Recent developments in technology have presented viable dosage alternatives for patients who may have difficulty swallowing tablets or liquids. Traditional tablets and capsules administered with an 8-oz. glass of water may be inconvenient or impractical for some patients. For example, a very elderly patient may not be able to swallow a daily dose of antidepressant. An eight-year-old with allergies could use a more convenient dosage form than an antihistamine syrup. A schizophrenic patient in the institutional setting can hide a conventional tablet under his or her tongue to avoid their daily dose of an atypical antipsychotic. A middle-aged woman undergoing radiation therapy for breast cancer may be too nauseous to swallow her H2-blocker. Fast-dissolving/disintegrating tablets (FDDTs) are a perfect fit for all of these patients.
FDDTs 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.
Table 1: List of Products Categorized by Technology
|micronized loratadine (10 mg), citric acid, gelatin, mannitol, mint flavor|
piroxicam (10 or 20 mg), gelatin, mannitol, aspartame, citric anhydrous
|rizatriptan (5 or 10 mg), gelatin, mannitol, aspartame, peppermint flavor|
|famotidine (20 or 40 mg), gelatin, mannitol, aspartame|
olanzapine (5, 10, 15 or 20 mg), gelatin, mannitol, aspartame, methylparaben sodium, propylparaben sodium
|ondansetron (4 or 8 mg), aspartame, gelatin, mannitol, methlparaben sodium, propylparaben sodium, strawberry flavor|
Dimetapp Quick Dissolve Children's Cold and Allergy Tablets (OTC)
|mirtazepine (15, 30, or 45 mg), aspartame, citric acid, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, mannitol, microcrystalline cellulose, polymethacrylate, povidone, sodium bicarbonate, starch, sucrose, orange flavor|
|acetaminophen (80 or 160 mg), inactive ingredients including mannitol (currently available in Canada)|
|Triaminic Softchew (OTC)|
|hyoscyamine sulfate (0.125 mg), aspartame, colloidal silicon dioxide, crospovidone, mint flavoring, magnesium stearate, mannitol, microcrystalline cellulose|
|zolmitriptan (2.5 mg), mannitol, microcrystalline cellulose, crospovidone, aspartame, sodium bicarbonate, citric acid, anhydrous, colloidal silicon dioxide, magnesium stearate, orange flavor|
|Benadryl Allergy & Sinus Fastmelt (OTC)|
|Children's Benadryl Allergy & Cold Fastmelt (OTC)|
The major advantage of the FDDT formulation is that it combines the advantages of both liquid and conventional tablet formulations, while also offering advantages over both traditional dosage forms.2 It provides the convenience of a tablet formulation, while also allowing the ease of swallowing provided by a liquid formulation. FDDTs allow the luxury of much more accurate dosing than the primary alternative, oral liquids.
A major claim of the some FDDTs is increased bioavailability compared to traditional tablets.1 Because of dispersion in saliva while still in the oral cavity, there can be pre-gastric absorption from some formulations in those cases where the drug dissolves quickly. Buccal, pharyngeal and gastric regions are all areas of absorption of the many formulations.3 However, other formulations show nearly identical plasma-concentration profiles.2 Any pre-gastric absorption avoids first pass metabolism and can be a great advantage in drugs that undergo a great deal of hepatic metabolism. However, if the amount of swallowed drug varies, there is the potential for inconsistent bioavailability. While the claimed increase in bioavailability is disputable, it is clear that the major advantage of these formulations is convenience.
Pharmaceutical marketing is another reason for the increase in available fast-dissolving/disintegrating products. As a drug entity nears the end of its patent life, it is common for pharmaceutical manufacturers to develop a given drug entity in a new and improved dosage form. A new dosage form allows a manufacturer to extend market exclusivity, while offering its patient population a more convenient dosage form or dosing regimen. In this regard, fast-dissolving/disintegrating tablet formulations are similar to many sustained release formulations that are now commonly available. An extension of market exclusivity, which can be provided by a fast-dissolving/disintegrating dosage form, leads to increased revenue, while also targeting underserved and undertreated patient populations. Although the cost to manufacture these specialized dosage forms exceeds that of traditional tablets, this additional cost is not being passed on to the consumer. Therefore, cost is generally not an issue when recommending these new dosage forms.
