OR WAIT null SECS
Patricia Van Arnum was executive editor of Pharmaceutical Technology.
Orally disintegrating tablets (ODTs) continue to attract attention as an alternative to conventional oral dosage forms.
Offering ease of use, the potential for increased patient compliance, and a way to extend the product life cycle of a drug, orally disintegrating tablets (ODTs) continue to make inroads into the market for solid-dosage forms.
Patricia Van Arnum
Definition of ODT
Generally, an ODT is a solid-dosage form that disintegrates and dissolves in the mouth (either on or beneath the tongue or in the buccal cavity) without water within 60 seconds or less (1). The US Food and Drug Administration's Center for Drug Evaluation and Research developed the following definition for an ODT as a new dosage form in 1998: "A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue" (2).
Earlier this year, FDA issued a draft guidance, Guidance for Industry: Orally Disintegrating Tablets (2), to recommend that, in addition to the original definition, ODTs be considered solid oral preparations that disintegrate rapidly in the oral cavity with an in vitro disintegration time of approximately 30 s or less, when based on the United States Pharmacopeia disintegration test method or alternative (see sidebar, "FDA issues ODT draft guidance").
The global ODT market (based on ex-factory sales to wholesalers) was estimated at $2.4 billion in 2004 and $3 billion in 2006, according to Technology Catalysts International (3). Table I lists select examples of ODT drugs that are commercialized on the US market.
Table I. Select examples of commercialized orally disintegrating tablets.
Recent market studies indicate that more than half of the patient population prefers ODTs to other dosage forms, and most consumers would ask their doctors for ODTs (70%), purchase ODTs (70%), or prefer ODTs to regular tablets or liquids (greater than 80%) (1).
Mechanism of ODT drugs
Generally, ODTs are formulated to disperse rapidly in the mouth, enabling medication to be swallowed without water, thereby increasing convenience and compliance across a broad range of indications and patient types, including the young, elderly, and active patients, explains Susan Banbury, project manager with Catalent Pharma Solutions (Swindon, UK). Following dispersion, the formulations are typically swallowed, and the drug is absorbed in the same way as conventional solid-oral dosage forms.
"However, ODTs may also be used to deliver drugs to the oral cavity, for local action or, in some cases, absorption across the oral mucosa, thereby avoiding first-pass hepatic metabolism and potentially increasing the rate and extent of uptake, and reducing undesirable metabolites," says Banbury (4). The potential for such pregastric absorption rests largely in the physicochemical characteristics of the drug molecule. The intrinsic taste of the drug is also a significant consideration for all ODT formulations.
Types of ODTs
For ease of comparison, ODTs may be categorized into two main groups: lyophilized formulations and loosely compressed tablets. Thin-film strips form a third category of solid, unit-dose, orally disintegrating products that aim to meet the same objectives of ease of administration, patient convenience, and improved compliance.
FDA issues draft ODT guidance
"Compressed tablet systems are based on conventional tableting technology and vary in their degree of hardness and friability," explains Rosie McLaughlin, director of product development at Catalent. "This variability results in varying disintegration characteristics depending on the exact materials and process used, but typically disintegration times are higher than for lyophilized ODT formulations." Also, friable products may require specific packaging considerations. Loosely compressed ODT tablets generally rely on water-soluble excipients and/or super disintegrants to achieve rapid disintegration (30–60 s) (5).
In response to growing interest for ODTs, several companies are advancing production capabilities and technologies.
Catalent Pharma Solutions, for example, recently added "Zydis" ODT commercial manufacturing capability at its facility in Somerset, New Jersey. A commercial Zydis line was installed into a space in existing buildings, which had originally been designed to accommodate future expansion. The line will be operational in 2007, and commercial production from the site is anticipated in 2009 pending associated regulatory filings.
"The Zydis process involves the preparation of an aqueous solution or suspension, from which individual units are dosed and freeze-dried," explains McLaughlin."The liquid-dosing process ensures good dose uniformity and facilitates containment of the active ingredient. The freezing process then results in a network of ice crystals that are sublimed during lyophilization to produce a highly porous structure, which facilitates the rapid dispersion characteristics of the product," she says.
