Elsevier

Phytomedicine

Volume 18, Issue 6, 15 April 2011, Pages 505-512
Phytomedicine

Oral bioavailability of silymarin phytocomplex formulated as self-emulsifying pellets

https://doi.org/10.1016/j.phymed.2010.10.012Get rights and content

Abstract

The objective of this study was to develop new solid self-emulsifying pellets to deliver milk thistle extract (silymarin). These pellets were prepared via extrusion/spheronisation procedure, using a self-emulsifying system or SES (Akoline MCM®, Miglyol®, Tween 80®, soy lecithin and propylene glycol), microcrystalline cellulose and lactose monohydrate. To select the most suitable formulations for extrusion and spheronisation, an experimental design of experiences was adopted. The screening amongst formulations (13 different blends) was performed preparing pellets and evaluating extrusion profiles and quality of the spheronised extrudates. The pellets were characterised for size and shape, density, force required to crush them. Although more than one type of pellets demonstrated adequate morphological and technological characteristics, pellets prepared from formulation 7 revealed the best properties and were selected for further biopharmaceutical investigations, including in vitro dissolution and in vivo trials on rats to study serum and lymph levels after oral administration of the pellets. These preliminary technological and pharmacokinetic data demonstrated that extrusion/spheronisation is a viable technology to produce self-emulsifying pellets of good quality and able to improve in vivo oral bioavailability of main components of a phytotherapeutic extract of more than 100 times by enhancing the lymphatic route of absorption.

Introduction

Standardized extracts from the fruit seeds of Silybum marianum (L.) Gaertn. (milk thistle, Asteraceae) are used in humans for the treatment of liver diseases of different etiologies (Morazzoni and Bombardelli 1995). The therapeutic use of these flavolignans is partly restricted by their insolubility in water. In particular, silybin, the main constituent, is sparingly soluble in water and spontaneously tends to form non-absorbable microcrystals, resulting in an unfavourable pharmacokinetics. The oral bioavailability of this extract is therefore limited and it is strictly dependent on the galenical preparation (Voinovich et al. 2009), as shown for various silymarin products on the market (Bulles et al. 1995). An innovative drug delivery system for these herbal actives, which would overcome these obstacles and consequently result in enhanced bioavailability, is therefore highly desirable. In order to achieve this goal, in this work, self-emulsifying pellets were developed and tested as a novel delivery system. This type of delivery system was designed in order to exploit its property to self-emulsify spontaneously and rapidly in the gastro-intestinal fluids, forming, under the gentle agitation given by gastro-intestinal motion, fine O/W emulsions. In such a system, the lipophilic drug is present in solution, in small droplets of oil. The large interfacial area generated by these small droplets, promotes drug diffusion into intestinal fluids (Pouton, 2000, O’Driscoll, 2002). Moreover, the emulsion droplets lead to a faster and more uniform distribution of the drug in the gastrointestinal tract, minimizing the irritation due to the contact between the drug and the gut wall (Charman et al., 1992, Shah et al., 1994, Khoo et al., 1998). In addition to the aforementioned effects, the improved drug bioavailability could be partly ascribed to the influence of the monoglyceride components of such self-emulsifying systems (SES), which are supposed to increase the permeability of the membrane (Chicco et al. 1999).

Up to now, solid self-emulsifying systems have been already produced by loading liquid SES on solid carriers using different technologies: extrusion/spheronisation (Newton et al., 2001, Wang et al., 2010), co-extrusion (Iosio et al. 2008), wet granulation in high shear mixer (Franceschinis et al. 2005), spray drying (Yi et al. 2008) or inclusion in microporous or cross-linked polymeric carriers (Chiellini et al. 2003) or in floating dosage form (Patel and Vavia 2010). The purpose of the present work is to apply the extrusion/spheronisation technology to the preparation of self-emulsifying pellets able to enhance the oral bioavailability of main components of milk thistle dry extract, silybin A and B. Additionally, the enhancement of the bioavailability was studied by measuring the rate of lymphatic absorption.

Section snippets

Materials

Milk thistle dry extract (containing 83% w/w silybin: 39% w/w silybin A and 44% w/w silybin B) was kindly donated by Indena® S.p.a., Milano. Microcrystalline cellulose (MCC, Microcel 101®, Faravelli, Milano, Italy), lactose monohydrate (LAC, Granulac 200®, Meggle, Wasserburg, Germany), mono- and di-glycerides (Akoline MCM®, AarhusKarlshamn, Sweden), polysorbate 80 (P, Montanox 80 VG PHA®, Seppic, Castres, France), medium chain fatty acids, C8–C10, (Migliol®812, Sasol GmbH Oleochemicals, Witten,

Results and discussion

After a set of preliminary trials with masses of different relative composition of three components (LAC, MCC, SES) and on the basis of previous similar experiences (Iosio et al. 2008), the quantitative limitations for each component were defined (Table 1 and Fig. 1). Among these constraints, to select the most suitable formulations for extrusion and spheronisation, 13 experimental blends have been considered with the help of an experimental design for mixture using NEMRODW program (Mathieu et

Acknowledgements

The authors would like to thank Indena, for kindly donating the dry extract used in this study, and F. Carli and E.E. Chiellini, for their helpful contributions on the droplet size analysis and A. Bargoni for technical assistance.

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