Lipid-based eye drop formulations for the management of evaporative dry eyes.

Dry eye disease is a progressive prevalent ocular surface disorder that arises from various factors and is characterized by insufficient quality and/or quantity of tears. The underlying pathophysiology is intricate and can progress to chronic, difficult-to-treat conditions. Multiple strategies and therapeutic approaches are utilized in its management that target one or more etiopathological components of dry eyes, which may include aqueous tear deficiency or evaporative dry eyes. The primary focus of this paper is on treatment alternatives that utilize lipids for the treatment of evaporative dry eyes. This may arise from either abnormal lipid production or inadequate lipid spreading caused by meibomian gland dysfunction. The hypothesis behind the development of these lipid-containing eye drops is that if they can imitate the lipid layer, they may be able to help in the management of the signs and symptoms of evaporative dry eyes. The lipids used in commercial formulations for dry eyes are mineral oil, castor oil, phospholipids, omega-3 fatty acid, and medium-chain triglycerides. The literature suggests the potential of lipid-containing eye drops to alleviate some of the signs and symptoms and enhance the quality of life for individuals suffering from evaporative dry eyes.

Chitosan nanoparticles laden contact lenses for enzyme-triggered controlled delivery of timolol maleate: A promising strategy for managing glaucoma.

To improve drug bioavailability, eye drops can be replaced by drug-eluting contact lenses. However, issues of drug leaching from lenses during manufacture and storage, and sterilization, currently limit their commercial application. To address the issues, stimuli-(lysozyme)-sensitive chitosan nanoparticles were developed to provide controlled ocular drug delivery. Nanoparticles were prepared by ionic gelation and characterized by TEM, X-ray diffraction, DSC, and FTIR. In the flux study, conventional-soaked contact lenses (SM-TM-CL) showed high-burst release, while with direct drug-only laden contact lenses (DL-TM-CL) the drug was lost during extraction and sterilization, as well as having poor swelling and optical properties. The nanoparticle-laden contact lenses (TM-Cht-NPs) showed controlled release of timolol for 120 h in the presence of lysozyme, with acceptable opto-physical properties. In the shelf-life study, the TM-Cht-NPs contact lenses showed no leaching or alteration in the drug release pattern. In animal studies, the TM-NPs-CL lenses gave a high drug concentration in rabbit tear fluid (mean = 11.01 µg/mL for 56 h) and helped maintain a low intraocular pressure for 120 h. In conclusion, the chitosan nanoparticle-laden contact lenses demonstrated the potential application to treat glaucoma with acceptable opto-physical properties and addressed the issues of drug-leaching during sterilization and storage.

In vitro and in vivo evaluation of cyclosporine-graphene oxide laden hydrogel contact lenses.

Drug-eluting contact lens can substitute the multiple eye drop therapy. However, loading hydrophobic drug like cyclosporine in the contact lens is very challenging, due to low drug uptake (via soaking method); and alteration in the swelling and optical properties which restricts its clinical application. To address the above issues, graphene oxide (GO, large surface area with oxygen containing functional groups) was incorporated in the contact lenses during fabrication. These GO-laden contact lenses (SM-GO-Cys) as well as blank contact lenses (SM-Cys) were soaked in the solution of cyclosporine. Alternatively, cyclosporine-laden contact lenses (DL-Cys-20) and cyclosporine-GO-laden contact lenses (DL-Cys-20-GO) were fabricated by adding drug and drug-GO (at various level of GO) during fabrication, respectively. Contact angle and swelling data showed increase in water holding capacity of GO laden contact lenses. Optical property was significantly improved due to molecular dispersion of drug on the surface of GO sheets. The drug uptake and in vitro release profile was improved with GO-laden contact lenses by soaking method (SM-GO-Cys-400n) due to hydrophobic interactions between GO and drug. Adding cyclosporine-GO (DL-Cys-20-GO-800n) during fabrication significantly improved drug release kinetics with higher drug leaching (during extraction and sterilization) due to increased swelling, improved dissolution and molecular dispersion of drug on GO sheets. Ocular irritation and histopathological studies demonstrated the safety of GO-contact lens. The in vivo drug release studies in the rabbit eye showed significant improvement in mean residence time (MRT) and area under the curve (AUC) using DL-Cys-20-GO-800n contact lens compared to eye drop solution with reduction in protein adherence value. The study demonstrated that the incorporation of GO into the contact lens can control the release of cyclosporine as well as improved the lens swelling and transmittance properties.

