Pharmaceutical Orally Disintegrating Tablets


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Over the past three decades, orally disintegrating tablets (ODTs) have gained much attention as a preferred alternative to conventional oral dosage forms such as tablets and capsules. An ODT is a solid dosage form that disintegrates and dissolves in the mouth (either on or beneath the tongue or in the buccal cavity) without water within 60 seconds or less. The US Food and Drug Administration Center for Drug Evaluation and Research (CDER) defines in the Orange Book an ODT as “A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue” (1). The European Pharmacopoeia however defines a similar term, orodisperse, as a tablet that can be placed in the mouth where it disperses rapidly before swallowing (2).


Descriptions of orally disintegrating dosage forms.

These tablets are distinguished from conventional sublingual tablets, lozenges, and buccal tablets which require more than a minute to dissolve in the mouth. In the literature, ODTs also are called orally disintegrating, orodisperse, mouth-dissolving, quick-dissolve, fast-melt, and rapid-disintegrating tablets and freeze-dried wafers (see sidebar, “Descriptions of orally disintegrating dosage forms”) (3–5).

ODTs release drug in the mouth for absorption through local oromucosal tissues and through pregastric (e.g., oral cavity, pharynx, and esophagus), gastric (i.e., stomach), and postgastric (e.g., small and large intestines) segments of the gastrointestinal tract (GIT). In this article, the term conventional oral dosage forms refers to tablets and capsules that must be swallowed with water for dissolution, release, and absorption of the drug in the stomach and GIT distal sites.

Recent market studies indicate that more than half of the patient population prefers ODTs to other dosage forms (6) and most consumers would ask their doctors for ODTs (70%), purchase ODTs (70%), or prefer ODTs to regular tablets or liquids (>80%) (7). These responses may, in part, be attributed to known ODT advantages such as ease of administration, ease of swallowing, pleasant taste, and the availability of several flavors (8). ODTs also offer clinical advantages such as improved safety and, in some cases, improved efficacy and other broader indications. In addition, several business needs are driving ODT technology development and the commercialization of new products such as the need for expanded product lines, improved life-cycle management, extended patent life, and marketing advantages.


Table I: Summary of orally disintegrating tablet products on the US market (3, 5).

At present, ODTs are the only quick-dissolving dosage form recognized by FDA and listed in Approved Drug Products with Therapeutic Equivalence Evaluations (also called the Orange Book) (3, 9). Table I lists several ODT products that are marketed in the United States. ODT products have been developed for numerous indications ranging from migraines (for which a rapid onset of action is important) to mental illness (for which patient compliance is important for treating chronic indications such as depression and schizophrenia) (3).

This article compares various ODT products and technologies and highlights their manufacturing processes, development issues, and future trends for these evolving dosage forms.

 

ODT product advantages and limitations

Dozens of ODT products have been launched worldwide over the past decade, with many new introductions in the past few years. More than 14 companies worldwide have an ODT platform technology and products in the R&D pipeline or several approved for marketing (10). Although these products have the common characteristic of quick disintegration and dissolution when placed in the mouth in the presence of saliva, their physical attributes vary.

For example, several techniques for making compressed tablets (e.g., DuraSolv, CIMA Labs, Eden Prairie, MN; OraSolv, CIMA Labs; and WOWTAB, Yamanouchi, Norman, OK) produce tablets that are easy to handle and can be packaged in blister packs or bottles. In contrast, some lyophilization manufacturing processes (e.g., Zydis, Cardinal Health, Dublin, OH) produce fragile freeze-dried tablets and compressed multiparticle tablets that can be packaged only in unit-dose blisters because of their high friability (8, 11, 12).

The administration of ODTs may not inherently result in a faster therapeutic onset, but it can circumvent problems such as difficulty in swallowing traditional solid oral dosage forms, particularly by pediatric and geriatric patients. The impetuses behind developing an ODT include clinical, medical, technical, business, and marketing advantages (see sidebar, “Possible benefits of orally disintegrating tablet drugs”) (7, 10, 13–16).


Possible benefits of orally disintegrating tablet drugs.

Despite these advantages, the application of this technology is limited by the amount of drug that can be incorporated into each unit dose. For lyophilized dosage forms, the drug dose must be lower than 400 mg for insoluble drugs and less than 60 mg for soluble drugs (3, 7). Because they dissolve quickly, ODTs cannot provide controlled or sustained release, except those that contain slow-dissolving, microparticulate-coated drugs, which quickly disperse and are swallowed.

