NPs showed a substantial improvement in the permeation of Fasudil via the cornea, along with slower release compared to the Fasudil aqueous solution. The results from the Hen's Egg Test Chorioallantoic Membrane (HET-CAM) and Bovine Corneal Opacity and Permeability (BCOP) tests indicated good conjunctival and corneal biocompatibility of the formulated chitosan nanoparticles, respectively. Lens epithelial cells displayed excellent tolerance to low concentrations of these nanoparticles (>94% cell viability). To the best of our knowledge, this is the first report on the ocular absorption pathway of topically applied Fasudil hydrochloride where the cornea has been identified as a potential barrier that could be overcome using Cs NPs.

Pharmacological treatment strategies of pterygium: Drugs, biologics, and novel natural products.

Pterygium is a fibrovascular tissue growth invading the cornea. Adjunctive treatment post-surgery includes conventional immunosuppressants as well as antiviral drugs. The use of large- and small-molecule antivascular endothelial growth factor (VEGF) agents remains an integral part of pterygium treatment as well as other neovascular conditions of the eye. Naturally occurring polyphenolic compounds have favorable characteristics for treating neovascular and inflammatory eye conditions, including good efficacy, stability, cost-effectiveness, and the versatility of their chemical synthesis. In this review, we discuss pharmacological treatments of pterygium. Natural products, such curcumin, ellagic acid, and chalcones, are reviewed, with emphasis on their potential as future pterygium treatments.

Sustained release ocular drug delivery systems for glaucoma therapy.

INTRODUCTION: Glaucoma is a group of progressive optic neuropathies resulting in irreversible blindness. It is associated with an elevation of intraocular pressure (>21 mm Hg) and optic nerve damage. Reduction of the intraocular pressure (IOP) through the administration of ocular hypotensive eye drops is one of the most common therapeutic strategies. Patient adherence to conventional eye drops remains a major obstacle in preventing glaucoma progression. Additional problems emerge from inadequate patient education as well as local and systemic side effects associated with adminstering ocular hypotensive drugs. AREAS COVERED: Sustained-release drug delivery systems for glaucoma treatment are classified into extraocular systems including wearable ocular surface devices or multi-use (immediate-release) eye formulations (such as aqueous solutions, gels; ocular inserts, contact lenses, periocular rings, or punctual plugs) and intraocular drug delivery systems (such as intraocular implants, and microspheres for supraciliary drug delivery). EXPERT OPINION: Sustained release platforms for the delivery of ocular hypotensive drugs (small molecules and biologics) may improve patient adherence and prevent vision loss. Such innovations will only be widely adopted when efficacy and safety has been established through large-scale trials. Sustained release drug delivery can improve glaucoma treatment adherence and reverse/prevent vision deterioration. It is expected that these approaches will improve clinical management and prognosis of glaucoma.

Overview of Tissue Engineering and Drug Delivery Applications of Reactive Electrospinning and Crosslinking Techniques of Polymeric Nanofibers with Highlights on Their Biocompatibility Testing and Regulatory Aspects.

Traditional electrospinning is a promising technique for fabricating nanofibers for tissue engineering and drug delivery applications. The method is highly efficient in producing nanofibers with morphology and porosity similar to the extracellular matrix. Nonetheless, and in many instances, the process has faced several limitations, including weak mechanical strength, large diameter distributions, and scaling-up difficulties of its fabricated electrospun nanofibers. The constraints of the polymer solution's intrinsic properties are primarily responsible for these limitations. Reactive electrospinning constitutes a novel and modified electrospinning techniques developed to overcome those challenges and improve the properties of the fabricated fibers intended for various biomedical applications. This review mainly addresses reactive electrospinning techniques, a relatively new approach for making in situ or post-crosslinked nanofibers. It provides an overview of and discusses the recent literature about chemical and photoreactive electrospinning, their various techniques, their biomedical applications, and FDA regulatory aspects related to their approval and marketing. Another aspect highlighted in this review is the use of crosslinking and reactive electrospinning techniques to enhance the fabricated nanofibers' physicochemical and mechanical properties and make them more biocompatible and tailored for advanced intelligent drug delivery and tissue engineering applications.

