Issue:April 2014

BUCCAL DELIVERY – Dissolvable Film Format Evolves to Buccal Drug Delivery Applications


INTRODUCTION

The permeability of mucous membranes provides a convenient route for the systemic delivery of new and existing therapeutic drugs. Drug delivery through various mucosal surfaces may improve bioavailability by bypassing the first-pass effects and avoiding the elimination of the drug within the gastrointestinal (GI) tract.1 Transmucosal drug delivery is being considered as an attractive delivery route for new and existing drug compounds, some of which are only available today through parenteral delivery. Of the various sites available for transmucosal drug delivery, the buccal mucosa and the sublingual area are the best suited sites for local as well as systemic delivery of drugs due to their physiological features.2

For compromised patient populations in which swallowing is difficult or the potential choking hazard is present, a buccal delivery device presents an effective dosage format with rapid onset and improved bioavailability compared to other oral formats. A number of buccal products are emerging for the treatment of chronic conditions, as well as breakthrough treatments for central nervous system conditions and pain therapies in the form of oral sprays, buccal films or tablets, and sublingual films or wafers.

As with transdermal applications, there are limitations to delivering higher molecular weight (Mw) compounds through buccal mucosal tissue. This is because the buccal and sublingual membranes contain a stratified (multilayered) epithelium that demonstrates differentiation of various cell layers. This is different than the single epithelium cell layer lining of the (GI) tract, thereby resulting in less resistance to permeability. Several approaches can be taken to increase the permeation of a drug through the buccal mucosal membrane. One of these approaches is to improve the bioadhesion properties to increase residence time and drug release of the device in the oral cavity. Another approach is to modify the physiochemical properties of the drug, such as a drug’s partition coefficient. A third approach, which is also used in transdermal drug delivery, is to employ the use of chemical permeation enhancers.3


FORMULATION FLEXIBILITY OF THE DISSOLVABLE FILM FORMAT

Dissolvable oral thin films (OTFs) are a proven technology for the systemic delivery of active pharmaceutical ingredients (APIs) and have been adopted as a practical alternative oral dosage format for over-the-counter and prescription drugs. The chemistry and art behind formulating drug-loaded films for buccal applications draws upon formulation expertise derived from traditional OTFs for GI delivery and from transdermal dosage forms.4 Through an extensive understanding of these dosage forms and by leveraging their similarities, formulators can effectively tailor a dissolvable film platform to add therapeutic value for delivering drug compounds through the oral mucosa.

Dissolvable films are typically composed of an aqueous polymer matrix. Water solubility, good film-forming capability, safety, variety of molecular weight (Mw) range, and drug compatibility make these materials suitable in many applications, including buccal transmucosal drug delivery. The availability of polymers across a wide molecular weight range allows for formulation flexibility to achieve a variety of physical properties, including drug-release rate, film strength, and disintegration rate. Combining low molecular weight and high molecular weight polymers allows for the optimization of various physical properties.5 The ability to adjust these ratios and formulate with a variety of polymer combinations provides substantial design latitude to the developer. Characteristics, such as thickness, dissolution rate, surface characteristics (texture), and mechanical properties (film strength), are customizable for each dissolvable film formulation.6

Dissolvable film employed in buccal systems may be designed as bioerodible mono- or multi-layer constructions, as well as non-eroding mono- or multi-layer systems, all featuring a mucoadhesive tailored for the desired dwell time. Bioerodible systems offer patients the convenience of rapid onset and complete system disintegration. Non-eroding systems are well suited for longer dwell time in the oral cavity (2 to 12 hours). A protective layer that may be designed into these systems reduces the variability of patient-to-patient bioerosion levels to deliver the active ingredient in a more predictable, controlled-release fashion. This protective outer layer also provides unidirectional drug release, reducing or preventing hepatic clearance due to GI absorption and metabolism.

The ideal transmucosal buccal film design would feature an API-loaded layer that bonds directly to the buccal site, while a second outer backing layer erodes at a designated rate equal to the time it takes for the entire drug concentration to be delivered to the system. Unidirectional drug release provides optimal bioavailability and negligible loss of drug to the saliva and GI tract. The slower eroding backing layer would offer layer during eating, drinking, and exposure to saliva to prevent the API layer from dissolving into the oral cavity until completion of the desired drug infusion time.

The next generation of buccal product designs will evolve to include options for controlled release up to 12 to 24 hours. The general challenge for controlled-release applications is to design systems that slowly erode over time without becoming dislodged and swallowed as a result of normal activities, such as eating and drinking. Increased residence times of new buccal delivery devices may make it possible to deliver sensitive biological compounds that would otherwise be deactivated in the GI tract and thereby can only be dispensed currently through an injectable dose. Product developers must be cognizant of an increased potential for irritation to occur for longer-wearing devices – some of these concerns can be addressed through proper mucoadhesion ingredient selection.


FORMULATING MUCOADHESION PROPERTIES

A number of unique factors must be taken into consideration when formulating bioadhesives for this challenging bonding environment. For example, the polymer layer that makes direct contact with the oral mucosa should demonstrate strong H-bonding groups to interact with mucus. Also, matrix polymers featuring a strong anionic charge with sufficient chain length and mobility will offer improved penetration of the mucosal layer to create chain entanglement with the mucus network. Formulations that feature surface tension characteristics similar to those of the mucosal tissue surface will promote wetting of the mucosal surface for improved intimate contact leading to formulation polymer chain mobility into the mucus layer.

Drug release and permeation through the mucosa is influenced by the mucosa microenvironment. Therefore, drug delivery systems for the oral mucosa are designed with the help of mucoadhesive polymers that are generally formulated for optimum chain length (molecular weight) and chemical functionality.7 The physiological pH 5.8 to 7.4 of the oral cavity typically tracks with the variability of saliva pH. At physiological pH, the mucosal layer carries a net negative charge due to the sialic acid and sulfate groups originating from mucus.