Pharmacists can expect to see an increase in the number of drug products available in FDDT formulations. (Currently available formulations are listed in TABLE 1.) Some pharmaceutical manufacturers have invested a great deal of resources into developing these FDDT technologies. Many of these tablets have been developed by a small number of innovator technology firms, thus enabling large manufacturers to enter into a contract with one of these firms to produce these new formulations, rather than designing a novel formulation and producing it in house via a new method.
Characteristics of Fast-Dissolving
FDDTs, as a novel dosage form, have several characteristics to distinguish them from the more traditional dosage forms. Taste-masking is of critical importance in the formulation of an acceptable FDDT. Traditional tablet formulations generally do not address the issue of taste masking, because it is assumed that the dosage form will not dissolve until passing the oral cavity. Many oral suspensions, syrups, and chewable tablets simply contain flavors, sugars and other sweeteners to overwhelm or complement the bitter taste of the drug.4
Current methods of taste masking in fast dissolving/disintegrating tablets include sweeteners and flavors; however, these are not a sufficient means for taste-masking many bitter drugs. Most of the FDDT technologies incorporate unique forms of taste masking as well. The primary methods of taste-masking include adsorption onto or complexation with carriers and spray coating of drug particles.1 Frequently, the active drug powder is coated, and the coating does not completely dissolve until the drug has been swallowed. Drugs that are particle-coated are more appropriately termed fast-disintegrating due to the delayed release of the active molecule until they are swallowed. Additionally, effervescence is a physical method of taste-masking utilized in some of the FDDTs.3 More detailed information on specific taste-masking procedures in fast-dissolving/disintegrating dosage forms is proprietary.
Currently, four fast-dissolving/disintegrating technologies have reached the U.S. market: Zydis (R.P. Scherer, Inc.),5-7 WOWTAB (Yamanouchi Pharma Technologies, Inc.)8, and OraSolv and DuraSolv (Cima Labs, Inc.).9,10 Three others are available outside the U.S.: FlashDose (Fuisz Technologies, Ltd.), Flashtab (Prographarm Group), and OraQuick (KV Pharmaceutical Co., Inc.).11 However, Biovail Corp. has recently filed an NDA for FDA approval for a FlashDose version of fluoxetine.12 Each technology has a different mechanism, and each fast-dissolving/disintegrating dosage form varies regarding the following:1
-Mechanical strength of
-Drug and dosage form stability;
-Rate of dissolution of drug formulation in saliva;
-Rate of absorption from the saliva solution; and
Specific properties of the various FDDT technologies are listed in TABLE 2.
For a tablet to be considered fast-dissolving/disintegrating, it must disintegrate in the saliva, while maintaining a pleasant taste and mouth feel, to allow maximal patient acceptability. Most of the fast dissolving tablet technologies use sugar-based excipients. Sugars are pleasant tasting, and are a good addition to other taste masking methods. They are also highly water soluble, and dissolve quickly in saliva. Many sugars also impart a pleasant mouth feel to the final product.1 However, because the amount of sugars in FDDTs is much smaller than in more traditional liquid dosage forms, these tablets can be used in children with poor oral hygiene or history of dental caries.
