Design, optimization, in vitro and in vivo evaluation of triamcinolone acetonide nanocrystals loaded in situ gel for topical ocular delivery.

Triamcinolone acetonide (TAA), a long-acting synthetic glucocorticoid, is commonly used for the management of posterior uveitis (PU) because of its anti-inflammatory and immunosuppressive characteristics. The commercially available formulation is in the suspension form advised for intravitreal injection, which has a number of serious problems. In the present research work, we prepared TAA nanocrystals (TAA-NCs) using the principles of design of experiments (DoE). The optimized TAA-NCs had a particle size of 243.0 ± 6.5 nm and a yield (%) of 89.4 ± 4.3%. The optimized TAA-NCs were suspended in a dual-responsive in situ gelling system, which has been previously reported by our team. The TAA-NCs loaded in situ gel (TAA-NC-ISG) formulations were evaluated for rheology, stability, in vitro and in vivo characteristics. The ocular pharmacokinetic investigations revealed that TAA-NCs loaded in situ gel achieved higher concentrations (Cmax of TAA-NC-ISG = 854.9 ng/mL) of the drug in vitreous humor and sustained (MRT0-∞ of TAA-NC-ISG = 11.2 h) the drug concentrations for longer duration compared to aqueous suspension of TAA-NCs (TAA-NC-Susp) and aqueous suspension of TAA with 20% hydroxypropyl ß-cyclodextrin(TAA-HP-ß-CD-Susp) reported in our previous work. This higher exposure of TAA by TAA-NC-ISG is due to the combined effect of the nanometric size of the TAA nanocrystals and the in situ gelling properties of the formulation.

Design and Optimization of Solid Lipid Nanoparticles Loaded with Triamcinolone Acetonide.

Principles of quality by design and design of experiments are acquiring more importance in the discovery and application of new drug carriers, such as solid lipid nanoparticles. In this work, an optimized synthesis of solid lipid nanoparticles loaded with Triamcinolone Acetonide is presented using an approach that involves Stearic Acid as a lipid, soy PC as an ionic surfactant, and Tween 80 as a nonionic surfactant. The constructed circumscribed Central Composite Design considers the lipid and nonionic surfactant quantities and the sonication amplitude in order to optimize particle size and Zeta potential, both measured by means of Dynamic Light Scattering, while the separation of unentrapped drug from the optimized Triamcinolone Acetonide-loaded solid lipid nanoparticles formulation is performed by Size Exclusion Chromatography and, subsequently, the encapsulation efficiency is determined by HPLC-DAD. The proposed optimized formulation-with the goal of maximizing Zeta potential and minimizing particle size-has shown good accordance with predicted values of Zeta potential and dimensions, as well as a high value of encapsulated Triamcinolone Acetonide. Experimental values obtained from the optimized synthesis reports a dimension of 683 ± 5 nm, which differs by 3% from the predicted value, and a Zeta potential of -38.0 ± 7.6 mV (12% difference from the predicted value).

Hybrids between H2S-donors and betamethasone 17-valerate or triamcinolone acetonide inhibit mast cell degranulation and promote hyperpolarization of bronchial smooth muscle cells.

Glucocorticoids represent the standard gold treatment of inflammation in asthmatic patients. More recently, H2S has been described to exert positive effect on this disease. Bearing in mind that an improved pharmacological activity and a reduced toxicity can be obtained through hybridization of different molecules, simultaneously modulating multiple targets, we designed and synthesized novel betamethasone 17-valerate and triamcinolone acetonide hybrids with well-known H2S-donor moieties. Synthesized compounds have been evaluated for the potential H2S-releasing profile both in cell-free environment and into the cytosol of bronchial smooth muscle cells (BSMCs). The two hybrids 4b and 5b were investigated by molecular modelling studies and results indicated that the steric accessibility of the isothiocyanate carbon atom can account for their different H2S releasing properties. Furthermore, the most promising derivatives 4b and 5b have been tested for inhibitory effect on mast cell degranulation and for the ability to induce cell membrane hyperpolarization in BSMCs. Significant inhibitory effect on mast cell degranulation was assessed, resulting to reduce ß-hexosaminidase release more efficiently than the corresponding native drugs. Both compounds determined a massive membrane hyperpolarization of BSMCs and proved to be 4-fold more effective compared to reference compound NS1619. These effects represent an enrichment of the pharmacological activity of the native drugs.

