Technol. The European Pharmacopoeia however defines a similar term, orodisperse, as a tablet that can be placed in the mouth where it disperses rapidly before swallowing (2). Gole et al., "Preparation of Pharmaceutical and Other Matrix Systems by Solid-State Dissolution," US Patent 5,215,756 (1993).
Scherer (now Cardinal Health), personal communication, (2005). These sugar-based macromolecules, often used as odor removers in household products, have a hole in the middle, allowing smaller molecules to fit inside. 9. 
40. 
Optical microscopy N. Sharma et al., "Manufacturing Technology Choices for Mouth Dissolving Tablets," Pharm. This vibrates, causing the particles to move and accelerate by as much as 100 times the force of gravity. In addition, ODTs may be suitable for the oral delivery of drugs such as protein and peptide-based therapeutics that have limited bioavailability when administered by conventional tablets. One strategy involves the use of cyclodextrins. 
7. The technology also incorporates taste-masking sweeteners and flavoring agents such as mint, cherry, and orange. The trays are stored in a freezer until a sufficient quantity has been prepared to fill the freeze dryer, and then they are transferred into the dryer. In general, an ODT is formulated as a bioequivalent line extension of an existing oral dosage form. In many cases, if a residual taste is only moderately unpleasant for patients, including flavor ingredients and sweeteners in the formulation can be sufficient to overcome this. 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). By using this website you understand and accept that Catalent tracks your website activities to be able to offer you a more tailored response or information to meet your requirements, and that your personal data will be held in accordance with our, Copyright 2022, Catalent, Inc - All Rights Reserved, Copyright 2020, Catalent, Inc - All Rights Reserved, Better pregastric absorption for certain drug compounds, Anti-psychotic (Parkinsons disease, schizophrenia), Embossing with corporate logos and product codes, Unique packaging, including child-resistant options, Taste masking and flavors formulated for specific markets, including pediatrics and veterinary medicine, Functional coating for controlled / sustained release applications, Potential interaction with other constituents of GI fluids, Use of bio-adhesives / absorption enhancers, Pre-gastric delivery (e.g. 35. As can be seen in Figure 3, the area under curve (AUC) over time is the same for the ODT taken both with and without water, and the standard capsule formulation. Technol. For lyophilized dosage forms, the drug dose must be lower than 400 mg for insoluble drugs and less than 60 mg for soluble drugs (3, 7). Cherukuri et al., "Process for Forming Quickly Dispersing Compressible Unit and Product Therefrom," US Patent 5,587,172 (1996). J.A. Table II summarizes the main characteristics of various ODT technologies and products from several innovator companies in the oral fast-dissolve tablet arena (15). Freeze-dried ODTs are manufactured and packaged in polyvinyl chloride or polyvinylidene chloride plastic packs, or they may be packed into laminates or aluminum multilaminate foil pouches to protect the product from external moisture (8). T.K. K. Ostrander, "Advances in Fast Dispersing Technologies-Zydis," paper presented at the annual meeting of the AAPS, Salt Lake City, UT, Oct. 29, 2003. Catalents recently developed Zydis Bio is able to present active macromolecules in a robust, convenient and fast-dispersing form. With this new process, tablets are made by combining noncompressible fillers with a taste-masking excipient and active ingredient into a dry blend. 5. Keep up with our latest articles, news and events. 45. 291336. 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. 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). Accepted: July 13, 2005. Stage 1 Mixing 44. In yet another modification, a solution of soluble drug can be sprayed onto a preformed matrix, following which the solvent is evaporated (8, 32). K. Sharma, W.R. Pfister, and T.K. In addition, the matrix may contain taste-masking agents such as sweeteners, flavorants, pH-adjusting agents such as citric acid, and preservatives to ensure the aqueous stability of the suspended drug in media before sublimation. The blend is compressed into tablets using a conventional rotary tablet press. Adults can have difficulties, too, for example bariatric patients often find swallowing a challenge, and those who have Parkinsons disease can be particularly badly affected.
