Orally Disintegrating Tablets Odts Biology Essay

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Oral drug delivery system is considered the safest, economical and most convenient gold standard drug delivery method in pharmaceutical industry having highest patient compliance. Patience compliance has always been a major factor in developing a drug delivery system. This has attracted scientists over the world to develop various fancy oral drug delivery systems. Orally disintegrating tablets, by overcoming previously encountered problems of drug administration and by contributing to patient life extension has gained remarkable market acceptability. Orally disintegrating tablets (ODTs) are most preferred and accepted solid dosage forms by the patients. These tablets disintegrate in the saliva in the mouth within a short period of time and are useful for populations having difficulty in swallowing. This article aims at providing a brief review on requirements for orally disintegrating tablets, their advantages and disadvantages, formulation aspects, various conventional and patented technologies for its manufacture, methods of evaluation and its applications.

Keywords: ODTs, Conventional technologies, Patented technologies, Superdisintegrants

INTRODUCTION

Drug delivery via oral route is the most preferred and accepted way of application by the patients. Among the entire pharmaceutical formulations solid dosage forms in the shape of tablets used orally have the most substantial and significant place (Peck et al., 1989). Owing to various advantages of solid dosage forms like high patient compliance, relative ease of production, ease of marketing, accuracy in dosing and better physical and chemical stability, these have become the most popular and preferable drug delivery systems (Joshi and Duriez, 2004; Marshall and Rudnic, 1990). There has been a significant transition of dosage forms from simple conventional tablets or capsules to sustained or modified release tablets or capsules to orally disintegrating tablets (Dixit and Puthli, 2009).

This form of drug delivery is also known as 'fast-melt', 'fast-disintegrating' or 'fast-dissolving' dosage forms and are a relatively novel dosage technology involving rapid disintegration or dissolution of the dosage forms either tablet or capsule (Ciper and Bodmeier, 2006; Mizumoto et al., 2005; Seager, 1998), into a solution or suspension in the mouth without the need for water (Sastry and Nyshadham, 2000; EU Pharmacopoeia, 2002a).

ODT is defined in the 'Orange Book' by US Food and Drug Administration Center for Drug Evaluation and Research (CDER) as "a solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue" (CDER, 1992).

In the European Pharmacopeia, orally disintegrating tablets are specified as "orodispersible tablets" and defined as "orodispersible tablets are uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed" (EU Pharmacopoeia 4.1, 2002).

ODTs, when introduced into mouth, start to dissolve or disintegrate immediately on the tongue even in the absence of external water. This facilitates easy administration of active pharmaceutical ingredients (APIs). Once the tablet disintegrates or dissolves, the active ingredient in tablet are absorbed in gastrointestinal tract resulting in the desired therapeutic effect. Until the tablet is swallowed, the active ingredient in the tablet remains in the oral cavity. After swallowing, there should be minimal or no residue in the mouth (Seong and Park, 2008).

Criteria for fast dissolving drug delivery system

Wagh et al., (2010); Bhowmik et al., (2009) and Shukla et al., (2009) mentioned the essential criteria for fast dissolving tablets.

Doesn't require water to swallow.

It should dissolve or disintegrate within few seconds in mouth.

It should mask the taste of unpleasant substances.

It should be portable.

No or minimum residue in the mouth after oral administration.

Shouldn't be affected by environmental conditions such as temperature and humidity.

Be able to incorporate large amounts of drug.

Flexibility to existing processing and packaging machinery.

Less friable and have sufficient hardness.

Utilizes cost effective production method.

Advantages of Orally Disintegrating Tablets

In addition to having the advantages of conventional tablet dosage forms, ODT formulations have various other advantages.

They are easy to swallow like the liquid dosage forms and superior to the oral liquid dosage forms since the dosage can be adjusted more correctly (Habibh et al., 2000)

Owing to their solid dosage forms, they have a better stability, an easier production process, smaller packing size and they are more convenient for the use of the patients (Seager, 1998; Habibh et al., 2000; Shukla et al., 2009).

