Organic cation transporter 1 in the lacrimal gland facilitates the entry of systemic drugs causing ocular surface toxicity.

Many of the daily systemic medications (parenteral and oral) used to treat various diseases are known to cause ocular toxicities - leading to vision loss. How these medications gain entry into the eye despite the ocular barriers is an important question to be addressed. Various reports show almost 30-40 % of systemic drugs causing ocular toxicity are organic cation in nature. We hypothesize these systemic drugs (cations) are non-specifically recognized as endogenous substrates by organic cation transporter (OCT1) in the lacrimal gland, thereby facilitating its entry into the anterior eye segment. Therefore, we studied the expression and localization of OCT1 in the lacrimal gland of rabbits. Further, to prove our hypothesis, OCT1 substrates (known as well as predicted from our previous Artificial Intelligence study) were administered intravenously in the presence and absence of topically administered OCT1 blockers. Our findings show, OCT1 gene and protein expression in the lacrimal gland, with its localization in the terminal acinar cells. The tear levels of intravenously administered substrates decreased in the presence of topical OCT1 blockers, indicating - a) the entry of systemic drugs into the eye via lacrimal secretion and b) OCT1 in the lacrimal gland is involved in the drug transport (substrates) from blood to the eye. Though the role of transporters in toxicity is well-known, the current study opens a new avenue for understanding the role of transporters in ocular toxicity.

Smartphone enabled miniaturized temperature controller platform to synthesize nio/cuo nanoparticles for electrochemical sensing and nanomicelles for ocular drug delivery applications.

Undoubtedly, various kinds of nanomaterials are of great significance due to their enormous applications in diverse areas. The structure and productivity of nanomaterials are heavily dependent on the process used for their synthesis. The synthesizing process plays a vital role in shaping nanomaterials effectively for better productivity. The conventional method requires expensive and massive thermal instruments, a huge volume of reagents. This paper aims to develop an Automatic Miniaturized Temperature Controller (AMTC) device for the synthesis of nickel oxide (NiO), copper oxide (CuO) nanoparticles, and nanomicelles. The device features a low-cost, miniaturized, easy-to-operate with plug-and-play power source, precise temperature control, and geotagged real-time data logging facility for the producing nanoparticles. With a temperature accuracy of ± 2 °C, NiO and CuO nanoparticles, and nanomicelles are synthesized on AMTC device, and are subjected to different characterizations to analyze their morphological structure. The obtained mean size of NiO and CuO is 27.14 nm and 85.13 nm respectively. As a proof-of-principle, the synthesized NiO and CuO nanomaterials are validated for electrochemical sensing of dopamine, hydrazine, and uric acid. Furthermore, the study is conducted, wherein, Dexamethasone (Dex) loaded nanomicelles are developed using AMTC device and compared to the conventional thin-film hydration method. Subsequently, as a proof-of-application, the developed nanomicelles are evaluated for transcorneal penetration using exvivo goat cornea model. Ultimately, the proposed device can be utilized for performing a variety of controlled thermal reactions on a minuscule platform with an integrated and miniaturized approach for various applications.

Potential of subconjunctival aflibercept in treating choroidal neovascularization.

The study aimed to evaluate the intraocular pharmacokinetics and efficacy of aflibercept after subconjunctival injection in animal models for treating choroidal neovascularization (CNV) associated with Age-Related Macular Degeneration (AMD). New Zealand albino rabbits received aflibercept (2000 µg/50 µl) in one eye, and the other eye was used as control. At 7, 14, 21 and 28 days, the animals were sacrificed to dissect the ocular tissues, and serum was collected at 1hr, 3 h, 1, 7, 14, 21 and 28 days. The concentration of aflibercept in various ocular tissues and serum were measured using the immunoassay technique. The concentration maximum (Cmax) at the Retinal Pigment Epithelium (RPE)-choroid complex and retina in treated eyes was 261.55 and 33.83 ng/gm, respectively. The area under the curve (AUC0-last) for RPE-Choroid and retina were 2094.02 and 290.33 days. ng/gm respectively. The time maximum (Tmax) for the ocular tissues was reached on day 7. In the vitreous humour, a lower level of aflibercept was retrieved. The Cmax (1766.84 ng/mL) in the serum was reached on day 1, followed by a decline in the concentration till the end of the study period. In treated eyes, the levels of aflibercept in most of the ocular tissues were maintained for at least 21 days above the invitro IC50 concentration. The results of the efficacy study show that subconjunctival aflibercept could reach the therapeutic target to inhibit CNV. The subconjunctival aflibercept could be a less invasive route for treating CNV with AMD.

