Revisiting the significance of nano-vitamin D for food fortification and therapeutic application.

OBJECTIVE: Vitamin D (a prohormone) is an important micronutrient required by the body for skeletal homeostasis and a range of non-skeletal actions. Calcitriol, the active form of vitamin D, regulates a variety of cellular and metabolic processes through both genomic and nongenomic pathways. Often prescribed for treating rickets and osteoporosis, vitamin D deficiency can exacerbate various other medical conditions. SIGNIFICANCE, METHODS, AND RESULTS: Despite its multifunctional uses, the sensitivity of vitamin D makes formulating an efficient drug delivery system a challenging task, which is further complicated by its poor aqueous solubility. Enhancing the oral absorption of vitamin D is vital in utilizing its full efficacy. Recent developments in encapsulation and nanotechnology have shown promising results in overcoming these constraints. CONCLUSION: This review thus offers an insight to adequately comprehend the mechanistic pharmacology of vitamin D, its pathophysiological role, and justification of its medical indications, along with the benefits of utilizing nanotechnology for vitamin D delivery.

Novel therapeutic interventions in cancer treatment using protein and peptide-based targeted smart systems.

Cancer, being the most prevalent and resistant disease afflicting any gender, age or social status, is the ultimate challenge for the scientific community. The new generation therapeutics for cancer management has shifted the approach to personalized/precision medicine, making use of patient- and tumor-specific markers for specifying the targeted therapies for each patient. Peptides targeting these cancer-specific signatures hold enormous potential for cancer therapy and diagnosis. The rapid advancements in the combinatorial peptide libraries served as an impetus to the development of multifunctional peptide-based materials for targeted cancer therapy. The present review outlines benefits and shortcomings of peptides as cancer therapeutics and the potential of peptide modified nanomedicines for targeted delivery of anticancer agents.

Intranasal pitavastatin attenuates seizures in different experimental models of epilepsy in mice.

This study was carried out to evaluate the effect of intranasal pitavastatin (PVS) on pentylenetetrazole (PTZ)-induced seizures, increasing current electroshock (ICES) seizures, and status epilepticus in mice. Intranasal PVS, 0.5 and 1.0mg/kg, showed significant increase in latency to PTZ-induced seizures and ICES seizure threshold compared to control; however, the effects were dose-dependent and were more significant at higher dose. Further, intranasal PVS (1.0mg/kg) but not intravenous PVS (50.0mg/kg) showed effective protection against PTZ-induced status epilepticus. No impairment in cognitive functions was observed following intranasal PVS (1.0mg/kg), thus making it a prospective therapeutic approach for acute seizures and status epilepticus.

Transungual Delivery of Ketoconazole Nanoemulgel for the Effective Management of Onychomycosis.

Ketoconazole (KCZ) nanoemulgel containing permeation enhancer was formulated as a vehicle for transungual drug delivery, and its efficacy to inhibit the growth of onychomycotic dermatophytes was investigated in vitro. Different components of oil-in-water nanoemulsions were moderately agitated by classical titration method and passed through a high-pressure homogenizer to formulate various nanoemulsions, which were further identified by constructing pseudo-ternary phase diagrams. Stress-stability testing was carried out for the nanoemulsions, and those that passed these tests were characterized for mean droplet size, zeta potential, morphology, pH, refractive index, viscosity and transmittance. Mean droplet size and zeta potential of the optimized nanoemulsion (NE3) were found to be 77.52 ± 0.92 nm (polydispersity index (PDI) = 0.128 ± 0.035) and -5.44 ± 0.67 mV, respectively. Optimized nanoemulsion was converted into nanoemulgel (NEG1) with 1% (w/w) of gelling agent (Carbopol® Ultrez 21) and 1%-2% (v/v) thioglycolic acid as permeation enhancer, and evaluated for pH, viscosity, spreadability, extrudability, tensile strength and bio-adhesion measurement. In vitro cumulative drug released at the end of 24 h from NE3, NEG1 and drug suspension were found to be 98.87 ± 1.29, 84.42 ± 2.78% and 54.86 ± 2.19%, respectively. Ex vivo transungual permeation values for KCZ through goat hooves from NE3, NEG1 and drug suspension were found to be 62.49 ± 2.98, 77.54 ± 2.88% and 38.54 ± 2.54%, respectively, in 24 h. The antifungal effect of NEG1 on Trichophyton rubrum and Candida albicans showed a significant (p < 0.05) zone of inhibition as compared to drug solution. Skin irritation and histopathology studies on rat skin showed the safe topical use and enhanced permeation of formulated nanoemulgel.

