Excessive architectural re-modeling of tissues in pulmonary fibrosis due to proliferation of myofibroblasts and deposition of extracellular matrix adversely affects the elasticity of the alveoli and lung function. Progressively destructive chronic inflammatory disease, therefore, necessitates safe and effective non-invasive airway delivery that can reach deep alveoli, restore the surfactant function and reduce oxidative stress. We designed an endogenous surfactant-based liposomal delivery system of naringin to be delivered as an aerosol that supports pulmonary mechanics for the management of pulmonary fibrosis. Phosphatidylcholine-based liposomes showed 91.5 ± 2.4% encapsulation of naringin, with a mean size of 171.4 ± 5.8 nm and zeta potential of −15.5 ± 1.3 mV. Liposomes with the unilamellar structure were found to be spherical and homogeneous in shape using electron microscope imaging. The formulation showed surface tension of 32.6 ± 0.96 mN/m and was able to maintain airway patency of 97 ± 2.5% for a 120 s test period ensuring the effective opening of lung capillaries and deep lung delivery. In vitro lung deposition utilizing Twin Stage Impinger showed 79 ± 1.5% deposition in lower airways, and Anderson Cascade Impactor deposition revealed a mass median aerodynamic diameter of 2.35 ± 1.02 μm for the aerosolized formulation. In vivo efficacy of the developed formulation was analyzed in bleomycin-induced lung fibrosis model in rats after administration by the inhalation route. Lactate dehydrogenase activity, total protein content, and inflammatory cell infiltration in broncho-alveolar lavage fluid were substantially reduced by liposomal naringin. Oxidative stress was minimized as observed from levels of antioxidant enzymes. Masson’s Trichrome staining of lung tissue revealed significant amelioration of histological changes and lesser deposition of collagen. Overall results indicated the therapeutic potential of the developed non-invasive aerosol formulation for the effective management of pulmonary fibrosis.

Acute respiratory distress syndrome (ARDS), a catastrophic illness of multifactorial etiology, involves a rapid upsurge in inflammatory cytokines that leads to hypoxemic respiratory failure. Dexamethasone, a synthetic corticosteroid, mitigates the glucocorticoid-receptor-mediated inflammation and accelerates tissue homeostasis towards disease resolution. To minimize non-target organ side effects arising from frequent and chronic use of dexamethasone, we designed biodegradable, lung-targeted microspheres with sustained release profiles. Dexamethasone-loaded lipopolymeric microspheres of PLGA (Poly Lactic-co-Glycolic Acid) and DPPC (Dipalmitoylphosphatidylcholine) stabilized with vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate) were prepared by a single emulsion technique that had a mean diameter of 8.83 ± 0.32 μm and were spherical in shape as revealed from electron microscopy imaging. Pharmacokinetic and biodistribution patterns studied in the lungs, liver, and spleen of Wistar rats showed high selectivity and targeting efficiency for the lung tissue (r_e 13.98). As a proof-of-concept, in vivo efficacy of the microspheres was tested in the lipopolysaccharide-induced ARDS model in rats. Inflammation markers such as IL-1β, IL-6, and TNF-α, quantified in the bronchoalveolar lavage fluid indicated major improvement in rats treated with dexamethasone microspheres by intravenous route. Additionally, the microspheres substantially inhibited the protein infiltration, neutrophil accumulation and lipid peroxidation in the lungs of ARDS bearing rats, suggesting a reduction in oxidative stress. Histopathology showed decreased damage to the pulmonary tissue upon treatment with the dexamethasone-loaded microspheres. The multipronged formulation technology approach can thus serve as a potential treatment modality for reducing lung inflammation in ARDS. An improved therapeutic profile would help to reduce the dose, dosing frequency and, eventually, the toxicity.

Sitagliptin (MK–0431) is a widely and commonly used oral hypoglycemic drug in the treatment of type 2 diabetes mellitus; patients typically take higher doses of this drug (50 mg, twice daily). One drawback is that only 38% of the drug is bound reversibly to plasma proteins and 79% is excreted in urine without being metabolized. To overcome this issue, there is a need for a better drug-delivery method to improve its efficacy in patients. It has been found that in existing formulations, the drug content is 72.5% ± 5% and the percentage yield is 84.9% ± 3%. In this study, sitagliptin nanoparticles (sizes ranging from 210 to 618 nm) were developed. The bioadhesion properties of the nanoparticles, as well as the swelling of the nanoparticles on the mucus membrane aided in sustained drug release. The pattern of drug release was in accordance with the Peppas model. Fourier-transform infrared (FTIR) spectroscopy demonstrated that there were no significant interactions between sitagliptin and chitosan. Differential scanning calorimetry (DSC) results showed an absence of drug peaks due to the fact that the drug was present in an amorphous state. Mucoadhesive nanoparticles were formulated using sitagliptin and were effective for about 12 hours in the gastrointestinal tract. When compared to conventional sitagliptin administration, use of a nanoparticle delivery system demonstrated greater benefits for use in oral delivery applications. This is the first time that a drug-delivery method based on the mucoadhesive properties of nanoparticles could prolong the drug-release time of sitagliptin.

