24. It is also possible to create ODTs from emulsions rather than suspensions or solutions of APIs. Technol. S.I. 
It is difficult to persuade infants and very young children to swallow them, and they may pose a choking hazard. 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). 
These sugar-based macromolecules, often used as odor removers in household products, have a hole in the middle, allowing smaller molecules to fit inside. The formed matrix structure is very porous in nature and rapidly dissolves or disintegrates upon contact with saliva (16). 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). Pre-gastric absorption can have significant advantages in terms of both a faster onset of action and the reduction of side-effects. 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. They resemble a traditional tablet, but have one important difference: they disintegrate rapidly in the mouth, and therefore do not need to be swallowed.
for the pharmaceutical industry throughout North America. One drawback to the dispersion of a tablet in the mouth is its taste. European Directorate for the Quality of Medicines, Pharmeuropa, 10 (4), 547 (1988), http://www.pheur.org, accessed March 19, 2005. 8. Tablets made with this process have higher mechanical strength and are sufficiently robust to be packaged in blister packs or bottles (5, 15). Characterizes solid-state phrase behavior, Characterization of moisture sorption properties and physical analytical chemistry (HPLC, UV, NIR, FTIR) 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). An additional advantage is the potential to avoid the need for cold-chain storage. The filled trays are passed through a liquid nitrogen freeze channel, causing the API solution or suspension to freeze very rapidly. 337356. Under this circumstance, it is assumed that the absorption of a drug molecule from the ODT occurs in the postgastric GIT segments, similar to the conventional oral dosage form. T.K. Orally disintegrating tablets (ODTs) have better patient acceptance and compliance and may offer improved biopharmaceutical properties, improved efficacy, and better safety compared with conventional oral dosage forms. ODT technology has not remained static over the past 30 years. 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. It is, for example, possible to make bi-layered tablets that permit two otherwise incompatible ingredients to be delivered in the same dosage form. 50 (4), 375382 (1998). One strategy involves the use of cyclodextrins.
Furthermore, any minor damage to the package may cause the wafer to collapse because of moisture absorption (34). 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. 16. 31. 29. 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).
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.
12. G.K.E.
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). 140. This would permit very lipophilic APIs to be formulated via dissolution in oil before freeze drying. 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).
For example, safety profiles may be improved for drugs that produce significant amounts of toxic metabolites mediated by first-pass liver metabolism and gastric metabolism and for drugs that have a substantial fraction of absorption in the oral cavity and segments of the pregastric GIT. Conventional tablet process. Ghosh, "Orally Disintegrating Tablets," AAPS Newsmagazine, 7 (6), 1921 (2004). In the long run, if such formulations gain regulatory acceptance, they could significantly improve the delivery of both biologic medicines and vaccines, particularly in environments where a lack of clean water and trained nurses present challenges to traditional drug administration. Biologic medicines are rarely orally available, not least because they cannot withstand the harsh acidic and enzyme-rich conditions in the gastrointestinal tract.
Additional technologies for manufacturing and packaging ODT dosage forms have been highlighted elsewhere (18, 19). 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). Accepted: July 13, 2005. 4. The Zydis technology requires specific characteristics for drug candidates and matrix-forming materials. With this new process, tablets are made by combining noncompressible fillers with a taste-masking excipient and active ingredient into a dry blend. In general, an ODT is formulated as a bioequivalent line extension of an existing oral dosage form. The drug can be added, along with other standard tableting excipients, during the granulation or blending processes. Other patented ODT technologies based on lyophilization include Lyoc (Farmalyoc, now Cephalon, Franzer, PA) and QuickSolv (Janssen Pharmaceutica, Beerse, Belgium). Catalents recently developed Zydis Bio is able to present active macromolecules in a robust, convenient and fast-dispersing form.
By paying close attention to advances in technologies, pharmaceutical companies can take advantage of ODTs for product line extensions or for first-to-market products. Table I lists several ODT products that are marketed in the United States. 
K. Cremer, "Orally Disintegrating Dosage Forms Provide Drug Life Cycle Management Opportunities," Pharm. The coating process is initiated by the addition of a reaction initiator, which is purified water in this case.
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 graph in Figure 1 shows a comparison between 10mg doses of selegeline in both traditional tablet and ODT formats, and a 1.25mg Zydis ODT. G.L. 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).
It also dilutes the dose, and the high molecular weight can lead to absorption problems.
Zydis ODT technology was first developed by RP Scherer (now part of Catalent) in the 1980s, and the first products reached patients in the early 1990s. Today, ODTs are more widely available as over-the-counter products for the treatment of allergies and cold and flu symptoms. The administration of ODTs may not inherently result in a faster therapeutic onset, but it can circumvent problems such as difficulty in swallowing traditional solid oral dosage forms, particularly by pediatric and geriatric patients. Ghosh and W.R. Pfister, Eds. 17 , 6172 (2000). The bulk API is formulated into a liquid solution or suspension. Technol. 2. Optical microscopy
Several drug delivery technologies that can be leveraged on improving drug therapy from ODTs have yet to be fully realized.
