Taste Masked Micropellets for Paediatric Use

INTRODUCTION

The application of bad tasting, often bitter APIs to children requires in most cases an effective taste optimisation. This can be achieved either by the addition of flavors or by masking the bad sensation. Hydrocortisone is on EMA unmet medical need priority list (2011) for the use in paediatric population for children suffering from all forms of Adrenal Insufficiency. As part of an European Commission Framework 7 Grant No. 281654 (work package 3), Glatt in cooperation with Diurnal Ltd (UK) developed in the TAIN project an immediate release formulation of hydrocortisone (Infacort®) for the treatment of adrenal insufficiency of neonates and children based on micropellets. Due to the bitter taste of the hydrocortisone a taste masking coating is necessary. The hypothesis is that the taste masking coat shall not retard the release of the hydrocortisone.

OBJECTIVE

Different polymers and ratios thereof were evaluated to obtain taste masked pellets [1]: • Ethylcellulose (EC) / Hydroxypropylmethylcellulose (HPMC) • Shellac • Shellac / Hydroxypropylmethylcellulose Hydrocortisone was layered on starter beads (Cellets 350), followed by a seal coat consisting of Hydroxypropylmethylcellulose. The taste masking was achieved by the application of ethylcellulose / hydroxypropyl methylcellulose, shellac or shellac / hydroxypropylmethylcellulose.

MATERIAL AND METHODS

Materials 

Hydrocortisone was purchased from Pfizer, Cellets 350 from Pharmatrans, HPMC from ShinEtsu. The taste masking polymers EC and shellac were from Colorcon and Harke Pharma (SBB Aquagold).

Methods 

Hydrocortisone pellets were produced by layering of Cellets 350 with API and binder (HPMC) using Glatt´s Wurster technology. With or without seal coating (HPMC), the pellets were taste masked by the application of EC / HPMC, shellac or shellac / HPMC, respectively [table 1].

Characterization of pellets 

The obtained pellets were characterized and compared concerning particle size (sieve analysis, Retsch AS200 control g), bulk density, residual moisture (loss on drying, Mettler Toledo Halogen Moisture Analyzer HB 43), and surface morphology (light microscopy, NIKON, SMZ-2T, stereo microscope, Moticam 2300 with Motic Image Plus 2.0, SEM and scanning electron microscopy (Nova Nano SEM 230, FEI).

In vitro dissolution 

In vitro dissolution was tested in 700 ml simulated gastric fluid pH 1,2, 75 rpm, applying USP method 2 (paddle) over 120 min. (n = 3).

The taste masking efficiency was analysed in phosphate buffer pH 7,0 (USP method 1), 25 rpm over 7 min. to simulate ´in mouth conditions´ (n = 3).

RESULTS & DISCUSSION

Formulations containing EC / HPMC (80 / 20) with or without seal coat exhibited the intended immediate release dissolution profiles (acc. to Ph. EU. 75 % release in 45 min.) for the tested coating levels 0,5 %, 1 % and 2 %. The dissolution rate decreased with increasing coating level. The applied seal coat resulted in an additional slight deceleration of the API release [figure 1].

Formulations containing a coating level of 4 % pure Shellac released below 3 % of API over the testing period, a coating level of 3 % resulted still in a strong retardation. Shellac / HPMC mixtures (75 / 25) resulted in a retardation for the 4 % coating level and in an immediate release formulation for the 3 % coating level [figure 2].

The taste masking of the HPMC / EC formulations tested in buffer pH 7,0, resulted in a very low release of API, within 3 min less than 3 %, within the testing period of 7 min less than 10 % API were released [figure 3].

CONCLUSION

The extremely bitter tasting API hydrocortisone was successfully taste masked maintaining an immediate release dissolution profile. Only cellulose based coating materials were applied. The formulation approach resulting in taste masked micropellets allows a flexible capsule filling over a wide range of dosages.

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1. Stoltenberg, I., Winzenburg, G., Breitkreutz, J. Solid Oral Dosage Forms for Children – formulations, excipients and acceptance issues, Eur. Ind. Pharm. 8 Feb., 4-7 (2011)

ACKNOWLEDGEMENT 

This work was funded by the Seventh Framework Programme (CORDIS FP7) of the European Commission, HEALTH. Call Identifier: FP7-HEALTH-2001- Single Stage-4.2.1. Project Identifier: 281654.

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Related Topics and Keywords

drug development, excipients, manufacturing, micropellet, Multiparticulates, ODTs, Oral Multiparticulates, orally disintegrating tablets (ODTs), paediatric, paediatrics, pediatric, pediatrics, pelletisation, taste masking