Simultaneous Intranasal Codelivery of Donepezil and Memantine in a Nanocolloidal Carrier: Optimization, Pharmacokinetics, and Pharmacodynamics Studies.

This work focuses on developing nanoemulsions using a low-energy emulsification method for the codelivery of donepezil and memantine in one dosage form intended to be administered via the intranasal route for enhanced brain delivery. The nanoemulsion formulation was prepared using a low emulsification technique and characterized using various microscopy and nasal ciliotoxicity studies. The safe nanoemulsion was intended for preclinical pharmacokinetics with brain distribution and pharmacodynamics in a scopolamine-induced murine model. The formulated nanoemulsion was 16 nm in size, with a zeta potential of -7.22 mV, and exhibited a spherical shape. The brain concentration of IN-administered NE for DPZ and MEM was ∼678 and 249 ng/mL after 15 min. This concentration is more than 2 times higher in amount when compared with NE administered via PO, free drug solution administered via IN and PO route both. However, the plasma concentration of IN-administered NE for DPZ and MEM was ∼3 and 28 ng/mL after 15 min. In pharmacodynamic studies, the efficacy of NE administered via the IN route was higher when compared with other groups in neurobehavioral, biochemical estimation, and gene expression studies. The results suggest that the IN route can be explored in the future for the delivery of actives via nanocolloidal carriers in the brain for neurological disorders and can serve as promising alternatives for conventional dosage forms and routes.

Transferrin decorated PLGA encumbered moxifloxacin nanoparticles and in vitro cellular studies.

PURPOSE: Complicated intra-abdominal infection (cIAI) management involves administering antibiotics that destroy the cell wall and the genesis of bacterial lipopolysaccharide (LPS). During the infectious state, the expression of transferrin receptors upregulates on the intestinal epithelial cells, which are considered the site of infection. In the present research, transferrin decorated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) encapsulated moxifloxacin (MOX) were developed for possible targeting of the receptors in the colon. SIGNIFICANCE: This study will explore more about the incorporation of transferrin as effective coating material in targeted drug delivery. METHODS: Nanoparticles were prepared using nano-emulsification and surface modification with transferrin was done by layer-by-layer methodology and evaluated by powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), FTIR, SEM, antibacterial activity, and cellular uptake studies. RESULTS: The formulated NPs exhibit a size of ≈170 nm, PDI ≈ 0.25, zeta potential ≈-4.0 mV, drug loading ≈ 6.8%, and entrapment efficiency of 82%. Transferrin-decorated NPs exhibit tailored release for almost 12 h and in vitro antibacterial activity for 14 h. The cellular uptake studies were done on a RAW264.7 cell line for better determination of transferrin uptake of fabricated NPs. CONCLUSION: The above study circumvents around the preparation of transferrin decorated PLGA encumbered MOX NPs intended for cIAI-induced sepsis. PLGA NPs provide tailored release of MOX with primary burst and followed by sustained release. These observations confines with antibacterial activity studies. The prepared transferrin-coated NPs were stable and effectively uptaken by RAW264.7 cells. However, future studies include the preclinical investigation of these NPs in sepsis-induced murine models.

Bilayer fixed-dose combination tablet for curcumin microparticles and piroxicam and in vitro evaluation.

Aim: In the present work, fixed-dose combination of bilayer tablets for piroxicam as and curcumin as immediate-release and sustained-release layer (SRL) respectively for management of inflammatory response. Materials & methods: The SRL include Curcumin polycaprolactone microparticles from spray drying. The tablet layers include Pearlitol 200SD, Microcrystalline cellulose PH101, Aerosil 200, talc each layer. Results: SEM studies confirm spherical microparticles. PXRD and DSC studies confirm the amorphous microparticles. In vitro studies exhibit, an immediate release and sustained release for Piroxicam and Curcumin after 2 h. Cellular uptake studies on RAW 264.7 cells confirm the complete internalization of microparticles. Conclusion: Therefore, it was concluded that microparticles can be formulated into a unit dosage form for the management of inflammation.

