Drug Delivery

ISSN: 1071-7544 (Print) 1521-0464 (Online) Journal homepage: http://www.tandfonline.com/loi/idrd20

Amphiphilic block copolymers-based mixed micelles for noninvasive drug delivery Hongyan Xu, Peimin Yang, Haifeng Ma, Weidong Yin, Xiangxia Wu, Hui Wang, Dongmei Xu & Xia Zhang To cite this article: Hongyan Xu, Peimin Yang, Haifeng Ma, Weidong Yin, Xiangxia Wu, Hui Wang, Dongmei Xu & Xia Zhang (2016): Amphiphilic block copolymers-based mixed micelles for noninvasive drug delivery, Drug Delivery, DOI: 10.3109/10717544.2016.1149743 To link to this article: http://dx.doi.org/10.3109/10717544.2016.1149743

Published online: 29 Feb 2016.

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Date: 02 March 2016, At: 02:19

http://informahealthcare.com/drd ISSN: 1071-7544 (print), 1521-0464 (electronic) Drug Deliv, Early Online: 1–9 ! 2016 Taylor & Francis. DOI: 10.3109/10717544.2016.1149743

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Amphiphilic block copolymers-based mixed micelles for noninvasive drug delivery Hongyan Xu, Peimin Yang, Haifeng Ma, Weidong Yin, Xiangxia Wu, Hui Wang, Dongmei Xu, and Xia Zhang

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Department of Pharmacy, People’s Hospital of Linzi District, Linzi, China

Abstract

Keywords

Amphiphilic block copolymers-based mixed micelles established as new drug-loading system showed superior characteristics in delivering drug such as improved solubility, enhanced stability, multifunctional carrier materials, targeting ability, and high bioavailability. Recently, there are increasing focuses on exploration and study of noninvasive routes, and the results present perfect feasibility, improved compliance and fewer aches and pains. The aim to apply mixed micelles to noninvasive alternative routes has driven massive pharmaceutical attention. Recently, various studies of micelles strategy for noninvasive routes have been conducted to overcome the inherent barriers for uptake across the gastrointestinal tract, mucosal membranes and other in vivo noninvasive barriers, and the result argues well. The objective of this article is to summary these studies and developments of mixed micelles used on noninvasive drug delivery and provide a reference for further research.

Amphiphilic copolymers, anti-cancer drugs, mixed micelles, noninvasive routes

Introduction In the current study, the injection routes have been the main form of drug delivery by adding appropriate solvent or disperse medium. But, injections result in the burden of frequent injections, bad compliance, pain, high cost, susceptibility to infection, and other adverse sides (Khafagy et al., 2007). Recently, owing to the rise of more convenient administer means and enhancing therapeutic effect, noninvasive delivery systems have caused a lot of attention and worth being researched and investigated (Zhang et al., 2014a). In spite of high therapeutic activity, low solubility and low permeability of poorly soluble drugs lead to bad absorption and poor bioavailability via the noninvasive administration. Therefore, there is a great urgent to develop efficient, feasible, economical, and safe formulations to increase the bioavailability of poorly water-soluble drugs delivery for noninvasive routes. The unceasing development of new drug delivery systems is driven by the need of clinical pharmacotherapy to improve therapeutic effect and lower adverse reaction. For plenty of reasons, micelles formed by amphiphilic block copolymers have received increasing attention over the past decades in drug delivery applications. First, it is confirmed that micelles with a core-shell structure can incorporate insoluble drugs into the hydrophobic inner core formed by hydrophobic blocks of copolymers to solubilize loading drugs. Second, the outer hydrophilic shell of micelles formed by hydrophilic Address for correspondence: Xia Zhang, Department of pharmacy, People’s Hospital of Linzi District, Linzi, Shandong Province 255400, China. Tel/Fax: +86 18678165761. Email: [email protected]