Exploring the Therapeutic Potential of Anti-VEGF Drugs for the Management of Diabetic Retinopathy: An Overview.

The discovery of antivascular endothelial growth factor medications has resulted in a substantial change in diabetic retinopathy treatment. The most common cause of diabetic retinopathy blindness is Diabetic Macular Edema. The pathophysiology of Diabetic Macular Edema is thought to include the well-known pro-angiogenic and pro-permeability factor vascular endothelial growth factor. Over the past decade, drugs that impede the functions of vascular endothelial growth factors have established themselves as a standard-of-care treatment for a range of ocular ailments and improved patients' clinical results with diabetic retinopathy and Diabetic Macular Edema, and their frequency has grown exponentially with the introduction of these agents Pegaptanib, Ranibizumab, and Aflibercept which are approved for ophthalmic indications, while Bevacizumab is used off-label. These medications delivered intravitreally have halted the vascular development of diabetic retinopathy. Various randomized trials have proven that antivascular endothelial growth factor medication is safe and effective in preserving vision. Following an extensive period of preclinical development aimed at enhancing and defining its biological impacts, these drugs were shown in clinical trials to be effective in treating diabetic retinopathy and other ophthalmic conditions. Data from various sources suggest that Pegaptanib, Ranibizumab, and Aflibercept are costly, while Bevacizumab is cost-effective, and in low and middle-income nations, it is thus a desirable therapy choice. However, issues with compounding, counterfeiting, and off-label usage restrict its availability in many nations. The pharmacology, pharmacokinetics, pharmacodynamics, adverse effects, and contraindications of antivascular endothelial growth factor agents are discussed, and the results of clinical trials evaluating their efficacy are summarized.

Combination of self-assembling system and N,O-carboxymethyl chitosan improves ocular residence of anti-glaucoma drug.

Glaucoma is known to be one of the principal causes of vision loss due to elevated intraocular pressure. Currently, latanoprost eye drops is used as first-line treatment for glaucoma; however, it possesses low bioavailability due to rapid precorneal clearance. A novel delivery system with a mucoadhesive property could overcome this problem. Therefore, we attempt to develop a combination of self-assembling latanoprost nanomicelles (Latcel) and a mucoadhesive polymer (N,O-carboxymethyl chitosan: N,O-CMC) to improve the corneal residence time. Latcel was developed using Poloxamer-407 by thin film hydration method, followed by the addition of N,O-CMC using simple solvation to obtain Latcel-CMC and characterized using various physicochemical characterization techniques. The particle size of Latcel-CMC was 94.07 ± 2.48 nm and a zeta potential of -16.03 ± 0.66 mV, with a sustained release for 24h whereas marketed latanoprost drops released 90 % of the drug within 1h. In vitro cytotoxicity studies, HET-CAM, and in vivo Draize test showed the biocompatibility of Latcel-CMC. Cellular uptake studies performed using fluorescein isothiocyanate (FITC) loaded nanomicelles in human corneal epithelial cells indicates the increased cellular uptake as compare to plain FITC solution. In vivo ocular residence time was evaluated in Wistar rats using Indocyanine green (ICG) loaded nanomicelles by an in vivo imaging system (IVIS), indicating Latcel-CMC (8h) has better residence time than plain ICG solution (2h). The Latcel-CMC showed improved corneal residence time and sustained release of latanoprost due to increased mucoadhesion. Thus, the developed N,O-Carboxymethyl chitosan based nanomicelles eye drop could be a better strategy than conventional eye drops for topical delivery of latanoprost to treat glaucoma.