The Optimal Dosing Regimen of Super Bioavailable Itraconazole in Obesity: An Experimental Rat Model Study.

Background Obesity may alter tissue distribution and clearance of several drugs, especially lipophilic ones. Itraconazole, a lipophilic drug, has been recently introduced in a super-bioavailable formulation (SB-ITZ) for the treatment of dermatophytosis. Evidence regarding optimal dosing of SB-ITZ in obesity is lacking. A current experimental study was planned to analyze tissue concentrations of SB-ITZ at different doses in obese and non-obese rats.  Materials and methods Thirty-six Wistar albino rats of either sex were divided into obese and non-obese rats equally. Further, rats in both categories were divided into three dosing groups. Group 1 received SB-ITZ 13 mg once daily in the morning, group 2 received SB-ITZ 13 mg in the morning and 6.5 mg in the evening, while Group 3 rats received SB-ITZ 13 mg twice daily, orally. Concentrations of SB-ITZ in the skin, serum, and fatty tissue were assessed in each group on days 7, 14, 21, and 28. Comparison of SB-ITZ concentrations in various tissues in obese and non-obese rats and inter-group comparison of tissue concentrations across the three dosing regimens was done at day 28 and expressed as Mean ± SD.36 Wistar rats were divided into obese and non-obese rats equally. Results At day 28, skin concentrations of SB-ITZ were 5.36±1.1, 8.9±1.7 and 10.13±1.7 µg/g in Groups 1, 2, and 3, respectively, in non-obese rats, which was statistically significant (p<0.05) than skin concentration of obese rats (2.72±0.6, 4.2±0.7 and 4.66±0.5 µg/g) for the corresponding dosing groups respectively. Skin concentration of SB-ITZ was statistically significant for Groups 2 and 3 as compared to Group 1. Still, no statistically significant difference was noted between Groups 2 and 3 in non-obese and obese rats. Fatty tissue concentration of SB-ITZ was comparable in all 3 dosing regimens in non-obese and obese rats. But on the intergroup comparison, a statistically significant difference was observed for Groups 2 and 3 against Group 1 (p<0.05). Increasing the dose of SB-ITZ increased serum concentration. In non-obese rats, a statistically significant difference was noted between Group 2 (74.33±6.6 ng/ml) and Group 1 (52.5±9.9 ng/ml); p<0.01 and also in Group 3 (81.33±6.8 ng/ml) against Group 1; p<0.01. Group 3 achieved significantly higher concentration than the other two groups in obese rats (Group 3; 72±5.3, Group 2; 60.5±4.3, and Group 1; 45±7 ng/ml; p<0.01). Conclusion Overall, skin, fatty tissue, and serum concentrations of SB-ITZ were higher in non-obese rats compared to obese rats in all three dosing groups. Moreover, skin and fatty tissue concentrations were proportionately higher than serum in all the groups in non-obese and obese rats. Though the skin concentration of non-obese rats was significantly higher than obese rats, skin concentration in obese rats was within the minimum inhibitory concentration (MIC) range, demonstrating the efficacy of all dosing regimens.

Development and Antibacterial Investigation of Linezolid-Loaded SPIONs and HPLC Method Development for Quantitative Analysis of Linezolid.

