By Scott D. Barnhart, MS, and Martha S. Sloboda, MBA
Flexibility fosters evolution of oral thin films
The dissolvable oral thin film (OTF) platform is proven and accepted for both localized and systemic drug delivery. This platform continues to be embraced by patients and caregivers alike for its ease of delivery, portability, and accurate dosing. Since the first commercial launch of OTFs for systemic drug delivery in 2004, the platform has evolved as more pharmaceutical researchers evaluate ways to apply the benefits of this technology across more markets and therapeutic classes.1 As a result of these efforts, researchers have extended the use of the technology into prescription, nutritional, and veterinary applications. Advances in chemistries and the manufacturing processes employed during the formulation and scale-up of this technology play a significant role in advancing the potential of OTFs beyond immediate release oral applications.
The chemistry and art behind formulating OTFs draw on polymer expertise derived from traditional solid, buccal, and transdermal dosage forms. By understanding these formats and leveraging their similarities, formulators can effectively deliver unique and compliant products out of the lab within a shortened product development time frame. The formulation flexibility of the OTF platform enables formulators to evaluate a broad range of excipients and active pharmaceutical ingredient (API) forms when embarking on new product development initiatives. This formulation flexibility may also increase a program’s chance for success by presenting chemists with a wider range of available material sets to produce both an acceptable and stable product.
When selecting an OTF to replace an existing product, the film’s dissolution rate, material selection, and absorption rate are all considered so that an equivalent or an improved product profile may be produced over existing liquids, capsules, and tablets. The robustness of thin film dosage forms has been demonstrated through 24-month International Conference on Harmonisation stability studies.
Ongoing research is extending dissolvable film technology to more complicated systems for modified or controlled release, including applications for topical delivery. In some cases, there is convergence with transdermal technology, enabling films to have more tangible adhesive properties such as increased dwell time in the mouth or other alternative delivery sites. This work relies on a strong understanding of the suitability, compatibility, and availability of material sets.
Robust OTFs are developed using current commercially available excipients that are generally regarded as safe. Most major suppliers of solid oral dosage forms materials now offer excipients that are appropriate for use in OTFs and potentially enhance disintegration properties.
The majority of film formulations are compounded as a liquid prior to being cast into films. A host of water, solvents, and combinations of both exist as process aides. Based on the solubility and compatibility of the API, a formulator can choose to develop a 100% water-based system, or, in the event that the API degrades in water, other pharmaceutically acceptable organic solvents. Solvent selection can also be used to enhance manufacturing efficiency based on the relative energy required to remove the volatile liquid during the film-casting process.
Significant research and expertise derived from the transdermal arena has resulted in a wide range of release liner technologies that may be used as processing aids in the manufacture of OTFs. These materials are composed of a plastic film or paper substrate coated with silicone or non-silicone chemistries for a clean release of the film when appropriate in the conversion process.
By coating a compounded liquid formulation to a continuous web of release liner material, film manufacturers are able to maintain the integrity of the OTF film product throughout the manufacturing process, because this component provides added strength, support, and environmental protection to wound rolls of OTF film prior to finishing. Release liners can be incorporated strictly as a processing aide that is removed in the film finishing stage, or, as seen in new product launches, they can remain affixed to the OTF to aid in dispensing and administering the drug product.
OTFs can integrate most available forms of APIs, including micronized, granulated, salt, and free-base forms. Both soluble and insoluble drugs have been successfully compounded into solutions, emulsions, or suspensions that have subsequently resulted in the launches of OTF products currently available on the market. Larger particle size compounds do present some constraints with regard to the final OTF’s thickness, but, in general, most API and nutritional compound particle size distributions fall within typical OTF production requirements.
A number of taste-masking options exist and have been employed in the development of OTFs. These include sophisticated masking technology specifically designed for highly bitter materials with an affinity for the oral cavity. Beyond palatability, key considerations in selecting any taste-masking approach include cost, impact to API particle size or mass, and solvent compatibility.
Researchers have some latitude when it comes to how much API can be incorporated and how other product attributes can be tailored for each thin film drug product. API concentrations are typically limited to 50% of the final unit mass; however, the size of the final unit strip is adjustable to deliver the proper dose. Thicker OTFs can be produced to yield higher strengths. In this case, the formulator determines at what point the thickness of the product detracts from the desired disintegration profile. Furthermore, a formulator can elect to produce multiple formulas to obtain multiple strengths for a specific API, or produce a single formula that is cut into multiple strengths based on the size of the unit area. For example, 10 mg strength of a given formula could become a 5 mg-strength dose by halving the unit size, with no additional formulary work required.
