Atorvastatin calcium inclusion complexation with polysaccharide arabinogalactan and saponin disodium glycyrrhizate for increasing of solubility and bioavailability

Abstract

The aim of the present investigation was to enhance the solubility and dissolution of atorvastatin calcium (ATV), a poorly water-soluble drug with larch polysaccharide arabinogalactan (AG) and disodium glycyrrhizate (NaGA) as carriers of drug delivery systems for improving its bioavailability. The interactions of ATV with AG or NaGA were investigated by DSC, XRD, SEM, and NMR techniques. The molecular weights of supramolecular systems-inclusion complexes and micelles-which are the hosts for ATV molecules were measured. On the other hand, the rapid storage assay (+ 40 °C for 3 months) showed that the chemical stability of ATV/AG and ATV/NaGA complexes had been enhanced compared with pure ATV. In vitro drug release showed a significant increase in ATV's dissolution rate after formation of a complex with NaGA or AG. Pharmacokinetic tests in vivo on laboratory animals showed a significant increase in ATV's bioavailability after its introduction as a complex with NaGA or AG. Moreover, ATV/AG and ATV/NaGA complexes showed a more prominent decrease of total cholesterol (TC) level compared to net ATV. Therefore, the novel mechanochemically synthesized complexes of ATV with AG or NaGA as drug delivery systems might be potential and promising candidates for hypercholesterolemia treatment and deserved further researches.

Solubility, Permeability, Anti-Inflammatory Action and In Vivo Pharmacokinetic Properties of Several Mechanochemically Obtained Pharmaceutical Solid Dispersions of Nimesulide

“…In the present study the NMR relaxation technique was applied to prove the formation of NIM inclusion complexes after dissolution of SD in aqueous solutions. Earlier we have shown that the spin-spin nuclear relaxation time T 2 of a drug molecules (carotenoids lutein and zeaxanthin [48], pesticides [49][50][51], anthelmintic drugs albendazole and praziquantel [10,12,44], curcumin [43,52], atorvastatin and simvastatin [42,53], and others [54]) is extremely sensitive to the mobility of the molecules in solution. Formation of inclusion complex with AG, GA or CDs results in a decrease of the diffusion mobility of molecules and leads to decrease in the observed relaxation time of corresponding protons.…”

“…Glycyrrhizic acid (GA) is a triterpene glycoside extracted from licorice root that demonstrates antiviral, anti-inflammatory, and anticancer properties [37,38]. Due to its amphiphilic properties, GA is capable of forming complexes and micelles [39] with a variety of hydrophobic molecules, substantially increasing their solubility, enhancing the permeability of drugs through cell membranes and their bioavailability [12,[40][41][42][43][44][45][46]. In addition, disodium glycyrrhizin (Na 2 GA) is a salt of GA which can undergo hydrolysis in aqueous solutions and form free GA. Its advantage is that the solution formed has lower viscosity in contrast with GA solutions as far as its potassium salts are concerned.…”

Current Evidence, Challenges, and Opportunities of Physiologically Based Pharmacokinetic Models of Atorvastatin for Decision Making

“…Solubility values in aqueous media for the amorphous and crystalline forms at 37 °C are 0.11–0.12 mg/mL in water, 0.01 mg/mL in HCl 0.1 N, and 0.72 and 0.70 mg/mL in sodium phosphate 0.05 M pH 7.4, respectively [ 16 ]. Great efforts have been performed to improve ATS oral bioavailability through formulation strategies to increase the solubility and/or dissolution rate of ATS-Ca such as micronization by antisolvent precipitation [ 15 ], microcapsulation [ 17 ], co-grinding techniques [ 18 ], co-amorphous formulations with nicotinamide [ 19 ], dry emulsions [ 13 ], inclusion complexes [ 20 ], and use of drug resinates [ 21 ]. Since ATS is administered mainly as the calcium salt, low solubility in the gastrointestinal (GI) tract should be considered in order to assess its PK characteristics.…”

“…However, the involvement of P-gp in ATS PK has been demonstrated in humans due to the polymorphisms in ABCB1 genotypes, thus suggesting that P-gp affects the enterohepatic recirculation of ATS [ 50 ]. Additionally, ATS is currently considered as a BCS class II (low solubility, high permeability), and many efforts have been made to increase its bioavailability enhancing its solubility [ 14 , 17 , 20 , 71 , 72 ]. For these reasons, solubility and P-gp activity become essential in ATS absorption and disposition.…”

Supramolecular Carotenoid Complexes of Enhanced Solubility and Stability—The Way of Bioavailability Improvement

“…Arabinogalactan is biodegradable, biocompatible and hydrophilic, contains different functional groups such as hydroxyl, carboxylic acid, that make it ideal for conjugation and delivery of carotenoids and drug molecules. There are many examples of increased solubility of hydrophobic drugs in the complexes with AG [72,73,74]. Some recent studies indicate also that AG has good adhesion to membrane surface, and is able to enhance the membrane permeability for both human and plant cell membranes [21,75].…”