As well as the drug active, other ingredients, such as sweeteners, colors, flavorings, and acidity modifiers, are often incorporated to increase palatability. We hope that the scientists will benefit from reading the recent advances in the field of oral mucosal delivery contained in this issue. One specimen of each test sample (product A and product B) was placed in a 100-mesh basket. Hygroscopicity of most formulations also leads to special packaging requirements for ODTs. 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. If a patient-friendly ODT is to be created, then more creative formulation methods will have to be applied. The use of the basket apparatus (USP 1) for dissolution testing of ODTs is also described. 
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. As an ODT is designed to reside in the mouth for only a number of seconds; it cannot avoid the taste buds. 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. If they can be delivered through the mucous membranes in the mouth, they could enter the bloodstream undamaged as the acidity of saliva is normally close to neutral, and none of the protease enzymes that digest proteins are present. Montville, NJ 07045 For this reason, sublingual tablet formulations should be designed to disintegrate and dissolve rapidly in saliva, without the aid of water. Here, the techniques currently available for the dissolution testing of ODTs have been reviewed. 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. The basket with the ODT was then placed for 60 s in a 30-ml beaker, containing 10 ml of buffer solution at pH 6.8. It is this layer that confers the desired taste-masking properties. 
We use cookies to improve your website experience. Technology Catalysts International Corporation. Non-compendial disintegration method. Orally disintegrating tablets or orodispersible tablets (ODTs) are solid oral dosage forms intended to disintegrate and disperse in the oral cavity prior to drug release, independent of the site of absorption. Boston, MA, PDA 2022 Universe of Pre-filled Syringes & Injection Devices Conference As an example, a beta-cyclodextrin ODT formulation was created of the very bitter tasting antihistamine, cetirizine. However, these dosage forms require more than 1 min to disintegrate in the oral cavity[6] or do not disintegrate at all. 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. Up to date, numerous drugs have been investigated for sublingual and buccal delivery; however, there are few products available in the market, which are mostly fast dissolving formulations. 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. 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. The similarity test (f2) statistic confirmed the similarity of the dissolution profiles at the respective pH values of 1.2 and 6.8. There are various other advantages, such as room-temperature stability, whereby cold chain distribution will not be required. 10. Current compendial requirements specify a disintegration and/or a dissolution test to check the quality of oral solid dosage forms.
These techniques are lyophilization, tablet moulding, sublimation, spray drying, flash heat process and films. 
Mean SD, n = 3. [2] The United States Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) drafted a guidance which states ODTs as a solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue. Beyond compendial requirements, some non-compendial tests are also used by manufacturers.
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. Copyright 2018-2022 Drug Development & Delivery. And, importantly, the two are bioequivalent. The buffer solutions were maintained at 37C. 3099067 The loss of bodyweight is indicative of disease severity, and those mice infected with influenza but who were unvaccinated lost significant amounts of weight. The drug released from orodispersible formulations is absorbed through pregastric (oral cavity, pharynx, and esophagus), and gastric segments. Leon Grother is Principal Scientist at Catalent Pharma Solutions in Swindon, UK. 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. 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. From the industrial point of view, development of different orally disintegrating formulations (tablet, films etc.) This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The release characteristics are then further optimized using various formulation techniques used for the manufacturer. A summary of the investigation and the test results are given in Table 4.
Although a general product performance test is desirable for orally disintegrating tablets (ODTs), the complexity of the release controlling mechanisms and short time-frame of release make such tests difficult to establish. Smaller particles make for a better mouthfeel in an ODT; larger particles give a gritty sensation as the tablets disintegrate. It also gives a rapid onset of action, which may be advantageous before or during acute episodes of conditions such as migraine or psychiatric events. Many taste unpleasant, or can produce burning, numbing, or tingling sensations. US patent application 20010014340, Oxford University Press is a department of the University of Oxford. The graph shown in Figure 3 shows the comparison of metabolites formed in a standard 10-mg selegeline tablet, and a 1.25-mg ODT formulation of the same active.
