Research ArticlePharmaceutics, Drug Delivery and Pharmaceutical TechnologyReduced Burst Release and Enhanced Oral Bioavailability in Shikimic Acid–Loaded Polylactic Acid Submicron Particles by Coaxial Electrospray
Introduction
Shikimic acid [SA, 3R, 4S, 5R-(−)-3, 4, 5trihydroxy-1-cyclohexene-1-carboxylic acid] was originally isolated in 1885 by Eykman from the fruit of Illicium religiosum Sieb.et Zucc. (known as Chinese star anise).1 After several decades since its appearance, SA has been shown to occupy a major position in market as an indispensable starting material for the synthesis of the antiviral drug, Oseltamivir (Tamiflu).2 In certain microorganisms, SA was presented as a metabolic precursor for the biosynthesis of aromatic compounds, such as amino acids, phenylalanine and tyrosine, indole derivatives, alkaloids, tannins, flavonoids, and lignin.2, 3, 4 Although SA was confirmed to be toxic and carcinogenic in rats,5 its derivatives, triacetylshikimic acid and isopropylidene shikimic acid, possessed anti-inflammatory properties as they could inhibit COX-1 and COX-2 activities and also decrease platelet aggregation and blood clot formation.6, 7 Besides, SA has been associated with multiple biological properties including antioxidant, antibacterial, and analgesic activities.8, 9 Moreover, Ma et al.10 also proved that the SA could prevent focal cerebral ischemic injury after middle cerebral artery thrombosis in rat. Altogether, these reports demonstrate that SA is a promising therapeutic agent for cardiovascular, peripheral, and cerebral vascular diseases and could be ideal for the treatment of acute coronary syndrome.
Currently, several researchers are active in the study of natural, biotechnological, and synthetic sources as well as pharmacological applications of SA.11, 12, 13 However, at the molecular level, SA studies on biological activities or preparation are very limited. Until now, to the best of our knowledge, no research has been reported on the in vitro analysis and in vivo bioavailability.
Nowadays, numerous efforts have been made to improve the bioavailability and solubility for poorly water soluble drugs, such as micelle, microemulsion, and microparticles.14, 15, 16 However, recent advances in nanotechnology (liposomes, nanocapsules, nanoparticles, microspheres, carbon nanotubes, and so forth) have shown promise for water-soluble drug in controlled drug release resulting in increased drug absorption. Such nanotechnology has also been useful in maintaining steady therapeutic levels of drugs over an extended period compared with traditional drug preparations.17, 18, 19, 20, 21 Among these nanocarriers, nanoparticles based on electrospray technique have emerged as one of the most useful modalities for suitable drug carriers. Electrospray is a simple and versatile procedure for the fabrication of particles with diameters varying from submicron to micron.22 It forms nanoparticles by vaporizing the solvent. The whole process is conducted with high voltage from a metal capillary tip to induce a charge on the surface of liquid, thus leading to the formation of nanoparticles of different sizes. In addition, a polymer solution could produce nonwoven fibrous mats with desired size range by controlling factors such as the solution and process parameters including applied voltages, collecting distances, and solution flow rates.23
In the nanoparticle formulation based on electrospray technique, particular interest has been focused on the use of polyester materials such as polylactic acid (PLA). PLA, one of the important candidates for nanoporous fibers fabricated for biomedical application, has been extensively used as microparticle carrier in drug delivery systems for many bioactive molecules owing to its nontoxic, excellent biocompatible and biodegradable properties.24 Bognitizki et al.25 was the first to fabricate nanostructured electrospun PLA fibers using dichloromethane solvent. It was reported that the incorporation of the inorganic particulate in the polymer matrix could change morphological structure of the nanofiber or nanoparticle.26 However, “initial burst” release, the phenomenon whereby a large part of the encapsulated drug is released in a short time just after administration, is one of the major disadvantages associated with the nanoparticles.27 Ibrahim et al.28 reported that the initial burst release of insulin led to an early loss of 66% of the protein dose from PLA microsphere. To overcome this limitation, coaxial electrospray method regarded as one of the most significant breakthroughs in this area opened a new way for generating nanoparticles from polymer solutions by manipulating 2 different liquids using a concentric spinneret.29 This specific electrospray technique uses the spray head assembled by axially inserting an inner capillary in an outer tube. Dual-capillary electrospray has been demonstrated to directly produce monodisperse droplets with the outer liquid encapsulating the inner one.30 Moreover, the separate liquid in different capillary offers great flexibility to encapsulate drugs of various types, such as proteins, enzymes, and antibiotics, without losing their bioactivity. The coaxial process has gradually been demonstrated to be a useful tool in preventing clogging of spinneret for continuous preparation of pure polymer nanoparticles such as polyvinylpyrrolidone and polyacrylonitrile.31, 32 Moreover, this system could show high drug encapsulation efficiency and mitigate the initial burst release because the drug is fully encapsulated in the core of particles.33
Till date, neither release behavior in vitro nor bioavailability in vivo of SA has been investigated. Hence, for the first time, phospholipid-coated SA-loaded PLA submicron particles based on coaxial electrospray method was successfully prepared to evaluate its release characteristics and bioavailability as against the free SA.