McLaughlin says the key advantage of the lyophilization technology used in the Zydis manufacture is the highly porous structure and consequent extremely rapid dispersion achieved (typically less than 5 s). The formulations are generally simple, typically incorporating two structure-forming agents with the API, in a ratio optimized for each product, plus any additives specifically required such as flavors, sweeteners, or pH modifying agents.
Select companies with orally disintegrating tablets technology.
In addition to conventional small molecules, the lyophilization process has also been shown to be suitable for the formulation of peptide and protein drug molecules. "Protein and peptide molecules are physically and chemically sensitive, and lyophilization processes are typically used in their manufacture owing to the relatively low stresses applied during processing (e.g. low temperatures)," says McLaughlin.
Several peptide and protein-based drugs use the Zydis ODT technology, including "Grazax, " a grass-pollen allergy vaccine by ALK-Abelló(Hoersholm, Denmark).
Catalent is providing commercial production of Grazax at its facility in Swindon, United Kingdom. In August 2007, Catalent reported that ALK-Abelló will fund a new production line for current and future tablet-based allergy products at Catalent's Swindon facility. Commercial production on the new line is expected to begin in 2010.
Eurand (Vandalia, Ohio) has partnered with GlaxoSmithKline (GSK, London) to develop an ODT formulation of an undisclosed compound. Last October, the companies signed a formulation development pact under which GSK is using Eurand's "AdvaTab" oral disintegration tablet technology and "Microcaps" taste-masking technology.
"The new formulation for GlaxoSmithKline dissolves in the mouth in approximately 30 seconds without water and without leaving a bitter or sour taste," said Eurand CEO Gearóid Faherty in a June 2007 release. GSK has started a registration bioequivalence study for the new formulation and will make a milestone payment of $1 million to Eurand in recognition of the initiation of this biostudy. GSK intends to file for marketing authorization in the United States by the end of 2007.
CIMA Labs, a subsidiary of Cephalon (Frazer, PA) is positioned in ODT technology through its "OraSolv" and "DuraSolv" platforms that are based on compressed-tablet technology. OraSolv is an ODT that combines taste-masked active drug ingredients with a low effervescence system. DuraSolv is an ODT that combines taste-masked active drug ingredients with or without a low effervescence system (1). Cima's parent company, Cephalon's "Lyoc" technology is an ODT platform that uses freeze-drying methods (see sidebar, "Companies with orally disintegrating tablet technology").
Challenges in ODT
Although ODTs offer benefits, there are factors to consider. "The challenges of developing ODT products are similar to those for conventional solid oral dosage forms in terms of the need to establish compatibility of the active drug substance with the excipients and process," explains McLaughlin. "In addition, the intended oral dispersion of the units means that the specific taste and mouthfeel characteristics of the drug substance are particularly relevant." Sweeteners and flavors are typically included to achieve a palatable formulation, but additional taste-masking strategies may also be required such as ion-exchange resins and active pharmaceutical ingredient (API) encapsulation.
"Another challenge is that ODTs are potentially less robust than conventional solid-oral dosage forms, given their formulation to achieve rapid disintegration (e.g.,increased friability and greater moisture sensitivity), so packaging requirements need to be considered early in the development process," says McLaughlin.
In the case of the Zydis ODT technology, the blister pack is an integral part of the product, forming the molds for the individual unit doses. Following freeze drying, the blister packs are sealed, and the units are not removed until the point of administration, thereby providing physical protection throughout the manufacturing and distribution process. The use of all aluminum blister packs also provides effective moisture protection throughout the product shelf-life, typically two to five years.
