Dataset Information

In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug.

ABSTRACT: This study aims to understand the absorption patterns of three different kinds of inhaled formulations via in silico modeling using budesonide (BUD) as a model drug. The formulations investigated in this study are: (i) commercially available micronized BUD mixed with lactose (BUD-PT), (ii) BUD nanocrystal suspension (BUD-NC), (iii) BUD nanocrystals embedded hyaluronic acid microparticles (BUD-NEM). The deposition patterns of the three inhaled formulations in the rats' lungs were determined in vivo and in silico predicted, which were used as inputs in GastroPlus™ software to predict drug absorption following aerosolization of the tested formulations. BUD pharmacokinetics, estimated based on intravenous data in rats, was used to establish a drug-specific in silico absorption model. The BUD-specific in silico model revealed that drug pulmonary solubility and absorption rate constant were the key factors affecting pulmonary absorption of BUD-NC and BUD-NEM, respectively. In the case of BUD-PT, the in silico model revealed significant gastrointestinal absorption of BUD, which could be overlooked by traditional in vivo experimental observation. This study demonstrated that in vitro-in vivo-in silico approach was able to identify the key factors that influence the absorption of different inhaled formulations, which may facilitate the development of orally inhaled formulations with different drug release/absorption rates.

SUBMITTER: Shi C

PROVIDER: S-EPMC8261257 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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<i>In vitro - in vivo - in silico</i> approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug.

Shi Changzhi C Ignjatović Jelisaveta J Liu Tingting T Han Meihua M Cun Dongmei D Đuriš Jelena J Yang Mingshi M Cvijić Sandra S

Asian journal of pharmaceutical sciences 20210105 3

This study aims to understand the absorption patterns of three different kinds of inhaled formulations <i>via in silico</i> modeling using budesonide (BUD) as a model drug. The formulations investigated in this study are: (i) commercially available micronized BUD mixed with lactose (BUD-PT), (ii) BUD nanocrystal suspension (BUD-NC), (iii) BUD nanocrystals embedded hyaluronic acid microparticles (BUD-NEM). The deposition patterns of the three inhaled formulations in the rats' lungs were determine ...[more]

PMID: 34276823

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Project description:Onychomycosis is a prominent fungal infection that causes discoloration, thickening, and mutilation leading to the separation of the nail from the nail bed. Treatment modalities for onychomycosis may include oral, topical, or combination therapy with antifungals and at times may require chemical or surgical intervention. The burden of side effects of antifungals is enormous, and therefore using molecular docking-based drug selection in context with the target keratin protein would ensure better disease management. Ciclopirox, Amorolfine HCl, Efinaconazole, Tioconazole, and Tavaborole were submitted for assessment, revealing that Amorolfine HCl is the best fit. Consequently, two formulations (Nail lacquer and nanoemulgel) were developed from Amorolfine HCl to validate the in silico screening outcomes. The formulations were further fortified with over-the-counter ingredients vis-a-vis with vitamin E in nail lacquer and undecylenic acid in nanoemulgel for their prominent roles in improving nail health. Both the formulations were systematically designed, optimized, and characterized. Amorolfine HCl containing nanoemulgel (NEG) was developed using undecylenic acid as an oil phase and thioglycolic acid as a penetration enhancer. The quality parameters evaluated were particle size, the zeta potential for nanoemulsion (NE) (78.04 ± 4.724 nm and -0.7mV, respectively), in vitro cumulative drug release (96.74% for NE and 88.54% for NEG), and transungual permeation (about 73.49% for NEG and 54.81% for NE). Nail lacquer was evaluated for the drying time, non-volatile content, and blush test. In vitro cumulative drug release of the developed nail lacquer and comparator marketed formulations were around 81.5% and 75%, respectively. Similarly, the transungual drug permeation was 6.32 μg/cm2 and 5.89 μg/cm2, respectively, in 24 h. The in silico guided preparation of both formulations containing Amorolfine HCl and over the counter ingredients is amenable for therapeutic use against onychomycosis and will be evaluated in the in vivo model.

Project description:Background and purposeInhaled corticosteroids (ICS) are the cornerstone of asthma pharmacotherapy and, acting via the glucocorticoid receptor (GR), reduce inflammatory gene expression. While this is often attributed to a direct inhibitory effect of the GR on inflammatory gene transcription, corticosteroids also induce the expression of anti-inflammatory genes in vitro. As there are no data to support this effect in asthmatic subjects taking ICS, we have assessed whether ICS induce anti-inflammatory gene expression in subjects with atopic asthma.Experimental approachBronchial biopsies from allergen-challenged atopic asthmatic subjects taking inhaled budesonide or placebo were subjected to gene expression analysis using real-time reverse transcriptase-PCR for the corticosteroid-inducible genes (official gene symbols with aliases in parentheses): TSC22D3 [glucocorticoid-induced leucine zipper (GILZ)], dual-specificity phosphatase-1 (MAPK phosphatase-1), both anti-inflammatory effectors, and FKBP5 [FK506-binding protein 51 (FKBP51)], a regulator of GR function. Cultured pulmonary epithelial and smooth muscle cells were also treated with corticosteroids before gene expression analysis.Key resultsCompared with placebo, GILZ and FKBP51 mRNA expression was significantly elevated in budesonide-treated subjects. Budesonide also increased GILZ expression in human epithelial and smooth muscle cells in culture. Immunostaining of bronchial biopsies revealed GILZ expression in the airways epithelium and smooth muscle of asthmatic subjects.Conclusions and implicationsExpression of the corticosteroid-induced genes, GILZ and FKBP51, is up-regulated in the airways of allergen-challenged asthmatic subjects taking inhaled budesonide. Consequently, the biological effects of corticosteroid-induced genes should be considered when assessing the actions of ICS. Treatment modalities that increase or decrease GR-dependent transcription may correspondingly affect corticosteroid efficacy.

Dataset Information

In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug.

Publications

<i>In vitro - in vivo - in silico</i> approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug.

Similar Datasets

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