W.R. Pfister and T.K. F. Wehling and S. Schuehle, "Base Coated Acid Particles and Effervescent Formulation Incorporating Same," US Patent 5,503,846 (1996). Ghosh, "Orally Disintegrating Tablets," AAPS Newsmagazine, 7 (6), 1921 (2004). The US Food and Drug Administration Center for Drug Evaluation and Research (CDER) defines in the Orange Book an ODT as "A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue" (1). 27. This strategy has been successfully applied to the antihistamine cetirizine, which has a very bitter taste. More than 35 products have been launched using this technology in more than 60 countries around the world. However, if the API is suitable, then careful ODT formulation can be used to ensure the drug is absorbed in the oral cavity rather than in the gastrointestinal tract. J. Hontz, "Development of a Rapidly Dissolving Famotidine Tablet," paper presented at the 41st Annual International Industrial Pharmaceutical Research Conference, Madison, WI, June 1999. M.C. In contrast to normal coating methods, no solvent is required, and the API retains 7085% potency w/w. 2022 MJH Life Sciences and Pharmaceutical Technology. The tablet retained all the fast dispersion characteristics of a standard ODT. The Bio ODT also holds out promise for oral vaccines. In the graph in Figure 6, the vaccine was administered sublingually to mice before they were challenged with influenza virus. Chem. 2022 MJH Life Sciences and Pharmaceutical Technology. Floss-based tablet technology (e.g., FlashDose, Biovail, Mississauga, ON, Canada) also is used to produce fast-dissolving tablets using a floss known as the shearform matrix (16, 21). Other patented ODT technologies based on lyophilization include Lyoc (Farmalyoc, now Cephalon, Franzer, PA) and QuickSolv (Janssen Pharmaceutica, Beerse, Belgium). Such collapse sometimes can be prevented by using various matrix-forming excipients such as mannitol that can induce crystallinity and hence, impart rigidity into the amorphous composite. G.L. As well as the patient groups identified above, a significant proportion of the general population finds swallowing tablets difficult, and an ODT can greatly increase compliance. FDA, Electronic Orange Book: Approved Drug Products With Therapeutic Equivalence Evaluations Current Through February 2005, http://www.fda.gov/cder/ob/default.htm, accessed March 18, 2005. The floss is mixed with an active ingredient and excipients followed by compression into a tablet that has fast-dissolving characteristics (3743). Future possibilities for improvements in ODTs and drug delivery are bright, but the technology is still relatively new. partially nonionized at the oral cavity's pH; ability to diffuse and partition into the epithelium of the upper GIT (log. C.C. 16. Then, the excipient is mixed with the active ingredient or active microparticles and with other standard tableting excipients and then compressed into tablets. Furthermore, any minor damage to the package may cause the wafer to collapse because of moisture absorption (34). 23. G.L. 3. Characterizes the API crystal form and identifies any changes during formulation and processing, Freeze-drying microscopy Laboratoire Lafon, "Galenic Form for Oral Administration and its Method of Preparation by Lyophilization of an Oil-in-Water Emulsion," European Patent 0,159,237 (1985). ODTs release drug in the mouth for absorption through local oromucosal tissues and through pregastric (e.g., oral cavity, pharynx, and esophagus), gastric (i.e., stomach), and postgastric (e.g., small and large intestines) segments of the gastrointestinal tract (GIT). Sastry and J. Nyshasham, "Process Development and Scale-Up of Oral Fast-Dissolving Tablets," in Drug Delivery to the Oral Cavity: Molecules to Market, T.K. If the size of the hole is matched to the API, it can trap the unpleasant tasting active, preventing it from coming into contact with the tongues taste receptors. All of these are well established and widely accepted ingredients in pharmaceutical formulations. Select products to compare by checking the boxes next to the items. Sastry, "An Overview of Fast Dispersing Technologies," paper presented at the annual meeting of the AAPS, Oct. 29, 2003. One strategy involves the use of cyclodextrins. QuickSolv disintegrates very rapidly but is limited to low drug content and can be used only with active ingredients that are insoluble in the extraction solvent (36). Copyright 2022 CompareNetworks, Inc. All rights reserved. This situation may have implications for drug safety and efficacy, which may need to be addressed and assessed in a marketing application for an ODT (13). T.K. Importantly, an ODT formulation can be bioequivalent to a traditional dosage form. The filled trays are passed through a liquid nitrogen freeze channel, causing the API solution or suspension to freeze very rapidly. In the most effective vaccine formulation, there was very little change in body weight across the period of monitoring. Characterizes moisture sorption properties and physical stability of lyophilized formulation in humidity, Characterization of hydrates and polymorphs, X-ray powder diffraction (XRPD) In a taste evaluation study of an ODT formulation incorporating beta-cyclodextrin, more than 80% of a group of 30 subjects judged the taste profile to be acceptable. 45. Our Swindon, U.K. facility is dedicated to Zydis unit production. 