INTRODUCTION:

For most therapeutic agents used to produce systemic effects, the oral route still represents the preferred way of administration owing to its several advantages and high patient compliance compared to many other routes. Tablets constitute a major portion of drug delivery systems that are currently available. However, many patient groups such as the elderly, children and patients who are mentally retarded, uncooperative, nauseated or on reduced liquid-intake/diets have difficulties swallowing these dosage forms. Those who are traveling or have little access to water are similarly affected. To fulfill these medical needs, pharmaceutical technologists have developed a novel oral dosage form known as Mouth Dissolving Tablets (MDTs) which disintegrate rapidly in saliva, usually in a matter of seconds, without the need to take water. Drug dissolution and absorption as well as onset of clinical effect and drug bioavailability may be significantly greater than those observed from conventional dosage forms. ^6,7,8,20

Ideal Properties of MDTs: ^1,5

1. A MDT should be dissolve in the mouth (i.e. in saliva) within seconds.

2. For its action, it should not require water or any liquid.

3. It has a pleasant mouth feeling.

4. Be compatible with taste masking and portable without fragility concern.

5. It should have high wet ability of recipients.

6. It should not have residue in the mouth after administration of the tablet.

7. The environmental conditions like the humidity and temperature have less effect on it.

8. It has more rapid absorption of the drug from pre-gastric.

9. The processing and packaging equipments have low cost.

10. Allow high loading of the drug.

11. The tablet structure should have a highly porous network area which tends to rapid onset of action.

Advantages of MDT: ^3,5

1. No need of water.

2. Better taste.

3. No chewing needed.

4. Improved stability.

5. Allows high drug loading.

6. Sustained release action.

7. Low Cost production.

8. Rapid drug therapy intervention.

9. High loading of drug is possible.

10. Have pleasant taste and minimum residue.

Disadvantages of MDT: ^1,5

1. Soluble diluents used for formulating MDTs may render hygroscopic dosage which may lead to stability issues.

2. The tablets may give unpleasant taste.

3. It may require specialized packing for hygroscopic and light sensitive drugs.

4. Precautions to be taken while administering immediately after removing from pack.

The need for Development of MDT:

1) Patient Factors:

Orally disintegrating dosage forms are particularly suitable for patients, who inconvenient to swallow traditional tablets and capsules with a glass of water. And also for those who undergoes radiation therapy, unwilling to take solid preparation. ^1,3

2) Effectiveness Factor:

Increased bioavailability and faster onset of action are a major claim of these formulations. Dispersion in saliva in oral cavity causes pregastric absorption. 3

3) Manufacturing and Marketing Factors:

Developing new drug delivery technologies and utilizing them in product development is critical for pharmaceutical industries to survive, regardless of their size. A new dosage form allows a manufacturer to extend market exclusivity, unique product differentiation, value-added product line extension, and extend patent protection, while offering its patient population a more convenient dosage form. This enhances revenue. ^1,3

Challenges in Formulating MDT:

1) Palatability:

As most drugs are unpalatable, Mouth dissolving drug delivery systems usually contain the medicament in a taste-masked form. Delivery systems disintegrate or dissolve in patient’s oral cavity, thus releasing the active ingredients which come in contact with the taste buds; hence, taste-masking of the drugs becomes critical to patient compliance. ^5,6

2) Mechanical Strength:

In order to allow MDTs to disintegrate in the oral cavity, they are made of either very porous and soft-molded compressed into tablets with very low compression force, which makes the tablets friable and/or brittle, difficult to handle, and often requiring specialized packing that may add to the cost. ^1,5

3) Hygroscopicity:

Several orally MDTs dosage forms are hygroscopic and cannot maintain physical integrity under normal conditions of temperature and humidity. Hence, they need protection from humidity. ^5,6

4) Amount of Drug:

The application of technologies used for MDTs is limited by the amount of drug that can be incorporated into each unit dose. This parameter is particularly challenging when formulating a fast-dissolving oral films or wafers. ^1,5,6

5) Aqueous Solubility:

Water-soluble drugs pose various formulation challenges because they form eutectic mixtures, which result in freezing-point depression and the formation of a glassy solid that may collapse upon drying because of loss of supporting structure during the sublimation process. ^5,6

6) Size of Tablet:

The degree of ease when taking a tablet depends on its size. It has been reported that the easiest size of tablet to swallow is 7-8 mm while the easiest size to handle was one larger than 8 mm. Therefore, the tablet size that is both easy to take and easy to handle is difficult to achieve. ^1,6

Formulation Technologies^6,8:

Conventional Technologies	Patented Technologies
Freeze drying	Zydus technology
Sublimation	Orasolv technology
Spray drying	Durasolv technology
Moulding	Wowtab technology
Mass extrusion	Flashdose technology
Direct compression	Flashtab technology
Cotton candy process	Oraquick technology

A) Conventional Technologies :

1) Freeze Drying or Lyophilization:

A process, in which water is sublimated from the product after freezing, is called freeze drying. Freeze drying process is one of the first generations of fast disintegrating dosage form. Freeze dried forms offer more rapid dissolution than other available solid products. ^4,6

Ø Advantage:

Pharmaceutical substances can be processed at non elevated temperature, thereby eliminating adverse thermal effects.

Ø Disadvantage:

a. Due to high cost of equipments, Lyophilization is relatively expensive and time consuming.

b. Fragility, which make the poor stability during storage under stressful condition.

2) Sublimation:

Porous tablets that exhibit good mechanical strength and dissolve quickly have been developed in this process. Inert solid ingredients were added to other tablet excipients and the blend was compressed into tablet. Sublimation generated a porous structure. The tablets dissolve within 10-20 seconds. ^6,7

3) Spray Drying:

Spray drying can be used to prepare rapidly dissolving tablets. This technique is based upon a particulate support matrix that is prepared by spray drying an aqueous composition containing support matrix and other components to form a highly porous and fine powder. This is then mixed with active ingredient and compressed into tablet. ^1,4

4) Moulding:

Tablets produced by moulding are solid dispersions. Physical form of the drug in the tablets depends whether and to what extent it dissolves in the molten carrier. The drug can exist as discrete particles or micro particles dispersed in the matrix. It can dissolve totally in the molten carrier to form solid solution. ^1,4,6

Ø Advantage:

a. Moulded tablets possess porous structure, which facilitates rapid disintegration.

b. Moulded tablets improve taste due to water-soluble sugars present in dispersion matrix.

Ø Disadvantage:

a. Moulded tablets lack good mechanical strength and can undergo breakage during handling and opening of blister packs

5) Mass Extrusion:

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 making their bitter taste. ^1,7

6) Direct Compression:

The direct compression is the most preferred technique to manufacture the tablets. MDTs can be fabricated using conventional tablet manufacturing and packaging machinery and also due to availability of tabulating excipients with improved flow, compressibility and disintegration properties, especially tablet disintegrates, effervescent agents and sugar based excipients. ^1,6

Ø Advantage:

a. High doses can be accommodated.

b. Easiest way to manufacture the MDT tablets.

c. Conventional equipment and commonly available excipients are used.

d. A limited number of processing steps are involved.

e. Cost-effectiveness.

7) Cotton-Candy Process:

This technology use to eliminate the bitter taste of the medicament .The Shear form technology is employed in the preparation of a matrix known as ‘floss’, made from a combination of excipients, either alone or with drugs. The floss is a fibrous material similar to cotton-candy fibers, commonly made of saccharides such as dextrose, sucrose, lactose and fructose at temperatures ranging between 180–266 °F. ^1,6,7

8) Nanonization:

A recently developed Nanomelt technology involves reduction in the particle size of drug to nanosize by milling the drug using a proprietary wet-milling technique. The nano crystals of the drug are stabilized against agglomeration by surface adsorption on selected stabilizers, which are then incorporated into MDTs. This method is advantageous for poorly water soluble drugs. ^1,7

9) Fast Dissolving Films (Solvent Casting):

In this technique, a non-aqueous solution is prepared containing water soluble film forming Polymers i.e. carboxy methylcellulose, hydroxypropyl methylcellulose, hydroxyl ethyl cellulose, drug and other taste masking ingredients, which is allowed to form a film after evaporation of solvents. This film, when placed in mouth, melts or dissolves rapidly, releasing the drug in solution or suspension form. ^1,6,7

10) Melt Granulation:

Super polystate incorporated in the formulation of ODT by melt granulation method where granules are formed by the molten form of this material. Super Polystate is a waxy material with have melting point of 33-37C. It acts as a binder, Increases the physical resistance of tablets, also helps in disintegration of tablets and solubilizes rapidly leaving no residue. ^4,6

Ø Advantages:

a. Neither solvent nor water used in this process.

b. Uniform dispersion of fine particle occurs.

c. Good stability at varying pH and moisture levels.

d. Fewer processing steps needed thus time consuming drying steps eliminated.