As previously mentioned, fragile products require special unit-dose packaging, which may add to the cost. Only a few technologies can produce tablets that are sufficiently hard and durable to allow them to be packaged in multidose bottles (e.g, DuraSolv, AdvaTab [Eurand, Vandalia, OH], and WOWTAB). Table II summarizes the main characteristics of various ODT technologies and products from several innovator companies in the oral fast-dissolve tablet arena (15).

Selection of ODT drug candidates


Table II: Orally disintegrating tablet manufacturers and technology characteristics (18).

Several factors must be considered when selecting drug candidates for delivery as ODT dosage forms. In general, an ODT is formulated as a bioequivalent line extension of an existing oral dosage form. Under this circumstance, it is assumed that the absorption of a drug molecule from the ODT occurs in the postgastric GIT segments, similar to the conventional oral dosage form.

But this scenario may not always be the case. An ODT may have varying degrees of pregastric absorption and thus, the pharmacokinetic profile (including the maximum plasma concentration, time to achieve maximal plasma concentration, and area under the plasma concentration time curve of an equal dose of an ODT and a conventional oral dosage form) will vary (3). Therefore, the ODT will not be bioequivalent to the conventional oral dosage form. Examples are cited in the literature in which the pharmacokinetic profiles and bioavailabilities of the same dose of drug in an ODT are not bioequivalent to the conventional oral dosage form. For example, ODT formulations of selegiline, apomorphine, and buspirone have significantly different pharmacokinetic profiles compared with the same dose administered in a conventional dosage form (17–19).


It is possible that these differences may, in part, be attributed to the drug molecule, formulation, or a combination of both. If significantly higher plasma levels and systemic exposure have been observed, pregastric absorption leading to the avoidance of first-pass metabolism may play an important role. This situation may have implications for drug safety and efficacy, which may need to be addressed and assessed in a marketing application for an ODT (13). For example, safety profiles may be improved for drugs that produce significant amounts of toxic metabolites mediated by first-pass liver metabolism and gastric metabolism and for drugs that have a substantial fraction of absorption in the oral cavity and segments of the pregastric GIT.

The ideal characteristics of a drug for dissolution in the mouth and pregastric absorption from an ODT include:

  • no bitter taste;
  • dose lower than 20 mg;
  • small to moderate molecular weight;
  • good solubility in water and saliva;
  • partially nonionized at the oral cavity’s pH;
  • ability to diffuse and partition into the epithelium of the upper GIT (log P >1, or preferably >2);
  • ability to permeate oral mucosal tissue (15).

In contrast, the following characteristics may render a drug unsuitable for delivery as an ODT:

  • short half-life and frequent dosing;
  • very bitter or otherwise unacceptable taste because taste masking cannot be achieved;
  • require controlled or sustained release.

ODT manufacturing processesThe following sections provide information about selecting ODT technologies and their underlying manufacturing processes. The principal ODT manufacturing processes include conventional, freeze-dried, and floss-based tableting technology (4, 16, 20). Additional technologies for manufacturing and packaging ODT dosage forms have been highlighted elsewhere (18, 19).

Conventional tablet process. The WOWTAB manufacturing technique is one successful method that features conventional tablet characteristics for ease of handling, packaging, and fast disintegration (20). The technology is based on a combination of new physically modified polysaccharides that have water dissolution characteristics that facilitate fast disintegration and high compressibility. The result is a fast-disintegrating tablet that has adequate hardness for packaging in bottles and easy handling.

The manufacturing process involves granulating low-moldable sugars (e.g.,mannitol, lactose, glucose, sucrose, and erythritol) that show quick dissolution characteristics with high-moldable sugars (e.g., maltose, sorbitol, trehalose, and maltitol). The result is a mixture of excipients that have fast-dissolving and highly moldable characteristics (11). The drug can be added, along with other standard tableting excipients, during the granulation or blending processes. The tablets are manufactured at a low compression force followed by an optional humidity conditioning treatment to increase tablet hardness (23).