History Received 10 November 2015 Revised 24 January 2016 Accepted 30 January 2016

blocks could protect loading drugs from direct damage of outside environment such as hydrolysis and enzymatic degradation to enhance the stability. And nano-sized micelles could contribute to avoid the uptake of the reticuloendothelial system to prolong circulation time and alter the biodistribution. As a consequence, micelles have been devised with the aim of improving the dissolution rate and stability of delivering drugs potentially. Furthermore, researches have proven that two or more copolymer materials could form mixed micelles system (MMs), compared to conventional individual micelles. MMs with multiple functionalities showed greater potential such as higher drug loading capacity, lower critical micelle concentration (CMC) values, stronger stability, longer release time, and higher bioavailability (Nishiyama & Kataoka, 2006; Ren et al., 2006). Amphiphilic copolymers-based MMs showed promising potential as delivery vehicle for noninvasive administration routes. In this article, we presented an overview of recent studies on MMs for noninvasive routes including oral, ocular, nasal delivery. Detailed examples are discussed.

The current situation and prospect of noninvasive drug delivery With low solubility and permeability of drugs, the injection routes have been the main drug delivery ways so far owing to their rapid-onset, reliable efficacy, and high bioavailability. Injections have achieved satisfying therapeutic effect in terms of application, but they also resulted in many burdens such frequent injections, bad compliance, aches and pains, high cost, risk of infection, and other adverse reactions (Khafagy et al., 2007). Moreover, once misuse or improper injection

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dosage happened, it was too hard to correct and remedy timely. In consequence, there are increasing focuses on the exploitation of noninvasive routes for drug delivery, and the results present perfect feasibility and prospect. These routes offer more convenient means than injection administration. First, compared to traditional injection routes, oral administration exhibited many valuable advantages, such as costeffectiveness, continuing effect, flexibility for meeting patient preference, and good compliance. Second, the ocular route showed less immunological reactions and bypassed first-pass hepatic metabolism as the desired location of drug delivery (Souza et al., 2014; Taha et al., 2014). In addition, nasal administration with ample vascular and predominant penetrability could make drug enter into the systemic circulation directly and avoid the first-pass hepatic metabolism, which contributed to lower doses and little side effects and rapid onset comparable to intravenous injection (Sintov et al., 2010; Kumar et al., 2016). Consequently, the efficient drugs absorption could be realized by noninvasive routes systemically. Meanwhile, there have been some shortcomings of noninvasive routes that needed to be solved such as first-pass metabolism in gastrointestinal (GI) tract, many barriers and bad compliance of ocular delivery, high cost, mucociliary clearance, dosing constraints and short dwell time from nasal administration preparation. Many researchers have been committed to develop new formulations and new technologies to improve bioavailability, compliance of patients, and safe medication of noninvasive drug delivery.

Drug Deliv, Early Online: 1–9

showed that MMs could enhance metal ion detection selectivity. And, zwitterionic VBA-b-MEMA diblock copolymer displayed structural inversion behavior between MEMA(poly(N-(morpholino)ethyl methacrylate))-core and VBA (poly(4-vinylbenzoic acid))-core micelles (Liu & Armes, 2003; Wang et al., 2006). Moreover, most of the copolymers exhibited excellent biocompatibility and biodegradability. For instance, Pluronic copolymers could inhibit drug-efflux of P-glycoprotein (P-gp) and metabolism of cytochrome P450, and bile salts showed strong solubilizing capacity, and poly(ethylene glycol; PEG) copolymers acted as a eminent stabilizer avoided the recognition of the reticuloendothelial system (Ma et al., 2011; Tan et al., 2013; Zhang et al., 2014b). In addition, nano-sized MMs in range of 20– 200 nm are enough large to avoid rapid elimination by glomerular filtration, and also small sufficiently to across blood vessels and facilitate passive targets to lower nonspecific organ toxicities (Li & Huang, 2008; Attia et al., 2011). Therefore, after drug being incorporated into amphiphilic copolymers-based MMs, the improved solubility and stability, passive targeting ability, simple preparation technology, and versatile carrier materials all contributed to ideal therapeutic effect via noninvasive drug delivery. Amphiphilic copolymers-based MMs would be an ideal carrier for noninvasive administration and be valuable to be further studied (Guo et al., 2004; Zhao et al., 2012; Zhang et al., 2015). MMs strategy for oral drug delivery

