Bootstrap Statistics and Its Application in Disintegration and Dissolution Data Analysis.

Disintegration time (DT) and rate of drug dissolution in different media are among the most widely studied crucial parameters for various types of drug products. In the ever-evolving landscape of generic formulation development, dissolution comparison of reference and test products is the major reliable in vitro method of establishing product similarity. This is one of the most widely accepted methods of proving pharma equivalency between two drug products. A well-studied match between the disintegration and dissolution profile of the test and reference formulations can ensure in vitro product similarity. Various statistical approaches have been employed to establish product performance similarity; among them, the similarity factor (f2) calculation based approach is the most widely accepted and explored method to date. However, the f2 statistics fail to predict the similarity of batches with unit-to-unit variability. Bootstrap statistical analysis of dissolution data between the test and reference products was introduced to overcome the problems associated with batches with unit variability. Bootstrap can also be applied to extract statistically significant results by treating a series of data from different batches, which can further help to understand the trend. The current review depicts different case study based approaches to show the applications of bootstrap statistics in disintegration and dissolution similarity evaluation for both conventional and additively manufactured solid dosage forms. It is concluded that bootstrap statistics can be a very promising and reliable data analytical tool for establishing in vitro product similarity for both conventional and additively manufactured formulations with a high level of intraunit variability.

Differences of SiHa (human cancer of cervix) and BMG-1 (brain glioma) cell lines as 2D and 3D cultures.

Cell cultures have seen much progress in the numbers available cell lines, their applications and culture techniques. Three dimensional cultures and co-cultures are examples of strategies that bring in vitro conditions closer to natural in vivo systems. We describe here, the formation of cell aggregates in three-dimensional conditions for the cell lines SiHa and BMG-1 utilizing agarose hydrogels. The optimal conditions for best aggregate formation were identified and the culture phases for the cell lines as monolayers and as aggregates were compared. Differences in protein profiles, susceptibility to a genotoxic drug and the antigenic properties of the protein extracts of the two cell lines, as can be induced by their aggregate formation were studied. The results from the four approaches indicate the usefulness of culturing cells as aggregates. Such systems using simple material and methods offer us an efficient way of utilizing cell lines for a variety of applications.

A 3D in-vitro biomimicking Caco-2 intestinal permeability model-based assessment of physically modified telmisartan towards an alkalizer-free formulation development.

Efficient telmisartan delivery for hypertension management requires the incorporation of meglumine and/or sodium hydroxide as an alkalizer in the formulation. Long-term use of powerful alkalis with formulation as part of chronic therapy can cause metabolic alkalosis, ulcers, diarrhea, and body pain. Here, we aimed to design a telmisartan formulation without alkalizers. Telmisartan properties were tailor-made by microfluidizer-based physical modification. After microfluidization, telmisartan nanosuspension was lyophilized to obtain telmisartan premix powder. The optimized telmisartan nanosuspension had an average particle size of 579.85 ± 32.14 nm. The lyophilized premix was characterized by FT-IR, DSC, and PXRD analysis to ensure its physicochemical characteristics. The solubility analysis of premix showed 2.2 times, 2.3 times, and 6 times solubility improvement in 0.1 N HCl, phosphate buffer pH 7.5, and pH 6.8 compared to pure telmisartan. A 3D in-vitro Caco-2 model was developed to compare apparent permeability of API and powder premix. It showed that the powder premix was more permeable than pure API. The tablet formulation prepared from the telmisartan premix showed a dissolution profile comparable to that of the marketed formulation. The technique present herein can be used as a platform technology for solubility and permeability improvement of similar classes of molecules.

Premix technologies for drug delivery: manufacturing, applications, and opportunities in regulatory filing.

Active pharmaceutical ingredients (APIs) and excipients can be carefully combined in premix-based materials before being added to dosage forms, providing a flexible platform for the improvement of drug bioavailability, stability, and patient compliance. This is a promising and transformative approach in novel and generic product development, offering both the potential to overcome challenges in the delivery of complex APIs and viable solutions for bypassing patent hurdles in generic product filing. We discuss the different types of premixes; manufacturing technologies such as spray drying, hot melt extrusion, wet granulation, co-crystal, co-milling, co-precipitation; regulatory filing opportunities; and major bottlenecks in the use of premix materials in different aspects of pharmaceutical product development.

Manifesting the Dasatinib-gallic acid co-amorphous system to augment anticancer potential: Physicochemical characterization, in silico molecular simulation, ex vivo permeability, and in vitro efficacy.