Ocular delivery of Amphotericin B: current challenges and future perspectives.

INTRODUCTION: Amphotericin B is a polyene antibiotic that is used as an off-label eye drop to treat fungal keratitis. Poor solubility, permeability and high susceptibility to hydrolytic degradation make it challenging to formulate a drug delivery system. Despite its drawbacks, it is a potent antifungal drug against Candida and other fungal species. However, it has not been explored much in ocular drug delivery. Hence, this review brings into focus the potential and increasing significance of Amphotericin B in ocular drug delivery. AREAS COVERED: In this review, we have systematically summarized the use of Amphotericin B in ocular diseases, the various formulation challenges for Amphotericin B, along with its off-label ocular usage, and stability concerns. The degradation mechanism of Amphotericin B in different conditions was discussed in this article as well. EXPERT OPINION: In the last few decades, several nanocarriers have been explored to improve the formulation challenges associated with Amphotericin B. Also, due to insufficient clinical studies and unknown toxicity profile, there is no US Food and Drug Administration (FDA) approved Amphotericin B formulation for ocular drug delivery. This review aims to offer thorough information about Amphotericin B in ocular drug delivery.

Complement Cascade 8 - Alpha and Calpain-2 in Extracellular Vesicles of Human Vitreous as Biomarkers of Infectious Endophthalmitis.

Purpose: Extracellular vesicles (EVs) are messenger pigeons of the cells that communicate about cellular microenvironment. In this study, we evaluated the expression of C8α and calpain-2 in EVs from vitreous of patients with bacterial endophthalmitis to assess its utility as a diagnostic marker. Methods: EVs were isolated from vitreous of patients with bacterial endophthalmitis (culture positive and culture negative) and noninfectious control by exosome isolation reagent and characterized, and the levels of C8α and calpain-2 was assessed by enzyme-linked immunosorbent assay in isolated EVs and direct vitreous. The receiver operating characteristic curve was generated to assess the diagnostic performance. Results: Scanning electron microscopy (SEM) and dynamic light scattering (DLS) confirmed the presence of EVs having a diameter (nm) of 275.2 ± 93, 92 ± 22, and 77.28 ± 12 in culture-positive (CP), culture-negative (CN), and control respectively. The expression level (ng/mL) of C8α in the EVs obtained from CP was 144 ± 22 and CN was 31.2 ± 9.8, which was significantly higher (P < 0.01) than control 3.7 ± 2.4. Interestingly, C8α is not expressed directly in the vitreous of CN and controls. Calpain-2 was significantly downregulated (P ≤ 0.0001) in CP (0.94 ± 0.16) and CN (0.70 ± 0.14) than control. The sensitivity and specificity of 1 for C8α and calpain-2 in the EVs implied that its diagnostic accuracy was significant. Conclusions: This study showed that the EV proteins C8α and calpain-2 could be suitable diagnostic markers for endophthalmitis. However, the presence of C8α in the EVs of CN samples but not in direct vitreous promises EVs as the future of diagnostics. Translational Relevance: Expression levels of EV-calpain-2 and EV-C8α could diagnose CN bacterial endophthalmitis.

Nanomicelles empower natamycin in treating fungal keratitis: An in vitro, ex vivo and in vivo study.

Fungal infections of cornea are important causes of blindness especially in developing nations with tropical climate. However, the challenges associated with current treatments are responsible for poor outcome. Natamycin is the only FDA-approved antifungal drug to treat fungal keratitis, but unfortunately due to its poor water solubility, it is available as suspension. The marketed suspension (5% Natamycin) has rapid precorneal clearance, poor corneal permeability, a higher frequency of administration, and corneal irritation due to undissolved suspended drug particles. In our study, we developed clear and stable natamycin-loaded nanomicelles (1% Natcel) to overcome the above challenges. We demonstrated that 1% Natcel could permeate the cornea better than 5% suspension. The developed 1% Natcel was able to provide sustained release for up to 24 h. Further, it was found to be biocompatible and also improved the mean residence time (MRT) than 5% suspension in tears. Therefore, the developed 1% Natcel could be a potential alternative treatment for fungal keratitis.