A hybrid ocular delivery system of cyclosporine-A comprising nanomicelle-laden polymeric inserts with improved efficacy and tolerability.

We report on hybrid nanomicelle-polymer inserts for improved delivery of cyclosporine A (CyA) to the surface of the eye. Hybrid inserts containing a nanomicellar formulation were prepared by the solvent casting method; their characteristics, in vitro release of CyA, eye irritation potential, nanomicelle distribution inside the insert, and in vivo pharmacokinetics of the most promising solid formulation (F3) were investigated. Nanomicelles capable of accommodating a therapeutically relevant amount of CyA (57.22 ± 5.90-68.52 ± 1.4 µg) were incorporated into five different polymeric formulations (F1-F5). The developed inserts displayed promising characteristics (size, weight, surface pH, and contact angle) that fulfill ocular tolerability requirements. Considering the technological properties and CyA in vitro release, F3 and F5 were the most promising formulations. SEM analysis suggested the F3 formulation as the potential prototype for CyA ocular delivery. The F3 formulation (CyA: 60.08 ± 2.85 µg) did not induce conjunctival irritation when HET-CAM assay was performed and was hence considered suitable for further study in a rabbit eye. The AUC value for CyA loaded in the F3 insert was about 2-fold greater than that obtained with the Ikervis® used as a control formulation. F3 produced a significant reduction (of about 7-folds) in the rate of CyA elimination from the tear fluid relative to Ikervis® and about 4-fold greater reduction than Nano-CyA (p = 0.0187). The ability of F3 to delay the elimination of the drug from the precorneal area is particularly desirable when treating dry eye syndrome. Furthermore, F3 did not induce ocular discomfort, a typical characteristic of solid ocular inserts, including commercially available ones.

Studies on Surfactants, Cosurfactants, and Oils for Prospective Use in Formulation of Ketorolac Tromethamine Ophthalmic Nanoemulsions.

Nanoemulsions (NE) are isotropic, dispersions of oil, water, surfactant(s) and cosurfactant(s). A range of components (11 surfactants, nine cosurfactants, and five oils) were investigated as potential excipients for preparation of ketorolac tromethamine (KT) ocular nanoemulsion. Diol cosurfactants were investigated for the effect of their carbon chain length and dielectric constant (DEC), Log P, and HLB on saturation solubility of KT. Hen's Egg Test-ChorioAllantoic Membrane (HET-CAM) assay was used to evaluate conjunctival irritation of selected excipients. Of the investigated surfactants, Tween 60 achieved the highest KT solubility (9.89 ± 0.17 mg/mL), followed by Cremophor RH 40 (9.00 ± 0.21 mg/mL); amongst cosurfactants of interest ethylene glycol yielded the highest KT solubility (36.84 ± 0.40 mg/mL), followed by propylene glycol (26.23 ± 0.82 mg/mL). The solubility of KT in cosurfactants was affected by four molecular descriptors: carbon chain length, DEC, log P and HLB. KT solubility was directly proportional to DEC and the HLB yet, inversely proportional to carbon chain length and log P. All surfactants, except Labrasol ALF, were non-irritant. The majority of cosurfactants were slightly irritant, butylene glycol was a moderate irritant, pentylene and hexylene glycols were strong irritants. These findings will inform experiments aimed at developing NE formulations for ocular administration of KT.

Polymeric long-acting drug delivery systems (LADDS) for treatment of chronic diseases: Inserts, patches, wafers, and implants.