Recent advances in ophthalmic preparations: Ocular barriers, dosage forms and routes of administration.

The human eye is a complex organ with unique anatomy and physiology that restricts the delivery of drugs to target ocular tissues/sites. Recent advances in the field of pharmacy, biotechnology and material science have led to development of novel ophthalmic dosage forms which can provide sustained drug delivery, reduce dosing frequency and improve the ocular bioavailability of drugs. This review highlights the different anatomical and physiological factors which affect ocular bioavailability of drugs and explores advancements from 2016 to 2020 in various ophthalmic preparations. Different routes of drug administration such as topical, intravitreal, intraocular, juxtascleral, subconjunctival, intracameral and retrobulbar are discussed with their advances and limitations.

Advances and challenges in the nanoparticles-laden contact lenses for ocular drug delivery.

The delivery of drugs that target ocular tissues is challenging due to the physiological barriers of the eye like tear dilution, nasolacrimal drainage, blinking, tear turnover rate and low residence time Drug-laden contact lenses can be a possible solution to overcome some of these challenges. Nanoparticles are being extensively studied as novel systems for loading drugs into therapeutic contact lenses. The versatile features of the organic and inorganic nanoparticles and their diverse physicochemical properties make it possible to load and sustain drug release from the contact lenses. Nevertheless, several issues remains to be solved before its clinical application and commercialization such as changes in contact lens swelling (water content), transmittance, protein adherence, surface roughness, tensile strength, ion and oxygen permeability and drug leaching during contact lens manufacture. However, clinical studies demonstrated the potential of therapeutic contact lenses to manage the scientific, commercial and regulatory challenges to make its place in the market. This review highlights the different methodologies used to fabricate nanoparticle-laden contact lenses and highlights the major advances and challenges to commercialization.

Controlled bimatoprost release from graphene oxide laden contact lenses: In vitro and in vivo studies.

Ocular drug delivery using contact lenses may be able to substitute for eye drop therapy. However, issues with hydrophobic drugs (like bimatoprost that is used to treat glaucoma) such as low drug uptake using a simple soaking method into preformed contact lenses and alteration in the swelling and transmittance of lenses restricts the application for drug delivery. This research uses graphene oxide (GO) to control the release of bimatoprost from contact lenses along with improvements in the drug uptake, and lens swelling and transmittance. GO was loaded into silicone hydrogel contact lenses by adding the GO at the same time as lenses were polymerized. These lenses were soaked in bimatoprost. Alternatively contact lenses, either with or without GO, were produced by adding bimatoprost during lens polymerization. GO improved contact lens swelling due to its water binding capacity and lens transmittance due to the molecular dispersion of bimatoprost on the surface of the GO which prevented the local precipitation of the drug. The bimatoprost uptake was not improved in the presence of GO. However, its in vitro release profile was improved. Adding bimatoprost and GO at the same time as lenses were polymerized (DL-GO-BMT) significantly decreased the loss of drug during extraction and sterilization in comparison to contact lenses (DL-BMT) without GO. As the amount of GO was increased, the DL-GO-BMT lenses showed a significant decrease in the burst and cumulative release of bimatoprost. Ocular irritation and histopathology reports demonstrated the safety of GO contact lens. The in vivo pharmacokinetic studies in the rabbit tear fluid showed significant improvement in mean residence time (MRT) and area under the curve (AUC) with DL-GO-0.2 µg-BMT-100 contact lens in comparison to eye drop solution. The study demonstrated that the addition of GO to contact lenses can control the release of bimatoprost as well as improved the lens swelling and transmittance. However, further optimization is needed to modulate the release of drug within the therapeutic level to manage glaucoma.

