Gautam Singhvi

Prediction of in vivo plasma concentration–time profile from in vitro release data of designed formulations of milnacipran using numerical convolution method

Abstract The aim of this study was to predict the in vivo plasma drug level of milnacipran (MIL) from in vitro dissolution data of immediate release (IR 50 mg and IR 100 mg) and matrix based controlled release (CR 100 mg) formulations. Plasma drug concentrations of these formulations were predicted by numerical convolution method. The convolution method uses in vitro dissolution data to derive plasma drug levels using reported pharmacokinetic (PK) parameters of a test product. The bioavailability parameters (Cmax and AUC) predicted from convolution method were found to be 106.90 ng/mL, 1138.96 ng/mL h for IR 50 mg and 209.80 ng/mL, 2280.61 ng/mL h for IR 100 mg which are similar to those reported in the literature. The calculated PK parameters were validated with percentage predication error (% PE). The % PE values for Cmax and AUC were found to be 7.04 and −7.35 for IR 50 mg and 11.10 and −8.21 for IR 100 mg formulations. The Cmax, Tmax, and AUC for CR 100 mg were found to be 120 ng/mL, 10 h and 2112.60 ng/mL h, respectively. Predicted plasma profile of designed CR formulation compared with IR formulations which indicated that CR formulation can prolong the plasma concentration of MIL for 24 h. Thus, this convolution method is very useful for designing and selection of formulation before animal and human studies.

Design and characterization of controlled release gastro-retentive floating tablet of an atypical psychotropic agent

The purpose of the present work was to design and evaluate the once daily sustained release matrix type gastro-retentive floating tablet of Quetiapine Fumarate base on hydrophilic matrices of HPMC, sodium CMC and Carbopol. Sodium bicarbonate was incorporated as a gas-generating agent to give buoyancy. In-vitro drug release studies were performed in pH 1.2 buffer using USP type II paddle at 50 rpm. The release rate of drug decreased with increasing polymer proportion of HPMC K15M from 20 to 60 mg. Formulation with desired drug release achieved with combination of sodium CMC and K15M in ratio of 1:3. The drug release mechanism was predominantly found to be Non-Fickian diffusion and Higuchi controlled.

Study the effect of formulation variables on drug release from hydrophilic matrix tablets of milnacipran and prediction of in-vivo plasma profile

Abstract The objective of this study was to design oral controlled release (CR) matrix tablets of Milnacipran using hydroxypropyl methylcellulose (HPMC) as the retardant polymer and to study the effect of various formulation factors such as polymer proportion, polymer viscosity, compression force and also the pH of dissolution medium on the in-vitro release of drug. Two viscosity grade of HPMC (15 K and 100 K) were used in the proportion of 50, 100, 150 and 200 mg per CR tablet. In-vitro release rate was characterized using various model dependent approaches and model independent dissolution parameters [T50% and T80% dissolution time, mean dissolution time (MDT), mean residence time (MRT), dissolution efficiency (DE)]. The statistical analysis was performed on all the model independent approaches using student t test and ANOVA. Results were found that as polymer concentration (50 mg to 200 mg) and viscosity (15 K to 100 K) increases, the MDT, MRT, T50% and T80% extended significantly. Drug release rate was found to be significantly different at different hardness. In-vivo human plasma concentration--time profile was predicted from in-vitro release data using convolution method. Predicted human pharmacokinetic parameters shows that the design CR formulation has capability to sustained the plasma drug level of milnacipran.

Microbiome as therapeutics in vesicular delivery

Microbiome refers to an ecological community of various symbiotic and pathogenic microorganisms, which plays a crucial role in human health and disease. The concept of novel drug delivery systems particularly the vesicular drug delivery systems is gaining massive attention. This emerging technology has started expanding its horizons in the area of microbiome delivery. This mini-review highlights the role of vesicular systems such as nanoparticles, liposomes etc. as a host/carrier for the microbiome in targeting various diseases. This review will be of interest for both the biological and formulation scientists to understand and explore the new vistas in the area of vesicular delivery system as carrier for microbiome delivery.

Pre-clinical pharmacokinetic-pharmacodynamic modelling and biodistribution studies of donepezil hydrochloride by a validated HPLC method

A simple, sensitive and robust HPLC–PDA assay was developed and validated for rapid determination of donepezil hydrochloride (DNP), a potent acetylcholinesterase inhibitor in rat plasma and tissues. All biological samples were prepared by the solid-phase extraction method using loratadine as an internal standard. Separation of the analytes was achieved on a Waters Nova-Pak C18 column (3.9 × 150 mm, 4 μm) using an isocratic mobile phase of acetonitrile and ammonium formate (pH 6.4; 0.01 M) (62 : 38% v/v) at a flow rate of 1 mL min−1. All validation parameter results were within the acceptable range described in the guidelines for bioanalytical method validation. The method showed linearity in the concentration range of 50–5000 ng mL−1 with LOD of 20 ng mL−1 and LLOQ of 50 ng mL−1. Moreover, the advantage of this method over previously published methods is the short analysis run time of 6 min in HPLC itself, alongside its application not only for plasma samples but also in tissues, with low LLOQ. The method was successfully applied for studying the compartmental pharmacokinetics, tissue distribution and pharmacodynamics. A two-compartmental micro model was statistically fitted for the assessment of pharmacokinetic parameters. The tissue distribution studies suggest that the kidneys, lungs and liver are the primarily responsible organs for metabolism and elimination of DNP. Pharmacodynamic studies were performed by measuring acetylcholinesterase inhibitory activity of DNP, which indicated that the pharmacokinetic and pharmacodynamic data are in correlation with each other.