As for any other dose form, the bioavailability of ODT products is governed by the physicochemical characteristics of the API and formulation optimization. "The extent of pregastric formulation is largely dependent on the physicochemical characteristics of the drug, but the formulation may aim to maximize the potential to optimize bioavailability, or minimize the effect to ensure bioequivalence with a perorally absorbed dosage form," says McLaughlin. Typical formulation variables considered are solubility and particle size of the API, formulation pH, and formulation constituents, in particular taste- masking agents.
Widening the scope of ODT
Industry observers point to broadening uses of ODT technology. These include the incorporation of macromolecules using ODT into vaccines. "The success for other peptide and protein products will depend on bioavailability requirements and the application of methods to overcome oral absorption barriers," says Catalent's Banbury. Other areas include: the incorporation of encapsulated APIs to achieve modified-release profiles within the convenience of an ODT; and the further development of super disintegrants for incorporation into conventional, compressed tablets, potentially widening the opportunity for ODT development to nonspecialist companies.
Another emerging area is the wider application of oral thin-strip technologies. "The use of thin-film strips is of growing interest in the pharmaceutical sector following the success of Listerine PocketPaks in the United States," observes Banbury.
Thin-film strip technology uses a range of water-soluble polymers and is reported to be able to incorporate water-soluble, insoluble, or taste-masked ingredients. The film is manufactured as a continuous sheet and then cut into individual doses prior to packing. The major limitations to this technology are the relatively low doses that can be accommodated (approximately 30 mg) and its moisture sensitivity requiring specific unit-dose packaging to protect the product and ensure shelf life, explains Banbury.
Thin-film technology has primarily been used in over-the-counter (OTC) products (see Table II). The 2004 global market (based on ex-factory sales to wholesalers) for oral-thin film technology in pharmaceutical (OTC) and nutraceutical products was $25 million, says Technology Catalysts. The market is projected to increase to $500 million in the 2007 timeframe, conditioned on the entry of higher revenue-generating OTC products and possibly prescription drug products entering the market (3).
Table II. Select examples of oral thin-film pharmaceuticals and nutraceuticals.
Companies with oral thin-film technologies and products include LTS Lohmann Therapy Systems (West Caldwell, NJ), Adhesives Research (GlenRock, PA), Applied Pharma Research (Balerna, Switzerland), and Meldex International (Cambridge, UK).
Adhesives Research provides active dissolvable films for Novartis's "Triaminic Thin Strips" pediatric cough and cold products and "Theraflu Thin Strips" cold and flu products. Its technology and product platform is "ARcare" dissolvable films.
Last month, Applied Pharma Research opened its US affiliate, Applied Pharma Research USA, in Charlotte, North Carolina. The company is in the final stages of developing ondansetron and donepezil formulations using its proprietary "RapidFilm" oral thin-film technology. The "Ondansetron RapidFilm" is a generic version of GlaxoSmithKline's "Zofran."
Meldex is developing DBP117, an oral film strip of a antimigraine drug. The company is positioning the product in the "triptan" market, which includes GlaxoSmithKline's "Imitrex" (sumatriptan) and AstraZeneca's "Zomig" (zolmitriptan). The product has passed the initial formulation phase and is due to commence scale-up manufacturing trials in the second half of 2007, according to the company. The product is planned for submission to US and European Union regulatory authorities during 2008.
Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ, 08830, tel. 732.346.3072, email@example.com
1. W. Pfister and T. Gosh, "Orally Disintegrating Tablets: Products, Technologies, and Development Issues," Pharm. Technol. 29 (10), 138–150 (2005).
2. FDA, Guidance for Industry: Orally Disintegrating Tablets draft guidance, (Rockville, MD, April 2007).
3. P. Van Arnum, "Outsourcing Solid-Dosage Manufacturing," Pharm.Technol. 30 (6), 44–52 (2006)
4. A. Clarke and J. Jankovic, "Selegeline Orally Disintegrating Tablet in the Treatment of Parkinson's Disease," Therapy 3 (3), 349–356 (2006).
5. R. Bohnacker et al., "Determination of the Disintegration Time of Mouth Melt Tablets with Texture Analyzer Method," Pharm. Ind. 67 (3), 327–335 (2005).