Lyotropic liquid crystalline phases: Drug delivery and biomedical applications.

Liquid crystal (LC)-based nanoformulations may efficiently deliver drugs and therapeutics to targeted biological sites. Lyotropic liquid crystalline phases (LLCPs) have received much interest in recent years due to their unique structural characteristics of both isotropic liquids and crystalline solids. These LLCPs can be utilized as promising drug delivery systems to deliver drugs, proteins, peptides and vaccines because of their improved drug loading, stabilization, and controlled drug release. The effects of molecule shape, microsegregation, and chirality are very important in the formation of liquid crystalline phases (LCPs). Homogenization of self-assembled amphiphilic lipids, water and stabilizers produces LLCPs with different types of mesophases, bicontinuous cubic (cubosomes) and inverse hexagonal (hexosomes). Moreover, many studies have also shown higher bioadhesivity and biocompatibility of LCs due to their structural resemblance to biological membranes, thus making them more efficient for targeted drug delivery. In this review, an outline of the engineering aspects of LLCPs and polymer-based LLCPs is summarized. Moreover, it covers parenteral, oral, transdermal delivery and medical imaging of LC in targeting various tissues and is discussed with a scope to design more efficient next-generation novel nanosystems. In addition, a detailed overview of advanced liquid crystal-based drug delivery for vaccines and biomedical applications is reviewed.

Delivery of gene editing therapeutics.

For the past decades, gene editing demonstrated the potential to attenuate each of the root causes of genetic, infectious, immune, cancerous, and degenerative disorders. More recently, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9 (CRISPR-Cas9) editing proved effective for editing genomic, cancerous, or microbial DNA to limit disease onset or spread. However, the strategies to deliver CRISPR-Cas9 cargos and elicit protective immune responses requires safe delivery to disease targeted cells and tissues. While viral vector-based systems and viral particles demonstrate high efficiency and stable transgene expression, each are limited in their packaging capacities and secondary untoward immune responses. In contrast, the nonviral vector lipid nanoparticles were successfully used for as vaccine and therapeutic deliverables. Herein, we highlight each available gene delivery systems for treating and preventing a broad range of infectious, inflammatory, genetic, and degenerative diseases. STATEMENT OF SIGNIFICANCE: CRISPR-Cas9 gene editing for disease treatment and prevention is an emerging field that can change the outcome of many chronic debilitating disorders.

A Comprehensive Review on Prospects of Polymeric Nanoparticles for Treatment of Diabetes Mellitus: Receptors-Ligands, In vitro & In vivo Studies.

As per International Diabetes Federation Report 2022, worldwide diabetes mellitus (DM) caused 6.7M moralities and ~537M adults suffering from diabetes mellitus. It is a chronic condition due to ß-cell destruction or insulin resistance that leads to insulin deficiency. This review discusses Type-1 DM and Type-2 DM pathophysiology in detail, with challenges in management and treatment. The toxicity issues of conventional drugs and insulin injections are complex to manage. Thus, there is a need for technological intervention. In recent years, nanotechnology has found a fruitful advancement of novel drug delivery systems that might potentially increase the efficacy of anti-diabetic drugs. Amongst nano-formulations, polymeric nanoparticles have been studied to enhance the bioavailability and efficacy of anti-diabetic drugs and insulin. In the present review, we summarized polymeric nanoparticles with different polymers utilized to deliver anti-diabetic drugs with in vitro and in vivo studies. Furthermore, this review also includes the role of receptors and ligands in diabetes mellitus and the utilization of receptor-ligand interaction to develop targeted nanoparticles. Additionally, we discussed the utility of nanoparticles for the delivery of phytoconstituents which aids in protecting the oxidative stress generated during diabetes mellitus.

Determination of Olmesartan in Bulk and Pharmaceutical Dosage Forms through the Development and Validation of Stability-indicating RP-HPLC Method.

