Formulation optimization, in vitro and in vivo evaluation of agomelatine-loaded nanostructured lipid carriers for augmented antidepressant effects.

The present study was intended to prepare and optimize agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) for augmented in vivo antidepressant potential. AGM-NLCs were optimized on several parameters including cumulative hydrophilic-lipophilic balance of surfactants, proportions of solid and liquid lipids, total amounts of drug and surfactants. AGM-NLCs were assessed for their physicochemical properties, in vitro AGM release and in vivo antidepressant effects in mice model. The optimized AGM-NLCs demonstrated spherical morphology with average particle size of 99.8 ± 2.6 nm, PDI of 0.142 ± 0.017, zeta potential of - 23.2 ± 1.2 mV and entrapment efficiency of 97.1 ± 2.1%. Thermal and crystallinity studies depict amorphous nature of AGM after its incorporation into NLCs. AGM-NLCs exhibit a sustained drug release profile after initial 2 h. Mice treated with AGM-NLCs exhibited reduced immobility time in behavioral analysis. Furthermore, cresyl violet staining demonstrated an improved neuronal morphology and survival in AGM-NLCs group. The concentrations and the expression of inflammatory markers (TNF-α and COX-2) in mice brain were significantly reduced by AGM-NLCs. Taken together, therapeutic effectiveness of AGM was markedly augmented in AGM-NLCs and thereby they could be promising nanocarriers for the effective delivery of antidepressants to brain.

Controlled therapeutic delivery of CO from carbon monoxide-releasing molecules (CORMs).

Carbon monoxide (CO) has been regarded as a "silent killer" for its toxicity toward biological systems. However, a low concentration of endogenously produced CO has shown a number of therapeutic benefits such as anti-inflammatory, anti-proliferative, anti-apoptosis, and cytoprotective activities. Carbon monoxide-releasing molecules (CORMs) have been developed as alternatives to direct CO inhalation, which requires a specialized setting for strict dose control. CORMs are efficient CO donors, with central transition metals (such as ruthenium, iron, cobalt, and manganese) surrounded by CO as a ligand. CORMs can stably store and subsequently release their CO payload in the presence of certain triggers including solvent, light, temperature, and ligand substitution. However, CORMs require appropriate delivery strategies to improve short CO release half-life and target specificity. Herein, we highlighted the therapeutic potential of inhalation and CORMs-delivered CO. The applications of conjugate and nanocarrier systems for controlling CO release and improving therapeutic efficacy of CORMs are also described in detail. The review concludes with some of the hurdles that limit clinical translation of CORMs. Keeping in mind the tremendous potential and growing interest in CORMs, this review would be helpful for designing controlled CO release systems for clinical applications.

Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability.

Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, in vivo pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by ∼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, Cmax, and lower Tmax than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.

Enhanced neuroprotective and antidepressant activity of curcumin-loaded nanostructured lipid carriers in lipopolysaccharide-induced depression and anxiety rat model.

The present study aims to develop curcumin-loaded nanostructured lipid carriers (CUR-NLCs) and investigate their neuroprotective effects in lipopolysaccharide (LPS)-induced depression and anxiety model. Nanotemplate engineering technique was used to prepare CUR-NLCs with Compritol 888 ATO and oleic acid as solid and liquid lipid, respectively. Poloxamer 188, Tween 80 and Span 80 were used as stabilizing agents for solid-liquid lipid core. The physicochemical parameters of CUR-NLCs were determined followed by in vitro drug release and in vivo neuroprotective activity in rats. The optimized CUR-NLCs demonstrated nanometric particle size of 147.8 nm, surface charge of -32.8 mV and incorporation efficiency of 91.0%. CUR-NLCs showed initial rapid followed by a sustained drug release reaching up to 73% after 24 h. CUR-NLCs significantly elevated struggling time and decreased immobility time in forced swim and tail suspension tests. A substantial increase in time spent and number of entries into the light and open compartments was observed in light-dark box and elevated plus maze models. CUR-NLCs improved the tissue architecture and suppressed the expression of p-NF-κB, TNF-α and COX-2 in brain tissues from histological and immunohistochemical analysis. CUR-NLCs improved the neuroprotective effect of curcumin and can be used as a potential therapeutics for depression and anxiety.

Potential and Applications of Nanocarriers for Efficient Delivery of Biopharmaceuticals.

During the past two decades, the clinical use of biopharmaceutical products has markedly increased because of their obvious advantages over conventional small-molecule drug products. These advantages include better specificity, potency, targeting abilities, and reduced side effects. Despite the substantial clinical and commercial success, the macromolecular structure and intrinsic instability of biopharmaceuticals make their formulation and administration challenging and render parenteral delivery as the only viable option in most cases. The use of nanocarriers for efficient delivery of biopharmaceuticals is essential due to their practical benefits such as protecting from degradation in a hostile physiological environment, enhancing plasma half-life and retention time, facilitating absorption through the epithelium, providing site-specific delivery, and improving access to intracellular targets. In the current review, we highlight the clinical and commercial success of biopharmaceuticals and the overall applications and potential of nanocarriers in biopharmaceuticals delivery. Effective applications of nanocarriers for biopharmaceuticals delivery via invasive and noninvasive routes (oral, pulmonary, nasal, and skin) are presented here. The presented data undoubtedly demonstrate the great potential of combining nanocarriers with biopharmaceuticals to improve healthcare products in the future clinical landscape. In conclusion, nanocarriers are promising delivery tool for the hormones, cytokines, nucleic acids, vaccines, antibodies, enzymes, and gene- and cell-based therapeutics for the treatment of multiple pathological conditions.

Modeling and optimization of phospholipase A1-catalyzed hydrolysis of phosphatidylcholine using response surface methodology for lysophosphatidylcholine production.

Modeling the phospholipase A1 (PLA1 )-catalyzed partial hydrolysis of soy phosphatidylcholine (PC) in hexane for the production of lysophosphatidylcholine (LPC) and optimizing the reaction conditions using response surface methodology were described. The reaction was performed with 4 g of PC in a stirred batch reactor using a commercial PLA1 (Lecitase Ultra) as the biocatalyst. The effects of temperature, reaction time, water content, and enzyme loading on LPC and glycerylphosphorylcholine (GPC) content in the reaction products were elucidated using the models established. Optimal reaction conditions for maximizing the LPC content while suppressing acyl migration, which causes GPC formation, were as follows: temperature, 60°C; reaction time, 3 h; water content, 10% of PC; and enzyme loading, 1% of PC. When the reaction was conducted with 40 g of PC under these conditions, the reaction products contained 83.7 mol % LPC and were free of GPC. LPC had a higher total unsaturated fatty acid content than original PC had and was mainly composed of linoleic acid (78.0 mol % of the total fatty acids).