The Perfect Pediatric Pill?

Maybelle Cowan-Lincoln Oral Disintegrating Tablets Make Dosing Challenges for Children Disappear Pediatric patients present unique challenges when it comes to administering medications. Solid oral dosing forms are particularly difficult for this population; children under four cannot swallow tablets, and capsules are often not an option until after 12 years of age. Many young patients also experience a fear of choking that can make taking any kind of pill nearly impossible.1 To overcome these issues, liquid formulations have been the standard dosing form for children. However, liquids have shortcomings of their own. Solubility can be an obstacle for both the excipients and the active ingredients, and stability may present a problem when a drug requires taste-masking additives or preservatives. In addition, liquid medications are particularly vulnerable to dosing errors. A study conducted by Regions Hospital in St. Paul, Minn., illustrated how prevalent these mistakes can be. In this study, the most commonly used dosing device was the household teaspoon. However, this tool is hardly accurate, as teaspoons can vary in volume from 2 mL to 10 mL. Even using the same spoon, different users can deliver doses ranging from 3 mL to 7 mL. Consequently, since 1975, the American Academy of Pediatrics has strongly recommended against using household teaspoons for measuring liquid medications.2 Specially designed dosing devices such as dosing cups and cylindrical spoons appear promising but do not solve the problem. In the Minnesota study, some participants confused the markings on a dosing cup for teaspoons and tablespoons, and the cylindrical spoon increased the risk of spillage. Similar to the action of a cotton candy machine, centrifugal action creates a floss which is then cooled, partially recrystallized, and finally compressed into ODTs. Another potential dosing error can result from misinterpreting the dosing chart on the liquid medication package. If a child’s weight is discordant with his/her age, the weight should be used to determine the correct dose. However, parents or caregivers may use the child’s age, resulting in either an overdose or a therapeutically inadequate amount. Beyond dosing accuracy, another challenge presented by liquids is taste masking. When drug developers are choosing medication flavors to cover the taste of an active ingredient, they must consider the fact that the pediatric palate responds to flavors very differently than that of an adult. Choosing tastes is made more complicated by cultural factors—different flavors are favored by the populations of different countries, and medications incorporating flavors that are regionally popular are considered more palatable in those regions. But, while a pleasant taste can help with compliance, manufacturers must be careful to avoid encouraging overconsumption by making medicine taste too much like a sweet treat.3 Newer dosing forms have emerged to meet the challenges posed by pediatric patients. One technology is the oral disintegrating tablet, a solid dosing form that disintegrates in the mouth within five to 30 seconds without chewing or liquids. Because this type of formulation does not require swallowing, it offers a significant advantage for children. In addition, the drug can be absorbed in multiple places in the gastrointestinal tract, from the pharynx down, resulting in greater bioavailability than traditional oral dosing technologies.4-6 continues below... Case Study: Fast-Acting Oral Thin Films Show Promise Another oral delivery system that can effectively meet the challenges of the pediatric population is the oral thin film. These fast-dissolving, mucoadhesive films are composed of the active ingredient, polymers, plasticizers, and surfactants, along with colors and flavorings to make the experience palatable. OTFs usually measure between 2 and 8 cm2 and are placed on or under the tongue, where they rapidly dissolve and release the drug at the application site.1,2 In addition to overcoming the pediatric swallowing challenge, OTFs offer several advantages over ODTs and conventional oral delivery systems. They can provide increased bioavailability for some drugs, potentially improve the onset of action, decrease dosing, and enhance a drug’s efficacy and safety profile. They can also be produced at a cost competitive with that of conventional tableting. There are numerous methods used to manufacture these minty-flavored wafers. The preferred method is solvent casting, because it employs equipment already common throughout the pharmaceutical manufacturing world. Water-soluble ingredients are dissolved to form a viscous solution; then the active ingredient is dissolved in a small amount of the solution. The solution containing the drug is then mixed with the viscous solution, and any entrapped air is vacuumed out. The final solution is cast as a film, dried, and cut into pieces.3 There are several challenges to achieving commercial scale production of OTFs. A key factor in the process is reaching sufficiently rapid speeds in the coating and drying operations. This can be facilitated by employing enough dryers of the correct type, either horizontal-nozzle, bow, or hot-flue. Another important consideration for production is taking the proper measures to prevent air and moisture from becoming entrapped in the film. Air in the OTFs would produce an uneven surface, and water would affect properties such as tensile strength, flexibility, and folding endurance. OTFs offer the pharmaceutical industry an attractive alternative to oral dosing form. They are portable, easy to use, and convenient, and they can be manufactured on equipment already used by drug manufacturers. —MCL References Malke S, Shidhaye