(W1030-08-50) Development of Delayed Release Capsule Formulations of a Nutraceutical Active Compound Using Hydrophilic Matrix Systems

Purpose: The advantages and considerations of using hypromellose as hydrophylic gel forming polymer for the development of delayed release matrix tablets are intensively studied compared to delayed release capsule formulation. [1]. For extended-release capsules formulations, excipients like ethylcellulose (hydrophobic polymer) or gums are used as coating/granulating agent for granules/pellets [2]. The aim of the study is to determine the effectiveness of hypromellose as matrix agent once filled into capsules. Understanding the potential impact of the densification of the plugs on the gel layer formation and thus also on the drug release profile using the dosator technology as semi-automated capsule filling technique [3].

Methods: Caffeine (Emprove^® essential) was selected as high soluble active ingredient and was purchased from Merck KGaA (Darmstadt, Germany). Three grades of hypromellose type 2208 TYLOPUR Xtend Nutra^® namely 4T, 15T and 100T, manufactured by SE Tylose GmbH & Co.KG. (Wiesbaden, Germany), microcrystalline cellulose PH 102 (MCC PH 102) as Pharmacel^® 102 from DFE Pharma (Goch, Germany), magnesium stearate from Sigma-Aldrich (Taufenkirchen, Germany), hypromellose based capsules Vcaps® Plus provided by Lonza (Colmar, France) were used for this study. Preparation of formulations and capsules filling: All the materials were mixed following the formulations listed in Table 1. A pre-trial was performed by hand filling of capsules size 0. Filling weight and dissolution profiles were analysed. Further experiments were conducted using a semi-automatic capsule filling machine Initia from MG2 (Pianoro, Italy) by the dosator technique (Figure 1). Filling weight and dissolution profiles at pH 1.2 were analysed. The dissolution profile was performed at pH 1.2, 37°C, paddle.

Results: Hand filling: 200 mg capsules filling weight was the maximum quantity of powder that could be filled into the capsules size 0 by hand. No slug could be obtained. The dissolution profiles measured showed a delayed release of caffeine over 5 hours but no significant differences could be seen between the formulations containing 10% hypromellose versus 20% hypromellose content (Figure 2). The viscosity range of the TYLOPUR Xtend Nutra^® 4T (Hypromellose 2208, 4000 mPa·s at 2% solution in water), TYLOPUR Xtend Nutra^® 15T (Hypromellose 2208, 15000 mPa·s at 2% solution in water), TYLOPUR Xtend Nutra^® 100T (Hypromellose 2208, 100000 mPa·s at 2% solution in water) didn’t have a strong effect on the decrease of the dissolution profile. Semi-automatic filling: The capsule filling weight increased to approximately 480 to 506mg. Soft plugs could be obtained by applying some compression into the dosator. Compared to the hand filling capsules, a delayed release of the caffeine was possible up to 10 hours with 20% hypromellose TYLOPUR Xtend Nutra^® 100T used into the formulation. Variations were seen depending on the hypromellose grade used (Figure 3).

Conclusion: A delayed release formulation based on caffeine as model active compound was achieved using hypromellose as a matrix polymer in capsule formulations. The dosing technique significantly influenced performance, with semi-automatic dosator filling allowing higher fill weights and compression, enhancing delayed release. TYLOPUR Xtend Nutra^® 100T at 20% showed the most pronounced retardation effect compared to lower-viscosity grades such as 4T and 15T.

References: 1. Bose S, Kaur A, Sharma SK. A review on advances of sustained release drug delivery system. Int Res J Pharm 2013; 4(6): 1-5.
2. Part I. AAPS PharmSciTech. 2016;17:1366–1375.
3. Madlmeir S, Loidolt P, G. Khinast J, Study of the capsule-filling dosator process via calibrated DEM simulations, International Journal of Pharmaceutics, Volume 567, 2019.

Capsule filling machine: Initia, MG2 and capsules size 0

Formulations of caffeine filled capsules

Dissolution profile at pH 1.2 of semi-automatic filled capsules