The OraSolv compressed tablet is another ODT manufacturing technology based on a conventional tableting process (11, 24–26). The technology involves the direct compression of active ingredients, effervescent excipients, and taste-masking agents (27). The tablet quickly disintegrates because effervescent carbon dioxide is produced upon contact with moisture. The effervescent excipient (known as effervescence couple) is prepared by coating the organic acid crystals using a stoichiometrically lesser amount of base material. The particle size of the organic acid crystals is carefully chosen to be larger than the base excipient to ensure uniform coating of the base excipient onto the acid crystals. The coating process is initiated by the addition of a reaction initiator, which is purified water in this case. The reaction is allowed to proceed only to the extent of completing the base coating on organic acid crystals. The required end-point for reaction termination is determined by measuring carbon dioxide evolution. Then, the excipient is mixed with the active ingredient or active microparticles and with other standard tableting excipients and then compressed into tablets.

The DuraSolv ODT technology is a second-generation technique based on the OraSolv technology. With this new process, tablets are made by combining noncompressible fillers with a taste-masking excipient and active ingredient into a dry blend. The blend is compressed into tablets using a conventional rotary tablet press. Tablets made with this process have higher mechanical strength and are sufficiently robust to be packaged in blister packs or bottles (5, 15). The technology can accommodate water-soluble and water-insoluble drugs in doses as large as 750 mg, which may contain multiple active ingredients.

The technology also incorporates taste-masking sweeteners and flavoring agents such as mint, cherry, and orange. Drug coatings also can be used to mask bitter drugs and to protect the drug from stomach acid–induced metabolism. As with all ODTs, products made with this process disintegrate in the mouth in 5–45 seconds and can be formulated to be bioequivalent to conventional tablet dosage forms (5).

Other ODT products made with conventional tableting processes include Frosta (Akina Inc., West Lafayette, IN), ProMelt (aaiPharma, Wilmington, NC), EasyTec Tablets (Antares Pharma, Exton, PA), Fast Oral Technology, D-Zolv (Capricorn Pharma Inc., Frederick, MD), and Oro-dispersible tablets (Grupo vita, Barcelona, Spain) (15).

Freeze-drying tablet process. R.P. Scher’s (now Cardinal Health’s) Zydis freeze-drying manufacturing process for ODT products (8, 28) has been the most commercially successful ODT technique. This process has been used to manufacture commercial ODTs for many drugs including desloratadine, lorazepam, piroxicam, loperamide, loratadine, enalapril, clonazepam, rizatriptan, domperidone, famotidine, chlorpheniramine maleate, scopolamine HBr, oxazepam, ondansetron, olanzapine, and selegiline (8, 16, 17, 29). The freeze-drying process involves the removal of water (by sublimation upon freeze drying) from the liquid mixture of drug, matrix former, and other excipients filled into preformed blister pockets. The formed matrix structure is very porous in nature and rapidly dissolves or disintegrates upon contact with saliva (16).

The Zydis technology requires specific characteristics for drug candidates and matrix-forming materials. Drug loading for water-insoluble drugs approaches 400 mg, and the upper limit for water-soluble drugs is ~60 mg. Ideal drug candidates for this method are insoluble drugs that have low water solubility, have fine particle size, and aqueous stability in the suspension.

Water-soluble drugs pose various formulation challenges because they form eutectic mixtures, which result in freezing-point depression and the formation of a glassy solid that may collapse upon drying because of the loss of supporting structure during the sublimation process (8, 30). Such collapse sometimes can be prevented by using various matrix-forming excipients such as mannitol that can induce crystallinity and hence, impart rigidity into the amorphous composite. The formation of highly water-soluble drugs into freeze-dried wafers is achieved by complexing them onto ion-exchange resins. This technique also helps achieve taste masking (8). Though the appropriate particle size for insoluble drugs is ~50 μm, drugs with larger particle sizes also can be formulated into freeze-dried wafers using suspending agents such as gelatin and flocculating agents such as xanthan gum (8, 31). In yet another modification, a solution of soluble drug can be sprayed onto a preformed matrix, following which the solvent is evaporated (8, 32).

Matrix formation and its characteristics are equally important for freeze-drying technology. Common matrix-forming agents include gelatin, dextran, or alginates which form glassy amorphous mixtures for providing structural strength; saccharides such as mannitol or sorbitol for imparting crystallinity, hardness, and elegance; and water, which functions as a manufacturing process medium during the freeze-drying step to induce the porous structure upon sublimation. In addition, the matrix may contain taste-masking agents such as sweeteners, flavorants, pH-adjusting agents such as citric acid, and preservatives to ensure the aqueous stability of the suspended drug in media before sublimation.

