Solidification of carvedilol loaded SMEDDS by swirling fluidized bed pellet coating

https://doi.org/10.1016/j.ijpharm.2019.05.055Get rights and content

Abstract

Self-(micro)emulsifying drug delivery systems (S(M)EDDS) have emerged as effective vehicles for enhancing bioavailability of poorly water soluble drugs, however solidification of the systems represents a major challenge. Objective of this study was development of carvedilol loaded liquid SMEDDS and transformation into solid pellets employing fluid-bed coating technologies. Carvedilol-loaded formulation of SMEDDS was comprised of Capmul® MCM EP, castor oil, Kolliphor® RH40 and PEG 400. The obtained liquid SMEDDS mixed with fillers and polymers was layered onto MCC pellets. Coating process was conducted in the modified, swirl-flow based fluid bed coating device, which was proved superior over the conventional Wurster fluid bed, with lower agglomeration rate. Use of polymer was essential for entrapping SMEDDS in the coating layer(s). Self-microemulsifying properties as well as fast drug release as one of main SMEDDS advantages were preserved in the solid products. Addition of lactose into the coating dispersion and applying intermediate and surface film coating to the pellets enabled higher drug loading and prevented sticking of the pellets during handling and storage. Present study indicates that the (swirling) fluid-bed pellet coating technology is a promising strategy for preparation of solid SMEDDS-coated pellets with adequate drug loading capacity and enhanced release of poorly water soluble drug.

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.

References (74)

  • E. Franceschinis et al.

    Self-emulsifying pellets in a lab-scale high shear mixer: Formulation and production design

    Powder Technol.

    (2011)
  • E. Franceschinis et al.

    Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption

    Int. J. Pharm.

    (2005)
  • H. Friedl et al.

    Development and evaluation of a novel mucus diffusion test system approved by self-nanoemulsifying drug delivery systems

    J. Pharm Sci.

    (2013)
  • A. Gonçalves et al.

    Production, properties, and applications of solid self-emulsifying delivery systems (S-SEDS) in the food and pharmaceutical industries

    Colloids Surf. A Physicochem. Eng. Asp.

    (2018)
  • D.J. Hauss et al.

    Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor

    J. Pharm. Sci.

    (1998)
  • M.E. Heber et al.

    Carvedilol for systemic hypertension

    Amer. J. Cardiol.

    (1987)
  • A.J. Humberstone et al.

    Lipid-based vehicles for the oral delivery of poorly water soluble drugs

    Adv. Drug. Deliver. Rev.

    (1997)
  • T. Iosio et al.

    Bi-layered self-emulsifying pellets prepared by co-extrusion and spheronization: Influence of formulation variables and preliminary study on the in vivo absorption

    Eur. J. Pharm. Biopharm.

    (2008)
  • K. Bolko Seljak et al.

    Self-microemulsifying tablets prepared by direct compression for improved resveratrol delivery

    Int. J. Pharm.

    (2018)
  • J.H. Kang et al.

    Effects of solid carriers on the crystalline properties, dissolution and bioavailability of flurbiprofen in solid self-nanoemulsifying drug delivery system (solid SNEDDS)

    Eur. J. Pharm. Biopharm.

    (2012)
  • M. Luštrik et al.

    Characteristics of pellet flow in a Wurster coater draft tube utilizing piezoelectric probe

    Powder Technol.

    (2013)
  • J. Mandić et al.

    Overview of solidification techniques for self-emulsifying drug delivery systems from industrial perspective

    Int. J. Pharm.

    (2017)
  • D.H. Oh et al.

    Comparison of solid self-microemulsifying drug delivery system (solid SMEDDS) prepared with hydrophilic and hydrophobic solid carrier

    Int. J. Pharm.

    (2011)
  • S. Onoue et al.

    Novel solid self-emulsifying drug delivery system of coenzyme Q10 with improved photochemical and pharmacokinetic behaviors

    Eur. J. Pharm. Sci.

    (2012)
  • M. Pohlen et al.

    A redispersible dry emulsion system with simvastatin prepared via fluid bed layering as a means of dissolution enhancement of a lipophilic drug

    Int. J. Pharm.

    (2018)
  • R.C. Rowe et al.

    The influence of pellet shape, size and distribution on capsule filling–a preliminary evaluation of three-dimensional computer simulation using a Monte-Carlo technique

    Int. J. Pharm.

    (2005)
  • M. Serratoni et al.

    Controlled drug release from pellets containing water-insoluble drugs dissolved in a self-emulsifying system

    Eur. J. Pharm. Biopharm.