Harnessing personalized tailored medicines to digital-based data-enriched edible pharmaceuticals.

Tailoring drug products to personalized medicines poses challenges for conventional dosage forms. The prominent reason is the restricted availability of flexible dosage strengths in the market. Inappropriate dosage strengths lead to adverse drug reactions or compromised therapeutic effects. The situation worsens when the drug has a narrow therapeutic window. To overcome these challenges, data-enriched edible pharmaceuticals (DEEP) are novel concepts for designing solid oral products. DEEP have individualized doses and information embedded in quick response (QR) code form. When data are presented in a QR code, the information is printed with edible ink that contains the drug in tailored doses required for the patients.

Combining donepezil and memantine via mannosylated PLGA nanoparticles for intranasal delivery: Characterization and preclinical studies.

The current work is focused on developing mannose-coated PLGA nanoparticles for delivering Donepezil and Memantine in one dosage form. The formulated nanoparticles were prepared using a simple emulsification technique. The final coated NPs exhibited 179.4 nm size and - 33.1 mV zeta potential and spherical shape. The concentration of IN-administrated MEM and DPZ mannose coated NPs in brain was ~573 and 207 ng/mL respectively. This amount accounts for 3 times more in comparison to uncoated NPs administered via intranasal and peroral routes. The plasma concentration of coated NPs administered via the intranasal route was various times less in comparison to other groups. In the field of pharmacodynamics, the administration of coated NPs via the IN route has shown superior efficacy in comparison to other groups in various investigations involving neurobehavioral assessments, gene expression analyses and biochemical estimations. The findings indicate that the IN route may be a potential avenue for delivering therapeutic agents using nanoparticles to treat neurological illnesses. This approach shows promise as a viable alternative to traditional dose forms and administration methods.

Rosemary oil low energy nanoemulsion: optimization, µrheology, in silico, in vitro, and ex vivo characterization.

Acetylcholine imbalance in the human brain causes dementia-related symptoms of Alzheimer's disease. Acetylcholinesterase (AChE) inhibitors prevent the lysis of acetylcholine in the brain and prevent dementia. Therefore, the present study aims to investigate the in silico and in vitro AChE potential of rosemary oil and then formulate it into nanoemulsion as an adjuvant with co-administration of Donepezil (Dz) with a thought for futuristic target for Alzheimer's diseases via the intranasal route. The aim for preparing this formulation was to add the AChE inhibition effect of the rosemary oil to the effect that acts as an additive effect along with Dz. The docking score of rosemary oil components on human cholinesterase 1GQR protein was found to be >-5 kcal/mol. In vitro AChE activity of rosemary oil confirms the prominent IC50 of oil at 0.001 µL/min. Nanoemulsion was prepared by low energy emulsification technique using Tween 80 as surfactant and ethanol or diethylene glycol monoethyl ether as cosurfactant. Droplet size, polydisperity index, and zeta potential of stable nanoemulsion was ∼16 nm, 0.1, and -6.05 mV for stable batch. High-resolution transmission electron microscopy microscopic studies depicted the spherical shape of the droplet. Micro rheology investigation of nanoemulsion clearly attributes to gel-sol-gel behaviour of formulated nanoemulsion. Thermal evaluation of nanoemulsion depicts the phase transition behaviour of ethanol-based nanoemulsion at 60 °C. Ex vivo nasal ciliotoxicity and permeation studies of formulation establish the safety of ethanol-based rosemary oil-loaded nanoemulsion and permeation mechanism of Dz from the nanoemulsion. In vitro permeation studies showed more drug penetration from the nanoemulsion as compared to the plain drug. The prepared nanoemulsion was found to be stable for 3 months at 4, 25, and 45 °C of storage. This low energy preparation method can be advantageous for the preparation of scalable nanoemulsion and can be a futuristic therapeutic for Alzheimer's disease.

Nanocrystals: An Approachable Delivery System for Anticancer Therapeutics.

