Original Research PaperUtilizing spray drying technique to improve oral bioavailability of apigenin
Graphical abstract
Introduction
Apigenin is a bioflavonoid that is found in most fruits and vegetables (Fig. 1a) [1]. It is available, in nature, as a dimer that is mainly isolated form the flower of Hypericum perforalum [2]. Apigenin available commercially as light yellow crystals and has shown anti-inflammatory, anti-carcinogenic, antibiotic, anti-viral, antidiabetic, and anti-oxidant properties [3], [4], [5], [6]. There was much interest in carcinogenesis, which is the early development of cancer, and dietary management to interfere with such process, which is considered a cancer chemoprevention therapy [7], [8].
The clinical benefits of apigenin have drawn the attention of the pharmaceutical industry. However, apigenin belongs to biopharmaceutical classification system (BCS) class II, which features low solubility and high permeability. It is a weak acid with solubility of 1.43, 1.56, and 2.16 μg/mL in pH 1.0, 6.8, and 7.5, respectively [9]. Apigenin has major ionization step with pKa at C7-OH of 7.86 and reported aqueous solubility of <2 μg/mL [10], [11], [12]. Several factors affect apigenin solubility including; particle size, selected solvent, pH, and temperature [13]. Furthermore, low oral bioavailability in animal model was reported [14]. Thus, one needs to overcome different barriers for successful apigenin delivery.
Pluronic F-127 (PL F-127), which is known as poloxamer 407, is a synthetic amphiphilic copolymer of ethylene oxide and propylene oxide at ratio of (PEO101-PPO56-PEO101). Polypropylene oxide form the hydrophobic core, whereas, polyethylene oxide represent the hydrophilic component. Hydrogen bonding between the ether group of the polymer and water molecules is mainly responsible for the polymer aqueous solubility. PL F-127 form micelles when the critical micelle concentration is reached. At high poloxamer concentrations, micelles are closely packed leading to gel-like behavior [15], [16]. In previous studies, PL F-127 was used extensively to improve the wettability, overall solubility, and bioavailability of different active pharmaceutical ingredients (APIs) [17], [18], [19].
Different techniques are used to provide solid dispersion system. Selecting a suitable polymeric carrier is critical to resist the crystallization of already amorphous API. The thermodynamic solubility of any API in the selected polymer should not be exceed [20]. Dissolving both API and carrier in mutual organic solvent makes it possible to spray dry the formulation. Spray drying of poorly soluble drugs is common in the pharmaceutical arena. However, the stability of high energy amorphous state of any API still the outmost challenge [21]. Other factors should be carefully considered during spray drying such as; viscosity of the solution, volatility of the selected solvent, feeding rate, thermal stability, and toxicity of the residual solvent amount.
Apigenin was formulated as nanocrystal using supercritical fluid, self-microemulsifying drug delivery system, complexation with β-cyclodextrin, and apigenin-phospholipid phytosome to improve the in vitro/ in vivo characteristics [11], [22], [23], [24]. However, for the authors spray drying technique was not utilized for apigenin in the literature. Therefore, in this study, an apigenin-PL F1-27 solid dispersion prepared using spray drying technique was investigated for the morphology, chemical interactions, thermal stability, crystallinity state, in vitro release profile, and the bioavailability in animal model.
Section snippets
Materials
Apigenin (Fig. 1a) was obtained from Beijing Mesochem Technology Co., Ltd (Beijing, China). Poloxamer (F-127, PL F-127) (Fig. 1b) was obtained from BASF (Ludwigshafen, Germany). HPLC grade methyl alcohol (methanol) and ethyl alcohol (ethanol) were obtained from Sigma Aldrich (St. Louis, MO, USA).
Solid dispersion formation using spray drying
Apigenin with PL F-127 were prepared in drug:polymer mass ratios of 1:1, 1:2, and 1:4. Each drug with the polymer, at the selected mass ratio, was dissolved in 500 ml of ethanol. Continuous stirring was
Solid dispersion formation and apigenin content
We have investigated the solubility of apigenin in different solvents including water. The solubility for apigenin at 25 °C was found to be 0.02, 1.2, and 1.6 mg/g for water, methanol, and ethanol, respectively [12]. Water is an excellent solvent when used for spray drying due to its high surface tension. In addition, organic solvents, alone or as cosolvents, are commonly used due to the lack of sufficient solubility in the aqueous media for most of the drugs. When the solution is sprayed
Conclusion
This work reveals the importance of solid dispersion techniques to improve BCS II drugs. Apigenin lacks sufficient aqueous solubility and proves that dissolution is the rate-limiting step. Spray drying technique was employed successfully to render a complete amorphous form. The selection of appropriate drug:polymer ratio is crucial for successful amorphous formation. Formulated apigenin showed much faster dissolution rate compared to the pure apigenin. PL F-127 significantly improved the
Acknowledgements
The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding the research through research group project number RGP-1438-013.
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