Many new excipients have improved physical, mechanical and/or chemical properties to solve formulation challenges. 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. Disintegration time monitored by a CCD camera, ODT placed in glass cylinder with a 10 mesh. 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. Figure 4 shows that the lower-dose ODT produces the same area under curve (AUC) as a conventionally formulated selegeline tablet. 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. [37,38] Tablet hardness and porosity are directly linked to the disintegration time. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Superdisintegrants, such as crosscarmellose sodium, starch glycolate and crospovidone, are responsible for rapid dissolution in the mouth. 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. Dissolution recommendations are also given in the FDA (CDER) dissolution database for ODTs. Privacy Policy/Terms and Conditions
November 1-3 He has worked within R&D for more than 15 years, primarily on Catalents Zydis ODT technology formulation and process development. 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. X-ray diffraction is used to determine the crystalline state of the API and relevant excipients; whether it is crystalline or amorphous will have a bearing on the structural integrity of the final dosage forms. Fax: (973) 299-7937. Orally Disintegrating Tablet and Film Technologies 6th Edition. Due to the nature of the dosage form and the existing standardized equipment, conventional methods of dissolution testing[48] could be extended to ODTs. Dosage forms that are applied via a similar route include medicated gums, sublingual tablets, buccal tablets and lozenges. ODT excipients are required to dissolve or disperse in the mouth without leaving any residue and to have a pleasant taste and efficient taste-masking properties.
Samples were withdrawn at standardized intervals and the amount released was quantified using HPLC-UV determination. Besides identity, purity and assay, additional product quality tests are used by manufacturers to reflect the quality of the dosage form. AAPS Pharm Sci 360 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. 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. Catalents Zydis Bio technology was developed as a way of achieving oral delivery of biologics. 219 Changebridge Road Cited by lists all citing articles based on Crossref citations.Articles with the Crossref icon will open in a new tab. (b) Product A after a disintegration time of 60 s. (c) Product B before disintegration. 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. The decision and requirement of such tests are based solely on product characteristics. The FDA's perspective is to define ODTs based on the product characteristics, despite the fact that many other dosage forms possess a disintegration behaviour with or without the aid of mechanical stress or liquids. By closing this message, you are consenting to our use of cookies. This assists in calculating the necessary times for freeze-drying, while ensuring that the frozen product does not melt during the drying process. (a) Product A before disintegration. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Orally disintegrating tablets were placed in a 100-mesh basket and then in a 30-ml beaker containing 10 ml buffer pH 6.8.
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.
Zydis technology has been used to formulate a number of commercial products, particularly those for which a fast onset of action is beneficial. October 18-19
[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. The unit is immersed in a shaking water bath at 150rev/min. 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. Cyclodextrins are sugar-based, ring-shaped macromolecules with holes in the middle that can trap smaller molecules inside if they are the right size. To investigate the suitability of the dissolution method as a performance indicator, in-vitro dissolution testing was performed on products A and B. Given the very short disintegration time of ODTs, the dissolution is independent of the disintegration time. One of the biggest challenges is to ensure rapid disintegration without negatively affecting the mechanical strength of the formulation. When a drug is absorbed within the mouth, it enters the bloodstream directly, thus avoiding the first-pass metabolism by the liver, where side-effect-causing metabolites may be formed. No solvent is needed for this coating process. [52] In such cases, a higher basket rotation speed of 100 rev/min is recommended, especially for quality control purposes. Another technique, dynamic vapor sorption, is used to determine the moisture sorption and desorption profiles. October 16-19 In a study commissioned by Hermes Pharma and conducted by Spiegel Institut Mannheim based on 2,000 individuals in Germany and North America (www.epmmagazine.com accessed Sep.23, 2016). 