A promising 'single' and 'dual' drug-nanocomposite enriched contact lens for the management of glaucoma in response to the tear fluid enzyme.

Glaucoma is a neurodegenerative condition that results in the damage of retinal ganglion cells due to elevated intraocular pressure (IOP). To curtail the limitations associated with conventional treatments such as eye drops and ocular suspensions, we have developed 'single' and 'dual' drug delivery contact lenses (CLs), that is, latanoprost (LP) and latanoprost-timolol (LP-TM) deliverable CLs, in response to lysozyme (Lyz), which is abundant in the lacrimal fluid. Since chitosan (CS) can entrap more of the drug and also undergo hydrolysis in the presence of Lyz, we have employed CS for the composite preparation. The CL fabrication was performed by free radical copolymerization of poly(2-hydroxyethyl methacrylate) (pHEMA) in the presence of the drug-loaded nanocomposite with UV-curing initiators using the pre-drug loading strategy. The surface morphological, optical and mechanical investigations confirmed the presence of the drugs, ≥80% transparency, the adequate flexibility and biocompatibility of both the CLs. The in vitro release experiments showed the release of 95.86% LP from LP-CL, and 83.87% LP and 86.70% TM from LP-TM-CL in the presence of 1.5 mg mL-1 of Lyz in 72 h. In vitro biocompatibility assay against human corneal epithelial (HCE) cells and ex vivo experiments on HET-CAM confirmed that the fabricated LP-CL and LP-TM-CL are well tolerated. Moreover, in vivo safety evaluations of CLs on New Zealand white rabbit eyes suggest no sign of irritation to the ocular tissues within 72 h of observation. Hence, the study suggests that the 'single' and 'dual' drug-loaded CLs could open a new avenue to manage glaucoma by maintaining mean diurnal IOP.

Development of potential orphan drug therapy of intravesical liposomal tacrolimus for hemorrhagic cystitis due to increased local drug exposure.

PURPOSE: The potent immunosuppressive effect of systemic tacrolimus is limited by the high incidence of severe adverse effects, including nephrotoxicity and hypertension. Intravesical application of tacrolimus is hindered by its poor aqueous solubility, justifying the search for novel delivery platforms such as liposomes. We evaluated the pharmacokinetics of tacrolimus encapsulated in liposomes (lipo-tacrolimus), which is being developed as a potential orphan drug indication for hemorrhagic cystitis. MATERIALS AND METHODS: A single dose of lipo-tacrolimus was instilled in the bladder with the rat under anesthesia. Also, tacrolimus was instilled intravesically or injected intraperitoneally in other rat groups. The tacrolimus dose was constant in all formulations at 200 µg/ml. At different times blood, urine and bladder samples were collected and stored at -80C until analysis. Tacrolimus levels in samples were analyzed using microparticle enzyme immunoassay II. RESULTS: The AUC of lipo-tacrolimus in serum at 0 to 24 hours was significantly lower than that of tacrolimus instillation or injection. Noncompartmental pharmacokinetic data analysis revealed maximum concentration of lipo-tacrolimus and tacrolimus in serum and urine at 1 and at 2 hours, respectively. Urine AUC(0-24) after intravesical administration was significantly higher than in the intraperitoneal group (p <0.05). Bladder tacrolimus AUC(0-24) did not differ significantly between the groups. CONCLUSIONS: Single dose pharmacokinetics revealed that bladder instillation of liposome encapsulated tacrolimus significantly decreased systemic exposure to instilled tacrolimus as well as vehicle related toxicity. Intravesical liposomal tacrolimus may be a promising approach as an orphan drug indication for hemorrhagic cystitis.

Role of organic cation transporters in the ocular disposition of its intravenously injected substrate in rabbits: implications for ocular drug therapy.

