Formulation of a lyophilized dry emulsion tablet for the delivery of poorly soluble drugs

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Abstract

The objective was to develop a dry emulsion tablet for the flash delivery of poorly water soluble drugs using a lyophilization technique. The influence of formulation parameters on the characteristics of the lyophilized dry emulsion (LDE) tablets was investigated. Oil-in-water emulsions were made using a medium chain triglyceride as the oil phase and a maltodextrin solution (5–20% w/v) as the water phase. In addition different emulsifier-tablet binder combinations were evaluated. The emulsions were filled into PVC blisters and freeze-dried. The resulting tablets were analyzed for strength, disintegration time, porosity and residual moisture. X-ray diffractions and scanning electron micrographs (SEM) of the fracture plane of the tablets were taken. Dissolution tests were performed on lyophilized tablets containing hydrochlorothiazide (HCT) as a model drug. A significant influence of the maltodextrin type on the tablet disintegration time was seen. Maltodextrin formulations with a high dextrose equivalent (DE) value (DE38) resulted in a faster disintegration time compared to DE12 and DE24 maltodextrin formulations (p<0.05). There was a significant influence of maltodextrin concentration on tablet strength, disintegration time and porosity. Tablet strength increased significantly with increasing maltodextrin concentration (p<0.05). The porosity of the tablets made with DE38 5%, 10% and 20% (w/v) was 92%, 85% and 81%, respectively. SEM pictures showed an increase in pore diameter with a decreasing maltodextrin concentration. No significant influence of Miglyol 812 concentration on tablet strength was observed. A significant influence of methylcellulose concentration, used as emulsifier-tablet binder (Methocel® E15LV), on tablet strength and disintegration time was observed. Dissolution tests on 25 mg HCT containing tablets resulted in a % HCT release of 35.1% and 24.1% for the LDE tablet and conventional tablet, respectively. No significant influence of the oil content in the LDE tablets on the HCT release was observed. It can be concluded that maltodextrins and methylcellulose are useful excipients in the formulation of LDE tablets. The concentration of maltodextrin, the medium chain triglyceride and methylcellulose influenced the tablet characteristics.

Introduction

Paediatric and geriatric patients may have difficulties swallowing or chewing pharmaceutical dosage forms for oral administration. Tablets that rapidly dissolve upon contact with saliva in the buccal cavity could present a solution to those problems and so there is an increased interest in fast dissolving dosage forms for buccal, sublingual and oral administration.

Solid state emulsions were described by Shively and Myers (1993). Shively reported on the production of solid state emulsions using sucrose and mineral oil (Shively, 1993). Dry emulsions prepared by spray drying an oil-in-water emulsion, containing lactose and maltodextrin in the aqueous phase and griseofulvin as model drug were evaluated as a potential drug delivery system (Pedersen et al., 1995). Freeze drying of an oil-in-water emulsion can be an alternative method for the production of dry emulsions. Bamba et al. (1995)reported that a slow cooling rate and the addition of amorphous cryoprotectants have the best stabilizing effects during lyophilization of oil-in-water emulsions. The characteristics of a dry emulsion containing griseofulvin prepared by lyophilization using mannitol as the solid support was reported by Vyas et al. (1992). Corveleyn and Remon (1997)proved that maltodextrins are a useful matrix forming agent in the formulation of freeze-dried tablets. Lyophilized dry emulsion tablets, using maltodextrins as amorphous cryoprotectant and solid support could be an interesting dosage form for the delivery of poorly soluble drugs. In this study, the influence of different formulation parameters on the characteristics of the lyophilized dry emulsion (LDE) tablets was investigated.

Dissolution studies were performed using hydrochorothiazide as a poorly soluble model drug.

Section snippets

Materials

The spray-dried maltodextrins (Eridania-Béghin Say-Cerestar, Vilvoorde, Belgium) had different dextrose equivalents (DE) and were obtained by enzymatic hydrolysis of corn starch (C★PUR01910 (DE=14), C★PUR01921 (DE=22), C★PUR01934 (DE=38)), potato starch (C★PUR01906 (DE=6)) and waxy maize starch (C★PUR01908 (DE=9)). Methylcellulose (Methocel® A15LV, 2% aqueous solution viscosity 15 mPa·s (20°C)), hydroxypropylmethylcellulose (Methocel® E15LV, 2% aqueous solution viscosity 15 mPa·s and Methocel®

Results and discussion

It has been reported that emulsified formulations result in an improved absorption of both phenytoin (Chakrabarti and Belpaire, 1978) and griseofulvin (Carrigan and Bates, 1973) compared to non-emulsified lipid formulations. Solid state emulsion refers to the dispersion of an immiscible oil phase within a solid phase (Myers and Shively, 1993). Due to the presence of an oil phase, active ingredients can be dissolved in the oil, eliminating the need for a cosolvent. Different techniques have been

Acknowledgements

The authors wish to thank Eridania-Béghin Say-Cerestar (Vilvoorde, Belgium) for the generous supply of the maltodextrins and for the use of the TAXT2 texture analyzer. Methocel® was kindly provided by Colorcon (Kent, UK). Prof. Wettinck (Lab. Non-Ferrometallurgie, University of Gent, Belgium) is kindly acknowledged for the use of the scanning electron microscope.

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