Development of Epigallocatechin 3-gallate-Loaded Hydrogel Nanocomposites for Oral Submucous Fibrosis.

Oral submucous fibrosis (OSF) is a chronic progressive disease associated with increased collagen deposition and TGF-ß1 release. The current therapy and management have been a limited success due to low efficacy and adverse drug reactions. This study aimed to evaluate epigallocatechin 3-gallate (EGCG) encapsulated nanoparticles loaded mucoadhesive hydrogel nanocomposite (HNC) for OSF. Developed HNC formulations were evaluated for their permeation behaviour using in vitro as well as ex vivo studies, followed by evaluation of efficacy and safety by in vivo studies using areca nut extract-induced OSF in rats. The disease condition in OSF-induced rats was assessed by mouth-opening and biochemical markers. The optimized polymeric nanoparticles exhibited the required particle size (162.93 ± 13.81 nm), positive zeta potential (22.50 ± 2.94 mV) with better mucoadhesive strength (0.40 ± 0.002 N), and faster permeation due to interactions of the positively charged surface with the negatively charged buccal mucosal membrane. HNC significantly improved disease conditions by reducing TGF-ß1 and collagen concentration without showing toxicity and reverting the fibroid buccal mucosa to normal. Hence, the optimized formulation can be further tested to develop a clinically alternate therapeutic strategy for OSF.

Co-delivery of lapatinib and 5-fluorouracil transfersomes using transpapillary iontophoresis for breast cancer therapy.

Combination chemotherapy, involving the intervention of two or more anti-neoplastic agents has been the cornerstone in breast cancer treatment, owing to the applications it holds in contrast to the mono-therapy approach. This research predominantly focussed on proving the synergy between Lapatinib (LPT) and 5-Fluorouracil (5-FU) and further enhancing its localized permeation via transfersome-loaded delivery and iontophoresis to treat breast tumors. The IC50 values for LPT and 5-FU were found to be 19.38 µg/ml and 5.7 µg/ml respectively and their synergistic effect was proven by the Chou-Talalay assay using CompuSyn software. Furthermore, LPT and 5-FU were encapsulated within transfersomes and administered via the transpapillary route. The drug-loaded carriers were characterized for their particle size, polydispersity index, zeta potential, and entrapment efficiency. The ex vivo rat skin permeation studies indicated that when compared to LPT dispersion and 5-FU solution, drug-loaded transfersomes exhibited better permeability and their transpapillary permeation was enhanced on using iontophoresis. Moreover, both LPT and 5-FU transfersomes were found to be stable for 3 months when stored at a temperature of 5 ± 3 °C. The results indicated that this treatment strategy could be an effective approach in contrast to some of the conventional treatments employed to date.

Recent advances in dual-drug co-amorphous systems.

Poor solubility of drugs and therapeutic candidates poses a significant challenge in drug research and development. Biopharmaceutical class II drugs exhibit limited absorption because of their weak solubility and high permeability. Co-amorphous systems (CAMs) have been studied widely as a way to improve the solubility of drugs. This review summarizes recent advancements in dual-drug CAMs, including improvements in formulation, manufacturing, and solid-state characterization, and highlights the importance of enhancing solubility and stability. It emphasizes the potential synergistic effects of two drugs in CAMs and explores formulation strategies and challenges related to maintaining the amorphous state. Case studies demonstrate the successful application of CAMs in combination therapies that offer improved therapeutic efficacy.

Controlled Release Technologies for Chronotherapy: Current Status and Future Perspectives.

The expression "as sure as night follows a day" emulates those certain cycles in the environment that are always stable. Circadian rhythms are a group of processes that occur within the body in synchronisation with the external factors in a 24 h cycle. Changes in lifestyle and work shifts have disrupted these stable rhythms, which is a leading cause of lifestyle diseases. Associations between these biological clocks and diseases are abundant. However, it is also known that certain drugs work more efficiently and have minimum toxicity when given during a particular phase of the circadian cycle. Chronotherapeutics focuses on treating diseases according to the endogenous processes which mediate xenobiotic metabolism and drug response at a cellular level. Therefore, treatment of those diseases that show aggravation of symptoms according to the circadian rhythms at a particular time is highly beneficial by chronotherapy. In this article, we have emphasised how the changes in rhythms caused diseases and how chronotherapeutic approaches such as controlled drug release technologies can be a better option for these circadian manipulations that seem to influence all types of disease conditions.