BACKGROUND: Linezolid (LNZ) is extremely prone to resistance. The development of resistance to LNZ should be taken into consideration when selecting this drug as a therapeutic option. It is well established that reactive oxygen species (ROS) generated by iron oxide nanoparticles (MNPs) could kill the infecting bacteria. So, we hypothesized the synergistic antibacterial effect of iron oxide nanoparticles and LNZ. OBJECTIVE: To study the release and antibacterial effects of LNZ-loaded superparamagnetic iron oxide nanoparticles (SPIONs) on Staphylococcus aureus and Streptococcus pneumoniae. METHOD: Ferrofluid containing SPIONs was synthesized via chemical co-precipitation method and stabilized by sodium lauryl sulphate (SLS). SPIONs were then loaded with LNZ and characterized for particle size, FT-IR, XRD, and entrapment efficiency. Further antibacterial activity of SPIONs and LNZ-loaded SPIONs was investigated. For the in vitro release findings, HPLC analytical method development and validation were performed. RESULTS: Isolation of LNZ was accomplished on a C-18 column with methanol-TBHS (tetra butyl ammonium hydrogen sulphate, 50:50, v/v). The eluate was monitored at 247 nm with a retention time of 4.175 min. The MNP's DLS measurement revealed monodispersed particles with an average size of 16.81 ± 1.07 nm and PDI 0.176 ± 0.012. In optimized formulation, 25 ± 1.75% (w/w) of the drug was found to be entrapped. XRD revealed uniform coating of oleic acid covering the entire magnetic particles' surface with no change in its crystallinity. An effective antimicrobial activity was observed at the lowered dose of drug. CONCLUSIONS: A robust HPLC method was developed to quantify the LNZ in MNPs, and outcomes showed that the reduced dose of LNZ incorporated in SPIONs was able to show similar activity as the marketed product. HIGHLIGHTS: Successfully reduction of the dose of LNZ was established with the aid of biocompatible MNPs to attain the equivalent antibacterial activity.

Design and Development of a Topical Nanogel Formulation Comprising of a Unani Medicinal Agent for the Management of Pain.

The oil of the Unani medicinal herb Baboona (Matricaria chamomilla) has shown potential in the management of pain. However, predicaments such as poor skin penetration, skin sensitization, liable to degradation, and volatile nature restrict its use. Therefore, our group for the first time has developed a carrier-based delivery system to facilitate the direct application of chamomile oil to the forehead. The developed nanogel was characterized for physical parameters such as compatibility, TEM, and stability studies. Further, it was also evaluated for pH, viscosity, spread ability, and extrudability, as well as through texture analyses, in vitro studies, and skin irritation tests. The formulation was successfully developed with all the necessary attributes. The in vitro studies revealed the enhanced skin penetration of chamomile oil nanogel. The in vivo studies were also performed in chemically induced pain models, mimicking migraine. The studies show significant improvement of the pain threshold for chamomile nanogel when compared to the positive control group and the results were comparable to marketed diclofenac formulations. Finally, the encapsulation into nanogel reduced the skin irritation property. The nanogel formulation showed promising effects in the pain management of migraine.

Dual approach utilizing self microemulsifying technique and novel P-gp inhibitor for effective delivery of taxanes.

In the present work, concomitant use of self-microemulsifying drug delivery systems (SMEDDS) and a novel third-generation P-gp inhibitor, GF120918 (elacridar), for the effective transport of taxanes (paclitaxel and docetaxel) across an in vitro model of the intestinal epithelium and uptake into tumor cells were investigated. On the basis of solubility studies and ternary phase diagrams, different SMEDDS formulations of taxanes were prepared and characterized. In caco-2 cell permeation study, paclitaxel-loaded SMEDDS along with GF120918 showed a four-fold increase in apparent permeability, while docetaxel-loaded SMEDDS in combination with GF120918 showed a nine-fold increase in permeability, as compared to plain drug solution. Cell uptake studies on A549 cells were performed with microemulsions formed from both SMEDDS formulations loaded with rhodamine 123 dye and showed good uptake than plain dye solution. Confocal laser scanning microscopic images further confirmed the higher uptake of both SMEDDS formulations in the presence of GF120918.