Only one of the three other methods outlined in Table 1 uses lyophilization, and tablets made this way typically take more than a minute to disperse. The ability through class-leading ZydisODT technology to deliver fast dissolve formulations of large molecule allergens, viral vaccines, and peptides. 35. 
Fix, "Advances in Quick-Dissolving Tablets Technology Employing WOWTAB," paper presented at the IIR Conference on Drug Delivery Systems, Washington DC, Oct. 1998. (CRC Press, New York, NY, 2005), pp.
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. 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.
Furthermore, it could help to generate a mucosal response, which is important for certain infections such as influenza, pneumonia and human papillomavirus (HPV). Ghosh, "Quick-Dispersing Oral Drug Delivery Systems," in Drug Delivery to the Oral Cavity: Molecules to Market, T.K. 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. Additional excipients are frequently incorporated, as well as these include high-intensity sweeteners, such as aspartame, acesulfame K and sucralose, pH modifiers, flavors and colors. Lyoc is a porous, solid wafer manufactured by lyophilizing an oil-in-water emulsion placed directly in a blister and subsequently sealed. Other ODT products made with conventional tableting processes include Frosta (Akina Inc., West Lafayette, IN), ProMelt (aaiPharma, Wilmington, NC), EasyTec Tablets (Antares Pharma, Exton, PA), Fast Oral Technology, D-Zolv (Capricorn Pharma Inc., Frederick, MD), and Oro-dispersible tablets (Grupo vita, Barcelona, Spain) (15). The formation of highly water-soluble drugs into freeze-dried wafers is achieved by complexing them onto ion-exchange resins. *To whom all correspondence should be addressed. Drug loading for water-insoluble drugs approaches 400 mg, and the upper limit for water-soluble drugs is ~60 mg.
more delivered to your inbox. They cover a wide gamut of therapeutic areas, with the majority in areas that benefit from the fast onset of action. 6. 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. This is important for use in a developing world setting. See our other sites .
QuickSolv tablets are made with a similar technology that creates a porous solid matrix by freezing an aqueous dispersion or solution of the matrix formulation. 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. 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. These factors will be discussed in a separate article. 27 (11), 92100 (2003). Syst. The technology is based on a combination of new physically modified polysaccharides that have water dissolution characteristics that facilitate fast disintegration and high compressibility. Orally Disintegrating Tablets: A Dosage Form Designed for Difficult Patient Populations. Both ibuprofen and acetaminophen have been successfully formulated in this way to date. Careful selection of formulation options and ingredients, including the selection of the matrix component and the pH, can optimize inprocess stability. If the active does not pass through the liver first, these drawbacks will be reduced. S.R. Gole et al., "Preparation of Pharmaceutical and Other Matrix Systems by Solid-State Dissolution," US Patent 5,215,756 (1993). An ODT may have varying degrees of pregastric absorption and thus, the pharmacokinetic profile (including the maximum plasma concentration, time to achieve maximal plasma concentration, and area under the plasma concentration time curve of an equal dose of an ODT and a conventional oral dosage form) will vary (3). Wong, "Method for Making Freeze-Dried Drug Dosage Form," US Patent 5,631,023 (1997). 18. Stage 2 Filling and freezing
Table 2 gives a list of examples of commercial products that are formulated using Zydis technology. Over the past three decades, orally disintegrating tablets (ODTs) have gained much attention as a preferred alternative to conventional oral dosage forms such as tablets and capsules. Pharmacol. Chem. Cherukuri et al., "Process for Forming Quickly Dispersing Compressible Unit and Product Therefrom," US Patent 5,587,172 (1996). W. Habib, R. Khankari, and J. Hontz, "Fast-Dissolve Drug Delivery Systems," Crit. Myers et al.,"Delivery of Controlled-Release Systems," US Patent 5,567,439 (1996). The blisters containing the dried Zydis units are then sealed via a heat-seal process to protect the product from varying environmental conditions and ensure long-term stability. The trays are removed from the dryer, the blisters sealed and split into strips, and finally, packed in cartons ready for delivery to the patient. 2022 MJH Life Sciences and Pharmaceutical Technology.
V. Agarwal, "Fast Dispersing Dosage Forms: Opportunities and Challenges in Packaging," paper presented at the annual meeting of the AAPS, Salt Lake City, UT, Oct. 29, 2003. partially nonionized at the oral cavity's pH; ability to diffuse and partition into the epithelium of the upper GIT (log. 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.
32. 27 (3), 3443 (2002). The DuraSolv ODT technology is a second-generation technique based on the OraSolv technology. The AUC was almost identical to that for a regular cetirizine tablet. All of our sites are subject to annual review so we can remain in highest compliance with: CATALENTS BEST-IN-CLASS FAMILY OF FAST DISSOLVE TECHNOLOGIES.
The coating is applied via a novel, proprietary method. 27.
ability to permeate oral mucosal tissue (15). Ghosh and W.R. Pfister, Eds. 40. 5 (3), 5054 (2005). 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. Stage 4 Sealing Orally disintegrating tablets (ODTs) provide an alternative to overcome these challenges. American Pharmaceutical Review is the leading review of business and technology
3.