Mixed micelles strategy for noninvasive drug delivery To overcome absorption barriers of noninvasive administration and improve drug bioavailability, various formulations have been investigated and studied such as solid dispersion, inclusion compound, lipid carriers, micelles, nanoparticles (Fathia & Varshosaz, 2013; Lacatusu et al., 2013; Li et al., 2013; Madane & Mahaj, 2014; Ge et al., 2015). Among these formulations, amphiphilic block copolymers-based MMs showed superior characteristics as an integrated multifunctional system such as high drug-loading capacity, greater thermodynamic stability, desired bioavailability, and attracted massive attention. The hydrophobic inner core encapsulates drugs, while the hydrophilic outer shell protects them from damage of external environment such as the GI tract, tear, and nasal mucus (Sezgin et al., 2006; Dou et al., 2014). As a novel platform, MMs augurs well with multi-functions from their component copolymers, as follows. Amphiphilic (PS(-bPNIPAM)-b-PCL) miktoarm star terpolymers were synthesized consisting of polystyrene, poly(e-caprolactone), and poly(N-isopropylacrylamide) to prepare micelle, which created a thermoresponsive nano-carrier for the first time (Zhang et al., 2009). In addition, Liu and colleagues made amphiphilic PCL-b-P(OEGMA) by poly(e-caprolactone; PCL) block and poly(oligo(ethylene glycol) monomethyl ether methacrylate; POEGMA) block, and linked the diblock copolymer with folic acid (FA) and DOTA-Gd (Gd) moieties to obtain functionalized MMs. The work achieved drugtargeted delivery and magnetic resonance (MR) imaging contrast enhancement (Liu et al., 2012). Hu et al. (2012)

Due to painless, acceptant and convenient characteristics, oral administration is the most common way of administration in the case of chronic therapies (Ross & Toth, 2005; Jin et al., 2008). However, drug absorption with poor permeability and low solubility is limited by GI mucosa barrier, which led to low oral bioavailability. MMs could solubilize and protect loading drugs and improve oral bioavailability and stability in GI tract of insoluble/unstable drugs (Bromberg, 2008; Gaucher et al., 2010). MMs could protect the drug against damage of gastric acid and enzymatic degradation to ensure the arrival of adequate drugs in diseased tissues (Gaucher et al., 2010). Moreover, the slow release of drug from MMs could prevent the rapid leakage and precipitation in the GI tract during the drug delivery. All these superiorities make MMs become ideal oral delivery vehicle for encapsulated drugs. A large number of experiments and researches were carried out in order to investigate oral drug absorption by MMs delivery system. Pluronic-MMs for oral drug delivery Pluronic, FDA-approved pharmaceutical excipient, is one of the most general carrier materials of MMs, which is an amphiphilic block copolymer composed of hydrophilic poly(ethylene oxide; PEO) and hydrophobic poly(propylene oxide; PPO) blocks arranging in PEO-PPO-PEO triblock structure (Batrakova & Kabanov, 2008; Figure 1). Linear poly(ethylene oxide)-poly (propylene oxide; PEO-PPO) was named as poloxamers and branched PEO-PPO as poloxamines (Chiappetta & Sosnik, 2007; Chiappetta et al., 2008; Jaime et al., 2008). Plenty of studies and findings showed that

Amphiphilic block copolymers-based mixed micelles

DOI: 10.3109/10717544.2016.1149743

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Figure 1. Chemical structure representation of Pluronic block copolymer and poloxamine TetronicÕ T904.