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.

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.

Advancement of cell-penetrating peptides in combating triple-negative breast cancer.

Extensive research efforts have been made and are still ongoing in the search for an ideal anti-cancer therapy. Almost all chemotherapeutics require a carrier or vehicle, a drug delivery system that can transport the drug specifically to the targeted cancer cells, sparing normal cells. Cell-penetrating peptides (CPPs) provide an effective and efficient pathway for the intra-cellular transportation of various bioactive molecules in several biomedical therapies. They are now well-recognized as facilitators of intracellular cargo delivery and have excellent potential for targeted anti-cancer therapy. In this review, we explain CPPs, recent progress in the development of new CPPs, and their utilization to transport cargoes such as imaging agents, chemotherapeutics, and short-interfering RNAs (siRNA) into tumor cells, contributing to the advancement of novel tumor-specific delivery systems.

A Comprehensive Study of Therapeutic Applications of Chamomile.

Chamomile has a long history of traditional medicinal uses. The two commonly used varieties with therapeutic applications are German chamomile known as Matricaria chamomilla L. and Roman chamomile or Chamaemelum nobile L. The plant contains many components, namely, flavonoids, terpenoids, and coumarins, which are responsible for its medicinal properties. The review discusses recent developments that help in establishing its role as a therapeutic agent in various areas as an anti-inflammatory, antioxidant, analgesic, antimicrobial, hepatoprotective, anti-allergic, anticancer, and anti-hypertensive agent. Not much is known about its role in the treatment of CNS disorders and metabolic syndromes, which are also discussed. The chemical components responsible for the therapeutic activity and the respective mechanism of action are also elaborated.

Nano Matrix Soft Confectionary for Oral Supplementation of Vitamin D: Stability and Sensory Analysis.

Vitamin D deficiency distresses nearly 50% of the population globally and multiple studies have highlighted the association of Vitamin D with a number of clinical manifestations, including musculoskeletal, cardiovascular, cerebrovascular, and neurological disorders. In the current study, vitamin D oil-in-water (O/W) nanoemulsions were developed and incorporated in edible gummies to enhance bioavailability, stability, and patient compliance. The spontaneous emulsification method was employed to produce a nano-emulsion using corn oil with tween 20 and lecithin as emulsifiers. Optimization was carried out using pseudo-ternary phase diagrams and the average particle size and polydispersity index (PDI) of the optimized nanoemulsion were found to be 118.6 ± 4.3 nm and 0.11 ± 0.30, respectively. HPLC stability analysis demonstrated that the nano-emulsion prevented the degradation and it retained more than 97% of active vitamin D over 15 days compared to 94.5% in oil solution. Similar results were obtained over further storage analysis. Vitamin D gummies based on emulsion-based gelled matrices were then developed using gelatin as hydrocolloid and varying quantities of corn oil. Texture analysis revealed that gummies formulated with 10% corn oil had the optimum hardness of 3095.6 ± 201.7 g on the first day which remained consistent on day 45 with similar values of 3594.4 ± 210.6 g. Sensory evaluation by 19 judges using the nine-point hedonic scale highlighted that the taste and overall acceptance of formulated gummies did not change significantly (p > 0.05) over 45 days storage. This study suggested that nanoemulsions consistently prevent the environmental degradation of vitamin D, already known to offer protection in GI by providing sustained intestinal release and enhancing overall bioavailability. Soft chewable matrices were easy to chew and swallow, and they provided greater patient compliance.

Recent advances in multifunctional dendrimer-based nanoprobes for breast cancer theranostics.