Nanodelivery of triamcinolone acetonide with PLGA-chitosan nanoparticles for the treatment of ocular inflammation.

Triamcinolone acetonide (TA) is widely indicated in the treatment of several ocular disorders, but the free drug suspension limits its clinical benefits and commercial compositions cause adverse ocular effects. In this study, TA was formulated in poly(d,l-lactide-co-glycolide) (PLGA)-chitosan (PLC) nanoparticles (NPs) for the treatment of ocular inflammatory diseases. TA-loaded PLC NPs exhibited excellent anti-inflammatory activity against human corneal epithelial (HCE) cells and significantly reduced the secretion of interleukin (IL)-6 in tumour necrosis factor (TNF)-α activated cells. In a rabbit model, TA-loaded PLC NPs did not show any typical clinical signs of eye inflammation and significantly alleviated inflammatory signs, compared with free TA suspension, at 24 h after a single dose. TA-loaded PLC NPs exhibited a greater aqueous humour transparency (%AHT), compared with that of normal saline (NS) or free TA suspension, indicating reduction in anterior chamber fogginess. Pharmacokinetic analysis of rabbit eyes revealed that TA-loaded PLC NPs peaked at 6 h. Substantial concentrations of TA were observed until 24 h, indicating the superiority of this PLC-based nanocarrier system. Overall, PLC-based NP formulations offer a new approach for the treatment of ocular inflammatory diseases.

Topical instillation of triamcinolone acetonide-loaded emulsomes for posterior ocular delivery: statistical optimization and in vitro-in vivo studies.

The objective of the present investigation was to formulate and characterize a novel lipid-based carrier-emulsomes loaded with triamcinolone acetonide (TA)/Nile red (NR) for non-invasive delivery to the posterior segment of the eye upon topical application. To optimize and delineate the effect of independent variables on dependent variables, Box-Behnken design (BBD) was adopted. The optimized batch was characterized for size, zeta potential, surface morphology by transmission electron microscopy, drug-excipient interaction by differential scanning calorimetry, osmolarity, pH, ex vivo transcorneal permeation, and stability studies. A short-term exposure (STE) test was performed on Statens Seruminstitut Rabbit Corneal (SIRC) cell lines to evaluate the in vitro ocular irritation. Precorneal retention study was performed in rabbit eyes. Confocal microscopy was used for ocular distribution studies in mice eye by preparing dye (Nile red)-loaded formulations. The surface response and contour plots along with ANOVA results demonstrated an interaction between the factors. The optimized batch had particle size of 131.17 ± 3.17 nm and entrapment efficiency of 71.56 ± 4.19%. TEM image showed unimodal, nano-sized emulsomes. TA-loaded emulsomes exhibited higher transcorneal permeation as compared to drug solution. In vitro irritation studies confirmed the safety of excipients for ophthalmic use. Fluorescence microscopic images obtained after ocular distribution studies showed strong fluorescence in inner and outer plexiform layers of the retina in comparison to dye solution confirming the delivery of dye to the posterior segment of mice eye after topical ocular instillation. Graphical abstract.

Development of Spray Formulations Applied to the Oral Mucosa Using Non-lamellar Liquid Crystal-Forming Lipids.

