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    Features

    Not Your Father’s Oral Thin Film

    A look at how oral film drug delivery is evolving.

    Not Your Father’s Oral Thin Film
    The overall oral thin film drug delivery market is expected to grow to approximately $2.1 billion by 2025 from about $1.2 billion in 2015.
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    Rodolphe Obeid, Vice President of Operations, IntelGenx06.04.20
    Nearly fifty years after oral films offered Americans the promise of minty fresh breath on the go, they continue to attract attention. Thin oral films have since delivered drugs for treating opioid addiction, amyotrophic lateral sclerosis (ALS), and schizophrenia, among other diseases - and many more are in development for chronic conditions such as migraines and neurological diseases such as Alzheimer's.

    But innovations in drug development are happening at a rapid clip. Drug developers and manufacturers are moving beyond traditional small molecule drugs to biologics, personalized therapies promise new ways of attacking cancer, and the aging population is driving demand for better, more convenient medications. Will oral thin films evolve, too?

    The overall oral thin film drug delivery market is expected to grow to approximately $2.1 billion by 2025 from about $1.2 billion in 2015, driven in large part by new products and technological advances in the manufacturing process for oral thin films, according to Roots Analysis Market Research. Demand is rising globally, and the market is growing particularly rapidly in North America, where there is an unmet need and a higher adoption rate. The U.S. Food and Drug Administration has approved approximately 11 oral film products, and more are in development.

    Early versions of the technology were brought to market to offer elderly or pediatric patients with swallowing difficulties an alternative to tablets and capsules, an advantage that stands today. It's estimated that approximately 15 million Americans suffer from difficulty swallowing, or dysphagia, with half of Americans over 60 experiencing some form of dysphagia in their lifetime. Despite their potential, early oral thin films were initially limited by their smaller dosages, reduced stability and potency.

    Thin oral films are easily placed on or under the tongue or against the cheek. Upon contact with saliva or buccal mucosa, the active pharmaceutical ingredient (API) is rapidly released and absorbed systemically or simply swallowed. Oral thin films deliver precise and flexible dosages as well. These attributes make oral films not only easy and convenient, but also convey medical benefits. With buccal or sublingual film delivery, drugs are absorbed quickly in the mouth. This limits gastrointestinal tract exposure and overcomes common challenges associated with tablets and capsules, such as first-pass metabolism, gastrointestinal side effects, and slow or limited absorption in the gastrointestinal tract. As a result, buccal or sublingual films may offer better bioavailability, reduced side effects and improved patient compliance.

    From a business standpoint, oral thin films also offer companies an easy way to protect their products as they go off-patent, extending the revenue life of the drug. Novel oral film applications of reformulated drugs can garner an extra three years of market exclusivity from the FDA or even seven years if the indication is for orphan drugs, as well as patent protection for up to 20 years. 
    While thin oral films have long been recognized for their potential to offer a more efficacious and convenient way to deliver drugs, recent advances in technology and manufacturing make novel applications—think vaccines and high-potency drugs—potential game-changers for drug delivery.

    Unlike early versions of oral thin films, today's oral films can integrate most APIs, including those that are water-soluble and insoluble. They can also be formulated for extended-release. Advances in taste-masking technologies that enhance taste by adding flavors or sweeteners, or that encapsulate the drug to bypass the taste buds to reduce bitterness have made oral thin film drug delivery more palatable as well. Multiple combinations can also be developed, primarily using two APIs in the same film with different absorption profiles. There is also potential for topical use.

    Still, oral thin films have their limitations. Because of the size of oral thin films, the drug load they can carry is limited to a relatively small amount. The larger surface area compared with tablets and capsules also makes them more sensitive to humidity and temperature, which means they must have special packaging for the products to be stable and safe. Dosage uniformity can also be a challenge. Those unstable at a buccal pH or that irritate the mouth are not ideally suited to oral film delivery. Co-administration of multiple drugs is also challenging because of the dissolution time. Lastly, as the drug dissolves in the mouth, taste remains a factor that needs to be addressed for each formula.

    Manufacturing advances
    Oral thin films are composed of single or multiple polymer-based layers, with the intended dose of API controlled by the size and thickness of the film's construction. Typically, oral thin films are about the size of a postage stamp, and the API is either dissolved or held in the polymer matrix of the film. Polymers are chosen to create the viscous bulk material that suspend homogeneously the undissolved ingredients and for how quickly they may dissolve or for the desired physical characteristics of the film. Typical polymers include polyethylene oxide, gelatin, hydroxpropyl methylcellulose, methylcellulose, carboxymethyl-cellulose, polyvinyl pyrrolidone, pectin and pullulan. Plasticizers are also added to the film to make them more robust or more flexible.

    Manufacturing oral films is a relatively quick and straightforward process compared with tablets and capsules, and because of the technology employed can be done continuously. However, the process requires a significant amount of knowledge and expertise to consistently generate a good product, with homogeneity of the API, chemical and physical stability, appealing taste and desired pharmacokinetic profile. The two most widely used processes for making oral thin films are solvent casting and hot metal extrusion, though there are others.

    Solvent casting involves either suspending or dissolving the API in a solvent media, such as organic or aqueous-based solvent, polymers, plasticizers and other ingredients. This bulk material is then cast into a thin layer on a release liner and sent into a heat source such as an oven or convection chamber to be dried. When the film is dry, it is then cut into strips and individually packaged. This process is well suited to heat-sensitive APIs because it's performed at a lower temperature compared with hot metal extrusion. Potential disadvantages of this method include residual solvents on the final product that could pose compliance challenges as well as the need to mitigate possible environmental hazards if the solvents are flammable.

