This has been proven with ibuprofen, which, if formulated as an ODT, could offer significant advantage to consumers in speed of onset. (a) Product A before disintegration. This is particularly important for biologic products, such as vaccines, that are destined for developing countries, where access to refrigeration cannot be relied upon, and in pandemic situations, where speed of distribution is key to success. Although no products made in this way are yet marketed, tablets have been formulated using a mass fraction of 15% olive oil-in-water emulsion. We use cookies to improve your website experience. This helps inform the choice of packaging and formulation characteristics, allowing the products to be marketed in all geographic regions, including those where high humidity is common. [37,38] Tablet hardness and porosity are directly linked to the disintegration time. He earned his BSc in Pharmaceutical Science from the University of Greenwich, London and his Masters in Industrial Pharmaceutical Science from the University of Manchester, UK. Current technologies employed for ODT manufacturing have been thoroughly reviewed elsewhere. 
These requirements led to a number of compendial monographs for individual products and, at times, the results obtained may not be reflective of the dosage form performance. In many instances, individual quality test methods developed by manufacturers are not reported in publicly available sources, although a number of alternative methods have been published and these are summarized in Table 3. Furthermore, they facilitate drug loading and are expected to remain unaffected by changes in humidity or temperature. (d) Product B after a disintegration time of 60 s. Summary of experimental conditions to test the performance of orally disintegrating tablets. [23], Since their introduction, ODTs have become widely accepted dosage forms, especially for paediatric and geriatric patients. He is responsible for driving the global marketing strategy for the oral drug delivery solutions business unit, including patient-centric Solutions, Zydis. As an ODT is designed to reside in the mouth for only a number of seconds; it cannot avoid the taste buds. Several factors affecting the disintegration time of the ODTs have been investigated. Orally disintegrating tablets are generally characterized by their high porosity, low density and low tensile strength. The results of the in-vitro dissolution test for products A and B are given in Figure 2. Catalents Zydis Bio technology was developed as a way of achieving oral delivery of biologics. Small displacements of the piston and disintegration rate are measured, With prior disintegration, pH6.8, 500ml, With prior disintegration, pH1.2, 500ml, Copyright 2022 Royal Pharmaceutical Society. There are several factors to be considered in formulating ODT products. A significant amount of analytical work is required when developing a new ODT. This has allowed ODTs containing 15 mg of the oil to be created, and an oil-soluble API could be dissolved in this before the tablet is formed. Orally disintegrating tablets, fast-diss . : Issue Theme: Orally disintegrating tablets, fast-dissolving, buccal and sublingual formulations, comoglu@pharmacy.ankara.edu.tr tcomoglu@yahoo.com, Medicine, Dentistry, Nursing & Allied Health. A summary of the investigation and the test results are given in Table 4. Hence, disintegration testing is usually insufficient to judge product performance of COSDFs. Superdisintegrants, such as crosscarmellose sodium, starch glycolate and crospovidone, are responsible for rapid dissolution in the mouth. The orally disintegrating tablet, or ODT, offers an easy-to-take alternative form to consumers of over-the-counter (OTC) treatments who perhaps do not have access to water, and patients of prescribed drugs who cannot, or will not, swallow standard oral dosage forms, such as tablets and capsules. The mucosal response that can occur is a further benefit in immunizations against infections, such as human papillomavirus, influenza, and pneumonia. Given the very short disintegration time of ODTs, the dissolution is independent of the disintegration time. The USP disintegration tester[47] with 700 ml of buffer solution adjusted to pH 6.8 to mimic salivary pH was used. Therefore, if the drug enters the bloodstream directly, these metabolites are not formed and the side-effects they cause cannot occur. In-vitro dissolution/drug release testing has become an increasingly powerful tool throughout the development of a drug product. The unit is immersed in a shaking water bath at 150rev/min. Search for other works by this author on: Present address: MJR PharmJet GmbH, Saarland University Medical Center, Building 7, 66424 Homburg, Germany. The objective of dissolution testing is to ensure the complete release of the drug into the medium within a reasonable amount of time. The in-vitro dissolution of products A and B was tested using the USP 2 paddle apparatus at 50 rev/min, 500 ml of dissolution medium at 37C. A pH-dependent drug release behaviour was observed for product B. Samples were withdrawn at standardized intervals and the amount released was quantified using HPLC-UV determination. Recently, higher doses of up to 200 mg have been launched, and peptide and protein products formulated in this way are also available. When referring to ODTs, the differences to other oral dosage forms having similar product characteristics, for example with respect to the site and route of application, the release behaviour should be clearly understood. October 16-19 [27,28], Extra measures such as special blister packs are required to avoid breakage or damage of dosage forms before use. Excipients, such as sweeteners, diluents, lubricants and superdisintegrants are appropriate for ODTs. This can be attributed to the advantages of the ODTs offer, such as ease of administration, ease of swallowing, pleasant taste and flavor. Disintegration of the dosage form in the oral cavity followed by wetting is the primary requisite for ODTs to release the API. [6] The physiological conditions of the oral cavity should be considered for in-vivo testing, including the biopharmaceutical properties of the API at a salivary pH of 5.57,[7,8] salivary flow rate and chronobiological state of the target population. Dissolution recommendations are also given in the FDA (CDER) dissolution database for ODTs. November 1-3 Technology Catalysts International Corporation. Also, in the case of ODTs, the active pharmaceutical ingredient (API) is intended to remain in the oral cavity after the disintegration, to be dissolved or dispersed in the saliva, and then absorbed via the oral mucosa for local or systemic therapy or subsequently swallowed and then absorbed through the gastrointestinal tract. By closing this message, you are consenting to our use of cookies. Here, the techniques currently available for the dissolution testing of ODTs have been reviewed.