We examined the physicochemical and biochemical properties of mono-O-(5,9,13-trimethyl-4-tetradecenyl)glycerol ester (MGE), including ease of handling, high bioadhesiveness, quick and stable in vivo self-organization (forming a non-lamellar lyotropic liquid crystal [NLLC]), and high biomembrane permeation enhancement. We prepared MGE oral mucosa-applied spray preparations containing triamcinolone acetonide (TA), which is widely used in the treatment of stomatitis, and we examined the usefulness of the MGE preparations compared with commercially available oral mucosal application preparations containing 2,3-dihydroxypropyl oleate (1-mono(cis-9-octadecenoyl)glycerol (GMO) (previously studied as an NLLC-forming lipid) preparation. As a result, the MGE preparation applied to the oral mucosa can rapidly formed an NLLC with reverse hexagonal or cubic structures, or a mixture, on contact with water. In addition, by adding hydroxypropyl cellulose to the MGE preparation, similar retention properties on the oral mucous membrane were obtained to that using marketed drug preparations. Furthermore, the MGE spray formulation on the oral mucosa showed an equivalent or higher TA release as well as oral mucous membrane permeability compared with commercial formulations. Because MGE forms a stable NLLC and is easy to handle compared with GMO, MGE was considered to be a useful pharmaceutical additive for a spray preparation applied to the oral mucosa in combination.

Microparticles-in-Thermoresponsive/Bioadhesive Hydrogels as a Novel Integrated Platform for Effective Intra-articular Delivery of Triamcinolone Acetonide.

Intra-articular (IA) injection of thermoresponsive hydrogels coupled with microparticles (MPs) possess the benefit of sustaining the anti-inflammatory drug effect within the joint cavity for rheumatoid arthritis treatment. Star-shaped thermoresponsive poly(polyethylene glycol) methacrylate [Poly(PEGMA)] copolymers were synthesized using free radical polymerization technique and fully characterized. Triamcinolone acetonide (TA)-loaded PLA/mPEG-PDL MPs, previously optimized, were integrated into the synthesized copolymer solutions at various concentrations and tested for their gelation temperatures. The MPs-in-hydrogel formulations were characterized using scanning electron microscope (SEM), viscosity measurements, ex vivo bioadhesion, and in vitro release studies. The anti-inflammatory effect of integrated systems was assessed in adjuvant-induced monoarthritic rat knee joints and compared to Kenacort and TA-loaded MPs. Two copolymers were successfully synthesized; G-1 = poly(PEGMA188-ME-co-PEGMA475-ME) and G-2 = poly(PEGMA246-EE-co-PEGMA475-ME). Using the tube inversion technique, the gel formation was found dependent on copolymer concentration. An irreversible aggregation was obtained at copolymer concentrations ≤10% (w/v), while a gel was formed at 20 and 30% (w/v) of both copolymers upon increasing temperature. The MP-hydrogel formulations were optimized at 20 and 30% (w/v) of G-1 and G-2 with gelation temperatures of 33 and 37 °C, respectively. SEM images revealed the porous microstructures of hydrogels and their adsorption on MP surfaces. The integrated formulas showed pseudoplastic behaviors, while the bioadhesion study confirmed their bioadhesiveness on excised cartilage. The in vitro release study confirmed drug sustainment from MPs-hydrogels compared to MPs. In vivo studies proved the superiority of MP-in-hydrogels in treatment of induced arthritis, relative to Kenacort and MPs alone, suggesting the applicability of this integrated platform in IA drug delivery.

Triamcinolone acetonide loaded-cationic nano-lipoidal formulation for uveitis: Evidences of improved biopharmaceutical performance and anti-inflammatory activity.

Topical administration of corticosteroids is the cornerstone treatment of anterior uveitis, but poor corneal penetration and retention cause hindrance in their therapeutic utility. The conventional eye drops are less valuable in conditions where inflammation reaches deeper regions of the eye. Therefore, there is a clear need for an effective drug delivery system, which can increase corticosteroid penetration after topical application. To address this, cationic nanostructured lipid carriers of the drug triamcinolone acetonide (cTA-NLC) were prepared. The cTA-NLC were prepared by a hot microemulsion method and evaluated for drug release, permeation, cell uptake, cytotoxicity, anti-inflammatory activity and ocular irritancy. The cTA-NLC are nanometric in size (< 200 nm), with a zeta potential of about +35 mv and % drug EE of 88 %. The nanocarriers exhibited slow and sustained release of around 84 % in 24 h and transcorneal drug permeation of 51 % in 8 h. The nanocarriers exhibited no cytotoxicity (% cell viability of>90 %). The cell uptake study showed that nanocarriers could retain inside the cells for 24 h. The developed formulation could significantly reduce the TNF-α level in LPS induced inflamed cells. The studies indicated that cTA-NLC could be a promising option for the topical treatment of uveitis.