5 Howick Place | London | SW1P 1WG. The compendial disintegration test alone cannot generally be recommended as a suitable method for in-vitro performance testing. Did you know that with a free Taylor & Francis Online account you can gain access to the following benefits? Differential scanning calorimetry is used to determine the melting point and other thermal events. ODTs are designed to disperse quickly within the oral cavity, removing the need to swallow a solid tablet or capsule. Restricted to tablets prepared by direct compression. There are several factors to be considered in formulating ODT products. FDA, United States Food and Drug Administration; USP, United States Pharmacopeia. Preclinical studies in mice have shown the potential of an ODT influenza vaccine. The vibration and collisions within the mixer result in a continuous polymer layer being formed. ODTs have become a standard dosage form for a number of medicines, where the fast onset of action or ease of dosing are important. FIP/RPSGB Workshop of Special Dosage Forms, In Vitro In Vivo Correlation (IVIVC) of Special Dosage Forms: Medicated Chewing Gums, Product performance test for medicated chewing gums, Suitability of in vitro drug release methodology for medicated chewing gums through demonstration of in vitro-in vivo relationship, In vitro and in vivo evaluation of nimesulide lyophilized orally disintegrating tablets, In vitro and in vivo characteristics of prochlorperazine oral disintegrating film, Bioequivalence assay between orally disintegrating and conventional tablet formulations in healthy volunteers, Orally disintegrating tablets friendly to pediatrics and geriatrics, Evaluation of fast disintegrating lansoprazole tablet in human subjects, Pharmacokinetics of olanzapine after single-dose oral administration of standard tablet versus normal and sublingual administration of an orally disintegrating tablet in normal volunteers, A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition, Technology Catalysts International Corporation, Mouth dissolving tablets an innovative technology, Fast-dissolving intraoral drug delivery systems, Mouth dissolving tablets II: an overview of evaluation techniques, Orally fast disintegrating tablets: developments, technologies, taste-masking and clinical studies, Salivary Flow and Composition in Healthy and Diseased Adults, Department of Oral and Maxillofacial Diseases, University of Helsinki, Evaluation of rapidly disintegrating tablets prepared by a direct compression method, Eurand: orally disintegrating tablets: a valuable life cycle management strategy, Evaluation of low-substituted hydroxypropylcelluloses (L-HPCs) as filler-binders for direct compression, Preparation, evaluation and optimization of rapidly disintegrating tablets, Particle Size Measurement: Powder Sampling and Particle Size Measurement, Evaluation of rapidly disintegrating tablets containing glycine and carboxymethylcellulose, Effects of disintegration-promoting agent, lubricants and moisture treatment on optimized fast disintegrating tablets, Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity, Evaluation of the disintegration time of rapidly disintegrating tablets via a novel method utilizing a CCD camera, Preparation of fast dissolving tablets based on mannose, A new method for disintegration studies of rapid disintegrating tablet, Evaluation of the disintegration properties of commercial famotidine 20 mg orally disintegrating tablets using a simple new test and human sensory test, General Chapter: 711 Dissolution: Apparatus 2, FIP/AAPS Joint Workshop Report: dissolution/in vitro release testing of novel/special dosage forms, Bioavailability of hydrochlorothiazide: conventional versus freeze-dried tablets, Development of sustained release fast-disintegrating tablets using various polymer-coated ion-exchange resin complexes, Dissolution testing of orally disintegrating tablets, Specifications: Test Procedures and Acceptance Criteria For New Drug Substances and New Drug Products: Chemical Substances Q6A, Clinical relevance of dissolution testing in quality by design, Commentary on AAPS Workshop: dissolution testing for the twenty-first century: linking critical quality attributes and critical process parameters to clinically relevant dissolution, 2012 The Authors. Disintegration of the dosage form in the oral cavity followed by wetting is the primary requisite for ODTs to release the API. It is inferred from the results that for the test ODT formulations, prior disintegration has no influence on the release behaviour. Regardless of the type of API that is being delivered, the fact that ODTs offer a route to pre-gastric absorption instead of parenteral delivery can offer some significant benefits to patients. 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.
