10. We use cookies to improve your website experience. AAPS Pharm Sci 360 Orally disintegrating tablets are generally characterized by their high porosity, low density and low tensile strength. 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. 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 choice of packaging materials is important, and each blister strip is sealed using specially designed, multi-layer foils that are resistant to moisture ingress. The procedure is based on the compendial disintegration test described by the USP, but other equivalent approaches providing similar results may be used. Given the very fast disintegration of ODTs, the relationship between disintegration and dissolution is worthy of closer scrutiny. Mathias Bayru is Catalent Pharma Solutions Group Product Manager for Drug Delivery Solutions. Therefore, if the drug enters the bloodstream directly, these metabolites are not formed and the side-effects they cause cannot occur. [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. Due to the nature of the dosage form and the existing standardized equipment, conventional methods of dissolution testing[48] could be extended to ODTs. The temperature of the test medium was maintained at 37C. Due to the absence of effective stirring at lower rotation speeds and entrapment of particles within the basket, the drug release rates are significantly lower and irreproducible. 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. ODT, orally disintegrating tablets; Ph. Search for other works by this author on: Present address: MJR PharmJet GmbH, Saarland University Medical Center, Building 7, 66424 Homburg, Germany. 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. Palm Springs, CA, DRUG DEVELOPMENT & DELIVERY 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. This is important, as a freeze-dried formulation can be sensitive to highly humid environments and can shrink and lose its rapid disintegration characteristics. Several process techniques can be involved in production of ODTs. A significant amount of analytical work is required when developing a new ODT. His market knowledge and expertise spans the launch and development of solid and sterile dosage forms, OTCs, and medical devices. [27,28], Extra measures such as special blister packs are required to avoid breakage or damage of dosage forms before use. Boston, MA, CPhI Worldwide All Rights Reserved. One of the biggest challenges is to ensure rapid disintegration without negatively affecting the mechanical strength of the formulation. 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. Based on experimental results, it appears that it may be feasible to rely on the dissolution test without a need for disintegration studies for selected ODTs on the market. The decision and requirement of such tests are based solely on product characteristics. Mean SD, n = 3. 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. Acceptance for a waiver of dissolution by disintegration for ODTs could only be extended based on the procedure described in the ICH Harmonised Tripartite Guideline Q6A decision tree #7. Moreover, the presence of a large volume of medium and the mechanical agitation does not accurately reflect the disintegration environment in vivo. If the cyclodextrin has the appropriate size of hole, the API will become trapped, which prevents it from touching the taste receptors on the tongue. Preclinical studies in mice have shown the potential of an ODT influenza vaccine. 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. There, the water sublimes, leaving behind the porous matrix structure of the ODT, often referred to as a wafer. Besides identity, purity and assay, additional product quality tests are used by manufacturers to reflect the quality of the dosage form. For both formulations, disintegration was complete in 60 s. In the case of product A, the disintegrated particles were retained in the 100-mesh basket. [711] Several initiatives are underway to standardize the test methods for these novel dosage forms. And, importantly, the two are bioequivalent. The list of compendial and non-compendial product quality tests are summarized in Table 2. To view this issue and all back issues online, please visit www.drug-dev.com. A summary of the investigation and the test results are given in Table 4. defines them as uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed. While liquid formulations can provide successful dosing options in some cases, the ODT can work in all of these situations. [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]. Hygroscopicity of most formulations also leads to special packaging requirements for ODTs. Technology Catalysts International Corporation. Fax: (973) 299-7937. technologies and commercialization of these products bring numerous marketing advantages such as expanded product lines, improved life-cycle management and extended patent life. For product B, after the disintegration test, gel formation was observed due to the presence of gelatin in the matrix. To learn about our use of cookies and how you can manage your cookie settings, please see our Cookie Policy. To investigate the suitability of the dissolution method as a performance indicator, in-vitro dissolution testing was performed on products A and B. A pH-dependent drug release behaviour was observed for product B. 