Spray-Drying, Solvent-Casting and Freeze-Drying Techniques: a Comparative Study on their Suitability for the Enhancement of Drug Dissolution Rates.

PURPOSE: Solid dispersions (SDs) represent the most common formulation technique used to increase the dissolution rate of a drug. In this work, the three most common methods used to prepare SDs, namely spray-drying, solvent-casting and freeze-drying, have been compared in order to investigate their effect on increasing drug dissolution rate. METHODS: Three formulation strategies were used to prepare a polymer mixture of polyvinyl-alcohol (PVA) and maltodextrin (MDX) as SDs loaded with the following three model drugs, all of which possess a poor solubility: Olanzapine, Dexamethasone, and Triamcinolone acetonide. The SDs obtained were analysed and compared in terms of drug particle size, drug-loading capacity, surface homogeneity, and dissolution profile enhancement. Physical-chemical characterisation was conducted on pure drugs, as well as the formulations made, by way of thermal analysis and infrared spectroscopy. RESULT: The polymers used were able to increase drug saturation solubility. The formulation strategies affected the drug particle size, with the solvent-casting method resulting in more homogenous particle size and distribution when compared to the other methods. The greatest enhancement in the drug dissolution rate was seen for all the samples prepared using the solvent-casting method. CONCLUSION: All of the methods used were able to increase the dissolution rate of the pure drugs alone, however, the solvent-casting method produced SDs with a higher surface homogeneity, drug incorporation capability, and faster dissolution profile than the other techniques.

Spatio-temporal control on the delivery of triamcinolone acetonide using polymeric nanoparticles reduces steroid induced cataract.

Development of topically administered drug delivery systems for the treatment of ocular diseases have majorly focused on enhancing bioavailability of drugs in the ocular tissues. However, control of spatial distribution of topically administered drugs so as to restrict/avoid drug bioavailability at sensitive ocular tissues that are prone to drug induced adverse effects has not been explored. In this study, we aimed to reduce the bioavailability of topically administered corticosteroid, triamcinolone acetonide (TA) in lens via controlled spatial distribution in order to minimize TA induced posterior subcapsular cataract (PSC). For this, a negatively charged polymeric core-shell nanoparticulate drug delivery system composed of polycaprolactone (PCL) core and pluronic® F-68 (PF68) shell was fabricated. For in vivo studies, coumarin-6 (COU) loaded nanoparticles (NPs) were fabricated and studied for their biodistribution after topical administration in mice eyes and compared with free COU biodistribution. The administered COU loaded NPs differentially distributed in mice eyes and showed lower bioavailability in lens compared to free COU. Further, in vivo efficacy of the delivery system for its ability to minimize the rate of PSC progression was evaluated in diabetic rats. The results demonstrated that TA loaded PCL-PF68 NPs decreased PSC progression compared to free TA when administered topically.

Microfibrillar polymeric ocular inserts for triamcinolone acetonide delivery.

Despite eye drops generally represent the most convenient, simple and patient-friendly formulations to treat ocular diseases, they suffer from poor retention on the ocular surface and low drug bioavailability leading to the necessity of prolonged and continuous treatment over time. Therefore, ocular insert could represent an innovative way to benefit from ocular topical administration while minimizing all the relevant limitation related to this route of administration. Polymeric non-erodible mucoadhesive ocular inserts should be comfortable and should rapidly adhere on the ocular surface, remain in situ for prolonged period, assure a reproducible and controlled drug release as well as act as transcorneal absorption promoters. In this study, a well-known aliphatic polyester, poly(1,4-butylene succinate) (PBS), was used as starting material to produce hydrophobic microfibrillar scaffolds by means of electrospinning technique. Plasma-assisted chemical surface functionalization of the PBS scaffolds with appropriate biopolymers (inulin, α,ß-poly(N-2-hydroxyethyl)-D,L-aspartamide, heparin) was carried out to confer to the final ocular inserts ad hoc properties as wettability, mucoadhesion and cytocompatibility on human corneal epithelial cells, by improving surface hydrophilicity without modifying the bulk properties of the material. The lipophilic drug triamcinolone acetonide was loaded into the obtained ocular insert and release studies were carried out to demonstrate the ability of drug loaded inserts to release the active until 30 days.