Section snippets
Materials
SA of purity 99% was supplied by Energy Chemical Co., Ltd. (Shanghai, China). PLA (pharmaceutical grade, molecular weight of 10,000) was produced by Jinan Daigang Biomaterial Co., Ltd. (Shandong, China). Phospholipid (soybean lecithin, analytical injection grade, with phosphatidyl-choline content of 70%) was purchased from Taiwei Pharmaceutical Co., Ltd. (Shanghai, China). Acetone of analytical grade was provided by Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). The filter membrane and
Characterization
Figure 2 shows the SEM images of the prepared particles based on electrospray and coaxial electrospray techniques. Figure 2a presents an irregular porous structure of PLA, with a rough surface, which was in accordance with other literature,43 whereas the electrospray particle (F-ES; Fig. 2b) exhibited a relatively flat surface with individual particles in ellipsoidal shape, demonstrating that the drug was finely filled in the holes. Moreover, drug particles on F-ES surfaces resulting from phase
Conclusions
In this study, the SA-loaded submicron particle was prepared successfully by coaxial electrospray technique. The in vitro release profile of SA from the coaxial electrospray particle reduced the burst release and presented a sustained release profile. In addition, intestinal absorption in situ studies indicated jejunum was the major absorption segment of SA compared to ileum and duodenum. Active transport and facilitated diffusion could be the main absorption mechanisms in drug absorption
Acknowledgments
This work was supported by the National Natural Science Foundation of China (30973677, 81373371), China Postdoctoral Science Foundation funded project (2015M571700), College Natural Science Research Foundation of Jiangsu Province (14KJB350002), Research Foundation for Distinguished Scholars (15JDG074). This work was also funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. The authors are grateful to Emmanuel Omari-Siawat, Jiangsu University, for English
References (55)
- et al.
Shikimic acid
Food Cosmet Toxicol
(1976) - et al.
Eichhornia crassipes: an advantageous source of shikimic acid
Revista Brasileira De Farmacognosia
(2014) - et al.
Enhanced oral bioavailability of capsaicin in mixed polymeric micelles: preparation, in vitro and in vivo evaluation
J Funct Foods
(2014) - et al.
PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug
J Control Release
(1999) - et al.
Electrospun P(LLA-CL) nanofiber: a biomimetic extracellular matrix for smooth muscle cell and endothelial cell proliferation
Biomaterials
(2004) - et al.
Effect of added nickel nitrate on the physical, thermal and morphological characteristics of polyacrylonitrile-based carbon nanofibers
Mater Sci Eng B
(2009) - et al.
Drug release characteristics of multi-reservoir type microspheres with poly(dl-lactide-co-glycolide) and poly(dl-lactide)
J Control Release
(2005) - et al.
Stability of insulin during the erosion of poly(lactic acid) and poly(lactic-co-glycolic acid) microspheres
J Control Release
(2005) - et al.
Coaxial electrospinning with sodium dodecylbenzene sulfonate solution for high quality polyacrylonitrile nanofibers
Colloid Surf A
(2012) - et al.
One-step preparation of chitosan solid nanoparticles by electrospray deposition
Int J Pharm
(2010)
Sustained release of drugs from films and kinetics of drug release
J Pharm Sci
Evaluation of mathematical models describing drug release from lipophilic matrices
Int J Pharm
Mechanism of sustained action medication: theoretical analysis of rate of release of solid drugs dispersed in solid matrices
J Pharm Sci
A simple equation for description of solute release I. Fickian and non-Fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs
J Control Release
Present and future applications of biomaterials in controlled drug delivery systems
Biomaterials
Controlled release of biologically active agents
J Pharm Sci
A reactive electrospinning approach for nanoporous PLA/monetite nanocomposite fibers
Mater Sci Eng C
Multiple responses optimization in the development of a headspace gas chromatography method for the determination of residual solvents in pharmaceuticals
J Pharm Anal
Controlled dual release of hydrophobic and hydrophilic drugs from electrospun poly(l-lactic acid) fiber mats loaded with chitosan microspheres
Mater Lett
Current strategies for sustaining drug release from electrospun nanofibers
J Control Release
Coaxial electrospinning for encapsulation and controlled release of fragile water-soluble bioactive agents
J Control Release
In situ perfusion model in rat colon for drug absorption studies: comparison with small intestine and Caco-2 cell model
J Pharm Sci
Recent advances in the understanding of uptake of microparticulates across the gastrointestinal lymphatics
Adv Drug Deliv Rev
Permeability properties of phospholipid membranes: effect of cholesterol and temperature
Biochim Biophys Acta
Shikimic acid (3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid)
Chem Rev
In vitro neuroprotective effect of shikimic acid against hydrogen peroxide-induced oxidative stress
J Mol Neurosci
Shikimic acid as a precursor in lignin biosynthesis
Nature
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This article contains supplementary material available from the authors by request or via the Internet at http://dx.doi.org/10.1016/j.xphs.2016.05.032.