The present study was conducted to test the hypothesis; OCT may be active from blood-to-vitreous for the uptake of its substrates. Ocular uptake of Tetraethylammonium (TEA) across blood ocular barriers and the tissue distribution was evaluated in vivo in New Zealand albino rabbits after intravenous administration. Quinidine (blocker) pretreatment resulted in a significant (p < 0.05) reduction in the Area Under the Curve (AUC) of TEA in vitreous (4.2 fold) and aqueous humor (1.8 fold) as compared to the control group which supports the role of OCT in uptake transport of its substrate across Blood ocular barrier. The blockade of OCT also affected the elimination of its substrate resulting in increased plasma levels. In most of the tissues, OCT are functionally present from apical to basolateral. The gene expression studies also showed the presence of OCT1, OCTN1 and OCTN2 in various ocular tissues studied. The present findings suggest that OCT are functionally active in blood ocular barriers and involved in the transport of its substrate from blood-to-vitreous humor.

Development of mucoadhesive Timolol loaded chitosan-nanocomposite to treat glaucoma.

Timolol Maleate is an aqueous soluble ß-blocker antiglaucoma drug used to suppress intraocular pressure. Several commercially available ocular formulations are not effective in delivering to the target site due to their water-soluble property and low mucoadhesiveness. Hence, there is a requirement for a highly mucoadhesive drug-loaded nanocomposite to suppress intraocular pressure with enhanced bioavailability. Herein, we have prepared a mucoadhesive Timolol-loaded graphene quantum dot-chitosan-nanocomposite to treat glaucoma in response to lysozyme, secreted in the tear fluid. The as-prepared nanocomposite has been characterized through high resolution-transmission electron microscopic, X-ray photoelectron spectroscopic, X-ray diffraction, and Fourier transform infrared spectral studies. The nanocomposite showed 93.74 % encapsulation efficiency with a loading capacity of 7.73 %. Further, 89.26 %, 95.62 %, and 99.29 % of drug release were observed from the nanocomposite in the presence of 1, 1.5, and 2 mg/mL of lysozyme. The mucoadhesion property has been confirmed by the increment in the particle size, fluorescence spectral variations, and Fourier transform infrared spectroscopic studies in the presence of mucin nanoparticles of size 291 nm. Interestingly, mucoadhesion has been demonstrated by pointing to the quenching in the luminescence of mucin. Further, in vitro biocompatibility assay on human corneal epithelial cells showed ≥80 % cell viability. Hence, this study offers the utilization of naturally secreting enzymes for drug delivery applications instead of uncontrolled pH and temperature-triggered releases.

Interaction of systemic drugs causing ocular toxicity with organic cation transporter: an artificial intelligence prediction.

Chronic disease patients (cancer, arthritis, cardiovascular diseases) undergo long-term systemic drug treatment. Membrane transporters in ocular barriers could falsely recognize these drugs and allow their trafficking into the eye from systemic circulation. Hence, despite their pharmacological activity, these drugs accumulate and cause toxicity at the non-target site, such as the eye. Since around 40% of clinically used drugs are organic cation in nature, it is essential to understand the role of organic cation transporter (OCT1) in ocular barriers to facilitate the entry of systemic drugs into the eye. We applied machine learning techniques and computer simulation models (molecular dynamics and metadynamics) in the current study to predict the potential OCT1 substrates. Artificial intelligence models were developed using a training dataset of a known substrates and non-substrates of OCT1 and predicted the potential OCT1 substrates from various systemic drugs causing ocular toxicity. Computer simulation studies was performed by developing the OCT1 homology model. Molecular dynamic simulations equilibrated the docked protein-ligand complex. And metadynamics revealed the movement of substrates across the transporter with minimum free energy near the binding pocket. The machine learning model showed an accuracy of about 80% and predicted the potential substrates for OCT1 among systemic drugs causing ocular toxicity - not known earlier, such as cyclophosphamide, bupivacaine, bortezomib, sulphanilamide, tosufloxacin, topiramate, and many more. However, further invitro and invivo studies are required to confirm these predictions.Communicated by Ramaswamy H. Sarma.

Urinary chemokines as noninvasive predictors of ulcerative interstitial cystitis.