S, Desai J, Kadam V. Oral films – patient compliant dosage form for pediatrics. The Internet Journal of Pediatrics and Neonatology. Available at: www.ispub.com/journal/the-internet-journal-of-pediatrics-and-neonatology/volume-11-number-2/oral-films-patient-compliant-dosage-form-for-pediatrics.html. Accessed March 13, 2012. Arya A, Chandra A, Sharma V, Pathak K. Fast dissolving oral films: an innovative drug delivery system and dosage form. Int J ChemTech Res. 2010;2(1):576-583. Greb E. Are orally dissolving strips easy for manufacturers to swallow? PharmTech.com. Jan. 21, 2009. Available at: http://license.icopyright.net/user/viewFreeUse.act?fuid=MTU0OTgxMTg%3D. Accessed March 13, 2012. The ODT dosing form is a viable option for numerous active ingredients. As long as a drug is water soluble, is permeable, and can be dosed at less than 20 mg, it is a candidate for delivery as an ODT. Taste is an important factor as well—because the tablet is dissolving in the mouth, it must be possible to mask the drug’s taste.7 Several widely prescribed pediatric medications are currently marketed as ODTs: Prevacid, an antiulcerative; Zofran, an antiemetic indicated to prevent the nausea and vomiting associated with chemotherapy; and Clarinex RediTabs, an antihistamine. In addition to these prescription brands, OTC products include Claritin RediTabs, Alavert, and Triaminic. There are two main types of ODT formulations. The first is a loosely compressed tablet manufactured using conventional tableting technology with lesser degrees of compaction, combined with water-soluble excipients and/or powerful disintegrants. The second type is a very porous, lyophilized (freeze-dried) formulation. Both categories exploit the rapid uptake of saliva to achieve fast disintegration. There are numerous processes used to manufacture the loosely compressed ODTs. One popular method is called the cotton candy process. The active ingredient is combined with sugar alcohols such as mannitol or sorbitol and melted. Similar to the action of a cotton candy machine, centrifugal action creates a floss which is then cooled, partially recrystallized, and finally compressed into ODTs. The lyophilization process involves trapping a drug in a matrix of fast-dissolving excipients including saccharides, gums and collapse protectants. Another method combines super disintegrants with highly volatile ingredients such as camphor or menthol. Once the active ingredient is added, the mixture is compressed into tablets and the volatile substances are removed by sublimation, leaving a very porous and easily disintegrating ODT. A simpler technique involves blending sugar alcohols with active ingredients and excipients, including solidifying agents, and then melting them together. The molten mixture is then poured into blister packaging wells and dried. Alternatively, the lyophilization process involves trapping a drug in a matrix of fast-dissolving excipients including: Saccharides to add hardness and pleasant texture; Gums to impart stability; and Collapse protectants to prevent long-term shrinkage. The ingredients are dissolved in water and the solution is poured into blister packs—or another unit dosing form—and freeze dried. This process avoids heating, making it suitable for drugs that would be adversely affected by elevated temperatures. References U.S. Department of Health and Human Services. Development of appropriate pediatric formulations and drug delivery systems SBIR (R43) application. Available at: http://grants.nih.gov/grants/guide/pa-files/PAR-11-304.html. Accessed March 13, 2012. Madlon-Kay DJ, Mosch FS. Liquid medication dosing errors. The Journal of Family Practice online. Available at: www.jfponline.com/Pages.asp?AID=2582. Accessed March 13, 2012. Gauthier P, Cardot JM. Developing drugs for children and the adjustment of medication – is it a new challenge or an adaptation of past ideas? Journal of Personalized Medicine online. Available at: www.mdpi.com/2075-4426/1/1/5/. Accessed March 13, 2012. Banbury S, MacGregor K. Fast-dispersing dosage forms for the pediatric market. Drug Deliv Technol. 2011;11(2):32-35. Stoltenberg I, Winzenburg G, Breitkreutz J. Solid oral dosage forms for children – formulations, excipients and acceptance issues. Journal of Applied Therapeutic Research. Available at: www.euromedcommunications.com/files/products/Stoltenberg%20Winzenburg%20Breitkreutz.pdf. Accessed March 13, 2012. Goel H, Rai P, Rana V, Tiwary A. Orally disintegrating systems: innovations in formulation and technology. Recent Pat Drug Deliv Formul. 2008;2(3):258-274. Strickley RG, Iwata Q, Wu S, Dahl TC. Pediatric drugs – a review of commercially available oral formulations. J Pharm Sci. 2008;97(5):1731-1774. Editor's Coice Parkash V, Maan S, Yadav SK, et al. Fast disintegrating tablets: Opportunity in drug delivery system. J Adv Pharm Technol Res. 2011;2(4):223-235. Ascher-Svanum H, Furiak NM, Lawson AH, et al. Cost-effectiveness of several atypical anti-psychotics in orally disintegrating tablets compared with standard oral tablets in the treatment of schizophrenia in the United States [published online ahead of print Feb. 21, 2012]. J Med Econ. Solanki SS, Dahima R. Formulation and evaluation of aceclofenac mouth-dissolving tablet. J Adv Pharm Technol Res. 2011;2(2):128-131. Kondo K, Niwa T, Ozeki Y, Ando M, Danjo K. Preparation and evaluation of orally rapidly disintegrating tablets containing taste-masked particles using one-step dry-coated tablets technology. Chem Pharm Bull (Tokyo). 2011;59(10):1214-1220. Gryczke A, Schminke S, Maniruzzaman M, Beck J, Douroumis D. Development and evaluation of orally disintegrating tablets (ODTs) containing ibuprofen granules prepared by hot melt extrusion. Colloids Surf B Biointerfaces. 2011;86(2):275-284.