Characterizes solid-state phrase behavior, Characterization of moisture sorption properties and physical analytical chemistry (HPLC, UV, NIR, FTIR) 43. Gregory, "Solid Shaped Particles," US Patent 4,758,598 (1988). At present, ODTs are the only quick-dissolving dosage form recognized by FDA and listed in Approved Drug Products with Therapeutic Equivalence Evaluations (also called the Orange Book) (3, 9). The technology involves the direct compression of active ingredients, effervescent excipients, and taste-masking agents (27). There are many patients for whom traditional tablets and capsules are not ideal dosage forms. 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. more delivered to your inbox. Plus, get special offers and
The drug can be added, along with other standard tableting excipients, during the granulation or blending processes. More recently, the Zydis Ultra formulation has been developed, which incorporates coated APIs for taste-masking purposes. The rapid onset of action is of benefit in drugs designed to treat acute conditions, such as migraines and psychiatric incidents, as well as conditions like insomnia. 17 , 6172 (2000). The fibers produced are usually amorphous in nature and are partially recrystallized, which results in a free-flowing floss (20).
Cherukuri and R. Fuisz, "Process and Apparatus for Making Tablets and Tablets Made Therefrom," US Patent 5,654,003 (1997). The filled trays are passed through a liquid nitrogen freeze channel, causing the API solution or suspension to freeze very rapidly. Characterizes the API crystal form and identifies any changes during formulation and processing, Freeze-drying microscopy Sastry, "An Overview of Fast Dispersing Technologies," paper presented at the annual meeting of the AAPS, Oct. 29, 2003. *To whom all correspondence should be addressed. 22. Chem. 25. Additional technologies for manufacturing and packaging ODT dosage forms have been highlighted elsewhere (18, 19). Figure 5 shows the difference between a standard ODT and the Bio ODT. Descriptions of orally disintegrating dosage forms. As an example, the drug selegeline is a monoamine oxidase B inhibitor used to treat Parkinsons disease and depression, but its active metabolites include methamphetamine, which leads to side-effects. Despite these advantages, the application of this technology is limited by the amount of drug that can be incorporated into each unit dose. For example, ODT formulations of selegiline, apomorphine, and buspirone have significantly different pharmacokinetic profiles compared with the same dose administered in a conventional dosage form (1719). The DuraSolv ODT technology is a second-generation technique based on the OraSolv technology. The inclusion of bioadhesives and absorption enhancers can promote absorption. These factors will be discussed in a separate article. 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. As with all ODTs, products made with this process disintegrate in the mouth in 545 seconds and can be formulated to be bioequivalent to conventional tablet dosage forms (5). William R. Pfister, PhD,* is a senior director of preclinical affairs at NexMed (USA), Inc., (Robbinsville, NJ). The ODTs have the potential for good long term stability, not least because of the low water activity in the dried product. 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. It is also possible to create ODTs from emulsions rather than suspensions or solutions of APIs. Future possibilities for improvements in ODTs and drug delivery are bright, but the technology is still relatively new. Ghosh, "Quick-Dispersing Oral Drug Delivery Systems," in Drug Delivery to the Oral Cavity: Molecules to Market, T.K. The solution or suspension is dosed into a pre-formed blister tray using a positive displacement pump, with the volume accurately measured to ensure the precise dose of API is present in each individual blister mold. 13. 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. This is important for use in a developing world setting. 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). This would permit very lipophilic APIs to be formulated via dissolution in oil before freeze drying. The convenience of the dosing, and the lack of requirement for cold chain storage, could permit faster distribution in pandemic and emergency situations, and would permit administration by less qualified healthcare professionals. A disadvantage of the wafers is that they are lightweight, fragile products and therefore must be dispensed in a special blister pack with a peelable backing foil (33). W. Habib, R. Khankari, and J. Hontz, "Fast-Dissolve Drug Delivery Systems," Crit. These responses may, in part, be attributed to known ODT advantages such as ease of administration, ease of swallowing, pleasant taste, and the availability of several flavors (8). The coating process is initiated by the addition of a reaction initiator, which is purified water in this case. We employ the most advanced equipment for our Zydis fast dissolve preformulations and formulations. 38. The tablet retained all the fast dispersion characteristics of a standard ODT. This pre-gastric absorption can reduce side effects caused by metabolites formed by liver enzymes. Chemical analysis of API in support of preformulation studies (e.g., solubility determinations, compatibility testing). 27 (10 Suppl), 1013 (2003). Determines particle size ranges relevant to Zydis suspension stability for insoluable API, Dynamic Vapor Sorption S.R. 23. The freeze drying process then proceeds as normal, followed by packaging. 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. Using otherwise standard ODT formulation technology, freeze dried ODTs, each containing 75mg of olive oil, were successfully made.