Dasatinib (DAB) has been explored for repurposing in the treatment of breast cancer (BC) due to its known effectiveness in treating leukemia, in addition to its role as a tyrosine kinase inhibitor. Gallic acid (GA) was chosen as a co-former due to its anticancer potential in BC, as demonstrated in several previous studies. DAB is a low-solubility drug, which is a significant hurdle for its oral bioavailability. To address this limitation, a DAB and GA co-amorphous (DAB-GA-CA) system was developed using liquid-assisted grinding and ball mill technology to enhance solubility, bioavailability, and anti-tumor efficacy. Physical characterization investigation revealed that the emergence of the halo diffractogram in PXRD, single glass transition temperature (Tg) value at 111.7 °C in DSC thermogram, and irregularly shaped blocks with loose, porous surfaces in SEM analysis indicated the formation of the DAB-GA-CA system at 1:1 M ratio. Furthermore, FTIR, Raman spectroscopy, in-silico molecular docking, and molecular dynamic studies confirmed the intermolecular hydrogen connections between DAB and GA. Moreover, the outcomes of the ligands (DAB and GA) and receptors (BCL-2, mTOR, estrogen receptor, and HER-2) docking studies demonstrated that both DAB and GA could interact with those receptors, leading to preventive action on BC cells. Additionally, the solubility and dissolution rate significantly improved at pH 6.8, and the permeability study indicated that DAB-GA-CA showed 1.9 times higher apparent permeability compared to crystalline DAB. Furthermore, in vitro cytotoxicity assessments of the DAB-GA-CA system revealed 3.42 times lower IC50 than free DAB. The mitochondrial membrane depolarization, apoptotic index, and reactive oxygen species formation in MCF-7 cells were also notably higher in the DAB-GA-CA system than in free DAB. Hence, this research suggests that the DAB-GA-CA system could substantially enhance oral delivery, solubility, and therapeutic efficacy.

Rebamipide nanocrystal with improved physicomechanical properties and its assessment through bio-mimicking 3D intestinal permeability model.

This study investigated the formulation and characterization of rebamipide nanocrystals (REB-NCs) to enhance the solubility and permeability of rebamipide, an anti-ulcer medication known for its low aqueous solubility and permeability, classified as BCS class IV. Employing high-pressure homogenization and wet milling techniques, we successfully achieved nanonization of rebamipide, resulting in stable nanosuspensions that were subsequently freeze-dried to produce REB-NCs with an average particle size of 223 nm. Comprehensive characterization techniques, including Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC) confirmed the crystalline nature of the nanocrystals and their compatibility with the selected excipients. The saturation solubility study revealed a remarkable three-fold enhancement in PBS pH 7.4 compared to rebamipide API, indicating the effectiveness of the nanocrystal formulation in improving drug solubility. Furthermore, 3D in-vitro permeability assessments conducted on Caco-2 cell monolayers demonstrated an noticeable increase in the permeability of REB-NCs relative to the pure active pharmaceutical ingredient (API), highlighting the promise of this formulation to enhance drug absorption. The dissolution profile of the nanocrystal tablets exhibited immediate release characteristics, significantly outperforming conventional formulations in terms of the dissolution rate. This research underscores the potential of nanomilling as a scalable, environment-friendly, and less toxic approach to significantly enhance the bioavailability of rebamipide. By addressing the challenges associated with the solubility and permeability of poorly water-soluble drugs, our outcome offers insightful information into developing efficient nanomedicine strategies for enhancing therapeutic outcomes.

Green Synthesized Nanoparticles as a Plausible Therapeutic Strategy Against Hepatocellular Carcinoma: An Update on its Preclinical and Clinical Relevance.

Green nanotechnology can offer notable advantages over the conventional drug delivery methods in terms of improved drug stability, drug-carrying capacity, site-specificity, and feasibility to apply different routes of administration with less systemic toxicities. Metal nanoparticles bio fabricated with phytoconstituents and microbial extracts have gained significant interest for the treatment of various solid tumors including hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is an aggressive cancer with a very poor prognosis. The current treatments of HCC fails to provide tumor specificity, causing many systemic toxicities and poor overall survival benefits especially for patients in advanced and terminal stages. A novel therapeutic approach with maximal therapeutic effect and minimum adverse effects are urgently required for HCC patients. Green synthesized metal nanoparticles offer significant anticancer effects along with minimal systemic toxicities because of their site-specific delivery into the tumor microenvironment (TME). Green synthesized metal nanoparticles can therefore be a highly beneficial strategy for the treatment of HCC if properly validated with preclinical and clinical studies. This review focuses on the preclinical evidence of the most widely studied green metal nanoparticles such as green synthesized silver nanoparticles, gold nanoparticles and selenium nanoparticles. We have also summarised the clinical studies and the patents approved for nanoparticles against HCC.

Use of telehealth services among Nepali living overseas during Covid-19 pandemic: The opportunities, limitations, lessons learned and recommendations.

There are estimated over 8 million Nepali migrants spread across various countries around the globe. Though the majority of them enjoy good health in general, a large proportion of them suffer from non-communicable diseases, mental health issues and communicable diseases. Telemedicine services, which are organized by Non-Resident Nepali Association (NRNA), have been proven to be effective in addressing some of the health and medical needs of the migrant Nepali workers. The purpose of this study is to assess the use of tele-health services among Nepali migrant population and examine the limitations. During the pandemic period from March 2020 through August 2021, Nepali in different countries utilized telehealth services. Mental health issues, chronic diseases, skin diseases were the most common ailments people sought telehealth services for. Many of them sought for urgent medical consultations related to Covid-19 symptoms and ailments. Digital gap, lack of cross-border regulations and unwillingness to utilize telemedicine were the challenges the service faced in the optimal utilization of such services. Training and education, use of easy Apps and subsidies from the government would help in the long-term use and sustainability of telehealth services amongst the Nepali migrants.

