Purpose: We developed a prototype fast-dissolving thin film of an active pharmaceutical ingredient (API), termed here as Compound A, a clinical-stage compound which has shown good intra-oral bioavailability but for which gastric exposure led to unacceptable degradation. Compound A is a viscous semi-solid at room temperature with high solubility in aqueous and various organic solvents. The fast dissolving film formulations consist of water-soluble polymers embedded with compound A, which quickly hydrate and dissolve when place in the oral cavity to provide rapid release of the API into the intra-oral environment without the need to swallow the formulation.
Methods: Fast dissolving films were prepared by solvent casting method. Excipients and compound A were dissolved in hydro-alcoholic solvent systems and then casted on a glass plate with thickness controlled by a film casting knife. Placebo and active (7% drug loading) films were prepared using various compendial film-forming polymers including HPMC, HPC, PVA-PEG copolymer, PVP, PVP-VA and poly (methacrylic acid, ethyl acrylate), plasticizers (e.g., PEG400, propylene glycol, glycerol and triethyl citrate), surfactants (e.g., sodium lauryl sulfate and poloxamer 407) and sweetener (sucralose). Films were dried at room temperature and cut into 2 cm x 2 cm pieces for analysis. Film thickness was measured at five locations using a Vernier caliper and weight variation was assessed. Folding endurance was determined by repeatedly folding a film at the same place until a visible crack is observed. Film surface morphology was evaluated by scanning electron microscope (SEM). Surface pH measurement was estimated by contacting a pH meter electrode by wetted films. Surface hydrophilicity was evaluated by contact angle measurement. In vitro disintegration testing was performed using both standard USP apparatus and in a petri dish with static small volume (5 mL) of water. In addition, the moisture sorption isotherms of films were obtained via dynamic vapor sorption (DVS).
Results: Based on the mechanical properties of placebo films, hydroxypropyl methocellulose (HPMC E15) and polyvinyl acetate (PVA) were selected for formulating API-containing films, with polyethylene glycol (PEG) or glycerol as plasticizing additives. HPMC based films were homogenous, transparent, had acceptably low self-adhesion (e.g. stickiness). HPMC films containing glycerol are more sticky than HPMC:PEG films. The presence of poloxamer resulted in color change (slightly opaque) and reduction of stickiness. The placebo PVA-PEG films were transparent. The active containing PVA-PEG films were opaque and have very low transparency. The presence of SLS and poloxamer promoted API:PVA-PEG phase separation and resulted in oily, non-homogenous films. All active containing films were 50-60 µm thick with minimal weight variation, good folding endurance, hydrophilic surfaces of neutral pH and fast in-vitro disintegration (Table 1). SEM micrographs show HPMC based films are smooth and uniform without cracks or transverse striations. Phase separation and highly porous morphology were observed on active containing PVA-PEG films (Figure 1). Dynamic vapor sorption experiments show all films absorb 5-7% and 30-40% moisture at 25 °C/50% RH and 25 °C/90% RH, respectively.
Conclusion: The results described here demonstrate that the semi-solid compound A can be successfully formulated as fast dissolving films for intra-oral delivery. Films prepared with HPMC as film former and PEG as plasticizer possessed the most desirable physical properties and disintegration performance. Films prepared from PVA-PEG show similar properties as HPMC based films except API-polymer phase separation was observed. The successful fast dissolving films may provide quick onset action with improved bioavailability and enhance patient compliance when compared to conventional oral solid dosage forms such as tablet.