Rapid dissolution and disintegration and high dose precision.

Their pleasant taste (palatability) is among the advantages of these dosage forms in comparison to the other conventional tablets or capsules.

Since the ODTs are designed to disperse or dissolve at once when they contact saliva, it is not necessary to chew the tablet or drink water to swallow the entire tablet. Advantages like comfort and increase in patient compliance can be gained with application of orally disintegrating tablets to patients such as the aged, paralyzed and bedridden ones who are not able to swallow as well as to the pediatric, geriatric and psychiatric patients who refuse to swallow (Sastri et al., 2000; Bandari et al., 2008).

Swallowing difficulty (dysphasia) that due to neoplasia, neuromuscular and metabolic disorders, infectious diseases, iatrogenic causes, anatomic abnormalities, autoimmune disorders and reasons such as stress/anxiety can be overcome with use of ODTs.

No first pass metabolism, hence reduction in dose and subsequent reduction in side effects.

Orally disintegrating tablet formulations also provide advantages in the industrial field such as diversity of products and extension of patent time

In spite of these advantages, orally disintegrating tablets are sensitive to temperature and humidity (Habibh et al., 2000). It is difficult to prepare active substances of high dosage like antibiotics in the orally disintegrating tablet form. Besides, patients on anticholinergic medicine or those suffering from dry mouth are also not suitable for using ODTs (Bharawaj et al., 2010).

Formulation challenges of ODTs

Mechanical strength

ODTs are made of porous or soft molded matrices in order to allow its disintegration in mouth. This makes tablet friable and handling becomes difficult (Krishnakanth et al., 2009; Patidar et al., 2011).

Palatability

ODTs are intended to be dissolved in mouth. Most of the drugs have bitter taste and comes in direct contact with the saliva. Hence, maintaining palatability is one of the major formulation challenges in development of ODTs (Brown, 2001).

Aqueous solubility

Water soluble drugs pose various formulation challenges results in freezing point depression and formation of glassy solids that may collapse upon drying. Such collapse can be prevented by using various matrix forming excipients like mannitol (Krishnakanth et al., 2009; Ghosh et al., 2005)

Amount of drug

The application for technologies used for ODTs is limited by the amount of drug into each unit dose.The drug dose must be lower than 400mg for insoluble drugs and 60mg for soluble drugs (Patidar et al., 2011)

Size of tablet

Tablets of size 7-8 mm are easy to swallow while tablets of size 8mm are easy to handle. Hence, tablet size that are both easy to handle and swallow are difficult to achieve.

Hygroscopicity

It poses one of the major challenges in formulating ODTs. Drugs in form of ODTs are hygroscopic in nature and hence need to be protected from humidity (Patidar et al., 2011).

Selection of drugs

Kumaresan (2008) and Willium (2005) mentioned the ideal characteristics of a drug for formulating as ODTs.

It should not have bitter taste.

Dose of the drug should be below 20mg.

It should have low molecular weight.

It should be stable both in water and in saliva.

It should not ionize at oral cavity pH.

The tablet should be able to diffuse and partition in upper GI epithelium. (logP>1, or preferably>2)

Should be able to permeate oral mucosal tissue.

Should not have short half life.

Do not require frequent dosing.

Important criteria for excipients used in formulation of ODTs

Manivannan (2009) described the following necessary criteria for excipients:

Should disintegrate rapidly.

Do not interact with the drugs in formulation.

Should be chemically inert.

Should not affect the efficacy of formulation.

Should not alter the organoleptic characteristics of the product.

Should be stable.

Should melt in the range of 30-35°C (Biradar et al., 2006).

Commonly used excipients for ODT preparation

Excipients commonly used in ODT preparation are shown in table 1.

Table 1: % of various excipients used

S.N

Excipients

% Used

1.

Disintegrants

1-15%

2.

Binders

5-10%

3.

Anti-static agents

0-10%

4.