Freeze-dried ODTs are manufactured and packaged in polyvinyl chloride or polyvinylidene chloride plastic packs, or they may be packed into laminates or aluminum multilaminate foil pouches to protect the product from external moisture (8). A disadvantage of the wafers is that they are lightweight, fragile products and therefore must be dispensed in a special blister pack with a peelable backing foil (33). Furthermore, any minor damage to the package may cause the wafer to collapse because of moisture absorption (34).

Other patented ODT technologies based on lyophilization include Lyoc (Farmalyoc, now Cephalon, Franzer, PA) and QuickSolv (Janssen Pharmaceutica, Beerse, Belgium). Lyoc is a porous, solid wafer manufactured by lyophilizing an oil-in-water emulsion placed directly in a blister and subsequently sealed. The wafer can accommodate high drug dosing and disintegrates rapidly but has poor mechanical strength (35). QuickSolv tablets are made with a similar technology that creates a porous solid matrix by freezing an aqueous dispersion or solution of the matrix formulation. The process works by removing water using an excess of alcohol (solvent extraction). QuickSolv disintegrates very rapidly but is limited to low drug content and can be used only with active ingredients that are insoluble in the extraction solvent (36).

Floss-based tablet technology. Floss-based tablet technology (e.g., FlashDose, Biovail, Mississauga, ON, Canada) also is used to produce fast-dissolving tablets using a floss known as the shearform matrix (16, 21). This floss is commonly composed of saccharides such as sucrose, dextrose, lactose, and fructose. The saccharides are converted into floss by the simultaneous action of flash-melting and centrifugal force in a heat-processing machine similar to that used to make cotton candy (37–43). The fibers produced are usually amorphous in nature and are partially recrystallized, which results in a free-flowing floss (20). The floss is mixed with an active ingredient and excipients followed by compression into a tablet that has fast-dissolving characteristics (37–43).

Future developments

Quick-dissolve tablets can offer several biopharmaceutical advantages such as improved efficiency over conventional dosage forms. For example, they require smaller amounts of active ingredient to be effective, improve absorption profiles, and offer better drug bioavailability than regular tablets and capsules. In addition, ODTs may be suitable for the oral delivery of drugs such as protein and peptide-based therapeutics that have limited bioavailability when administered by conventional tablets. These products usually degrade rapidly in the stomach. Because drugs delivered in ODTs may be absorbed in the pregastric sites of highly permeable buccal and mucosal tissues of the oral cavity, they may be suitable for delivering relatively low-molecular weight and highly permeable drugs.

The overall preclinical, clinical, and biopharmaceutical development programs necessary to support successful ANDA and NDA marketing applications for ODTs were recently reviewed (44) and presented in detail in a symposium on this topic (13, 45). Several clinical pharmacological and biopharmaceutical aspects of ODT development also must be considered. These factors will be discussed in a separate article.

Summary

Orally disintegrating tablets (ODTs) have better patient acceptance and compliance and may offer improved biopharmaceutical properties, improved efficacy, and better safety compared with conventional oral dosage forms. Prescription ODT products initially were developed to overcome the difficulty in swallowing conventional tablets with water among pediatric, geriatric, and psychiatric patients with dysphagia. Today, ODTs are more widely available as over-the-counter products for the treatment of allergies and cold and flu symptoms. The target population has expanded to those who want convenient dosing anywhere, anytime, without water. The future potential for ODTs is promising because of the availability of new technologies combined with strong market acceptance and patient demand. Dozens of ODT products have been commercialized, and the market size for ODTs will continue to expand as the technology is used to deliver large-molecular weight biopharmaceutical therapeutics such as proteins and peptides when coupled with the appropriate permeation enhancers. By paying close attention to advances in technologies, pharmaceutical companies can take advantage of ODTs for product line extensions or for first-to-market products.

Future possibilities for improvements in ODTs and drug delivery are bright, but the technology is still relatively new. Several drug delivery technologies that can be leveraged on improving drug therapy from ODTs have yet to be fully realized.

William R. Pfister, PhD,* is a senior director of preclinical affairs at NexMed (USA), Inc., (Robbinsville, NJ). Tapash K. Ghosh is a senior clinical pharmacology and biopharmaceutics reviewer at the US Food and Drug Administration (HFD 880), 9201 Corporate Blvd., Room N224, Rockville, MD 20850.

No official support or endorsement of this article by FDA is intended or should be inferred.

*To whom all correspondence should be addressed.

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