PSSRC Pharmaceutical Solid State Research Cluster
Taste masked solid lipid pellets containing metformin hydrochloride produced by solventfree cold extrusion/spheronization G.F. Petrovick, M. Pein, J. Breitkreutz Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Duesseldorf, Germany +49 211 8114116
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INTRODUCTION Metformin is a biguanide used for the treatment of type II diabetes mellitus. High tablet sizes and a bitter and metallic taste of this API, especially when tablets are divided, have a negative impact on patient compliance. Solid lipids as excipients have the advantages of lacking toxicity and good tastemasking attributes. in the present study, a recently improved extrusion/spheronization technique for powdered lipids [1] should be applied to produce taste-masked solid lipid based pellets containing a high load of metformin hydrochloride.
MATERIALS AND METHODS Extrusion of hard fat (Witocan® 42/44), ternary solid lipid mixtures containing metformin (Table 1), and drug-free control, were performed using a co-rotating twin-screw extruder (Mikro 27GL-28D, Leistritz) at 33 …. °C (feed rate: 40 g·min-1, screw speed: 50 rpm, die plate: 91 dies with 0.5 mm in diameter and 1.35 mm length). Batches of 300 g extrudates were rounded using a RM 300 spheronizer (Schlüter), for 15 minutes, at 1500 rpm. The jacket temperature was set to 30 °C. Additionally, an IR light was used to heat the materials surface until 33 °C. Taste masking assessment of the pellets was Table 1. Evaluated formulations performed using [%] F1 F2 F3 F4 F5 F6 Placebo the Insent taste Metformin 80 70 50 80 70 50 sensing system Witocan TS-5000Z. 20 30 50 15 22.5 37.5 100 42/44 The applied Dynasan sensors are - 2.5 3.75 6.25 114 shown in Table Precirol - 2.5 3.75 6.25 2. Measurement ATO 5 setup was deTable 2: eTongue sensors fined according Sensor Corresponding taste sensation to Woertz [2]. SB2AAE Umami API solutions SB2CT0 Saltiness (0.01 to 15 SB2CA0 Sourness mg·ml-1) were SB2AE1 Astringency SB2AC0 Bitterness of cationic substances analyzed prior SB2AN0 Bitterness of cationic or neutral to measurement substances for etongue SB2C00 Bitterness of anionic substances calibration. Pellets according to 1 g metformin hydrochloride were stirred in a glass beaker with 100 mL purified water at 37 °C. After 30 and 60 seconds the samples were filtered under pressure and measured afterwards.
RESULTS AND DISCUSSION A linearity range was observed for all sensors (Fig. 1), starting from concentrations of 0.50 mg·ml-1, indicating good sensor sensitivity towards metformin hydrochloride. A principal component analysis (PCA) was performed using the sensor responses for the formulations F1-F3 and F4-F6, separately. The results were very similar. The PCA map for the pellets containing only Witocan® 42/44 as binder (F1-F3) is depicted in Figure 2. Each formulation Fig. 1. Sensor responses to metformin hydrochloride showed more similar sensor responses to the drug-free formulation than to the API indicating improved taste masking characteristics. As expected, samples, which released metformin over 60 s (e.g. F1_60s) were located more closely to the pure API than those, which were released over only 30 s (e.g. F1_30s). To simplify the differentiation of all prepared drugcontaining formulations (F1F6), the Euclidean distances (Fig. 3) were calculated. For normalization, the distance between the pure API and the Placebo was considered as referred maximum Fig. 2. PCA map for the pellets F1 to F3, containing the information of all 7 sensors, data was ctr scaled, each formulation was measured in in % (as these triplicate two samples were assumed to taste most differently). Based on this assumption, drugloaded pellets based on Witocan® 42/44 only (F1-F3) present better taste masking characteristics compared to pellets with ternary mixtures (F4-F6). Additionally, higher amounts of lipids led to pellets presenting better taste masking characteristics (Figure 3). Fig. 3. Euclidean distances to the placebo Euclidean distance
REFERENCES [1] Petrovick, G.F., et al., 2014, data to be published. [2] Woertz, K., et al., J Pharm Biomed Anal 2010, 51, 497-506.
CONCLUSION Results of an etongue evaluation (PCA and Euclidean distances) proved the investigated extrusion/spheronization technique to be applicable for the preparation of taste-masked solid lipid metformin hydrochloride pellets. 9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology – 2014 – Lisbon, Portugal
