Preparation and evaluation of self-microemulsifying drug delivery system of oridonin

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Abstract

The objective of this study was to develop self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability of the poorly water-soluble drug, oridonin. The influence of the oil, surfactant and co-surfactant types on the drug solubility and their ratios on forming efficient and stable SMEDDS were investigated in detail. The SMEDDS were characterized by morphological observation, droplet size and zeta-potential determination, cloud point measurement and in vitro release study. The optimum formulation consisted of 30% mixture of Maisine 35-1 and Labrafac CC (1:1), 46.7% Cremopher EL, and 23.3% Transcutol P. In vitro release test showed a complete release of oridonin from SMEDDS in an approximately 12 h. The absorption of oridonin from SMEDDS showed a 2.2-fold increase in relative bioavailability compared with that of the suspension. Our studies demonstrated the promising use of SMEDDS for the delivery of oridonin by the oral route.

Introduction

Oridonin (Fig. 1.), an ent-kaurane diterpenoid compound (C20H28O6), is isolated from the Chinese herb Raddosia rubescens (Hamsl.) Hara. Oridonin has shown various pharmacological and physiological effects such as anti-tumor, anti-bacteria, scavenging active oxygen free radicals, and anti-inflammatory properties (Fuji et al., 1989, Osawa et al., 1994, Zhang et al., 1999). The remarkable effect on treating human cancers especially esophageal and hepatic carcinoma has drawn great attention during the last 30 years (Zhang and Ren, 2003). Mechanisms of oridonin action include: inhibiting cell growth in many cancer cells; inducing cell apoptosis; inhibiting DNA, RNA and protein synthesis (Ikezoe et al., 2003, Leung et al., 2005, Li and Zhang, 1988, Liu et al., 2004). All of the commercially available tablets are crude extracts with low oridonin content leading to correspondingly low therapeutic effect and requiring a large dose (6–15 tablets per day). In addition, its poor solubility in water contributes to high variability in absorption. In order to improve the solubility and bioavailability, some efforts have been made in recent years, such as the study of oridonin-solid liquid nanoparticles for injection (Zhang et al., 2005). The oral route is the most physiologically beneficial and easily accepted by patients. Therefore, it is necessary to develop alternative oral routes of administration to enhance the bioavailability of poorly water-soluble drugs, and furthermore obtain more successful therapeutic effects.

The use of self-microemulsifying drug delivery system (SMEDDS) is one of the most interesting approaches to improving the solubility, dissolution and oral absorption for poorly water-soluble drugs (Constantinides and Scalart, 1997, Hauss et al., 1998, Holm et al., 2003, Kommura et al., 2001). A commercially available SMEDDS preparation is Neoral® (cyclosporine A). Now, much more attention has been focused on SMEDDS due to its excellent efficiency in delivering poorly water-soluble drugs and achieving an increase in bioavailability. SMEDDS are isotropic mixtures of oil, surfactant, co-surfactant, and drug substance. Microemulsion can be generated rapidly upon gentle mixing with water or aqueous media. It is thought that the microemulsion is spontaneously formed by the combined action of the specific pharmaceutical excipients with low free energy. The microemulsion droplets dispersed in the gastrointestinal tract provide large surface area and promote a rapid release of dissolved form of the drug substance and/or mixed micelles containing drug substance, and they may be also responsible for transporting the drug through the unstirred water layer to the gastrointestinal membrane for absorption. In addition to the enhanced dissolution of drugs by SMEDDS, another factor contributing to the increasing bioavailability is that lymphatic transport is responsible for a portion of the entire drug uptake as well. The lipid composition of SMEDDS may be related to facilitate the extent of lymphatic drug transport by stimulating lipoprotein formation and intestinal lymphatic liquid flux (Iwanaga et al., 2006, Porter et al., 2007). Over the past decades, SMEDDS have been extensively investigated to deliver various kinds of drugs (Cui et al., 2005, Kang et al., 2004, Kim et al., 2000, Khoo et al., 1998, Pouton, 2000, Wei et al., 2005). Only a few studies have been reported on the effective composition of traditional Chinese medicines (Cui et al., 2005, Wu et al., 2006).

The aim of our present study was to develop a SMEDDS formulation of oridonin to improve its oral bioavailability.

Section snippets

Chemicals and reagents

Oridonin was purchased from Nanjing Qingze Medical Technology Development. Co., Ltd. (Nanjing, China) with a purity of 98.2%. Polyoxyethyleneglycerol triricinoleate 35 caster oil (Cremopher EL®) and Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40®) were donated by BASF, Germany. Glyceryl monolinoleate (Maisine 35-1®), Caprylic/Capric triglyceride (Labrafac CC), PEG-8 glycol caprylate (Labrasol®), diethylene glycol monoethyl ether (Transcutol P®) were provided by Gattefosse, France;

Screening of oils and surfactants

The consideration for screening formulation of SMEDDS usually involves: the formulation composition should be simple, safe, and compatible; it should possess good solubility; a large efficient self-microemulsification region which should be found in the pseudo-ternary phase diagram, and have efficient droplet size after forming microemulsion (Constantinides, 1995, Klous et al., 2004, Kommura et al., 2001, Subramanian et al., 2004).

Appropriate vehicles should have good solubilizing capacity of

Conclusion

A SMEDDS containing poorly water-soluble drug, oridonin, was formulated for oral application. The components and their ratio ranges for the formulation of SMEDDS were obtained by solubility study, pseudo-ternary phase diagram construction, and droplet size analysis. The optimum formulation of the SMEDDS consisted of 30% mixture of Maisine 35-1 and Labrafac CC (1:1), 35% Cremopher EL, and 35% Transcutol P, which had sufficient drug loading, rapid self-microemulsification in aqueous media, and

Acknowledgements

This work was financially supported by Shanghai Municipal Committee of Science and Technology (Grant No.0243nm026) and Shanghai Education Committee (Grant No. 07ZZ53). The authors are very grateful to Dr. Don. Green's comments and suggestions on the manuscript.

References (31)

  • K. Osawa et al.

    Antibacterial trichorabdal diterpenes from Rabdosia trichocarpa

    Phytochemistry

    (1994)
  • C.W. Pouton

    Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems

    Eur. J. Pharm. Sci.

    (2000)
  • W. Wu et al.

    Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system

    Eur. J. Pharm. Biopharm.

    (2006)
  • Q.-Z. Zhang et al.

    Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain

    Int. J. Pharm.

    (2004)
  • P.P. Constantinides

    Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects

    Pharm. Res.

    (1995)
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