Pluronic copolymers could increase the drug absorption and inhibit drug-efflux of P-gp and metabolism of cytochrome P450. Chiappetta et al. designed and prepared antiretroviral efavirenz (EFV)-loaded MMs composed of poloxamer Pluronic F127 (F127) and poloxamine TetronicÕ T904 (T904) for oral administration (Lindenberg et al., 2004; Chiappetta et al., 2011; Tshweu et al., 2014; Figure 1). EFV is a strongly non-nucleoside reverse transcriptase inhibitor with very low water solubility (about 4 mg/mL) and significant individual variation, which is urgent to overcome them. EFVloaded MMs were obtained by dissolving F127 and T904 in phosphate-citrate buffer solution (pH 5.0) at 4  C. Then the EFV was added and shaken at 25  C until drug dissolution. In this study, F127:T904 (50:50) MMs and F127:T904 (25:75) MMs were prepared at weight ratios of 50:50 and 25:75 of F127:T904, respectively. Pure F127 (10% weight/volume concentration) and T904 (7% and 10%) micelles were prepared as controls, and named as pF127 (10%), pT904 (7%), and pT904 (10%). After being entrapped in MMs, the solubility of EFV was increased from 4 mg/mL up to 34 mg/mL (around 8500 times) in water. In previous studies, the absorption process across the intestinal epithelium was significantly affected by structural features of drugs-loaded delivery system, such as the size, physicochemical property of carrier materials, and zeta-potential values (Gaucher et al., 2010; Tshweu et al., 2014). Nano-sized MMs could be internalized in the form of intact structure by fluid-phase pinocytosis (Luo et al., 2002; Mathot et al., 2007). All the undiluted EFV-loaded micelles showed small particle size between 20 and 27 nm with slight differences. EFV-loaded F127:T904 (25:75) MMs (27.8 mg/mL/h) exhibited higher AUC value than EFV-loaded F127:T904 (50:50) MMs (19.6 mg/mL/h) at 40 mg/kg of oral dosage. Combining with a remarkable increase of the AUC value of pT904 (10%) micelles (45.3 mg/mL/h), these results convincingly confirmed that the smaller size, the higher oral absorption (27.8 nm of F127:T904 (50:50), 21.7 nm of F127:T904 (25:75) and 20.8 nm of pT904 (10%)). The developed F127:T904 MMs successfully encapsulate and deliver antiretroviral EFV to

improve the pediatric pharmacotherapy of the human immunodeficiency virus (HIV) infection. Taxanes, a potent anticancer agent, have shown a broadspectrum of great inhibitory activity on various cancers including non-small cell lung cancer, breast cancer, prostate cancer, ovarian cancer, and so forth. Taxanes were solubilized by surfactant Cremophor EL, Tween 80, and ethanol as commercial injection forms to improve bioavailability for clinical application, while these solubilizers cause several adverse effects (Yang et al., 2007). It is imperative to search safer carrier materials and drug-delivery ways to increase the solubility and dissolution to improve the bioavailability. Dahmani and colleagues prepared Pluronic-MMs to enhance oral bioavailability of paclitaxel (PTX; Dahmani et al., 2012). The MMs were comprised of Pluronic copolymers (F127 or P188) and low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate. The LHR conjugate was synthesized by covalently bonding all-trans retinoic acid-NH2 to low molecular weight heparin (LMWH) via amide formation (Hou et al., 2011). Then probe-type ultrasonic and dialysis method was used to prepare PTX-loaded MMs. Among different weight ratios (0:4, 1:4, 2:4, 3:4, 4:4) of Pluronic and LHR, Pluronic/LHR-MMs at 1:4 weight ratio showed optimal characters, and exhibited appropriate average size (131–135 nm), low CMC value (0.049 mg/mL for F127/ LHR-MMs, 0.055 mg/mL for P188/LHR-MMs), high drug loading content (26.92% for F127/LHR-MMs, 25.82% for P188/LHR-MMs), and high thermodynamic stability. In release study, PTX-loaded P188/LHR-MMs showed a slight faster release compared to PTX-loaded F127/LHR-MMs, and both of them displayed slower release than the commercial formulation TaxolÕ, that could be attributed to more hydrophilic character of P188 than F127 (Kabanov et al., 2002). Besides, probably owing to the desulfation of heparin in acid environment, the drug release was accelerated as the pH descends (Motlekar & Youan, 2008). PTX-loaded MMs achieved markedly higher oral bioavailability, with Cmax and AUC values being 7.5–9.2 times and 15–20 times higher than control group. Pluronic/LHR-MMs system was valuable

