The oral route is the most common route of drug administration in view of its convenience and patient acceptance, even more so in the case of chronic therapies . Many existing and new therapeutic entities are characterized by a low degree of water solubility leading to poor and erratic oral bioavailability . In order to overcome this hurdle, several strategies such as micronization [3, 4], formation of solid solutions , microemulsification , and novel drug delivery systems, including nanoparticles , lipid-based vesicles [8, 9], have been proposed. Among these approaches, polymeric micelles, constituted of amphiphilic block copolymers, have attracted much attention in the decade [10–12]. Generally, block copolymers with concentration above the critical association concentration (CAC) self-assemble into spherical polymeric micelles with a core–shell structure in water: the hydrophobic segments aggregate to form an inner core being able to accommodate hydrophobic drugs with improved solubility by hydrophobic interactions; the hydrophilic shell consists of a brush-like protective corona that stabilizes the micelles in aqueous solution [13–15]. Polymeric micelles as novel drug vehicles present numerous advantages, such as reduced side effects of drugs, selective targeting, stable storage, stable toward dilution, and prolonged blood circulation time [15, 16]. Furthermore, polymeric micelles possess a nanoscaled size with a narrow distribution. They can protect drugs against premature degradation in vivo owing to their core–shell architecture [17, 18]. More importantly, polymeric micelles are fabricated according to the physicochemical properties of drugs and the compatibility between the core of micelles and drug molecules [15, 19]. From the pharmaceutical point of view, these amphiphilic carriers can solubilize more poorly water-soluble drugs within their hydrophobic core than most surfactant micelles. Since most of polymeric micelles are intended to be administered intravenously , the development of polymeric micelles via the oral route has been attracted attention ,,. Francis et al.  reported that the polymeric micelles exhibited high stability in gastric and intestinal fluids and no significant cytotoxicity toward Caco-2 cells, and the apical-to-basal permeability of Cyclosporine A (CyA) across Caco-2 cells increased significantly when loaded in polymeric micelles compared to free CyA. However, the absorption enhancement of drug loaded in polymeric micelles by oral delivery to rats has remained elusive. These prompted us to investigate the suitability of polymeric micelles as carriers to enhance the oral absorption of BCS Class II (i.e., low solubility–high permeability) drugs.
In the present study, CyA which belongs to BCS Class II was selected as a model drug. CyA is a highly lipophilic cyclic undecapeptide of 11 amino acids, and a highly effective immunosuppressive agent which is widely used in clinic for prevention of allograft rejection after organ transplantation and treatment of autoimmune disease [23–25]. Nevertheless, the oral bioavailability of CyA is low and irregular  due to the large molecular weight (1202 Da), low solubility in water (23 μg/mL at room temperature) , very high lipophilicity (log P = 2.92) , a substrate of P-glycoprotein, and vulnerable to intestinal mucosa and liver P450 3A4. The currently available oral formulation of CyA is in the form of a microemulsion containing a high concentration of Cremophor RH40 which has been reported to induce undesirable side effects, such as nephrotoxicity and induction of anaphylactic reactions in sensitized patients, although the oral absorption of CyA was remarkably enhanced. Consequently, there has been an urgent requirement to design and develop a novel dosage form of CyA aimed at decreasing the side effects of the current formulation while preserving the bioavailability of the drug.
The purposes of this study were to design and evaluate CyA-loaded polymeric micelles in vitro. Therefore, monomethoxy poly(ethylene glycol)–poly(lactide) (mPEG–PLA) with molecular weight of 2500, 5000, 10000, and 15000 Da for PLA block were strategically designed and synthesized by ring-opening polymerization ofd,l-dilactide (d,l-LA) in the presence of mPEG with molecular weight of 5000 Da, respectively. The micelles preparation, CyA solubilization, and micelles properties were investigated by the size measurement, drug loading content (LC), encapsulation efficiency (EE), stability in gastrointestinal tract, and in vitro drug release. Intestinal absorption in situ and ex vivo of CyA-loaded polymeric micelles was assessed, respectively.