Oral disintegrating tablets (ODTs): A new trend in drug delivery

 ABSTRACT

The most common and preferred route of drug administration is through the oral route. ODTs are gaining importance among novel oral drug-delivery system as they have improved patient compliance and have some additional advantages compared to other oral formulation. They are also solid unit dosage forms, which disintegrate in the mouth within a minute in the presence of saliva due to super disintegrants in the formulation. Thus, this type of drug delivery helps a proper peroral administration in pediatric and geriatric population where swallowing is a matter of trouble. Various scientists have prepared ODTs by following various methods. However, the most common method of preparation is the compression method. Other special methods are molding, melt granulation, phase-transition process, sublimation, freeze-drying, effervescent method, cotton candy process, mass-extrusion etc. Since these tablets dissolve directly in the mouth, so, their taste is also an important factor. Various approaches have been taken in order to mask the bitter taste of the drug. A number of scientists have explored several drugs in this field. Like all other solid dosage forms, they are also evaluated in the field of hardness, friability, wetting time, moisture uptake, disintegration test, and dissolution test. [1,2]

Keywords:  oral disintegrating tablets, superdisintegrants, patented technologies, disintegration.

INTRODUCTION

Drug delivery through oral route is the most common and preferred route of drug administration both for solid and liquid dosage forms. Tablets and capsules are the most popular solid dosage forms. However, many people face difficulty in swallowing tablets and hard gelatin capsules. This difficulty in swallowing is called dysphasia.[3] ODTs are solid dosage forms containing medicinal substances which disintegrate rapidly, usually in a matter of seconds, when placed on the tongue. ODTs disintegrate and or dissolve rapidly in the saliva without the need for water. Some tablets are designed to dissolve in saliva remarkably fast, within a few seconds, and are true fast-dissolving tablets. Others contain agents to enhance the rate of tablet disintegration in the oral cavity, and are more appropriately termed fast-disintegrating tablets, as they may take up to a minute to completely disintegrate. When put on tongue, this tablet disintegrates instantaneously, releasing the drug, which dissolves or disperses in the saliva. Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablet dosage form. This type of drug delivery is becoming popular day by day due to its numerous advantages [4].

FORMULATION DEVELOPMENT OF ODTs

For ODTs, the key challenges are producing tablets with optimum tablet hardness, rapid disintegration and overcoming the bitter taste exhibited by many actives.

Selection of active pharmaceutical ingredient is one of the most important parameters to formulate ODTs. It should be dissolved in the oral cavity and absorbed. Also, it shouldn’t have bitter taste. It is better if it is in low dose, small to moderate molecular weight, good solubility in water and/or saliva, non-ionized property in pH 5.5-7.4 and ability to be absorbed via oral mucosa. 

The demand for ODTs has been increasing day by day. But the number of fillers/binders /disintegrant which can be used for ODT formulations is limited because these bulk excipients have to fulfill special requirements, such as being soluble in water, pleasant taste, mouth feel, sweetness, and rapid dispersibility. The increased popularity of ODTs on the market has been the main driver behind the creation of ready-to-use platforms by the excipients industry. The challenge for manufacturers is to create a tablet that will satisfy the requirement for fast disintegration but at the same time it have the mechanical properties that enable it to be produced efficiently. Several ready to use excipients are available for ODT.

An ideal bulk excipient for ODT forms should have the following properties: 

• Disperses and dissolves in the mouth within a few seconds without leaving any residue 
• Masks the drug’s offensive taste and offers a pleasant mouth feel 
• Enables sufficient drug loading and remains relatively unaffected by changes in humidity or temperature 

Because ODT formulations typically use high levels of superdisintegrants to achieve rapid disintegration in the mouth, it is important to select a disintegrant that provides optimal performance. The disintegrant should produce rapid disintegration, a smooth mouth feel, good flow, and high compactability. The order of superdisintegrants in enhancing the dissolution rate in ODTs is crospovidone (CPV) > croscarmellose sodium (CCS) > sodium starch glycolate (SSG). L-HPC is the first choice as a disintegrant of Japanese pharma company. L-HPC has similar capability to the other super disintegrants. 

Excipients with particle size larger than 200–250 μm in water are considered poorly acceptable. However, which passes through both 250 and 710 µm screens indicates improved mouthfeel as compared to the formulations which produces dispersion of particles larger than 250 μm.