Thermoresponsive liquid crystalline formulation of Exemestane: Design and structural characterization.

Exemestane (EXE), a drug used for the treatment of breast cancer, has limited aqueous solubility of 0.08 mg/mL and log P∼ 4.22. The only available marketed formulation in form of tablets possess limitations of poor oral absorption (∼ 42 %), low solubility, extensive hepatic metabolism and numerous adverse effects due to its peripheral absorption. In order to address these issues, an alternative route of topical application is attempted through a lamellar liquid crystal based formulation. Pluronic® was used as stabilizer due to its higher surface activity and gelling properties. The solubility enhancement of EXE was achieved using liquid crystal formulation. We have investigated the effect of concentration of oil, Smix (surfactant - cosurfactant mixture) and EXE on lattice parameter, rheology and drug release for various combinations of the formulation. The small angle x-ray scattering (SAXS) measurement demonstrated an evidence of a lamellar structure with lattice parameter ∼15 nm, which increases with corresponding increase in oil and EXE due to increase in hydrophobic interactions leading to an expansion of lamella. The inter lamellar distance decreases at higher surfactant concentration, due to the distribution of the same amount of oil and drug within larger concentration of surfactant molecules. The rheology measurement exhibited gel like properties at low shear rate indicating soft gel formation, which converts to Newtonian type flowing liquid at higher shear rate. At constant Smix with increasing oil content, the viscosity decreases, which is attributed to the dilution of the lamellar structures with oil. The temperature sweep rheology reveals a change in the viscosity near physiological temperature, which may be attributed to the structural transition of lamellae. The formulation remains gel like at room temperature, which aids in proper application to skin and converts it to free flowing liquid above 37 °C. The invitro drug release of optimized formulation for 24 h was ∼ 38 % at 37 °C, which increased to 50 % at 42 °C. Accordingly, this formulation containing thermoresponsive lamellar liquid crystal gels of EXE represents a viable option for hyperthermia induced enhanced drug release. The characteristic and advantageous features offered by this formulation includes improved bioavailability of EXE due to enhanced solubility, permeability and absorption.

Tailored Doxycycline Hyclate Loaded In Situ Gel for the Treatment of Periodontitis: Optimization, In Vitro Characterization, and Antimicrobial Studies.

Currently, periodontitis is treated by oral dosage forms (antibiotics) which shows systemic side effects and failed to reach the therapeutic concentration (above minimum inhibitory concentration, MIC) in the periodontal pocket. The present study aimed to overcome the above issues, by designing tailored doxycycline hyclate laden in situ gel by Poloxamer 407, chitosan, and polyethylene glycol 600. The in situ gel-forming system has attracted attention owing to its ability of sustained drug release above MIC, easy administration (syringeability), and high drug retention (localization) in the periodontal cavity. The Box-Behnken design (BBD) was used to tailor and optimize the concentration of Poloxamer 407 (X1 = 14.3%), chitosan (X2 = 0.58%), and polyethylene glycol 600 (X3 = 1.14%) to achieve sufficient syringeability (149 N), t90% (1105 min), and viscosity at non-physiological condition (512 cps) and physiological condition (5415 cps). The optimized in situ gel was clear and isotonic (RBCs test). The gelation temperature of the optimized in situ was 34 ± 1°C with sufficient mucoadhesive strength (26 ± 2 dyn/cm2), gel strength (29 ± 2 sec), and texture profile for periodontal application. The in vitro drug release studies showed sustain release from optimized in situ gel (24h) in comparison to marketed gel (7h). The antimicrobial activity (cup plate technique) of the in situ gel was equivalent to the marketed doxycycline gel, which suggests that the doxycycline hyclate retained its antimicrobial efficacy when formulated as in situ gelling system. In conclusion, BBD was effectively utilized to optimize in situ gel with minimum level of polymers to achieve the required characteristics of the in situ gel for sustaining drug delivery to treat periodontitis.

Oral bioavailability improvement of felodipine using tailored microemulsion: Surface science, ex vivo and in vivo studies.