BACKGROUND: Angiotensin II type 1 (AT 1) receptor antagonist (angiotensin receptor blocker [ARB]) called Olmesartan medoxomil (OLM) prevents angiotensin II from acting on the renin-angiotensin-aldosterone pathway, which is a crucial factor in the development of hypertension. OLM is reported to rapidly hydrolyze into its active metabolite, Olmesartan, in plasma after oral treatment. OBJECTIVE: The objective of the ongoing study was to develop an easy-to-use, precise, and reliable RP-HPLC method for the determination of Olmesartan in bulk as well as pharmaceutical dosage forms. METHODS: The stability indicating HPLC method for assay includes the use of Kromasil 100-5-C8 (100 mm × 4.6 mm) column, UV detector 265 nm, and mobile phase composition was a mixture of Acetonitrile: water (70:30) and flow rate of 1.0 mL/min. ICH guidelines were followed in the method's validation. To assess the method's specificity and stability in showing characteristics, stress degradation studies were carried out. The working standard solution of Olmesartan was exposed to 0.1 N HCl at room temperature, 0.1 N NaOH at room temperature, 30 percent hydrogen peroxide by volume, and UV radiation in order to conduct a degradation study. RESULTS: The retention periods of the drug were found to be 1.36 and 1.47 min for standard and sample solutions, respectively. The degradation behaviour of drug under different conditions was studied. The drug was found susceptible to acidic, alkaline and oxidative conditions while it was found stable in photolytic condition. The developed stability-indicating RP-HPLC method for assay was validated as per ICH Q2 guidelines and the validation parameters such as accuracy, precision and specificity were obtained within the accepted criteria. CONCLUSION: It may be concluded that this method is stability-indicating and specific and can successfully be applied to analyze tablet dosage form containing Olmesartan.

Advances in 4D printing: from stimulation to simulation.

The advancement of four-dimensional (4D) printing has been fueled by the rise in demand for additive manufacturing and the expansion in shape-memory materials. The printing of smart substances that respond to external stimuli is known as 4D printing. 4D printing allows highly controlled shapes to simulate the physiological milieu by adding time dimensions. The 4D printing is suitable with current progress in smart compounds, printers, and its mechanism of action. The 4D printing paradigm, a revolutionary enhancement of 3D printing, was anticipated by various engineering disciplines. Tissue engineering, medicinal, consumer items, aerospace, and organ engineering use 4D printing technology. The current review mainly focuses on the basics of 4D printing and the methods used therein. It also discusses the time-dependent behavior of stimulus-sensitive compounds, which are widely used in 4D printing. In addition, this review highlights material aspects, specifically related to shape-memory polymers, stimuli-responsive materials (classified as physical, chemical, and biological), and modified materials, the backbone of 4D printing technology. Finally, potential applications of 4D printing in the biomedical sector are also discussed with challenges and future perspectives.

Development of favipiravir loaded PLGA nanoparticles entrapped in in-situ gel for treatment of Covid-19 via nasal route.

In 2019 the emergence of SARS-COV-2 caused pandemic situation worldwide and claimed ∼6.4 M lives (WHO 2022). Favipiravir (FAV) is recommended as a therapy for Covid-19 which belongs to BCS class III with a short half-life of 2-5.5h. Thus, the objective of current study was the development of favipiravir loaded PLGA nanoparticles (NPs) by box-behnken design. Moreover, these NPs were entrapped in thermosensitive gel to increase the permeation through nasal route. The nanoparticles exhibit particle size of 175.6 ± 2 nm with >70 ± 0.5 %EE. NPs showed PDI (0.130) and zeta potential (-17.1 mV) suggesting homogeneity and stability of NPs. DSC, XRD, and FTIR studies concluded absence of any interaction of FAV and the excipients. SEM and AFM studies demonstrated spherical morphology of NPs with smooth surface. The NPs entrapped in-situ gel showed clarity and pH 5.5-6.1. The gelation temperature of NPs dispersed in-situ gel was found in the range of 35 °C -37 °C. The gel has viscosity in range of 34592-4568 cps. The texture analysis profile of gel showed good gelling properties. Dissolution study suggested a sustained release of FAV from NPs (24h) and NPs dispersed gel (32h) as compared to FAV solution (4h). The gel showed good mucoadhesion properties (9373.9 dyne/cm2). Ex-vivo permeation through nasal mucosa of goat elucidated NPs dispersed gel demonstrated significantly higher permeation than solution and NPs. Therefore, it would be a prospective formulation to combat Covid-19 infection with high patient compliance.

Lyotropic liquid crystals for parenteral drug delivery.

The necessity for long-term treatments of chronic diseases has encouraged the development of novel long-acting parenteral formulations intending to improve drug pharmacokinetics and therapeutic efficacy. Lately, one of the novel approaches has been developed based on lipid-based liquid crystals. The lyotropic liquid crystal (LLC) systems consist of amphiphilic molecules and are formed in presence of solvents with the most common types being cubic, hexagonal and lamellar mesophases. LC injectables have been recently developed based on polar lipids that spontaneously form liquid crystal nanoparticles in aqueous tissue environments to create the in-situ long-acting sustained-release depot to provide treatment efficacy over extended periods. In this manuscript, we have consolidated and summarized the various type of liquid crystals, recent formulation advancements, analytical evaluation, and therapeutic application of lyotropic liquid crystals in the field of parenteral sustained release drug delivery.

