spacer
home > pmps > summer 2012 > mission dissolvable
PUBLICATIONS
Pharmaceutical Manufacturing and Packing Sourcer

Mission Dissolvable


Oral thin film technology offers formulation flexibility and can naturally transition to transmucosal drug delivery – especially through the medium of buccal applications.

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 benefits of dissolvable film technology include fast, accurate dosing in a safe, efficacious format that offers convenience for the patient and caregiver alike.

Why Buccal Delivery?

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 (nasal, rectal, vaginal, ocular and oral mucosa) may improve bioavailability by bypassing the first pass effects and avoiding the elimination of the drug within the gastrointestinal 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 (the inner cheek area) and the sublingual area (floor of the oral cavity) are the best suited sites for local as well as systemic delivery of drugs, due to their physiological features (1). The buccal mucosal site offers a smooth, immobile surface with high vascular perfusion, in contrast to the sublingual mucosal site, which lacks an immobile mucosal surface. The lack of an immobile surface derives from the fact that the sublingual space is constantly washed by saliva from the sublingual salivary ducts. However, one must consider that the sublingual mucosal membrane is much thinner (190μm) than the buccal mucosal membrane (580μm) (2). This difference in thickness may explain the difference in permeability (Kp) of the mucosal membranes, 579 x 10-7 cm/min vs 973 x 10-7 cm/min for the buccal mucosa and floor of the mouth, respectively (3). When compared to other mucosal areas, the buccal mucosa is more tolerant to potential allergens, with less impact for irreversible damage, and relatively lower enzymatic activity (4).

For compromised patient populations where swallowing is difficult or where a potential choking hazard is present, a buccal delivery device presents an elegant and effective dosage format with improved bioavailability when compared to other oral formats. Buccal devices offer advantages to caregivers for administration, in that the buccal area is easily accessible and generally a well-tolerated site by patients as it does not require swallowing for the device to deliver an efficacious systemic dose with rapid onset. A number of buccal products are emerging for the treatment of chronic conditions, as well as breakthrough treatments for central nervous conditions and pain therapies in the form of oral sprays, buccal films or tablets, and sublingual films or wafers.

As with transdermal applications, formulators are limited by the ability to deliver 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 in the form of keratinisation. This is different from the single epithelium cell layer lining the gastro-intestinal 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 drugs partition coefficient. A third approach, which is also used in transdermal drug delivery, is to employ the use of chemical permeation enhancers (5).

Formulation Flexibility of the Dissolvable Film Format

The chemistry and art behind formulating drug-loaded films for buccal applications draws on formulation expertise derived from traditional OTFs for gastro-intestinal delivery and from transdermal dosage forms (6). Through an extensive understanding of these dosage forms and by exploiting their similarities, formulators can effectively tailor a dissolvable film platform to add therapeutic value for delivering drug compounds through the oral mucosa. This flexibility enables formulators to evaluate a broad range of excipients and APIs.

Typically dissolvable films are composed of an aqueous polymer matrix. Cellulose derivatives, hydrocolloids, acrylate copolymers, gums and polysaccharides are a few examples of the many chemistries available to the formulator. Water solubility, good film forming capability, safety, variety, 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 Mw and high Mw polymers allows for the optimisation of various physical properties (7). 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 customisable for each dissolvable film formulation (8). Physical attributes are greatly affected by the selection of the polymer molecular weights in the film matrix. Additives present in the dissolvable film formulation will also play a role in defining final properties. For instance, increased disintegration time and mechanical strength are expected from films comprised of either high Mw polymer(s) or a higher ratio of high Mw to low Mw polymer. Thickness and mass also play a role in determining the physical properties of dissolvable films. Constructions comprised predominantly of low Mw polymers prepared at different thicknesses will result in a wide range of disintegration rates.

Dissolvable films for buccal applications can be designed as an erodible monolayer or as a multi-layer construction. 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 systemic circulation. Unidirectional drug release provides optimal bioavailability and negligible loss of drug to the saliva and GI tract. The slower eroding backing layer would offer protection to the drug-containing mucosal 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.

Formulating Mucoadhesion Properties

While the buccal mucosa provides an accepted site for drug delivery, it is paramount that the device is designed with the appropriate mucoadhesive properties to assure adequate residence time in the oral cavity for proper dosing. By combining the benefits of filmforming technology with predictable mucoadhesive properties for increased dwell times, the possibility of utilising the dissolvable film platform for transmucosal drug delivery, including buccal and sublingual delivery sites, is possible. Buccal films are generally better tolerated than oral gels and buccal tablets due to the film platform’s ability to offer a relatively longer residence time, flexibility to conform to the buccal mucosa and greater comfort.