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for further study as oral drug delivery vehicle for loading poor soluble drugs. Pluronic-mediated inhibitory activity on drug-efflux of P-gp decreased elimination of loaded drug, which indicated that Pluronic-MMs appeared as outstanding drug delivery system to improve oral drug absorption.

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Bile salts-MMs for oral drug delivery Based on excellent biocompatible and biodegradable properties and solubilizing capacity of bile salts, they have been applied extensively to solubilize drugs and enhance the absorption (Mrestani et al., 2003; Seulki et al., 2006; Zhang et al., 2015; Figure 2). Bile salts-MMs have been widely investigated as drug delivery systems, which are formed by mixing with phospholipids, glycerides and Pluronic, and so forth (Zhang et al., 2015). Cephalosporins, such as cefpirom (Cp) and cefodizim (Cd), are highly hydrophilic drugs. Due to the infeasibility of active and passive transport across cell membranes, Cp and Cd could be only administrated by injection. The study will be very interesting and provide a platform for developing new formulations to improve the very low bioavailability and overcome limited application of highly hydrophilic Cp and Cd via oral administration. After being incorporated into polysorbate-20/sodium glycodeoxycholic acid (SDC) MMs, loaded Cp and Cd showed high oral bioavailability (Mrestani et al., 2010). First, SDC and polysorbate-20 were dissolved in phosphate buffer solution (pH 7.4) to obtain SDC solution and polysorbate-20 solution, respectively. Then SDC solution was added to polysorbate-20 solution under stirring, standing for 18 h. Cp or Cd was dissolved in the solution and stirred for 25 min under ultrasonic bath to obtain Cp- and Cd-loaded MMs. The pharmacokinetics study displayed that plasma concentrations of Cp- and Cd-loaded MMs experimental groups were significantly higher than that of Cp-or Cd-buffer solution control groups after intraduodenal administration (i.d.). AUC (11 533 mg/mL/min of Cp-loaded MMs, 17 646 mg/mL/min of Cp-loaded MMs) values of experimental groups were increased by 22- and 17.7-fold compared to that of control groups (524 mg/mL/min of Cp-buffer solution, 995 mg/mL/ min of Cd-buffer solution), with Cmax (67 mg/mL of Cploaded MMs, 70 mg/mL of Cp-loaded MMs) of experimental groups being increased by 22.3 and 17.5 times than that of control groups (3 mg/mL of Cp-buffer solution, 4 mg/mL of Cd-buffer solution). In conclusion, Bile salts-MMs could increase the oral bioavailability of high hydrophilic Cp and Cd, which developed a new application of MMs. Dong and his colleagues improved solubility of poorly soluble fenofibrate (FB) by preparing FB-loaded bile salt/phospholipid MMs and achieved high oral bioavailability by forming MMs precursor (preMM) pellets (Dong et al., 2013). By the ternary phase diagram, the optimal bile salt and phospholipid weight ratio of prepared FB-loaded MMs was selected at 4:6. Then the FB-loaded MMs were deposited onto pellets by the fluid-bed coating technology, with polyethylene glycol (PEG) 6000 as the dispersion matrix to increase the solubilizing ability of MMs on FB (Lei et al., 2011; Oliveira et al., 2011; Chen et al., 2013). When the FB-loaded preMM pellets redispersed in aqueous solution, the particle size of renewed FB-loaded

Figure 2. Structural formulas of sodium cholate.