Non-oral long-acting drug delivery systems (LADDS) encompass a range of technologies for precisely delivering drug molecules into target tissues either through the systemic circulation or via localized injections for treating chronic diseases like diabetes, cancer, and brain disorders as well as for age-related eye diseases. LADDS have been shown to prolong drug release from 24 h up to 3 years depending on characteristics of the drug and delivery system. LADDS can offer potentially safer, more effective, and patient friendly treatment options compared to more invasive modes of drug administration such as repeated injections or minor surgical intervention. Whilst there is no single technology or definition that can comprehensively embrace LADDS; for the purposes of this review, these systems include solid implants, inserts, transdermal patches, wafers and in situ forming delivery systems. This review covers common chronic illnesses, where candidate drugs have been incorporated into LADDS, examples of marketed long-acting pharmaceuticals, as well as newly emerging technologies, used in the fabrication of LADDS.

Monocaprin eye drop formulation to combat antibiotic resistant gonococcal blindness.

Neisseria gonorrhoeae bacteria are acknowledged as an urgent threat to human health because this species has developed resistances to all of the antibiotics used clinically to treat its infections. N. gonorrhoeae causes the sexually transmitted disease gonorrhoea, but also causes blindness when the bacteria infect the eyes. Infants are particularly susceptible, acquiring the infection from their mothers at birth. We have shown that the monoglyceride monocaprin rapidly kills N. gonorrhoeae and other bacterial species and is non-irritating in ocular assays. Here we show that the physical and chemical properties of monocaprin make it ideal for use in a thickened eye drop formulation to combat eye infections. Monocaprin-containing formulations were assessed using analytical techniques and for antimicrobial activity in vitro and in ex vivo infections. Monocaprin-containing formulations retained activity after three years and are non-irritating, unlike preparations of povidone iodine in our assays. A recommended formulation for further development and investigation is 0.25% monocaprin in 1% HPMC with 1% polysorbate 20.

Retinal cell regeneration using tissue engineered polymeric scaffolds.

Degenerative retinal diseases, such as age-related macular degeneration (AMD), can lead to permanent sight loss. Although intravitreal anti-vascular endothelial growth factor (VEGF) and steroid injections are effective for the management of early stages of wet and/or neovascular AMD (nAMD), no proven treatments currently exist for dry AMD or for the advanced geographic atrophy of the retina that follows. Tissue engineering (TE) has recently emerged as a promising alternative to repair retinal damaged and restore its functions. Here, we review recent advances in TE, with a particular emphasis on retinal regeneration. We provide an overview of retinal diseases, followed by a comprehensive review of TE techniques, cells, and polymers used in the fabrication of scaffolds for retinal cell regenerations, in particular the retinal pigment epithelium (RPE).

Engineering and Development of Chitosan-Based Nanocoatings for Ocular Contact Lenses.

This article reports on electrohydrodynamic atomization to engineer on-demand novel coatings for ocular contact lenses. A formulation approach was adopted to modulate the release of timolol maleate (TM) using chitosan and borneol. Polymers polyvinylpyrrolidone and poly (N-isopropylacrylamide) were utilized to encapsulate TM and were electrically atomized to produce optimized, stationary contact lens coatings. The particle and fiber diameter, thermal stability, material compatibility of the formed coatings, their in vitro release-modulating effect, and ocular tolerability were investigated. Results demonstrated highly stable nanomatrices with advantageous morphology and size. All formulations yielded coatings with high TM encapsulation (>88%) and excellent ocular biocompatibility. Coatings yielded biphasic and triphasic release, depending on composition. Kinetic modeling revealed a noticeable effect of chitosan; the higher the concentration, the more the release of TM because of chitosan swelling, with the mechanism changing from Fickian diffusion (1% w/v; n = 0.5) to non-Fickian (5% w/v, 0.45

Ophthalmic gels: Past, present and future.