Table 2: Comparison of Fast-Dissolving/Disintegrating Technologies
|ZYDIS (R.P. SCHERER, INC.)|
|First to market||Do not push tablet through foil||Dissolves in 2 to 10 seconds|
|Freeze Dried||Do not use dosage form from damaged package||May allow for pre-gastric absorption leading to enhanced bioavailability|
|Sensitive to degradation at humidities >65%|
|ORASOLV (CIMA LABS, INC.)|
|Unique taste masking||Packaged in patented foil packs||Disintegrates in 5 to 45 seconds depending upon the size of the tablet|
|Lightly compressed||No significant change in drug bioavailability|
|DURASOLV (CIMA LABS, INC.)|
|Similar to Orasolv, but with better mechanical strength||Packaged in foil or bottles||Disintegrates in 5 to 45 seconds depending upon the size of the tablet|
|If packaged in bottles, avoid exposure to moisture or humidity||No significant change in drug bioavailability|
|WOWTAB (YAMANOUCHI PHARMA TECHNOLOGIES, INC.)|
|Compressed dosage form||Package in bottles||Disintegrates in 5 to 45 seconds depending upon the size of the tablet|
|Proprietary taste masking||Avoid exposure to moisture or humidity||No significant change in drug bioavailability|
|SMOOTHMELT action gives superior mouth feel|
Most FDDTs lack the mechanical strength common to traditional tablets. Many products are very lightweight and fragile requiring them to be individually packaged. Patients should be advised not to push these tablets through the foil film, but instead, peel the film back to release the fast-dissolving tablet. For these same reasons, it is essential that these product not be stored in backpacks of in the bottom of purses.
Due to the formulation of FDDTs, they are also more susceptible to degradation via temperature and humidity. Some of the newest FDDT formulations are dispensed in a conventional stock bottle. Pharmacists are advised to take care when dispensing such formulations to ensure they are not exposed to high levels of moisture or humidity. Excess handling of tablets can introduce enough moisture to initiate dissolution of the tablet matrix.3 As with most other drugs, patients should be advised to avoid storing FDDTs in the medicine cabinet in the bathroom. In particular, patients taking Zydis formulations should use them within six months of opening the laminated foil pouch and immediately after opening its individual blister packaging.3
Counseling Points for
Pharmacists are in the ideal position to become familiar with the different technologies, and educate their patients on what to expect upon taking their first dose. The majority of patients receiving FDDT preparations have little understanding of this new dosage form. Patients may be surprised when tablets begin to dissolve in the mouth. They might expect a faster onset of therapeutic action. Clarification from the pharmacist can avoid any confusion or misunderstanding. As with all dosage form technologies, some patient populations are better served by their use than others. Patients who concurrently take anticholinergic medications may not be the best candidates for these drugs. Similarly, patients with Sjögren's syndrome or dryness of the mouth due to decreased saliva production may not be good candidates for these tablet formulations. Although no water is needed to allow the drug to disperse quickly and efficiently, most technologies utilize the body's own salivation. Decreased volume of saliva may slow the rate of dissolution/disintegration and decrease the bioavailability of the product.
Although chewable tablets have been on the market for some time, they are not the same as the new FDDTs. Patients for whom chewing is difficult or painful can use these new tablets easily. FDDTs can be used easily in children who have lost their primary teeth, but do not have full use of their permanent teeth.
Patients may mistake fast-dissolving/disintegrating for effervescent tablets. Pharmacists may wish to stress the difference between the use of quick-dissolving and effervescent tablets. The Cima technologies, OraSolv and DuraSolv, use slight effervescence. Patients may experience a pleasant tingling on the tongue with OraSolv and DuraSolv.
Pharmacists have been alerted to exercise additional care when dispensing new prescriptions for FDDT formulations. Most such products are available in the same strengths as traditional dosage forms. Prescribing physicians must make an additional notation for the dispensing of a FDDT. A physician may also mistakenly believe the drug brand name is Zydis, for example, without identifying a specific drug.12 Verification with the prescribing practitioner may be necessary in some cases and can clear up any confusion.
There are not commercially available fast-dissolving/disintegrating products for all of our patients' needs. Pharmacists may wish to consider compounding as a unique way to treat the unmet needs of individual patients. When a manufactured FDDT is not available, compounding pharmacists can consider tablet triturates. These largely forgotten dosage forms have fast-disintegrating properties similar to many manufactured products.
