Poly(sodium methacrylate, methyl methacrylate) to design highly loaded orodispersible films

INTRODUCTION In the design of a new technological platform for orodispersible films (ODF), the following aspects have to be considered. First, ODF should exhibit suitable mechanical properties to overcome the tensile stress generated during the manufacturing procedures. Secondly, ODF should disintegrate in few minutes as well as other orodispersible dosage forms. Thirdly, the stickiness of ODF should be also avoided to favour the patients’ handling. As a matter of fact, polymers used to design ODF are highly hygroscopic materials that can become sticky upon exposure to the ambient humidity [1]. This work aims to evaluate the use of poly(sodium methacrylate, methyl methacrylate) (NaPMM) [2] to design ODF prepared by casting technique, using PEG400 as plasticizer. The impact of the polymer/plasticizer ratio and the residual water content on film properties was investigated using placebo ODF. Moreover, the drug loading capacity of the ODF was assessed using ketoprofen (KP) and paracetamol (PAR), as model drugs. MATERIALS NaPMM was prepared salifying a 15% w/w Eudragit®S100 (Evonik Industries, G) aqueous suspension with sodium hydroxide [2]. KP (MIAT S.p.A., I); PAR (Farmalabor, I); PEG400 and Tween®80 (Carlo Erba Reagenti, I); Span®80 (Croda, E). METHODS ODF preparation The casting solutions were obtained adding PEG400 to the NaPMM solution in different polymer/plasticizer ratio (90/10 - 40/60 % w/w). In drug-loaded ODF, active ingredients were added to the slurry to reach a final concentration of 25%, 50% w/w for KP and 50%, 70% w/w for PAR. The dispersion was cast at the rate 1 m/min over a silicone release liner to obtain film thickness of about 100 μm (Mathis LTE-S(M), CH). The drying conditions were set to vary the different residual water content in ODF. Films were cut and packed in individual airtight seal packs using a triple layer film and stored at 25±1 °C until use. ODF characterization The residual water content of ODF was expressed as loss of drying (LOD), which was determined gravimetrically using a thermobalance and (Gilbertini, I) keeping samples at 105 °C until constant weight. ODF stickiness was evaluated by thumb tack test and probe tack test. Mechanical properties Flexibility: the test was carried out by bending a ODF over an 8-mm mandrel. Films were considered flexible if no cracks over the bending area were visible at a 5x magnification. Tensile properties: the test was conducted 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 (σmax), percent elongation at break () and Young’s modulus (Y) were determined for each sample. Disintegration test The disintegration test was carried out in water on 2x3 cm sample using a Ph. Eur. apparatus. ATR-FTIR spectroscopy The ATR-FTIR spectra of raw Eudragit®S100 and drug loaded ODF were collected over the wavenumber region 4000–650 cm−1 (32 runs) using a SpectrumTMOne spectrophotometer (PerkinElmer, USA). RESULTS Placebo ODF, containing PEG400 in the 10-30 % w/w range and 10-15 % w/w of LOD, were homogeneously transparent in appearance, easy-to-handle and able to disintegrate within 30 s. Non-sticky films were obtained only for PEG400 content lower than 40% w/w (Table 1). At higher concentrations, the ODF stickiness increased with the residual water content. In particular, the probe tack test evidenced that, at the highest LOD value in ODF plasticized by 40% w/w of PEG400, the maximum detachment stress should not exceed 12±2 kPa to assure a film ease to handle. Figure 1 exemplifies the possible tensile patterns of placebo ODF. At low strain values, a linear region, associated to the reversible deformation, was evident. Increasing the strain, the behaviour shifted from elastic to plastic, the curve lost linearity and the deformation became irreversible, until the maximum force was reached. Then, three profiles were identified increasing the PEG400 concentrations and/or LOD values (Figure 1). First, the maximum force value was followed by a significant decrease of the stress, indicating local reduction of the cross section, namely “necking”, that propagated along the length of the sample until rupture (code N). Secondly, the film showed a tear behaviour characterized by a slow and smooth decrease of cross section upon increasing the tensile stress (code T). Finally, the elongation at break at values higher than 200% indicated formulations characterized by a ductility unsuitable for packaging (code D). From a quantitative point of view, increasing the PEG400 concentration, both σmax and Y values dropped down and the ductility prevailed (Table 1). This trend, along with the progressive increase of the  values, is in line with a plasticization-dominated mechanism. NaPMM plasticized by 20% w/w PEG400 allowed up to 70% w/w of PAR loading (20.5 mg/cm2), without significant alteration of tensile and disintegration properties. In case of KP (pKa=4.45), the drug substance was efficiently loaded up to 50% w/w (8.3 mg/cm2); however, the ODF swelled without disintegrating within 30 min along with the shift of pH medium from 7.6 to 4.4. ATR-FTIR spectroscopy evidenced that this feature was attributed to a partial protonation of NaPMM (Figure 2) since the intensity of anti-symmetrical (1560 cm-1) and symmetrical vibrations (1300-1400 cm–1) of the carboxylate groups underwent a significant depression in presence of KP with respect to the placebo film. Nevertheless, the addition of 5% w/w surfactants (i.e., Tween® 80 and Span® 80) to the composition allowed 25% w/w KP-loaded ODF to disintegrate within 30 s without compromising the film mechanical properties. CONCLUSION All the presented data underlined the versatility of NaPMM to design ODF with satisfactory tensile properties and high drug content (50-70 % w/w). REFERENCES 1. Cilurzo, F.; Musazzi, U.M.; Franzè S.; Selmin, F.; Minghetti, P. Orodispersible dosage forms: biopharmaceutical improvements and regulatory requirements. Drug Discov. Today., in press (2017). 2. Cilurzo, F.; Minghetti, P.; Selmin, F.; Casiraghi, A.; Montanari, L. Polymethacrylate salts as new low-swellable mucoadhesive materials, J. Control. Rel., 88, 43-53 (2003).