Aqueous gels formulated using hydrophilic polymers (hydrogels) along with those based on stimuli responsive polymers (in situ gelling or gel forming systems) continue to attract increasing interest for various eye health-related applications. They allow the incorporation of a variety of ophthalmic pharmaceuticals to achieve therapeutic levels of drugs and bioactives at target ocular sites. The integration of sophisticated drug delivery technologies such as nanotechnology-based ones with intelligent and environment responsive systems can extend current treatment duration to provide more clinically relevant time courses (weeks and months instead of hours and days) which will inevitably reduce dose frequency, increase patient compliance and improve clinical outcomes. Novel applications and design of contact lenses and intracanalicular delivery devices along with the move towards integrating gels into various drug delivery devices like intraocular pumps, injections and implants has the potential to reduce comorbidities caused by glaucoma, corneal keratopathy, cataract, diabetic retinopathies and age-related macular degeneration. This review describes ophthalmic gelling systems with emphasis on mechanism of gel formation and application in ophthalmology. It provides a critical appraisal of the techniques and methods used in the characterization of ophthalmic preformed gels and in situ gelling systems along with a thorough insight into the safety and biocompatibility of these systems. Newly developed ophthalmic gels, hydrogels, preformed gels and in situ gelling systems including the latest in the area of stimuli responsive gels, molecularly imprinted gels, nanogels, 3D printed hydrogels; 3D printed devices comprising ophthalmic gels are covered. Finally, new applications of gels in the production of artificial corneas, corneal wound healing and hydrogel contact lenses are described.

Fatty Acid Based Microemulsions to Combat Ophthalmia Neonatorum Caused by Neisseria gonorrhoeae and Staphylococcus aureus.

The bacterial species Neisseria gonorrhoeae (N. gonorrhoeae) and Staphylococcus aureus (S. aureus) are amongst the main microorganisms that cause ophthalmia neonatorum. The current treatment involves the use of various antibiotics such as ciprofloxacin, cephalosporin, ceftriaxone and cefotaxime. However, this treatment strategy is becoming more ineffective due to the antibiotic resistance in N. gonorrhoeae. The current study explores the potential use of fatty acid based microemulsions (ME) to prevent N. gonorrhoeae and S. aureus infections in new-borns' eyes without harmful side effects such as corneal or conjunctiva irritation. Pseudo-ternary phase diagrams were constructed to evaluate microemulsion regions and six different α-linolenic acid based microemulsions were prepared. The prepared formulations were characterized for α-linolenic acid content, size, transparency, zeta potential, Polarized light Microscopy, antimicrobial activity and ex vivo ocular toxicity. The mean droplet size of the ME formulations was in the range of 190.4 to 350.5 nm and polydispersity index (PDI) values were in the range of 0.102 to 0.561. All formulations were found stable upon storage for at least 8 weeks. In addition, self-diffusion coefficients determined by nuclear magnetic resonance (NMR) reflected that the diffusability of water increased at higher than 30% w/w water, while that of fatty acids and surfactants was in reverse. The antimicrobial efficacy of microemulsions was determined against N. gonorrhoeae and S. aureus. It was concluded that all microemulsions have strong antimicrobial effects against N. gonorrhoeae and S. aureus. Finally, bovine corneal opacity permeability (BCOP) and hen's egg chorioallantoic (HET-CAM) tests results showed that all microemulsion formulations were not strong ocular irritants.

Development and characterisation of electrospun timolol maleate-loaded polymeric contact lens coatings containing various permeation enhancers.