Multi-Targeting Approach in Selection of Potential Molecule for COVID-19 Treatment.

The coronavirus disease (COVID-19) is a pandemic that started in the City of Wuhan, Hubei Province, China, caused by the spread of coronavirus (SARS-CoV-2). Drug discovery teams around the globe are in a race to develop a medicine for its management. It takes time for a novel molecule to enter the market, and the ideal way is to exploit the already approved drugs and repurpose them therapeutically. We have attempted to screen selected molecules with an affinity towards multiple protein targets in COVID-19 using the Schrödinger suit for in silico predictions. The proteins selected were angiotensin-converting enzyme-2 (ACE2), main protease (MPro), and spike protein. The molecular docking, prime MM-GBSA, induced-fit docking (IFD), and molecular dynamics (MD) simulations were used to identify the most suitable molecule that forms a stable interaction with the selected viral proteins. The ligand-binding stability for the proteins PDB-IDs 1ZV8 (spike protein), 5R82 (Mpro), and 6M1D (ACE2), was in the order of nintedanib > quercetin, nintedanib > darunavir, nintedanib > baricitinib, respectively. The MM-GBSA, IFD, and MD simulation studies imply that the drug nintedanib has the highest binding stability among the shortlisted. Nintedanib, primarily used for idiopathic pulmonary fibrosis, can be considered for repurposing for us against COVID-19.

Molecular pathways and role of epigenetics in the idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with unknown etiological factors that can progress to other dangerous diseases like lung cancer. Environmental and genetic predisposition are the two major etiological or risk factors involved in the pathology of the IPF. Among the environmental risk factors, smoking is one of the major causes for the development of IPF. Epigenetic pathways like nucleosomes remodeling, DNA methylation, histone modifications and miRNA mediated genes play a crucial role in development of IPF. Mutations in the genes make the epigenetic factors as important drug targets in IPF. Transcriptional changes due to environmental factors are also involved in the progression of IPF. The mutations in human telomerase reverse transcriptase (hTERT) have shown decreased life expectancy in IPF patients. The TERT-gene is highly expressed in chronic smokers and makes the role of epigenetics evident. Drug like nintedanib acts through vascular endothelial growth factor receptors (VEGFR), while drug pirfenidone acts through transforming growth factor (TGF), which is useful in IPF. Gefitinib, a tyrosine kinase inhibitor of EGFR, is useful as an anti-fibrosis agent in preclinical models. Newer drugs such as Celgene-CC90001 and FibroGen-FG-3019 are currently under investigations acts through the modulating epigenetic mechanisms. Thus, the study on epigenetics opens a wide window for the discovery of newer drugs. This study provides an elementary analysis of multiple regulators of epigenetics and their roles associated with the pathology of IPF. Further, this review also includes epigenetic drugs under development in preclinical and clinical stages.

Advances and challenges in nintedanib drug delivery.

INTRODUCTION: Nintedanib (N.T.B) is an orally administered tyrosine kinase inhibitor that has been approved recently by U.S.F.D.A for idiopathic pulmonary fibrosis (I.P.F) and systemic sclerosis-associated interstitial lung disease (S.Sc-I.L.D). N.T.B is also prescribed in COVID-19 patients associated with I.P.F. However, it has an extremely low bioavailability of around 4.7%, and hence, researchers are attempting to address this drawback by different approaches. AREAS COVERED: This review article focuses on enlisting all the formulation attempts explored by researchers to increase the bioavailability of N.T.B while also providing meaningful insight into the unexplored areas in formulation development, such as targeting of the lymphatic system and transdermal delivery. All the patents on the formulation development of N.T.B have also been summarized. EXPERT OPINION: N.T.B has the potential to act on multiple diseases that are still being discovered, but its extremely low bioavailability is a challenge that is to be dealt with for obtaining the full benefit. Few studies have been performed aiming at improving the bioavailability, but there are unexplored areas that can be used, a few of which are explained in this article. However, the ability to reproduce laboratory results when scaling up to the industry level is the only factor to be taken into consideration.