Rodent models for dry eye syndrome: Standardization using benzalkonium chloride and scopolamine hydrobromide.

Dry eye disease is a highly prevalent ocular condition that significantly affects the quality of life and presents a major challenge in ophthalmology. Animal models play a crucial role in investigating the pathophysiology and developing effective treatments. The goal of this study was to compare and standardize two dry eye disease rodent models and explore their recovery aspects. We have standardized benzalkonium chloride and scopolamine-induced dry eye disease models which represents two different classes of the dry eye i.e., evaporative dry eye and aqueous deficient dry eye, respectively. After the development of dry eye conditions, a self-recovery period of seven days was granted to assess the reversal of the induced changes. The dry eye condition was assessed by measuring tear volume, corneal slit lamp imaging, and histological examination of the cornea, the lacrimal and the harderian gland. The study indicated the development of chronic inflammation of the cornea and lacrimal gland in the case of benzalkonium after five days of the treatment, while the scopolamine treated group showed chronic inflammation of the lacrimal gland after five days and corneal inflammation after seven days of administration. The recovery study suggested that after discontinuation of inducing agent, the dry eye symptoms were still persistent suggesting the utility of the model in evaluating dry eye treatments. The study highlights the comparative changes in both models along with recovery which can serve as a base for drug discovery and development against dry eye disease.

Single step fabrication of hollow microneedles and an experimental package for controlled drug delivery.

Hollow microneedle arrays (HMNs) are an excellent choice for managing chronic diseases requiring the administration of multiple drug doses over a prolonged duration. However, HMNs have gained partial success due to limitations in their manufacturing capabilities, and cumbersome processes. In the present study, polymeric HMNs were fabricated using a novel single-step drop-casting process without needing cleanroom facilities, and sophisticated instrumentation. When drop casted on the pyramidal tip stainless steel needles, the optimized polymer solution allowed the reproducible formation of desired height HMMs on a detachable acrylic base. To enable broader applications, the base with HMNs was integrated into an experimental package built to deliver a dose of âˆ¼ 5 µL per 30° clockwise rotation of the actuator, allowing multiple metered drug dose administrations. The fabricated HMNs were optically imaged, and tested for mechanical integrity and stability. The working and functional utility of the HMNs package in delivering metered drug doses was demonstrated by delivering vitamin B12 (ex vivo) and insulin (in vivo), respectively. The optimized process can be used for the large-scale manufacturing of HMNs and the experimental package shows the potential to be further developed into a wearable device.

Human papillomavirus infection, cervical cancer and the less explored role of trace elements.

Cervical cancer is an aggressive type of cancer affecting women worldwide. Many affected individuals rely on smear tests for the diagnosis, surgery, chemotherapy, or radiation for their treatment. However, due to a broad set of undesired results and side-effects associated with the existing protocols, the search for better diagnostic and therapeutic interventions is a never-ending pursuit. In the purview, the bio-concentration of trace elements (copper, selenium, zinc, iron, arsenic, manganese, and cadmium) is seen to fluctuate during the occurrence of cervical cancer and its progression from pre-cancerous to metastatic nature. Thus, during the occurrence of cervical cancer, the detection of trace elements and their supplementation will prove to be highly advantageous in developing diagnostic tools and therapeutics, respectively. This review provides a detailed overview of cervical cancer, its encouragement by human papillomavirus infections, the mechanism of pathology, and resistance. Majorly, the review emphasizes the less explored role of trace elements, their contribution to the growth and inhibition of cervical cancer. Numerous clinical trials have been listed, thereby providing a comprehensive reference to the exploration of trace elements in the management of cervical cancer.

In vitro antibacterial activity and in vivo pharmacokinetics of intravenously administered Amikacin-loaded Liposomes for the management of bacterial septicaemia.