Diluents

0-85%

1. Superdisintegrants

Super disintegrants, via its swelling and water absorption properties provide quick disintegration. On swelling, the wetted surface of the carrier increases, thereby, promoting the wetability and dispersibility of the system. This further enhances disintegration and dissolution (Sandipan and Sahu, 2008).

Swelling index is calculated by using the formula.

Swelling Index = [(Final volume - Initial volume) / Initial volume)] X 100

Examples: Croscarmellose sodium, crospovidone, carmellose, carmellose calcium, sodium starch glycolate, ion exchange resins (e.g. Indion 414).

Various Superdisintegrants employed in the manufacture of ODTs (table 2).

Table 2: Superdisintegrants employed in ODT

Superdisintegrants

Nature

Mechanism of Action

Crosscarmellose

Modified cellulose or Cross linked cellulose

Wicking due to fibrous structure swelling with minimal gelling

Crosspovidone

Cross linked PVP

Water wicking, swelling and possibly some deformation recovery

Aliginic acid NF

Cross linked Aliginic acid

Wicking action

Soy

polysaccharides

Natural disintegrant

Calcium silicate

Wicking action

Sodium starch glycolate

Modified starch

Rapid and extensive swelling with minimal gelling

Ion exchange resin

Resins

L-HPC

Low hydroxyl propyl cellulose

Both swelling and wicking

Acrylic acid derivatives

Poly (Acrylic acid) Superporous hydrogel

Wicking action

Sodium Alginate

Sodium salt of Alginic acid

Swelling

Effervescent mixture

Citric acid, tartaric acid and sodium bicarbonate

Effervescence

Important criteria for selection of superdisintegrants

Disintegration: Superdisintegrants by wicking saliva into tablets should generate volume expansion and increase hydrostatic pressure necessary for rapid disintegration of the tablets in mouth.

Compactability: At a given compression force, it should have acceptable hardness and low friability in order to produce robust tablets without the need for specialized packaging.

Mouth feel: Small particles are preferred to avoid grittiness in mouth. Tablets that form a gel-like consistency on contact with water produces a gummy texture which may be objectionable to many consumers.

Flow: As compared to 2-5 wt % of superdisintegrants in conventional tablet formulation, ODT formulations use higher amounts of superdisintegrants which may affect the flow properties of the total blend (Camarco et al., 2006).

Effective at low concentration with higher disintegrating efficacy (Khinchi et al., 2010).

2. Binders

Binders are used to keep the composition of ODTs together during compression. They may either be solid, liquid, semisolid or polymeric in nature.

Examples: Cellulosic polymers, povidones, polyvinyl alcohols and acrylic polymers (ammoniomethacrylate copolymer, polyacrylate, and polymethacrylate).

3. Antistatic agent

An antistatic agent is used to reduce the buildup of static electricity generally caused by the triboelectric effect.

Examples: colloidal silica (Aerosil), precipitated silica (Sylod.FP244), talc, maltodextrins, beta-cyclodextrin, etc. (Shaikh et al., 2010)

4. Lubricants

Lubricants are used to remove surface grittiness and aid in the transport of drugs down the oesophagus into the stomach.

Examples: Magnesium stearate, stearic acid, leucine, sodium benzoate, talc, magnesium lauryl sulphate, liquid paraffin, etc.

5. Flavours

Flavours impart suitable taste to the formulation.

Examples: Peppermint flavour, clove oil, anise oil, eucalyptus oil, vanilla, citrus oils, fruit essences, etc. (Kumaresan, 2008)

6. Sweeteners

Sweeteners enhance the palatability of the formulated tablets.

Examples: Sorbitol, mannitol, maltitol solution, xylitol, erythritol, sucrose, fructose, maltose, aspartame, sugars derivatives, etc. (Khinchi et al., 2010)

7. Fillers

Fillers increase the bulk of the tablet.

Examples: Spray dried Mannitol, sorbitol, xylitol, calcium carbonate, magnesium carbonate, calcium phosphate, etc.

