Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles
© Dian et al.; licensee Springer. 2014
Received: 28 October 2014
Accepted: 9 December 2014
Published: 18 December 2014
To improve its poor aqueous solubility and stability, the potential chemotherapeutic drug quercetin was encapsulated in soluplus polymeric micelles by a modified film dispersion method. With the encapsulation efficiency over 90%, the quercetin-loaded polymeric micelles (Qu-PMs) with drug loading of 6.7% had a narrow size distribution around mean size of 79.00 ± 2.24 nm, suggesting the complete dispersibility of quercetin in water. X-ray diffraction (XRD) patterns illustrated that quercetin was in amorphous or molecular form within PMs. Fourier transform infrared spectroscopy (FTIR) indicated that quercetin formed intermolecular hydrogen bonding with carriers. An in vitro dialysis test showed the Qu-PMs possessed significant sustained-release property, and the formulation was stable for at least 6 months under accelerated conditions. The pharmacokinetic study in beagle dogs showed that absorption of quercetin after oral administration of Qu-PMs was improved significantly, with a half-life 2.19-fold longer and a relative oral bioavailability of 286% as compared to free quercetin. Therefore, these novel soluplus polymeric micelles can be applied to encapsulate various poorly water-soluble drugs towards a development of more applicable therapeutic formulations.
Oral administration is by far the easiest and most acceptable route of drug delivery, especially for the long-term medication of patients . But about 40% of the approved active molecules have low solubility, resulting in poor oral bioavailability. Many efforts have been devoted to the development of oral sustained-release systems that can not only improve drug bioavailability leading to better efficacy and less administration frequencies but also decrease the fluctuation of plasma drug concentration to lower side effects . In recent decades, emerging nanotechnology provides a novel platform to solve the solubility problem of drugs [3, 4]. Especially, polymeric micelles as a promising drug delivery system is a new research hotspot , most current studies concentrated on developing polymeric micelles for injection drug delivery . Drug-loaded micelles in the systemic circulation characterizes long retention time and excellent tissue permeability and can gather in the diseased tissue to gain passive targeting [7, 8]. Furthermore, polymeric micelles with stable, biocompatible, and solubilizing properties have drawn considerable attention for oral administration.
Polymeric micelles with inner ‘core’ and outer ‘shell’ are formed by amphiphilic copolymers composed of hydrophilic and hydrophobic chains that can self-assemble in water above the critical micelle concentration (CMC) . A polymeric micelle has the ability to encapsulate a hydrophobic drug into their cores and deliver the drug to the desired site at the concentration exceeding the intrinsic solubility of the drug. Moreover, the encapsulated drug can be not only protected from contact with the GI contents which likely induce degradation and metabolism but also conferred with the characteristics of sustained-release and direct uptake by cells. Many studies have proven that nanoparticles can transport across the intestinal membrane through paracellular or trancellular routes , while maintaining their integrity . Therefore, the oral formulation based on nanosized polymeric micelles was expected to achieve the advantages of nanoparticles, such as enhanced permeability and retention (EPR) effects.
But clinical use of quercetin is limited due to its poor water solubility and instability in physiological media , leading to poor bioavailability . Polymeric micelles are regarded as excellent candidates for anticancer drug delivery, and several anticancer drugs delivered by amphiphilic polymer micelles have already been preceded to clinical study or market [23, 24]. Recently, polymer micelles have been utilized for quercetin formulation too .
Soluplus, an amphiphilic polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Figure 1B), was introduced by BASF. This graft copolymer has a polyethylene glycol (PEG) backbone as hydrophilic part and vinylcaprolactam/vinyl acetate side chains as lipophilic structure. So, micelles can be formed in aqueous solution above the CMC of 7.6 mg · L-1 (Figure 1C) .
The objective of this study was to develop a nanomicelle delivery system by using soluplus and poloxamer 407(F127), which could solubilize quercetin in aqueous media, reaching the clinically relevant concentration and delivering quercetin in a controlled manner. The previously reported preparation method was slightly modified to produce soluplus micelles with suitable size, charge, and stable properties. Powder X-ray diffraction (XRD) was employed to identify the physical state of quercetin in the polymeric micelles. Taking advantage of their permeation-enhancing effect, the soluplus nanomicelles were evaluated in vivo as potential vehicles, and the pharmacokinetic profile of orally administered quercetin encapsulated in micelles was investigated.