Systemic delivery of amikacin is a widely adopted treatment modality for severe infections like sepsis. However, the current course of treatment requires repeated bolus doses of amikacin, prolonged hospitalization, and continuous therapeutic monitoring to manage the severe adverse effects. Amikacin has short half-life, which further challenges the delivery of sufficient systemic concentrations when administered by intravenous route. To solve this issue, novel delivery systems, amikacin liposomes (Ak-lip) were developed and evaluated for its antibacterial efficacy (agar plate diffusion and resazurin microtiter assay) and in vivo drug release in Sprague-Dawley rats. The Ak-lip were prepared by modified thin film hydration method and optimized based on particle size and Zeta potential. The zone of inhibition for Ak-lip and amikacin was found to be 22 mm and 26 mm against Staphylococcus aureus. The minimum inhibitory concentrations (MIC) of amikacin and Ak-lip against Staphylococcus aureus were found to be 3 µg/mL and 9 µg/mL, and for Pseudomonas aeruginosa were 0.6 µg/mL and 0.9 µg/mL respectively. The in vivo pharmacokinetic parameters were determined using Gastroplus™. A significant difference in the pharmacokinetic parameters (AUC, Cmax) was observed between amikacin and Ak-lip. The developed formulation showed good colloidal stability and sustained release profile up to 72 h which can reduce dosing frequency, minimize hospitalization and improve bactericidal activity at lower concentrations paving the path for improved therapeutic interventions in the treatment of sepsis.

Oil-free eye drops containing Cyclosporine A/cyclodextrin/PVA supramolecular complex as a treatment modality for dry eye disease.

According to the global mapping of dry eye disease (DED), nearly 5 to 50 % of people suffer from DED, and this number is on the rise. The drug of choice Cyclosporine A (CsA) exhibits poor ocular bioavailability due to high molecular weight and lipophilicity. Moreover, formulations of CsA currently available are in the form of oil-based emulsions that are known to cause ocular irritation and pain. In this study, sulfobutylether-ß-cyclodextrin (SBE-ß-CD) based binary and ternary supramolecular complexes of CsA were developed as completely oil-free, and particle-free eye drops to treat DED. The physicochemical characterizations were supplemented with relevant in silico studies, to ascertain the findings. Further, the efficacy of the complexes was evaluated in the scopolamine-induced mouse model of DED. The complexation improved the CsA solubility by ~21-fold, with ~4-fold improvement in dissolution and transcorneal permeation. The non-irritancy and non-toxicity were confirmed by hen's egg chorioallantoic membrane assay and cytotoxicity assay using human corneal epithelial cells, respectively. The in vivo treatment with the ternary CD complex demonstrated better management of the dry eye supported by the tear volume assessment, corneal fluorescein staining, and histopathological studies of the cornea, lacrimal gland, and harderian gland. The study demonstrates the potential of the supramolecular complex as an alternative to the oil-based formulation of eye drops for drugs that show low solubility and poor corneal permeation.

A Sensitive Spectrofluorimetric Method for Curcumin Analysis.

Curcumin (CUR), a natural polyphenolic compound extracted from the rhizomes of Curcuma longa, is used as a pharmaceutical agent, spice in food, and as a dye. Currently, CUR is being investigated for cancer treatment in Phase-II clinical trials. CUR also possesses excellent activities like anti-inflammatory, anti-microbial, and anti-oxidant, therefore quality control is crucial. The present research work was to develop a new, simple, validated and time-saving rapid 96-well plate spectrofluorimetric method for the determination of CUR. The developed method was compared with routinely used high performance liquid chromatography (HPLC) technique. The developed method were found to be linear in the concentration range of 15 to 3900 ng/mL with R2 ≥ 0.9983 for spectrofluorimetric and 50-7500 ng/mL with R2 ≥ 0.9999 for HPLC method. Accuracy, intraday and interday precision was adequate, with RSD lower than the suggested limits. The limits for the detection and the quantification of CUR were 7 and 15 ng/mL for spectrofluorimetric, and 25 and 50 ng/mL for HPLC respectively. The Bland-Altman analysis demonstrated the similarities between the two methods. The 96-well plate method was successfully applied to determine CUR in solid lipid nanoparticles (SLNs) and chitosan nanoparticles (Chi-NPs). The developed spectrofluorimetric method can hence serve as a possible replacement for the HPLC method for the quantification of CUR in healthcare and food products.