Despite exponential growth in research relating to sustained and controlled ocular drug delivery, anatomical and chemical barriers of the eye still pose formulation challenges. Nanotechnology integration into the pharmaceutical industry has aided efforts in potential ocular drug device development. Here, the integration and in vitro effect of four different permeation enhancers (PEs) on the release of anti-glaucoma drug timolol maleate (TM) from polymeric nanofiber formulations is explored. Electrohydrodynamic (EHD) engineering, more specifically electrospinning, was used to engineer nanofibers (NFs) which coated the exterior of contact lenses. Parameters used for engineering included flow rates ranging from 8 to 15µL/min and a novel EHD deposition system was used; capable of hosting four lenses, masked template and a ground electrode to direct charged atomised structures. SEM analysis of the electrospun structures confirmed the presence of smooth nano-fibers; whilst thermal analysis confirmed the stability of all formulations. In vitro release studies demonstrated a triphasic release; initial burst release with two subsequent sustained release phases with most of the drug being released after 24h (86.7%) Biological evaluation studies confirmed the tolerability of all formulations tested with release kinetics modelling results showing drug release was via quasi-Fickian or Fickian diffusion. There were evident differences (p<0.05) in TM release dependant on permeation enhancer.

Stainless steel with tailored porosity using canister-free hot isostatic pressing for improved osseointegration implants.

Porous biomedical implants hold great potential in preventing stress shielding while improving bone osseointegration and regeneration. In this paper, a novel approach is introduced to control the porosity of 316L stainless steel implants by using canister-free hot isostatic pressing (CF-HIPing). The proposed approach uses cold isostatic pressing (CIPing) to generate powder compacts with various particle sizes, followed by CF-HIPing. 316L stainless steel samples with controlled porosity, and mechanical and biological properties were successfully achieved. The results showed a significant increase in the samples' porosity with increasing powder size. Porous structures with a strength of 108-360 MPa, Vickers hardness of 25-49 HV and elastic modulus between 17 and 50 GPa were produced using a particle size range of 5-50 µm. The effect of samples with various porosities on the in vitro response of mouse pre-osteoblastic cells in terms of toxicity and proliferation was studied. All samples showed that they had a minimal toxic effect on the osteoblasts. Samples with low porosity, prepared using a particle size of 5 µm, were believed to hinder the transport of nutrients and oxygen to the cells and hence had lower proliferation. In addition, samples prepared using a particle size range of 16-50 µm were associated with an increased proliferation and are therefore expected to improve the rate of bone osseointegration.

Electrically atomised formulations of timolol maleate for direct and on-demand ocular lens coatings.

Advances in nanotechnology have enabled solutions for challenging drug delivery targets. While the eye presents numerous emerging opportunities for delivery, analysis and sensing; issues persist for conventional applications. This includes liquid phase formulation localisation on the ocular surface once administered as formulated eye-drops; with the vast majority of dosage (>90%) escaping from the administered site due to tear production and various drainage mechanisms. The work presented here demonstrates a single needle electrohydrodynamic (EHD) engineering process to nano-coat (as an on demand and controllable fiber depositing method) the surface of multiple contact lenses rendering formulations to be stationary on the lens and at the bio-interface. The coating process was operational based on ejected droplet charge and glaucoma drug timolol maleate (TM) was used to demonstrate surface coating optimisation, bio-surface permeation properties (flux, using a bovine model) and various kinetic models thereafter. Polymers PVP, PNIPAM and PVP:PNIPAM (50:50%w/w) were used to encapsulate the active. Nano-fibrous and particulate samples were characterised using SEM, FTIR, DSC and TGA to confirm structural and thermal stability of surface coated formulations. More than 52% of nano-structured coatings (for all formulations) were <200nm in diameter. In vitro studies show coatings to exhibit biphasic release profiles; an initial burst release followed by sustained release; with TM-loaded PNIPAM coating releasing most drug after 24h (89.8%). Kinetic modelling (Higuchi, Korsmeyer-Peppas) was indicative of quasi-Fickian diffusion whilst biological evaluation demonstrates adequate ocular tolerability. Results from permeation studies indicate coated lenses are ideal to reduce dosing regimen, which in turn will reduce systemic drug absorption. Florescent microscopy demonstrated probe and probe embedded coating behaviour from lens surface in vitro. The multiple lens surface coating method demonstrates sustained drug release yielding promising results; suggesting both novel device and method to enhance drug activity at the eyes surface which will reduce formulation drainage.