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  1. Kumbhar SA, Kokare CR, Shrivastava B, Gorain B
    Ann Pharm Fr, 2020 May 06.
    PMID: 32387177 DOI: 10.1016/j.pharma.2020.04.005
    A novel, simple reversed-phase high-performance liquid chromatographic (RP-HPLC) analytical method was developed and validated for the quantitative determination of asenapine from various nanoemulsion components during pre-formulation screening. The developed method was validated according to ICH Q2 (R1) guidelines. The developed and validated method was precisely and accurately quantified asenapine in various oils, surfactants and co-surfactants. The separation of asenapine was carried out on Hypersil BDS C18, 250×4.6mm, 5μm particle size column using methanol: acetonitrile (90:10) as mobile phase with a flow rate of 1mL.min-1. Measurement at 270nm for the concentration range of 5 to 50μg.mL-1 of the analyte was found to be linear with the determination coefficient (r2) of 0.999 as calculated by the least square regression method. The validated method was sensitive with LOD of 10.0ng.mL-1 and LOQ of 30.0ng.mL-1. Further, the method was precise and accurate, where the intraday and interday precision values were ranged from 0.70-0.95 and 0.36-0.95, respectively with the corresponding accuracy were ranged from 98.80-100.63 and 98.36-100.63. This developed and validated RP-HPLC method for asenapine was applied in the quantitative determination and screening of various oils, surfactants, and co-surfactants during the development of the asenapine maleate nanoemulsion.
  2. Kumbhar SA, Kokare CR, Shrivastava B, Gorain B, Choudhury H
    J Pharm Sci, 2021 04;110(4):1761-1778.
    PMID: 33515583 DOI: 10.1016/j.xphs.2021.01.021
    Delivering therapeutics to the brain using conventional dosage forms is always a challenge, thus the present study was aimed to formulate mucoadhesive nanoemulsion (MNE) of aripiprazole (ARP) for intranasal delivery to transport the drug directly to the brain. Therefore, a TPGS based ARP-MNE was formulated and optimized using the Box-Behnken statistical design. The improved in vitro release profile of the formulation was in agreement to enhanced ex vivo permeation through sheep mucous membranes with a maximum rate of permeation co-efficient (62.87  cm h-1 × 103) and flux (31.43  μg cm-2.h-1). The pharmacokinetic profile following single-dose administration showed the maximum concentration of drug in the brain (Cmax) of 15.19 ± 2.51  μg mL-1 and Tmax of 1 h in animals with ARP-MNE as compared to 10.57 ± 1.88  μg mL-1 and 1 h, and 2.52 ± 0.38  μg mL-1 and 3 h upon intranasal and intravenous administration of ARP-NE, respectively. Further, higher values of % drug targeting efficiency (96.9%) and % drug targeting potential (89.73%) of ARP-MNE through intranasal administration were investigated. The studies in Wistar rats showed no existence of extrapyramidal symptoms through the catalepsy test and forelimb retraction results. No ex vivo ciliotoxicity on nasal mucosa reflects the safety of the components and delivery tool. Further, findings on locomotor activity and hind-limb retraction test in ARP-MNE treated animals established its antipsychotic efficacy. Thus, it can be inferred that the developed ARP-MNE could effectively be explored as brain delivery cargo in the effective treatment of schizophrenia without producing any toxic manifestation.
  3. Kumbhar SA, Kokare CR, Shrivastava B, Gorain B, Choudhury H
    Int J Pharm, 2020 Aug 30;586:119499.
