Many of us are familiar with the minty, breath-freshening strips that dissolve instantly on your tongue. Available at any convenience store, these thin strips don’t require chewing or swallowing. Imagine if these could serve as a means of drug delivery. With oral thin films (OTFs), drug developers are trying to achieve just that.

OTFs are a drug delivery system that offer many advantages over more standard systems. These are essentially polymeric films that deliver therapeutic moieties into the oral cavity for absorption there or via the gastrointestinal (GI) tract. With easy administration, the drugs directly enter the circulatory system, acting quickly and delivering a larger proportion of the active compound per dose.

While OTFs have been available for decades, their popularity has increased drastically in recent years. There is an increased demand from patients who have trouble swallowing (37 percent of the population), which typically includes children, the elderly, and those experiencing nausea. The growing elderly population is likely to further increase demand.

There are currently only 11 OTFs on the market. These treat a wide variety of medical conditions, ranging from schizophrenia to migraines. As OTFs become more common, the industry still has yet to fully understand the methods and proficiency needed to optimize development and overcome limitations.

An OTF Overview
There are two main types of OTFs:

 1. Oromucosal, which adhere to various parts of the oral cavity and slowly release the drug into the patient’s systemic circulation

 2. Orodispersible, which break down immediately upon contact with saliva. Within orodispersible films, there are two subtypes: orally disintegrating and orally dissolving.
(Figure 1)
 

OTFs are typically characterized by three sets of attributes: organoleptic, mechanical, and performance. Organoleptic attributes appeal to the senses, such as color and taste, and do not affect drug performance, but rather patient acceptance of the drug. Mechanical properties, such as elongation at break and tear resistance, are important for manufacturing, handling and transportation. Performance attributes indicate how the film will function in vivo, such as OTF uniformity and disintegration/dissolution rates.

Advantages
A key advantage of OTFs is they are patient friendly. Compared to other systems, they have a larger surface area that allows for faster wetting, disintegration and dissolution. This means patients don’t need to chew, swallow, or take with water to ingest the drug. Further, the films can have a pleasant flavor and color, making them easier to administer in children.

Another advantage is that OTFs allows for precise dosing and flexibility. They can be perforated and manipulated in size and thickness to deliver highly uniform doses. This is great for low-dose prescriptions, often needed for children and also adults who may need partial doses. Because the films can carry a small drug load, the system is good for drugs in development where production doesn’t yet include large doses.

Recently researchers have found that OTFs can incorporate a wider range of drug types, allowing for increased applications. It is a common misconception that OTFs can only carry water-soluble drugs. Recent research has shown that BCS Class II/IV drugs (classified as having low solubility by the Biopharmaceutical Classification System) can be incorporated into orally disintegrating films.

Manufacturing for OTFs, which requires only two steps, is much simpler than for tablets and capsules. This is because films can be developed with powderless and aqueous-based processes without solvents, allowing for continuous processing.

OTFs are also ideal for patent-expiring drugs. By reformulating a drug as an OTF and receiving FDA approval for a novel oral film application, the drug is then entitled to a three-year period of market exclusivity.

Limitations
Some of the positive attributes of OTFs also come with a negative side. Although research continues to emerge, OTFs still require more research and optimization to deliver a wider range of drugs, particularly water-insoluble ones. Because OTFs rely on polymers to increase drug solubility, scientists must employ new particle engineering techniques and find innovative ways to incorporate and solubilize OTFs carrying water-insoluble drugs. In addition, while it is great that OTFs can carry a small drug load, this is also limiting because they can typically only deliver 10 to 20 mgs, causing constraints for drugs where larger doses are needed. Further, some of the physical attributes that make OTFs patient friendly can cause packaging complications. For example, the larger surface area makes them more sensitive to humidity and temperature.

Testing OTF characteristics is also complicated. The US Pharmacopeia has not designated any methods or monographs for testing properties, such as disintegration and dissolution. Currently, there is some inaccuracy when assessing performance because methods and endpoints haven’t been clearly defined. Guidance cannot be drawn from the USP-prescribed disintegration and dissolution tests for tablets and capsules because there are too many variances between the two systems (ex: dosage forms and endpoint determination). Moreover, standard non-biological methods don’t accurately capture the film or drug’s behavior in vivo. Water or other biorelevant media cannot perfectly mimic the oral cavity’s saliva, and currently, there’s no rigorous method to simulate stress from the tongue and palate.

To accurately test these drugs for dissolution, methods should account for variations in the degree and nature of saliva in a patient’s mouth. This will become increasingly important as researchers incorporate more poorly soluble micro- and nano-particles. One example is the USP IV, a flow-through cell dissolution apparatus, which has been useful in testing films containing drug nano-particles, particularly to distinguish variable particle sizes and formulation effects.

These challenges make it complicated for companies to develop and test OTFs. Companies must have experience in developing formulations and navigating regulatory systems that oversee OTF development. We need more methods like the USP IV to elevate the industry’s quality control.

While some companies may attempt this without the correct expertise or with trial-and-error manufacturing, a more targeted and precise technique is bound to be more successful. Specifically, a customized method that determines OTF components based on chemical properties would be helpful.

As more research is conducted on improving the utility of OTFs, and more teams gain the necessary expertise needed for formulation, this novel drug delivery system will eventually become a standard for many pharmaceutical products.