PURPOSE: Based on basic research findings an increase in chemokines and cytokines (CXCL-1 and 10, nerve growth factor and interleukin-6) is considered responsible for inflammation and afferent sensitization. In this cross-sectional study we tested the hypothesis that select chemokines are increased in the urine of patients with ulcerative and nonulcerative interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: Midstream urinary specimens were collected from 10 patients with ulcerative and nonulcerative interstitial cystitis/painful bladder syndrome, respectively, and from 10 asymptomatic controls. Urinary levels of 7 cytokines were measured by a human cytokine/chemokine assay. Nerve growth factor was measured by enzyme-linked immunosorbent assay. RESULTS: Urinary levels of most chemokines/cytokines were tenfold to 100-fold lower in asymptomatic controls vs patients with ulcerative and nonulcerative interstitial cystitis/painful bladder syndrome. Univariate comparison of 8 tested proteins in the ulcerative vs nonulcerative groups revealed a significant fivefold to twentyfold increase in CXCL-10 and 1, interleukin-6 and nerve growth factor (ANOVA p<0.001). CONCLUSIONS: Differential expression of chemokines in ulcerative and nonulcerative subtypes of interstitial cystitis/painful bladder syndrome suggests differences in paracrine signaling between the 2 entities.

Retinal Pathophysiological Evaluation in a Rat Model.

A posterior segment eye disease like diabetic retinopathy alters the physiology of the retina. Diabetic retinopathy is characterized by a retinal detachment, breakdown of the blood-retinal barrier (BRB), and retinal angiogenesis. An in vivo rat model is a valuable experimental tool to examine the changes in the structure and function of the retina. We propose three different experimental techniques in the rat model to identify morphological changes of retinal cells, retinal vasculature, and compromised BRB. Retinal histology is used to study the morphology of various retinal cells. Also, quantitative measurement is performed by retinal cell count and thickness measurement of different retinal layers. A BRB breakdown assay is used to determine the leakage of extraocular proteins from the plasma to vitreous tissue due to the breakdown of BRB. Fluorescence angiography is used to study angiogenesis and leakage of blood vessels by visualizing retinal vasculature using FITC-dextran dye.

Formulation and development of tacrolimus-gellan gum nanoformulation for treatment of dry eye disease.

The present study aimed at the development and evaluation of tacrolimus gellan gum nanoparticles (TGNPs) for the effective management of dry eye disease (DED) following topical application. TGNPs were developed by ionotropic gelation between gellan gum and aluminum chloride. Developed TGNPs were nanosized (274.46 ± 8.90 nm) with high % encapsulation efficiency (74.2 ± 2.4%) and loading capacity (36.14 ± 1.7%). The nanosize and spherical morphology of TGNPs was confirmed by transmission electron microscopy (TEM) and atomic force microscopy (AFM). Fourier transform infrared spectroscopy (FTIR) revealed no interaction between drug and GG. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) confirms the conversion of crystalline tacrolimus to amorphous post encapsulation in the nanoparticle. TGNPs showed prolonged drug release throughout 12 h and higher pre-corneal retention compared to tacrolimus solution. HET-CAM studies, histopathological evaluation, and Draize test confirmed the safety of the formulation for ocular use. Further, the pharmacodynamic studies using experimental DED in rabbits showed that TGNPs are effective in treating symptoms of DED. In conclusion, topical delivery of TGNPs could hold potential for efficient management of DED.

Topical Tacrolimus Progylcosomes Nano-Vesicles As a Potential Therapy for Experimental Dry Eye Syndrome.

The present work aimed to evaluate the efficacy of topical tacrolimus (0.01%) loaded propylene glycol (PG) modified nano-vesicles (Proglycosomes Nano-vesicles, PNVs) for the treatment of experimental dry eye syndrome (DES) in rabbits. DES was induced by topical application of atropine (1.0%) and benzalkonium chloride (0.1%) aqueous solution. PNVs treatment (PNV group) was compared with tacrolimus solution 0.01% (TAC group) and untreated group and healthy group were used as controls. PNV treated animals showed improved clinical performance with marked increase in tear production and tear break-up time (TBUT). Further, PNVs also subside ocular inflammation as evident from absence of matrix metalloprotenaise-9 and normal ocular surface temperature (32.3 ± 0.34 °C). Additionally, PNVs have positive effect on ocular and epithelial damage observed through low ocular surface staining score and improved globlet cell density. The PNV treatment was found to more effectively compared to TAC solution and most of the parameters were close to those of healthy animals. In conclusion, tacrolimus PNV formulation (0.01%) could be a potential therapy for treatment of dry eye syndrome.

