Research paper
Spray coated pellets as carrier system for mucoadhesive drug nanocrystals

https://doi.org/10.1016/j.ejpb.2005.09.005Get rights and content

Abstract

High pressure homogenization can be employed to produce drug nanocrystals with a number of advantages, like improved solubility behaviors, better drug targeting or even increased mucoadhesiveness. To obtain a controlled drug delivery system it is necessary to transform the resulting nanosuspension into a solid dosage form. The present study shows the feasibility to use a mucoadhesive nanosuspension of poorly soluble hydrocortisone acetate produced by high pressure homogenization as layering dispersion in a fluidized bed process, followed by the application of an enteric coating to achieve a controlled drug release. To point out the advantages of drug nanocrystals the new fomulation was compared with a formulation containing micronized drug. Both formulations were characterized with regard to their particle size and crystallinity by using laser diffractometry, photon correlation spectroscopy and X-ray diffraction. The pellet morphology was characterized by using the environmental scanning electron microscopy (ESEM). In the in vitro dissolution tests an accelerated dissolution velocity and an increased drug release could be shown for the pellets containing drug nanocrystals.

Introduction

In order to improve the drug targeting and to enhance the oral bioavailability of problematic drugs, for instance peptides, proteins and poorly soluble drugs, new drug delivery systems have to be developed. Chitosan, a natural polymer obtained by the alkaline deacetylation of chitin, has many interesting properties for oral drug delivery. Chitosan based dosage forms are able to adhere to mucosal surfaces, the decreased absorption distance increases the local drug concentration without dilution or degradation in luminal fluids (an important factor for better drug absorption or local treatment). The direct mucosa contact prevents labile drugs, such as proteins, from degradation and chitosan is able to open tight junctions which leads to a better absorption of proteins [1]. The adherence to the mucosa leads to a prolonged drug release as well. For that reason many approaches were attempted in the development of chitosan containing dosage forms, such as tablets, capsules, microparticles or multiparticulate pellet systems.

Multiparticulate drug delivery systems, particularly coated pellet systems, possess many advantages in comparison to single-unit dosage forms, such as more predictable gastric emptying [2] and more uniform drug dispersion in the gastrointestinal (GI) tract with less inter- and intraindividual variability in bioavailability [3]. Important ways for the pellet preparation are solution layering (from aqueous or non-aqueous drug solutions) and, for less soluble drugs, dispersion layering. For suspension layering, normally micronized drugs, obtained by jet-milling or wet-grinding, are employed [4]. In case of poorly soluble or practically insoluble drugs the micronization often results in a low and varying bioavailability, especially if colonic drug delivery is desired. One approach to increase the solubility of such problematic drugs is the nanonization by using the high pressure homogenization, i.e. preparation of drug nanocrystals [5], [6]. Due to the reduced particle size within the nanometer range after high pressure homogenization, the drug nanocrystals show an increased dissolution velocity and higher saturation solubility in comparison to micronized drugs [7]. This leads to a higher bioavailability of drugs administered as nanosuspension [8], [9]. Smaller particles have also shown a higher affinity to inflamed gut regions [10].

The combination of the advantages of the mucoadhesion principle and nanonization of the drug consequently leads to dosage forms with increased efficiency [11], [12]. In order to obtain a controlled release dosage form with better physical stability the nanosuspension has to be transformed into a solid, dry, multiparticulate product, for instance into a pellet formulation.

To date only few data are available on the incorporation of drug nanocrystals into solid dosage forms, although one multiparticulate dosage form containing drug nanocrystals has already entered the market (Emend® by Merck, pellets containing aprepitant). The first study dealing with this topic was performed by Vergote et al. [13]. The approach of this study was to incorporate nanocrystalline ketoprofen as spray-dried powder into controlled release matrix pellets. The direct incorporation of a mucoadhesive nanosuspension into an enteric coated matrix pellets without a drying step could be shown by Möschwitzer et al. [14].

The new approach in this study was to formulate the poorly soluble model drug hydrocortisone acetate (1.41 mg/100 mL) [15] as mucoadhesive nanosuspension, which can be directly used as a layering dispersion in a fluidized bed process. The pellet morphology was investigated by electron microscopy. The dissolution profiles were examined with regard to the size of the drug particles and the coating level of the enteric polymer.

Section snippets

Materials

Micronized hydrocortisone acetate (HCA) was purchased from Synopharm (Barsbüttel, Germany). Poloxamer 188 from BASF (Ludwigshafen, Germany), chitosan chloride (Protasan® CL 213) from Novamatrix (Drammen, Norway), Acetonitrile from Merck (Darmstadt, Germany), Triethylcitrate (TEC) from Sigma (Steinheim, Germany) and water was supplied by Millipore MilliQ-Plus. Eudragit® L 30 D-55 was kindly provided as a gift from Röhm (Darmstadt, Germany).

High pressure homogenization/preparation of the layering dispersions

The nanonized layering dispersion (formulation A) was

Nanosuspension preparation and size measurement results

The preparation of drug nanocrystals by high pressure homogenization, established by Mueller et al., is a well known technique to increase the solubility and dissolution velocity of poorly soluble drugs, either in aqueous or in non-aqueous media [5], [6]. Cavitation and shear forces during the high pressure homogenization lead to a particle size reduction of the drug. This consequently leads to a larger surface area with an increased dissolution velocity, derived from the Noyes–Whitney

Conclusions

Pellets containing drug nanocrystals were successfully produced by layering the freshly prepared nanosuspension directly onto sugar spheres using a fluidized bed coater. Afterwards an enteric coating was applied to achieve a pH-dependent drug release by using the same equipment. The used chitosan chloride works as a binder in the layering process as a physical stabilizer for the nanosuspension, as well as a mucoadhesive excipient, to increase the drug bioavailability. The comparison between

Acknowledgements

JM and RHM wish to thank the Berliner Nachwuchsförderung for financial support (grant No. 038087). JM would like to acknowledge the valuable support of Katja Bringe (University of Bonn) and the support with materials by Röhm Pharma.

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