All of the patients described earlier will benefit greatly from FDDT formulations. The elderly patient, for example, could be prescribed Remeron SolTab for depression. With a pharmacist's intervention and assistance, all of these patients could be more properly treated with greater convenience.
Characteristics of Fast-Dissolving Tablets
|ZYDIS (R.P. Scherer, Inc.)|
Zydis, the best known of the fast-dissolving/disintegrating tablet preparations, was the first marketed new technology tablet. The tablet dissolves in the mouth within seconds after placement on the tongue.5 Thirteen products are currently available using Zydis technology.4 In the U.S., they include: Claritin Reditab, Dimetapp Quick Dissolve, Feldene Melt, Maxalt-MLT, Pepcid RPD, Zofran ODT and Zyprexa Zydis. On the worldwide market, other Zydis formulations are available for oxazepam, lorazepam, loperamide, and enalapril.7
A Zydis tablet is produced by lyophilizing or freeze-drying the drug in a matrix usually consisting of gelatin. The product is very lightweight and fragile, and must be dispensed in a special blister pack. Patients should be advised not to push the tablets through the foil film, but instead peel the film back to release the tablet. The Zydis product is made to dissolve on the tongue in 2 to 3 seconds.3 The Zydis formulation is also self-preserving because the final water concentration in the freeze-dried product is too low to allow for microbial growth.3
The Zydis formulation utilizes flavors and sweeteners to optimize the taste of the dosage form. In addition, it utilizes microencapsulation with specialized polymers or complexation with ion exchange resins to mask the bitter tasting drug. The combination of lyophilization and taste masking creates a product that is both pleasing to the eye and also to the senses of taste and touch.3
A major claim of the Zydis product is increased bioavailability compared to traditional tablets.1 Because of its dispersion and dissolution in saliva while still in the oral cavity, there can be a substantial amount of pregastric absorption from this formulation. Buccal, pharyngeal and gastric regions are all areas of absorption of the Zydis formulation.3 Any pre-gastric absorption avoids first-pass metabolism and can be an advantage in drugs that undergo a great deal of hepatic metabolism. However, if the amount of swallowed drug varies, there is the potential for inconsistent bioavailability. While the claimed increase in bioavailability is debatable, it is clear that the major advantage of the Zydis formulation is convenience.
There are some disadvantages to the Zydis technology. The process of freeze-drying is a relatively expensive manufacturing process. As mentioned earlier, the Zydis formulation is very lightweight and fragile, and therefore should not be stored in backpacks or the bottom of purses. Finally, the Zydis formulation has poor stability at higher temperatures and humidities. It readily absorbs water, and is very sensitive to degradation at humidities greater than 65%.3 If there is any pinhole or minor damage to the package, the patient may find the lyophilized product has collapsed due to absorption of moisture. As with most other drugs, patients should be advised to avoid storing the Zydis technology in the medicine cabinet in the bathroom. Patients should use their Zydis formulation within six months of opening the laminated foil pouch and immediately after opening its individual blister packaging.5
|ORASOLV (Cima Labs, Inc.)|
OraSolv was Cima's first fast-dissolving/disintegrating dosage form. The OraSolv technology, unlike Zydis, disperses in the saliva with the aid of almost imperceptible effervescence. The OraSolv technology is best described as a fast-disintegrating tablet; the tablet matrix dissolves in less than one minute, leaving coated drug powder. The taste-masking associated with the OraSolv formulation is two-fold. The unpleasant flavor of a drug is not merely counteracted by sweeteners or flavors; both coating the drug powder and effervescence are means of taste-masking in OraSolv. This technology is frequently used to develop over-the-counter formulations.9 The major disadvantage of the OraSolv formulations is its mechanical strength. The OraSolv tablet has the appearance of a traditional compressed tablet. However, the OraSolv tablets are only lightly compressed, yielding a weaker and more brittle tablet in comparison with conventional tablets. For that reason, Cima developed a special handling and packaging system for OraSolv. An advantage that goes along with the low degree of compaction of OraSolv is that the particle coating used for taste masking is not compromised by fracture during processing. Lyophilization and high degrees of compression, as utilized in OraSolv's primary competitors, may disrupt such a taste masking approach.
