Elsevier

Powder Technology

Volume 207, Issues 1–3, 15 February 2011, Pages 113-118
Powder Technology

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

https://doi.org/10.1016/j.powtec.2010.10.016Get rights and content

Abstract

In this investigation, the preparation of solid self-emulsifying drug delivery systems (solid-SEDDS) by means of a wet granulation process was optimized in a lab-scale high shear mixer in order to improve the dissolution rate of piroxicam, a poorly water-soluble model drug. With this aim, the classic liquid granulation binder was replaced with an oil-in-water microemulsion, loaded with the drug.

The microemulsion formulations were first selected on the basis of phase diagrams and their physicochemical properties, such as viscosity and droplet size. The best microemulsions were then used to prepare solid-SEDDS while maintaining the composition of the solid carrier and the operating conditions of the lab-scale high shear mixer used in this study.

These pellets demonstrated an emulsifying capability and their piroxicam release was significantly enhanced with respect to pure drug. Since their dissolution was a function of pellet size fraction, in the subsequent step the yield of the best performing fraction was further increased by modifying experimental conditions for pellet production (impeller speed and amount of povidone). In this way, the 400 μm pellet size fraction of the selected formulation was produced with a percentage yield of 42.5 by wt., with satisfactory technological properties and unchanged drug dissolution performance.

Graphical Abstract

In this paper, solid self-emulsifying drug delivery systems have been produced by means of a wet granulation process using an emulsion as a binder in order to increase oral bioavailability of piroxicam. The process has been optimized by setting the amount of povidone and the impeller speed during massing time.

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Research Highlights

► Self-emulsifying pellets were prepared and optimized in high shear mixer. ► The pellets demonstrated emulsifying capability. ► Solid-SEDDS significantly improved the piroxicam dissolution rate.

Introduction

Self-emulsifying drug delivery systems (SEDDS) are lipid-based formulations [1] and are defined as isotropic mixtures of natural or synthetic oils, surfactants and/or co-surfactants, which form microemulsion droplets on dilution with physiological fluid. They are able to spread readily in the gastrointestinal (GI) tract, where the digestive motility of the stomach and intestine provides the agitation necessary for self-emulsification.

The self-emulsification process is specific to the nature of the oil/surfactant pair, surfactant concentration, oil/surfactant ratio and temperature at which self-emulsification occurs. Some parameters have been proposed to characterize the self-emulsifying performance; these include rate of emulsification, microemulsion size distribution and the charge of resulting droplets. Among them, microemulsion droplet size is considered a decisive factor in self-emulsification/dispersion performance since it determines the rate and extent of drug release and absorption. The key step for SEDDS formulation is to find a suitable oil surfactant mixture that can dissolve the drug within the required therapeutic concentration. Liquid SEDDS can then be used to fill either soft or hard gelatin capsules [2], [3].

The drawback of this system includes GI tract irritation due to high surfactant concentrations, high manufacturing costs, interaction of the fill with the capsule shell, as well as problems due to storage temperature [4], [5]. These inconveniences can be avoided by preparing solid self-emulsifying drug delivery systems (solid-SEDDS). Such systems require the solidification of SEDDS into powder/nanoparticles to create various solid dosage forms. Solid-SEDDS combine the advantages of solid dosage forms (e.g. low production costs, high stability and reproducibility) with those of SEDDS (i.e. enhanced solubility and bioavailability) [6], [7], [8].

According to the Biopharmaceutic Drug Classification System (BCS) proposed by Amidon et al. [9], piroxicam, chosen as the model drug, is a class II molecule and its dissolution is the rate-controlling step in vivo drug absorption. Several techniques have been used to improve the oral bioavailability of piroxicam by accelerating its dissolution rate. These include mainly solid dispersion techniques based on cyclodextrin inclusion complexes, polyvinylpyrrolidone, and polyethylene glycols 4000 and 6000 [10], [11], [12], [13].

The aim of this study was to prepare solid-SEDDS by the high shear wet granulation process using a microemulsion as a liquid binder in order to increase the dissolution rate of piroxicam. Further experiments have been conducted with the purpose of optimizing the formulation of a solid carrier and experimental conditions.

Section snippets

Materials

Piroxicam (PX) EP-grade was provided by FIS (Vicenza, Italy). Propylene glycol-monolaurate (Lauroglycol™ 90), Diethylene glycol monoethyl ether (Transcutol® HP), medium chain triglycerides (Labrafac™ Lipophile WL1349), oleoyl macrogolglycerides (Labrafil® M1944 CS®) and caprylocaproyl macrogolglycerides (Labrasol®) were obtained from Gattefossé (Saint-Priest, France). Polyoxyl-35-castor oil (Cremophor® EL) was supplied by BASF (Ludwigshafen, Germany) and Monohydrate Lactose (LAC) by Meggle

Results and discussion

Absorption of compounds with aqueous solubility lower than 0.1 mg/ml (class II molecule) is often limited by the low dissolution rate. In this case, oral bioavailability can be increased by improving the drug dissolution rate using lipid formulations such as solid-SEDDS. These systems can be produced by a wet granulation process using a microemulsion as the liquid binder. The most important criterion for the selection of the components of microemulsion is to select the formulations in which the

Conclusions

The results show that the correct selection of microemulsion is a key factor in the preparation of self-emulsifying pellets in a high shear mixer, in order to be able to tailor appropriately the stability and amount of drug loaded and, in particular, to ascertain a suitable fluid binder and to obtain final pellets with the desired drug release characteristics. Once the pellet formulation matching all these requirements is defined, the best performing pellet size fraction can be optimized in

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