27 (10 Suppl), 1013 (2003). Additional technologies for manufacturing and packaging ODT dosage forms have been highlighted elsewhere (18, 19). buccal, sublingual, oesophageal), pH relatively neutral (5.5 7.2 depending on salivary flow rate), Potential for sublingual / buccal absorption, Solid, unit doses presented in protective pack, Low temperature processing minimizes manufacturing losses of labile drugs, Solution / suspension dosing achieves good content uniformity for low dose actives, Solid dosage form and low water activity aids long term stability, Liquid processing facilitates containment of potent drugs in production, Tailored to meet the known product requirements such as API unit dose, Consideration of the relevant API characteristics identified during the technical evaluation of preformulation data, A range of prototype Zydisformulations prepared under different processing conditions (bench-scale); analytical techniques applied as appropriate to determine the compatibility of a candidate API with the Zydistechnology, Short-term (4 week) accelerated physical stability studies typically undertaken before recommendations for a full development program are made, Operational excellence and efficiency via Lean Six Sigma principles, Full in-house analytical and regulatory services, Full characterization of your API and associated Zydisformulations via expert analysis and interpretation of data throughout the development process to provide a robust data package in support of regulatory filings, Smart full-lifecycle management from molecule to market with Lean efficiency standards, Expert handling and maximization of potent and controlled drugs, Bench, pilot, and full-scale cGMP manufacturing, Pilot line with controlled and potent drug capabilities, FDA and MCA audited Controlled drug capabilities. ODT products have been developed for numerous indications ranging from migraines (for which a rapid onset of action is important) to mental illness (for which patient compliance is important for treating chronic indications such as depression and schizophrenia) (3). more delivered to your inbox. In general, an ODT is formulated as a bioequivalent line extension of an existing oral dosage form. Syst. Parakh and A. Gothoskar, "A Review of Mouth Dissolving Tablet Technologies," Pharm. It is difficult to persuade infants and very young children to swallow them, and they may pose a choking hazard. R. Yarwood, "Zydis: A Novel, Fast Dissolving Dosage Form," Manuf. This article compares various ODT products and technologies and highlights their manufacturing processes, development issues, and future trends for these evolving dosage forms. This is important, as the larger the particles, the more gritty and unpleasant the mouthfeel will be in an ODT. As an example, the 32 amino acid peptide calcitonin, which has a molecular weight of 3432, was formulated as an ODT. Technol. 41. Only a few technologies can produce tablets that are sufficiently hard and durable to allow them to be packaged in multidose bottles (e.g, DuraSolv, AdvaTab [Eurand, Vandalia, OH], and WOWTAB). An additional advantage is the potential to avoid the need for cold-chain storage. R.P. The challenges of oral delivery of proteins & peptides well documented and are not limited to: ZydisBio sub-lingual delivery overcomes these challenges: Benefits of ZydisBio for peptide & protein drugs. D. Brown, "Orally Disintegrating Tablets: Taste Over Speed," Drug Deliv. Technol. R. Fuisz, "Ulcer Prevention Method Using a Melt-Spun Hydrogel," US Patent 5,622,717 (1997). The freeze-drying process involves the removal of water (by sublimation upon freeze drying) from the liquid mixture of drug, matrix former, and other excipients filled into preformed blister pockets. K. Ostrander, "Advances in Fast Dispersing Technologies-Zydis," paper presented at the annual meeting of the AAPS, Salt Lake City, UT, Oct. 29, 2003. Because they dissolve quickly, ODTs cannot provide controlled or sustained release, except those that contain slow-dissolving, microparticulate-coated drugs, which quickly disperse and are swallowed. The formed matrix structure is very porous in nature and rapidly dissolves or disintegrates upon contact with saliva (16). Cherukuri and R. Fuisz, "Process and Apparatus for Making Tablets and Tablets Made Therefrom," US Patent 5,654,003 (1997). G.K.E. Myers et al.,"Delivery of Controlled-Release Systems," US Patent 5,567,439 (1996). The Bio formulation, administered sublingually, gives a significantly higher AUC. Dozens of ODT products have been commercialized, and the market size for ODTs will continue to expand as the technology is used to deliver large-molecular weight biopharmaceutical therapeutics such as proteins and peptides when coupled with the appropriate permeation enhancers. More than a billion of the ODTs are manufactured every year in Catalents UK facility in Swindon. The basic framework of the Zydis ODT is provided by matrix and structure forming ingredients. Several factors must be considered when selecting drug candidates for delivery as ODT dosage forms. Determines particle size ranges relevant to Zydis suspension stability for insoluable API, Dynamic Vapor Sorption 5 (3), 5054 (2005). Wong, "Method for Making Freeze-Dried Drug Dosage Form," US Patent 5,631,023 (1997). For example, they require smaller amounts of active ingredient to be effective, improve absorption profiles, and offer better drug bioavailability than regular tablets and capsules. 