Surfactant-free solid dispersion of BCS class IV drug in an amorphous chitosan oligosaccharide matrix for concomitant dissolution in vitro - permeability increase

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Abstract

Saccharides have been applied as a water-soluble matrix for dispersing hydrophobic drugs homogeneously without the need to use surfactants in amorphous solid dispersions (ASD). Up to now, concomitant permeability improvement of BCS Class IV drug by such matrices have not been much appreciated. Herein, an amorphous chitosan oligosaccharide (COS) was used as matrix to prepare surfactant-free ASD of BCS class IV drug by the ball milling method, with curcumin (CUR) as a model drug. The DSC, XRPD, FTIR and physical stability experiments indicated that CUR was in an amorphous state with high physical stability and exhibited potential interactions with COS in the ASD. Non-sink dissolution in vitro studies showed the maximum dissolution concentration of all CUR-COS ASD (CUR and COS at weight ratios of 1:1, 1:2 and 1:4) reached ranging from 97.85 to 101.21 μg/mL, far above that of pure CUR. The supersaturated concentration remained for at least 24 h under non-sink condition. Caco-2 cell model revealed that, compared to the pure CUR group, the apparent permeability coefficients were increased by 1.72–4.44-fold in all three CUR-COS ASD, which was mainly attributed to opening the tight junctions of Caco-2 cells by COS. The pharmacokinetic study showed that all CUR-COS ASD groups exhibited significant enhancements in AUC0-∞, with 1.55–3.01-fold that of pure CUR (p < 0.01). Tmax of CUR was shortened after oral administration of all three ASD. The current study demonstrates the amorphous COS could be used as a promising matrix in ASD for enhancing the oral bioavailability of BCS class IV drug by improving dissolution behavior and membrane permeability.

Introduction

Novel pharmaceuticals which possess strong efficacies are being developed every day. Unfortunately, more than half of potential therapeutic agents show low water solubility which results in a limited bioavailability (Amidon et al., 1995; Lipinski, 2002; Thayer, 2010). With regard to the Biopharmaceutics Classification System (BCS) IV class drugs, the poor solubility as well as permeability are serious drawbacks that lower their bioavailability. To date, many attempts have been made to solve this problem. Lipid-based drug delivery systems whose mechanism was reported to be digestion of exogenous lipids is one of the physicochemical approaches (Li et al., 2012). Polymer nanocarriers such as polymeric micelles, nanoparticles and dendrimers have also been proved to enhance the drug bioavailability by designing ideal properties of the formulations (Chen et al., 2018). Furthermore, the hydrophobic drug was engineered to nanocrystal for improving formulation performance by increasing surface area/volume-ratio (Kocbek et al., 2006; Van Eerdenbrugh et al., 2008). However, owing to the drawbacks in developing the above-mentioned methods such as difficulties in scale-up, applicable quality control tests, confirmation of different procedures and wherein variants, development of drug formulations is still driven by trial and error (Ghadi and Dand, 2017).

Over the last decades, amorphous solid dispersions (ASD) has been commonly used as a technology for the formulation of hydrophobic drugs (Zhaojie et al., 2014). Super-saturation or over-dissolution is the dissolution properties of amorphous drugs under the non-sink dissolution conditions. Owing to the lack of crystalline lattice energy of the amorphous status, the concentration of super-saturation is significantly higher than the equilibrium solubility of its crystalline form (Liu et al., 2018; Miao et al., 2018). Commonly, water-soluble polymers, including polyvinylpyrrolidone (Hernandez-Patlan et al., 2018), poloxamer (Hu et al., 2015), soluplus (Parikh et al., 2018), cellulose derivatives (Li et al., 2013) and enteric polymers etc., are generally used in ASD formulations to maintain such “super-saturation” (Sun and Lee, 2015). Nowadays, the amorphous sugar-based matrix has also been proved to be effective in dispersing the drugs stably. The surfactant-free ASD used sugar as a matrix to enhance the water solubility and maintain supersaturation in physiological fluids (Chistyachenko et al., 2015; Takeda et al., 2017). Therefore, the development of such sugar-based ASD would expand the kinds of the carrier matrix, which could be applied for drugs with low aqueous solubility.

Chitosan oligosaccharide (COS), also called as chitosan oligomer or chitooligosaccharide, is produced by hydrolysis of the chitosan with a polymerization degree no larger than 20, and an average molecular weight <3900 Da (Mourya et al., 2011). It has been reported that COS is non-toxic and biocompatible, with a substantial exhibition of antioxidative, antimicrobial, anti-inflammatory, immuno-stimulating and anticancer activities (Muanprasat and Chatsudthipong, 2017). Due to its higher water solubility and lower viscosity, COS has also been widely used in the biomedical field, drug formulation development and functional food production (Wang et al., 2011). Most of all, COS was reported to improve intestinal absorption by its tight junction-opening effect on the intestinal epithelium (Gao et al., 2008). Our previous study also demonstrated that COS increased bioavailability of the ingredients (phenylethanoid glycosides, forsythoside A and chlorogenic acid), which was attributed to opening the tight junctions for enhancing apparent permeability coefficient in Caco-2 cell model (Zhou et al., 2014a; Zhou et al., 2014b; Zhou et al., 2013). Therefore, it is conceivable that designing solid dispersion with an amorphous COS as the matrix would enhance membrane permeability and substantially contribute to the increased bioavailability of BCS Class IV Drug.