Enhanced Antibacterial Activity of Doxycycline and Rifampicin Combination Loaded in Nanoparticles against Intracellular Brucella abortus.

INTRODUCTION: Brucellosis is a zoonotic disease that is prevalent in livestock animals. The bacteria reside inside the macrophage cells of the host. The WHO has endorseda combination treatment therapy for brucellosis against the conventional monotherapy to avoid relapse and resistance. Therefore, we developed nanoparticles incorporating doxycycline and rifampicin in combination. AIM: The aim of the study is to develop polymeric nanoparticles incorporating doxycycline as well as rifampicin and investigate the antibacterial activity of nanoparticles in U937 human macrophage cells infected with B. abortus. METHODS: Polymeric nanoparticles were developed by the emulsion-solvent diffusion method, and characterization was performed. RESULTS: The nanoparticles with high entrapment efficiency of both the drugs were developed successfully. Scanning electron microscopy revealed a spherical morphology with a size ranging ~450nm, which can be easily engulfed by the macrophages. Zeta potential confirmed the colloidal stability. Differential scanning calorimetry and X-ray diffraction suggested amorphization of doxycycline and rifampicin in nanoparticles. Fourier transfer infrared spectroscopy could not confirm the interaction of drugs with AOT. In vitro haemolysis study confirmed the safety of nanoparticles (<10%) for IV administration. Further, nanoparticles revealed the sustained release of both drugs, which followed diffusion kinetics. Nanoparticles were found stable for 6 months as per WHO guidelines. The internalization study revealed nanoparticles could be easily uptaken by U-937 human macrophage cells. The efficacy study demonstrated significantly high antibacterial activity of nanoparticles as compared to free drug solution in U937 human macrophages cells infected with Brucella abortus. CONCLUSION: It can be concluded that the developed nanoparticles entrapping doxycycline and rifampicin combination can be considered as a promising delivery system for enhancing the antibacterial activity against Brucella abortus.

Human respiratory viral infections: Current status and future prospects of nanotechnology-based approaches for prophylaxis and treatment.

Respiratory viral infections are major cause of highly mortal pandemics. They are impacting socioeconomic development and healthcare system globally. These emerging deadly respiratory viruses develop newer survival strategies to live inside host cells and tricking the immune system of host. Currently, medical facilities, therapies and research -development teams of every country kneel down before novel corona virus (SARS-CoV-2) which claimed ~2,828,629 lives till date. Thus, there is urgent requirement of novel treatment strategies to combat against these emerging respiratory viral infections. Nanocarriers come under the umbrella of nanotechnology and offer numerous benefits compared to traditional dosage forms. Further, unique physicochemical properties (size, shape and surface charge) of nanocarriers provide additional advantage for targeted delivery. This review discusses in detail about the respiratory viruses, their transmission mode and cell invasion pathways, survival strategies, available therapies, and nanocarriers for the delivery of therapeutics. Further, the role of nanocarriers in the development of treatment therapy against SARS-CoV-2 is also overviewed.

Enhanced antimalalarial activity of a prolonged release in situ gel of arteether-lumefantrine in a murine model.

The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) for treatment of falciparum malaria. Arteether (ART), an artemisinin derivative, is effective against Plasmodium falciparum, but it is available only as painful oily intramuscular (i.m.) injections. We formulated lyotropic liquid crystalline preconcentrates of ART and Lumefantrine (LUM) ACT with and without biodegradable polymer for antimalarial therapy. Following i.m. injection, both formed intact gels in situ due to rapid transition into liquid crystalline phase (LCP) which was confirmed by small angle neutron scattering (SANS), X-ray diffraction (XRD), polarization optical microscopy (POM) and rheological changes. Ex vivo release studies revealed prolong release of ART-LUM over 72 h from polymeric lyotropic liquid crystalline phases (P-LLCPr). In vitro hemolysis assay and myotoxicity studies confirmed intramuscular safety. Treatment with ART-LUM P-LLCPr conferred complete protection with no mortality at 1/40th of therapeutic dose in modified Peter's four-day suppressive test as compared to marketed ART formulation resulted in 100% mortality within 20 days. In the clinical simulation model, P-LLCPr treatment resulted in complete cure with no recrudescence or mortality at 1/20th of therapeutic dose, while marketed formulation which resulted in 100% mortality. The high efficacy with significantly reduced dose and a single administration with single shot therapy suggest ART-LUM P-LLCPr as a promising new patient friendly alternative for antimalarial therapy.