Multifunctional role of exosomes in viral diseases: From transmission to diagnosis and therapy.

Efforts to discover antiviral drugs and diagnostic platforms have intensified to an unprecedented level since the outbreak of COVID-19. Nano-sized endosomal vesicles called exosomes have gained considerable attention from researchers due to their role in intracellular communication to regulate the biological activity of target cells through cargo proteins, nucleic acids, and lipids. According to recent studies, exosomes play a vital role in viral diseases including covid-19, with their interaction with the host immune system opening the door to effective antiviral treatments. Utilizing the intrinsic nature of exosomes, it is imperative to elucidate how exosomes exert their effect on the immune system or boost viral infectivity. Exosome biogenesis machinery is hijacked by viruses to initiate replication, spread infection, and evade the immune response. Exosomes, however, also participate in protective mechanisms by triggering the innate immune system. Besides that, exosomes released from the cells can carry a robust amount of information about the diseased state, serving as a potential biomarker for detecting viral diseases. This review describes how exosomes increase virus infectivity, act as immunomodulators, and function as a potential drug delivery carrier and diagnostic biomarker for diseases caused by HIV, Hepatitis, Ebola, and Epstein-Barr viruses. Furthermore, the review analyzes various applications of exosomes within the context of COVID-19, including its management.

A novel high throughput 96-well-based fluorimetric method to measure amikacin in pharmaceutical formulations: development using response surface methodology.

An aminoglycoside antibiotic, amikacin, is used to treat severe and recurring bacterial infections. Due to the absence of a chromophore, however, amikacin must be extensively derivatized before being quantified, both in analytical and bioanalytical samples. In this study, for the first time, we developed a simple and sensitive method for measuring amikacin sulfate using spectrofluorimetry with a 96-well plate reader, based on the design of the experiment's approach. To develop a robust and reproducible spectrofluorimetric method, the influence of essential attributes, namely pH of the buffer, heating temperature, and concentration of reagents, were evaluated using univariate analysis followed by multivariate analysis (central composite design). International Conference of Harmonization guidelines were used to validate the optimized method. The developed technique is linear from 1.9 to 10 µg/ml with a regression coefficient of 0.9991. The detection and quantification limits were 0.649 µg/ml and 1.9 µg/ml, respectively. For the developed method, both intraday and interday precision (%RSD) were less than 5%. Using the method, amikacin concentrations were quantified in prepared amikacin liposomes and commercial formulations of Amicin®. The developed method greatly reduces sample volume and is a rapid, high throughput microplate-based fluorescence approach for the convenient and cost-effective measurement of amikacin in pharmaceutical formulations. In comparison with previously published approaches, the suggested method allowed for quick analysis of a high number of samples in a short amount of time (96 samples in 125 sec), resulting in an average duration of analysis of 1.3 sec per sample.

A supramolecular thermosensitive gel of ketoconazole for ocular applications: In silico, in vitro, and ex vivo studies.

The incidence of corneal fungal infections continues to be a growing concern worldwide. Ocular delivery of anti-fungal drugs is challenging due to the anatomical and physiological barriers of the eye. The ocular bioavailability of ketoconazole (KTZ), a widely prescribed antifungal agent, is hampered by its limited aqueous solubility and permeation. In the study, the physicochemical properties of KTZ were improved by complexation with sulfobutylether-ß-cyclodextrin (SBE-ß-CD).KTZ-SBE-ß-CD complex was studied in silico with docking and dynamics simulations, followed by wet-lab experiments.The optimized KTZ-SBE-ß-CD complex was loaded into a thermosensitivein situ gel to increase corneal bioavailability. The supramolecular complex increased the solubility of KTZ by 5-folds and exhibited a 10-fold increment in drug release compared to the pure KTZ. Owing to the diffusion, thein situ gel exhibited a more sustained drug release profile. Theex vivocorneal permeation studies showed higher permeation from KTZ-SBE-ß-CD in situ gel (flux of ∼19.11 µg/cm2/h) than KTZin situ gel (flux of ∼1.17 µg/cm2/h). The cytotoxicity assays and the hen's egg chorioallantoic membrane assay (HET-CAM) confirmed the formulations' safety and non-irritancy. In silico guided design of KTZ-SBE-ß-CD inclusion complexes successfully modified the physicochemical properties of KTZ. In addition, the loading of the KTZ-SBE-ß-CD complex into an in situ gel significantly increased the precorneal retention and permeation of KTZ, indicating that the developed formulation is a viable modality to treat fungal keratitis.