While liquid formulations can provide successful dosing options in some cases, the ODT can work in all of these situations. [50,51] The normal testing time is between 30 and 60 min, as described in individual monographs, with Q NLT 60% in 30 min or 80% in 60 min. For many other APIs, this is not the case. The amount of drug released from both formulations was about 1% and 7% of the label claim, respectively, after 60 s. With less than 10% of the API dissolved at the time of disintegration, this method proved unsuitable as it would be difficult to judge the performance of the product in vitro. Another innovative possibility is the prospect of formulating a two-layer ODT that would allow two different ingredients to be incorporated within each dose. Differential scanning calorimetry is used to determine the melting point and other thermal events. It may be waived on a product-by-product basis. A number of technologies are available to create ODTs. All Rights Reserved. As can be seen in the graph in Figure 5, the AUC for the ODT, taken both with and without water, is essentially the same as a standard 10-mg formulation. The wetting is usually achieved by the volume (0.51.5 ml/min) of stimulated saliva[29] in the mouth. Product A is a fast dissolving tablet which contains disintegrants and taste-masking agents, whereas product B is a lyophilized platelet containing gelatin and mannitol. These include Catalents Zydis, To view this issue and all back issues online, please visit, is Principal Scientist at Catalent Pharma Solutions in Swindon, UK. Register a free Taylor & Francis Online account today to boost your research and gain these benefits: Orally disintegrating tablets, fast-dissolving, buccal and sublingual formulations, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey, Faculty of Pharmacy, Ankara University, Ankara, Turkey, Pharmaceutical Development and Technology. The use of the basket apparatus (USP 1) for dissolution testing of ODTs is also described. Web design and development by WalkerTek. The drug release was complete for both products A and B within the tested time. In place of a fluidized bed coating method, in the Zydis Ultra process, API particles are mixed with micronized polymer agglomerates in a vessel that has an acoustic vibrator. Subsequently, a non-compendial disintegration method was used. [49] Suitability of the USP 2 at 100 rev/min has also been reported. Not only does it offer the potential for a faster onset of action, but by removing that first-pass metabolism of the liver, side-effect profiles can be greatly improved. The ODT products differ significantly in their manufacturing and formulation techniques. One of the biggest challenges is to ensure rapid disintegration without negatively affecting the mechanical strength of the formulation. These include Catalents Zydis ODTs, which are made via freeze-drying technology, and others, such as loosely compressed tablets. There are regional variations in the thickness of the epithelium that can be exploited; the sublingual epithelium is typically 100-200 m, while the buccal membrane is thicker, at 500-800 m. Many new excipients have improved physical, mechanical and/or chemical properties to solve formulation challenges. Restricted to tablets prepared by direct compression. The list of compendial and non-compendial product quality tests are summarized in Table 2.
