(W0930-03-19) Improved Distribution of Water Insoluble Components in Soluble Thin Film Formulations

Purpose: Poor distribution of water insoluble components in polymer films can lead to reduced homogeneity of active pharmaceuticals, uneven dispersal of excipient components, and potentially high inter-batch variability related to functionality. Thin films formulations are attractive for drug delivery purposes (1); they are small and lightweight and do not need to be swallowed or taken with water, which increases flexibility and comfort for patients (particularly those with dysphagia). Hydrophilic polymer thin films are promising surface-mediated drug delivery systems for local and/or systemic drug delivery in the oral cavity. Additionally, thin films present a viable alternative for delivering proteins and peptides, which are often labile in the GI tract. This research is focused on demonstrating the feasibility of incorporating hydrophobic ingredients into a hydrophilic polymer thin film. Using Hypromellose (HPMC) as a hydrophilic polymer base, we incorporated either Ibuprofen as a model poorly soluble API, or ethyl cellulose (EC) as a potential release rate modifying water insoluble excipient (two types of EC were investigated, either powdered or aqueous dispersion, to evaluate compatibility).

Methods: HPMC (Methocel^® E50; IFF Pharma Solutions, Wilmington, DE) was used to make a 6% w/v solution using a hot-cold solubilization method. Briefly, 6 g of HPMC E50 was slowly added to a glass beaker containing 50 mL preheated deionized water (85 ℃) whilst stirring, to prevent aggregation. The resulting suspension was cooled by adding 50 g ice to obtain a 100 mL volume, and covered as the HPMC dissolved before reaching room temperature (20 ℃). (i) Ibuprofen film casting: Ibuprofen (1 g) was added to 100 mL of the 6% w/v HPMC E50 solution and stirred overnight. 10 mL of the ibuprofen/HPMC suspension was cast using a K control coater (RK Print Coat Instruments, Royston, Hertfordshire, UK) either at 70 ℃ (above the thermal gelation temperature (Tgel) of 6% w/v E50 HPMC), or at room temperature (below the Tgel) before drying overnight on the casting stage to ensure complete dryness. (ii) Ethyl cellulose film casting: (a) 0.25 g powdered EC (Sigma-Aldrich, Saint Louis, MO) was added to a 100 mL 6% w/v HPMC E50 solution and stirred overnight; (b) 1.35 mL of Surelease^® aqueous EC (Colorcon Inc., West Point, PA) was added to a 100 mL 6% w/v HPMC E50 solution (0.25 % w/w EC equivalent in final dried film) and stirred overnight. Each EC-containing suspension was cast at 70 ℃ using the K control coater, and allowed to dry overnight to ensure dryness.

Results: Figure 1 shows the resultant thin films containing ibuprofen under magnification. As shown in Figure 1a, the API can clearly be seen as aggregates throughout the film. Since this film was cast below the thermal gelation of the HPMC solution, the drug was able to move freely at the initial stages of the drying process, which resulted in the observed aggregation. Conversely, the film cast above the thermal gelation temperature does not show the same signs of API aggregation, and therefore has a higher degree of homogeneity of the model insoluble drug. Figure 2a shows a film containing just HPMC E50 cast above the Tgel at 70 ℃. This image indicates the film was uniform and transparent in appearance. Figure 2b is a photograph of the resultant film following the addition of EC as a dry powder to a cooled 6% w/v HPMC E50 casting solution. This image clearly indicates a high level of aggregation for the model water insoluble excipient EC, even when cast above the Tgel. No such aggregation was observed with the same concentration of EC when it was introduced as Surelease to the HPMC solution, as shown in Figure 2c. Adding EC as a pseudolatex and casting above the Tgel allowed a uniform film to form, which is opaque compared to the EC free film in Figure 2a.

Conclusion: Water insoluble components can be successfully incorporated into an aqueous based polymeric thin film containing hypromellose. By casting the film above the thermal gelation temperature of a particular grade of HPMC, a high degree of homogeneity can be obtained for either for ibuprofen (insoluble API) or EC (insoluble excipient) combined as a pseudolatex. Further studies are being conducted to evaluate the impact of this approach on the dissolution rates of active ingredients.

References: 1. Gilhotra, R.M., Ikram, M., Srivastava, S. and Gilhotra, N., 2014. A clinical perspective on mucoadhesive buccal drug delivery systems. Journal of biomedical research, 28(2), p.81.

Acknowledgements: The authors would like to acknowledge support for this project from International Flavors and Fragrances (IFF).

Figure 1. 20x Magnification of 6% w/v HPMC E50 containing 1% w/v ibuprofen. (a) Cast below Tgel at 20 ℃, (b) Cast above Tgel at 70 ℃.

Figure 2. 6% w/v HPMC E50 containing films cast above Tgel at 70 ℃. (a) 6% w/v HPMC E50 alone; (b) HPMC film with 0.25% w/v EC added as a powder; (c) 0.25% w/v EC added as a peudolatex dispersion.