Soluplus® was friendly supplied by BASF Auxiliary Chem. Co., Ltd. (Shanghai, China). Poloxamer 407 (PEO98POP67PEO98) was obtained from BASF (Ludwigshafen, Germany). Quercetin (Qu) was purchased from Shanxi Sciphar Biotech. Co. Ltd. (Shanxi, China). Methanol (high-performance liquid chromatography (HPLC) grade) was purchased from Fisher Scientific, Waltham, MA, USA. Milli-Q grade water purified through a Millipore system (ELGA LabWater, Sartorius, UK) was used throughout this study. All solvents were used without further purification.
Beagle dogs were obtained from Experimental Animal Center of Sun Yat-sen University (Guangzhou, China). Beagle dogs were provided with standard food and water at will and were exposed to alternating 12-h periods of light and darkness. Relative humidity and temperature were maintained at 50% and 25°C, respectively. All care and handling of animals were performed with the approval of Institutional Authority for Laboratory Animal Care of Sun Yat-sen University.
Preparation of quercetin-loaded soluplus polymeric micelles
Quercetin-loaded polymeric micelles (Qu-PMs) were formed by a modified film dispersion method using soluplus and F127. Briefly, soluplus (10 mg) and quercetin (7 mg) were dissolved together in organic solvent acetone, followed by evaporation under reduced pressure in a rotary evaporator at 35°C. The deionized water was then added into the polymer and drug solution, allowing the self-assembly of soluplus and quercetin to form quercetin-encapsulated polymeric micelles with core-shell structure (Figure 1C) at 650 rpm. Finally, the prepared Qu-PMs were lyophilized for future application.
Determining the optimum concentration of F127
Then the optimum concentration of F127 required for preparing the desirable Qu-PMs was determined based on particle size and encapsulation efficiency.
Determining the optimum stirring time
The optimum time of magnetic stirring for the preparation of Qu-PMs was determined on the basis of particle size and encapsulation efficiency.
Optimization of drug loading
Qu-PMs were prepared using different theoretical Qu loading, i.e., 5%, 7%, and 9% of polymer on the basis of preliminary experiment, to determine the optimum percentage of Qu in soluplus matrix and its effects on particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency of Qu-PMs. The magnetic stirring time (2 h), stabilizer concentration (1% of F127), and aqueous ratio were kept constant.
Characterization of Qu-PMs
Particle size and zeta potential measurements
The particle size and PDI of Qu-PMs were determined by using a Malvern Instruments Zetasizer Nano ZS90 (Malvern Instruments, Malvern, UK) on the basis of photon correlation spectroscopy. The dispersion of Qu-PMs was diluted in double distilled water and measured at 25°C for analysis. The particle size and PDI were obtained by cumulate analysis using the MALVERN software. The Zeta potential of Qu-PMs also measured by using a Malvern Instruments Zetasizer Nano ZS90 (Malvern Instruments, Malvern, UK). All experiments were repeated three times.
Transmission electron microscopy
The surface morphology of Qu-PMs was examined by using a transmission electron microscope (TEM; H66009IV, Hitachi, Chiyoda-ku, Japan). The dispersion of Qu-PMs were placed on a copper grid covered with nitrocellulose, negatively stained with phosphotungstic acid, and allowed to dry at room temperature.
The X-ray diffraction patterns of pure Qu, void PMs, physical mixture of void PMs and Qu, and Qu-PMs were obtained by using an X-ray powder diffractometer (Bruker AXS, Madison, WI, USA) at a voltage of 40 kV and 25 mA with a scanned angle from 5° ≤ 2θ ≤ 50° at a scan rate of 0.9 · min-1.