MMs was slightly increased from 55 nm to 87.4 nm compared to the original drug-loaded MMs, and the reconstituted solution appeared clear and transparent state. Pharmacokinetic experiment on male Beagle dogs by oral administration, solid dispersion pellets (FB and PEG mixture deposited onto inert PVC pellets), and LipanthylÕ (commercial capsule product of FB) were prepared as controls. FB was metabolized into fenofibric acid in body. So, the plasma concentration was determined in accordance with fenofibric acid instead of FB concentration. The pharmacokinetic result exhibited that the FB-loaded preMM pellets significantly increased oral bioavailability of FB than LipanthylÕ and solid dispersion pellets, respectively. Regarding Cmax and AUC values, 0.397 ± 0.162 mg/mL and 1.451 ± 0.394 mg/mL/h of Lipanthyl, 0.662 ± 0.222 mg/mL and 2.837 ± 1.459 mg/mL/h of solid dispersion pellets, with 0.874 ± 0.395 mg/mL and 4.123 ± 2.263 mg/mL/h of FB-loaded preMM pellets are powerful evidence that bile salt/phospholipid MMs are ideal candidates of poorly water-soluble drugs for oral delivery. Furthermore, the addition of core-forming reagents could enhance the micellar stability and extend releasing time. Basing on this, Zhu et al. added polyvinylpyrrolidone (PVP) into sodium cholate/phospholipid mixture to prepare sodium cholate/phospholipid/PVP MMs for delivering capsaicin, which displayed powerful inhibitory activities on inflammation, cancer and oxidant (Lee et al., 2007; Zhu et al., 2010,2014). Medical-grade PVP-K30, a highly hydrophilic, biocompatible, and flexible material, is a promising coreforming reagent for making more stable MMs. The capsaicinloaded MMs showed small particle size (around 15.8 nm), facilitate long circulation time and biodistribution by bypassing the reticuloendothelial system (Li et al., 2011; Dou et al., 2014). High encapsulation efficiency (92.3%), enhanced stability and better slow-release character of capsaicinloaded MMs were achieved with the addition of PVP (Zhu et al., 2010; Duan et al., 2013). Free capsaicin suspensions acted as control group with 0.5% (w/v) CMC-Na being suspending agent. In pharmacokinetics research, capsaicinloaded MMs exhibited higher AUC value (9158 ng/mL/h versus 3786 ng/mL/h) and latter Tmax (4 h versus 0.75 h) than

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DOI: 10.3109/10717544.2016.1149743

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control group. High oral absorption might be attributed to improved solubility, small particle size, enhanced stability and long circulation time (Wang et al., 2011; Dahmani et al., 2012; Dou et al., 2014). According to previous reports, drug-loaded micelles as a drug reservoir were incapable to across the brush border membrane intactly. However, drugs encapsulated thoroughly in the inner core of MMs could prolong release time, and hydrophilic shell contributed a slower elimination phase to enhance the pharmaceutical absorption. PEG-MMs for oral drug delivery PEG copolymers act as a stabilizer of MMs surrounding the core by forming hydrogen bonds with water molecules, which are invisible in the circulatory system by avoiding the recognition of the reticuloendothelial system. Owing to excellent biodegradability and hydrophilia, FDA-approved PEG could invest PEG-MMs with medication safety and protective capability. Amphiphilic monomethoxy poly(ethylene glycol)-b-poly(e-caprolactone; mPEG-PCL) copolymer is neutral and low toxicity, and often serves as carrier material of MMs and achieve excellent drug loading capacity and release characteristic (Figure 3). Stiripentol (STP) as model drug was encapsulated into mPEG-PCL/sodium oleate MMs to enhance the efficacy of treating myoclonic epilepsy in infants via oral absorption (Zhang et al., 2014c). In this study,