Cancer accounts for the high mortality rate and limits the life expectancy of an individual. As per the WHO report of 2020, cancer accounts for >10 million deaths globally. Scientists are continuously pitching toward the development of novel techniques to combat this menace and enhance the efficacy of prevailing molecules. In the early phases of the drug development process, >40% of promising new therapeutic molecules are hydrophobic. Low aqueous solubility results in compromised bioavailability on administration. This limitation is a major drawback for the therapeutic use of anticancer drugs. Drug nanocrystals (NCs) have sparked a lot of interest in drug delivery. This might be due to their excellent physicochemical characteristics like tailored dissolution, high drug loading efficiency, extended circulation period, and high structural stability. There are 'n' a number of the characteristics that make drug nanocrystals a promising formulation for the treatment of cancer. In the last few years, many hydrophobic or lipophilic drugs like camptothecin, paclitaxel, cyclosporin, busulfan, and thymectacin have been formulated as drug nanocrystals against anticancer therapeutics. Various formulation technologies have been developed in conjunction with nanocrystal development. This includes top-down approaches, bottom-up approaches, as well as combination technology. In this article, we will focus on the various manufacturing processes, biological fate and therapeutic applications of NCs, and future perspectives in the management of cancer.

Biocompatible Nanomaterials for Burns.

The skin being the largest organ, protects our body against harmful chemicals, pathogens, and physical agents. It constitutes primarily three layers: epidermis, dermis, and subcutaneous layers. Injuries occurring due to burning remain localized to the skin or other organic tissues caused by flame, extreme heat, and close contact with chemicals or heated objects. Conventional treatments are available for the treatment of burns; however, they are expensive and might completely replace autologous tissue transfer. Nanotechnology-based approaches include organic nanoparticles, dendrimers, hydrogels, etc. Biocompatibility usually refers to the ability of biomaterials to perform their respective functions centered on medical therapy without causing any systemic or local effects. Polymeric materials like a natural (chitosan and hyaluronic acid) and synthetic (polylactic acid and polycaprolactone) materials are employed as biomaterials. Various preclinical and clinical studies were performed in animal models. In this review, the authors have discussed elaborately the biocompatible polymers, which are used in the treatment of burn wounds. Afterwards, a brief discussion on the polymers, pre-clinical and clinical studies, and regulatory concerns related to nanomaterials have also been covered.

Recent nanoengineered diagnostic and therapeutic advancements in management of Sepsis.

COVID-19 acquired symptoms have affected the worldwide population and increased the load of Intensive care unit (ICU) patient admissions. A large number of patients admitted to ICU end with a deadly fate of mortality. A high mortality rate of patients was reported with hospital-acquired septic shock that leads to multiple organ failures and ultimately ends with death. The patients who overcome this septic shock suffer from morbidity that also affects their caretakers. To overcome these situations, scientists are exploring progressive theragnostic techniques with advanced techniques based on biosensors, biomarkers, biozymes, vesicles, and others. These advanced techniques pave the novel way for early detection of sepsis-associated symptoms and timely treatment with appropriate antibiotics and immunomodulators and prevent the undue effect on other parts of the body. There are other techniques like externally modulated electric-based devices working on the principle of piezoelectric mechanism that not only sense the endotoxin levels but also target them with a loaded antibiotic to neutralize the onset of inflammatory response. Recently researchers have developed a lipopolysaccharide (LPS) neutralizing cartridge that not only senses the LPS but also appropriately neutralizes with dual mechanistic insights of antibiotic and anti-inflammatory effects. This review will highlight recent developments in the new nanotechnology-based approaches for the diagnosis and therapeutics of sepsis that is responsible for the high number of deaths of patients suffering from this critical disease.

Lymphatic targeting for therapeutic application using nanoparticulate systems.

