Innovative pulmonary targeting of terbutaline sulfate-laded novasomes for non-invasive tackling of asthma: statistical optimization and comparative in vitro/ in vivo evaluation

Abstract

Asthma represents a globally serious non-communicable ailment with significant public health outcomes for both pediatrics and adults triggering vast morbidity and fatality in critical cases. The β₂-adrenoceptor agonist, terbutaline sulfate (TBN), is harnessed as a bronchodilator for monitoring asthma noising symptoms. Nevertheless, the hepatic first-pass metabolism correlated with TBN oral administration mitigates its clinical performance. Likewise, the regimens of inhaled TBN dosage forms restrict its exploitation. Consequently, this work is concerned with the assimilation of TBN into a novel non-phospholipid nanovesicular paradigm termed novasomes (NVS) for direct and effective TBN pulmonary targeting. TBN-NVS were tailored based on the thin film hydration method and Box-Behnken design was applied to statistically optimize the formulation variables. Also, the aerodynamic pattern of the optimal TBN-NVS was explored via cascade impaction. Moreover, comparative pharmacokinetic studies were conducted using a rat model. TBN elicited encapsulation efficiency as high as 70%. The optimized TBN-NVS formulation disclosed an average nano-size of 223.89 nm, ζ potential of -31.17 mV and a sustained drug release up to 24 h. Additionally, it manifested snowballed in vitro lung deposition behavior in cascade impactor with a fine particle fraction of 86.44%. In vivo histopathological studies verified safety of intratracheally-administered TBN-NVS. The pharmacokinetic studies divulged 3.88-fold accentuation in TBN bioavailability from the optimum TBN-NVS versus the oral TBN solution. Concisely, the results proposed that NVS are an auspicious nanovector for TBN pulmonary delivery with integral curbing of the disease owing to target specificity.

Keywords: Box-Behnken design; Bronchial asthma; novasomes; pharmacokinetics; pulmonary targeting; terbutaline sulfate.

Figure 1.

Model diagnostic plots of the three independent variables (a) linear correlation plots between actual and predicted values for various responses of TBN-NVS, (b) normal quantile-quantile plots of residual errors and (c) plot of residual error vs. model predicted responses.

Figure 2.

(a) Response 3D plots and (b) cube plot for the effect of cholesterol (X₁), Span 60 (X₂) and stearic acid (X₃) concentrations on the entrapment efficiency percent (Y₁).

Figure 3.

(a) Response 3D plots and (b) cube plot for the effect of cholesterol (X₁), Span 60 (X₂) and stearic acid (X₃) concentrations on the particle size (Y₂).

Figure 4.

(a) Response 3D plots and (b) cube plot for the effect of cholesterol (X₁), Span 60 (X₂) and stearic acid (X₃) concentrations on the accumulative % drug release after 8 h (Y₃).

Figure 5.

Transmission electron micrograph of the optimized TBN-NVS formulation.

Figure 6.

Effect of storage on the EE%, particle size and ζ potential of the optimized TBN-NVS formulation.

Figure 7.

Light photomicrographs showing histopathological sections of (a) control untreated rat lung and (b) rat lung received an intratracheal suspension of TBN-NVS formulation (200X H & E).

Figure 8.

TBN plasma concentration time profiles after administration of oral TBN solution, i.t TBN solution and i.t TBN-NVS suspension.