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As a BCS IV drug, ursolic acid (UA) has low oral bioavailability mainly because of its poor aqueous solubility/dissolution, poor permeability, and metabolism by cytochrome P450 (CYP) isozymes, such as CYP3A4. Most UA preparations demonstrated a much higher dissolution than that of its crystalline form yet a low drug concentration in plasma due to their lower consideration or evaluation for the permeability and metabolism issues. In the current study, a supramolecular coamorphous system of UA with piperine (PIP) was prepared and characterized by powder X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy. In comparison to crystalline UA and UA in physical mixture, such coamorphous system enhanced solubility (5.3-7-fold in the physiological solution) and dissolution (7-8-fold in the physiological solution within 2 h) of UA and exhibited excellent physical stability under 90-day storage conditions. More importantly, the pharmacokinetic study of coamorphous UA in rats exhibited 5.8-fold and 2.47-fold improvement in AUC 0-∞ value, respectively, compared with its free and mixed crystalline counterparts. In order to further explore the mechanism of such improvement, the molecular interactions of a coamorphous system in the solid state were investigated. Fourier transform infrared spectroscopy, solid-state 13 C nuclear magnetic resonance spectroscopy, and density functional theory modeling suggested that intermolecular hydrogen bonds with strong interactions newly formed between UA and PIP after coamorphization. The in vitro permeability studies across Caco-2 cell monolayer and metabolism studies by rat hepatic microsomes indicated that free PIP significantly increased the permeability of UA and inhibited the enzymatic metabolism of UA by CYP3A4. However, PIP in the coamorphous combination exhibited a much lower level in the bioenhancing than its free form arising from the synchronized dissolution characteristic of the preparation (only 60% of PIP released in comparison to its free counterpart in 2 h). The in situ loop study in rats proposed that the acid-sensitive dissolution in the stomach of the coamorphous preparation helped to improve the effective free drug concentration, thereby facilitating PIP to play its role in bioenhancing. The current study offers an exploratory strategy to overcome poor solubility/dissolution, poor permeability, and metabolism by cytochrome P450 isozymes of the BCS IV drug to improve its oral bioavailability.

Parkinson's disease (PD) is the most widespread form of dementia where there is an age related degeneration of dopaminergic neurons in the substantia nigra region of the brain. Accumulation of α-synuclein (αS) protein aggregate, mitochondrial dysfunction, oxidative stress, and neuronal cell death are the pathological hallmarks of PD. In this context, amalgamation of curcumin and piperine having profound cognitive properties, and antioxidant activity seems beneficial. However, the blood-brain barrier (BBB) is the major impediment for delivery of neurotherapeutics to the brain. The present study involves formulation of curcumin and piperine coloaded glyceryl monooleate (GMO) nanoparticles coated with various surfactants with a view to enhance the bioavailability of curcumin and penetration of both drugs to the brain tissue crossing the BBB and to enhance the anti-parkinsonism effect of both drugs in a single platform. In vitro results demonstrated augmented inhibition of αS protein into oligomers and fibrils, reduced rotenone induced toxicity, oxidative stress, and apoptosis, and activation of autophagic pathway by dual drug loaded NPs compared to native counterpart. Further, in vivo studies revealed that our formulated dual drug loaded NPs were able to cross BBB, rescued the rotenone induced motor coordination impairment, and restrained dopaminergic neuronal degeneration in a PD mouse model.

Nanotechnology-based drug products are emerging as promising agents to enhance the safety and efficacy of established chemotherapeutic molecules. Carbon nanotubes (CNTs), especially multiwalled CNTs (MWCNTs), have been explored for this potential owing to their safety and other desired attributes. Docetaxel (DTX) is an indispensable anticancer agent, which has wide applicability in variety of cancers. However, the potential of DTX is still not completely harvested due to problems like poor aqueous solubility, low tissue permeability, poor bioavailability, high first pass metabolism, and dose-related toxicity. Hence, it was proposed to attach DTX to MWCNTs and coadminister it along with piperine with an aim to enhance the tissue permeation, anticancer activity, and bioavailability. The Fourier transform infrared, UV, and NMR spectroscopic data confirmed successful conjugation of DTX to MWCNTs and adsorption of piperine onto MWCNTs. The codelivery MWCNT-based system offered drug release moderation and better cancer cell toxicity than that of plain DTX as well as DTX-CNT conjugate. The pharmacokinetic profile of DTX was exceptionally improved by the conjugation, in general, and coadministration with piperine, in specific vis-à-vis plain drug. Hence, the dual approach of MWCNTs conjugation and piperine coadministration can serve as a beneficial option for enhancement of the performance of DTX in cancer chemotherapy.