Breast cancer (BC) undoubtedly is one of the most common type of cancers amongst women, which causes about 5 million deaths annually. The treatments and diagnostic therapy choices currently available for Breast Cancer is very much limited . Advancements in novel nanocarrier could be a promising strategy for diagnosis and treatments of this deadly disease. Dendrimer nanoformulation could be functionalized and explored for efficient targeting of overexpressed receptors on Breast Cancer cells to achieve targeted drug delivery, for diagnostics and to overcome the resistance of the cells towards particular chemotherapeutic. Additionally, the dendrimer have shown promising potential in the improvement of therapeutic value for Breast Cancer therapy by achieving synergistic co-delivery of chemotherapeutics and genetic materials for multidirectional treatment. In this review, we have highlighted the application of dendrimer as novel multifunctional nanoplatforms for the treatment and diagnosis of Breast Cancer.

Novel Strategies for the Bioavailability Augmentation and Efficacy Improvement of Natural Products in Oral Cancer.

Oral cancer is emerging as a major cause of mortality globally. Oral cancer occupies a significant proportion of the head and neck, including the cheeks, tongue, and oral cavity. Conventional methods in the treatment of cancer involve surgery, radiotherapy, and immunotherapy, and these have not proven to completely eradicate cancerous cells, may lead to the reoccurrence of oral cancer, and possess numerous adverse side effects. Advancements in novel drug delivery approaches have gained popularity in cancer management with an increase in the number of cases associated with oral cancer. Natural products are potent sources for drug discovery, especially for anticancer drugs. Natural product delivery has major challenges due to its low solubility, poor absorption, inappropriate size, instability, poor permeation, and first-pass metabolism. Therefore, it is of prime importance to investigate novel treatment approaches for the delivery of bioactive natural products. Nanotechnology is an advanced method of delivering cancer therapy with minimal damage to normal cells while targeting cancer cells. Therefore, the present review elaborates on the advancements in novel strategies for natural product delivery that lead to the significant enhancement of bioavailability, in vivo activity, and fewer adverse events for the prevention and treatment of oral cancer. Various approaches to accomplish the desired results involve size reduction, surface property modification, and polymer attachment, which collectively result in the higher stability of the formulation.

A Validated, Rapid and Cost-Efficient HPTLC Method for Quantification of Gamma-Linolenic Acid in Borage Oil and Evaluation of Antioxidant Activity.

Borage oil that is extracted from (Borago officinalis Linn.) is a well-known medicinal plant having various medicinal benefits. In this work, an affordable, simple, reliable, rapid and easily accessible high-performance thin-layer chromatography (HPTLC) method was developed for the estimation of gamma-linolenic acid (GLA) in borage oil. HPTLC method employs thin-layer chromatography (TLC) aluminum plates precoated with silica gel (G60F254) as the stationary phase, and the mixture of hexane:toulene:glacial acetic acid (3:7:1, v/v/v) was used as the mobile phase. Densitometric analysis of the TLC plates was carried out at 200 nm. The developed method showed well-resolved spots with retention factor (Rf) value of 0.53 ± 0.04 for GLA. Various experimental conditions like saturation time for chamber, solvent phase migration and width of the band were studied intensely for selecting the optimum conditions. The method validation was performed for parameters like linearity, accuracy, specificity and precision. The values of limit of detection and limit of quantification for GLA were found to be 0.221 and 0.737 µg/band, respectively. In nutshell, the developed HPTLC method was found to be highly sensitive for the estimation of GLA in the herbal oil samples and formulations.

Stability-indicating ultra-performance liquid chromatography method for the estimation of thymoquinone and its application in biopharmaceutical studies.