15. Myers et al., "Ulcer Prevention Method Using a Melt-Spun Hydrogel," US Patent 5,622,719 (1997). 27 (10 Supp), 2229 (2003). A structure former, usually mannitol chosen for its high compatibility and its well-known documented properties - is also added. 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). Copyright 2022 CompareNetworks, Inc. All rights reserved. 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). Conventional tablet process. The ability through class-leading ZydisODT technology to deliver fast dissolve formulations of large molecule allergens, viral vaccines, and peptides. Recent market studies indicate that more than half of the patient population prefers ODTs to other dosage forms (6) and most consumers would ask their doctors for ODTs (70%), purchase ODTs (70%), or prefer ODTs to regular tablets or liquids (>80%) (7). 12. 140. By administering these molecules sublingually or buccally, these problems might be avoided. More than 35 products have been launched using this technology in more than 60 countries around the world. The frozen units are then transferred to large-scale freeze dryers for the lyophilization process. F. Wehling et al.,"Pediatric Effervescent Dosage Form," US Patent 5,223,264 (1993).
The formation of highly water-soluble drugs into freeze-dried wafers is achieved by complexing them onto ion-exchange resins. G.K.E. Quick-dissolve tablets can offer several biopharmaceutical advantages such as improved efficiency over conventional dosage forms. No official support or endorsement of this article by FDA is intended or should be inferred. In contrast, some lyophilization manufacturing processes (e.g., Zydis, Cardinal Health, Dublin, OH) produce fragile freeze-dried tablets and compressed multiparticle tablets that can be packaged only in unit-dose blisters because of their high friability (8, 11, 12). 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. (CRC Press, New York, NY, 2005), pp. Technol. It also dilutes the dose, and the high molecular weight can lead to absorption problems. 3 (6), 5861 (2001). Iles et al., "Freeze-Dried Dosage Forms and Methods for Preparing the Same," US Patent 5,188,825 (1993). 261290. A lower dose is required as the active is not metabolized by the liver before it reaches the bloodstream. (CRC Press, New York, NY, 2005), pp. The OraSolv compressed tablet is another ODT manufacturing technology based on a conventional tableting process (11, 2426). 2022 MJH Life Sciences and Pharmaceutical Technology. 27 (11), 92100 (2003). Myers et al.,"Delivery of Controlled-Release Systems," US Patent 5,567,439 (1996). All rights reserved. T.K. Several factors must be considered when selecting drug candidates for delivery as ODT dosage forms. In the graph in Figure 6, the vaccine was administered sublingually to mice before they were challenged with influenza virus. 5 (3), 5054 (2005). The saccharides are converted into floss by the simultaneous action of flash-melting and centrifugal force in a heat-processing machine similar to that used to make cotton candy (3743). Tapash K. Ghosh is a senior clinical pharmacology and biopharmaceutics reviewer at the US Food and Drug Administration (HFD 880), 9201 Corporate Blvd., Room N224, Rockville, MD 20850. 36. T.K. 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). 10. The required end-point for reaction termination is determined by measuring carbon dioxide evolution. Pharmacol. 29.
39. 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. 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 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.J. Stage 4 Sealing 37. J. Chu, "Product Development, Scale-Up and Technology Transfer Aspects of Fast Dispersing Dosage FormsWOWTAB," paper presented at the annual meeting of the AAPS, Salt Lake City, UT, Oct. 29, 2003. The lyophilization based manufacturing process and its low temperatures reduces the potential for heat damage to the biologics. Through expert analysis and interpretation of data, our Zydisfast dissolve technology team will fully characterize your API and associated Zydisformulations throughout the development process to provide a robust data package in support of regulatory filings. (CRC Press, New York, NY, 2005), pp. very bitter or otherwise unacceptable taste because taste masking cannot be achieved. It is possible that these differences may, in part, be attributed to the drug molecule, formulation, or a combination of both. Because drugs delivered in ODTs may be absorbed in the pregastric sites of highly permeable buccal and mucosal tissues of the oral cavity, they may be suitable for delivering relatively low-molecular weight and highly permeable drugs. Furthermore, if the drug is absorbed within the oral cavity rather than being digested, it avoids the first pass of the liver. Although it is still early days for ODT formulation of biologics, the model studies already carried out indicate its clear potential. Furthermore, any minor damage to the package may cause the wafer to collapse because of moisture absorption (34). Most are relatively low doses of small molecule APIs, although doses up to 200mg have also been marketed and peptide and protein products have also been commercialized.