The OraSolv technology is utilized in six marketed products: four Triaminic Softchew formulations, Tempra FirsTabs, and Remeron SolTab.
|DURASOLV (Cima Labs, Inc.)|
DuraSolv is Cima's second-generation fast-dissolving/disintegrating tablet formulation. Produced in a fashion similar to OraSolv, DuraSolv has much higher mechanical strength than its predecessor due to the use of higher compaction pressures during tableting. The DuraSolv product is thus produced in a faster and more cost-effective manner. DuraSolv is so durable that it can be packaged in either traditional blister packaging or vials.
The newest DuraSolv formulation, NuLev, is actually dispensed in a conventional stock bottle. Pharmacists are advised to take care when dispensing such DuraSolv formulations from stock bottles to ensure they are not exposed to high levels of moisture or humidity. Excess handling of tablets can introduce enough moisture to initiate dissolution of the tablet matrix.9
One disadvantage of DuraSolv is that the technology is not compatible with larger doses of active ingredients, because the formulation is subjected to such high pressures on compaction. Unlike OraSolv, the structural integrity of any taste masking may be compromised with high drug doses. The drug powder coating in DuraSolv may become fractured during compaction, exposing the bitter-tasting drug to a patient's taste buds. Therefore, the DuraSolv technology is best suited for formulations including relatively small doses of active compound.10 DuraSolv is currently available in two products: NuLev and Zomig ZMT.
|WOWTAB (Yamanouchi Pharma Technologies, Inc.)|
The WOWTAB fast-dissolving/disintegrating tablet formulation has been on the Japanese market for a number of years. It has just recently been introduced into the U.S. The WOWTAB technology utilizes sugar and sugar-like (e.g., mannitol) excipients. The two different types of saccharides are combined to obtain a tablet formulation with adequate hardness and fast dissolution rate.1 Due to its significant hardness, the WOWTAB formulation is a bit more stable to the environment than the Zydis or OraSolv. It is suitable for both conventional bottle and blister packaging. The taste masking technology utilized in the WOWTAB is proprietary, but claims to offer superior mouthfeel due to the patented SMOOTHMELT action.8
The WOWTAB product dissolves quickly in 15 seconds or less.8 The WOW in WOWTAB signifies the tablet is to be given With Out Water. Two WOWTAB formulations currently on the U.S. market are Benadryl Allergy & Sinus FASTMELT and Children's Benadryl Allergy & Cold FASTMELT.
|Other Technologies Not Yet on the U.S. Market|
FlashDose (Fuisz Technologies, Ltd.), Flashtab (Prographarm Group), and OraQuick (KV Pharmaceutical Co., Inc.) are three formulations on the worldwide market which will likely reach the United States in the near future. Biovail Corp. recently announced the filing of an NDA for a FlashDose version of zolpidem tartrate. These technologies are similar to Zydis, WOWTAB, OraSolv and DuraSolv in that they dissolve or disperse on the tongue within a minute. However, each also has unique characteristics to differentiate itself from the competition.
|FLASHDOSE (Fuisz Technologies, Ltd.)|
Fuisz Technologies has three oral drug delivery systems that are related to fast dissolution. The first two generations of quick-dissolving tablets, Soft Chew and EZ Chew, require some chewing. However, these paved the way for Fuisz's most recent development, FlashDose. The FlashDose technology utilizes a unique spinning mechanism to produce a floss-like crystalline structure, much like cotton candy. This crystalline sugar can then incorporate the active drug and be compressed into a tablet. This procedure has been patented by Fuisz and is known as Shearform. The final product has a very high surface area for dissolution. It disperses and dissolves quickly once placed onto the tongue.1
Interestingly, by changing the temperature and other conditions during production, the characteristics of the product can be altered greatly. Instead of a floss-like material, small spheres of saccharides can be produced to carry the drug. The process of making microspheres has been patented by Fuisz, and is known as CEFORM1 and serves as an alternative method of taste masking.