8. Surface active agents

It enhances solubilization by reducing interfacial tension.

Examples: Sodium dodecyl sulfate, sodium lauryl sulfate, tweens, spans, polyoxyethylene stearate.

9. Colour

It is used to make the product more elegant and improve the organoleptic characteristics.

Examples: Sunset yellow, red iron oxide, amaranth, etc.

PRODUCTION TECHNOLOGIES OF ODTs

Production Technologies

Conventional Technologies

Patented Technologies

Freeze drying

Zydis Technology

Tablet Molding

2. Durasolv Technology

Spray Drying

3. Orasolv Technology

Sublimation

4. Wowtab Technology

Direct Compression

5. FlashDose Technology

Suspension Spray Coating

6. FlashTab Technology

Mass Extrusion

7. Oraquick Technology

Cotton Candy process

8. Nanocrystal Technology

Hot-melt Extrusion

Microwave irradiation

ODTs can be classified into three generations according to differences in the preparation method.

First generation ODTs were prepared by a freeze-drying method. This method was developed and commercialized by Cardinal Health as Zydis® (Seager, 1998). The method of preparation used was freeze-drying drug suspensions with specific additives, which was filled into the pockets of the press through packing (PTP).

Second generation ODTs were prepared by drying the drug and additives after tabletting their wet mass. This preparation method was developed by Tushima (2001) and commercialized as EPM® tablets.

Third-generation ODTs were developed where dry mass including the drug and saccharides were tabletted. Many researchers modified this method, and many different types of ODTs have been generated using this approach. For example, WOWTAB-DRY® was completed by applying the crystalline transition of amorphous sucrose after tabletting (Mizumoto, 2005; Sugimoto et al., 2005, 2001, 2006a, b). OraSolv® was prepared by low-pressure compression with foaming agents (Wehling et al., 1991), and Flashtab® was prepared by low-pressure compression of dry powder granules containing the drug, disintegrants, and microcrystalline cellulose (Cousin et al., 1995).

However, the ODTs developed as the first to third generations have disadvantages of high porosity, low density, and low hardness in order to achieve their rapid disintegration rates. These properties resulted in extremely brittle tablets which made pharmacists and patients difficult to handle them in the hospital and at home. Furthermore, special equipment, such as a freeze-dryer for wet mass filled into PTP packaging, a tabletting machine for wet mass methods, and drying and wetting chambers for the crystalline transition of amorphous sucrose, are required to prepare these ODTs.

In order to overcome the above mentioned problems, the tablet hardness of ODTs should be improved while retaining their rapid disintegration rate.

In the manufacture of orally fast disintegrating tablets, various technologies can be applied.

Conventional Technologies for ODTs

1. Freeze drying

ZYDIS® (R.P. Scherer, Swindon, UK), using freeze drying processes, is one of the first generations of fast disintegrating dosage forms. In this method, the drug is mixed in water soluble matrix, which is then transferred to the preformed blister with peelable foil, as the zydis units are not strong enough to withstand being pushed through the lidding foil of a conventional blister.

Water is then removed by sublimation using freeze drying. Incorporation of lyophilization is a pharmaceutical technology which allows drying of heat sensitive drugs and biological at low temperature under conditions that allow removal of water by sublimation. Lyophilization results in preparations, which are highly porous, with a very high specific surface area, which dissolve rapidly (5sec.) and show improved absorption and bioavailabity (Shukla et al., 2009).

2. Moulding

In this method, molded tablets are prepared by using water-soluble ingredients so that the tablets dissolve completely and rapidly. The powder blend is moistened with a hydro-alcoholic solvent and is molded into tablets under pressure lower than that used in conventional tablet compression. The solvent is then removed by air-drying. Molded tablets are very less compact than compressed tablets. These possess porous structure that enhances dissolution (Shukla et al., 2009; Dobetti, 2001)

3. Spray Drying

The formulations contained hydrolyzed and unhydrolyzed gelatin as a supporting agent for the matrix, mannitol as a bulking agent and sodium starch glycolate/croscaramellose as a disintegrant. Disintegration and dissolution were further enhanced by adding an acid (e.g. citric acid) or an alkali (e.g., sodium bicarbonate). The suspension of above excipients was spray-dried to yield a porous powder which was compressed into tablets. Tablets manufactured by this method disintegrated in < 20sec. in an aqueous medium (Shukla et al., 2009).