However, these dosage forms require more than 1 min to disintegrate in the oral cavity[6] or do not disintegrate at all. 5 Howick Place | London | SW1P 1WG. Time required by the ODT to pass through sinker screen, Water dropped at a rate of 4ml/min over the ODT placed in wire cloth No. No solvent is needed for this coating process. This material may not be published, broadcast, rewritten, or redistributed withoutpermission. Recent developments have made it possible to formulate a number of different types of medicine as ODTs that at first sight, one might think would not be compatible with this type of oral dosage form. To view this issue and all back issues online, please visit www.drug-dev.com. The orally disintegrating tablet, or ODT, offers an easy-to-take alternative form to consumers of over-the-counter (OTC) treatments who perhaps do not have access to water, and patients of prescribed drugs who cannot, or will not, swallow standard oral dosage forms, such as tablets and capsules. It can be easier to give a medication to a child using an ODT and of course, in the animal health arena, it can be a significant challenge to get pets or livestock to swallow tablets. Dosage forms that are applied via a similar route include medicated gums, sublingual tablets, buccal tablets and lozenges. He has worked within R&D for more than 15 years, primarily on Catalents Zydis ODT technology formulation and process development. Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine. [4] The FDA's dissolution database[5] contains 23 dissolution/drug release methods for ODTs, which constitutes about 4% of all dissolution tests listed. Many taste unpleasant, or can produce burning, numbing, or tingling sensations. For products A and B, in-vitro dissolution testing could be a potential indicator of the product performance in vivo, rather than the disintegration test. Samples were withdrawn after 60 s, filtered, and the drug released into the medium was determined by HPLC-UV analysis. The composition of saliva produced at varying rates of secretion by the same person with special reference to calcium and phosphorus, A New Method of Characterizing the Buccal Dissolution of Drugs, The composition of unstimulated whole saliva of healthy dental students. Various options are available to optimize and tailor the patients experience of taking a medication that includes Zydis technology, for example, blister strips can be customized with multiple combinations of perforations, thumb-peel tabs to allow for easy opening, and printing options too, including helpful directions, regimen information or product branding. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. [53] As far as the dissolution testing is concerned, it is fair to assume that the application of the Quality by Design concept to link dissolution testing to the clinical quality attributes during the product development phase and to the manufacturing would reduce extensive product quality tests on the end product.[54,55]. Fax: (973) 299-7937. For product B, after the disintegration test, gel formation was observed due to the presence of gelatin in the matrix. They offer significant advantages to both patients and consumers of OTC medications, and although their advantage over conventional tablets is perhaps more obvious when thinking of the young and old, there are many people outside of these groups who have difficulty swallowing tablets and capsules and would welcome an ODT alternative dose form. This assists in calculating the necessary times for freeze-drying, while ensuring that the frozen product does not melt during the drying process. For example, fast disintegrating, fast melting and mouth dissolving tablets are all categorized as ODTs. The API still has 70%-85% potency w/w compared to uncoated particles. Therefore, formulators continue to explore alternative approaches to enhance absorption of the drugs across oral mucosa. Cyclodextrins are sugar-based, ring-shaped macromolecules with holes in the middle that can trap smaller molecules inside if they are the right size. European Directorate for the Quality of Medicines, Council of Europe. Biologics usually have to be dosed via injection or infusion, because the complex structures can rarely withstand the highly acidic enzyme-containing environment in the gastrointestinal tract. In-vitro dissolution test. The loss of bodyweight is indicative of disease severity, and those mice infected with influenza but who were unvaccinated lost significant amounts of weight. [52] In such cases, a higher basket rotation speed of 100 rev/min is recommended, especially for quality control purposes. Sublingual formulations exert similar characteristics to orally disintegrating formulations such as the short residence time in the mouth, rapid disintegration and dissolution, both being crucial for drug absorption following administration of sublingual tablets. In order to increase the precision of the disintegration method, modification of conventional methods of testing is needed. The acidic buffer (pH 1.2) was chosen to dissolve the gelatin present in the drug product matrix. Eur.) The compendial disintegration test alone cannot generally be recommended as a suitable method for in-vitro performance testing. This is important, as a freeze-dried formulation can be sensitive to highly humid environments and can shrink and lose its rapid disintegration characteristics. It is inferred from the results that for the test ODT formulations, prior disintegration has no influence on the release behaviour. Leon Grother is Principal Scientist at Catalent Pharma Solutions in Swindon, UK. Recent developments in ODT technology have widened the range of actives that can be formulated and product types that are possible. It is not only patients at either end of the age spectrum the very old and the very young who suffer from an inability to swallow, or dysphagia, either, with a recent study indicating that 70% of younger people aged 16-34 who were surveyed reporting that they had difficulties swallowing tablets and capsules.1 Pre-existing conditions may affect compliance too, and those with mental health issues may not want to take their medications, instead, secreting the tablets in their mouth before disposing of them later, or saving them for misuse or even self-harm in the form of an overdose. This delivery route extends numerous advantages over the other delivery routes such as oral, parenteral and dermal, due to its rich blood supply, rapid onset of action, avoidance of the first pass metabolism as well as enzymatic degradation, which results in enhanced bioavailability, increased patient compliance, and ease of self-medication. In particular, the promise of formulating biologics and ODT vaccines that do not require a healthcare worker to administer them, as with many that are injected, or that do not require cold storage and transit, often to the less accessible parts of the world where so many vaccines are required, is hugely exciting. If a patient-friendly ODT is to be created, then more creative formulation methods will have to be applied. The bioavailability of ODTs is mostly comparable with that of other oral dosage forms such as conventional tablets and capsules, and bioequivalence has already been demonstrated for selected formulations. [711] Several initiatives are underway to standardize the test methods for these novel dosage forms. FDA, United States Food and Drug Administration; USP, United States Pharmacopeia. The structure of a Zydis tablet is key to its rapid dispersal properties, as the tablets are highly porous.