Breaking the barriers for the delivery of amikacin: Challenges, strategies, and opportunities.

Hypodermic delivery of amikacin is a widely adopted treatment modality for severe infections, including bacterial septicemia, meningitis, intra-abdominal infections, burns, postoperative complications, and urinary tract infections in both paediatric and adult populations. In most instances, the course of treatment requires repeated bolus doses of amikacin, prolonged hospitalization, and the presence of a skilled healthcare worker for administration and continuous therapeutic monitoring to manage the severe adverse effects. Amikacin is hydrophilic and exhibits a short half-life, which further challenges the delivery of sufficient systemic concentrations when administered by the oral or transdermal route. In this purview, the exploitation of novel controlled and sustained release drug delivery platforms is warranted. Furthermore, it has been shown that novel delivery systems are capable of increasing the antibacterial activity of amikacin at lower doses when compared to the conventional formulations and also aid in overcoming the development of drug-resistance, which currently is a significant threat to the healthcare system worldwide. The current review presents a comprehensive overview of the developmental history of amikacin, the mechanism of action in virulent strains as well as the occurrence of resistance, and various emerging drug delivery solutions developed both by the academia and the industry. The examples outlined within the review provides significant pieces of evidence on novel amikacin formulations in the field of antimicrobial research paving the path for future therapeutic interventions that will result in improved clinical outcome.

Cyclodextrin based bone regenerative inclusion complex for resveratrol in postmenopausal osteoporosis.

Recent preclinical studies have shown that resveratrol (RSV), is a promising remedy for osteoporosis owing to its estrogenic, anti-inflammatory, and antioxidant properties. However, RSV has met limited success due to its poor oral bioavailability and inefficient systemic delivery. In this study, we prepared the inclusion complex of RSV with sulfo-butyl ether ß-cyclodextrin (SBE-ß-CD) to enhance the aqueous solubility of RSV. The in-silico docking studies and Physico-chemical characterization assays were performed to understand the interaction of RSV inside the SBE-ß-CD cavity. The in vivo safety assessment of RSV-SBE-ß-CD inclusion complex (R-CDIC) was performed in healthy Wistar rats. The efficacy of the inclusion complex against postmenopausal osteoporosis was further investigated in ovariectomized (OVX) rat model. The alteration in the bone micro-architectural structure was evaluated by microcomputed tomographic scanning, serum biochemical estimations, biomechanical strength and histopathological investigation. Administration of RSV-SBE-ß-CD inclusion complex was found to be safe and significantly improved micro-architectural deterioration induced by estrogen withdrawal. Results of bone morphometry and biomechanics study further emboldened the efficacy claim of the RSV-SBE-ß-CD complex. Thus, the present study demonstrated the efficacy of the RSV-SBE-ß-CD inclusion complex for treating osteolytic degradation in osteoporosis.

Next-generation contact lenses: Towards bioresponsive drug delivery and smart technologies in ocular therapeutics.

In contrast to the conventional ocular formulations, contact lenses are well known for their diverse applications ranging from bio-sensing, prevention of myopia, cosmetics, and drug delivery. With a tremendous change in the lifestyle, contact lenses for therapeutic purposes have increased several fold. Contact lenses as medicated lenses suffer from several disadvantages, and to overcome the same numerous approaches have been explored. Researches worldwide have come a long way from cyclodextrin-based and vitamin E-based modified contact lenses to bioinspired approaches to enhance the effectiveness of the drug-eluting contact lenses. The bioinspired approach exploits bioinspired polymeric systems to enhance biocompatibility, specific molecule recognition technique by molecular imprinting, or stimuli-responsive system to improve the biocompatibility, drug loading, and drug delivery efficacy of the drug-eluting contact lenses. Moreover, recent innovations in ocular therapeutics such as nanowafers and microneedle contact lenses, and ocular patches have gained tremendous attention in ocular therapeutics. Another potential application of the contact lenses are smart lenses applied in the biosensing and diagnosis of various ocular disorders. The review summarizes and discusses the widespread therapeutic applications of next-generation contact lenses and various fabrication approaches, including its clinical implications, efforts taken by researchers in exploring the novel materials and diverse forms of the lenses, mechanisms of drug release, clinical trials, and their toxicity and safety concerns.