Methods for the preparation of ODTs are also very important and each offers advantages and disadvantages. For example, although lyophilization produces tablets with very fast disintegration (<5 s), the tablets are often less robust and usually require special packaging. The two most common and widely used methods for formulation and preparation of ODTs are the direct compression and the fusion methods or sublimation.

The world's top three leading ready to use excipients for ODT which are highly acceptable are based in Japan and Germany. It does not need any special processing. It can be blended and followed by tabletting.

First ODT, received USFDA approval, Claritin(loratadine) in category of antihistaminic manufactured by lyophilization technology in Dec.1996.

The Center for Drug Evaluation and Research (CDER), a part of the US Food and Drug Administration (FDA), has defined an ODT as a “a solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue”. Two key characteristics that a dosage form labelled as an ODT must possess is a rapid disintegration time of 30 s or less, and a tablet weight of 500 mg or less. Tablets that take longer than 30 seconds to disintegrate or are dosed with liquids may be more appropriately considered to be chewable or oral tablets. ODTs are also different from chewable tablets in that they eliminate the need for chewing or drinking liquids. Liquefaction of the ODT occurs on the tongue, followed by the patient swallowing the liquid.

In the guidance for industry document “Size, Shape, and Other Physical Attributed of Generic Tablets and Capsules” published by CDER, US FDA, it is recommended that drug manufacturers develop quality target product profiles (QTPPs) for drug candidates. For ODTs, parameters such as disintegration time and tablet size are key components of QTPPs. Drug release from an ODT is composed of a sequence of events or processes which include initial tablet disintegration, followed by drug dissolution and subsequent drug absorption.  Sublingual tablets (placed under the tongue) and buccal tablets (placed in the side of the cheek or high up between the inside and of the upper lip and gum) are also sometimes classified as ODTs.

REGULATORY PERSPECTIVE OF THE READY TO USE EXCIPIENTS FOR ODTs [5,6]

There are no processes or mechanisms in place to evaluate the safety of pharmaceutical excipients independent of APIs, since excipients are only approved as a component of new drug products. The FDA requires that the new drug applications (NDAs) and Abbreviated New Drug Applications (ANDAs) include information about all components of the drug products, including excipients. To identify previously reviewed excipients, the FDA looks to several sources, such as Generally Recognized As Safe (GRAS) status, favorable reviews by the Joint Experts Committee on Food Additives, inclusion in USP/ NF, and/or reviews of other NDAs. These excipients are identified in FDA’s Inactive Ingredient Guide (IIG). However, the absence of excipient reviews that are independent of APIs present problems for companies that seeks to use new or novel excipients in their drug products. In its May 2005, Guidance for Industry, the FDA detailed recommendations on safety evaluations [7,8] According to that guidance, with the absence of a chemical change during processing, ready to use excipients can be considered generally regarded as safe (GRAS) if the parent excipients are also GRAS- certified by the regulatory agencies. Hence, these excipients do not require additional toxicological studies. Ready to use excipients have yet to find their way into official monographs, which is one of the major obstacles to their success in the marketplace. The mixture of excipients was presented as a topic to the National Formulary and was assigned a priority on the basis of the use of the mixture in marketed dosage forms in which processing has provided added functional value to the excipient mixture.

SYNONYMS OF ODTs

MECHANISM OF TABLET DISINTEGRATION

METHODS OF PREPARATION OF ODTs

There are several methods for the preparation of ODTs, but the prepared products vary in their properties depending on the method of preparation. The properties in which they vary are mechanical strength of the tablets, swallowability, bioavailability, drug dissolution in saliva, stability, and to some extent taste. [9] The two most common and widely used methods for formulation and preparation of ODTs are the direct compression and the fusion methods or sublimation.

MOLDING METHOD

Tablets formed by molding process are highly porous in structure, resulting in high rate of disintegration and dissolution. This process includes moistening, dissolving, or dispersing the drugs with a solvent then molding the moist mixture into tablets by applying lower pressure in compression molding, but always lower than the conventional tablet compression. Molded tablets have low mechanical strength, which results in erosion and breakage during handling.

DIRECT COMPRESSION

Direct Compression is the simplest and most cost-effective tablet manufacturing technique for ODTs as they can be fabricated using conventional tablet manufacturing and packaging machinery and also due to availability of tableting excipients with improved flow, compressibility and disintegration properties, especially tablet disintegrants, effervescent agents and sugar-based excipients. A type of disintegrant and its proportion are of prime importance. There are number of factors which affect disintegration like particle size distribution, contact angle, pore size distribution, tablet hardness, water absorption capacity and type and proportion of disintegrants. 