13. Using otherwise standard ODT formulation technology, freeze dried ODTs, each containing 75mg of olive oil, were successfully made. They cover a wide gamut of therapeutic areas, with the majority in areas that benefit from the fast onset of action. The particle size of the organic acid crystals is carefully chosen to be larger than the base excipient to ensure uniform coating of the base excipient onto the acid crystals. L. Dobetti, "Fast-Melting Tablets: Developments and Technologies," Pharm. Ghosh, "Quick Dissolving Oral Dosage Forms: Clinical Pharmacology, Biopharmaceutical, and Regulatory Considerations," paper presented at the annual meeting of the American Association of Pharmaceutical Scientists (AAPS), Salt Lake City, UT, Oct. 29, 2003. One drawback to the dispersion of a tablet in the mouth is its taste. If significantly higher plasma levels and systemic exposure have been observed, pregastric absorption leading to the avoidance of first-pass metabolism may play an important role. Chemical analysis of API in support of preformulation studies (e.g., solubility determinations, compatibility testing). DeRoche et al., "Consumer Preference for Orally Disintegrating Tablets Over Conventional Forms of Medication: Evolving Methodology for Medication Intake in Dysphagia," lecture presented at the 12th Annual Meeting of the Dysphagia Research Society, San Francisco, CA, Oct. 24, 2003. 2. Drug coatings also can be used to mask bitter drugs and to protect the drug from stomach acidinduced metabolism. The overall preclinical, clinical, and biopharmaceutical development programs necessary to support successful ANDA and NDA marketing applications for ODTs were recently reviewed (44) and presented in detail in a symposium on this topic (13, 45). Ideal drug candidates for this method are insoluble drugs that have low water solubility, have fine particle size, and aqueous stability in the suspension. 140. 8. Common matrix-forming agents include gelatin, dextran, or alginates which form glassy amorphous mixtures for providing structural strength; saccharides such as mannitol or sorbitol for imparting crystallinity, hardness, and elegance; and water, which functions as a manufacturing process medium during the freeze-drying step to induce the porous structure upon sublimation. Floss-based tablet technology. As Figure 4 shows, the ODT made using a standard fluidized bed coating technique is released very rapidly, whereas those using the new LabRAM ResonantAcoustic Mixer technique have a retarded release, which is indicative of tastemasking. Ghosh and W.R. Pfister, Eds. The AUC was almost identical to that for a regular cetirizine tablet. 12. 43. Though the appropriate particle size for insoluble drugs is ~50 m, drugs with larger particle sizes also can be formulated into freeze-dried wafers using suspending agents such as gelatin and flocculating agents such as xanthan gum (8, 31). Body weight loss, which is an indicator of the extent of the disease, was greatest for the unvaccinated and infected control group, which is demonstrated by the results shown on the lowest set of data points on the graph and shows rapid weight loss after day 2 of the study. 1. More recently, the Zydis Ultra formulation has been developed, which incorporates coated APIs for taste-masking purposes. No liquid is required when taking the medication either, which is a significant advantage when on the go. Water-soluble drugs pose various formulation challenges because they form eutectic mixtures, which result in freezing-point depression and the formation of a glassy solid that may collapse upon drying because of the loss of supporting structure during the sublimation process (8, 30). T.K. This would almost certainly improve compliance, and offer an improved safety profile compared to an injectable vaccine. N. Sharma et al., "Manufacturing Technology Choices for Mouth Dissolving Tablets," Pharm. The wafer can accommodate high drug dosing and disintegrates rapidly but has poor mechanical strength (35). 50 (4), 375382 (1998). Rev.Therap. The matrix typically comprises bovine or fish gelatin, although non-gelatin polysaccharide polymers can also be used. 39. This floss is commonly composed of saccharides such as sucrose, dextrose, lactose, and fructose. Table 2 gives a list of examples of commercial products that are formulated using Zydis technology. The other two technologies are both loosely compressed tablets, which take between 15 and 20 seconds to disperse. 5 (1), 3437 (2005). S.R. Stage 2 Filling and freezing In yet another modification, a solution of soluble drug can be sprayed onto a preformed matrix, following which the solvent is evaporated (8, 32). More than 14 companies worldwide have an ODT platform technology and products in the R&D pipeline or several approved for marketing (10). 20. As previously mentioned, fragile products require special unit-dose packaging, which may add to the cost. The ideal characteristics of a drug for dissolution in the mouth and pregastric absorption from an ODT include: In contrast, the following characteristics may render a drug unsuitable for delivery as an ODT: The following sections provide information about selecting ODT technologies and their underlying manufacturing processes. In addition, several business needs are driving ODT technology development and the commercialization of new products such as the need for expanded product lines, improved life-cycle management, extended patent life, and marketing advantages.
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