the mPEG-PCL block copolymer was synthesized by a modified ring-opening polymerization method (Shen et al., 2008; Zhang et al., 2014c). Sodium oleate, a highly safe pharmaceutical excipient, is conducive to prepare smaller, uniform and more stable MMs, then the prepared STP-loaded mPEG–PCL/sodium oleate MMs showed small particle size (44.2 nm), narrow distribution (PDI ¼ 0.087) and high zeta potential (30.3 mV; Honary & Zahir, 2013). Compared to free drug, the mPEG–PCL/sodium oleate MMs significantly improved the solubility of STP (10 mg/mL versus 49.17 mg/ mL) and presented remarkable sustained-release property. Based on measured pharmacokinetic parameters, the STP absorption in MMs was improved by 444% than STP suspensions by oral administration. Moreover, the STP-loaded MMs also showed higher oral bioavailability than marketed powder for oral suspension (DiacomitÕ), which might be related to the presence of sodium oleate as an absorption enhancer. Therefore, it has been proved that the mPEG–PCL/ sodium oleate MMs system could enhance oral bioavailability of STP and be potential oral delivery carrier for poorly watersoluble drugs. And after that, Dou et al. (2014) prepared and evaluated new PEGylated MMs for oral docetaxel (DTX) delivery. The PEGylated MMs were composed of monomethylol poly(ethylene glycol)-poly(D,L-lactic acid; mPEGPLA), D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) and stearic acid (SA) grafted chitosan oligosaccharide (CSO; CSO-SA) copolymers (Figure 3). CSO-SA was

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obtained by covalently combining carboxyl groups of SA with amine groups of CSO (Figure 4). Then DTX-loaded mPEGPLA/TPGS/CSO-SA MMs were prepared and optimized and exhibited small size (34.96 nm), high drug loading (19.15%) and low CMC (2.11  105 M). DTX-loaded mPEG-PLA/ TPGS MMs without adding CSO-SA and DTX solution containing Tween-80 and ethanol were prepared as control group for pharmacokinetics studies. The DTX-loaded mPEGPLA/TPGS/CSO-SA MMs group showed slower release compared to control group in simulated gastric/intestinal fluid (SGF/SIF), which might be attributed to the inhibiting effect of CSO-SA on water into the core of micelles (Hu et al., 2006). DTX-loaded mPEG-PLA/TPGS/CSO-SA MMs showed higher AUC (889.59 ng/mL/h) compared to DTXloaded mPEG-PLA/TPGS MMs (764.25 ng/mL/h) and DTX solution (353.63 ng/mL/h). All results indicated that the developed mPEG-PLA/TPGS/CSO-SA MMs were promising for delivering DTX via oral administration. All promising superiorities of PEG-MMs were beneficial to improve peroral absorption of loading drugs, such as increased contact area, reduced particle size, good reproducibility and stability in GI fluids. The PEG moiety is independent of electrolytes and other substances in GI to conserve their intact MMs structure and reduce damage during delivery. Furthermore, great inhibitory activity of TPGS and CSO-SA copolymer materials on P-gp efflux pump promoted more transepithelial drug delivery to improve oral bioavailability.

residence time, unstable absorption, and metabolism of enzymes caused some absorbing barriers. MMs could encapsulate loading drugs into inner core to facilitate ophthalmic drug delivery. Lin et al. prepared Pluronic (F127)/chitosan (Ch) MMs as delivery vehicle for ocular hypotensive agents, metipranolol (MTP; Lin & Chang, 2013). It has been proved that Pluronic-based MMs improved the solubility of incorporating drugs. Ch with fantastic bioadhesion was used to overcome the low mucoadhesion of F127 to prolong residence time on absorption site for improving ocular bioavailability of MTP (Prabaharan & Mano, 2005). In the process of preparation, Span-80 as a surfactant and glutaraldehyde as a cross-linker were added into MTP-loaded F127/Ch MMs. Based on a series of tests, MTP-loaded F127/Ch MMs modified by 0.5 wt.% of Ch and 28 wt.% F127 was considered optimum formula with homogenous particle size around 138 nm, spherical morphology, high encapsulation efficiency (84.6%), and excellent stability. In addition, MTP-loaded F127/Ch MMs achieved enough concentration in due course and maintain a long releasing time. The results of in vivo study showed promising ocular bioavailability. The drug-loaded preparations needed to stay in the eye tissue for several hours and caused irritation. So carrier materials of ocular drug-loaded MMs must be biocompatible and nonirritating, and greatly adhesive, which require further investigation and look for new materials to increase ocular bioavailability. MMs strategy for nasal drug delivery