FREEZE-DRYING METHOD

Freeze drying is the process in which water is sublimed from the product after it is frozen. This technique creates an amorphous porous structure that can dissolve or disperse rapidly. A typical procedure involved in the formulation of ODT using this technique is mentioned here. The active drug constituent is dissolved or dispersed in an aqueous solution of a carrier/polymer. The mixture is done by weight and poured in the walls of the preformed blister packs. The trays holding the blister packs are transfer through liquid nitrogen freezing tunnel to freeze the drug solution or dispersion. Then the frozen blister packages are placed in refrigerated cabinets to continue the freeze - drying process. After freeze-drying the aluminium foil backing is applied on a blister-sealing machine. Finally, the blisters are packaged and shipped. The freeze-drying method has demonstrated improved absorption and increase in bioavailability of drug. The major disadvantages of lyophilisation method are that it is expensive method and time consuming. Tablets prepared by this process have low mechanical strength, poor stability at higher temperature and humidity, but glossy amorphous structure resulting in highly porous, lightweight product. There are various patents on this technology. [ 10]

MELT GRANULATION

Melt granulation technique is a process by use of which pharmaceutical powders are efficiently agglomerated by a melt able binder. The advantage of this technique compared to a conventional granulation technique is that no water or organic solvents are required. Because there is no drying step involved, the process is less time consuming and uses less energy than wet granulation. It is a useful technique to increase the dissolution rate of poorly water-soluble drugs.

PHASE TRANSITION

Phase transition is a process by compressing powder containing two sugars alcohols. One with high and another with low melting point, and they are heated at a temperature between their melting point and then compressed finally in order to get the tablets. Example of sugar alcohols are erythritol (melting point: 122°C), xylitol (melting point: 93-95°C), trehalose (97°C), and mannitol (166°C). After heating, tablet hardness was increased due to an increase in interparticle bonds or the bonding surface area in tablets induced by phase transition of lower melting point sugar alcohol. [11]

SUBLIMATION

This process involves addition of some inert volatile substances like urea, urethane, naphthalene, camphor, menthol, etc to other excipients and the compression of blend into tablet. Conventional compressed tablets that contain highly water-soluble ingredients often fail to dissolve rapidly because of low porosity of the matrix. Hence, to produce porous matrix, volatile ingredients are used that are later subjected to a process of sublimation. Sublimation is a process in which water passes directly from solid state to vapour state without passing through liquid state. 

EFFERVESCENT METHOD

ODTs are also prepared by effervescent method by mixing sodium bicarbonate and tartaric acid of concentration 12% (w/w) along with super disintegrants like pregelatinized starch, sodium starch glycolate, crospovidone, and croscarmellose. First, sodium bicarbonate and tartaric acid were preheated at a temperature of 80°C to remove absorbed/residual moisture and thoroughly mixed in the motor. Finally, the blends are compressed in the punch. 

COTTON CANDY PROCESS

In this process Shear form technology is used in the preparation of a matrix known as FLOSS, made from the combination of the recipients either alone or with the drugs. The fibrous nature of the floss is similar to the cotton-candy fibres. The floss is commonly made of saccharides such as sucrose, dextrose, lactose and fructose at temperatures ranging between 180–260°F. Other polysaccharides such as polymaltodextrins and polydextrose can be converted into fibres at 30-40% lower temperature range.

MASS-EXTRUSION

This technology involves softening the active blend using the solvent mixture of water-soluble polyethylene glycol and methanol and subsequent expulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments using heated blade to form tablet. The dried cylinder can also be used to coat granules for bitter drugs and thereby achieve taste masking.

PATENTED TECHNOLOGIES FOR ODTs [12,13,14,15]

There are number of patented technologies which were developed for the formation of ODTs. Few widely considered methods are as follows:

ZYDUS TECHNOLOGY

Zydis techniqueis owned by Scherer, a subsidiary of Cardinal Health. This technology uses freeze drying process for manufacturing of the tablets. The Zydis product is made to dissolve on the tongue in 2-3 seconds. Zydis formulation is very lightweight, fragile and has poor stability at higher temperatures and humidities.

QUICK-DIS TECHNOLOGY

The novel intra-oral drug delivery system, trademarked as Quick-Dis™, is Lavipharm’s proprietary patented technology and is a thin, flexible, and quick-dissolving film. When the film is placed on the top or the floor of the tongue, it is retained at the site of application and rapidly releases the active agent for local or systemic absorption. The typical disintegration time is only 5-10 seconds for the Quick-Dis™. 

