Solidification of carvedilol loaded SMEDDS by swirling fluidized bed pellet coating
Graphical abstract
Introduction
Enhancing solubility of poorly water-soluble active pharmaceutical ingredients (APIs) is one of the key challenges for pharmaceutical technologists as it enables achieving adequate biopharmaceutical properties of the pharmaceutical product. Self-(micro)emulsifying drug delivery systems (S(M)EDDS) have emerged as effective vehicles for enhancing oral bioavailability of poorly water soluble drugs by different mechanisms. In addition to increasing solubility and avoiding drug dissolution step in the gastrointestinal tract (GIT) the correct choice of excipients can also improve drug absorption by inhibition of P-glycoprotein-mediated drug efflux and avoidance of first-pass metabolism in the liver by increased lymphatic transport directly to the systemic circulation (Balakrishnan et al., 2009, Constantinides and Yiv, 1995, Friedl et al., 2013, Humberstone and Charman, 1997, Pouton and Porter, 2008).
A BCS class II drug carvedilol (CARV), a vasodilating noncardioselective β-blocker used in the treatment of certain cardiovascular diseases (Colucci et al., 1996, Dargie, 2001, Ruffolo et al., 1990), is a very suitable candidate for incorporation into SMEDDS, since it is not only poorly soluble in water (Brook et al., 2007) but also undergoes extensive first-pass metabolism in the liver (Heber et al., 1987, Morgan, 1994).
SMEDDS are a mixture of lipids, surfactants, co-surfactants or co-solvents in specific ratio that spontaneously form microemulsion in contact with water. Currently available marketed formulations are in a form of hard or soft gelatine capsules filled with liquid or semi-solid SMEDDS (Thomas et al., 2013). To avoid high investment costs and low production rate of this capsule liquid filling technology and also enhance product stability, researchers are investigating different SMEDDS solidification techniques that are detailly described in many review articles (Gonçalves et al., 2018; Joyce et al., 2018, Mandić et al., 2017, Tan et al., 2013). Despite the large number of studies in the field, no solid SMEDDS (sSMEDDS) are available on the market yet as solidification of these systems represents a major challenge for achieving high drug loading while preserving self-emulsifying properties that are responsible for bioavailability enhancement (Li et al., 2013). Most researchers are focused on highly porous carriers enabling high SMEDDS and consequently drug loading, followed by (direct) compression into tablets (Bolko Seljak et al., 2018, Gumaste et al., 2013, Weerapol et al., 2015, Mura et al., 2012). However, adsorption of SMEDDS to these carriers is linked with risk of incomplete drug release (Agarwal et al., 2009, Bolko Seljak et al., 2018, Chavan et al., 2015, Van Speybroeck et al., 2012;). Spray drying is another promising technique for solidification of SMEDDS (Kim et al., 2015, Oh et al., 2011, Onoue et al., 2012) and further compressing of produced powders/granules into tablets (Čerpnjak et al., 2015), nevertheless special care must be given to the selection of solid excipients to avoid impairment of self-emulsifying properties (Kang et al., 2012, Li et al., 2013). Recently solidification of SMEDDS by hotmelt extrusion, another industrially viable technology, was also investigated (Silva et al., 2018).
Alternatively, solid SMEDDS can also be formulated as self-(micro)emulsifying pellets that merge all the advantages of SMEDDS with those typically associated to pellets, known as multiunit and flexible, patient friendly dosage form enabling controlled drug release, and reduced local irritation in GIT (Abdalla and Mäder, 2007, Ghebre-Sellassie, 1989, Liu et al., 2014).
The most investigated method for self-emulsifying pellet production is an extrusion spheronization technology, a well established multistep process known for its ability to produce pellets with minimal excipients necessary (Abdalla et al., 2008, Iosio et al., 2008, Serratoni et al., 2007, Wang et al., 2010. Zhang et al., 2012), appropriate only for thermally stable drugs and SEDDS excipients (Hengsawas Surasarang et al., 2017, Huang et al., 2016). Wet granulation as more straightforward technique was also reported to enable successful production of self-emulsifying pellets by using high-shear mixer (Franceschinis et al., 2005, Franceschinis et al., 2011). Low SMEDDS content and possible stickiness of the pellets are reported as major disadvantages of self-emulsifying pellets. Among industrially applicable approaches, preparation of self-microemulsifying pellets by fluid bed coating/layering technology is also highly remarkable, since it is a one-step process and the technology is already widely used in the pharmaceutical industry. In addition fast drug release is expected if drug loaded SMEDDS is layered on the inert pellet cores as no disintegration of the dosage form is needed for drug release. Utilizing this technique for production of pellets risk for degradation of thermally instable drug and/or SMEDDS is reduced.
