Evaluation in vitro and in vivo of curcumin-loaded mPEG-PLA/TPGS mixed micelles for oral administration

https://doi.org/10.1016/j.colsurfb.2016.01.017Get rights and content

Highlights

Abstract

The aim of this work is to prepare and characterize curcumin-loaded methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA)/D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) mixed micelles (CUR-MPP-TPGS-MMs), analyze the influence of formulation on enhancing the solubility of curcumin in water, and evaluate the improvement of intestinal absorption after oral administration. CUR-MPP-TPGS-MMs were prepared using the thin film diffusion method and optimized with the uniform design. The optimal CUR-MPP-TPGS-MMs were provided with high drug-loading (16.1%), small size (46.0 nm) and spherical shape. Low critical micelle concentration (CMC) and superior dilution stability showed that CUR-MPP-TPGS-MMs could keep integrity during the dilution of gastrointestinal fluid. In vitro drug release study indicated a sustained release of curcumin from CUR-MPP-TPGS-MMs in simulated gastrointestinal solution. The absorption mechanism of passive diffusion was obtained by measuring in situ intestinal absorption of CUR-MPP-TPGS-MMs in rats, and the best absorption segment was found to be the duodenum. The pharmacokinetics was evaluated in rats at the dose of 75 mg/kg by intragastric administration. The Cmax and mean retention time (MRT0–24) for CUR-MPP-TPGS-MMs were both increased, and the relative bioavailability of micelle formulation to curcumin suspension was 927.3%. These results suggested that mPEG-PLA/TPGS mixed micelle system (MPP-TPGS-MMs) showed great potential in improving oral bioavailability of curcumin.

Introduction

Oral administration, for its convenience and compliance, is preferred to other drug delivery routes especially for those patients with long-term medication [1]. Actually, in terms of many oral drugs, the bioavailability and curative effect are usually unsatisfactory. In gastrointestinal tract, three physiological barriers including physical, chemical and biochemical obstacles can explain the low bioavailability of current oral medication. Firstly, the intestinal epithelium and upper mucus as physical barriers can restrict the transport of drugs. Epithelial cells are connected through tight junctions forming natural impediment against the absorption of molecules [2]. On the surface of epithelium, mucus layer consists of water and crosslinked glycoproteins-mucins which represent negative charge [3]. Due to the higher moisture content, mucus layer can decrease the diffusion rate of hydrophobic drugs [4], [5]. Secondly, the chemical barriers refer to the gastric acid, bile and various digestive enzymes. These digestive fluid and ferments may cause the degradation of oral drugs and influence further absorption into human blood [6]. Another is the biochemical obstacle made up of metabolic enzymes and p-glycoprotein efflux of epithelial cells. They can inactivate drug features and transfer molecules from cytoplasm back to gastrointestinal lumen [7]. Furthermore, the liver first-pass effect also blocks the absorption efficiency of drugs into blood circulation. Thus, for improving oral bioavailability, the key point is to discover an efficacious strategy which can avoid or inhibit physiological barriers and facilitate drug transport across intestinal epithelial cells.

Curcumin is a yellow polyphenol compound and has been reported for its potential biological activities such as anti-bacterial or anti-fungal infection [8], [9], anti-gastriculcer [10], anti-ulcerative colitis [11] and anti-gastrointestinal cancer [12]. The activity of curcumin against cancer cells was significant in arresting cell cycle [13], inducing apoptosis by caspase induction or p53 signalling [14], [15], inhibiting cell proliferation and metastasis with modulation of pro-inflammatory or growth factors [16], [17], [18]. However, curcumin was critically limited in clinical application due to its low water-solubility [19], instability in alkaline or neutral solution, rapid metabolism in gastrointestinal tract and short plasma half-life [20], [21]. Compared with intravenous administration, the poor oral bioavailability (about 1% in rats) was confirmed by Yang and Jurenka [22], [23]. Hence, improving the solubility and stability of curcumin is the premise for desirable oral bioavailability.

Considering drug and physiological influences, different oral formulations have been developed in recent years such as nanoparticles, microspheres, microemulsions, micelles [24], [25], [26]. Polymeric micelles have been widely studied because of the smaller size, self-assembly ability, solubilization and protective effect for unstable drugs [27], [28]. TPGS is selected as one carrier material to form micelle structure. Besides solubilization, TPGS can inhibit P-gp mediated mutidrug resistance through influencing the activity of P-gp ATPase [29]. However, the high CMC value of TPGS often leads to the low stability of micelle dissociation in vivo [30]. With respect to this problem, TPGS is generally mixed with other amphiphilic materials such as PEG-phosphatidyl ethanolamine (PEG-PE) and PEG-distearoylphosphatidylethanolamine (PEG-DSPE) to increase stability and solubilization capacity [30], [31]. Similar to the above references, amphiphilic MPP is used as a carrier material for its excellent self-assembly ability and drug loading efficiency [32], [33]. PLA chains as hydrophobic part can form the micelle core encapsulating lipophilic molecules, and have been popularly used due to its biodegradability, non-toxicity and biocompatibility [34], [35]. With combination of PEG molecules, micelles can evade the adsorption of opsonins and further clearance of reticuloendothelial system [36]. The PEG corona can entangle water molecules forming hydrophilic shell and provide enough steric stability between micelles [37], [38]. Therefore, it can hypothesize that the application of TPGS and MPP as carriers for drug delivery can facilitate drug permeation across intestinal wall and improve absorption efficiency.

In the present study, MPP-TPGS-MMs were prepared to encapsulate curcumin for increasing drug solubility in water, protecting drugs against unfavourable gastrointestinal environment and enhancing the absorption of curcumin in digestive lumen. CUR-MPP-TPGS-MMs were optimized using the uniform design and characterized with the relative physicochemical properties. The absorption mechanism of CUR-MPP-TPGS-MMs was investigated by in situ intestinal perfusion experiment in rats. Moreover, the oral bioavailability of CUR-MPP-TPGS-MMs was evaluated in rats.

Section snippets

Reagents and chemicals

Curcumin was purchased from Sigma–Aldrich (St. Louis, MO, USA). MPP (mPEG2000-PLA2000) was supplied by Jinan Daigang Biotechnology Co., Ltd. (Jinan, China). TPGS was purchased from Wuhan Yuancheng Co., Ltd. (Wuhan, China). Tween® 80 was obtained from Shanghai Tai Wei Pharmaceutical Co., Ltd. (Shanghai, China). Methanol used for HPLC analysis was of HPLC grade. Ethyl acetate, dichloromethane, acetone, and other chemicals were of analytical grade.

Animals

Male Wistar rats (weight 250 ± 20 g) were provided by

Optimization of micelle preparation technology

To get the optimal preparation technology, single-factor experiments were carried out and the results are provided in Table 1. From the observed values at different levels, single factors like volume of hydration medium, hydration temperature, mass ratio between MPP and TPGS, and dosage of curcumin showed obvious effects on DL%, EE% and PD%, so these would be further studied in uniform experiments. Due to the little impact that other factors had on indicators, the final organic solvent and

Conclusion

CUR-MPP-TPGS-MMs were successfully prepared with high DL% and low PD%. The prepared mixed micelles were shown in spherical shape with small size. Low CMC value ensured better stability of micelles while diluted by gastrointestinal fluid. The in vitro drug release test revealed that CUR-MPP-TPGS-MMs represented a sustained release profile, which is consistent with the superior dilution stability. In situ intestinal absorption study indicated that passive diffusion was the main transcelluar way

Acknowledgment

This work is supported by a research grant (No.2013G0021815) from Department of Shandong Science and Technology, P.R.China.

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