Improvement of Solubility and Oral Bioavailability of Rutin by Complexation with 2-Hydroxypropyl-β-cyclodextrin

Abstract

The object of this study was to enhance the solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The interaction of rutin with cyclodextrins (CyDs) was evaluated by the solubility, and ultraviolet (UV) and circular dichroism (CD) spectrophotometries. The chemical and enzymatic stability of rutin was examined in an alkaline buffer solution and in rat small intestinal homogenates, respectively. Dissolution rates of rutin and its CyD complexes were measured by the dispersed amount method. In vivo absorption studies of rutin after oral administration via conventional tablet containing rutin alone or its beta-CyD complexes was performed on beagle dogs. The stability constants calculated from the phase solubility method increased in the order of HP-gamma-CyD < G2-beta-CyD < beta-CyD < HP-beta-CyD. Spectroscopic studies also revealed that HP-beta-CyD and beta-CyD formed a relatively more stable inclusion complex with rutin. The dissolution rates of rutin increased by the complexation with CyDs in the order of rutin alone < HP-beta-CyD < or = beta-CyD. HP-beta-CyD inhibited the hydrolysis of rutin in the alkaline buffer solution and the small intestinal homogenates of rats, suggesting that HP-beta-CyD may stabilize rutin in a gastrointestinal tract after oral administration. When the tablet containing rutin or its beta-CyD complexes was administered to beagle dogs, the plasma levels of homovanillic acid (HVA) (a major stable metabolite of rutin) after oral administration of HP-beta-CyD complex were much higher than in either that of rutin alone or in its beta-CyD complex. The in vivo absorption study suggests that HP-beta-CyD increased the oral bioavailability of rutin from the gastrointestinal tracts of beagle dogs because of the increase in solubility, faster dissolution rate, and gastrointestinal stability. HP-beta-CyD has a significant advantage with respect to providing high aqueous solubility while maintaining a lack of toxicity in oral pharmaceutical preparations of rutin.

Cyclodextrin: A Promising Candidate in Enhancing Oral Bioavailability of poorly Water Soluble Drugs

“…Hence, the results showed that the prepared apigenin-hydroxypropyl-β-cyclodextrin inclusion complex serves as a potential approach for new oral therapeutic agent formulation. 19 Miyake et al 39 improved solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-β-cyclodextrin. The in vivo absorption study revealed that hydroxypropyl-β-cyclodextrin increased the oral bioavailability of rutin from the gastrointestinal tracts due to increase in solubility, faster dissolution rate, and gastrointestinal stability.…”

Solid self-nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of glimepiride: development and antidiabetic activity in albino rabbits

“…In these drugs, dissolution of the drug is the rate limiting step in the absorption process. To triumph over these obstacles, numbers of formulation approaches are reported including the use of surfactants (Allaboun et al, 2003;Balakrishnan et al, 2004;Chakraborty et al, 2009), lipids (Yeap et al, 2013), permeation enhancers (Burcin et al, 2010;Beg et al, 2011), formation of salt (Li et al, 2005;Serajuddin, 2007), co-crystallization (Shan & Zaworotko, 2008;Qiao et al, 2011;Chadha et al, 2012), solid dispersions (Serajuddin, 1999), inclusion complexes with cyclodextrins and modified cyclodextrins (Miyake et al, 2000;Veiga et al, 2000;Wang et al, 2000;Bannwart et al, 2001;Carrier et al, 2007;Gamsiz et al, 2010a,b;Gamsiz et al, 2011;Badr-Eldin et al, 2008;Kumar et al, 2013), nanosuspensions (Patravale et al, 2004), and colloidal vesicles like liposomes (Nazzal et al, 2002a;Manconi et al, 2013;Yang et al, 2013), and niosomes (Khazaeli et al, 2007;Bayindir & Yuksel, 2010;SezginBayindir et al, 2013;Jin et al, 2013) In modern years, self-nanoemulsifying drug delivery systems (SNEDDS) are the most popular and commercially feasible lipid-based formulation approach for improving oral bioavailability of poorly water soluble and lipophilic drugs (Pouton, 2006;Date, 2007;Shweta et al, 2011). SNEDDS are precisely defined as an isotropic multi-component drug delivery systems composed of a synthetic or natural oil, surfactant, and co-surfactant that have a unique ability of forming fine oil in water micro-or nano-emulsion upon mild agitation followed by dilutio...…”

Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble grapefruit flavonoid Naringenin: design, characterization,in vitroandin vivoevaluation

“…Various strategies have been used to overcome the problems associated with oral absorption and bioavailability issues of poorly soluble drugs, such as particle size reduction (Aungst, 1993), complexation with cyclodextrins (Miyake et al, 2000), salt formation, solid dispersions (Sinha et al, 2010), use of surfactant, nanoparticles, nanocarriers (Bali et al, 2011), Nanoemulsions , self-emulsifying drug delivery system , prodrug formation, etc. Approaches used in past to improve the dissolution and bioavailability of NRG include complexation with b-cyclodextrin (Tommasini et al, 2004), phospholipid complexes (Semalty et al, 2010), solid dispersion with PVP (Kanaze et al, 2006), etc.…”