Earlier studies have shown COS, in the application of liposomes and nanoparticles as surface modifiers, obtained the enhancement of permeability and systemic absorption (Aam et al., 2010; Wang et al., 2016). Besides, it has been demonstrated that COS hold promise in DNA delivery as micelles, nanoparticles, similar to chitosan (Wang et al., 2011). However, there was still no study performed on ASD taking COS as matrix to increase the oral bioavailability.

Recently, Curcumin (CUR), a natural polyphenolic compound existed in Curcuma longa, attracted increasing attention worldwide due to many biological efficacies, such as anti-inflammatory, antioxidant, anticancer, antimicrobial and antiangiogenic functions (Mirzaei et al., 2017). However, as a BCS Class IV drug, the therapeutic application of CUR remains limited because of its poor water solubility (0.96 μg/mL in simulated gastric fluid, pH = 1.0) (Fan et al., 2018), weak membrane permeability (0.7 × 10−7 cm/s in Caco-2 cell model) (Dempe et al., 2013) and low bioavailability (about 0.47%) (Gutierres et al., 2015). The current study aims to test the hypothesis that by surfactant-free solid dispersion of BCS Class IV drugs, which selected CUR as the model agent, in an amorphous COS matrix would enhance the in vivo bioavailability by not only increasing dissolution and stability but also improving permeability across the membrane of the epithelial cells.

Section snippets

Materials

Curcumin (CUR, Fig. 1) with purity of 98% was provided by Yuanye Biotechnology Co., Ltd. (Shanghai, China). Chitosan oligosaccharide (COS, Fig. 1) with the molecular weight <1000 Da and >90% degree of deacetylation, was obtained from Zhejiang golden shell pharmaceutical Co., Ltd. (Zhejiang, China). Tween-80 and methanol were purchased from National drug group chemical reagents Co., Ltd. (Shanghai, China). Verapamil was bought from Yuanye Biotechnology Co., Ltd. (Shanghai, China). Acetonitrile,

Preparation of CUR-COS ASD

Various techniques such as melting, solvent evaporation and ball milling usually applied to solid dispersion preparation. Among these, the melting method possesses certain drawbacks such as operation in high temperature and difficulty in the later process including product harvesting and pulverization. Solvent evaporation method also confronts the challenge to remove the residual solvent. However, ball milling could be considered as a “green” method because of being free of organic solvents or

Conclusion

Taking the potential merits and reduced adverse effects into account, ASD could be regarded as appropriate formulations for delivery of hydrophobic pharmaceutical ingredients. However, there is little research focused on BCS Class IV drugs by ASD up to now. The current study used amorphous COS as matrix to prepare surfactant-free ASD by the ball milling method, with CUR as a model drug. The DSC, XRPD, FTIR and physical stability study indicated that CUR is in an amorphous state with well

Acknowledgments

The authors acknowledge financial support from the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and the funding from the National Natural Science Foundation of China (81873013).

Declaration of interest

The authors declare no conflicts of interest.

References (41)

  • C. Liu et al.

    Oral bioavailability enhancement of beta-lapachone, a poorly soluble fast crystallizer, by cocrystal, amorphous solid dispersion, and crystalline solid dispersion

    Eur. J. Pharm. Biopharm.

    (2018)
  • H. Mirzaei et al.

    Phytosomal curcumin: a review of pharmacokinetic, experimental and clinical studies

    Biomed. Pharmacother.

    (2017)
  • C. Muanprasat et al.

    Chitosan oligosaccharide: biological activities and potential therapeutic applications

    Pharmacol. Ther.

    (2017)
  • D.D. Sun et al.

    Probing the mechanisms of drug release from amorphous solid dispersions in medium-soluble and medium-insoluble carriers

    J. Control. Release

    (2015)
  • B. Van Eerdenbrugh et al.

    Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products

    Int. J. Pharm.

    (2008)
  • G. Wang et al.

    Preferential tumor accumulation and desirable interstitial penetration of poly(lactic-co-glycolic acid) nanoparticles with dual coating of chitosan oligosaccharide and polyethylene glycol-poly(D,L-lactic acid)

    Acta Biomater.

    (2016)
  • M. Zhaojie et al.

    Amorphous solid dispersion of berberine with absorption enhancer demonstrates a remarkable hypoglycemic effect via improving its bioavailability

    Int. J. Pharm.

    (2014)
  • W. Zhou et al.

    Effect of chito-oligosaccharide on the oral absorptions of phenolic acids of Flos Lonicerae extract

    Phytomedicine

    (2014)
  • W. Zhou et al.

    Effect of chito-oligosaccharide on the intestinal absorptions of phenylethanoid glycosides in Fructus Forsythiae extract

    Phytomedicine

    (2014)
  • B.B. Aam et al.

    Production of chitooligosaccharides and their potential applications in medicine

    Mar. Drugs

    (2010)
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