pH-Responsive polymeric micelles based on amphiphilic chitosan derivatives: Effect of hydrophobic cores on oral meloxicam delivery
Graphical abstract
Introduction
Self-assembled, core–shell polymeric micelles prepared from amphiphilic copolymers in aqueous solution have been widely studied in oral drug delivery systems (Xue et al., 2009, Yang et al., 2011, Zhang et al., 2012b). The inner hydrophobic core of micelles contains hydrophobic drugs. The outer hydrophilic shell provides a stable interface between the hydrophobic core and the surrounding aqueous solution, protects the hydrophobic drugs from environmental stimuli (e.g., gastric pH, enzyme, temperature), and decreases drug side effects on healthy cells and tissues (Ghaemy et al., 2014).
An oral administrative route is the most preferred route for drug delivery due to its convenience, minimal pain, simplicity, and suitability for chronic therapy (Xu et al., 2013, Yang et al., 2011). However, many drugs have low bioavailability due to poor water solubility and are not readily absorbed in the gastrointestinal (GI) tract (Li et al., 2009, Lu and Park, 2013). As is known, pH levels in the GI tract vary from highly acidic in the stomach (pH 1–3) to neutral or slightly alkaline in the duodenum (pH 6) and along the jejunum and ileum (pH 6–7.5) (Felber et al., 2012, Xu et al., 2013). Because of this wide variability, pH-triggered release mechanisms are widely used in controlled drug delivery. A pH-responsive polymeric micelle-based carrier for oral drug administration can be designed to enhance the stability of micelles in the stomach and achieve a controlled release in the intestines. Poly(acrylic acid) (PAA) and poly(methacrylic acid) (PMAA) have pendant carboxyl groups with pKa values of approximately 5–6 and are commonly used as pH-responsive polymers in pH-sensitive polymeric micelles. Xue et al. (2009) prepared a pH-sensitive amphiphilic diblock copolymer, poly(acrylic acid-b-dl-lactide) (PAAc-b-PDLLA), to encapsulate prednisone acetate. They observed gradual drug release at pH 1.4 and burst release at pH 7.4. The pendant carboxyl groups in PAA maintain collapsed states and are protonated in the low pH environment of the stomach; however, PAA swells in the intestines, ionizes, and releases protons (Sant et al., 2004). Yang et al., 2011, Yang et al., 2012 developed self-assembled, pH-sensitive micelles from amphiphilic copolymer brushes (e.g., poly(methyl methacrylate-co-methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether monomethacrylate) [P(MMA-co-MAA)-b-PPEGMA] containing ibuprofen and poly(lactide)-b-poly(methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether monomethacrylate) (PLA-b-MAA-b-PPEGMA) for nifedipine). These studies found that drug release rates increased when the MAA blocks were modified.
Chitosan (CS) amphiphilic derivatives have recently been studied for use as polymeric micelles (PMs) for drug delivery systems because of their biocompatible, biodegradable and low toxicity properties. For example, PEGylated CS-based PMs have been examined as intracellular delivery carriers for anti-tumor targeting therapies, and the anticancer effects of stearyl-grafted CS-based atorvastatin nanostructured PMs have been studied (Hu et al., 2008, Mekhail et al., 2012). In our previous work, novel pH-responsive N-benzyl or N-naphthyl and N,O-succinyl chitosan were successfully synthesized by reductive N-arylation and N,O-succinylation, respectively, and applied in oral curcumin (Sajomsang et al., 2014) and oral meloxicam (MX) deliveries (Woraphatphadung et al., 2015). We found that among various physical encapsulation methods, evaporation resulted in the greatest MX loaded into N-naphthyl-N,O-succinyl chitosan (NSCS) PMs. The MX release behaviors were pH dependent. MX is a class of non-steroidal anti-inflammatory drugs (NSAID) with poor aqueous solubility. It is a class of enolic acid derivatives that have analogous ionization behavior. It has two dissociation constants (pKa), 1.09 and 4.18 and the isoelectric point (pI) of MX was 2.63 (Hilal et al., 1999). MX is cationic at pH < pI, zwitterionic at pH = pI, and anionic at pH > pI. Therefore, the solubility of MX increased when pH was raised from pH 3 to 8 (Samprasit et al., 2013). The efficacy of MX depended on its physicochemical properties such as ionization constant (pK), solubility and partition coefficient. In addition, an important obstacle in low bioavailability of the orally administered drug is water insolubility. Using PMs, poorly soluble drugs can be successfully solubilized in aqueous media, which increases the water solubility of the drug. Moreover, PMs can protect the drug from the harsh environment of the gastrointestinal (GI) tract (e.g., gastric pH and enzymes) and stabilizes the micelles (Yokoyama, 2011). The aim of this study was to synthesize and fabricate pH-responsive CS-based PMs. The influence of the inner core in term of aliphatic and aromatic (naphthyl, octyl and benzyl) moieties of PMs on the loading efficiency and stability of MX-loaded micelles was studied. The morphology, particle size, in vitro cytotoxicity, drug release and small intestine permeation study were also investigated.
Section snippets
Materials
Chitosan (CS) was purchased from OilZac Technologies Co., Ltd. (Bangkok, Thailand). The degree of deacetylation (DDA = 96% ± 2) was determined by NMR spectroscopy (Sajomsang et al., 2014, Woraphatphadung et al., 2015). The number average molecular weight (Mn), weight average molecular weight (Mw), and polydispersity index (PDI; Mw/Mn) of CS were determined to be 7,633 g/mol, 15,746 g/mol and 2.06, respectively, using gel permeation chromatography (GPC) (Woraphatphadung et al., 2015).
Synthesis and characterization of amphiphilic chitosan derivatives
All amphiphilic chitosan derivatives, NSCS, OSCS and BSCS, were synthesized by reductive N-amination and N,O-succinylation (Fig. 1) (Sajomsang et al., 2014, Woraphatphadung et al., 2015). The N-alkyl or N-aryl CSs were formed from the corresponding Schiff base intermediates before reduction of sodium borohydride. The successful synthesis of all amphiphilic CS derivatives was confirmed by ATR-FTIR, 1H NMR and elemental analysis. The series of amphiphilic CS derivatives with different N
Conclusion
pH-Responsive amphiphilic chitosan derivatives, (NSCS, OSCS, and BSCS) with different hydrophobic moieties, were successfully synthesized. All types of polymeric micelles were carried out in aqueous solution with and without incorporation of hydrophobic drug (MX) by evaporation method. The chemical structure of hydrophobic moieties (naphthyl, octyl and benzyl) and initial drugs to polymers affected on the MX loading efficacy and the stability, while both hydrophobic and hydrophilic moieties
Acknowledgments
The authors would like to acknowledge the Commission of Higher Education (Thailand) and the Thailand Research Fund through the Golden Jubilee Ph.D. Program (Grant No. PHD/0027/2556), the Thailand Research Fund (TRG5480019), the Nagai Award Thailand 2015 from Nagai foundation Tokyo, the Thailand Toray Science Foundation (TTSF) in 2010, the Silpakorn University Research and Development Institute, and the National Nanotechnology Center (NANOTEC), Thailand.
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