The lymphatic system has grasped attention of researchers to a greater extent. The conventional methods of lymphatic delivery are now being modified to include nanotechnology to enhance the targeting of the drug at the specific pathological site. Scientists have worked successfully on different drug loaded nanocarriers that are modulated for the lymphatic system targeting for the treatment of various fatal diseases. Huge strides have been made in methods of delivery of these drugs either individually or in combination along with nanoparticles, therapeutic genes, and vaccines. However, the products introduced for commercial use are almost near nil. Altogether, there are challenges that need to be resolved and studies that are meant to be done for further improvements. The current review focuses on the understanding and pathophysiology of the lymphatic system and changes that occur during disease, drug characteristics, and physicochemical parameters that influence the lymphatic uptake of drugs and different nanocarriers. We further highlight different potential results obtained over the years with nanocarriers and other delivery methods to effectively target the lymphatic system for their therapeutic application. The challenges and drawbacks governing the lack of products available clinically have also been discussed.

Stimuli-responsive Polymeric Nanosystems for Therapeutic Applications.

BACKGROUND: Recent studies have been reported emerging polymeric nanoparticles as a promising particulate carrier system for controlled and targeted drug delivery. Stimuli-responsive nanocarriers have shown characteristics, such as high drug uptake at specific sites or targeted cells with an advantage of no drug leakage. These stimuli-responsive polymeric systems are used to functionalize nanocarriers, such as dendrimers, metallic nanoparticles, polymeric nanoparticles, liposomal nanoparticles, and quantum dots. OBJECTIVE: The study reviews the potential of smart stimuli-responsive carriers for therapeutic application and their behavior in external or internal stimuli, like pH, temperature, redox, light, and magnetic field. These stimuli- responsive drug delivery systems exhibit different drug release patterns in in vitro and in vivo studies. Stimuli- responsive nanocarriers are useful for both hydrophilic and hydrophobic drugs and release them on applied stimulus. This review highlights the recent development in the physical properties of polymeric materials and their application in stimuli-responsive specific drug delivery. CONCLUSION: The stimuli (smart, intelligent, programmable) drug delivery systems provide site-specific drug delivery with potential therapy for cancer, neurodegenerative, and lifestyle disorders. The stimuli-responsive- based nanocarriers are developing at a fast pace, and there is a huge demand for biocompatible and biodegradable responsive polymers for effective and safe delivery.

Recent trends of natural based therapeutics for mitochondria targeting in Alzheimer's disease.

Alzheimer's disease (AD) is the most ubiquitous neurodegenerative disorder with impaired cognitive functionality. Till date, the specific pathophysiology related to AD is still elusive. Recent reports suggest mitochondrial dysfunctionality like oxidative stress, Ca2+ disbalance, apoptosis, decrease energy and its metabolism plays an important. Recent reports about mitochondrial mechanisms and dynamics in AD unravelled new insights of molecular targets. Targeting multi-pathway via natural products may attenuate and prevent the mitochondria dysfunctionality. In this review, we have focused on the pathophysiology events of mitochondrial dysfunction in AD as well as mitochondrial fusion and fission mechanisms, role of aging in multicellular organisms, and how these connect to cell cycle regulation, and transmission of energy status.

Recent highlights on Omicron as a new SARS-COVID-19 variant: evolution, genetic mutation, and future perspectives.

COVID-19 has affected the lives of billions of people and is a causative agent for millions of deaths. After 23 months of the first reported case of COVID-19, on 25th November 2020, a new SARS-COVID-19 variant, i.e. Omicron was reported with a WHO tagline of VoC that trembled the world with its infectivity rate. This fifth VoC raised the concern about neutralising ability and adequate control of SARS-COVID-19 infection due to mass vaccination drive (nearly more than 4.7 billion individuals got vaccinated globally till December 2021). However, the present scenario of VoCs highlights the importance of vaccination and public health measures that need to be followed strictly to prevent the fatality from Omicron. The world still needs to overcome the hesitancy that poses a major barrier to the implementation of vaccination. This review highlights the SARS-COVID-19 situation and discusses in detail the mutational events that occurred at a cellular level in different variants over time. This article is dedicated to the scientific findings reported during the recent outbreak of 2019-2022 and describes their symptoms, disease, spread, treatment, and preventive action advised. The article also focuses on the treatment options available for Covid-19 and the update of Omicron by expert agencies.