One way this can be achieved is via the Zydis Ultra formulation. The procedure is based on the compendial disintegration test described by the USP, but other equivalent approaches providing similar results may be used. People also read lists articles that other readers of this article have read. In contrast, those who were given the oral vaccine showed no significant loss in bodyweight, even after they were challenged with the influenza virus. In both cases; the hepatic first-pass effect as well as gastric degradation is avoided; therefore, the efficacy is enhanced. Time for the ODT to pass through the 10-mesh screen considered as disintegration time, Mouth dissolving tablet placed on a wire gauze immersed in the medium is compressed by a rotary shaft, Rotation speed and mechanical stress control the disintegration time, Constant penetration force using flat-ended probe is applied to the mouth dissolving tablet concomitantly while immersing in the aqueous medium. Time taken for the ODT to pass through the wire cloth considered as disintegration time, Charge coupled device (CCD) camera method, Disintegration of ODT placed on a grid placed over a stirring element contained in a dissolution medium. Preclinical studies in mice have shown the potential of an ODT influenza vaccine. [30,39] The USP recommends use of 1000 ml of aqueous buffer solution to determine the disintegration time with a mechanical agitation of about 2932 cycles/min. 219 Changebridge Road A number of technologies are available to create ODTs. For industrially manufactured pharmaceutical dosage forms, product quality tests and performance tests are required to ascertain the quality of the final product. Mr. Bayru has more than 12 years of experience in the pharmaceutical industry, and prior to joining Catalents marketing team, held roles as Marketing Manager for several CDMOs and Senior Scientist for Big Pharma companies. The dissolution conditions were 500 ml of buffer solution adjusted to pH 6.8 for products A and B, and additionally pH 1.2 for product B. Intrabuccaly rapidly disintegrating tablet. The compendial disintegration method was thus deemed unsuitable for ODTs, since the large volume, mechanical agitation and lack of homogeneous mixing in the medium (as assessed by sampling at different points in the disintegration vessel) precluded discrimination between the products. The United States Pharmacopeial Convention, General Chapter: 1151 Pharmaceutical Dosage Forms, The United States Pharmacopeia and The National Formulary, European Directorate for the Quality of Medicines, Council of Europe, General Monograph on Dosage Forms: Tablets: Oro Dispersible Tablets, Guidance for Industry: Orally Disintegrating Tablets, The United States Food and Drug Administration, Center for Drug Evaluation and Research, FDA-Recommended Dissolution Methods. He earned his BSc in Pharmaceutical Science from the University of Greenwich, London and his Masters in Industrial Pharmaceutical Science from the University of Manchester, UK. Boston, MA, CPhI Worldwide But where it is feasible, if the ODT is designed correctly, then it is possible to ensure that the active will be absorbed buccally or sublingually, without being swallowed. He has worked within R&D for more than 15 years, primarily on Catalents Zydis, is Catalent Pharma Solutions Group Product Manager for Drug Delivery Solutions. The choice of packaging materials is important, and each blister strip is sealed using specially designed, multi-layer foils that are resistant to moisture ingress. By avoiding the need for injection, there would be none of the pain, and potential for injection site reactions, that can engender reluctance to immunization among patients and parents. defines them as uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed. The taste-masking is provided by the presence of a coating around particles of the API, which can be as small as 100 m in size. ODTs has become a common term for dosage forms based on their disintegration patterns, with a multitude of technologies and a wide array of formulation strategies. To investigate the suitability of the dissolution method as a performance indicator, in-vitro dissolution testing was performed on products A and B. Boston, MA, PDA 2022 Universe of Pre-filled Syringes & Injection Devices Conference In order to test the applicability of the compendial USP disintegration method[47] for ODTs, two different commercially available ODT products containing a non-steroidal anti-inflammatory drug (product A) and a centrally acting drug (product B) were chosen.
These techniques are lyophilization, tablet moulding, sublimation, spray drying, flash heat process and films. [1622] A few ODT formulations circumvent the first pass effect through pre-gastric absorption of the API. The ingredients are all dissolved or suspended in water, accurately dosed into blister trays, and then frozen in liquid nitrogen freeze tunnels before being placed in freeze dryers. The prospect of formulating biologics as ODTs offers even more promise for the dose form. This is achieved via a matrix of fish or bovine gelatin, or by using one of several non-gelatin polymers, plus structure-forming mannitol, which also aids in the solubilizing of the tablet. Given the very fast disintegration of ODTs, the relationship between disintegration and dissolution is worthy of closer scrutiny. These result from some of the active metabolites generated by liver enzymes, including methamphetamine. 3099067 Disintegration time monitored by a CCD camera, ODT placed in glass cylinder with a 10 mesh. Orally disintegrating tablets were placed in a 100-mesh basket and then in a 30-ml beaker containing 10 ml buffer pH 6.8. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only.
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