Eudragit® RL film forming solution for cutaneous administration: an optimization study

INTRODUCTION The passive transport rate of a molecule through a homogeneous barrier is proportionally related to its degree of saturation in the vehicle when no significant interactions occur. Therefore, drug supersaturation in topical formulations is a tool to enhance the penetration into stratum corneum [1]. As supersatured systems are thermodynamically instable over the storage period, those systems which become supersaturated only after dose actuation, seem to be more promising. Among them, film- forming systems (FFS) have recently proposed as an alternative to transdermal patches. Their basic composition requires a film-forming polymer and a volatile solvent approved for topical use [2]. The current work aimed to study the effect of formulation compositions on physicochemical and biopharmaceutical properties of FFS based on Eudragit® RL. Acetone and isopropyl alcohol were mixed in different proportions to investigate the ability to dissolve the formulation components, form the film on the skin and guarantee the flurbiprofen permeation. The influences of type and concentration of plasticizer, i.e. triacetin or tributhylcitrate,on film mechanical properties were also investigated, taking into account that the film has to to adapt to skin movement. EXPERIMENTAL SETUP Materials Eudragit® RL PO (Evonik, G); tributhylcitrate (TBC, Morflex, USA); triacetin (TRI, Sigma Aldrich, I); flurbiprofen (FP, Farmalabor, I). Formulation compositions FFS were prepared by adding 10-20-30 % w/w Eudragit® RL to different blends of isopropyl alcohol/acetone (90/10, 80/20, 70/30, 60/40, v/v) with or without plasticizer. The number of placebo formulations prepared was 36. FP was dissolved in the selected FFS in the appropriate amount. Characterization of placebo films The stickiness of placebo films obtained by a solvent casting-evaporation technique was characterized by a probe tack test. The elasticity was assessed in comparison with human stratum corneum (SC), by using a tensile testing machine (Instron 5965, ITW Test and Measurement Italia S.r.l., I). Human SC strips (8x16 mm) or film samples (7x20 mm) were positioned between two pneumatic jaws, separated at a distance of 8 mm. The upper jaw, connected to the 50 N cell load transducer mounted on top of the crosshead, rose at a speed of 2 mm min-1. Young modulus (Y) was calculated as the slope of the linear portion of the stress-strain curve. Drying evaporation rate The drying evaporation rate was evaluated by holding a 80 μL sample at 32 °C for 1 h. The mass loss over time was monitored by a TGA 2050 Thermogravimetric Analyser (TA Instruments, USA). In vitro permeation studies The in vitro permeation studies were carried out with Franz diffusion cells using human epidermis as membrane. Aliquots of 10 μL FFS were used as donor phase. RESULTS AND DISCUSSION An optimal FFS should form quickly a uniform film at skin surface after spraying and, thus, a film forming temperature lower than 32 °C is required. Moreover, the formed film should be non-sticky to avoid adhesion to the patient’s clothes. Table 1 enlists the composition of 6 of the 36 designed formulations which complied these requirements and presented a tack value lower than 1 MPa. To be flexibles when applied topically, a film is required to have a Y lower than that of human stratum corneum (Y = 55.4±13.0 MPa, Table 1). The results evidenced that Y was influenced by the composition of organic solvents with respect to the plasticizer type: in films with TBC, Y decreased increasing acetone content; an opposite behavior was observed for films with TRI (Table 1). As TBC resulted more effective in reducing Y values, formulations 1, 2 and 3 were selected for drug loading. Both the plasticizer content and organic solvent composition influenced the FP permeation (Table 2). Considering the TGA results (Table 2), the TBC content is the main parameter influencing the FP permeability. The higher the TBC content, the lower the FP flux. This was ascribed to a modification in drug thermodynamic activity. Moreover, the solvent evaporation rate appeared to influence the FP permeation: the faster the evaporation rate, the lower the drug absorption (Table 2, Form. 1 vs Form. 3). The latter result could be explained on the basis of the mechanism of drug deposition from a volatile system. The volatile solvent carries the drug into the upper layer of the stratum corneum prior to solvent evaporation. The longer the contact time, the deeper the penetration of the solvent and drug into skin. Aming to deepen the information on the biopharmaceutical performances of FFS, the effect of drug dose and concentration on skin permeation profile of FP was studied using formulation no. 1 (Figure 1). As expected, increasing the applied volume (20 μL), but decreasing the drug concentration (2%), only a slight decrease of the FP permeated amount was noticed despite a presumable reduction of the drug thermodynamic activity in the film forming solution Indeed, drug flux resulted not statistically different (J=1.64±0.86 μg/cm2*h) to that measured by formulation no. 1. These data suggested that the solvents evaporation rate is the most relevant factor influencing the FP skin permeation. Conversely, an increase in the applied volume (100 μL) or in the drug concentration (8%) enhanced the FP permeation (Figure 1). Moreover, at the highest drug concentration, the marked change in the slope evident after 7 h could be due to a high degree of supersaturation of the system with a consequent drug precipitation (Figure 1). This hypothesis was also confirmed by the formation of visible crystals on the dried film. Table 2. Permeation parameters and drying rate of formulation 1-3 loaded with 4% FP. CONCLUSIONS All together, these results show that FFS can effectively sustain the drug permeation through the skin and evidence the importance of each component of the formulation (i.e., namely organic solvent composition and amount and type of plasticizer), on the drug delivery. Interestingly, the proposed formulations allow to minimize the lag-time which is tipical of medicated plasters. In the case of all tested FFS, the lag time was negiglible; while the flurbiprofen plaster presented on marketed presented a lag- time higher than 1 h [3]. ACKNOWLEDGEMENTS The Authors would like to thank “Linea 2 - Dotazione annuale per attività istituzionali - 2015” for the financial support. REFERENCES 1. Cilurzo F. et al. Curr Pharm Des. 21, 2733-2744 (2015). 2. Gennari C.G.M. et al. Int J Pharm. 511, 296–302 (2016). 3. Cilurzo F. et al. Drug Dev. and Ind. Pharm., 41, 183-189 (2015).