Factors Influencing COVID-19 Vaccine Uptake among Nepali People in the UK: A Qualitative Study.

Vaccination saves lives and can be an effective strategy for preventing the spread of the COVID-19, but negative attitudes towards vaccines lead to vaccine hesitancy. This study aimed to explore the factors influencing the uptake of the COVID-19 vaccine in the Nepali community in the United Kingdom (UK). This qualitative study included in-depth interviews with 20 people from Nepal living in the UK. Interviews were conducted by a native-Nepali speaker and all interviews were audio-recorded, transcribed, and translated into English before being analysed thematically. Our study found that attitudes towards COVID-19 are generally positive. Nine overlapping themes around barriers to COVID-19 vaccination were identified: (a) rumours and mis/disinformation; (b) prefer home remedies and yoga; (c) religion restriction; (d) concern towards vaccine eligibility; (e) difficulty with online vaccine booking system; (f) doubts of vaccine effectiveness after changing the second dose timeline; (g) lack of confidence in the vaccine; (h) past bad experience with the influenza vaccine; and (i) worried about side-effects. Understanding barriers to the uptake of the COVID-19 vaccine can help in the design of better targeted interventions. Public health messages including favourable policy should be tailored to address those barriers and make this vaccination programme more viable and acceptable to the ethnic minority communities in the UK.

Multidisciplinary approach to COVID-19 risk communication: a framework and tool for individual and regional risk assessment.

The COVID-19 pandemic has exceeded over sixty-five million cases globally. Different approaches are followed to mitigate its impact and reduce its spreading in different countries, but limiting mobility and exposure have been de-facto precautions to reduce transmission. However, a full lockdown cannot be sustained for a prolonged period. An evidence-based, multidisciplinary approach on risk zoning, personal and transmission risk assessment in near real-time, and risk communication would support the optimized decisions to minimize the impact of coronavirus on our lives. This paper presents a framework to assess the individual and regional risk of COVID-19 along with risk communication tools and mechanisms. Relative risk scores on a scale of 100 represent the integrated risk of influential factors. The personal risk model incorporates age, exposure history, symptoms, local risk and existing health condition, whereas regional risk is computed through the actual cases of COVID-19, public health risk factors, socioeconomic condition of the region, and immigration statistics. A web application tool ( http://www.covira.info ) has been developed, where anyone can assess their risk and find the guided information links primarily for Nepal. This study provides regional risk for Nepal, but the framework is scalable across the world. However, personal risk can be assessed immediately from anywhere.

Human papillomavirus genotype distribution in cervical cancer biopsies from Nepalese women.

BACKGROUND: Cervical cancer (CC) is the leading cause of morbidity and mortality from cancer in Nepalese women. Nearly all cases of CC are caused by infection with certain genotypes of human papillomavirus (HPV). Data on HPV genotype distribution in Nepalese CC patients is sparse. We aimed to determine the distribution of HPV genotypes in biopsies of CC tissue from Nepalese women. METHODS: This study examined 248 archived paraffin-embedded tissue specimens from CC cases from patients of B.P. Koirala Memorial Cancer Hospital, Bharatpur, Chitwan, Nepal. DNA was extracted from the biopsies and HPV detection performed by PCR. HPV genotyping was then carried out by a reverse line hybridization technique capable of identifying 36 distinct HPV genotypes. RESULTS: Most of the samples were from tumors that had been designated by hospital pathologists as squamous cell carcinoma (77.6%). 165 of the 248 samples contained DNA of sufficient quality for rigorous PCR testing. All the analyzable specimens were positive for HPV. The most common HPV genotypes, in decreasing order of frequency were 16, 18, 45, 33, 52, 56 and 31; most were found as single infections (94.5%). Together, HPV types 16, 18, and 45 were found in 92% of the tumor samples. CONCLUSION: This study strengthens the knowledge-base of HPV genotype distribution in CC cases in Nepal. Hopefully, this information will be useful to the medical community and public health policy-makers in generating improved HPV-surveillance, -prevention and -treatment strategies in Nepal.

Recurrent Kikuchi-Fujimoto disease: case report.

Kikuchi-Fujimoto disease, also known as histiocytic necrotising lymphadenitis, is a self-limiting condition of uncertain aetiology characterised by lymphadenopathy, pyrexia, and neutropenia. Some reported cases have been associated with systemic lupus erythematosus and there have been suggestions that Kikuchi's disease could represent a mild form of lupus but without definite evidence. We describe an unusual case of histiocytic necrotising lymphadenitis in an Asian woman who had recurrent episodes for five years before a diagnosis was made.