FLASH DOSE TECHNOLOGY

Flash dose technology has been patented by Fuisz. Nurofenmeltlet, a new form of ibuprofen as melt-in mouth tablets, prepared using flash dose technology is the first commercial product launched by Biovail Corporation.The Flash Dose technology uses a unique spinning mechanism so as to produce a floss-like crystalline structure, much like cotton candy.

FLASHTAB TECHNOLOGY

Prographarm laboratories have patented the Flash tab technology. Tablet prepared by this system consists of an active ingredient in the form of microcrystals. The tablets produced are reported to have good mechanical strength and disintegration time <1 minute.

WOWTAB TECHNOLOGY

Wowtab® technology was developed by Yamanouchi Pharma Technologies, USA. The WOW in the WOWTAB signifies the tablet is to be given without water. This technology utilizes sugar and sugar-like excipients. The two different types of saccharides are combined to obtain a tablet formulation with adequate hardness and fast dissolution rate. The two different saccharides are those with high moldability like maltose, mannitol, sorbitol, and oligosaccharides (good binding property) and low moldability like lactose, glucose, mannitol, xylitol (rapid dissolution). Tablets produced from this technology will have sufficient hardness to maintain the physical characteristics of the dosage form during production until it comes in contact with moisture such as saliva in mouth. Erythritol was found to be the best sugar for this type of formulation, showing rapid disintegration which is unaffected by tablet hardness.

LYOC TECHNOLOGY

Lyoc technology is owned by Cephalon Corporation. CIMA is a subsidiary of Cephalon, and currently manages the Lyoc R and D efforts. This was the first freeze drying- based technology introduced for ODTs.

MECHANISM OF TABLET DISINTEGRATION [16]

• Swelling 
• Wicking (Porosity and capillary action)
• Particle repulsive forces
• Deformation recovery
• Heat of wetting
• Chemical reaction (Acid-Base reaction)
• Enzymatic reaction

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IDEAL CHARACTERISTC OF ODTs

ADVANTAGE OF ODTs

DISADVANTAGE OF ODTs

CONCLUSION

ODTs have potential advantages over conventional solid dosage form. This drug delivery is one of the great inventions of all the novel drug-delivery systems. They have improved patient compliance, convenience, bioavailability, and rapid onset of action. However, common people are not much aware of this delivery system. Therefore, pharmacists are responsible to spread the knowledge regarding this system. It is the duty of the pharmacist to counsel the patients regarding its use, advantages, storage and maintenance. This dosage form should be handled carefully since they do not have sufficient mechanical strength. Patients who suffer from dryness of mouth should not be prescribed ODTs, since minimum volume of saliva is necessary for it to disintegrate/dissolution. This dosage form is very much suitable for children having no primary teeth and for geriatric patients who have lost their teeth permanently. Thus, in near future, it is expected that this delivery system will get much importance as that of conventional delivery.

Not many biologics have been subject to ODT formulation technology for obvious reasons of drug degradation by first pass metabolism. However, drugs with a wide variety of therapeutic indications such as proton pump inhibitors, NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), antipsychotics, antiemetics, antihistamines etc., have been successfully formulated as ODTs.

ACKNOWLEDGEMENT

The authors are grateful to Mr. Gaurav Tripathi, Works Manager, Mr. Sanjay Chauhan, Sr. Manager, Supply Chain, and Ms. Monika Tomar, Manager-R&D, Sigachi Industries Private Limited, Telangana, India for support.

FUNDING

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST

The author declares that he does not have any financial and personal relationships with other people or any other organizations that could inappropriately influence this research work

QUERY

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17. Photo courtesy: Google

ABBREVIATIONS

ODTs:Oral Disintegtaing Tablets,APIs:Active Pharmaceutical Ingredients,CDER: Center for Drug Evaluation and Research, FDA:Food and Drug Administration , QTPPs: Quality Target Product Profiles sodium, NDAs:New Drug Applications,ANDAs:Abbreviated New Drug Applications, GRAS:Generally Recognized As Safe,IIG: Inactive Ingredient Guide (IIG),R&D: Research and Development,NSAIDs: Non-Steroidal Anti-Inflammatory Drugs,FDTS: Fast Dissolving Tablets 

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About the Author 

Dr. Ajay Kumar Singh, M.Sc. (Gold Medalist), Ph.D. is the author and founder of “Pharma Solutions by Dr. Ajay”. For more helpful articles, please visit our blog. Need Help: Ask Question