The tablet retained all the fast dispersion characteristics of a standard ODT.
14. Technol. Several clinical pharmacological and biopharmaceutical aspects of ODT development also must be considered. The wafer can accommodate high drug dosing and disintegrates rapidly but has poor mechanical strength (35). More than a billion of the ODTs are manufactured every year in Catalents UK facility in Swindon. 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. K. Sharma, W.R. Pfister, and T.K. As the water is vaporized without going through the liquid state, it does not redissolve the solid ingredients, instead, leaving behind a porous gelatin framework. Myers et al., "Apparatus for Making Rapidly Dissolving Dosage Units," US Patent 5,871,781 (1999). Dozens of ODT products have been launched worldwide over the past decade, with many new introductions in the past few years.
However, if it is very bitter, or produces a burning or numbing sensation, more sophisticated taste-masking techniques will be necessary. These products usually degrade rapidly in the stomach.
The process works by removing water using an excess of alcohol (solvent extraction). This vibrates, causing the particles to move and accelerate by as much as 100 times the force of gravity. A Publication of 23.
The aluminum packaging provides a high moisture barrier and good environmental protection, and acceptable storage has been demonstrated at room temperature for multiple peptide and protein compounds.
The target population has expanded to those who want convenient dosing anywhere, anytime, without water.
The freeze drying process then proceeds as normal, followed by packaging.
H. Seager, "Drug Delivery Products and the Zydis Fast-Dissolving Dosage form," J. Pharm. The tablet quickly disintegrates because effervescent carbon dioxide is produced upon contact with moisture. F. Wehling et al.,"Pediatric Effervescent Dosage Form," US Patent 5,223,264 (1993). The Bio ODT also holds out promise for oral vaccines. 61 , 3637 (1990). This process has been used to manufacture commercial ODTs for many drugs including desloratadine, lorazepam, piroxicam, loperamide, loratadine, enalapril, clonazepam, rizatriptan, domperidone, famotidine, chlorpheniramine maleate, scopolamine HBr, oxazepam, ondansetron, olanzapine, and selegiline (8, 16, 17, 29). In the literature, ODTs also are called orally disintegrating, orodisperse, mouth-dissolving, quick-dissolve, fast-melt, and rapid-disintegrating tablets and freeze-dried wafers (see sidebar, "Descriptions of orally disintegrating dosage forms") (35).
No liquid is required when taking the medication either, which is a significant advantage when on the go. J.A.
K. Deepak, "Orally Disintegrating Tablets," Tablets and Capsules 7 , 3035 (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 (10 Suppl), 1013 (2003). 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.
Quick-dissolve tablets can offer several biopharmaceutical advantages such as improved efficiency over conventional dosage forms.
Prescription ODT products initially were developed to overcome the difficulty in swallowing conventional tablets with water among pediatric, geriatric, and psychiatric patients with dysphagia. J. Aurora and V. Pathak, "Oral Disintegrating Technologies: Oral Disintegrating Dosage Forms: An Overview," Drug Deliv. N. Sharma et al., "Manufacturing Technology Choices for Mouth Dissolving Tablets," Pharm. In the graph in Figure 6, the vaccine was administered sublingually to mice before they were challenged with influenza virus. Stage 3 Lyophilization
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.
The result is a fast-disintegrating tablet that has adequate hardness for packaging in bottles and easy handling. 261290. Not all APIs can be formulated in such a way that pre-gastric absorption is possible. To make the tablets, the excipients are first dissolved or suspended in purified water, and the API added. Particles as small as 100m can be coated, significantly smaller than the 200400 m particles that conventional coating is successful for.
ODTs also offer clinical advantages such as improved safety and, in some cases, improved efficacy and other broader indications. 11. 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). Technol. Ghosh, "Intraoral Delivery Systems: An Overview, Current Status and Future Trends," in Drug Delivery to the Oral Cavity: Molecules to Market, T.K. We employ the most advanced equipment for our Zydis fast dissolve preformulations and formulations. 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. F. Wehling and S. Schuehle, "Base Coated Acid Particles and Effervescent Formulation Incorporating Same," US Patent 5,503,846 (1996). The technology can accommodate water-soluble and water-insoluble drugs in doses as large as 750 mg, which may contain multiple active ingredients.
Cherukuri and R. Fuisz, "Process and Apparatus for Making Tablets and Tablets Made Therefrom," US Patent 5,654,003 (1997). 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. By sequentially dosing two separate matrix solutions with different gelling or density characteristics in this way, a single ODT with acceptable quality characteristics can be achieved. Floss-based tablet technology. 22. F. Wehling et al., "Effervescent Dosage Form With Microparticles," US Patent 5,178,878 (1993). In this article, the term conventional oral dosage forms refers to tablets and capsules that must be swallowed with water for dissolution, release, and absorption of the drug in the stomach and GIT distal sites. Technol.
As previously mentioned, fragile products require special unit-dose packaging, which may add to the cost. 25. 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.
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