(T1030-03-19) Influence of Key Formulation Factors in Oral Thin Film – Part 2 (Polyethylene Oxide)

Purpose: The effects of key formulation parameters on oral thin films made from polyethylene oxide polymer (POLYOX™) were evaluated. Loratadine and Ibuprofen were selected as model drugs. We investigated the effect polymer molecular weight (MW), formulation solids content, plasticizer, and model drug concentrations on manufacturing process and properties of simple oral thin films. Previously, we evaluated hydroxypropyl methylcellulose (HPMC), as a film forming polymer in part 1 of the study.

Methods: Formulations with a solids content of 6-30% consisting of polyethylene oxide (POLYOX^TM WSR N10, N80, N750; different MW) as the film forming polymer; polyethylene glycol (PG) or glycerol (Gly) (0-5% w.r.t. polymer) as a water soluble plasticizer; loratadine or Ibuprofen (15% w/w, w.r.t. polymer) as the model drugs; polysorbate 80 as a wetting agent (0.2% w/w) and Food Red No. 40 (0.2% w/w) as a coloring agent were prepared. The polymer was screened through a 20-mesh sieve, then polymeric solutions were prepared using a hot/cold method. Approximately half of the required water was heated to above 90°C (194°F) and stirred to form a vortex, then the powder was added to the vortex and mixed until all particles were dispersed. The remainder of the water was then added as cold water to lower the temperature of the dispersion and solubilize the polymer. For active formulations, the drug was dispersed into the cold solution containing plasticizer/colorant/surfactant using a high shear mixer followed by stirring at 60 rpm for 2 hours. Stirring continued at below 25°C for at least 30 minutes to ensure full hydration followed by 15 minutes solicitation to remove air bubbles. The viscosity of the formulations was measured using a digital rotational viscometer. Films were cast using a draw down technique on a glass surface and air dried at room temperature. The resultant films were cut into 3 X 4 cm pieces and evaluated for appearance, stickiness, and ease of peeling. Physical properties including thickness, disintegration time (DT), and mechanical strength were measured (n=5). Loratadine and Ibuprofen prototype films were selected for drug release evaluation. Thickness was measured at five locations of the rectangular films using a micrometer. DT was measured in 15 mL artificial simulated saliva (pH 6.2) in a glass Petri dish using a stopwatch. Mechanical strength of the films was evaluated via a puncture test method using a texture analyzer.

Results: The POLYOX™ N10 placebo formulations with 20-30% solids resulted in tacky films that were difficult to peel and not uniform at higher solid content. Films prepared without a plasticizer were less than tacky compared to films with a plasticizer. POLYOX™ N80, a higher viscosity grade of polymer, in formulation with 15-20% solids produced acceptable films. The viscosity of placebo formulations of POLYOX® N80 with 15% solids was 2160-2861 mPa⋅s, and for 20% solids, was > 10,000 mPa⋅s. This indicated the solid content directly influenced formulation viscosity. Adding plasticizer reduced the polymer solution viscosity while due to the high flexibility of POLYOX™ polymers, it is not necessary to use plasticizer. POLYOX™ N750 formulations targeting 6-8% solids did not produce an acceptable film (Fig 1). Combinations of POLYOX™ N750 with a lower viscosity grade polymer were then screened at 10-15% solids. Film made from higher solid content and higher molecular weight polymers had higher breaking force and mechanical strength. The mechanical strength of the film increased with increasing the film thickness. The prototype film formulation with 10% solids containing 22% N10, 63% N750 and 15% loratadine or Ibuprofen was not tacky and easy to peel with a nice appearance (Fig. 2). The films with a thickness range of 80-90 µm had a disintegration time (DT) of 45-92 seconds. The film containing glycerol as plasticizer had a shorter DT as compared to those with propylene glycol (PG). DT of the Ibuprofen films with 50-70µm thickness was 60 seconds and with 130µm thickness was > 2 minutes. Loratadine film disintegrated in 74-78 seconds which was faster than DT (95 seconds) of a marketed product, Listerine® film. The result of loss on drying (LOD) measurement indicated a higher value for Listerine® (10.43%) compared to 1-4% for POLYOX™ films. The results of dissolution testing of the prototype films are shown in Fig 3. Both APIs released > 85% of the drug in < 5 minutes.

Conclusion: Simple film formulations based on polyethylene oxide polymers (POLYOX™) using loratadine and ibuprofen as two poorly soluble model drugs were produced via a solvent casting method and evaluated. The solid content, polymer grades (molecular weights), as well as type and level of plasticizer were found critical for formulation processability and film properties. Two prototype films were selected based on their short disintegration time and high mechanical strength for dissolution studies . Both prototypes displayed a full release in < 10 minutes and were identified as good candidates for further development using polyethylene oxide as film forming polymer.

Fig1. Effect of solid content and plasticizer on processability of POLYOX™ N750 placebo films. (a) The film with plasticizer was tacky and difficult to peel. (b) The film with lower solid content and without plasticizer was not tacky and easy to peel.

Fig2. Loratadine film. The prototype loratadine Film formulation with 10% Solids (22% N10 , 63% N750 and 15% loratadine) was not tacky and easy to peel with a nice appearance)