FAST DISSOLVING DRUG DELIVERY SYSTEM

INTRODUCTION

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 patients 3. 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.
DEFINITION
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.

3. Hygroscopicity:

Several fast dissolving dosage forms are hygroscopic and cannot maintain physical integrity
under normal condition from humidity which calls for specialized product packaging14.

4. Friability:

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

1. Freeze drying or lyophilization
2. Tablet Molding

3. Direct compression

4. Spray drying

5. Sublimation

6. Taste masking

7. 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 sublimation 21. 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 trolendomycin 22.
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 granted 24.
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.

b. Molding

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 mould 26. 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 tablets 27-30. 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.

d. Sublimation

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 table 31-33. 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 technology 36. 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.

Sugar-based Excipients

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
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 polymers 42.
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.

Mass Extrusion47
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

Description
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 g/mL, 25C) 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
Materials
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.

Methods
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

System DP5 DE15 DE60

VALD 10.18 0.25 8.51 0.74 11.89 0.42

PM1 23.22 1.06 23.43 0.53 39.04 2.42
PM2 38.48 5.97 39.41 3.16 62.74 2.93
SD1 69.89 3.42 67.46 0.57 90.8 0.14
SD2 86.80 0.42 80.03 1.39 98.53 2.99

Advantages of Mouth dissolving tablets

 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

FORMULATION DESIGN AND OPTIMIZATION OF MOUTH

DISSOLVING TABLETS

Description
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;

-Mouth feel;

-Rate of dissolution of drug formulation in saliva;

-Swallowability;

-Rate of absorption from the saliva solution; and

-Overall bioavailability.

Various Technologies

1.

Zydis Technology

2.

Durasolv Technology

3.

Orasolv Technology

4.

Flash Dose Technology

5.

Wowtab Technology

6.
 Flashtab Technology

7.

Oraquick Technology

8.

Quick Dis Technology

9.

Nanocrystal Technology

a.Zydis 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%.

b.Durasolv Technology
 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 selfbinding shearform matrix termed as "floss". Shearform
matrices are prepared by flash heat processing and are of two types. Single 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.

e.Wowtab Technology

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.
g.Oraquick Technology

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.

i.Nanocrystal Technology

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

Technology Company's Name Technology Base

Durasolv, Orasolv CIMA Labs Inc. Molding
Flash Tab Ethypharm Molding
Wow Tab Yamanouchi pharma Molding
Zydis R. P. Scherer, Inc. Freeze dried Wafers
Flash Dose Fuisz Technology, Ltd. Cotton candy Process
Ziplets Eurand Molding
Fast Melt Elan Corp. Molding

Table 3: Comparison of Fast Dissolving Techniques

ZYDIS (R.P. SCHERER, INC.)

Novelty Handling/Storage Drug Release/Bioavailability
Do not push tablet through
First to market Dissolves in 2 to 10 seconds
foil
Do not use dosage form May allow for pre-gastric absorption
Freeze Dried
from damaged package leading to enhanced bioavailability
Sensitive to degradation at
humidities >65%
ORASOLV (CIMA LABS, INC.)
 Novelty Handling/Storage Drug Release/Bioavailability
Packaged in patented foil Disintegrates in 5 to 45 seconds
Unique taste masking
packs depending upon the size of the tablet
No significant change in drug
Lightly compressed
bioavailability
DURASOLV (CIMA LABS, INC.)
Novelty Handling/Storage Drug Release/Bioavailability
Similar to Orasolv, but
Disintegrates in 5 to 45 seconds
with better mechanical Packaged in foil or bottles
depending upon the size of the tablet
strength
 If packaged in bottles, avoid
No significant change in drug
exposure to moisture or
bioavailability
humidity
WOWTAB (YAMANOUCHI PHARMA TECHNOLOGIES, INC.)
Novelty Handling/Storage Drug Release/Bioavailability
Disintegrates in 5 to 45 seconds
Compressed dosage form Package in bottles depending upon the size of the
tablet
Avoid exposure to moisture No significant change in drug
Proprietary taste masking
or humidity bioavailability
FLASHDOSE (Fuisz Technologies, Ltd.)
Novelty Handling/Storage Drug Release/Bioavailability
Unique spinning mechanism to
produce a floss-like crystalline Avoid exposure to moisture
Dissolves within 1 minute
structure, much like cotton or humidity
candy
Require specialized
Enhanced bioavailability
packaging
FLASHTAB (Prographarm Group)
Novelty Handling/Storage Drug Release/Bioavailability
Compressed dosage form
Avoid exposure to moisture
containing Drug as Dissolves within 1 minute
or humidity
microcrystals
 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

Hardness
 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.

Friability

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 37C 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

1. 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.
50

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 0.5C. 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 Sjgren'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

CONCLUSION
 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.

REFERENCES

1. Seager, H., " Drug-deliver Products and the Zydis Fast-dissolving Dosage Form", J.
Pharm. and Pharmacol., 1998, 50, 375-382.
2. Habib W, Khankari R, Hontz J., "Fast-dissolving Drug Delivery Systems", Critical
Reviews TM Therapeutic Drug Carrier Systems, 2000, 17(1), 61-72.

3. Brown, D., Drug Delivery Tech., 2004.

4. Parakh, S. R. and Gothoskar, A. V., Pharma. Tech., November 2003, 92- 100.

5. Kuchekar, B. S., Badhan, A. C., Mahajan, H. S., Pharma Times, June 2003, 35, 7-9.

6. Lalla, J. K. and Sharma, A. H., Indian Drugs, 1994, 31(11), 503-508.

7. CIMA Labs, Inc. CIMA--Technologies. 25 May 2001

http://www.cimalabs.com/tech.htm
8. Profile Resources at Business. com. Cima Labs - Profile. 27 May 2001
http://www.business.com/directory/pharmaceuticals_and_biotechnology/drug_deliv
ery_systems/cima_labs/

9. Yamanouchi Pharma Technologies, Inc. WOWTAB. 20 June 2001

http://www.ypharma.com/wowtab.shtml

10. 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.

11. Corveleyn, S. and Remon, J.P., " Freeze- Dried Disintegrating Tablets", US patent
No., US6 010719. 2000.

12. Masaki, K., " Intrabuccally Disintegrating Preparation and Production Thereof",
US patent No., US5466464, 1995.

13. Pabley, W.S., Jager, N.E. and Thompson S.J., "Rapidly Disintegrating Tablet", US
patent No., US5298261, 1994.

14. . European Directorate for quality of Medicines, Pharmaeuropa, 1998, 10(4), 547.

15. Reddy, L. H., Ghose, B. and Rajneesh, Indian J. Pharm. Sci., 2002, 64(4): 331- 336.

16. Kuchekar, B. S. and Arumugam, V., Indian J. Pharm. Edu., 2001, 35, 150.

17. Bhaskaran, S., and Narmada, G. V., Indian Pharmacist, 2002, 1(2), 9-12.

18. Indurwade, N. H., Rajyaguru, T. H. and Nakhat, P. D., Indian Drugs, 2002, 39(8),
405-09.
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