Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-ß-Cyclodextrin and Hydrophilic Auxiliary Substances.

The purpose of this study was to improve the aqueous solubility, dissolution, and pharmacodynamic properties of a BCS class II drug, ezetimibe (Eze) by preparing ternary cyclodextrin complex systems. We investigated the potential synergistic effect of two novel hydrophilic auxiliary substances, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and L-ascorbic acid-2-glucoside (AA2G) on hydroxypropyl-ß-cyclodextrin (HPBCD) solubilization of poorly water-soluble hypocholesterolemic drug, Eze. In solution state, the binary and ternary systems were analyzed by phase solubility studies and Job's plot. The solid complexes prepared by freeze-drying were characterized by Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and scanning electron microscopy (SEM). The log P values, aqueous solubility, dissolution, and antihypercholesterolemic activity of all systems were studied. The analytical techniques confirmed the formation of inclusion complexes in the binary and ternary systems. HPBCD complexation significantly (p < 0.05) reduced the log P and improved the solubility, dissolution, and hypocholesterolemic properties of Eze, and the addition of ternary component produced further significant improvement (p < 0.05) even compared to binary system. The remarkable reduction in log P and enhancement in solubility, dissolution, and antihypercholesterolemic activity due to the addition of TPGS or AA2G may be attributed to enhanced wetting, dispersibility, and complete amorphization. The use of TPGS or AA2G as ternary hydrophilic auxiliary substances improved the HPBCD solubilization and antihypercholesterolemic activity of Eze.

Preparation and pharmacodynamic assessment of ezetimibe nanocrystals: Effect of P-gp inhibitory stabilizer on particle size and oral absorption.

Drug nanocrystals have been widely accepted as potent formulations to overcome poor solubility, dissolution and bioavailability problems of hydrophobic drugs. The present study aimed to develop drug nanocrystals of ezetimibe (Eze), a model BCS class II and hypocholesterolemic drug using bottom up precipitation methods. D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), and L-ascorbic acid-2-glucoside (AA2G), were the two stabilizers whose potential in developing Eze nanocrystals was investigated. Particle size and zeta potential portrayed the potential of both the stabilizers in producing Eze nanocrystals. The optimized nanocrystal formulations were evaluated for in-vitro solubility, dissolution, solid state characters and in-vivo pharmacodynamic performance. The nanocrystal formulations remarkably increased the solubility of the drug (p<0.05 compared to pure drug). Pure drug could not dissolve more than 28.9% during the 60 min dissolution study whereas the drug nanocrystals prepared with AA2G and TPGS presented t90% at 41.33 ± 2.58 and 16.07 ± 2.32 min, respectively. The PXRD and DSC studies confirmed the retention of crystallinity and the SEM images indicated lack of aggregation in dried nanocrystals. The TPGS nanocrystals presented significantly superior pharmacodynamic activity upon oral administration. The current study corroborated TPGS nanocrystals to be a promising choice of formulation for the oral delivery of Eze.

Drug nanocrystals: four basic prerequisites for formulation development and scale-up.

Drug nanocrystals have been studied since the 1990s and there are already six therapeutic nanocrystal products on market and many more in clinical trials. Nanocrystals are encapsulating-carrier free nanoparticles wherein 100% drug loading could be achieved. This signifies that nanocrystals, among other nanoparticulate products, could be more easily manufactured even at the initial formulation development stages to evaluate the effect of size reduction on the bioavailability of drugs. Additionally, a drug nanocrystal is considered not as a generic product but as a "new drug" by FDA. Process characterization, equipment choice, robust formulation and stability are discussed as four basic prerequisites for formulation development and scale-up of drug nanocrystals. The fast growing and relatively superior market profile of nanocrystals amongst other nanoparticle systems is due to their rational formulation design and production simplicity. In this emerging scenario, keeping an eye on the four basic prerequisites can further improve the success of drug nanocrystals.

Overview of P-glycoprotein inhibitors: a rational outlook

P-glycoprotein (P-gp), a transmembrane permeability glycoprotein, is a member of ATP binding cassette (ABC) super family that functions specifically as a carrier mediated primary active efflux transporter. It is widely distributed throughout the body and has a diverse range of substrates. Several vital therapeutic agents are substrates to P-gp and their bioavailability is lowered or a resistance is induced because of the protein efflux. Hence P-gp inhibitors were explored for overcoming multidrug resistance and poor bioavailability problems of the therapeutic P-gp substrates. The sensitivity of drug moieties to P-gp and vice versa can be established by various experimental models in silico, in vitro and in vivo. Ever since the discovery of P-gp, the research plethora identified several chemical structures as P-gp inhibitors. The aim of this review was to emphasize on the discovery and development of newer, inert, non-toxic, and more efficient, specifically targeting P-gp inhibitors, like those among the natural herb extracts, pharmaceutical excipients and formulations, and other rational drug moieties. The applications of cellular and molecular biology knowledge, in silico designed structural databases, molecular modeling studies and quantitative structure-activity relationship (QSAR) analyses in the development of novel rational P-gp inhibitors have also been mentioned.

Glicoproteína-p (P-gp), uma glicoproteína de transmembrana permeável, é um membro da superfamília (ABC) de cassete de gene de ligação de ATP que funciona especificamente como um carreador mediado pelo transportador de efluxo ativo primário. É amplamente distribuído por todo o corpo e apresenta uma gama diversificada de substratos. Diversos agentes terapêuticos vitais são substratos para P-gp e sua biodisponibilidade é reduzida ou a resistência é induzida devido ao efluxo de proteínas. Portanto, os inibidores da P-gp foram explorados para a superação da resistência a múltiplas drogas e problemas de biodisponibilidade deficiente dos substratos terapêuticos da P-gp. A sensibilidade das moléculas da droga à P-gp e vice-versa, pode ser estabelecida por vários modelos experimentais in silico, in vitro e in vivo. Desde a descoberta da P-gp, diversas pesquisas identificaram várias estruturas químicas como inibidores da P-gp. O objetivo deste presente estudo foi o de enfatizar a descoberta e desenvolvimento de inibidores mais novos, inertes, atóxicos e mais eficazes, visando especificamente os da P-gp, como aqueles entre os extratos vegetais, excipientes e formulações farmacêuticas, e outras moléculas racionais de droga. As aplicações do conhecimento de biologia celular e molecular, bancos de dados estruturais in silico, estudos de modelagem molecular e análises da relação quantitativa estrutura-atividade (QSAR) no desenvolvimento de novos inibidores racionais da P-gp também foram mencionados.