[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. The test is only to ensure the complete disintegration of the unit, which is acceptable for dosage forms where dissolution is limited by disintegration. For example, ODTs can be made from very lipophilic APIs, by way of using an oily emulsion in place of the aqueous solution or suspension that is normally the starting point for an ODT formulation. JPP 2012 Royal Pharmaceutical Society, This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model), MTH-3 sensitizes oral cancer cells to cisplatin via regulating TFEB, A comprehensive review of phytochemistry, pharmacology and quality control of plants from the genus, Eplerenone reduces renal ischaemia/reperfusion injury by modulating Klotho, NF-B and SIRT1/SIRT3/PGC-1 signalling pathways, Docetaxel in combination with metformin enhances antitumour efficacy in metastatic breast carcinoma models: a promising cancer targeting based on PEGylated liposomes, Phytochemical profile and protective effects on myocardial ischaemia-reperfusion injury of sweated and non-sweated, About Journal of Pharmacy and Pharmacology, Orally Disintegrating Tablet Formulations, https://doi.org/10.1111/j.2042-7158.2012.01473.x, http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm, http://www.aptalispharmaceuticaltechnologies.com/pdf/EURX_Article_March_2007.pdf, http://worldwide.bose.com/electroforce/en/assets/pdf/Products/sellsheet_3100_022409_low.pdf, Receive exclusive offers and updates from Oxford Academic, Dissolution (not less than 75% (Q) in 60min), Dissolution (not less than 80% (Q) in 15min), Identification, purity, assay, dissolution, Operated at 100rev/min, 900ml dissolution medium. Subsequently, a non-compendial disintegration method was used. During this time, he has gained expertise in freeze-drying and is a named inventor on several patents related to formulation of lyophilized dosage forms. Therefore, formulators continue to explore alternative approaches to enhance absorption of the drugs across oral mucosa. 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. 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. 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. For industrially manufactured pharmaceutical dosage forms, product quality tests and performance tests are required to ascertain the quality of the final product. 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. Furthermore, they facilitate drug loading and are expected to remain unaffected by changes in humidity or temperature. Samples were withdrawn after 60 s, filtered, and the drug released into the medium was determined by HPLC-UV analysis. This has been proven with ibuprofen, which, if formulated as an ODT, could offer significant advantage to consumers in speed of onset. For conventional oral solid dosage forms (COSDFs), disintegration is often considered to be the prerequisite for subsequent dissolution. The mucosal response that can occur is a further benefit in immunizations against infections, such as human papillomavirus, influenza, and pneumonia.
This can be attributed to the advantages of the ODTs offer, such as ease of administration, ease of swallowing, pleasant taste and flavor. If the taste of the active ingredient, or the sensation it generates on the tongue, is not too unpleasant, the simple strategy of including flavor ingredients and sweeteners in the formulation can be sufficient to make it acceptable to patients. [711] Several initiatives are underway to standardize the test methods for these novel dosage forms. Search for other works by this author on: Present address: MJR PharmJet GmbH, Saarland University Medical Center, Building 7, 66424 Homburg, Germany. [27,28], Extra measures such as special blister packs are required to avoid breakage or damage of dosage forms before use. [19] The market share of ODTs has grown significantly in recent times, with more than 450 commercial over-the-counter and prescription ODT products having marketing authorization in the United States, European Union and in Japan.[24]. A significant amount of analytical work is required when developing a new ODT. Recently, higher doses of up to 200 mg have been launched, and peptide and protein products formulated in this way are also available. Prior to the dissolution test, three individual units of the samples were allowed to disintegrate in a 100-mesh basket placed in a 30-ml beaker containing 10 ml of the buffer solution adjusted to pH 6.8 for 60 s. The sample suspension in the beaker was then transferred directly to the dissolution vessel and the testing was carried at 50 rev/min for 1 h using the paddle apparatus (USP 2). The difference between the release profiles of the two can be seen in Figure 2. [49] Suitability of the USP 2 at 100 rev/min has also been reported.