    (2007)
  • L.A.D. Silva et al.

    Preparation of a solid self-microemulsifying drug delivery system by hot-melt extrusion

    Int. J. Pharm.

    (2018)
  • B. Singh et al.

    Optimized nanoemulsifying systems with enhanced bioavailability of carvedilol

    Colloids Surf. B. Biointerfaces.

    (2013)
  • N. Thomas et al.

    Recent developments in oral lipid-based drug delivery

    J. Drug Deliv. Sci. Technol.

    (2013)
  • Z. Tian et al.

    Solidification of nanostructured lipid carriers (NLCs) onto pellets by fluid-bed coating: preparation, in vitro characterization and bioavailability in dogs

    Powder Technol.

    (2013)
  • T. Tran et al.

    Formulation of self-nanoemulsifying drug delivery systems containing monoacyl phosphatidylcholine and Kolliphor® RH40 using experimental design

    Asian J Pharm Sci.

    (2018)
  • N. Vora et al.

    Development and in-vitro evaluation of an optimized carvedilol transdermal therapeutic system using experimental design approach

    Asian. J. Pharm. Sci.

    (2013)
  • Z. Wang et al.

    Solid selfemulsifying nitrendipine pellets: preparation and in vitro/in vivo evaluation

    Int. J. Pharm.

    (2010)
  • Y. Weerapol et al.

    Enhanced dissolution and oral bioavailability of nifedipine by spontaneous emulsifying powders: effect of solid carriers and dietary state

    Eur. J. Pharm. Biopharm.

    (2015)
  • D. Yeom et al.

    Development of a solidified self-microemulsifying drug delivery system (S-SMEDDS) for atorvastatin calcium with improved dissolution and bioavailability

    Int. J. Pharm.

    (2016)
  • H. Yuasa et al.

    Suppression of agglomeration in fluidized bed coating. II. Measurement of mist size in a fluidized bed chamber and effect of sodium chloride addition on mist size

    Int. J. Pharm.

    (1999)
  • Cited by (17)

    • A study on the improved dissolution and permeability of ticagrelor with sodium oleate in a ternary system

      2022, Journal of Molecular Liquids
      Citation Excerpt :

      As a result, solubility improvement studies are often warranted to achieve solubilization. Many approaches, such as solid dispersions (SDs) [35,37], complexation [18], self-micro and nano-emulsifying drug delivery systems (SMEDDS and SNEDDS, respectively) [22,25,27], nanoparticles [6,11], micelles [5,7] and nanocrystals [3,10,33] have been used to increase the solubility of drugs. The oral bioavailability of drugs belonging to Class II of the Biopharmaceutics Classification System (BCS) must be improved as good permeability is only achieved when solubility is increased [20].

    • Development and exploration on flowability of solid self-nanoemulsifying drug delivery system of morin hydrate

      2022, Advanced Powder Technology
      Citation Excerpt :

      Understanding of powder flow properties are essential in pharmaceutical manufacturing, as the flow from the hopper, transportation, handling, tablet production, capsule filling, packaging, and scale-up operations [20]. Moreover, the powder flow is crucial for understanding the manufacturing process design, hopper design, operation conditions, storage, and quality requirements [21]. The inadequate powder flow was attributed to uneven filling of capsule shell, significant variation in tablet weight, drug content, tablet hardness, and particle segregation that often caused quality differentiation of products, batch rejection, and financial loss.

    • Evaluation of solid carvedilol-loaded SMEDDS produced by the spray drying method and a study of related substances

      2021, International Journal of Pharmaceutics
      Citation Excerpt :

      After redispersion of liquid SMEDDS in water, a monodisperse microemulsion was obtained, with a droplet size (Z-average value, Z-avg) of 23.1 nm and a low PDI (0.072). Aqueous dispersion of CARV-loaded SMEDDS was polydisperse (PDI 0.458) due to detection of two peaks: the first attributed to the droplets of microemulsion (22.3 nm), and the second to the nanoparticles of precipitated drug (149.4 nm), as reported in our previous study (Mandić et al., 2019). The redispersion time of liquid SMEDDS was immediate, as expected.

    • pH-sensitive castor oil/PEG-based polyurethane films for drug delivery

      2021, Journal of Drug Delivery Science and Technology
    • Solubilization of tadalafil using a tartaric acid and chitosan-based multi-system

      2021, International Journal of Biological Macromolecules
    View all citing articles on Scopus
    View full text