4. Sublimation

Sublimation has been used to produce MDTs with high porosity. A porous matrix is formed by compressing the volatile ingredients along with other excipients into tablets, which are finally subjected to a process of sublimation. Inert solid ingredients with high volatility (e.g. ammonium bicarbonate, ammonium carbonate, benzoic acid, camphor, naphthalene, phthalic anhydride, urea and urethene) have been used for this purpose. They can be used to prepare porous tablets of good mechanical strength. Solvents such as cyclohexane and benzene were also suggested for generating the porosity in the matrix (Shukla et al., 2009; Bharawaj et al., 2010).

Fig. 1 explains how the sublimation makes the surface of dosage form porous for enhancement of dissolution properties.

Steps Involved in sublimation.jpg

Fig. 1: Sublimation Process

5. Direct Compression Method (Disintegrant Addition)

In this method, tablets are compressed directly from the mixture of the drug and excipients without any preliminary treatment. The mixture to be compressed must have adequate flow properties and cohere under pressure thus making pretreatment as wet granulation unnecessary. The other factors to be considered are particle size distribution, contact angle, pore size distribution, tablet hardness and water absorption capacity. All these factors determine the disintegration. The disintegrant addition technology is cost effective and easy to implement at industrial level. The basic principle involved in formulating Fast-dissolving tablets by disintegrant addition technique is addition of superdisintegrants in optimum concentration so as to achieve rapid disintegration along with the good mouth feel. Gas evolving disintegrants have been used to formulate fast dissolving tablets. The evolution of carbon dioxide as a disintegration mechanism called OROSOLV and DURASOLV have been described in two US Patents assigned to CIMA Lab (Shaikh et al., 2010).

Suspension spray-coating method

ODT, which had high tablet hardness and a fast disintegration rate, was designed using a simple preparation method (Okudaa et al., 2009). The new ODTs were composed of rapid disintegration granules spray-coated with a suspension of appropriate additives using a fluidized-bed granulator. The appropriate additives for the rapid disintegration granules were chosen from several saccharides and disintegrants.

Fig. shows Suspension spray coating method for the manufacture of ODTs.

The specific properties of RDGs prepared in this study are summarized as follows:

• Large specific surface area and small micro-pore (4.42nm as an average radius)

• High circularity measure and high fluidity

• Low plastic deformation

• Small particle size

These properties are essential for RDGs to prepare ODTs that show high compressibility, high tablet hardness, rapid disintegration in the oral cavity, and better mouth feeling.

Example: To obtain rapid disintegration granules (RDGs), a saccharide, such as trehalose, mannitol, or lactose, was spray-coated with a suspension of corn starch using a fluidized-bed granulator (suspension method). As an additional disintegrant, crospovidone, light anhydrous silicic acid, or hydroxypropyl starch was also included in the suspension.

Fig. 2 shows structure of rapidly disintegrating particles containing micronized ethylcellulose and disintegration using Spray coating method.

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Fig. 2: Structure of rapidly disintegrating particles containing micronized ethylcellulose and disintegration using Spray coating method.

Mass Extrusion

This technology involves softening the active blend using the solvent mixture of water-soluble polyethylene glycol and methanol and subsequent 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 (Bhaskaran and Narmada, 2002)

Cotton Candy Process

This process is so named as it utilizes a unique spinning mechanism to produce floss-like crystalline structure, which mimic cotton candy. Cotton candy process (Meyers et al., 1995) involves formation of matrix of polysaccharides or saccharides by simultaneous action of flash melting and spinning. The matrix formed is partially re-crystallized to have improved flow properties and compressibility. This candy floss matrix is then milled and blended with active ingredients and excipients and subsequently compressed to MDTs.