Repurposing pharmaceutical excipients as an antiviral agent against SARS-CoV-2.

The limited time indorsed to face the COVID-19 emergency and large number of deaths across the globe, poses an unrelenting challenge to find apt therapeutic approaches. However, lead candidate selection to phase III trials of new chemical entity is a time-consuming procedure, and not feasible in pandemic, such as the one we are facing. Drug repositioning, an exploration of existing drug for new therapeutic use, could be an effective alternative as it allows fast-track estimation in phase II-III trials, or even forthright compassionate use. Although, drugs repurposed for COVID-19 pandemic are commercially available, yet the evaluation of their safety and efficacy is tiresome and painstaking. In absence of any specific treatment the easy alternatives such as over the counter products, phytotherapies and home remedies have been largely adopted for prophylaxis and therapy as well. In recent years, it has been demonstrated that several pharmaceutical excipients possess antiviral properties making them prospective candidates against SARS-CoV-2. This review highlights the mechanism of action of various antiviral excipients and their propensity to act against SARs-CoV2. Though, repurposing of pharmaceutical excipients against COVID-19 has the edge over therapeutic agents in terms of safety, cost and fast-track approval trial burdened, this hypothesis needs to be experimentally verified for COVID-19 patients.

Injectable in-situ gel depot system for targeted delivery of biologics to the retina.

In current clinical settings, frequent intravitreal (IVT) injections of anti-vascular endothelial growth factors are used due to their short in-vivo half-life and rapid clearance from the back of the eye. The IVT injections are associated with pain, risk of infection, retinal detachment, and financial burden. Biologics molecules can undergo physical, chemical, and enzymatic degradation during formulation development and in the biological environment. Moreover, the complex ocular structures also act as a rate-limiting barrier for these biologics. Thus, delivering stable and clinically relevant biologics concentration to the back of the eye is still a challenge. Compare to other drug delivery platforms, injectable in-situ gelling depot systems (IISGDs) have emerged as an effective system for biologics delivery. In this review, we have discussed various biologics used in ocular therapeutics and their associated challenges. Different routes of delivery and associated tissue barriers are also discussed. Different types of IISGDs developed to date for biologics delivery to the back of the eye were also covered. To conclude, various critical parameters related to the formulation development process and injectable depot systems that need careful consideration and further investigations were highlighted.

Novel water soluble sterile natamycin formulation (Natasol) for fungal keratitis.

The purpose of this study was to develop, characterize and evaluate novel water soluble formulation for its topical and intrastromal application. Natamycin complexed with cyclodextrin was characterized by Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The complexed powder was used to formulate 1% w/v aqueous natamycin formulation (Natasol 1%) for topical use. The developed formulation was subjected to stability testing at various conditions. Single and multi-dose trans-corneal permeation of Natasol 1% was evaluated in New Zealand Albino rabbits in comparison with marketed 5% natamycin suspension. Sterile unpreserved Natasol (0.01% w/v natamycin) formulation was also developed for intrastromal injection. Both formulations were evaluated for the ocular toxicity. FTIR and DSC studies revealed successful complexation of natamycin that further protected the degradation at various stability conditions. Single dose trans-corneal permeation studies revealed that Natasol 1% attained Cmax at one hr and maintain its intraocular concentration 5 and 2.5 times higher at 4th and 6th hr compared to 5% natamycin suspension. Multi-dose kinetics revealed the steady state pharmacokinetics after hourly and two hourly dosing schedules. Topical Natasol 1% and sterile unpreserved Natasol 0.01% intrastromal injection, did not show any ocular toxicity in the animals. To conclude, the newly developed topical 1% w/v natamycin formulation was found to be non-inferior to 5% natamycin topical suspension. It is expected to increase patient compliance for the treatment of fungal keratitis.