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1.
Bioorg Chem ; 126: 105900, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35671644

RESUMO

Encouraged by the potent anti-depression activities of incensole (1) and incensole acetate (2) isolated from the resin of Boswellia papyrifera in our previous work, different derivatives of 1 and 2 were synthesized in the present study. The reaction of 1 with m-CPBA afforded the mono-epoxide derivative 3a, while the same reaction with 2 led to three different epoxide derivatives 3a, 3b, and 3c. Oxidation of 1 with PCC to get compound 3b, however along with the target 3b, the reaction gave three interesting side products (3c-3e). Oxime (3b-1) resulted from the reaction of 3b with hydroxylamine hydrochloride in pyridine, while epoxidation of 2 generate three epoxide products (4a-4c). The structures of all products were unambiguously confirmed using NMR and Mass spectrometry. Compounds 3a-e and 4a-c (0.1-3 mg/kg, i.p.) demonstrated promising anti-depression activities in classical mouse models of depression of FST and TST. The results showed that compounds 3a-e and 4a-c (0.1-3 mg/kg, i.p.) caused dose dependent reduction in immobility time compared to the vehicle control, with 3c-3e and 4b-4c demonstrating higher potency and efficacy. The findings of the open field test excluded the motor effects of these compounds, thus further confirming their anti-depression activity. Preliminary investigation into their mechanism of action using GABA antagonist, PTZ and molecular docking has predicted that compounds 3e and 4c bind at the GABA binding site of GABAA receptor to produce GABAergic effects. Furthermore, the promising anti-depression potency of compounds 1 and 2 and their derivatives make them lead compounds for drug discovery.


Assuntos
Boswellia , Franquincenso , Animais , Boswellia/química , Diterpenos , Compostos de Epóxi , Camundongos , Simulação de Acoplamento Molecular , Receptores de GABA-A
2.
Int J Pharm ; 598: 120376, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33617949

RESUMO

Aerosolization is a non-invasive approach in drug delivery for localized and systemic effect. Nanostructured lipid carriers (NLCs) are new generation versatile carriers, which offer protection from degradation and enhance bioavailability of poorly water soluble drugs. The aim of this study was to develop and optimize NLC formulations in combination with optimized airflow rates (i.e. 60 and 15 L/min) and choice of medical nebulizers including Air jet, Vibrating mesh and Ultrasonic nebulizer for superior aerosolization performance, assessed via a next generation impactor (NGI). Novel composition and combination of NLC formulations (F1 - F15) were prepared via ultrasonication method, employing five solid lipids (glycerol trimyristate (GTM), glycerol trilaurate (GTL), cetyl palmitate (CP), glycerol monostearate (GMS) and stearic acid (SA)); and three liquid lipids (glyceryl tributyrate (GTB), propylene glycol dicaprylate/dicaprate (PGD) and isopropyl palmitate (IPP)) in 1:3 w/w ratios (i.e. combination of one solid and one liquid lipid), with Beclomethasone dipropionate (BDP) incorporated as the model drug. Out of fifteen BDP-NLC formulations, the physicochemical properties of formulations F7, F8 and F10 exhibited desirable stability (one week at 25 °C), with associated particle size of ~241 nm, and >91% of drug entrapment. Post aerosolization, F10 was observed to deposit notably smaller sized particles (from 198 to 136 nm, 283 to 135 nm and 239 to 157 nm for Air jet, Vibrating mesh and Ultrasonic nebulizers, respectively) in all stages (i.e. from stage 1 to 8) of the NGI, when compared to F7 and F8 formulations. Six week stability studies conducted at 4, 25 and 45 °C, demonstrated F10 formulation stability in terms of particle size, irrespective of temperature conditions. Nebulizer performance study using the NGI for F10 identified the Air jet to be the most efficient nebulizer, depositing lower concentrations of BDP in the earlier stages (1-3) and higher (circa 82 and 85%) in the lateral stages (4-8) using 60 and 15 L/min airflow rates, when compared to the Vibrating mesh and Ultrasonic nebulizers. Moreover, at both airflow rates, the Air jet nebulizer elicited a longer nebulization time of ~42 min, facilitating aerosol inhalation for prophylaxis of asthma with normal tidal breathing. Based on characterization and nebulizer performance employing both 60 and 15 L/min airflow rates, the Air jet nebulizer offered enhanced performance, exhibiting a higher fine particle dose (FPD) (90 and 69 µg), fine particle fraction (FPF) (70 and 54%), respirable fraction (RF) (92 and 69%), and lower mass median aerodynamic diameter (MMAD) (1.15 and 1.62 µm); in addition to demonstrating higher drug deposition in the lateral parts of the NGI, when compared to its counterpart nebulizers. The F10 formulation used with the Air jet nebulizer was identified as being the most suitable combination for delivery of BDP-NLC formulations.


Assuntos
Beclometasona , Nebulizadores e Vaporizadores , Administração por Inalação , Aerossóis , Sistemas de Liberação de Medicamentos , Lipídeos , Tamanho da Partícula
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