1. Overcoming Unpleasant Taste of Metformin Hydrochloride by Cold Extrusion/Spheronization Employing Solid Lipid Binders
Gustavo F. Petrovick, Miriam Pein-Hackelbusch, Jörg Breitkreutz
PSSRC
Pharmaceutical Solid State Research Cluster
Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Düsseldorf, Germany
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INTRODUCTION
Metformin hydrochloride is used in the treatment of type II diabetes mellitus. Tablet sizes and extreme bitter taste of this API, especially when tablets are splitted or crushed, have a negative impact on patient compliance. Solid lipids as excipients for oral dosage forms have advantages of lack of toxicity and good taste-masking attributes. Therefore, in the present study, a recently improved extrusion/spheronization method employing solid lipids should be applied to produce taste-masked pellets containing high drug loads of metformin HCl.
RESULTS AND DISCUSSION
A linearity range was observed for all sensors (fig. 1), beginning at concentrations of 0.50 mg·ml-1 until higher concentrations, indicating good sensor sensitivity towards metformin.
A principal component analysis (PCA) was performed using the sensor responses for the formulations F1-F3 and F4-F6, separately. The PCA map for the pellets containing only hard fat as binder is depicted in fig. 2a. and for the pellets based on the ternary mixture in fig. 2b. Considering the first principal component (PC1), which contains most of tnses
MATERIALS AND METHODS
Extrusion of hard fat (Witocan® 42/44), ternary solid lipid mixtures containing 50-80% of metformin HCl (Table 1), and a drug-free control formulation (placebo) 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 spheronizer (RM 300, Schlüter), for 15.min at 1,500.rpm. The jacket temperature was set to 30 °C. Additionally, an IR light was used to heat the materials surface until 33 °C according to [1]. Taste-masking assessment of the pellets was performed using the Insent taste sensing system TS-5000Z.
performedllets
Fig. 1. Sensor responses to metformin hydrochloride
which contains most of the information, the pellets F2, F3, F5 and F6 showed more similar responses to the drug-free formulation than to pure API, indicating an improvement on their taste-masking properties. As expected, samples, which released metformin over 60 s were located more closely to the pure API than those r ….
more closely to pure API than those released over only 30 s due to a higher drug release at this time. Likewise, the higher the amount of lipids, the better the taste-masking properties toward metformin´s bitter taste. To allow a visual differentiation of all formulations, Euclidean distance was calculated and converted to % (fig. 3). The distance between pure API and the Placebo was considered as maximum taste change (from unpleasant to pleasant taste response). The pellets based on hard fat only (F1-F3) present a similar taste-masking pattern compared to pellets with the ternary lipid mixtures (F4-F6): the higher the amount of lipids, the better the taste-masked properties. A
Table 1. Investigated formulations
[%] F1 F2 F3 F4 F5 F6
Placebo
Metformin HCl 80 70 50 -
Witocan 42/44 20 30 15
22.5
37.5
100
Dynasan 114
2.5
3.75
6.25
Precirol ATO 5 B
The used sensors are shown in Table 2. Measurement setup was performed according to [2]. API solutions (0.01 to 15 mg·ml-1) were analyzed prior to measurement for electronic tongue calibration. Pellets amount containing 500.mg metformin HCl were stirred in a glass beaker with 100 mL purified water at 37.°C. After 30 and 60 s the samples were filtered under pressure and measured.
Fig. 2. PCA map for the pellets (A) F1 to F3 and (B) F4 to F6, containing the information of all 7 sensors, data was centered scaled
Table 2: Electronic tongue set of sensors
Sensor
Corresponding taste sensation
SB2AAE
Umami
SB2CT0
Saltiness
SB2CA0
Sourness
SB2AE1
Astringency
SB2AC0
Bitterness of cationic substances
SB2AN0
Bitterness of cationic or neutral substances
SB2C00
Bitterness of anionic substances
REFERENCES
[1] Petrovick, G.F., et al., Eur J Pharm Biopharm 2015, 92, 15-21
[2] Woertz, K., et al., J Pharm Biomed Anal 2010, 51,
[3] Petrovick, G.F., et al., Int J Pharm 2016, 506,
Fig. 3. Euclidean distances to the drug-free pellet
CONCLUSION
Results of an electronic tongue evaluation proved that the investigated extrusion/spheronization technique employing solid lipid was suitable to overcome the unpleasant taste of metformin HCl producing taste-masked lipid pellets containing high drug load of this API.
III ABCF Congress – 2016 – Porto Alegre, Brazil