Date Published: September 16, 2019
Publisher: Springer International Publishing
Author(s): Géza Jakab, Dóra Bogdán, Károly Mazák, Ruth Deme, Zoltán Mucsi, István M. Mándity, Béla Noszál, Nikolett Kállai-Szabó, István Antal.
Baicalin is a flavone glycoside extracted from Scutellaria baicalensis, a traditional Chinese herbal medicine. Numerous pharmacological effects of baicalin were reported (e.g. antioxidant, anxiolytic); nevertheless, the most important physicochemical properties influencing the pharmacokinetic behaviour and the concomitant oral bioavailability have not yet been described in a comprehensive study. The aim of this project was to characterize the acid-base, lipophilicity, biorelevant solubility and permeability properties of the drug substance and providing scientific data to support the dosage form design. Another important objective was the comparative evaluation of six various baicalin-cyclodextrin (CD) inclusion complexes along with the creation of a suitable Drug Delivery System (DDS) for this BCS IV drug. Biorelevant profiling was carried out by NMR-pH titrations, saturation shake-flask and distribution coefficients (logP) measurements, while CD inclusion studies were fulfilled by experimental methods (phase solubility, 1H/13C NMR, 2D ROESY) and computational approaches. Due to low aqueous solubility (67.03 ± 1.60 μg/ml) and low permeability (Papp = 0.037 × 10−6 cm/s), baicalin is classified as BCS IV. The γ-CD complexation significantly increased the solubility of baicalin (~ 5 times). The most promoted chemical shift change occurred in baicalin-γ-CD complex. Computational studies showed disparate binding pattern for baicalin in case of β- and γ-CD; furthermore, the calculated complexation energy was − 162.4 kJ mol−1 for β-CD, while it was significantly stronger for γ-CD (− 181.5 kJ mol−1). The physicochemical and structural information of baicalin and its CD complexes introduced herein can create molecular basis for a promising DDS with enhanced bioavailability containing a bioactive phytopharmacon.
Scutellaria baicalensis Georgi (S. baicalensis G.) is one of the most elemental herbs in traditional Chinese herbal medicine known as Huang Qin . The root is officially listed in the Chinese Pharmacopoeia and was assumed in European Pharmacopoeia (Ph.Eur.) 9th Edition last year . The major bioactive components in the dried root are baicalin (7-D-glucuronic acid-5,6-dihydroxyflavone) and its aglycone, baicalein (5,6,7-trihydroxyflavone) . Baicalin has attracted increasing scientific attention because of its various pharmacological activities such as antioxidant, antitumor, anti-inflammatory and hepatoprotective effects [4, 5].
In this paper, the detailed physicochemical characterization of baicalin was demonstrated, which provided valuable information to design the proper formulation and delivery route for this BCS IV active phytopharmaceutical ingredient. Low bioavailability could be overcame by cyclodextrin complexation; therefore, six different derivates were examined to study solubility enhancement along with stability and geometry of inclusion complex. Molecular modelling analysis pointed out different binding patterns and complexation energy for each baicalin-CD complex. In accordance with our previous hypothesis, thermodynamically the most favourable complex proved to be baicalin-γ-CD host-guest complex (ΔE = − 181.5 kJ mol−1), in which fact was confirmed by phase-solubility (≈ 5.5 times solubility enhancement) and NMR spectroscopic measurements. The demonstrated theoretical and experimental methods could be adopted in the formulation development and analysis cyclodextrins containing neutral drugs. The future research direction is the solidification and optimization of baicalin-γ-CD inclusion complex and the phytopharmacological investigation in a Drug Delivery System.