Fourier transform infrared spectrometer
The Fourier transform infrared spectroscopy (FTIR) spectra of Qu, void PMs, physical mixture of void PMs and Qu, and Qu-PMs were recorded on a Nicolet 5700 FTIR spectroscopy (Thermo, Waltham, MA, USA) using a Smart OMNI-sampler accessory. The samples were put on KBr plates. The FTIR spectra were recorded at 1 cm-1 resolution, with the range of 400 to 4,000 cm-1.
Encapsulation efficiency (EE)
The content of Qu encapsulated in PMs was determined by membrane filter method. 0.5 mL of Qu-PMs was filtered through the 0.22-μm membrane, while non-encapsulated Qu was retained on the membrane. The filtrate which contained Qu-PMs was demulsificated with methanol and analyzed for entrapped Qu content by high-performance liquid chromatography (HPLC). All experiments were repeated three times.
In vitro release
In vitro release of Qu from Qu-PMs was undertaken by the dialysis bag method . The dialysis bags (MWCO 14000, Millipore, Boston, MA, USA) were immersed in double-distilled water for 24 h prior to loading with 2 mL of Qu-PMs dispersion or quercetin solution (equivalent to 4 mg of Qu). The loaded bags were putted into a conical flask and soaked in 100 mL of 35% (v/v) ethanol, and the flask was placed in a water bath at 37°C ± 0.5°C and stirred rate of 100 rpm. The release medium (5 mL) was taken out at time intervals of 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0, 48.0, 72.0, 96.0, 120.0, 144.0, 168.0, 192.0, 216.0, 240 h and added with the same volume of fresh medium to adjust a sink condition [29, 30]. The content of Qu was determined by HPLC. Each test was carried out in triplicate.
To assess the stability of Qu-PMs, the freeze dried Qu-PMs were putted into 5-mL glass vials, sealed with plastic caps and placed in an accelerated stability chamber with temperature of 30°C ± 2°C and RH of 65% ± 5% for 6 months. The formulations were evaluated for changes in particle size, PDI, and entrapment efficiency, besides physical appearance and ease of reconstitution [31, 32].
In vivo pharmacokinetics study after oral administration
To compare the pharmacokinetics of Qu-PMs with those of pure Qu after oral administration, an animal experiment was in favor of the Ethical Committee of the Sun Yat-sen University (Guangzhou, China) and performed in accordance with the National Institute of Health and Nutrition Guidelines for the Care and Use of Laboratory Animals.
Six beagle dogs (1.2 to 2.0 years of age) weighing 12 to 14 kg were acclimatized in an environmentally controlled breeding room for 1 week, before fasting overnight before the experiments, but allowed to drink water only. These dogs were randomly distributed into two groups each made up of three dogs. Dogs in one group were given pure Qu dispersed in Milli Q water containing 0.3% (v/v) CMC-Na, while dogs in the other group were administered Qu-PMs dissolved in distilled water. All the formulations were administrated at an equivalent dose of Qu 16 mg · kg-1 by oral gavage. Blood samples of 3 mL were collected from the hind leg vein and placed into heparinized tubes at time intervals of 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 24.0, 36.0, and 48.0 h after oral administration. The plasma was segregated and the samples were kept at -20°C until analysis.
Qu was assayed using an HPLC method. In sample analysis, a 100 μL plasma sample aliquot was blended with protein-precipitating methanol agent (200 μL) and 0.25% HCL (100 μL) were added and vortexed for 2 min, then heated at 50°C for 10 min. After centrifugation at 12,000 rpm for 10 min, the supernatant was analyzed by HPLC. Qu analysis was carried out by injecting an aliquot (100 μL) of sample into the HPLC column (an odyssil C18 column, 4.6 × 250 mm, 5 μm) with a precolumn (4.6 × 12.5 mm, 5 μm), using a mobile phase making up of methanol 0.2% phosphoric acid (60:40, v/v) at a flow rate of 1.0 mL · min-1. The detection wavelength was 375 nm .
Pharmacokinetic parameters were estimated with one compartmental model using the 3P87 software (published by the State Food and Drug Administration of China for pharmacokinetic study). The Cmax (highest peak concentration), Tmax (the time at which Cmax reached), and the AUC0-∞ (the total area under the curve) were determined. The Mann-Whitney U-test was analyzed statistically. The results of the test were evaluated as mean values ± SD (standard deviation), and that of p < 0.05 analysis was significant statistically difference.