FLASHTAB (Prographarm Group)
The Flashtab technology is yet another fast-dissolving/disintegrating oral tablet formulation. It utilizes most of the same excipients as in conventional compressed tablets. A disintegrating agent and a swelling agent are used in combination with coated drug particles in this formulation to produce a tablet that disintegrates in the mouth in under one minute.1
|ORAQUICK (KV Pharmaceutical Co., Inc.)|
|The OraQuick fast-dissolving/disintegrating tablet formulation utilizes a patented taste masking technology. KV Pharmaceutical claims its microsphere technology, known as MicroMask, has superior mouthfeel over taste-masking alternatives.11 The taste masking process does not utilize solvents of any kind, and therefore leads to faster and more efficient production. Also, lower heat of production than alternative fast-dissolving/disinte-grating technologies makes OraQuick appropriate for heat-sensitive drugs. KV Pharmaceutical also claims that the matrix that surrounds and protects the drug powder in microencapsulated particles is more pliable, meaning tablets can be compressed to achieve significant mechanical strength without disrupting taste-masking. OraQuick claims quick dissolution in a matter of seconds, with good taste-masking.13 There are no products using the OraQuick technology currently on the market, but KV Pharmaceutical has products in development such as analgesics, scheduled drugs, cough and cold, psychotropics, and anti-infectives.|
1. Chang RK, Guo X, Burnside B, Couch R. Fast-Dissolving Tablets, Pharm Technol 2000; 24(6):52-58. 2. Habib W, Khankari R, Hontz J, Fast-Dissolve Drug Delivery System. Crit Rev Ther Drug Carrier Syst 2000;17:61-72. 3. Seager H. Drug-deliver Products and the Zydis Fast-dissolving Dosage Form. J Pharm and Pharmacol 1998; 50:375-382. 4. Anon. Flavors and Flavoring. Int J Pharm Compounding 1997; 1:90-92. 5. Schering Corporation. Product Information for Claritin Brand of Loratadine. September 2000. 6. Pharmalicensing.com. Zydis - A Fast Dissolving Dosage Form. 25 May 2001 http://www.pharmalicensing.com/licensing/displicopp/256. 7. Express Pharm Pulse. 23 November 2000. Melt-in-Mouth Tablets: Innovative oral drug delivery system. 27 May 2001 http://expresspharmapulse.pugmarks.net/php231100/ndds.html. 8. Yamanouchi Pharma Technologies, Inc. WOWTAB. 20 June 2001 http://www.ypharma.com/wowtab.shtml. 9. CIMA Labs, Inc. CIMA--Technologies. 25 May 2001 http://www.cimalabs.com/tech.htm. 10. Profile Resources at Business.com. Cima Labs - Profile. 27 May 2001 http://www.business.com/directory/pharmaceuticals/drug_delivery_systems/cima_labs. 11. KV Pharmaceutical Company. Drug Delivery Technologies (technical bulletin) found in part at KV Pharmaceutical Company. OraQuick. 27 May 2001 http://www.kvpharma.com/tech/3_1_oraquick.html and KV Pharmaceutical Company. Quick-Dissolving Tablets. 27 May 2001 http://www.kvpharma.com/tech/3_quick_dissolving_tablets.html. 12. Biovail Pharmaceuticals. Products. 22 Feb 2002 http://www.biovailpharm.com/products.shtml. 13. Proulx SM and Melchiorre HA. New Dosage Forms Lead to Confusion. US Pharm. 2001; 26(2):68-70.