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. In-vitro dissolution test. Mr. Bayru earned his Masters degree in Pharmacology and his MBA from Montpellier University. These points can be summarized[25,26] as follows: (1) do not require water to swallow and should dissolve or disintegrate in the mouth within a few seconds; (2) allow high drug loading and compatible with taste-masking and other excipients; (3) have a pleasant mouth feel and leave minimal or no residue in the mouth after oral administration; (4) avoid local irritations in particular if used for longterm treatment; (5) exhibit low sensitivity to humidity and temperature; (6) be adaptable and amenable to existing processing and packing machinery; and (7) have sufficient strength towithstand the rigors of the manufacturing process and post-manufacturing handling. The results of the in-vitro dissolution test for products A and B are given in Figure 2. Figure 1 is an electron micrograph image of the matrix. The ODT products differ significantly in their manufacturing and formulation techniques. Smaller particles make for a better mouthfeel in an ODT; larger particles give a gritty sensation as the tablets disintegrate. US patent application 20010014340, Oxford University Press is a department of the University of Oxford. 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. European Directorate for the Quality of Medicines, Council of Europe. 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. October 18-19 If a patient-friendly ODT is to be created, then more creative formulation methods will have to be applied. 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. Time for the probe to penetrate into the ODT is measured, Application of very low force (10mN) to the ODT placed on holder followed by an addition of 5ml of aqueous medium. For example, fast disintegrating, fast melting and mouth dissolving tablets are all categorized as ODTs. 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. It is this layer that confers the desired taste-masking properties. Samples were withdrawn at standardized intervals and the amount released was quantified using HPLC-UV determination. ODTs are designed to disperse quickly within the oral cavity, removing the need to swallow a solid tablet or capsule. [37,38] Tablet hardness and porosity are directly linked to the disintegration time. [4] The FDA's dissolution database[5] contains 23 dissolution/drug release methods for ODTs, which constitutes about 4% of all dissolution tests listed. FDA, United States Food and Drug Administration; USP, United States Pharmacopeia. One way this can be achieved is via the Zydis Ultra formulation. 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. 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. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. 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. It is inferred from the results that for the test ODT formulations, prior disintegration has no influence on the release behaviour. Hence, development of new technologies and new disintegrants are still in progress. People also read lists articles that other readers of this article have read. CycloLab Cyclodextrin Research & Development Ltd. Partnership Opportunities in Drug Delivery (PODD), PDA 2022 Universe of Pre-filled Syringes & Injection Devices Conference. Furthermore, for systemic effect, sublingual route provides faster absorption when compared to buccal route. Absorption enhancers and bioadhesives can be included in the ODT formulation to promote absorption. Copyright 2018-2022 Drug Development & Delivery. The similarity factor (f2) value for product A at pH 6.8 was 66.19, and for product B at pH 1.2 was 79.42. November 1-3 The United States Pharmacopeial Convention. Dissolution recommendations are also given in the FDA (CDER) dissolution database for ODTs. 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. This can be attributed to the advantages of the ODTs offer, such as ease of administration, ease of swallowing, pleasant taste and flavor. The agitation of the medium was varied between 50 and 75 rev/min depending on whether sample mounding (coning) was observed. The difference between the release profiles of the two can be seen in Figure 2. More than three-quarters of a test group claimed its taste profile was acceptable and that the reformulated product incorporating Zydis technology was more pleasant tasting than the standard formulation. Orally Disintegrating Tablet and Film Technologies 6th Edition. Boston, MA, PDA 2022 Universe of Pre-filled Syringes & Injection Devices Conference There are several factors to be considered in formulating ODT products. [23], Since their introduction, ODTs have become widely accepted dosage forms, especially for paediatric and geriatric patients. 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. Beyond compendial requirements, some non-compendial tests are also used by manufacturers. Over the past three decades, orally disintegrating tablets (ODTs) as well as films, which require less than a minute to dissolve in the mouth, have gained more attention as an alternative to conventional sublingual, buccal formulations and lozenges. In many cases, a single point dissolution is required for ODTs; exceptions include where a controlled release behaviour is intended. Several factors affecting the disintegration time of the ODTs have been investigated. 