Felodipine is a calcium channel blocker, which shows low oral bioavailability (<15%) owing to poor water solubility and high first pass metabolism. The aim of the present investigation was to study the surface science (dynamic surface tension) and characteristics of microemulsion (Capmul MCM, Tween 20 and polyethylene glycol) to enhance the oral bioavailability of felodipine by improving permeability of the drug in the intestine. The paper is the first attempt to study the stability of oil-water interface of microemulsion using bubble tensiometer. The Smix at 2:1 ratio showed the maximum microemulsion area which did not alter in the presence of drug. The microemulsion batch coded Fe-O5-Smix45 (5% Capmul MCM and 45% Smix) was selected based on transmittance (>99%), dilution (stable after 100 times dilution with water), size (15.1 nm), dispersibility (grade A) and thermodynamic stability studies. The dynamic surface tension at newly created surface indicate the stability of surfactant film at the oil/water interface. The microemulsion was also stable in the presence of drug and in different buffer phases. The ex vivo intestinal permeability studies showed significant increase in the microemulsion permeation (74.1% after 1 h) in comparison to the felodipine suspension (16.9% after 1 h). The in vivo pharmacokinetic parameters in the rat model confirmed the improvement in oral bioavailability with microemulsion (relative bioavailability = 21.9) in comparison to the felodipine suspension, due to high surface area of oil droplets and its lymphatic uptake via transcellular route. In conclusion, the stable microemulsion offers a promising approach to improve the oral bioavailability of felodipine which can help to reduce the dose and its associated side effects.

Novel Poly(vinylpyrrolidone)-Coated Silicone Contact Lenses to Improve Tear Volume During Lens Wear: In Vitro and In Vivo Studies.

Poly(vinylpyrrolidone) (PVP-K90) is widely used to manage dry eye syndrome (DES). The marketed eye drop solutions (high dose) need frequent instillation, affecting the routine lifestyle of patients. PVP-K90-laden contact lenses can be used to overcome the limitations of eye drop solutions (low bioavailability and frequent instillation). However, the conventional methods of PVP-K90 loading show poor loading capacity and short duration of effect. In the present study, we have developed PVP-K90-coated contact lenses via a short curing approach to increase the PVP-K90 loading capacity with a sustained release profile to manage dry eye syndrome. PVP-K90 was loaded by a soaking method (SM-PVP), direct loading (during fabrication, DL-PVP), a combination of soaking and direct loading (DL-SM-PVP), and a novel coating process (SM-PVP-C and DL-SM-PVP-C). The swelling studies suggested improvement in the water uptake (hydration) property of the contact lenses due to the presence of PVP-K90. The optical transparency was within an acceptable range. The in vitro release of PVP-K90 was in the following order: PVP-coated contact lens (168 h) > DL-SM-PVP (168 h) > DL-PVP (96 h) > SM-PVP (72-96 h). PVP-coated contact lenses showed a high burst effect (lubricating effect) and sustained release (3161-448 ng/h between 24 and 168 h) due to high PVP loading/coating in comparison to the uncoated respective contact lenses (964-113 ng/h between 24 and 96 h). In animal studies, the PVP-K90-coated contact lens showed higher tear volume in comparison to the respective uncoated contact lenses and an eye drop solution. This study demonstrates a novel approach of coating a high amount of PVP-K90 on contact lenses for sustained release to manage several ocular diseases like dry eye syndrome, conjunctivitis, and other ocular injuries.

Multiple drug delivery from the drug-implants-laden silicone contact lens: Addressing the issue of burst drug release.