Dilution and microfiltration of particulate corticosteroids for spinal epidural injections: impact on drug concentration and agglomerate formation.

Particulate corticosteroids have been described to lead to greater pain improvement compared with their non-particulate counterparts when used in epidural injections. It is hypothesised that filtering may significantly impact their concentration and long-term efficacy. We investigated if passing particulate suspensions through different commonly-used filters affects drug dosage. Two particulate corticosteroid formulations, triamcinolone acetonide and methylprednisolone acetate, were mixed at different concentrations with either bupivacaine hydrochloride or 0.9% sodium chloride. Solutions were passed through a 5-µm and a 0.2-µm filter. Mass spectroscopy results indicated a complete loss of corticosteroid from the solutions using both filters, and light microscopy imaging demonstrated agglomerate formation, suggesting that filtering interferes with drug dosage. The choice of diluents must also be considered to reduce large agglomerate formation. Clinicians should be aware of the consequences of filtering particulate suspensions and carefully consider the selection of diluent when considering treatment plans.

The role of vehicle metamorphosis on triamcinolone acetonide delivery to the skin from microemulsions.

After application to the skin surface, a topical formulation is submitted to changes in composition produced by evaporation of volatile components, penetration of components into the skin and extraction of skin components ("vehicle metamorphosis"). The aim of this work was to study the effect of vehicle metamorphosis on skin delivery from microemulsions containing triamcinolone acetonide. The microemulsions were prepared and characterized for water evaporation kinetics, in vitro release and skin permeation and retention. Skin retention experiments were performed on full thickness pig ear skin, in both occluded infinite and un-occluded finite dose conditions. For comparison purposes, two creams, the commercial Ledercort® and a vanishing cream, were tested. With triamcinolone acetonide water evaporation does not modify skin retention, probably for the lipophilic nature of the drug. However, if water is eliminated from the microemulsions, the performance is reduced, probably because drug partitioning from vehicle to stratum corneum is disfavored. If a water-soluble drug (methyl prednisolone sodium succinate) is used, infinite dose application in occlusive conditions increases in a significant way the amount of drug retained in the skin. The involved mechanisms are probably stratum corneum swelling and increase of stratum corneum/viable epidermis partitioning.

Intra-articular injection of triamcinolone acetonide releasing biomaterial microspheres inhibits pain and inflammation in an acute arthritis model.

Inflammation of the synovium and joint capsule is a main driver of pain in an osteoarthritic (OA) joint. Triamcinolone acetonide (TAA) is a classical corticosteroid that reduces synovitis and alleviates pain, albeit transiently. Biomaterial-based local TAA release may prolong the suppression of pain without the need for multiple injections. Polylactic-co-glycolic acid (PLGA) formulations of TAA prolong OA pain relief to a limited extent. A novel polyesteramide (PEA) microsphere platform allows for extended release in the OA joint for over 3 months. To evaluate their effect on pain and inflammation, TAA-loaded microspheres were intra-articularly delivered to the knee joint in a rat model of acute arthritis induced by intra-articular injection of streptococcal cell wall peptidoglycan-polysaccharide (PGPS) and subsequent flare-ups by intravenous PGPS injections. PEA-loaded microspheres were benchmarked with TAA-loaded PLGA microspheres and bolus TAA injection. TAA treatments were injected intra-articularly before the first induced flare-up. TAA-loaded PEA and PLGA microspheres reduced joint swelling and signs of pain-like behavior over the entire study period, as assessed by weight bearing and referred mechanical hypersensitivity, whereas bolus suspension was effective for a shorter time period. TAA-loaded PEA microspheres reduced lameness to a greater extent than TAA-loaded PLGA microspheres. In conclusion, a single intra-articular injection of TAA-loaded PEA microspheres reduced joint swelling and induced longer pain relief compared to bolus injection. Hence relief of inflammation and pain by PEA-based delivery of TAA may prove to be effective and durable.