Results and discussion
Preparation of Qu-PMs
Different process variables including stabilizer concentration, magnetic stirring time, and theoretical drug loading were optimized for the preparation of Qu-PMs.
Effect of stabilizer concentration
Effect of stirring time
Optimum of drug loading
Effects of initial drug loading on size, PDI, zeta potential, and EE (mean ± SD, n = 3)
Drug loading (%)
59.97 ± 3.70
0.183 ± 0.023
-13.4 ± 0.20
93.24 ± 3.05
79.00 ± 2.24
0.154 ± 0.044
-17.10 ± 2.30
95.91 ± 4.05
111.2 ± 3.45
0.134 ± 0.082
-15.1 ± 1.60
75.06 ± 3.19
Properties of Qu-PMs
Particle size and morphology of Qu-PMs
Fourier transform infrared spectrometer
Storage stability studies
Characterization of freeze dried Qu-PMs with 5% mannitol after 6 months of storage at 30°C ± 0.5°C and 65% ± 5% RH (mean ± SD, n = 3)
63.76 ± 2.35
65.63 ± 3.71
0.151 ± 0.023
0.183 ± 0.056
92.06 ± 2.41
90.36 ± 3.84
Ease of redispersion
By mere shaking
By mere shaking
In vitro release
Fitting of Qu release data from Qu-PMs into various mechanism models
y = 0.246 t + 8.291
ln(1 - y) = 0.004 t - 16.129
y = 4.018 t1/2 - 0.081
In vivo pharmacokinetics
Pharmacokinetic parameters of quercetin in serum after oral administration (mean ± SD, n = 3)
5.24 ± 1.32
7.56 ± 3.28
5.31 ± 1.08
7.02 ± 2.02
37.68 ± 16.8
107.84 ± 54.4
4.94 ± 2.03
10.81 ± 3.7
7.18 ± 2.25
27.09 ± 7.8
286 ± 3.23
What is more, the half-life (T1/2) of Qu-PMs was 2.19-fold longer than that of pure quercetin (Table 4), indicating a maximum residence time (MRT) of quercetin in the systemic circulation remarkably extended for Qu-PMs after oral administration. As the AUC0–∞ value of Qu-PMs was significantly larger than that of pure quercetin, the relative oral bioavailability of Qu-PMs calculated from AUC0–∞ values was about 286% (p < 0.05) comparing with pure quercetin. These results implied an enhanced bioavailability of quercetin was achieved through incorporation of drug into PMs.
The main purpose of this study was to prepare an aqueous formulation which could improve the oral bioavailability of the hydrophobic quercetin. In this regard, a nanocarrier system based on soluplus PMs was developed in this study and as anticipated, the pharmacokinetic results indicated the bioavailability of the delivered quercetin was enhanced. When administered via oral route, PMs may be absorbed through specialized M-cells of the Peyer’s patches in the small intestine . Though the PMs showed the potential to enhance the oral bioavailability of poorly water-soluble drugs, the underlying mechanisms of enhancement, however, are still unclear and provoke future research interests.
Quercetin was loaded into nanosized polymeric micelles based on amphiphilic polymers soluplus using a modified film dispersion method. The stable Qu-PMs showed sustained release of entrapped quercetin for up to 10 days in vitro, and more importantly, a sustained plasma level and enhanced systemic bioavailability of quercetin in vivo. Thus, the Qu-PMs provide a promising carrier candidate with efficient delivery of quercetin for therapeutic treatment in near future. Moreover, this study explores an interesting alternative approach for design and fabrication of novel polymeric micelles as delivery systems for bioactive compounds.
The authors gratefully acknowledge the Medical Scientific Research Foundation of Guangdong Province, China (No A2013427), Administration of Traditional Chinese Medicine of Guangdong Province, China (No 20131261), Doctoral Fund of Guangdong Medical College (No XB13096), and International Science and Technology Cooperation Projects of Dongguan (No 2013508152013), Project Creative Young Talents in Colleges and Universities Guangdong Province (2014LYM0003) for the financial support.
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