Lyotropic liquid crystal nanoparticles: A novel improved lipidic drug delivery system

Abstract Lipid-based liquid crystalline nanoparticles have attracted great attention in the field of drug delivery. These systems consist of amphiphilic lipid molecules which self-assemble in aqueous environments to form complex three-dimensional structures. This complex structure can hold both hydrophilic and hydrophobic drugs and can release at different predetermined rates. The advent of lipid-based liquid nanocrystals or lyotropic liquid crystal (LLC) nanoparticles having highly ordered, thermodynamically stable, internal nanostructure has added a new dimension in formulation studies and has garnered a lot of interest amongst the scientific community. These novel lipidic systems have been proven for several advantages, such as multi-drug loading, high drug entrapment efficiency, potential for controlled and targeted release through functional modifications, reduced toxicity and biodegradable nature. This chapter gives an overview of recent advances and current status of LLC nanoparticles, especially with respect to method of preparations, physichochemical characterizations, biopharmaceutical performance, and applications in the field of drug delivery for different therapeutic areas. This review has focused in detail on the various phases of LLCs and potential materials of composition and their phase transition behavior with respect to various factors, knowledge of which would, in turn, help the reader in selecting the method of preparation and suitable characterization techniques. In addition, potential problems and possible future research directions for industrial scale-up and translation from bench to bed are highlighted.

MicroRNAs as biological regulators in skin disorders

microRNAs are being investigated as promising therapeutic targets and biomarkers for different disease conditions. miRNAs serve as essential regulators of cell differentiation, proliferation and survival. The involvement of miRNAs in the functioning and regulation of the skin cells and skin diseases is a rapidly advancing area in dermatological research. miRNAs have been identified to play a key role in the pathogenesis, diagnosis, and treatment of the skin diseases. Skin is one of the largest organs of the body, primarily functioning as the first line of defence against external insults including bacteria, virus and other pathogens. Various miRNAs have been identified to demonstrate significant effects in various skin inflammatory conditions such as wounds, cancer, psoriasis, scleroderma, dermatomyositis. The current review explores the possible roles of the miRNAs in skin disorders and reports relating to the clinical trials involving skin diseases and miRNAs. The review has also compiled the information of the databases available, which correlates the miRNAs with different diseases and give details about targeting interactions of miRNA.

Multi-drug resistant Mycobacterium tuberculosis & oxidative stress complexity: Emerging need for novel drug delivery approaches

Tuberculosis (caused by Mycobacterium tuberculosis, Mtb) treatment involves multiple drug regimens for a prolonged period. However, the therapeutic benefit is often limited by poor patient compliance, subsequently leading to treatment failure and development of antibiotic resistance. Notably, oxidative stress is a crucial underlying factor that adversely influences the various treatment regimens in tuberculosis. Little information is available with advanced drug delivery systems that could be effectively utilized, in particular, for targeting the oxidative stress in tuberculosis. Thus, this presents an opportunity to review the utility of various available, controlled-release drug delivery systems (e.g., microspheres, liposomes, niosomes, solid lipid nanoparticles, dendrimers) that could be beneficial in tuberculosis treatments. This will help the biological and formulation scientists to pave a new path in formulating a treatment regimen for multi-drug resistant Mtb.

Emerging landscape in psoriasis management: From topical application to targeting biomolecules

Psoriasis is a chronic autoimmune skin disorder affecting 2-3% of the world population. It has characteristic features such as increased keratinocyte proliferation and production of inflammatory mediators. The treatment involves various strategies including topical, systemic, phototherapy and biologics. Topical therapies are preferred for mild to moderate psoriasis conditions over the systemic therapies which are ideal in severe disease conditions. The systemic therapies include immunosuppressants, biological agents and recently approved phosphodiesterase-4 (PDE4) inhibitors. There are various limitations associated with the existing therapies where the new findings in the pathogenesis of psoriasis are paving a path for newer therapeutics to target at the molecular level. Various small molecules, PDE-4 inhibitors, biologics, and immunomodulator proved efficacious including the new molecules targeting Janus kinases (JAK) inhibitors that are under investigation. Furthermore, the role of genetic and miRNAs in psoriasis is still not completely explored and may further help in improving the treatment efficacy. This review provides an insight into various emerging therapies along with currently approved treatments for psoriasis.

Gene therapy and type 1 diabetes mellitus

BACKGROUND Type 1 diabetes mellitus (T1DM) is an autoimmune disorder characterized by T cell-mediated self-destruction of insulin-secreting islet β cells. Management of T1DM is challenging and complicated especially with conventional medications. Gene therapy has emerged as one of the potential therapeutic alternatives to treat T1DM. This review primarily focuses on the current status and the future perspectives of gene therapy in the management of T1DM. A vast number of the studies which are reported on gene therapy for the management of T1DM are done in animal models and in preclinical studies. In addition, the safety of such therapies is yet to be established in humans. Currently, there are several gene level interventions that are being investigated, notably, overexpression of genes and proteins needed against T1DM, transplantation of cells that express the genes against T1DM, stem-cells mediated gene therapy, genetic vaccination, immunological precursor cell-mediated gene therapy and vectors. METHODS We searched the current literature through searchable online databases, journals and other library sources using relevant keywords and search parameters. Only relevant publications in English, between the years 2000 and 2018, with evidences and proper citations, were considered. The publications were then analyzed and segregated into several subtopics based on common words and content. A total of 126 studies were found suitable for this review. FINDINGS Generally, the pros and cons of each of the gene-based therapies have been discussed based on the results collected from the literature. However, there are certain interventions that require further detailed studies to ensure their effectiveness. We have also highlighted the future direction and perspectives in gene therapy, which, researchers could benefit from.