Design of a free-solvent formulation for the extemporaneous preparation of orodispersible films

INTRODUCTION: When an approved medicinal product does not satisfy the needs of special populations, the drug product has to be re-formulated or extemporaneously compounded. Among the available strategies, the preparation of orodispersible films (ODF) is gaining a growing interest in pediatric or dysphagic populations because of the possibility to combine the advantages of oral solid and liquid dosage forms [1]. However, several technical and economic criticisms limit the extemporaneous preparation of ODF in a pharmacy setting. This work aimed to study the processability of a free-solvent formulation based on maltodextrins (MDX) by appositely designed hot-melt ram extrusion 3D printer in order to prepare extemporaneously ODF with tailored surface and shape. MDX were used as the main formulation components since ODF preparation by hot-melt extrusion has already been documented [2]. Paracetamol (PAR) was loaded as a model drug. EXPERIMENTALS Materials MDX DE 6 (Glucidex® IT6) were kindly obtained by Roquette (F). PAR, glycerine (GLN) and titanium dioxide (TiO2) were purchased from Farmalabor (I). Glycine (GLY) was purchased from ACEF. (I). All solvents were of analytical grade unless specified. ODF preparation A cartesian FDM 3D printer (Futura Group Srl, I) was modified reinforcing the frame and replacing the FDM apparatus with an in-house vertical 60-mL ram extruder (operative temperatures: 40-200 °C) ending with a luer-lock system suitable for the insertion of commercially available needles. The preparation of ODF formulations (Table 1) consisted of three simple technological operations. First, MDX, PAR, and other excipients were mixed in a mortar and wetted with the plasticizer (i.e., GLN). Then, the mixture was fed in the ram extruder and heated up to 85 °C. Finally, ODF (2x3 cm) were individually printed on the aluminum foil and sealed without further manipulations. Preliminarily, the operative conditions of the preparation method, namely the relative distance between the extruder needle and the mobile plate, the speed of the mobile plate and the filling angle, were set-up to maximize the ODF printability. ODF characterization The residual water content of ODF was expressed as the loss of drying (LOD) determined gravimetrically at 105 °C using a thermobalance (Gilbertini, I). The stickiness of ODF was evaluated by thumbtack test, using the following score system: A (no sticky), B (sticky), and C (very sticky). The tensile properties were tested according to ASTM D882-02 test using an Instron 5965 texture analyser, equipped with a 50 N load cell (Instron, UK). Initial grip separation and crosshead speed were 40 mm and 12.5 mm/min, respectively. The tensile strength (TS), percent elongation at break (E%) and Young’s modulus (Y) were determined for each sample. The disintegration test was carried out in deionized water using a Ph. Eur. apparatus. The dissolution studies were performed using a Ph. Eur. basket dissolution apparatus. ODF were dissolved in 900 mL of deionized water at 37±1 °C, under constant stirring at 50 rpm. The PAR contents were assayed at 243 nm by UV-Vis spectrometer (Lambda 25, Perkin Elmer, I). RESULTS All printed ODF appeared homogeneous. They showed relatively low LOD values (≤ 10% w/w) and dissolved in less than 3 min, complying with Ph. Eur. specifications for orodispersible dosage forms. Their weight and thickness of ODF ranged 30-45 mg/cm2 and 150-250 μm, respectively. As shown in Table 1, the composition of the mixture impacted significantly on the ODF printability. Unlike formulations with 20% w/w of GLN (i.e., F9-F12), those containing 16% w/w of GLN (i.e., F1-F2) were not consistently extruded through an 18 G needle unless the addition of 2.5% w/w of GLY (i.e., F3-F4), which acted as non-traditional plasticizer. Regardless the MDX/GLY ratio, the higher concentrations of GLN and GLY, the higher elasticity of ODF. [ Table 1 omissis] The addition of TiO2 decreased the Y values of ODF due to its effect as nanofiller: the resulting higher elasticity of ODF can be useful for permitting its easier peeling from the packaging foil. When PAR was loaded (Table 2), ODF appeared whitish and no significant differences were observed in terms of thickness, weight and the disintegration time with respect to the corresponding placebo formulations (Table 1). PAR was loaded in the ODF up to 12 mg/cm2 (Table 2). [Table 2 omissis] Regardless of the ODF composition, the uniformity of dosage units was maintained within the Ph. Eur. limits (L1 ± 15%). However, the loading of PAR altered the tensile properties of ODF: the drug increased the TS and decreased E% values (Table 1). In particular, a significant decrease of ODF elasticity was observed only in the ODF plasticized by 16% w/w of GLN. As shown in Figure 1, the dissolution of printed ODF resulted superimposable to those having the same composition and prepared by casting technique [2]. In both cases, the 80% of drug dissolved in less than 6 min. However, the dissolution profile was influenced by GLN content: ODF with 20% w/w of GLN dissolved faster (t80 ≤ 2 min) than those with 16% w/w (t80 ≈ 6 min). [Figure 1 omissis] CONCLUSION This work demonstrated that MDX based formulations can be printed by hot-melt ram extrusion 3D printing to obtain ODF with a good handling and acceptable uniformity of drug content. Moreover, the ODF can be printed directly to the packaging materials, limiting the manipulations of dosage form by the pharmacist. Such a novel technology appears promising to compound ODF in a pharmacy setting without using solvents or the need of drug loaded filaments and edible films as starting materials. REFERENCES 1. Cilurzo, F., Musazzi, U.M., Franzé, S., Selmin, F., Minghetti, P. Orodispersible dosage forms: biopharmaceutical improvements and regulatory requirements, Drug Discov. Today 23, 251-259 (2018). 2. Cilurzo, F., Cupone, I.E., Minghetti, P., Selmin, F., Montanari, L. Fast dissolving films made of maltodextrins. Eur. J. Pharm. Biopharm. 70, 895-900 (2008).