title: Drug solubilization mechanism of α-glucosyl stevia by NMR spectroscopy.
abstract: We investigated the drug solubilization mechanism of α-glucosyl stevia (Stevia-G) which was synthesized from stevia (rebaudioside-A) by transglycosylation. (1)H and (13)C NMR peaks of Stevia-G in water were assigned by two-dimensional (2D) NMR experiments including (1)H-(1)H correlation, (1)H-(13)C heteronuclear multiple bond correlation, and (1)H-(13)C heteronuclear multiple quantum coherence spectroscopies. The (1)H and (13)C peaks clearly showed the incorporation of two glucose units into rebaudioside-A to produce Stevia-G, supported by steviol glycoside and glucosyl residue assays. The concentration-dependent chemical shifts of Stevia-G protons correlated well with a mass-action law model, indicating the self-association of Stevia-G molecules in water. The critical micelle concentration (CMC) was 12.0 mg/mL at 37°C. The aggregation number was 2 below the CMC and 12 above the CMC. Dynamic light scattering and 2D (1)H-(1)H nuclear Overhauser effect spectroscopy (NOESY) NMR experiments demonstrated that Stevia-G self-associated into micelles of a few nanometers in size with a core-shell structure, containing a kaurane diterpenoid-based hydrophobic core and a glucose-based shell. 2D (1)H-(1)H NOESY NMR measurements also revealed that a poorly water-soluble drug, naringenin, was incorporated into the hydrophobic core of the Stevia-G micelle. The Stevia-G self-assembly behavior and micellar drug inclusion capacity can achieve significant enhancement in drug solubility.
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan; School of Traditional Chinese Medicine, China Pharmaceutical University, 24, Tongjiaxiang, Nanjing, 210009, China.
authors: Junying
authors: J
authors: Zhang
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan.
authors: Kenjirou
authors: K
authors: Higashi
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan.
authors: Keisuke
authors: K
authors: Ueda
authors: Osaka University of Pharmaceutical Sciences, 4-20-1, Nasahara, Takatsuki, Osaka, 569-1094, Japan.
authors: Kazunori
authors: K
authors: Kadota
authors: Osaka University of Pharmaceutical Sciences, 4-20-1, Nasahara, Takatsuki, Osaka, 569-1094, Japan.
authors: Yuichi
authors: Y
authors: Tozuka
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan; Department of Manufacturing Pharmacy, Faculty of Pharmacy, Mahidol University, 447 Sri Ayudhya Road, Ratchatewi, Bangkok, 10400, Thailand.
authors: Waree
authors: W
authors: Limwikrant
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan.
authors: Keiji
authors: K
authors: Yamamoto
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan. Electronic address: moribe@faculty.chiba-u.jp.
authors: Kunikazu
authors: K
authors: Moribe
mesh_terms: D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045786:Diterpenes, Kaurane / Q000138:chemical synthesis / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry*; D044950:Flavanones / Q000737:chemistry*; D005960:Glucosides / Q000138:chemical synthesis / Q000737:chemistry*; D008823:Micelles; D053758:Nanoparticles; D010316:Particle Size; D066244:Proton Magnetic Resonance Spectroscopy; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*; D014867:Water / Q000737:chemistry*
chemical_list: D045786:Diterpenes, Kaurane; D005079:Excipients; D044950:Flavanones; D005960:Glucosides; D008823:Micelles; D014867:Water; C005273:naringenin
keywords: Aggregation number; Drug solubility improvement; Micelle; Nuclear Overhauser effect spectroscopy; Nuclear magnetic resonance; α-Glucosyl stevia