    The hot metal extrusion process heats and combines the dry ingredients with an extruder screw until they melted and thoroughly mixed. The melted material then goes through a flat extrusion die that presses and shapes the film. Elongation rollers may be used to vary the thickness and strength of the film before it is cooled, cut, and packaged. Because of the high temperatures used in this process, there's a risk of degradation. Additionally, any water contained in the ingredients could negatively impact the film's uniformity and strength because of gaps created during the heating process.
    One limitation with manufacturing is the length of time it takes to dry oral thin films. Since elevated temperatures cannot be used with many of the drugs, the films must be air dried at low temperatures over the course of a day, reducing production time.

    In the future, 3D printing could make oral film manufacturing even easier and allow for more customized products but could also take a significant amount of time to produce. Over the past several years, 3D printing has gained interest across multiple industries, and many manufacturers are giving the technology serious consideration.

    While inkjet printing technologies may be too cost-prohibitive, flexographic printing offers an alternative. This technique applies a Fountain roller that transfers ink containing the API in a solution or suspension that transfers the ink to another roller, the Anilox roller. This roller accurately measures the amount of ink required for uniform thickness to the plate cylinder, which holds the polymeric strip. Pressure is applied to print the ink onto the polymer. The advantage of this process is that the film is already manufactured and dried before printing. Therefore, there is a reduced risk of lower API activity due to heat. Production efficiency is also high at an average of 530 films per minute. The drawback to this process is the potential risk of contamination and the requirement for a large print roller.

    Future applications and markets
    While still not in widespread use, oral thin films that incorporate poorly water-soluble drugs could gain more traction as new techniques and strategies for improving solubility are developed. More manufacturers are using organic solvents, and adding solubility enhancers and organic acids to improve solubility. Nanoparticles are being used as carriers for poorly water-soluble drugs and APIs are being micronized to reduce particle size. Other alternatives, such as solid solution, are also an option to increase the solubility of the drug.

    The growth in biopharmaceuticals in general and personalized therapies, more specifically, is also driving innovations in oral film drug delivery. Multilayer film designs could allow for controlled delivery of APIs, and advancements in materials and formulations may pave the way for the more convenient delivery of higher weight molecular drugs than are administered today by oral film.

    As the oral film market moves beyond its traditional focus on small molecules to deliver biologics, vaccines also hold potential for delivery via oral film. Emerging vaccines in development based on DNA, liposomes, particulates, and virus-like particles could be optimized for oral thin films. The buccal mucosa, which contains many immune cells, may be particularly well suited to this type of vaccine delivery. When the oral film comes in contact with saliva, the drug dosage quickly dissolves into the buccal mucosa to deliver the vaccine and elicit an immune response. With buccal administration, there is no first-pass effect, so only a small quantity of vaccine is needed, and the bioavailability is increased. It is also an easy, convenient, and potentially cost-effective method of administration.

    One challenge to vaccine delivery via oral film is the potential for antigen degradation in the saliva. Devising the right particulate formulation to avoid degradation could expand the opportunities for vaccine delivery via oral film. An oral film could also be developed in multiple layers to protect the vaccine from degradation and could be developed in nano or microparticulate form to address these challenges. Buccal and sublingual administration also allow for both systemic and local activity.

    Conventional vaccines may also be administered by oral film. There are several vaccines in film dosage forms being developed today, including those for measles, bacterial typhoid, and rotavirus. Potential to avoid the cold chain is also an attractive path for vaccines in film formulation. Oral film vaccine formulation could also overcome some of the most vexing challenges of conventional vaccines, mainly the difficulty in maintaining a consistent temperature from production to administration. The World Health Organization estimates that more than half of vaccines developed are wasted each year globally due to temperature control and supply chain-related issues. 

    Oral films are also becoming an attractive delivery vehicle for cannabis and other controlled substances, due to their discrete nature, potential fast onset of activity and abuse-resistant features. Companion animals could also represent an opportunity for expansion of oral films, notably because administering medication to companion animals is well recognized as inconvenient and a challenge to compliance.

    As the market for oral thin films grows, it's becoming increasingly important to be able to test and evaluate their effectiveness in a consistent and standard way. To date, the U.S. Pharmacopeia has not released any standard methods for evaluating the essential properties of oral thin films, such as adhesiveness, disintegration or dissolution. In contrast, tablets and capsules have well-defined standards that make it easier to evaluate their effectiveness and manufacturability. Evaluating dissolution is particularly challenging for oral thin films because of the difficulty of reproducing the environment of the oral cavity in vitro.

    Innovations in technology and science have enabled oral thin films to extend far beyond over-the-counter products to deliver drugs to treat a broad spectrum of diseases and conditions. As the population ages and drug development shifts to more personalized treatments, oral films continue to evolve and will play an even more significant role in drug delivery. 


    Rodolphe Obeid, M.Eng., Ph.D, is vice president of operations at IntelGenx Corp. He oversees all operational activities, including manufacturing, packaging, facilities and maintenance, production planning and supply chain management. In addition, he manages process development and manufacturing scale-up of all internal and external pharmaceutical film projects. Dr. Obeid holds a Ph.D. in polymer chemistry from the University of Montreal, Canada and two Masters in polymer science and chemical engineering from the University of Strasbourg, France. He is the co-inventor of several issued and pending patents, and has published numerous scientific articles in recognized international journals and conferences.
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