Ø Disadvantages:

a. Requires high energy input.

b. It cannot suitable for heat-sensitive materials.

c. Higher-melting-point binders require high melting temperatures.

(B) Patented Technologies:

1) Zydis Technology:

Zydis formulation is a unique freeze dried tablet. In this drug is dissolved within the matrix of fast-dissolving carrier material. When formulation is put into the mouth, the freeze dried structure disintegrates instantaneously and does not require water to aid swallowing. The Zydis matrix is composed of many materials such as Dextran, Sorbitol/ Mannitol, Gelatin, Water, various gums, Glycine etc. ^1,7

Ø Advantages:

a. They are self-preserving formulation.

b. Suitable for pediatric patients

c. Avoids first-pass metabolism

Ø Disadvantages:

a. Expensive manufacturing process.

b. Poor stability at higher and humidities and temperature.

c. The freeze-drying is time consuming process.

2) OraSolv Technology:

This technology is patented by CIMA Labs. This includes use of effervescent disintegrating agents compressed with low pressure to produce the MDTs. It involves blending the microencapsulated API with magnesium oxide and mannitol to aid in the release of the drug from the polymeric coating. Tablets are compressed to a hardness of 6-25 N and packaged in blister cards. On contact with saliva, the effervescent system promotes disintegration of the tablet. Carbon dioxide is generated by a reaction of the formulation components with saliva in the mouth. ^1,6

Ø Advantages:

a. Applicable for drug strengths in the range of 1 mg to 750 mg.

b. PakSolvR is a “dome-shaped” blister package that prevents the vertical movement of the tablet within the depressions.

c. PakSolvR also offers light, moisture, and child resistance.

Ø Disadvantages:

a. Both OraSolv and DuraSolv products are sensitive to moisture due to the presence of the effervescent system and must be packaged appropriately.

3) DuraSolv Technology:

This technology has a formulation similar to the OraSolv technology, combining taste masked drug micro particles containing formulation, was developed by CIMA labs, consist of a drug, fillers and the lubricants. The tablets are prepared by conventional tab letting equipment and have good rigidity. ^1,6,7

Ø Advantages:

a. DuraSolv technology is good for tablets having low amount (125 mcg to 500 mg) of active ingredients.

b. This technology enables packaging flexibility; tablets can be bottled and blistered.

Ø Disadvantages:

a. The technology is not suitable for larger doses of active ingredients.

4) Wow tab Technology:

Yamanauchi pharmaceutical company patented this technology. ‘wow’ means ‘without water’. WOWTAB means the tablet is to be given without water. The active ingredients may constitute up to 50% w/w of the tablet. In this technique, Saccharides of both low and high mould ability are used to prepare the granules. This technology utilizes sugar-like excipients. ^1,7

Ø Advantages:

a. Dissolves quickly in 15 seconds or less.

b. Can be packed in both into conventional bottle and blister packs.

5) Flash Dose Technology:

This technology is patented by Fuisz. This system uses the combination of both Shearform and Ceform technologies are helpful in order to mask the bitter taste of the drug. A sugar based matrix, called ‘Floss’ is used. ^1,6,7

Ø Disadvantages:

a. Can accommodate only up to 600 mg of drug.

b. Specialized packing of tablets is required.

6) Flashtab Technology:

Prographarm laboratory have a patent over this technology. In this technology, microgranules of the taste-masked active drug are used. These may be prepared by using conventional techniques like coacervation, microencapsulation, simple pan coating methods and extrusion-spheronisation. 1,6

7) Oraquick Technology:

K. V. S. Pharmaceuticals have a patent over this technology. It utilizes taste masking microsphere technology called as micromask, which provides superior mouth feel over taste masking alternatives, significant mechanical strength, and quick dissolving of product. ^1,7

8) Pharmaburst Technology:

SPI Pharma, New Castle has a patent over this technology. It utilizes the co-processed excipients to develop MDTs, which dissolves within 30-40 seconds. This technology involves dry blending of drug, flavour, and lubricant followed by compression into tablets.^6,7

9) Nanocrystal Technology:

Elan, King of Prussia has a patent over this technology. This technology includes 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 method avoids manufacturing process such as granulation, blending, and tab letting^{. 1,7}

Ø Advantages:

a. Highly potent and hazardous drugs are mostly used.

b. Useful for manufacturing small quantities of drugs.

c. Manufacturing losses are less or negligible.

d. Wide range of doses (up to 200 mg of API per unit).

10) Frosta Technology:

A new technology called Frosta (Akina) was developed for making FMTs. The technology utilizes the conventional wet granulation process and tablet press for cost-effective production of tablets. The Frosta tablets are mechanically strong with friability of less than 1% and are stable in accelerated stability conditions .Frosta tablets can melt in less than 10 seconds in the oral cavity.^1,6

Criteria for Drug Selection: ^3,6

The ideal characteristics of a drug for mouth dissolving tablet include:

1) Drug should have good stability in Water and saliva.

2) Drug has ability to permeate the oral mucosa.

3) Drug has pleasant taste.

4) Have the ability to diffuse and partition into the epithelium of the upper GIT

5) Small to moderate molecular weight.

6) Low dose drugs preferably less than 50mg.

7) Short half life and frequent dosing drugs are unsuitable for MDT.

Excipients used in MDT’s preparation: ^6,9

Name of the Excipients	% used
Superdisintegrant	1-15%
Binders	5-10%
Antistatic agent	0-10%
Diluents	0-85%

Superdisintegrant

Example

Mechanism Of action

Crosscarmellose,

Ac-Di-Sol,

Nymce ZSX,

VivasolRL-HPC

Crosslinked

Cellulose

Swells 4-8 folds in LT 10 seconds.

Swelling and wicking both.

Sodium starch , glycolate, Explotab

Cross linked

Starch

-Swells 7-12 folds

in < 30 seconds.

Soy polysaccharides,

Emcosoy

Natural super

disintegrate

Crosspovidon M,

Kollidon,

Polyplasdone

Cross linked

PVP

Swells very little and returns to original size after compression but act by capillary action.

1) Super Disintegrants:

Superdisintegrant are playing major role in MDT. Which are effective at low concentrations. They have greater disintegrating efficiency and they are more effective intra granularly. This superdisintegrants act by swelling and causes tablet to accelerated absorption of water leading to an enormous increase in the volume of granules to promote disintegration. ^4,9

2) Bulking Materials:

Bulking materials contributes functions of a diluents, filler and cost reducer. Bulking agents improve the textural characteristics. It enhances the disintegration in the mouth. The material such as mannitol, polydextrose, lactitol, direct compressible lactose and starch hydrolystate are added in the range of 10-90% by weight of the final composition. ^6,9

3) Lubricants:

Lubricants remove grittiness and assist in the drug transport mechanism from the mouth down into the stomach. ⁶

4) Taste Masking:

Taste masking achieved by flavoring and perfuming agents. It can be obtained from either natural or synthetic origin. Natural products include fruit juices, aromatic oils like peppermint and lemon oils, herbs, spices, and distilled fractions of these. Apart from these many compositions are showing effective taste-masking abilities with improved flavor such as alkaline earth oxide, alkaline earth hydroxide, or an alkaline hydroxide.⁹

5) Emulsifying Agent:

Emulsifying agents give rapid disintegration and drug release without chewing, swallowing or drinking water. They are useful in stabilizing the immiscible blends and enhancing bioavailability. A wide range of emulsifiers including alkyl sulfates, propylene glycol esters and lecithin is used in wide range. These agents can be added in the range of 0.05-15% by weight of the final composition. These dosage forms may be suitable for the oral delivery of drugs. ^4,6

MDT products in Indian market: ^1,2

S. No.	Brand Name	Active Ingredients	Company
1	Nimulid-MD	Nimesulide	Panacea
2	Biotech Zyrofmeltab	Rofecoxib	Zydus Cadila
3	Valus	Valdecoxib	Glenmark
4	Olanexinstab	Olanzepine	Ranbaxy
5	Manza BDT	Olanzepine	Orchid
6	Remeron Sol Tab	Mirtazapine	Organon

Evaluation of MDT:

1) Hardness/Crushing Strength:

It is measured using conventional hardness testers. A significant strength of ODT is difficult to achieve due to the specialized processes and ingredients used in the manufacturing. The limit of crushing strength for an ODT must be in a lower range to facilitate early disintegration in the mouth. ^3,4

2) Friability:

All methods of manufacturing of ODT are responsible for increasing the % friability values. Thus, it is necessary that this parameter should be evaluated and the results are within bound limits (0.1-0.9%). To achieve % friability within limits for an ODT is a challenge to the formulator. ^3,4,6

3) Wetting Time:

Wetting time of dosage form is related with the contact angle. The wetting time of the tablets can be measured using a simple procedure; five circular tissue papers of 10 cm diameter are placed in a petridish with a 10 cm diameter. Ten milliliters of water-soluble dye (eosin) solution is added to petridish. A tablet is carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet is noted as the wetting time. ^3,4

4) Moisture Uptake Studies:

A moisture uptake study for ODT is useful for stability of the formulation. Ten tablets from each formulation were kept in a desiccators over calcium chloride at 37°C for 24 h. The tablets were then weighed and exposed to 75% relative humidity, at room temperature for 2 weeks. Required humidity was achieved by keeping saturated sodium chloride solution at the bottom of the desiccators for 3 days. One tablet as control (without superdisintegrant) was kept to assess the moisture uptake due to other excipients. Tablets were weighed and the percentage increase in weight was recorded. ^4,6

5) Disintegration Test:

The disintegration test for MDT should mimic disintegration in mouth with in salivary contents. The time for disintegration of ODTs is generally <1 min and actual disintegration time, that patient can experience ranges from 5 to 30 s. The standard procedure of performing disintegration test has several limitations and it is not suitable to measurement very short disintegration times.^3,6

6) Dissolution Test:

Dissolution conditions for drugs listed in a pharmacopoeia monograph, is a good place to start with scouting runs for a bioequivalent ODT. USP dissolution apparatus 1 and 2 can be used. Kancke proposed USP 2 Paddle apparatus, which is the most suitable and common choice for MTDs, with a paddle speed of 50 rpm commonly used. The USP 2 Paddle apparatus at 50-100 rpm is suitable for dissolution testing of taste-masked drug as well. ⁴

Future Prospects:

Therapeutics that has limited bioavailability when administered by conventional tablets, these products usually degrade rapidly in the stomach. Should next generation drugs are predominantly protein or peptide based, tablets may no longer be the dominant format for dosing such moieties. Injections generally are not favored for use by patients unless facilitated by sophisticate auto injectors. Inhalation is one good alternative system to deliver these drugs, but the increased research into biopharmaceuticals so far has generated predominantly chemical entities with low molecular weights. The developments of enhanced oral protein delivery technology by MDTs which may release these drugs in the oral cavity are very promising for the delivery of high molecular weight protein and peptide. ^3,5

CONCLUSION:

Mouth dissolving tablets (MDTs) are innovative drug delivery systems and have potential advantages over conventional dosage forms, with their improved patient compliance, convenience, bioavailability and rapid onset of action. Though considerable research has been done in the formulation, development and technologies for MDTs, more intensive investigations are to be carried out in this promising area to result in newer cost effective technologies and better product. ^3,4

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Received on 06.10.2016 Modified on 09.11.2016

Research J. Pharm. and Tech. 2017; 10(1): 355-361.

DOI: 10.5958/0974-360X.2017.00072.5

Technology	Advantages	Disadvantages
Freeze drying	Immediate dissolution (2-10 s)	Very poor physical resistance, high cost of production, sensitive to humidity.
Tableting (sublimation)	Good physical resistance	Extra equipments for heating, not applicable to volatile and heat sensitive drugs.
Molding	Very rapid dissolution (5–15 s) High dose	High cost of production, Weak mechanical strength, possible limitations in stability.
Tableting (standard)	Low cost of production, high dose ,good physical resistance	Significant effects of the size and hardness of the tablets on disintegration property.
Tableting (effervescent)	Good physical resistance, pleasant effervescent mouths feel.	Operating in controlled low humidity need of totally impermeable blister
Tableting(Humidity treatment)	Good physical resistance, pleasant mouth feels.	Extra equipments for Drying, limitations in stability, high cost of production.