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. Figure 4 shows that the lower-dose ODT produces the same area under curve (AUC) as a conventionally formulated selegeline tablet. Web design and development by WalkerTek. Dissolution Methods, Comparative pharmacokinetics and safety of lansoprazole oral capsules and orally disintegrating tablets in healthy subjects, Saliva as an analytical tool in toxicology, Studies on the chemistry of mixed human saliva III. Another innovative possibility is the prospect of formulating a two-layer ODT that would allow two different ingredients to be incorporated within each dose. Catalents Zydis Bio technology was developed as a way of achieving oral delivery of biologics. 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. 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). The use of the basket apparatus (USP 1) for dissolution testing of ODTs is also described. 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. Therefore, the desired product characteristic for an ODT includes a disintegration time of less than 30 s without any aid. 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. He has worked within R&D for more than 15 years, primarily on Catalents Zydis ODT technology formulation and process development. 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 wetting is usually achieved by the volume (0.51.5 ml/min) of stimulated saliva[29] in the mouth. This could be particularly beneficial if those ingredients were otherwise incompatible, whether it were two different APIs or an API and an excipient, for example, vitamins B and C; and the artificial sweetener, aspartame, which is unstable above pH 6.5 and so is incompatible with many basic excipients and APIs, such as calcium carbonate. He is responsible for driving the global marketing strategy for the oral drug delivery solutions business unit, including patient-centric Solutions, Zydis. In contrast to a traditional coating, the coated API inside is released slowly, a phenomenon that indicates that taste-masking has been achieved, while still meeting the US Pharmacopeial convention (USP) criteria for immediate release. [5], Compendial USP monographs for orally disintegrating tablet products and FDA recommended dissolution methods. [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]. 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. In addition, ODTs provide clinical advantages such as improved safety and, in some cases, improved efficacy. After lidding the blister strips may be packed into outer cartons. 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. Recent developments in ODT technology have widened the range of actives that can be formulated and product types that are possible. (d) Product B after a disintegration time of 60 s. Summary of experimental conditions to test the performance of orally disintegrating tablets. Chewable Oral Drug Products: What's New with In Vitro Drug Release? Currently, ODTs are evaluated using the disintegration test for conventional dosage forms described in the phamacopeias. Recent market studies indicate that more than half of the patient population prefers orally disintegrating dosage forms and most consumers would ask their doctors for ODTs (70%), purchase ODTs (70%). 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. Zydis technology has been used to formulate a number of commercial products, particularly those for which a fast onset of action is beneficial. In order to increase the precision of the disintegration method, modification of conventional methods of testing is needed. Dosage forms that are applied via a similar route include medicated gums, sublingual tablets, buccal tablets and lozenges. 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. 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. 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. Montville, NJ 07045 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. The loss of bodyweight is indicative of disease severity, and those mice infected with influenza but who were unvaccinated lost significant amounts of weight. Recently, higher doses of up to 200 mg have been launched, and peptide and protein products formulated in this way are also available. 1. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. [3] They can further be characterized as solid dosage forms that disintegrate in the oral cavity leaving an easy-to-swallow residue. 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). Another technique, dynamic vapor sorption, is used to determine the moisture sorption and desorption profiles. In the future, it is expected that new quality control methods for ODTs will be developed to accommodate more specifically the technological aspects of these pharmaceutical dosage forms. List of product quality tests for orally disintegrating tablets. The API still has 70%-85% potency w/w compared to uncoated particles. [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 structure of a Zydis tablet is key to its rapid dispersal properties, as the tablets are highly porous. In-vitro dissolution testing using the USP paddle apparatus 2[48] is a compendial requirement for ODTs and the dissolution profiles are comparable with conventional immediate release dosage forms. Eur., European Pharmacopeia; USP, United States Pharmacopeia. 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. For conventional oral solid dosage forms (COSDFs), disintegration is often considered to be the prerequisite for subsequent dissolution. For many other APIs, this is not the case. 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. The prospect of formulating biologics as ODTs offers even more promise for the dose form.