Microneedles for Extended Transdermal Therapeutics: A Route to Advanced Healthcare.

Sustained release of drugs over a pre-determined period is required to maintain an effective therapeutic dose for variety of drug delivery applications. Transdermal devices such as polymeric microneedle patches and other microneedle-based devices have been utilized for sustained release of their payload. Swift clearing of drugs can be prevented either by designing a slow-degrading polymeric matrix or by providing physiochemical triggers to different microneedle-based devices for on-demand release. These long-acting transdermal devices prevent the burst release of drugs. This review highlights the recent advances of microneedle-based devices for sustained release of vaccines, hormones, and antiretrovirals with their prospective safe clinical translation.

Molybdenum-based hetero-nanocomposites for cancer therapy, diagnosis and biosensing application: Current advancement and future breakthroughs.

In recent years, there have been significant advancements in the nanotechnology for cancer therapy. Even though molybdenum disulphide (MoS2)-based nanocomposites demonstrated extensive applications in biosensing, bioimaging, phototherapy, the review article focusing on MoS2 nanocomposite platform has not been accounted for yet. The review summarizes recent strategies on design and fabrication of MoS2-based nanocomposites and their modulated properties in cancer treatment. The review also discussed several therapeutic strategies (photothermal, photodynamic, immunotherapy, gene therapy and chemotherapy) and their combinations for efficient cancer therapy along with certain case studies. The review also inculcates various diagnostic techniques viz. magnetic resonance imaging, computed tomography, photoacoustic imaging and fluorescence imaging for diagnosis of cancer.

Derma rollers in therapy: the transition from cosmetics to transdermal drug delivery.

Derma roller, a device rolled onto the skin to form micropores, is extensively used for cosmetic purposes. The pores thus created are utilized to either result in the induction of collagen production, leading to glowing and wrinkle-free skin or for permeating the applied formulations to the site of action within the skin. Recent studies have shown the benefits of using derma rollers for transdermal delivery of drugs. In the nascent stage, this approach paves a way to successfully breach the stratum corneum and aid in the movement of medications directed towards the dermis and the hair follicles. The review essentially summarizes the evidence of the use of derma rollers in cosmetic setup, their designing, and the preclinical and clinical reports of efficacy, safety, and concerns when translated for pharmaceutical purposes and transdermal drug delivery.

Lipid vesicles: A versatile drug delivery platform for dermal and transdermal applications.

Topical and transdermal application of active pharmaceutical ingredients to the skin is an attractive strategy being explored by formulation scientists to treat disease conditions rather than the oral drug delivery. Several approaches have been attempted, and many of them have emerged with significant clinical potential. However, the delivery of drugs across the skin is an arduous task due to permeation limiting barriers. It, therefore, requires the aid of external agents or carrier systems for efficient permeation. Lipid-based vesicular systems are carriers for the transport of drugs through the stratum corneum (dermal drug delivery) and into the bloodstream for systemic action (transdermal drug delivery) overcoming the barrier properties. This review article describes the various vesicular systems reported for skin delivery of actives with relevant case studies. The vesicular systems presented here are in the order of their advent from conventional systems to the advanced lipid vesicles. The design and development of drugs in vesicular systems have brought a new dimension to the treatment of disease conditions overcoming the permeation limiting barriers, thus improving its efficacy.

Improved Oral Pharmacokinetics of Pentoxifylline with Palm Oil and Capmul® MCM Containing Self-Nano-Emulsifying Drug Delivery System.