A fixed combination of bimatoprost/timolol eye drop solution is used to manage the elevated intra-ocular pressure in glaucoma patients, including individuals whose condition is poorly controlled by monotherapy. Eye drop solutions are generally given in high dose, due to poor ocular bioavailability. The high ocular dose of bimatoprost and timolol lead to hyperaemia and systemic cardiac side effects respectively. Here, we introduce multiple implant-laden contact lenses (IM) to passively deliver timolol, bimatoprost and hyaluronic acid at therapeutically relevant doses without high burst release. The drug-loaded implants were individually implanted in the outer periphery of the silicone contact lenses. Atomic force microscopy showed the smooth surface of the implant contact lens, as the implants were inside the contact lens matrix. The implant lens (IM) showed major loss of drugs [timolol = 60.60%, bimatoprost = 61.75% and HA = 46.03%] during the monomer extraction and wet sterilization, while the option of dry radiation sterilization (IM-R lens) and hydration for 24 h prior to use showed relatively lower loss of drugs [timolol = 16.87%, bimatoprost = 47.95% and HA = 24.41%]. The in-vitro drugs release data of IM-R lens, showed sustained release for 72 h, with low burst release in comparison to the soaked (SM) and direct drug-laden contact lenses (DL). The in vivo drug release data in the rabbit tear fluid showed sustained release using IM-R lens in comparison to the SM lens and eye drop therapy. The burst release with the IM-R lens was many folds reduced, which could bypass the side effects associated with multiple eye drop therapy. The in vivo pharmacodynamic study in the rabbit model showed peak and valley profile with multiple eye drop therapy, while IM-R lens showed prolong reduction in intra ocular pressure (IOP) for 120 h. The study demonstrates the application of implantation technology to deliver multiple drug through contact lenses to treat glaucoma.

Tailored gatifloxacin Pluronic® F-68-loaded contact lens: Addressing the issue of transmittance and swelling.

Loading of gatifloxacin in contact lenses affects critical lens properties (optical and swelling) owing to drug precipitation in the contact lens matrix. The presence of Pluronic® F-68 in the packaging solution creates in-situ micelles in the contact lens to dissolve gatifloxacin precipitates and provide sustained drug release. The micelles further improved the drug uptake from the drug-packaging solution to create an equilibrium of drug between the lens matrix and the packaging solution. In this study, we optimized gatifloxacin-pluronic-loaded contact lenses to achieve the desired optical transmittance, swelling, and gatifloxacin loading capacity as well as sustained drug delivery. Optimization of gatifloxacin-pluronic-loaded contact lens was carried out using a 32 factorial design by tailoring the concentration of Pluronic® F-68 in the packaging solution (X1) and the amount of gatifloxacin in the monomer solution (X2) to achieve the desired lens properties. The optimized batch (X1 = 0.3%w/v and X2 = 0.3%w/v) showed an optical transmittance of 92.84%, swelling of 92.36% and gatifloxacin loading capacity of 92.56 µg. The in vitro flux data of the optimized batch (GT-Pl-CL) showed sustained release up to 72 h, whereas soaked contact lenses (SM-CL) and direct gatifloxacin-loaded contact lenses (DL-CL) showed a sustained release up to 48 h. The in vivo gatifloxacin release data for rabbit tear fluid showed sustained release with a high gatifloxacin level for the GT-Pl-CL lens in comparison to the SM-CL and the eye drop solution. This study demonstrates the application of the 32 full factorial design to optimize gatifloxacin-pluronic-loaded contact lenses to achieve the desired optical transmittance, swelling, and drug loading capacity.

Cyclosporine laden tailored microemulsion-gel depot for effective treatment of psoriasis: In vitro and in vivo studies.

Psoriasis is a widespread chronic disease affecting 1-3 % of total population. In major cases (>80 %), it is treated by topical application of corticosteroids. However, the topical route is very challenging due to physico-chemical nature of diseased stratum corneum and so no single treatment works for every patient. The oral route showed severe side effects due to systemic immunosuppression, which can be avoided by topical route. The aim of the research work was to investigate cyclosporine loaded microemulsion based gel for effective cyclosporine permeation and retention in the skin tissue for psoriasis treatment. The pseudo ternary phase diagram at three Smix ratios (2:1, 1:1, and 1:2; Tween 80: isopropyl alcohol) were constructed using isopropyl myristate as oil phase. The Smix at 2:1 ratio showed large microemulsion area. The transmission electron microscope images showed spherical non-aggregated oil globules with the size < 50 nm. The selected microemulsion (Cy-2-ME12O55SM) was incorporated in Carbopol 940 gel for topical application. The ex vivo diffusion study showed improved permeation (>24 h) with microemulsion-gel in comparison to cyclosporine suspension. The microemulsion-gel was non-irritating on the rabbit skin. In drug retention studies, microemulsion-gel showed high drug retention (trapping, 38.92 %) in the skin tissue, which was due to destabilization of microemulsion after penetration in the skin layer causing precipitation of cyclosporine. The depot effect due to cyclosporine precipitates could be helpful for sustained effect of cyclosporine for the effective treatment of psoriasis.