For coating of small particles, particularly pellets, bottom spray Wurster coating chamber is commonly used. Since it is a one-step technique, the advantage lies in a use of a single piece of equipment for pellet coating and drying, in addition to uniform coating layer deposition and acceptable process yield (Christensen and Bertelson, 1997, Porter and Bruno, 1990). On the other hand the agglomeration of particles can occur, in particular when coating small particles (Fukumori et al., 1992, Yuasa et al., 1999). Luštrik and coworkers (Luštrik et al., 2012) showed that when using a conventional bottom spray Wurster coating chamber (CW), pellets with a smaller diameter received significantly less coating material, compared to those with larger diameters. Whereas with the swirl generator-equipped Wurster chamber (SW) nearly uniform coating thickness was achieved regardless of the pellet size. Also coating process yield was improved and degree of agglomeration reduced (Dreu et al., 2012).
Up to now only few studies have investigated the fluid bed coating/layering techniques involving SMEDDS and lipid solidification. Lei et al. (Lei et al., 2011) have shown that up to 40% of the liquid SNEDDS can be entrapped in the coating layer with the use of film coating polymer, however increased coating weight (up to 400%) significantly decreased the redispersion rate. An outer layer of PVP K30 protected the pellets from aggregating and did not significantly affect redispersion rate. Tian et al. (Tian et al., 2013) converted liquid nanostructured lipid carriers to solidified pellets by fluid-bed coating technique where PVP K17 was used as coating polymer and fast fenofibrate release was achieved. Reconstituted nanostructured lipid carriers had significantly larger particle size than liquid formulation, however similar in vitro and in vivo performance.
The aim of our study was to originate CARV-loaded SMEDDS coated pellets employing (swirling) fluid-bed layering technology as a well-established one-step technique in industrial pharmacy. Various oils and surfactants were screened for CARV solubility and (pseudo)ternary phase diagrams were constructed for selected combinations of excipients to obtain optimal SMEDDS composition. CARV-loaded SMEDDS were included in coating dispersion sprayed on nonpareil pellet cores. The use of oily dispersion during the coating process can result in extensive formation of pellet agglomerates. To avoid agglomeration phenomena during the production of high SMEDDS loaded pellets with preserved self-emulsifying properties, adaptation of construction, process and formulation parameters and their influence on coating performance was studied.
Section snippets
Materials
Carvedilol and Pharmacoat® 606 were provided by Krka, d.d., Novo mesto, Slovenia. PVP K30, mannitol and lactose 200 mesh were provided by Lek, d.d., Ljubljana. PEG 6000, Tween® 80 and Tween® 85 were obtained from Fluka, Switzerland. Kollicoat® IR and Cremophor EL® were obtained from BASF Corporation, USA. Kolliphor® RH 40, Tween® 20 and PEG 400 were obtained from Sigma Aldrich, USA, Tween® 20 and Span® 80 from Merck KGaA, Darmstadt, Germany. Labrasol® and Peceol™ were obtained from Gattefossé,
Formulation of liquid SMEDDS
With an aim to originate SMEDDS-coated pellets with high CARV loading, the liquid SMEDDS with desired characteristics, such as high capacity to solubilize CARV and formation of stable (micro)emulsion with droplet size below 100 nm after dispersing in aqueous media, was firstly developed. CARV solubility and stability studies were performed in selected triglycerides and mixed glycerides with medium chain fatty acids, long chain fatty acids, surfactants, co-solvent and their mixtures to define
Conclusion
Present study confirmed that fluid bed coating technique is an appropriate method for SMEDDS solidification, which enables relatively high CARV content in SMEDDS coated pellets. Success of the coating process depends greatly on process and construction variables. In order to achieve high process yield and minimize pellet agglomeration parameters such as dispersion flow rate, inlet air humidity, atomizing pressure and product temperature must be set appropriately. With swirl-flow generator the
Declaration of Competing Interest
None.
Acknowledgements
This study was supported by the Slovenian Research Agency through the P1-0189 research programme and by Krka, d.d., Novo mesto, Slovenia. D. Žganc is thanked for his help in the experimental work.
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