Physical and Chemical Compatibility of Extended-Release Triamcinolone Acetonide (TA-ER) with Common Local Anesthetics.

INTRODUCTION: Intra-articular (IA) corticosteroids are used extensively for the treatment of patients with knee osteoarthritis pain. In clinical practice, local anesthetics are frequently combined with corticosteroids prior to IA injection to provide rapid-onset analgesia. From this common practice there is no evidence to suggest that the addition of local anesthetics to corticosteroid preparations, including triamcinolone acetonide (TA), alters the physical properties or efficacy of the corticosteroid. Triamcinolone acetonide extended-release (TA-ER, formerly FX006) is a novel, microsphere-based TA formulation that demonstrated analgesic efficacy in phase 2 and 3 randomized controlled trials. METHODS: The current study assessed the compatibility of TA-ER and lidocaine, ropivacaine, and/or bupivacaine in vitro. The TA-ER and local anesthetic mixtures were assayed for changes in syringeability, pH, particle size, percentage free drug, purity, and appearance compared with TA-ER alone. RESULTS: By these measures, the combination of local anesthetics with TA-ER did not negatively impact the chemical or physical properties of TA-ER when compared to TA-ER controls. CONCLUSION: These results demonstrate that lidocaine, bupivacaine, and ropivacaine are physically and chemically compatible with TA-ER, suggesting that local anesthetic solutions can be added to TA-ER preparations in clinical practice without adversely affecting TA-ER in vitro product characteristics. FUNDING: Flexion Therapeutics, Inc.

A Kinetic Approach to Determining Drug Distribution in Complex Biphasic Systems.

Pharmaceutical emulsions contain multiple components, such as micellar, aqueous, and oil phases, leading to complex drug transfer and equilibrium phenomena. These complex components present challenges for the bioequivalence assessment of the drug products. The objective of the study was to develop a method that can probe the underlying mechanism and process of drug distribution. The concept of drug partitioning into biphasic systems was used to simplify the complex transfer phenomenon. A kinetic method was developed taking into account the biphasic diffusion. Using this approach, both the rate (kinetics) and the extent (equilibrium) of distribution can be determined. For method development purpose, 3 model compounds (triamcinolone acetonide, difluprednate, and cyclosporine), with expected partition coefficient values ranging from 2 to 6, were tested using the kinetic method and the traditional shake-flask method. The values obtained by the 2 methods for all compounds correlated well (r2 = 0.825). Various organic and aqueous solvents which are commonly encountered in formulations were also tested to determine the impact of phase composition on drug distribution. The kinetic method was found to offer more flexibility in terms of solvent composition and can lead to better understanding for drug distribution and potential drug release in complex biphasic systems.

Evaluation of controlled-release triamcinolone acetonide-loaded mPEG-PLGA nanoparticles in treating experimental autoimmune uveitis.

Uveitis is a recurrent, sight-threatening intraocular inflammatory disease and is treated with glucocorticoids in clinical practice. In the present study, methoxypoly(ethyleneglycol)-poly(dl-lactide-co-glycolic acid) (mPEG-PLGA) nanoparticles in combination with triamcinolone acetonide (TA) were fabricated using a modified double emulsification method. Further, we characterized the TA-loaded nanoparticles, and investigated the effects of TA-loaded nanoparticles on experimental autoimmune uveitis rats, including histopathological examination and the alterations in interleukin (IL)-17 and IL-10 at mRNA and protein levels in either aqueous humor or serum. As a result, the TA-loaded nanoparticles were a well-defined spherical shape with a mean particle size of 82 nm. The in vitro release profile showed that the TA-loaded nanoparticles could sustain for more than 45 days, and possessed higher anti-inflammatory effects compared to TA alone after pathological examination, resulting in decreased IL-17 and elevated IL-10 levels in both aqueous humor and serum. Based on these findings, it can be concluded that TA-loaded mPEG-PLGA nanoparticles can potentially provide a better anti-inflammatory effect in treating chronic and recurrent uveitis in clinical practice.

In situ forming phase-inversion implants for sustained ocular delivery of triamcinolone acetonide.