Lidocaine tripotassium phosphate complex laden microemulsion for prolonged local anaesthesia: In vitro and in vivo studies.

Lidocaine is widely used as a local anaesthetic in the clinical practice to manage pre- and post-operative pain, skin burns, etc. However, the short duration of action (< 2 h) of marketed dosage forms limit their ability to meet clinical needs. Herein, we prepared a lidocaine-tPP(tri potassium phosphate)-complex loaded microemulsion to achieve greater penetration, followed by destabilization of microemulsion in the skin layer to precipitate oil-complex to produce a depot effect in the skin for prolonging the effects of anaesthesia. The lidocaine-tPP-complex-microemulsion was compared with lidocaine base loaded microemulsion, marketed ointment USP and lidocaine HCl. The pseudo ternary phase diagrams at three Smix ratios (1:2, 1:3 and 1:4; Pluronic F127: PEG 400) were constructed using Capmul MCM C8 EP as oil phase. The Smix at 1:4 ratio showed large microemulsion area in comparison to 1:2 and 1:6 ratio. The lidocaine base (LD-1:4-ME10O45SM and LD-1:4-ME20O45SM) and lidocaine-tPP-complex (LDC-1:4-ME10O45SM and LDC-1:4-ME20O45SM) loaded microemulsion batches (1:4 ratio) were thermodynamically stable. The ex vivo diffusion study showed sustained release up to 12 h with microemulsion batches, in comparison to lidocaine HCl (4 h) and ointment base (7 h). The selected LDC-1:4-ME20O45SM batch was non-irritating on the rabbit skin. In drug retention studies, LD-1:4-ME20O45SM and LDC-1:4-ME20O45SM batches showed 2.68- and 3.93-fold greater lidocaine retention in comparison to ointment USP. The radiant heat tail-flick test showed prolong local anaesthesia using LDC-1:4-ME20O45SM in comparison to ointment USP. The findings suggest that lidocaine-tPP-complex loaded microemulsion could be a potential strategy for providing prolong local anaesthesia.

Plackett-Burman design for screening of critical variables and their effects on the optical transparency and swelling of gatifloxacin-Pluronic-loaded contact lens.

The optical and swelling properties of gatifloxacin-loaded contact lens decrease owing to the precipitation of gatifloxacin (on hydration) in the matrix structure of the contact lens. This paper focuses on the use of Pluronic F68 both inside and outside (in the packaging solution) the contact lens to form micelles to dissolve the gatifloxacin precipitates and not limited to sustain the release of gatifloxacin. The aim of this study was to screen the critical variables affecting the optical and swelling properties of gatifloxacin-loaded contact lens. The independent variables investigated were the concentration of Pluronic F68 incorporated in the monomer solution to fabricate the lens (X1, %w/v), the concentration of Pluronic F68 in the packaging solution (X2, %w/v), the concentration of gatifloxacin incorporated in the monomer solution (X3, %w/v), the concentration of gatifloxacin incorporated in the packaging solution during autoclave (X4, %w/v), the concentration of gatifloxacin incorporated in the packaging solution during extraction (X5, %w/v), the time (stabilization time) after the addition of gatifloxacin and Pluronic F68 to the monomer solution before the fabrication of the lens (X6, h), the pH of the packaging solution (X7), the temperature of the extracted solution (X8, °C), and the curing time for fabricating the contact lens (X9, min). The gatifloxacin-loaded contact lenses were characterized for their optical transmittances after sterilization on day 1 (Y1, %), optical transmittances after 7 days of sterilization (Y2, %) and swelling percentages after 7 days of sterilization (Y3, %). The selected variables showed responses that were in the ranges 53.5% to 97.2%, 51.3% to 92.6%, and 50.3% to 83.7% for Y1, Y2, and Y3, respectively. The data suggest that the presence of Pluronic F68 inside the contact lens (X1) reduced the optical and swelling properties of the contact lens, whereas the presence of Pluronic F68 in the packaging solution (X2) improved them through micelle formation. The other variables (X3 to X9) did not exhibit significant effects on the swelling and transmittance. This study revealed the potential of Plackett-Burman design to screen the selected critical variables that affected the optical and swelling properties of gatifloxacin-loaded contact lens.