Active pharmaceutical ingredients (APIs) in ionic liquids: An effective approach for API physiochemical parameter optimization.

Ionic liquids (ILs) are widely used as solvents, co-solvents and permeation enhancers in the biomedical and pharmaceutical fields. There are many advantages to using active pharmaceutical ingredients (APIs) in the production of ILs for drug delivery, including the ability to tailor solubility, improve thermal stability, increase dissolution, regulate drug release, improve API permeability, and modulate cytotoxicity on tumor cells. Such an approach has shown significant potential as a tool for drug delivery. As a result, APIs converted into ILs are used as active components in solutions, emulsions, and even nanoparticles (NPs). In this review, we explore the use and physiochemical characteristics of APIs via ILs, including improvements of their physicochemical properties in preformulation and formulation development.

Wearable smart devices in cancer diagnosis and remote clinical trial monitoring: Transforming the healthcare applications.

During the past two decades, the era of digitalization in pharmaceutical device manufacturing has gained significant momentum for maintaining human health. From various available technologies, internet of things (IoT) sensors are being increasingly used as wearable devices (e.g., smart watches, wrist bands, mobile phones, tablets, implantable pumps, etc.) that enable real-time monitoring of data. Such devices are integrated with smart materials that typically monitor the real-time data (blood pressure, blood sugar, heart and pulse rate, cytokine levels, etc.) to advise patients and physicians. Hence, there has been a great demand for wearable devices as potential tools for remote clinical trial monitoring in cancers and other diseases and they are proving to be very cost-effective.

Therapeutic Application of Microsponges-based Drug Delivery Systems.

Microsponges delivery systems (MDS) are highly porous, cross-linked polymeric systems that activate due to temperature, pH, or when rubbed. MDS offer a wide range of advantages, like controlled drug release, site-specific action, stability over a broad range of pH, less irritation, cost-effectiveness, and improved patient compliance. They can be transformed into various dosage forms like creams, gels, and lotions. MDS are suitable for the treatment of topical disorders like acne, psoriasis, dandruff, eczema, scleroderma, hair loss, skin cancer, and other dreadful diseases. The applications of MDS in drug delivery are not limited to topical drug delivery but are also explored for oral, parenteral, and pulmonary drug deliveries. Microsponges have been studied for colon targeting of drugs and genes. Additionally, MDS have several applications such as sunscreen, cosmetics, and over-the-counter (OTC) products. Furthermore, MDS do not actuate any irritation, genotoxicity, immunogenicity, or cytotoxicity. Therefore, this review extensively highlights microsponges, their advantages, key factors affecting their characteristics, their therapeutic applications in topical disorders and in cancer, their use as cosmetics, as well as recent advances in MDS and the associated challenges.

Preparation, Characterization, and Evaluation of Curcumin-Graphene Oxide Complex-Loaded Liposomes against Staphylococcus aureus in Topical Disease.

This study describes the development and characterization of curcumin with graphene oxide complex (CUR + GO) loaded into liposomes for treating skin disease. The developed complex was characterized by X-ray diffraction and showed a broad halo pattern, confirming the amorphous nature of the resulting complex. Furthermore, scanning electron microscopy revealed the irregular porous morphology of the complex-highlighting loss of the crystallinity and the emergence of the amorphous phase. Additionally, the liposomes showed long-term stability at 2-8 °C and 25 ± 2 °C/60 ± 5%RH with nonsignificant variations in the particle size, polydispersity index, and zeta potential. Overall, optical and high-resolution transmission electron microscopy images of liposomes showed a consistent shape, and no aggregation with uniform particle size distribution was observed. Furthermore, the cumulative drug release in the first 6 h was 71.24 and 64.24% for CUR-loaded liposomes and CUR-GO-loaded liposomes, respectively. The lower value of drug release might be attributed to the complex development. The drug release model found the first order with non-Fickian diffusion process, which is often observed at higher n > 0.5. The antibacterial activity of the CUR with GO-loaded liposome (D2) offered higher anti-microbial activity over other formulations against the mentioned bacterial microorganism that causes skin diseases.

