Quality by Design Methodology Applied to Process Optimization and Scale up of Curcumin Nanoemulsions Produced by Catastrophic Phase Inversion.

In the presented study, we report development of a stable, scalable, and high-quality curcumin-loaded oil/water (o/w) nanoemulsion manufactured by concentration-mediated catastrophic phase inversion as a low energy nanoemulsification strategy. A design of experiments (DoE) was constructed to determine the effects of process parameters on the mechanical input required to facilitate the transition from the gel phase to the final o/w nanoemulsion and the long-term effects of the process parameters on product quality. A multiple linear regression (MLR) model was constructed to predict nanoemulsion diameter as a function of nanoemulsion processing parameters. The DoE and subsequent MLR model results showed that the manufacturing process with the lowest temperature (25 °C), highest titration rate (9 g/minute), and lowest stir rate (100 rpm) produced the highest quality nanoemulsion. Both scales of CUR-loaded nanoemulsions (100 g and 500 g) were comparable to the drug-free optimal formulation with 148.7 nm and 155.1 nm diameter, 0.22 and 0.25 PDI, and 96.29 ± 0.76% and 95.60 ± 0.88% drug loading for the 100 g and 500 g scales, respectively. Photostability assessments indicated modest loss of drug (<10%) upon UV exposure of 24 h, which is appropriate for intended transdermal applications, with expected reapplication of every 6-8 h.

Inhalation Delivery of Host Defense Peptides (HDP) using Nano- Formulation Strategies: A Pragmatic Approach for Therapy of Pulmonary Ailments.

Host defense peptides (HDP) are small cationic molecules released by the immune systems of the body, having multidimensional properties including anti-inflammatory, anticancer, antimicrobial and immune-modulatory activity. These molecules gained importance due to their broad-spectrum pharmacological activities, and hence being actively investigated. Presently, respiratory infections represent a major global health problem, and HDP has an enormous potential to be used as an alternative therapeutics against respiratory infections and related inflammatory ailments. Because of their short half-life, protease sensitivity, poor pharmacokinetics, and first-pass metabolism, it is challenging to deliver HDP as such inside the physiological system in a controlled way by conventional delivery systems. Many HDPs are efficacious only at practically high molar-concentrations, which is not convincing for the development of drug regimen due to their intrinsic detrimental effects. To avail the efficacy of HDP in pulmonary diseases, it is essential to deliver an appropriate payload into the targeted site of lungs. Inhalable HDP can be a potentially suitable alternative for various lung disorders including tuberculosis, Cystic fibrosis, Pneumonia, Lung cancer, and others as they are active against resistant microbes and cells and exhibit improved targeting with reduced adverse effects. In this review, we give an overview of the pharmacological efficacy of HDP and deliberate strategies for designing inhalable formulations for enhanced activity and issues related to their clinical implications.

Alginate Microspheres Elicit Innate M1-Inflammatory Response in Macrophages Leading to Bacillary Killing.

Particulate drug delivery systems (PDDS) have been broadly explored as platforms for delivery of drugs, enzymes, cells, and vaccines for pharmaceutical applications. Studies suggest that microspheres (MS) can stimulate innate immune cells even without a drug payload; however, less is known regarding how they impact host cells in dealing with the bacillary infection. We examined the role of drug-free inhalable alginate microspheres (A-MS) on phagocytosis efficiency and subsequent immune cell activation in Escherichia coli-infected THP-1-derived macrophages. Alginate particles have been widely investigated as carriers for prolonged delivery of bioactive (i.e., drugs, diagnostics, and vaccines). A-MS were fabricated by industry scalable spray-congealing process using divalent cation-induced gelification. E. coli-infected macrophages (multiplicity of infection (MOI 1:10) were treated with drug-free A-MS, where we found a consistent moderate reduction in bacillary viability. Particles were more efficiently and rapidly phagocytized by infected macrophages as compared with normal macrophage cells. Subsequently, A-MS induced markers of M1 macrophage responses and stimulated the processing and secretion of pro-inflammatory cytokines (IL-6, IL-12). It also notably augmented the generation of reactive oxygen species (ROS) and nitric oxide (NO) in infected cells. Results illustrate that, the blank A-MS (without a drug payload) able to moderately check the growth of intracellular E. coli (without significant cytotoxicity) by modulating the M1 inflammatory response by host cells. This "added value" can be utilized in the design and development of therapeutic system with the additional advantage of immune-modulatory activity, in addition to serving as a drug carrier.

Heparin-Encapsulated Metered-Dose Topical "Nano-Spray Gel" Liposomal Formulation Ensures Rapid On-Site Management of Frostbite Injury by Inflammatory Cytokines Scavenging.

The critical time window between the incidence of frostbite injury and the initiation of treatment in remote snowbound areas is a determining factor for an effective therapeutic response. It is an emergency condition and challenging to treat due to the poor vascularity of affected body parts, and it requires immediate action. In addition to cold trauma-induced tissue damage, the inflammatory mediators majorly contribute to pathologic aggravations. We have designed and evaluated a topical "nano-spray gel (NSG)" formulation, which is based on a combination of liposomal heparin sodium (Hp) and ibuprofen (Ibu) for rapid relief of frostbite injury in extremely low temperatures. The scientific literature suggests that heparin is associated with rapid endothelial cell repair, normalizing blood circulation in capillaries, and has a potential role in wound healing. Hp-containing liposomes were prepared by the extruder method, which suitably formulated an ibuprofen-containing gel to obtain a nano-Spray formulation (HLp-Ibu-NSG) applicable for topical delivery. A single spray puff of the formulation delivers ∼154 mg of the gel, which corresponds to ∼205 U of heparin. In this study, heparin liposomes exhibited significant healing of wound in vitro (scratch assay, fibroblast cells) and in vivo (wound healing in Sprague Dawley rats) at a low dose. In the rat model of frostbite injury, the HLp-Ibu-NSG formulation demonstrated significant reduction in the wound area (up to ∼96%) and improvement of histopathology in 14 days as compared to the control groups. No edema and erythema were detected post-treatment of HLp-Ibu-NSG in the affected area. The underlying mechanism was delineated as a modulation of the inflammatory cytokine (IL-6, TNF-α, IL-10, IL-4) mediators at the wound site and blood circulation to foster frostbite healing. Future clinical studies on the nano-spray gel are required to evaluate its efficacy for the treatment of frostbite symptoms. The instant on-site application of this formulation might be helpful in saving extremities of soldiers, mountaineers, and pilgrims having frostbite.