Oral bioavailability of silymarin phytocomplex formulated as self-emulsifying pellets
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.
References (30)
- et al.
Formulation and in vitro and in vivo characterisation of a phenytoin self-emulsifying drug delivery system (SEDDS)
Eur. J. Pharm. Sci.
(2008) - et al.
Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories
Int. J. Pharm.
(1999) - et al.
Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs
Eur. J. Pharm. Sci.
(2005) - et al.
Self-emulsifying pellets prepared by wet-granulation in high-shear mixer: influence on formulation variables and preliminary study on the in vitro absorption
Int. J. Pharm.
(2005) - et al.
Bi-layered self-emulsifying pellets prepared by co-extrusion and spheronisation: influence of formulation variables and preliminary study on the in vivo absorption
Eur. J. Pharm. Biopharm.
(2008) - et al.
Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine
Int. J. Pharm.
(1998) - et al.
The influence of formulation variables on the properties of pellets containing a self-emulsifying mixture
J. Pharm. Sci.
(2001) Lipid-based formulations for intestinal lymphatic delivery
Eur. J. Pharm. Sci.
(2002)- et al.
Investigation on the co-extrudability and spheronisation properties of wet masses
Int. J. Pharm.
(2001) - et al.
Self-emulsifying drug delivery systems (SEDDS) with polyglycolized glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs
Int. J. Pharm.
(1994)
Solid state mechanochemical simultaneous activation of the constituents of the Silybum marianum phytocomplex with crosslinked polymers
J. Pharm. Sci.
Enhancing effect of Labrafac Lipophile WL 1349 on oral bioavailability of hydroxysafflor yellow A in rats
Int. J. Pharm.
Solid self-emulsifying nitrendipine pellets: preparation and in vitro/in vivo evaluation
Int. J. Pharm.
Analysis of silibinin in rat plasma and bile for hepatobiliary excretion and oral bioavailability application
J. Pharm. Biomed. Anal.
Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system
Eur. J. Pharm. Biopharm.
Cited by (43)
Design and evaluation of combined atorvastatin and ezetimibe optimized self- nano emulsifying drug delivery system
2020, Journal of Drug Delivery Science and TechnologyCitation Excerpt :Self-emulsifying drug delivery systems are isotropic mixtures of oils (natural or synthetic), surfactants (solid or liquid), hydrophilic solvents and co-solvents/surfactants [4]. Self-emulsifying systems posses lots of unique properties compared to other formulation strategies such as nanoparticles, solid dispersions and lipid based formulations [5,6]. These systems can emulsify rapidly and spontaneously in the gastrointestinal tract (GIT) when they diluted with GI fluids and create fine oil/water micro and nano-emulsions upon mild agitation [7,8].
Effect of amphiphilic graft co-polymer-carrier on physical stability of bosentan nanocomposite: Assessment of solubility, dissolution and bioavailability
2018, European Journal of Pharmaceutics and BiopharmaceuticsCitation Excerpt :This indicates the prime importance of solubility in relation to bioavailability [3]. Poor solubility of drugs has been addressed through the development of new drug delivery approaches such as reducing the particle size of the drug, micronisation [4], inclusion complexation [5,6], salt formation [7], pH adjustment [8], co-solvency [9–11], the liquisolid technique [12], supercritical fluid technology [13] and the use of self-emulsifying micro-emulsion systems [14]. Bosentan is a dual endothelin receptor antagonist used in the treatment of pulmonary arterial hypertension (PAH).
Preparation of a solid self-microemulsifying drug delivery system by hot-melt extrusion
2018, International Journal of PharmaceuticsCitation Excerpt :Safety can also be improved because solid systems are less irritating to the gastrointestinal mucosa (Tang et al., 2008; Singh et al., 2014). S-SMEDDS have been prepared by incorporating liquid SMEDDS (L-SMEDDS) into powders using different techniques, such as adsorption on solid carriers (Krupa et al., 2014), wet granulation by high-shear mixer (Franceschinis et al., 2005), spray drying (Yi et al., 2008), extrusion/spheronization (Iosio et al., 2011; Wang et al., 2010), and conventional wet (Deshmukh and Kulkarni, 2014) and melt granulation (Kishore et al., 2015). Hot-melt extrusion (HME) is an emerging process in the pharmaceutical industry, which has been successfully applied to enhance the solubility of poorly water-soluble drugs, allowing high drug loading and content uniformity (Crowley et al., 2007, Thiry et al., 2015).
Overview of solidification techniques for self-emulsifying drug delivery systems from industrial perspective
2017, International Journal of PharmaceuticsExtrusion–spheronization a promising pelletization technique: In-depth review
2016, Asian Journal of Pharmaceutical SciencesQuality-by-design based development of a self-microemulsifying drug delivery system to reduce the effect of food on Nelfinavir mesylate
2016, International Journal of PharmaceuticsCitation Excerpt :In addition, Tween 80 has highest emulsification efficiency with HLB of 15. It was found to be acceptable in SMEDDS formulation containing Carvedilol (Wei et al., 2005), silymarin (Iosio et al., 2011), Agaricoglyceride (Han and Han, 2011), Candesartan Cilexetil (Nekkanti et al., 2010). Therefore, a combination of Maisine 35–1 with Tween 80 and Transcutol HP was expected to provide maximum solubility of NFM.