Pentoxifylline (PTX), an anti-hemorrhage drug used in the treatment of intermittent claudication, is extensively metabolized by the liver resulting in a reduction of the therapeutic levels within a short duration of time. Self-nano-emulsifying drug delivery system (SNEDDS) is well reported to enhance the bio-absorption of drugs by forming nano-sized globules upon contact with the biological fluids after oral administration. The present study aimed to formulate, characterize, and improve the oral bioavailability of PTX using SNEDDS. The formulated SNEDDS consisted of palm oil, Capmul® MCM, and Tween® 80 as oil, surfactant, and co-surfactant, respectively. The mixture design module under the umbrella of the design of experiments was used for the optimization of SNEDDS. The dynamic light-scattering technique was used to confirm the formation of nanoemulsion based on the globule size, in addition to the turbidity measurements. In vivo bioavailability studies were carried out on male Wistar rats. The pharmacokinetic parameters upon oral administration were calculated using the GastroPlus software. The optimized SNEDDS had a mean globule size of 165 nm with minimal turbidity in an aqueous medium. Bioavailability of PTX increased 1.5-folds (AUC = 1013.30 ng h/mL) as SNEDDS than the pure drug with an AUC of 673.10 ng h/mL. In conclusion, SNEDDS was seen to enhance the bioavailability of PTX and can be explored to effectively control the incidents of intermittent claudication.

Development and Investigation of Vitamin C-Enriched Adapalene-Loaded Transfersome Gel: a Collegial Approach for the Treatment of Acne Vulgaris.

Adapalene-loaded transfersome gel containing vitamin C as a combination therapy for the management of acne vulgaris was developed in the present study. The transfersome was prepared by reverse-phase evaporation, and the effect of various process parameters were investigated by the Design of Experiment (DOE) approach and optimized based on the particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE). The selected tranfersomes were further evaluated for their thermal behavior and morphology by transmission electron microscopy and turbidity measurements and incorporated into a gel with/without vitamin C. The gel was evaluated and compared with the marketed product (Adiff gel) for various physicochemical parameters, and in vivo studies in testosterone-induced rat models of acne. The prepared transfersomes had PS in the range of 280 to 400 nm, PDI values of 0.416 to 0.8, ZP of - 38 to - 20 mV, and % EE of 32 to 70%. DSC studies confirmed a positive interaction of the components in the transfersome. Surface morphology confirmed that the vesicles were spherical, unilamellar, and discrete. A relative deformability study showed higher elasticity of the transfersomes compared with Adiff aqs gel. Ascorbyl-6-palmitate in adapalene-loaded transfersome gel containing vitamin C (ADVTG) was found to have a good antioxidant free radical-scavenging activity. An in vitro drug release study showed that the sustained release of the transfersomal formulations was attributed to the flexibility of the vesicles by which penetration was increased. ADVTG was found to be promising in treating acne compared with the marketed product. Graphical Abstract.

Supramolecular cyclodextrin complex: Diversity, safety, and applications in ocular therapeutics.

Approximately 30-70% of the existing and new chemical entities exhibit poor aqueous solubility. For topical ocular delivery, drug molecules need to possess both hydrophilic and lipophilic nature to enable absorption through the aqueous tear layer and permeation through the corneal lipophilic barrier. To overcome the aqueous solubility related issues, various techniques such as solid dispersion, particle size reduction, cyclodextrin complexation, co-solvency, prodrug, derivatization, and salt formation are being explored in the healthcare sector. Cyclodextrin inclusion complexation techniques have been established by several pharmaceutical industries for systemic administration allowing a transition from the lab to the clinics. Though cyclodextrins are exploited in ocular drug delivery, there are prevailing concerns regarding its absorption enhancing capacity and mechanism, retention at the ocular surfaces and, irritation and toxicity profiles. In the present review, the efforts taken by various research groups to address the concerns of using cyclodextrin and its derivatives in ocular therapeutics are summarized. Also, considerations and utility of cyclodextrin systems in fabricating newer formulations such as contact lens, inserts, and implants have been discussed in the review.