Optimization of Surfactant- and Cosurfactant-Aided Pine Oil Nanoemulsions by Isothermal Low-Energy Methods for Anticholinesterase Activity.

Highly stable pine oil-loaded nanoemulsions were evaluated for nutraceutical and storage stability applications. Pine oil-loaded nanoemulsion preparation was done with pine oil as the oily phase and additionally with different ratios of the non-ionic surfactant (Tween 80) and cosurfactant (ethanol) in an aqueous solution using the isothermal low-energy or spontaneous emulsification method. A transparent and stable nanoemulsion was obtained with a combination of pine oil (5 wt %), surfactant mixture (35 wt %), and water quantity sufficient (qs) by the isothermal low-energy method. The mean droplet size and ζ-potential of the fabricated nanoemulsion were ≈14 nm and -3.4 mV, respectively. The size of the transparent nanoemulsion increased to ∼45 nm and showed turbidity at 60 °C. Microrheological investigation highlighted the gel-sol-gel conversion in the presence of applied angular frequency at 25 °C. The loss modulus shifted to lower frequency at 60 °C in comparison to other temperatures. The anticholinesterase (AChE) inhibition activity of the pine oil-loaded nanoemulsion suggested a possible therapeutic value, and at 0.10% concentration of the nanoemulsion, the AChE inhibition activity was ≈95.72 ± 5.59%. These studies have important implications in fabrication and optimization of a nanoemulsion as a delivery system for combating reminiscence in Alzheimer's disease and application in the nutraceutical-based industry. This isothermal low-energy method offers an advantage of preparing an edible oil delivery system using simple and rapid operational parameters.

Recent advances in lipid-engineered multifunctional nanophytomedicines for cancer targeting.

Cancer is a leading cause of death in many countries around the world. However, the efficacy of current treatments available for variety of cancers is considered to be suboptimal due to the pathophysiological challenges associated with the disease which limits the efficacy of the anticancer drugs. Moreover, the vulnerability towards off-target effects and high toxicity also limits the use of drugs for the treatment of cancers. Besides, the biopharmaceutical challenges like poor water solubility and permeability of the drugs, along with the absence of active targeting capability further decreases the utility of drugs in cancer therapy. As a result of these deficiencies, the current therapeutic strategies face noncompliance to patients for providing meaningful benefits after administration. With the advancements in nanotechnology, there has been a paradigm shift in the modalities for cancer treatment with the help of phytomedicine-based nanosized drug delivery systems coupled with variegated surface-engineering strategies for targeted drug delivery. Among these delivery systems, lipid-based nanoparticles are considered as one of the highly biocompatible, efficient and effective systems extensively explored for anticancer drug delivery. These include diverse range of systems including liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipidic carriers and supramolecular carriers, which alters pharmacokinetic and biodistribution of the drugs for active targeting to the desired site of action by overcoming the biopharmaceutical challenges associated with anticancer drug delivery. The present review endeavours to provide a comprehensive account on the recent advances in the application of lipid-based nanostructured systems for improving the pharmacotherapeutic performance of phytomedicines for cancer targeting application.

Potential of nanoparticulate based delivery systems for effective management of alopecia.

In recent times, more than 50 % of the global population is facing hair-related issues (alopecia) which is seen mostly amongst the people in the age group of 30-40 years. The conventional topical dosage forms available in the market falls short in effectively managing alopecia. Despite various advancements in topical dosage forms, it is still disposed to limited clinical application and provides poor penetration of drug molecules into the skin. The exact etiology of alopecia is still unknown and various researchers link lifestyle, hereditary, and auto immune-based events with its existence. Nanoparticulate-based delivery are hence brought in use to enhance the permeability properties of the drug. In comparison to conventional methods nanotechnology-based drug delivery system tames drug molecules to a specific site with much better efficacy. This review is engrossed in the journey and role of nano technological-based drug delivery in the management of alopecia and its clinical application.