Effect of gold nanoparticles on timolol uptake and its release kinetics from contact lenses: In vitro and in vivo evaluation.

Contact lenses are ideally suited for extended drug delivery to the ocular tissues, but incorporation of any particulate system affects the critical properties of the contact lens. Timolol loading by the conventional soaking method does not significantly alter the critical properties of the contact lens. However, there are challenges of low drug loading and high burst release. This research work aimed to investigate the effect of gold nanoparticles (GNPs) on loading and its release kinetics from the contact lens using the soaking method. In one approach, GNPs were loaded into the timolol soaking solution (GNPs-SS), and in another approach, GNPs were incorporated into the contact lenses (GNPs-CL) during fabrication. The contact lenses were soaked at two different concentrations of timolol (i.e., 2 mg/ml and 4 mg/ml). Swelling and optical transmittance were not significantly affected by the presence of GNPs in the contact lenses. A significant uptake/loading of timolol using the GNPs in both the approaches was observed. The in vitro flux data showed no significant improvement in the release rate profiles of timolol when using both approaches. However, the in vivo study in the rabbit tear fluid showed high timolol concentration with the GNPs-laden contact lens at all timepoints in comparison to the soaked contact lenses without GNPs. The in vivo pharmacodynamic study in rabbits showed a 2 mmHg average fall in intraocular pressure (72 h) using the GNPs-laden contact lenses, while the soaked contact lenses without GNPs and eye drops solution (0.5 %w/v) showed 2 mmHg. The drug distribution study in the ocular tissue showed a significant improvement in the drug deposition with the GNPs-laden contact lenses in the ciliary muscle and conjunctiva. This study successfully demonstrated the potential of GNPs to enhance the uptake of drug from the drug soaking solution to treat glaucoma without compromising the critical properties of contact lens. STATEMENT OF SIGNIFICANCE: In this study, we have overcome the limitation of the conventional soaking method of low drug loading and high burst release from the contact lenses. We have investigated the effect of gold nanoparticles (GNPs) on the timolol loading and its release kinetics from the contact lenses. The study revealed the potential of GNPs to enhance the uptake of timolol from the timolol soaking solution to treat glaucoma without compromising the critical lens properties.

Optimization of a novel in situ gel for sustained ocular drug delivery using Box-Behnken design: In vitro, ex vivo, in vivo and human studies.

The aim of the present research work was to formulate, optimize and evaluate the in-situ gel for the ophthalmic drug delivery using the combination of gellan gum and carbopol 934P. The Box-Behnken design was applied to optimize the concentration of gellan gum (X1), carbopol 934P (X2) and benzododecenium bromide (X3) to achieve the maximum viscosity [at physiological condition; 35 °C, pH 7.4, and simulated tear fluid (STF)], mucoadhesive strength, permeability coefficient and sustained release of the drug from the gel with constraint on the viscosity under the non-physiological condition (25 °C, pH 5). Response surface plots were drawn, the statistical validity of the polynomials was established, and optimized formulation was selected by the feasibility and grid search. The design proposed the optimized batch by selecting the independent variables as gellan gum (0.55% w/v), carbopol 934P (0.35% w/v) and benzododecenium bromide (0.013% w/v) to achieve the maximum viscosity (3363 cps) at physiological condition, mucoadhesive strength (22.35 dyn/cm2), t90% (1200 min), permeability coefficient (1.36 × 10-5 sq.cm/sec), with minimum viscosity (131 cps) under the non-physiological condition. The combination of gellan gum and carbopol 934P improved the gelation (synergistic effect) characteristics of the in situ gel. The optimized in situ gel was clear, isotonic, pH 4.7 and showed pseudoplastic flow, high in vitro gelling capacity, low contact angle, acceptable hardness (51018 gm), compressibility (64617 gm) and adhesiveness (74 gm) values for the ocular application. The ex vivo study showed the significant protection of the mast cell from the degranulation. The ocular irritation and histopathology studies in the rabbit eyes confirmed the safety of in situ gel for human use. The in vivo drug release studies showed the presence of drug in the rabbit tear fluid up to 3 h in comparison to just 1 h with the eye drop solution. The contact time of the in situ gel in the human eye was 15.0 ±â€¯2.5 min, which was >2 folds higher than the marketed gel (6.0 ±â€¯3.2 min), which could reduce the dosing frequency and total dose of drug. The Box-Behnken design facilitated the optimization of in situ gel for sustained ophthalmic drug delivery.