An understanding of mucus composition allows for the design of transmucosal drug delivery systems optimised for bioadhesion. Drug release and permeation through the mucosa is influenced by the mucosa microenvironment. Therefore, drug delivery systems for the oral mucosa are designed and formulated with the help of mucoadhesive polymers, which are generally formulated for optimum chain length (molecular weight) and chemical functionality (9). The physiological pH (5.8-7.4) of the oral cavity typically corresponds 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.

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 (10) 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.

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 keratinised 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 when 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 organised 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 drugs pKa for promoting optimum absorption.

Researchers have some latitude in how much API can be incorporated into a dissolvable film formulation. API concentrations are typically limited to about 50 per cent of the final unit mass (11); however, the size of the final product is adjustable to deliver the proper dose. 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. There is a limitation in the size of the final buccal product typically 1 to 5cm2, therefore this limited surface area dictates that the APIs must be fairly potent.

Looking forward, the use of micronised and nano-particle APIs in a film can open the door for potentially more effective drug delivery methods. With increased surface area of the API combined with a larger directcontact 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 on the mucosal tissue, early stage work suggests that this type of system has the potential to effectively deliver drugs in a shorter timeframe.

References

  1. Shojaei AH, Buccal mucosa as a route for systemic drug delivery: a review, J Pharm Pharmaceut Sci 1 (1): pp15-30, 1998
  2. Schroeder HE, Differentiation of Human Oral Stratified Epithelium, Karger, Basel, p33, 1981
  3. Squier CA et al, Lipid Content and Water Permeability of Skin and Oral Mucosa, J Invest Dermatol 96: p123, 1991
  4. Giannola LI, De Caro V, Giandalia G, Siragusa MG, Campisi G and Wolf A, Current status in buccal drug delivery, Pharmaceutical Technology Europe, May 2008
  5. Shanker G, Kumar CK, Gonugunta CS, Kumar BV, Veerareddy PR, Formulation and Evaluation of Bioadhesive Buccal Drug Delivery of Tizanidine Hydrochloride Tablets, AAPS PhamSciTech June: pp530-539, 2009
  6. Barnhart S and Sloboda M, Advancing oral delivery: Flexibility fosters the evolution of oral thin films, Pharmaceutical Formulation and Quality, 12(1): pp18-20, 2010
  7. Moritz C, Films that dissolve diagnostics manufacturers’ needs, Medical Design Technology 10(10): pp11-13, 2006
  8. Barnhart S and Vondrak B, Dissolvable films for flexible product format in drug delivery, Pharmaceutical Technology, supplement, April 2008
  9. Figueiras A, Pais Alberto and Feiga F, A Comprehensive Development Strategy in Buccal Drug Delivery, AAPS PharmSciTech, 11(4): pp1,703- 1,712, 2010
  10. Punitha S and Girish Y, Polymers in mucoadhesive buccal drug delivery system – A review, Int J Res Pharm Sci 1(2): pp170-186, 2010
  11. Van Arnum P, Pediatric Formulations: Technical and Regulatory Considerations, Pharmaceutical Technology August supplement, 2009
  12. Patel V M et al, Buccal Delivery, Drug Delivery Technology 7(9): pp54-60, 2007

Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

spacer
Scott D Barnhart is the Technical Director for ARx, LLC, a whollyowned subsidiary of Adhesives Research, Inc. With more than 20 years of R&D experience, Scott’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. Scott earned his BSc in Chemistry and Biology from The Pennsylvania State University and his MSc in Organic Chemistry from Shippensburg University.

spacer
Scott D Barnhart
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

MedPharm’s CSO and University of Reading Professor co-author new book on dermal formulation development

MedPharm’s Chief Scientific Officer and Co-Founder, Professor Marc Brown and University of Reading’s Professor Adrian Williams have co-authored the new book: ‘The Art and Science of Dermal Formulation Development”. It is the latest addition to ‘Drugs and the Pharmaceutical Sciences’, a series of textbooks and monographs published by CRC Press.
More info >>

White Papers

The Impact of Components on Drug Quality and Risk Mitigation

West Pharmaceutical Services, Inc.

Expectations for quality by regulatory agencies are increasing at a very fast pace, especially for prefilled drug delivery formats, thanks to increased focus on reducing risk to patient safety. The trend has resulted in delays for new drug applications, more recalls of marketed products and even drug shortages if the container system and drug contents are suspect for quality issues. The pharmaceutical market is now requiring manufacturers of containers and components to meet new expectations with a quality culture and very high product reliability. The need to bridge the gap and provide superior quality products has been a driver for manufacturing technology investments, more robust control strategies and the introduction of next generation elastomer components.
More info >>

 
Industry Events

The Universe of Pre-filled Syringes and Injection Devices

22-23 October 2019, The Swedish Exhibition & Congress Centre Gothia Towers Hotel

PDA’s Universe of Pre-filled Syringes and Injection Devices has become the must-attend meeting for everyone working in the field, and is now the world’s largest conference on this subject
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement