FAST DISSOLVING DRUG DELIVERY SYSTEM
K M MuneefHH, Kathirvel
National College of Pharmacy, Manassery, Calicut
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. However, some patients, particularly pediatric and geriatric patients, have difficulty swallowing or chewing solid dosage forms1. Many pediatric and geriatric patients are unwilling to take these solid preparations due to fear of choking2. 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 patients3. Fast-dissolving drug delivery systems have rapidly gained acceptance as an important new way of administering drugs. There are multiple fast-dissolving OTC and Rx products on the market worldwide, most of which have been launched in the past 3 to 4 years. There have also been significant increases in the number of new chemical entities under development using a fast-dissolving drug delivery technology.
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.
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 form4,5.
The advantage of Fast Dissolving Dosage Forms are increasingly being recognized in both industry and academia6 Their growing importance was underlined recently when European Pharmacopoeia adopted the term "Orodispersible Tablet" as a tablet that to be placed in oral cavity where it disperses rapidly before swallowing7.
FIELD OF THE INVENTION
The present invention relates to a fast dissolving tablet comprising a pharmacologically active ingredient, such as a vitamin, antipyretic-analgesic-antiinflammatory agent, antihypertensive drug, psychotropic drug, antidiabetic drug or the like, and a carbohydrate, having an adequate strength and capable of dissolving and disintegrating at a high rate in the oral cavity and to a method of producing the tablet.
BACKGROUND OF THE INVENTION
Recently much research has been undertaken in the geriatric field ranging from the physiology of aging to the design of drugs and pharmaceutical preparations to daily care and assistance. According to, inter alia, the silver science research conducted by the Japanese Ministry of Health and Welfare, there is an interesting research report entitled `Studies for the construction of new pharmaceutical preparations and new packaging containers optimal for administration to elderly subjects` (Masayasu Sugihara, Tokyo Women's Medical College, and others) (Aug. 22, 1989 issue of the Yakuji Nippo). By way of illustration, as such new preparations, a) buccal dissolution type preparations, b) paste-like preparations and c) jelly-like preparations are described. Particularly, buccal dissolution type and paste-like preparations are claimed to be easy for elderly persons to ingest and excellent in stability.
The buccal dissolution type preparations, in particular, contain polyethylene glycol 1000 as the base which dissolves in the oral cavity and an oleaginous base as the base which melts at the temperature prevailing in the oral cavity and, in consideration of sensory factors such as taste and texture as well as moldability, further contain sucrose and mannitol. These are molded by filling the pocket of a vinyl chloride molding sheet for pressthrough package (PTP) use with a heat-melted medicated base and allowing it to cool and take form. In this manner, a buccal dissolution type solid preparation for elderly persons is manufactured.
ADVANTAGES OF FDT
1. Improved patient compliance 2. Rapid onset of action and may offer an improved bioavailability. 3. Patient having difficulty in swallowing tablet can easily administer this type of dosage form 4. Useful fro pediatric, geriatric and psychiatric patients 5. Suitable during traveling where water is may not be available 6. Gives accurate dosing as compared to liquids 7. Good chemical stability. 8. Free of need of measuring, an essential drawback in liquids.
SALIENT FEATURES OF FAST DISSOLVING DRUG DELIVERY SYSTEM8-12
- Ease of administration for patients who are mentally ill, disabled and uncooperative.
- Requires no water
- Quick disintegration and dissolution of the dosage form.
- Overcomes unacceptable taste of the drugs.
- Can be designed to leave minimal or no residue in the mouth after administration and also to provide a pleasant mouth feel.
- Allows high drug loading.
- Ability to provide advantages of liquid medication in the form of solid preparation.
- Adaptable and ameanable to existing processing and packaging machinery
- Cost- effective
CHARACTERISTICS OF FAST DISSOLVING DELIVERY SYSTEMS13
1. Ease of Administration:
Fast Dissolving Delivery Systems are easy to administer and handle hence, leads to better patient compliance. Usually, elderly people experience difficulty in swallowing the conventional dosage forms (tablets, capsules, solutions and suspensions) because of tremors of extremities and dysphasia. Fast Dissolving Delivery Systems may offer a solution for these problems.
2. Taste of the Medicament:
As most drugs are unpalatable, mouth dissolving delivery systems usually contain the medicament in taste masked form. Delivery systems dissolve or disintegrate in patient's mouth, thus releasing the active ingredients which come in contact with the taste buds and hence, taste masking of the drugs becomes critical to patient compliance.
Several fast dissolving dosage forms are hygroscopic and cannot maintain physical integrity under normal condition from humidity which calls for specialized product packaging14.
In order to allow fast dissolving tablets to dissolve in the mouth, they are
made of either very porous and soft- moulded matrices or compressed into tablets with very low compression force, which makes the tablets friable and/or brittle which are difficult to handle, often requiring specialized peel-off blister packaging. To overcome this problem, some companies introduced more robust forms of fast dissolving tablets.
5. Mouth feel15,16:
Mouth feel is critical, and patients should receive a product that feels pleasant. Any large particles from the disintegrating tablet that are insoluble or slowly soluble in saliva would lead to an unpleasant gritty feeling. This can be overcome by keeping the majority of the particles below the detectable size limit. In some cases, certain flavors can imbibe an improved mouth feel perception, resulting in a product that is perceived as being less gritty, even if the only change is the flavor. Effervescence can be added to aid disintegration and improve mouth feel by reducing the "dryness" of a product.
APPROACHES FOR FAST DISSOLVING TABLETS
The fast-dissolving property of the tablet is attributable to a quick ingress of water into the tablet matrix resulting in its rapid disintegration. Hence, the basic approaches to developing fast dissolving tablets include maximizing the porous structure of the tablet matrix, incorporating the appropriate disintegrating agent, and using highly water-soluble excipients in the formulation.
CONVENTIONAL TECHNIQUES USED IN THE PREPARATION OF FAST DISSOLVING DRUG DELIVERY SYSTEMS
Various technologies used in the manufacture of Fast dissolving tablets include
- Freeze –drying or lyophilization
- Tablet Molding
- Direct compression
- Spray drying
- Taste masking
- Mass extrusion
a). Freeze drying or Lyophilization20
A process in which water is sublimated from the product after freezing. Lyophilization is a pharmaceutical technology which allows drying of heat sensitive drugs and biologicals at low temperature under conditions that allow removal of water by sublimation21. Lyophilization results in preparations, which are highly porous, with a very high specific surface area, which dissolve rapidly and show improved absorption and bioavailability. Jaccard and Leyder used lyophilization to create an oral pharmaceutical preparation that not only dissolve rapidly but also improved the bioavailability of several drugs such as spironolactone and trolendomycin22. Corveleyn and Remon studied various formulation and process parameters by using hydrochlorthiazide as a model drug23 on the basis of which US Patent 6,010,719 was granted24. Tablets prepared by lyophilization, are fragile and possess low mechanical strength, which make them difficult to handle and they also exhibit poor stability on storage under stressed conditions.
Tablet produced by moulding are solid dispersion. Moulded tablets disintegrate more rapidly and offer improved taste because the dispersion matrix is in general made from water soluble sugars. The active ingredients in most cases is absorbed through the mucosal lining of the mouth. The manufacturing process of molding tablets involves moistening the powder blend with a hydroalcoholic solvent followed by pressing into mold plates to form a wetted mass (compressing molding). The solvent is then removed by air drying. Thus the process is similar to what is used in the manufacture of tablet triturates. Such tablets are less compact than compressed tablets and possess a porous structure that hastens dissolution.
Molded forms are also prepared using a heat-molding process that involves setting the molten mass that contains a dispersed drug25. The heat-molding process uses an agar solution as a binder and a blister packaging well as a mold to manufacture a tablet. The process involves preparing a suspension that contains a drug, agar, and sugar (e.g., mannitol or lactose), pouring the suspension into the blister packaging well, solidifying the agar solution at room temperature to form a jelly, and drying at -300C under vacuum. Another process used is called
no-vacuum lyophilization, which involves the evaporation of a solvent from a drug solution or suspension at standard pressure. Pebley et al., evaporated a frozen mixture containing a gum (e.g., acacia, carageenan, guar, tragacanth, or xanthan), a carbohydrate (e.g., dextrose, lactose, maltose, mannitol, or maltodextrin), and a solvent in a tablet shaped mould26. Moulded tablets typically do not possess great mechanical strength. Erosion and breakage of the moulded tablet often occur during handling and opening of blister packs.
c. Spray drying
Spray drying is a process by which highly porous, fine powders can be produced. Spray-dryers are invariably used in the pharmaceutical industry to produce highly porous powders. Allen et al. have reported applying this process to the production of fast dissolving tablets27-30. The formulations that were produced contained hydrolyzed and unhydrolyzed gelatin as a support agent for the matrix, mannitol as a bulking agent, and sodium starch glycolate or crosscarmellose as a disintegrant. Disintegration and dissolution was further enhanced by adding an acid (e.g., citric acid) or an alkali (e.g., sodium bicarbonate). The formulation was spray dried to yield a porous powder. Tablets manufactured from this powder disintegrated in less than 20 s in an aqueous medium.
The key to rapid disintegration for mouth dissolving tablets is the presence of a porous structure in the tablet matrix. Conventional compressed tablets that contain highly water-soluble ingredients often fall to dissolve rapidly because of low porosity of the matrix. Hence. To generate porous matrix, volatile ingredients are used that are later subjected to a process of sublimation. In studies conducted by Heinemann and Rothe, Knitsch et al., and Roser and Blair, inert solid ingredients that displayed high volatility (e.g., ammonium bicarbonate, ammonium carbonate, benzoic acid, camphor, hexamethonium tetramine, naphthalene, phthalic anhydride, urea, and urethane were compressed along with other excipients into a table31-33. The volatile material was then removed by sublimation, leaving behind a porous matrix. Solvents such as cyclohexane and benzene were also suggested for the generation of porosity in the matrix. Koizumi et al. applied sublimation technology to manufacture tablets that rapidly dissolve in saliva34. Mannitol is used as a matrix former, and camphor was used as a sublimating agent. The tablets dissolved in 10-20 s and displayed satisfactory handling properties. Makino et al. reported a method using water as pore-forming material35. A mixture of drug and a carbohydrate (e.g., erythritol, glucose, maltitol, sucrose, xylitol). The water was then removed, yielding highly porous tablets with satisfactory mechanical strength and a high dissolution rate.
e. Direct compression
It is the easiest way to manufacture tablets. Conventional equipment, commonly available excipients and a limited number of processing steps are involved in direct compression. Also high doses can be accommodated and final weight of tablet can easily exceed that of other production methods. This technique can now be applied to fast dissolving tablets because of the availability of improved tablet excipients, especially tablet disintegrants and sugar-based excipients.
EXCIPIENTS OF FDDTs
Addition of Disintegrants
Addition of disintegrants in fast dissolving tablets, leads to quick disintegration of tablets and hence improves dissolution. In many fast dissolving tablet technologies based on direct compression, the disintegrants principally affect the rate of disintegration and hence the dissolution. The introduction so-called superdisintegrants and a better understanding of their properties have increased the popularity of this technology36. Tablet disintegration time can be optimized by concentrating the disintegrants. Below critical concentration, tablet disintegration time is inversely proportional to disintegrants concentration. Above the critical concentration level, however, disintegration time remains approximately constant or even increases37.
Microcrystalline cellulose, cross linked carboxymethyl cellulose sodium, cross linked polyvinyl pyrrolidone and partially substituted hydroxypropyl cellulose, though water insoluble, absorb water and swell due to capillary action and are considered as effective disintegrants in the preparation of first dissolving tablets.
Bi et al.38 and Watanbe et al.,39
used microcrystalline cellulose (MCC) and low substituted hydroxypropyl cellulose (HPC) to manufacture rapidly disintegrating tablets. The ratios of MCC to HPC varied from 8:2 to 9:1. Ito and Sugihan investigated applying agar powder as a disintegrants because the powder absorbs water and swells considerably without forming a gel at physiological temperatures40.
Fast disintegration of tablets can also be achieved by incorporating effervescent disintegrating agents, which generates carbon dioxide. This phenomenon also resulted in partial taste masking of unacceptable taste of the drug41. The major drawback of effervescent excipients is their hygroscopicity (i.e., the ability to absorb atmospheric moisture). Hence, their manufacture requires control of humidity conditions and protection of the final product. This is reflected by the overall cost of the product.
Another approach to fast dissolving tablets by direct compression is the use of sugar-based excipients (e.g., dextrose, fructose, isomalt, maltitok, maltose, mannitol, sorbitol, starch hydrolyse, polydextrose, and xylitol), which display high aqueous solubility and sweetness, and hence, impart taste masking and a pleasing mouthfeel.
Taste masking is an essential requirement for fast dissolving tablets for commercial success. Taste masking of the active ingredients can be achieved by various techniques. Drugs with unacceptable bitter taste can be microencapsulated into pH sensitive acrylic polymers42. Cefuroxime axetil is microencapsulated in various types of acrylic polymers (e.g., Eudragit E, Eudragit L-55 and Eudragit RL) by solvent evaporation and solvent extraction techniques.
These polymer microspheres showed efficient taste masking and complete dissolution in a short period. Fine granules of drug and disintegrant (e.g. low substituted hydroxypropyl cellulose) when coated with a water insoluble polymer (e.g. ethylcellulose) masked the bitter taste of sparfloxacin43. The addition of low substituted hydroxypropyl cellulose as disintegrant to the drug in cores, resulted in increased dissolution rate and bioavailability of sparfloxacin compared to its conventional tablets 44.
Ozer and Hincal45 reported a simple coacervation method using gelatin, and anhydrous sodium sulphate as coacervating agent for taste making of beclamide. Beclamide is an anti-epileptic drug with unpleasant taste. It is microencapsulated into gelatin, with sodium sulphate as coacervating agent, and glutaraldehyde as hardening agent. The microcapsules after formation are dehydrated using alcohol. The core: wall substance ratio was 1:1, and the taste could be successfully masked.
A novel technique for taste masking of macrolides (e.g. erythromycin and clarithromycin) is reported by Yajima et al, 46. Monoglycerides having a low melting point which can form good elaborate film, and easily soluble in intestine, and polymers which are insoluble in the mouth (pH 5-8), but are freely soluble in stomach (pH 1-4), are selected for taste masking of drugs with unpleasant taste. The polymer is dissolved or dispersed in monoglyceride, and the drug is granulated with above mixture and the resultant granules are cooled.
This technology involves softening the active blend using the solvent mixture of water soluble polyethylene glycol, using methanol and expulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments using heated blade to form tablets. The dried cylinder can also be used to coat granules of bitter tasting drugs and thereby masking their bitter taste.
ENHANCEMENT OF DISSOLUTION PROFILE BY SOLID DISPERSION
Valdecoxib, 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide, a novel COX-2 inhibitor, is a potent nonsteroidal anti-inflammatory drug that is indicated for amenorrhea and various osteopathic and inflammatory conditions.1 Although it has excellent oral bioavailability (87%), its poor aqueous solubility (10 μg/mL, 25°C) makes its absorption dissolution rate limited and thus delays onset of action. Solid dispersion, which was introduced in the early 1970s,2 is essentially a multicomponent system, having drug dispersed in and around hydrophilic carrier(s).
Solid dispersion technique has been used for a wide variety of poorly aqueous soluble drugs such as nimesulide,3 ketoprofen,4 tenoxicam,5 nifedipine,6 nimodipine,7 ursodeoxycholic acid,8 and albendazole.9 Various hydrophilic carriers, such as polyethylene glycols,10 polyvinylpyrrolidone,11 hydroxypropyl methylcellulose,12 gums,7 sugar,13 mannitol,14 and urea,8 have been investigated for improvement of dissolution characteristics and bioavailability of poorly aqueous-soluble drugs.
Polyvinylpyrrolidone (PVP) has been used for the preparation of solid dispersion as a component of the binary system for various drugs such as sulindac,15 fenofibrate,16 tenoxicam,5 tacrolimus,17 and flurinazine.18
The present work aims to evaluate the potential of the solid dispersion technique for development of fast-dissolving tablets of valdecoxib using PVP as the hydrophilic carrier. Furthermore, the study undertakes to investigate kneading as a method for preparation of such binary systems, their solid-state characterization, interaction in the liquid state, and attempts to see the possible mechanism of improved dissolution rate.
MATERIALS AND METHODS
Valdecoxib (VALD) was a gift sample from Ajanta Pharma (Mumbai, India). Polyvinyl pyrrolidone (PVP-K30) was kindly provided by BASF India (Mumbai). All reagents and solvents used were of analytical grade.
Preparation of PVP-VALD Solid Dispersion
A mixture of PVP and VALD (1:1 and 1:2 by weight) was wetted with water and kneaded thoroughly for 30 minutes in a glass mortar. The paste formed was dried under vacuum for 24 hours. Dried powder was passed through sieve no. 60 and stored in a dessicator until further evaluation.
Physical mixtures (PM) were obtained by pulverizing in a glass mortar and carefully mixing accurately weighed (1:1 and 1:2 by weight) amounts of VALD and PVP.
For convenience, all binary systems were given a code name, which is summarized in Table 1.
Table 1. Percentage Dissolution and Dissolution Efficiency of Valdecoxib From Different Binary Systems in Comparison With Original Drug
10.18 ± 0.25
8.51 ± 0.74
11.89 ± 0.42
23.22 ± 1.06
23.43 ± 0.53
39.04 ± 2.42
38.48 ± 5.97
39.41 ± 3.16
62.74 ± 2.93
69.89 ± 3.42
67.46 ± 0.57
90.8 ± 0.14
86.80 ± 0.42
80.03 ± 1.39
98.53 ± 2.99
Advantages of Mouth dissolving tablets
- Improved patient compliance 2. Rapid onset of action and may offer an improved bioavailability. 3. Patient having difficulty in swallowing tablet can easily administer this type of dosage form 4. Useful fro pediatric, geriatric and psychiatric patients 5. Suitable during traveling where water is may not be available 6. Gives accurate dosing as compared to liquids 7. Good chemical stability. 8. Free of need of measuring, an essential drawback in liquids
FORMULATION DESIGN AND OPTIMIZATION OF MOUTH DISSOLVING TABLETS
The tablet is the most widely used dosage form because of its convenience in terms of self-administration, compactness, and ease in manufacturing. However, geriatric and pediatric patients experience difficulty in swallowing conventional tablets, which leads to poor patient compliance.
To overcome this weakness, scientists have developed innovative drug delivery systems known as "melt in mouth" or "mouth dissolve (MD)" tablets. These are novel types of tablets that disintegrate/dissolve/disperse in saliva. Their characteristic advantages such as administration without water, anywhere, anytime lead to their suitability to geriatric and pediatric patients. They are also suitable for the mentally ill, the bed-ridden, and patients who do not have easy access to water. The benefits, in terms of patient compliance, rapid onset of action, increased bioavailability, and good stability make these tablets popular as a dosage form of choice in the current market.1,2
The basic approach used in the development of the fast-dissolving tablet is the use of superdisintegrants. Croscarmellose sodium, sodium starch glycolate, and crospovidone were screened in the present study, and the best one was used for further studies. Another approach used in developing MD tablets is maximizing pore structure of the tablets. Freeze-drying3,4 and vacuum-drying5-7 techniques have been tried by researchers to maximize the pore structure of tablet matrix. Freeze drying is cumbersome and it yields a fragile and hygroscopic product. Therefore, it was decided to adopt the vacuum-drying technique in the present investigation. Vacuum drying was adopted after addition of a subliming agent to increase porosity of the tablets. It is likely that a porous hydrophilic matrix will easily pick up the disintegrating medium and break quickly.
PATENTED TECHNOLOGIES FOR FAST DISSOLVING TABLETS
Some patented technologies are described here. Each technology has a different mechanism, and each fast-dissolving/disintegrating dosage form varies regarding the following48:
-Mechanical strength of final product;
-Drug and dosage form stability;
-Rate of dissolution of drug formulation in saliva;
-Rate of absorption from the saliva solution; and
- Zydis Technology
- Durasolv Technology
- Flash Dose Technology
- Wowtab Technology
- Flashtab Technology
- Oraquick Technology
- Quick –Dis Technology
- Nanocrystal Technology
Using concept of Gregory et al.51 Scherer has patented the Zydis technology. 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. 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.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. A major claim of the Zydis product is increased bioavailability compared to traditional tablets.
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.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. The amount of drug that could be incorporated should generally be less than 60 mg for soluble drugs.
The partical size of the insoluble drugs should be less than 50mm and not more than 200mm to prevent sedimentation during processing52. 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%.
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. 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.
c. Orasolv Technology
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. DuraSolv tablets are prepared by using conventional tabletting equipment and have good rigidity(friability less than that 2%). 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, pouches or vials.
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.
d.Flash Dose Technology
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.
Flash dose tablets consists of self–binding shearform matrix termed as "floss". Shearform matrices are prepared by flash heat processing and are of two types. ØSingle floss or Unifloss, consisting of a carrier, and two or more sugar alcohols, of which one is xylitol.
Dual floss consists of a first shearform carrier material (termed "base floss", contains a carrier and at least one sugar alcohol generally sorbitol), and a second shearform binder matrix ("binder floss", contains a carrier and xylitol). 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 CEFORM and serves as an alternative method of taste masking.
The Wowtab fast-dissolving/disintegrating tablet formulation has been on the Japanese market for a number of years. Wowtab technology is patented by Yamanouchi Pharmaceutical Co. The WOW in Wowtab signifies the tablet is to be given "With Out Water". It has just recently been introduced into the U.S. The Wowtab technology utilizes sugar and sugar-like (e.g., mannitol) excipients. This process uses a combination of low mouldability saccharides (rapid dissolutio) and high mouldability saccharide(good binding property).The two different types of saccharides are combined to obtain a tablet formulation with adequate hardness and fast dissolution rate.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. The Wowtab product dissolves quickly in 15 seconds or less.
f. Flashtab Technology
Prographarm laboratories has patented the Flashtab technology56. This technology involves the preparation of rapidly disintegrating tablet which consists of an active ingredient in the form of microcystals. Drug microgranules may be prepared by using the conventional techniques like coacervation, extrusion-spheronization, simple pan coating methods and microencapsulation. The microcrystals of microgranules of the active ingredient are added to the granulated mixture of excipients prepared by wet or dry granulation, and compressed into tablets. All the processing utilized the conventional tabletting technology, and the tablets produced are reported to have good mechanical strength and disintegration time less than one minute.
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 alternatives57. 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..
h. Quick –Dis Technology
Lavipharm Laboratories Inc. (Lavipharm) has invented an ideal intraoral fast-dissolving drug delivery system, which satisfies the unmet needs of the market(Table 3). The novel intraoral drug delivery system, trademarked Quick-Dis™, is Lavipharm's proprietary patented technology and is a thin, flexible, and quick-dissolving film. 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 and/or systemic absorption. The Quick-Dis™ drug delivery system can be provided in various packaging configurations, ranging from unit-dose pouches to multiple-dose blister packages.
The typical disintegration time, which is defined as the time at which the film begins to break when brought into contact with water, is only 5 to 10 seconds for the Quick-Dis™ film with a thickness of 2 mm. The dissolving time, which is defined as the time at which not less than 80% of the tested film is dissolved in aqueous media, is around 30 seconds for Quick Dis™ film with a thickness of 2 mm. The typical release profile of an active ingredient exhibited by a Quick-Dis™ drug delivery system is 50% released within 30 seconds and 95% within 1 minute.
For fast dissolving tablets, Elan's proprietary NanoCrystal technology can enable formulation and improve compound activity and final product characteristics. Decreasing particle size increases the surface area, which leads to an increase in dissolution rate. This can be accomplished predictably and efficiently using NanoCrystal technology. NanoCrystal particles are small particles of drug substance, typically less than 1000 nanometers (nm) in diameter, which are produced by milling the drug substance using a proprietary wet milling technique
NanoCrystal colloidal dispersions of drug substance are combined with water-soluble GRAS (Generally Regarded As Safe) ingredients, filled into blisters, and lyophilized. The resultant wafers are remarkably robust, yet dissolve in very small quantities of water in seconds. This approach is especially attractive when working with highly potent or hazardous materials because it avoids manufacturing operations (e.g., granulation, blending, and tableting) that generate large quantities of aerosolized powder and present much higher risk of exposure. The freeze-drying approach also enables small quantities of drug to be converted into ODT dosage forms because manufacturing losses are negligible.
Table 2: Some Patented Technologies For Fast Dissolving Tablets
CIMA Labs Inc.
R. P. Scherer, Inc.
Freeze dried Wafers
Fuisz Technology, Ltd.
Cotton –candy Process
Table 3: Comparison of Fast Dissolving Techniques
ZYDIS (R.P. SCHERER, INC.)
First to market
Do not push tablet through foil
Dissolves in 2 to 10 seconds
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
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
FLASHDOSE (Fuisz Technologies, Ltd.)
Unique spinning mechanism to produce a floss-like crystalline structure, much like cotton candy
Avoid exposure to moisture or humidity
Dissolves within 1 minute
Require specialized packaging
FLASHTAB (Prographarm Group)
Compressed dosage form containing Drug as microcrystals
Avoid exposure to moisture or humidity
Dissolves within 1 minute
EVALUATION OF FAST MOUTH DISSOLVING TABLETS OF TERBUTALINE SULPHATE
(A) General Appearance And Physical Parameters
a) Thickness of Tablets
The thickness of six tablets was measured using Vernier calipers. The
extent to which the thickness of each tablet deviated from ± 5% of the standard
value was determined.
b) Taste, Colour, Odour of Tablets
Organoleptic properties such as taste, colour, odour were evaluated. Ten tablets from each batch were randomly selected and taste tested, colour visually compared and odour checked.
c) Hardness and Friability of Tablets
The Tablet was determined by Monsanto Hardness Tester. The tester consists of a barrel containing a compressible spring held between two plungers. The lower plunger is placed in contact with the tablet, and a zero reading is taken. The upper plunger is then forced against a spring by turning a threaded bolt until the tablet fractures. As the spring is compressed, a pointer rides along a gauge in the barrel to indicate the force. zero reading is deducted from it. Six tablets from each batch were selected and evaluated, and the average value with standard deviation was recorded.
Tablets was performed in a Roche Friabilator. It consists of a plastic chamber that revolves at 25 rpm. About ten tablets were weighed together and then placed in the chamber. The friabilator was operated for 100 revolutions and the tablets were subjected to the combined effects of abrasion and shock because the plastic chamber carrying the tablets drops them at a distance of six inches with every revolution. The tablets are then dusted and re-weighed
d) Wetting Time of Tablets
A piece of tissue paper folded twice was placed in a small petridish (Internal Diameter = 6.5 cm) containing 6 ml of simulated saliva pH (Phosphate buffer pH 6.8). A tablet was put on the paper, and the time required for complete wetting was measured. Six trials for each batch were performed; average time for wetting with standard deviation was recorded.
e) Moisture Uptake by the Tablets
Ten tablets from each formulation were kept in a desiccator, over calcium chloride at 37ºC for 24 hours. The tablets were then weighed and exposed to 75% RH, at room temperature for two weeks in the dessicator. Required humidity was achieved by keeping saturated Sodium chloride solution at the bottom desiccator for three days. Tablets were re-weighed and the percentage increase in the weight was recorded in each days.
(B) Drug Content and Release Studies
- Assay of Pooled Sample of Tablets
As in IP ,twenty tablets were weighed and powdered. A quantity of powder equivalent to 5mg of Terbutaline sulphate was accurately weighed and transferred into a 50 ml volumetric flask, added 30 ml of distilled water. After shaking for 10 minutes, the volume was made upto 50 ml. The solution was filtered, first 5 ml of the filtrate was rejected, and after suitable dilution (here10 times), the sample was analyzed spectrophotometrically at 276.0 nm and the percentage of Terbutaline Sulphate in the solution was determined.
b) Weight Variation and Uniformity of Drug content.
Weight variation test :
Uniformity of weight test as described in the IP was followed. Twenty tablets were selected at random and average weight was determined. Then individual tablets were weighed and the individual weight was compared with the average weight. The percentage deviation was calculated and checked for weight variation. Using this procedure weight variation range of all batches of formulations were determined and recorded.
Uniformity of drug content:
Uniformity of drug content test as described in the IP was followed. One tablet was powdered and transferred to a 25 ml volumetric flask. 15 ml of distilled water was added and the mixture shaken for 10 minutes. The volume was made up and filtered. The first 5 ml of the filtrate was rejected, and after suitable dilution (here 10 times) the sample was analyzed spectrophotometrically at 276.0 nm, and the drug was determined. This test was carried out individually for five tablets from each batch of formulations and the drug content range of five from minimum to maximum was recorded.
f) In-vitro Dissolution Studies
In-vitro dissolution study was performed by using USP Type II Apparatus (Paddle type) [Electrolab (TDT-06T) Tablet Dissolution Tester] at 100 rpm. Distilled water 900 ml was used as dissolution medium, and the temperature of which maintained at 37 ± 0.5ºC. Aliquots of dissolution medium (10 ml) was withdrawn at specific time intervals (3 minutes) and was filtered and the first 5 ml of the filtrate was rejected. The amount of drug dissolved was determined by UV spectrophotometer by measuring the absorbance of the sample at 276.0 nm. Three trials for each batch were performed and average percentage drug release with standard deviation was calculated and recorded. .
COUNSELING POINTS FOR FDDTS
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
Besides delivering drug to the body, a drug delivery system aim to improve patient compliance and convenience, and fast dissolving tablets are no exception. The introduction of fast dissolving dosage forms has solved some of the problems encountered in administration of drugs to the pediatric and elderly patient, which constitutes a large proportion of the world's population. Hence, patient demand and the availability of various technologies have increased the market share of Fast dissolving tablets, which in turn prolongs the patent life of a drug. Keeping in view of the advantages of the delivery system, rapidly disintegrating dosage forms have been successfully commercialized, and because of increased patient demand, these dosage forms are expected to become more popular.
Seager, H., " Drug-deliver Products and the Zydis Fast-dissolving Dosage Form", J. Pharm. and Pharmacol., 1998, 50, 375-382.
Habib W, Khankari R, Hontz J., "Fast-dissolving Drug Delivery Systems", Critical Reviews TM Therapeutic Drug Carrier Systems, 2000, 17(1), 61-72.
Parakh, S. R. and Gothoskar, A. V., Pharma. Tech., November 2003, 92- 100.
Kuchekar, B. S., Badhan, A. C., Mahajan, H. S., Pharma Times, June 2003, 35, 7-9.
Lalla, J. K. and Sharma, A. H., Indian Drugs, 1994, 31(11), 503-508.
CIMA Labs, Inc. CIMA--Technologies. 25 May 2001 http://www.cimalabs.com/tech.htm
Profile Resources at Business. com. Cima Labs - Profile. 27 May 2001 http://www.business.com/directory/pharmaceuticals_and_biotechnology/drug_delivery_systems/cima_labs/
Yamanouchi Pharma Technologies, Inc. WOWTAB. 20 June 2001 http://www.ypharma.com/wowtab.shtml
Corveleyn, S. and Remon, J.P., " Formulation and Production of Rapid Disintegrating Tablets by Lyophilization using Hydrochlorthiazide as a Model Drug", Int. J. Pharm., 1997, 152, 215-225.
Corveleyn, S. and Remon, J.P., " Freeze- Dried Disintegrating Tablets", US patent No., US6 010719. 2000.
Masaki, K., " Intrabuccally Disintegrating Preparation and Production Thereof", US patent No., US5466464, 1995.
Pabley, W.S., Jager, N.E. and Thompson S.J., "Rapidly Disintegrating Tablet", US patent No., US5298261, 1994.
. European Directorate for quality of Medicines, Pharmaeuropa, 1998, 10(4), 547.
Reddy, L. H., Ghose, B. and Rajneesh, Indian J. Pharm. Sci., 2002, 64(4): 331- 336.
Kuchekar, B. S. and Arumugam, V., Indian J. Pharm. Edu., 2001, 35, 150.
Bhaskaran, S., and Narmada, G. V., Indian Pharmacist, 2002, 1(2), 9-12.
Indurwade, N. H., Rajyaguru, T. H. and Nakhat, P. D., Indian Drugs, 2002, 39(8), 405-09.