Mucoadhesive properties are effectively evaluated by determining the adhesive strength between the polymer matrix and a substrate, in this case, the buccal mucosa.8 Several mucoadhesive tests have been explored in the literature, which typically measure the force required to detach a device from the substrate through the application of an external force. Testing of mucoadhesion properties measure how successfully a device will bond, and can help to predict how well this bond can withstand normal activities, such as the force applied by tongue abrasion, talking, swallowing, etc. within the oral cavity.

ARx has developed mucoadhesion testing methodologies similar to those reported in the literature, but has adapted these tests to meet the end-user’s specific requirements. Synthetic membranes are selected to simulate similar responses to those of viable mucosal membranes in order to achieve comparable results between test and reference products. Testing is usually conducted at 37°C, pH 6.4 to 7.2 to be comparable to the physiological environment of the oral cavity.

The most relevant test parameters for measuring mucoadhesive performance include: • Compression Force – This measurement mimics the forces present during application of the device to a substrate (buccal mucosa) and can also provide information on creep compliance of the device.

Dwell Time – The duration of time the device is permitted to reside on the membrane prior to removal. Dwell times for testing purposes range from instantaneous to about 60 seconds.

Peeling Force – The force required to remove the device from the membrane.

Ultimate Hydration of Device –The amount of moisture present during device/membrane equilibration and prior removal. Hydration of the device is based on chemical composition, dwell time, and thickness/mass of the system. Hydration affects how well the device interacts and adheres to the membrane.

APIS FOR BUCCAL DRUG DELIVERY

Dissolvable films that are employed in buccal drug delivery applications ideally contain APIs that are lipophilic due to the requirement for permeation through a stratified, lipid-rich oral epithelium. This epithelium layer is not as keratinized as the stratum corneum of skin, which is composed of lipid bilayers that form lamellae. The intercellular spaces of the oral epithelium, on the other hand, are relatively hydrophilic compared to skin. Various epithelial sites within the oral cavity vary in terms of the lipid concentration residing in the intercellular spaces because they do not contain the highly organized lipid lamellar layer that is found in the stratum corneum. The environment of the oral epithelium’s intercellular spaces is predominantly aqueous, containing varying degrees of lipid content that arise from the membrane-coating granules of the basal cells.

The lipophilicity limitation may eliminate some APIs from consideration; however, many drug compounds and corresponding salt forms can be formulated in a vehicle with a selected pH buffer to take advantage of the drug’s pKa for promoting optimum absorption. Care must be exercised to avoid irritation to the mucosal tissue when pH buffering becomes significantly different from the physiological pH.

Researchers have some latitude in how much API can be incorporated into a dissolvable film formulation. API concentrations are typically limited to about 50% of the final unit mass; however, the size of the final product is adjustable to deliver the proper dose.9 Thicker films can be produced to yield higher strengths. In the case of buccal applications, it is up to the product designer to determine at what point the thickness or overall size of the buccal drug delivery device becomes unacceptable to the patient. Because there is a limitation in the size of the final buccal product, typically 1 to 5 square centimeters, this limited surface area dictates that the APIs must be fairly potent. As in transdermal drug delivery applications, the incorporation of chemical penetration enhancers can facilitate the transport of difficult APIs across the buccal mucosa and thereby allow for the delivery of compounds with a higher molecular weight. Some common penetration enhancers used to increase permeability, include sulfoxides, alkyl-azones, pyrrolidones, alcohols and alkanols, glycols, surfactants, and terpenes.10 Looking forward, the use of micronized and nano-particle APIs that form a dispersed phase within a film can open the door for potentially more effective drug delivery methods. Ultimately forming a solid-state solution of the API within the polymer matrix is the primary goal for improving bioavailability. With increased surface area of the API combined with a larger direct-contact surface area of film, there is the potential to improve bioavailability and to increase uptake from the mucosal surface. By modifying the residence time of the buccal delivery device while in contact with the mucosal tissue, early stage work suggests this type of system has the potential to effectively deliver drugs in a shorter timeframe.

CONCLUSION

Two important considerations for the next generation of drug delivery technologies are overall cost and compliance to improve the patient experience and tailored drug delivery. The buccal and sublingual oral mucosa will continue to be an area of growing interest for drug delivery as researchers evaluate ways to improve bioavailability, patient compliance, and product lifecycle beyond tablet and injectable formats.

Formulators experienced in the art of designing with excipients and polymers enable the specialized delivery of a variety of APIs. The range of formulation flexibility available through dissolvable film platforms provides product developers a basis of proven experience through the success gained through the oral thin film format. This flexibility ranges from dissolution rates broad enough to create bioerodible mono- or multilayer constructions, as well as non-eroding mono- or multi-layer systems. Combining dissolvable film technology with a tailored transmucosal adhesive ensures the desired dwell time for proper dosing, while opening the door to the possibility for controlled-release buccal applications. To view this issue and all back issues online, please visit www.drug-dev.com.

REFERENCES

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Scott D. Barnhart is the Technical Director for ARx, LLC, a wholly owned subsidiary of Adhesives Research, Inc. With more than 25 years R&D experience, Mr. Barnhart’s career has focused on drug matrix formulation and process capabilities for transdermal drug delivery systems and the development of the company’s dissolvable film platform technologies. He earned his BS in Chemistry and Biology from The Pennsylvania State University and his MS in Organic Chemistry from Shippensburg University. Contact Mr. Barnhart at Adhesives Research, P.O. Box 100, Glen Rock, PA 17327; E-mail: sbarnhart@arglobal.com or phone: (717) 227-3206.