Looking forward, the use of micronized and nanoparticle APIs in OTFs opens the door for drug delivery methods that are potentially more effective. With the increased surface area of the API and the larger direct-contact surface area of the film, it may be possible to improve bioavailability and increase uptake from the mucosal surface. Early stage work suggests that by modifying the residence time of the OTF on the mucosal tissue in conjunction with the micronized or nano-API, drugs may be delivered effectively in a shorter time frame.
Based on precision adhesive coating technologies used for decades in the transdermal industry, the manufacturing techniques for OTFs are well understood and lend themselves to holding exceptionally tight tolerances throughout the process. The precision-coating techniques derived from transdermal production are now used to produce OTF base chemistries in final individual doses with unit tolerances as tight as ± 2.5% around the potency target.2 Specialized coat weight monitoring systems and liquid deposition techniques enable any OTF product to hold and maintain consistent cross and downstream uniformity during manufacture. This continuous process monitoring also lends itself to process analytical technology initiatives and helps to identify any processing variability in real time.
Coating technology from other markets continues to advance OTF production and cost-effectiveness. Multi-functional mixers drawn from the food industry enable multiple products to be manufactured out of the same process footprint. New approaches in coating techniques are leading to more sophisticated OTF constructions. An example of this can be seen in the adhesive coating techniques utilized in the electronics market for enabling multi-lane simultaneous coating.3 Applying this technique to OTF manufacturing may enable the coating of incompatible materials, or synergistic chemistries, side by side without triggering any pre-dose reaction.
Packaging has commonly been a single-unit dosage format that accommodates one or two strips per pouch and enables product portability. It also allows for multiple count options to accommodate dispensing needs and regional requirements. However, a number of new, stable formats are emerging that maintain dose integrity while also offering a more cost-effective dispensing option that complies with stability and regulatory requirements.
The manufacturing flexibility of OTFs reduces capital requirements and capacity consumption. It also enables formulators to consider new options for delivery. Because these manufacturing approaches are also well understood and controlled, robust, efficient development can occur from bench to commercial scale.
The Future of OTFs
The application of OTFs now extends beyond traditional immediate release oral dosage forms. Development of topical films, probiotic strips, and controlled release products is a testament to the delivery format’s flexibility, proven robustness, and stability.4
The future of OTF formulation and processing is a direct reflection of evolving healthcare needs. Demographically, most established markets have aging populations that benefit from simple products that are easy to dispense and dose. As emerging markets require flexibility in the number of units dispensed at any given time and providers continue to look for options that can increase compliance, minimize dosage levels and frequency, and reduce costs, OTFs have increasingly become the solution to satisfy all of these needs. In addition, development teams are able to capitalize on the flexibility of OTFs by adapting the technology for their program.
Barnhart is technical director and Sloboda is business manager at ARx LLC. Reach them at email@example.com or (717) 227-3206 and firstname.lastname@example.org or (717) 227-3326.
- In-PharmaTechnologist.com. Novartis launches first systemic OTC in film strip format. Available at: www.in-pharmatechnologist.com/Materials-Formulation/Novartis-launches-first-systemic-OTC-in-film-strip-format. Accessed February 14, 2010.
- Van Arnum P. Pediatric formulations: technical and regulatory considerations. PharmTech.com website. Available at: http://pharmtech.findpharma.com/pharmtech/Formulation+Article/Pediatric-Formulations-Technical-and-Regulatory-Co/ArticleStandard/Article/detail/615617. Accessed February 14, 2010.
- Greb E. Are orally dissolving strips easy for manufacturers to swallow? PharmTech.com website. Available at: http://pharmtech.findpharma.com/ pharmtech/Article/Are-Orally-Dissolving-Strips-Easy-for-Manufacturer/ArticleStandard/Article/detail/576124. Accessed February 14, 2010.
- PR Newswire. Ganeden Biotech introduces the first probiotic thin strip. PR Newswire website. Available at: http://news.prnewswire.com/ViewContent. aspx?ACCT=109&STORY=/www/story/09-15-2009/0005094056&EDATE=. Accessed February 14, 2010.