MMs strategy for ocular drug delivery Ophthalmic drug delivery showed high absorption rate, low occurrence rate of immunological reactions, and increased bioavailability by bypassing first-pass hepatic metabolism. For these reasons, eye tissues may be desired drug delivery location (Raju & Goldberg, 2008). It is reported that nanoscaled drug delivery systems benefited ophthalmic administration, such as nanoparticles, micelles, and liposomes (Civiale et al., 2009; Li et al., 2009; Gupta et al., 2010). But drug loss by tear fluid and nasolacrimal duct, short

Olanzapine (OZ), an antipsychotic drug for treating brain diseases, was apt to be pumped out by P-gp in blood–brain barrier (BBB) and metabolized by first-pass effect, which suffer9ed great loss before reaching the desired sites and led to low brain permeability (Altamura et al., 2003; Srivastava & Ketter, 2011; Jafari et al., 2012). Based on the unique physical contact of nasal cavity and cranial cavity in the anatomy, nasal mucosal delivery could facilitate drugs across BBB conveniently and effectively by avoiding first-pass metabolism, bypassing efflux of P-gp and reducing the side effects.

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Moreover, nasal drug delivery has been widely investigated on account of following reasons: numerous microvilli resulting in a large absorption area; rich blood vessels; rapid onset and direct drug delivery into blood circulation system. Therefore, intranasal delivery might be a promising route, which could directly deliver drugs into circulation system via the olfactory mucosa of nasal cavity (Misra & Kher, 2012). Owing to improved solubilization, enhanced stability, prolonged circulation time, and nano-carriers beneficial to nasal mucosal absorption, MMs were developed and investigated as a potential candidate for nasal administration (Kumar et al., 2008; Seju et al., 2011; Misra & Kher, 2012). Pluronic L121 (L121)/Pluronic P123 (P123) MMs were prepared for brain targeting of OZ via intranasal delivery (Abdelbary & Tadros, 2013). The optimized OZ-loaded L121/P123 MMs at 1:8:32 weight ratio of OZ: L121: P123 was achieved with small size (58.55 nm), high DL (1.84%) and EE (75.03%), controlled drug release feature (Wei et al., 2009; Kulthe et al., 2011). Through evaluation of toxicity on sheep nasal mucosa segments, OZ-loaded MMs showed favorable bio-safety (Seju et al., 2011). In addition, pharmacokinetic experiments conducted in rats revealed that OZ in L121/P123 MMs could be transported directly to the brain and achieved significantly high drug concentration in the brain. All these results confirmed that the developed OZ-loaded L121/P123 MMs would be a promising noninvasive delivery system by intranasal administration to brain (Wang et al., 2003; Zhang et al., 2004; Vyas et al., 2005). Many studies via intranasal delivery of drugs-loaded MMs have been designed and developed, and the results indicate that high drug absorption can be achieved. Despite the promising results, the development of nasal drug treatment also exposes some problems such as occurrence of nasal irritation, the potential for damage on the normal function of nasal mucosa and nasal-ciliary and intra- and interindividual variability in bioavailability. Therefore, it is urgent and necessary to search other polymer materials with better biocompatibility and more moderate irritation to form MMs for drug nasal delivery.

Conclusion Owing to numerous advantages including reduced pain, high safety in administration, and desired bioavailability, there are increasing focuses on the investigation and study of noninvasive administration methods. The primary task of noninvasive absorption is across the inherent physiological barriers. Through the past decades of research and development, amphiphilic block copolymers-based mixed micelles have displayed the feasibility and potential as noninvasive drug delivery vehicle, which could significantly improve the solubility and stability of loading drug and achieve adequate absorption. In this review, successful drug delivery of mixed micelles for noninvasive administration was highlighted, and these lessons were aimed to provide reference for further study.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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