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Tablets & Capsules March 2015 17 verting a parenteral product into an oral dosage form is one example. Yet some manufacturers lack the expertise required to reformulate their products to use a new delivery method. In such cases, companies have turned to "open innova- tion," a partnership model in which the R&D team col- laborates with one or more outside organizations, including universities, clinics, or companies with special- ized expertise. The open-innovation approach reduces development costs as companies seek to generate addi- tional revenue from their products. Open innovation is the middle ground between going it alone and outright acquiring a company with specialized expertise or a pro- prietary technology. Yet not all new products or reformulations are readily accepted. In fact, some reformulations face head- winds in the marketplace because payers, physicians, and consumers balk at pay- ing for the new products when less expensive gener- ics can do the job. That's why R&D teams must look closely at drug delivery when considering reformulations and choose a method that not only extends the product's lifecycle but gen- uinely benefits patients and caregivers by improving clin- ical outcomes. Assessing orally dissolving films The criteria for assessing a new delivery method for novel or existing molecular entities include ease of manu- facturing, as well as pharmacological considerations, such as toxicity, solubility and, if a combination product is being explored, how the molecule interacts with the other API(s). In the case of oral soluble films, R&D teams should answer the following questions: • What is the specific product profile? • Is there an initial formulation that will enable you to assess the product's stability? • Would film technology be a superior option for patient populations who, for example, have motor impairment issues, trouble swallowing, or an inabil- ity or unwillingness to undergo injections? • Compared to other delivery systems, would film technology offer equal or improved pharmacokinet- ics, as it would when rapid peak plasma concentra- tion is needed? This is especially important with central nervous system treatments, such as migraine medications, and when an improved side-effect pro- file is sought, especially to minimize gastrointestinal side effects. • Depending on the target disease or condition, does film technology offer a more palatable, less painful, or more convenient route of drug administration than other delivery systems? After accounting for those considerations, determine the API-load limit, which for films ranges from milliliters in the single digits to 100,000 milliliters. Films are often a better option for patients with gastrointestinal distur- bances, especially when formulators are seeking to accel- erate peak concentrations. A number of film-based drug products are based on so-called 505(b)(2) molecules for which full safety and effectiveness data are available. These data can be cited in new drug applications, speed- ing approval and reducing the time and expense of the traditional approval path. Drug delivery Upon contact with the patient's mucosa, the film—a mixture of polymers and excipients—begins to dissolve, releasing the API at a rate determined by the product's compositional profile. Because the film formulation controls the release rate, it determines the pharmacoki- netic parameters and the amount of API exposure. Questions to answer during formulation include: • How do the surface area and rate of film dissolution affect exposure to the API? • How well do mucoadhesion and unidirectional absorption provide consistent product delivery? • How does the release rate affect the optimization of kinetics? This is critically important because the release rate (sustained versus quick) has a direct impact on the pharmacokinetic profile, including T max and C max . Film technology offers manufacturers considerable flexibility, and formulators can optimize API delivery by adjusting the weight and type of polymers used, film thickness, film surface area, and the API-to-excipient ratio. Prototypes are made to compare how different excipients and processes affect the film's organoleptics (taste, sight, smell, and touch). The prototypes are used for in-house, ex-vivo model testing on animals to deter- mine directional bioavailability. Once these studies are completed, pre-clinical testing on humans follows. Manufacturing Most commercial manufacturers of pharmaceutical oral soluble films use the film casting process, which starts with an aqueous base mix. The product is then put through a coating head and cast onto a substrate, after which it is dry-coated and cut into strips to the target dimensions. First, prototypes are made in R&D on lab-scale equipment, and the technical transfer/engineering group develops the manufacturing process. Customized flavors and colors are also determined during the prototype stage. Multilayer dissolvable films have been made from hydroxypropyl methylcellulose, methylcellulose, pullu- Formulators can control API delivery by adjusting the weight and type of polymers used, film thickness, film surface area, and the API-to-excipient ratio.