    PMID: 32505580 DOI: 10.1016/j.ijpharm.2020.119499
    The tight junctions between capillary endothelial cells of the blood-brain barrier (BBB) restricts the entry of therapeutics into the brain. Potential of the intranasal delivery tool has been explored in administering the therapeutics directly to the brain, thus bypassing BBB. The objective of this study was to develop and optimize an intranasal mucoadhesive nanoemulsion (MNE) of asenapine maleate (ASP) in order to enhance the nasomucosal adhesion and direct brain targetability for improved efficacy and safety. Box-Behnken statistical design was used to recognize the crucial formulation variables influencing droplet size, size distribution and surface charge of ASP-NE. ASP-MNE was obtained by incorporating GRAS mucoadhesive polymer, Carbopol 971 in the optimized NE. Optimized ASP-MNE displayed spherical morphology with a droplet size of 21.2 ± 0.15 nm and 0.355 polydispersity index. Improved ex-vivo permeation was observed in ASP-NE and ASP-MNE, compared to the ASP-solution. Finally, the optimized formulation was found to be safe in ex-vivo ciliotoxicity study on sheep nasal mucosa. The single-dose pharmacokinetic study in male Wistar rats revealed a significant increase in concentration of ASP in the brain upon intranasal administration of ASP-MNE, with a maximum of 284.33 ± 5.5 ng/mL. The time required to reach maximum brain concentration (1 h) was reduced compared to intravenous administration of ASP-NE (3 h). Furthermore, it has been established during the course of present study, that the brain targeting capability of ASP via intranasal administration had enhanced drug-targeting efficiency and drug-targeting potential. In the animal behavioral studies, no extrapyramidal symptoms were observed after intranasal administration of ASP-MNE, while good locomotor activity and hind-limb retraction test established its antipsychotic activity in treated animals. Thus, it can be concluded that the developed intranasal ASP-MNE could be used as an effective and safe tool for brain targeting of ASP in the treatment of psychotic disorders.
  4. Choudhury H, Gorain B, Pandey M, Kumbhar SA, Tekade RK, Iyer AK, et al.
    Int J Pharm, 2017 Aug 30;529(1-2):506-522.
    PMID: 28711640 DOI: 10.1016/j.ijpharm.2017.07.018
    Docetaxel (DTX) is one of the important antitumor drugs, being used in several common chemotherapies to control leading cancer types. Severe toxicities of the DTX are prominent due to sudden parenteral exposure of desired loading dose to maintain the therapeutic concentration. Field of nanotechnology is leading to resist sudden systemic exposure of DTX with more specific delivery to the site of cancer. Further nanometric size range of the formulation aid for prolonged circulation, thereby extensive exposure results better efficacy. In this article, we extensively reviewed the therapeutic benefit of incorporating d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS, or simply TPGS) in the nanoparticle (NP) formulation of DTX for improved delivery, tumor control and tolerability. TPGS is well accepted nonionic-ampiphilic polymer which has been identified in the role of emulsifier, stabilizer, penetration enhancer, solubilizer and in protection in micelle. Simultaneously, P-glycoprotein inhibitory activity of TPGS in the multidrug resistant (MDR) cancer cells along with its apoptotic potential are the added advantage of TPGS to be incorporated in nano-chemotherapeutics. Thus, it could be concluded that TPGS based nanoparticulate application is an advanced approach to improve therapeutic efficacy of chemotherapeutic agents by better internalization and sustained retention of the NPs.
  5. Gorain B, Rajeswary DC, Pandey M, Kesharwani P, Kumbhar SA, Choudhury H
    Curr Pharm Des, 2020;26(19):2233-2246.
    PMID: 32167424 DOI: 10.2174/1381612826666200313125613
    Increasing incidence of demented patients around the globe with limited FDA approved conventional therapies requires pronounced research attention for the management of the demented conditions in the growing elderly population in the developing world. Dementia of Alzheimer's type is a neurodegenerative disorder, where conventional therapies are available for symptomatic treatment of the disease but possess several peripheral toxicities due to lack of brain targeting. Nanotechnology based formulations via intranasal (IN) routes of administration have shown to improve therapeutic efficacy of several therapeutics via circumventing blood-brain barrier and limited peripheral exposure. Instead of numerous research on polymeric and lipid-based nanocarriers in the improvement of therapeutic chemicals and peptides in preclinical research, a step towards clinical studies still requires wide-ranging data on safety and efficacy. This review has focused on current approaches of nanocarrierbased therapies on Alzheimer's disease (AD) via the IN route for polymeric and lipid-based nanocarriers for the improvement of therapeutic efficacy and safety. Moreover, the clinical application of IN nanocarrier-based delivery of therapeutics to the brain needs a long run; however, proper attention towards AD therapy via this platform could bring a new era for the AD patients.
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