Contact lenses with dual drug delivery for the treatment of bacterial conjunctivitis.

Currently, bacterial conjunctivitis is treated by frequent administration of antibiotic eye drop solutions, which is tedious and patient noncompliant. Contact lenses could be ideal medical devices to sustain the release of ophthalmic drugs, but the incorporation of the latter can alter the optical and physical properties of the lenses. In addition, many contact lens users have reported the pink eye syndrome, making them unsuitable as ocular medical devices. In the present study, we have designed a novel type of lenses containing semi-circular rings loaded with moxifloxacin HCl (a broad spectrum antibiotic) and hyaluronic acid (a comfort agent), respectively, in order to treat bacterial conjunctivitis without altering the critical lens properties. The drug loaded rings were implanted separately within the periphery of the contact lenses using the modified cast moulding technology. The atomic force microscopy report showed an average roughness of 22.27 nm for the implant lens, which was significantly lower in comparison to the marketed Freshlook® (116.27 nm) contact lens. The major amount of moxifloxacin HCl was leached (68.16-74.55%) during the monomer extraction and wet sterilization (autoclave) steps; hence the lenses were terminally sterilized by radiation and packaged under dry condition (dehydrated). The in vitro release data showed release for moxifloxacin HCl and hyaluronic acid up to 96 h. The in vivo drug release studies showed significant improvement [>MIC for Staphylococcus aureus] in the drug residence time in comparison to the eye drop therapy. The in vivo efficacy study in the staphylococcus aureus induced conjunctivitis showed equivalent healing effect with the single implant contact lens in comparison to the frequent high dose eye drop therapy. The study demonstrated the successful application of the implantation technology to co-deliver moxifloxacin HCl and hyaluronic acid from the contact lenses for the extended period of time to treat conjunctivitis.

Mechanism of organic pollutants sorption from aqueous solution by cationic tunable organoclays.

A variety of quaternary ammonium salts with different carbon chain lengths were used to modify and convert montmorillonite clay to organoclays. The surface modification attributing to the wettability was investigated using various techniques. The zeta-potential values of all clays showed pH dependency. The prepared organoclays were utilized for phenol (protic) and nitrobenzene (aprotic) adsorption in a batch system, with pH and contact time as variables. The optimized removal for phenol and nitrobenzene within 30 min of equilibrium observed at pH 9.0 and 5.0, respectively. Observed equilibrium data followed the Langmuir monolayer adsorption kinetics with two adsorption sites (outer-layer and interlayer) for purified clay, and third additional sites for organoclays. Kinetic studies revealed that the adsorption of phenol was in the order of mono- > tetra- > di- > benzyl-substituted organoclays, which is similar to the hydrophilicity order. However, the exact opposite trend of adsorption was observed for nitrobenzene. From the performed quantitative study, it is inferred that -OH functional phenol and -NO2 functional nitrobenzene have an affinity towards the hydrophilic clay surface and hydrophobic surfaces of quaternary ammonium salts as its first preference, respectively. This study brings promising observations and implications to the vital structural-property relationship for selective adsorption of pollutants from aqueous solutions.