The objectives of this study were to develop biodegradable poly-lactic-co-glycolic acid (PLGA) based injectable phase inversion in situ forming system for sustained delivery of triamcinolone acetonide (TA) and to conduct physicochemical characterisation including in vitro drug release of the prepared formulations. TA (at 0.5%, 1% and 2.5% w/w loading) was dissolved in N-methyl-2-pyrrolidone (NMP) solvent and then incorporated 30% w/w PLGA (50/50 and 75/25) polymer to prepare homogenous injectable solution. The formulations were evaluated for rheological behaviour using rheometer, syringeability by texture analyser, water uptake and rate of implant formation by optical coherence tomography (OCT) microscope. Phase inversion in situ forming formulations were injected into PBS pH 7.3 to form an implant and release samples were collected and analysed for drug content using a HPLC method. All formulations exhibited good syringeability and rheological properties (viscosity: 0.19-3.06 Pa.s) by showing shear thinning behaviour which enable them to remain as free-flowing solution for ease administration. The results from OCT microscope demonstrated that thickness of the implants were increased with the increase in time and the rate of implant formation indicated the fast phase inversion. The drug release from implants was sustained over a period of 42 days. The research findings demonstrated that PLGA/NMP-based phase inversion in situ forming implants can improve compliance in patient's suffering from ocular diseases by sustaining the drug release for a prolonged period of time and thereby reducing the frequency of ocular injections.

Kenalog modified by ionizing radiation induces intrinsic apoptosis mediated by elevated levels of reactive oxygen species in melanoma cancer.

Kenalog is a synthetic glucocorticoid drug used to treat various cancers including ocular and choroidal melanoma. However, the drug achieves rarely sustainable results for patients. To overcome this difficulty, the structure of Kenalog was altered by ionizing radiation (IR) to develop a more effective anticancer agent for treatment of various skin cancers. The anticancer effect of modified Kenalog (Kenalog­IR) was assessed in melanoma cancer cells in vitro. The assessment of mitochondrial functions by MTT assay revealed significant inhibition of melanoma cancer cell viability by Kenalog­IR compared to Kenalog. Moreover, Kenalog­IR­induced apoptotic cell death was associated with the intrinsic mitochondrial pathway by triggering the release of intrinsic apoptosis molecules through activation of caspase­related molecules in concentration and time­dependent manners. Furthermore, it was observed that Kenalog­IR­induced apoptosis was associated with the generation of reactive oxygen species (ROS) with increased G2/M cell cycle arrest. Collectively, Kenalog­IR may be a potential suppressor of skin­related cancer in particular melanoma cancer.

Controlled non-invasive iontophoretic delivery of triamcinolone acetonide amino acid ester prodrugs into the posterior segment of the eye.

This study investigated short duration transscleral iontophoretic delivery of four triamcinolone acetonide (TA) amino acid ester prodrugs (TA-AA) (alanine, Ala; arginine, Arg; isoleucine, Ile and lysine, Lys) using whole porcine eyes globes in vitro. Post-iontophoretic biodistribution of TA was quantified by UHPLC-MS/MS in the different ocular compartments (cornea, aqueous humor, sclera, ciliary body, choroid and retinal pigmented epithelium (RPE), neural retina and vitreous humor). Transscleral iontophoresis (3 mA/cm2 for 10 min) increased total drug delivery of the TA-AA prodrugs by 14-30-fold as compared to passive diffusion. The TA-AA prodrugs had distinct biodistribution profiles - the penetration depth achieved was dependent on their physicochemical properties (e.g. lipophilicity for TA-Ile) and susceptibility to hydrolysis (e.g. TA-Arg). Intraocular drug distribution was also influenced by prodrug binding to melanin (TA-Lys). Interestingly, under conditions of equivalent charge (6 mA/cm2 for 5 min vs. 1.5 mA/cm2 for 20 min, i.e. 1.44 C respectively) the longer duration (20 min) at lower current density resulted in ∼6 times more TA delivery into the vitreous humor. Overall, the study provided further evidence of the potential of transscleral iontophoresis for the non-invasive treatment of posterior segment inflammatory diseases.