Thymoquinone (THQ) is known for its neuroprotective and anti-convulsant properties in preclinical studies. We herewith describe a simple, rapid, selective, sensitive and stability-indicating UPLC method for the estimation of THQ and its application to biopharmaceutical studies such as in vitro release from nanoparticulate system and in vivo pharmacokinetic study. The method employed gradient elution using a Waters Acquity HSS-T3 C(18) (100 × 2.1 mm, 1.8 µm) UPLC column. The mobile phase consisted of water and acetonitrile, pumped at a flow rate of 0.5 mL/min. The injection volume was 5 µL and THQ was monitored at 294 nm wavelength with a total run time of 6 min. In solution as well as in plasma, the method was found to be linear (r ≥ 0.998), precise (CV ≤ 2.45%) and accurate (recovery ≥ 84.8%) in the selected concentration range of 0.1-0.8 µg/mL. Forced degradation studies revealed that THQ undergoes degradation under acidic, basic, oxidation and UV light stress conditions. However, the developed UPLC method could effectively resolve degradation product peaks from THQ. Further, no interference was found at the retention time of THQ from any plasma components, indicating selectivity of the developed method. For solutions, the limits of detection and quantitation of the method were found to be 0.001 and 0.0033 µg/mL, respectively; while in plasma they were 0.006 and 0.02 µg/mL, respectively. The validated method was successfully applied to quantify THQ in dissolution medium as well as oral in vivo pharmacokinetic study of THQ suspension and THQ- solid lipid nanoparticle (THQ-SLN) formulation. A 2-fold increase in the relative bioavailability was observed with the THQ-SLN compared with THQ. The results indicate that the SLN significantly increased plasma concentrations and retention within the systemic circulation.

Nanostructured Therapeutic Systems of PUFAs for the Treatment of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is a typical category of the most common and aggressive brain tumors, with a high incidence in older adults, particularly in males. Although the etiology of GBM has not been fully elucidated, yet it is characterized by highly proliferative activity in the glial cells. Its complete resection is impossible, and radiotherapy is not always efficient for complete relief. Thus, GBM remains a therapeutic challenge in neurooncology as there is no treatment that provides significant improvement in the survival rate of patients. In this regard, the identification of newer drug therapy for the treatment of GBM is gaining popularity. However, identifying new targets and developing new leads for screening suitable drug candidates require the investment of resources like time, money, and efforts. It has been observed in many research studies that the use of polyunsaturated fatty acids (PUFAs) as therapeutic moieties for cancer treatment has yielded significant interest owing to their cost-effective availability, limited side effects, and insensitivity towards drug resistance. Nevertheless, the implications of nanostructured therapeutic systems in delivering the PUFAs can provide significant improvement in their biopharmaceutical performance and antitumor activity over the existing alkylating agents used as chemotherapeutic drugs in GBM. Currently, various studies have shown that PUFAs, especially γ-linolenic acid (GLA), have selective tumoricidal action and the ability to reduce antioxidant contents of the glioma tumor cells. In this regard, the present review endeavors to provide an insight into the applications of nanomedicinal drug carriers used for delivering the PUFAs for the effective treatment of GBM and associated diseases.

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.

Formulation development, optimization, and in vitro assessment of thermoresponsive ophthalmic pluronic F127-chitosan in situ tacrolimus gel.

To overcome problems associated with topical delivery of tacrolimus (TCS), a thermoresponsive in situ gel system containing pluronic F127 (PL), and chitosan (CS) was developed, to enhance the precorneal retention, and to sustain the release of the drug. The PL-CS in situ gel was optimized using a 2-factor-3-level central composite experimental design by selecting the concentration of PL and CS as independent variables while gelation time, gelation temperature, and spreadability as dependent variables. The optimized formulation was developed using 22.5 g PL and 0.3 g CS, gels at 33.6 °C, in 22.93 s, and showed the spreadability of 6.2 cm. In vitro studies conducted for the optimized gel revealed the sustained release of TCS (81.73% in 4 h) and improved corneal permeation (74.13% in 4 h), compared with TCS solution. The mechanism of release of TCS followed the Higuchi model with Fickian diffusion transport. Further, histopathology and HET-CAM studies revealed that the developed gel was non-irritating and safe for ocular administration.