Widespread presence of pharmaceuticals and their metabolites in the environment of industrialized countries is an emerging global concern. Potential contamination of the soil and water by such pharmacologically active substances poses serious ecotoxicological implications. Several studies assessing the long-term ecological risks of pharmaceutical contaminants mainly focus on the risk assessment of the parent drug, while the potential contributions of their metabolites is often neglected. Presence of selective serotonin and norepinephrine reuptake inhibitor venlafaxine, an antidepressant drug, and its metabolites is a matter of serious concern for aquatic systems, since they are difficult to remove by traditional wastewater treatment processes. The concentration of VEN present in water is reportedly one of the highest among pharmaceuticals; however, the long-term effects of its metabolites have not yet been systematically studied. Given the consideration to complex and time-consuming effluent treatment, and realizing the importance of levels of venlafaxine and its metabolites, a simple and accurate analytical method for quick determination is needed. We designed a selective colorimetric method by using oxidative coupling of drug molecules with 3-methyl-2-benzothiazolinone hydrazone hydrochloride (MBTH) reagent, to quantify the presence of venlafaxine and its metabolites in aquatic samples, with special emphasis on effluent. The method was validated for selectivity, specificity and robustness as per the ICH Q2 guidelines to assess its suitability in pharmaceutical samples, as well. Highly sensitive and green economical analytical method was successfully established for estimation of venlafaxine and its metabolites in aquatic samples. The method was quick, as it involved minimum processing steps. The method was accurate and linear in the range of 0.5 to 80 ppm and could successfully detect lowest concentration of 1.3 ppm, thus qualifying its applicability for the desired purpose to check the presence of trace levels of VEN or its metabolites in aquatic samples or in pharmaceutical formulations.

Objectives: The aim of this study was to formulate a novel BCS class II antifungal formulation of itraconazole and optimise its critical quality attributes (CQAs) using a Quality by Design (QbD) approach. Methods: Material attributes and CQAs were identified using risk assessment according to the International Conference of Harmonization (ICHQ9) quality guidelines. The material attributes were found to be the ratios of surfactant (Tween 80) and co-surfactant (Transcutol). The CQA selected for optimization was dissolution. A screening design was performed on the surfactant and co-surfactant to fix the ratio of Smix, resulting in four optimized ratios: 1:1, 1:3, 5:3, and 5:1. Pseudo ternary phase diagrams were constructed, and ranges for excipients were fixed. Based on the results of the screened ratios, a Mixture Design – Design of Experiment (DoE) was used for optimization. Findings: Optimized runs of ten runs for dissolution were achieved by the application of the mixture design, with formulation F2 showing a maximum release of 93.35%. Novelty: Quality by Design (QbD) can be utilized to optimize the CQAs of a novel BCS class II antifungal formulation, itraconazole. Keywords: QbD, Screening design, Mixture design, Extreme vertices, SEDDS, Itraconazole

To formulate a novel Biopharmaceutics Classification System class II antihyperlipidemic drug and optimize its critical quality attributes using a quality-by-design approach. Atorvastatin was the drug of choice in this study. The material and critical quality attributes were identified by risk assessment, as per the International Conference of Harmonization Quality Guidelines. Material attributes were found to be the amounts of microcrystalline cellulose and croscarmellose sodium; the critical quality attribute selected for optimization was dissolution. A screening design with five experimental runs was performed for the amounts of croscarmellose sodium and microcrystalline cellulose in the ranges of 11–21 mg and 80–160 mg, respectively. The response surface methodology was used for optimization based on the results of the screening batches. A full factorial central composite design with 10 experimental runs was performed using microcrystalline cellulose and croscarmellose sodium in the range of 80–120 mg and 11–20 mg, respectively. Of these runs, batch R1 showed a drug release of 92.47% in 30 min with microcrystalline cellulose (120 mg) and croscarmellose sodium (16 mg). Quality by Design can be applied to optimize critical quality attributes and meet the desired Quality Target Product Profile. Keywords: Quality by Design, Screening design, Full factorial design, Central composite design, Atorvastatin