Spray-Drying of Hydroxypropyl β-Cyclodextrin Microcapsules for Co-Encapsulation of Resveratrol and Piperine with Enhanced Solubility

The synergistic therapeutic benefits of resveratrol (RES) and piperine (PIP) have been proven for the treatment of various diseases. This study reports, for the first time, spray-drying of hydroxypropyl β-cyclodextrin (HP-β-CD) microcapsules for combined delivery of resveratrol and piperine. Phase solubility studies indicated that there was a strong interaction between the active ingredients and HP-β-CD, and both active ingredients can bind stably to HP-β-CD. The results of FTIR, XRD, and DSC demonstrated that RES-PIP/HP-β-CD inclusion complexes were successfully formed, with the RES and PIP encapsulated into the hollow spherical cavity of HP-β-CD. The results of SEM showed that the spray-dried microcapsules displayed a smooth surface and uniform particle size. Upon the formation of the spray-dried microcapsules, both RES and PIP presented significantly enhanced solubility. The results of DPPH and ABTS+ scavenging activity assays showed that the spray-drying process did not adversely influence the antioxidant activity of the bioactives, and the addition of PIP increased the antioxidation performance of RES.

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The consumption of functional food products or dietary supplements fortified with bioactive substances is gaining popularity due to increased awareness of consumers for imparting health benefits. Co-encapsulation and simultaneous delivery of multiple bioactive substances in a single-wall system has been regarded as a novel approach for the development of health products with synergistic effects. Resveratrol (RES), a natural non-flavonoid polyphenol compound, is widely presented in natural plants such as grapes, strawberries, peanuts, knotweed, mulberry, etc. The earliest attention to RES is related to the interesting phenomenon of the “French Paradox”. Although the French consume a high-fat diet, the incidence of cardiovascular disease is relatively low. So far, RES has been reported to have various pharmacological effects, such as anti-cancer [3], anti-inflammatory, antioxidant, and cardiovascular protection. It is probably the most common phytoalexin that has both been used in traditional medicine and explored in modern healthcare. However, the poor aqueous solubility, instability, and rapid metabolism of RES has significantly limited the efficacy of its therapeutic benefits.
Different approaches have been reported for enhancing the oral bioavailability of RES, such as micelles, solid dispersions, nanoparticles, and nano-emulsions. Piperine (PIP), an alkaloid compound and the main active component of black pepper, has been disclosed, which could enhance the bioavailability of many pharmaceutical ingredients through various proposed mechanisms, such as the inhibitory action on various hepatic and other metabolizing enzymes. Johnson et al. reported that with the addition of PIP, the in vivo exposure and maximum serum concentration of RES were increased to 229% and 1544%, respectively. Jadhav et al. reported that the oral bioavailability of RES was increased by 5.7-fold when delivered by PIP-loaded mixed micelles. Wightman et al. reported that co-supplementation of PIP with RES enhanced the bioefficacy of RES with regard to the increase of cerebral blood flow. Meanwhile, pharmacological studies have shown that PIP presents potential therapeutic effects, such as anti-inflammatory, cytoprotective effects, and antioxidant. The codelivery of PIP with RES would be a promising method to improve the bioperformance of RES with synergistic beneficial effects.
Even though PIP possesses bioenhancer properties, the solubility and dissolution behaviors of the co-encapsulated bioactive substances have important impacts on the absorption of RES. He et al. reported that unfavorable bioavailability of RES was observed for RES and PIP cocrystals due to the reduced dissolution and apparent solubility of the bioactive substances. Therefore, it is necessary to develop a co-encapsulation technology to achieve solubilization of the bioactive substances. Improving the solubility of bioactive ingredients by preparing an inclusion complex has become a promising technology. Cyclodextrin (CD) is a cyclic oligosaccharide derived from starch. The outer surface of CDs is hydrophilic, while the inner cavity is hydrophobic, which can accommodate insoluble molecules. Hydrophobic β-cyclodextrin (HP-β-CD) is one of the most widely used CDs because its cavity is compatible with common guests and with high safety.
The aim of this study is to improve the solubility of RES and PIP by preparing an inclusion complex with HP-β-CD through spray-drying. To the best of our knowledge, this is the first study on co-encapsulation of RES and PIP via the spray-drying technique. As a powder production method commonly used in food and pharmaceutical fields, spray-drying possesses the advantages of being rapid, low-cost, and easily scalable. Phase solubility studies were performed to evaluate the stability of RES and PIP in HP-β-CD. The complexes were characterized by various analytical techniques to confirm their formation. The structural and thermal properties of the spray-dried microcapsules were analyzed by Fourier transform infrared spectroscopy (FITR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). The antioxidant capacity of RES was evaluated by measuring the clearance of 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2’-Azinobis-3-ethylbenzthiazoline-6-sulphonate (ABTS). Furthermore, the water solubility of the inclusion complexes was assessed to verify the solubility enhancement of RES and PIP.



RES (99%), PIP (97%), ABTS (97%), and HP-β-CD (97%) were purchased from Aladdin (Shanghai, China). DPPH (98%) was purchased from Ryon (Shanghai, China). Hydrochloric acid, anhydrous ethyl alcohol, sodium hydroxide, and potassium dihydrogen phosphate of analytical grade were purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Acetonitrile of HPLC grade was obtained from Merck Co., Ltd. (Waldbronn, Germany). Distilled water was used in all experimental procedures, which was provided by a laboratory water purification system (Hitech Instruments Co., Ltd., Shanghai, China).

Yang, X.; Shen, J.; Liu, J.; Yang, Y.; Hu, A.; Ren, N.; Cheng, Z.; Liu, W. Spray-Drying of Hydroxypropyl β-Cyclodextrin Microcapsules for Co-Encapsulation of Resveratrol and Piperine with Enhanced Solubility. Crystals 202212, 596. https://doi.org/10.3390/cryst12050596

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