Hot-melt extrusion (HME) method

Hot-melt extrusion (HME) is widely used in the pharmaceutical industry as a process to prepare drug delivery systems such as granules, pellets, sustained release tablets and even transmucosal/ transdermal systems. Recently, hot-melt extrusion was introduced as an alternative taste masking technique where, for example, anionic active substances can interact with the functional groups of positively charged polymers. These interactions facilitate the creation of Hydrogen Bridge bonding and consequently mask the active's bitter taste (Andreas et al., 2011).

Microwave irradiation

A major challenge in the development of orally disintegrating tablets (ODTs) is to achieve a good balance between tablet hardness and disintegration time. In this study, an advanced method was demonstrated to improve these opposing properties in a molded tablet using a one-step procedure that exploits the swelling induced by microwave treatment. Wet molded tablets consisting of the delta form of mannitol and silicon dioxide were prepared and microwave-heated to generate water vapor inside the tablets (Syusuke et al., 2011).

Fig. 3 shows microwave irradiation method for manufacture of ODTs.

1-s2.0-S0378517311006302-fx1.jpg

Fig. 3: Microwave irradiation process.

Patented Technologies for ODTs

Panigrahi et al., (2010) has described following patented technologies in his review on ODTs.

1. Zydis Technology

Zydis formulation is a unique freeze dried tablet in which drug is physically entrapped or dissolved within the matrix of fast-dissolving carrier material. The Zydis product is made to dissolve on the tongue in 2 to 3 seconds. Zydis products are packed in blister packs to protect the formulation from moisture in the environment.

2. Durasolv Technology

Durasolv is the patented technology of CIMA labs. The tablets made by this technology consist of a drug, fillers and a lubricant. Tablets are prepared by using conventional tableting equipment.

3. Orasolv Technology

Orasolv Technology has been developed by CIMA labs. In this system active medicament is taste masked. It also contains effervescent disintegrating agent. Tablets are made by direct compression technique.

4. Wowtab Technology

Wowtab Technology is patented by Yamanouchi Pharmaceutical Co. WOW means "Without Water ". In this process, combination of low mouldability saccharides and high mouldability saccharides is used to obtain a rapidly melting strong tablet. The active ingredient is mixed with a low mouldability saccharide and granulated with a high mouldability saccharide and compressed into tablet.

5. Flash Dose Technology

Flash dose technology has been patented by Fuisz. Flash dose tablets consist of self binding shearform matrix termed as "floss". Shearform matrices are prepared by flash heat processing.

6. Flashtab Technology

Prographarm laboratories have patented the Flashtab technology. Tablets prepared by this system consist of an active ingredient in the form of microcrystals. Drug microgranules may be prepared by using the conventional techniques like coacervation, microencapsulation, and extrusion- spheronisation. All the processing utilized conventional tabletting technology (Biradar et al., 2006).

7. Oraquick Technology

The Oraquick fast dissolving/disintegrating tablet formulation utilizes a patented taste masking technology. KV Pharmaceutical claims its microsphere technology, known as Micro Mask. KV Pharmaceutical also claims that the matrix that surrounds and protects the drug powder in microencapsulated particles is more pliable.

8. Nanocrystal Technology

Decreasing particle size increases the surface area, which leads to an increase in dissolution rate. NanoCrystal particles are small particles of drug substance, typically less than 1000 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 ingredients, filled into blisters, and lyophilized. The resultant wafers are remarkably robust, yet dissolve in very small quantities of water in seconds (Sharma et al., 2010)

Various Conventional and Patented Technologies have their individual advantages and disadvantages (table 3 and 4).

Table 3: Advantages and Disadvantages of Conventional technologies

S.no.

Technology

Advantages

Disadvantages

1.

Freeze-drying

Immediate dissolution (<5s)

Very poor physical resistance.

High cost of production.

Low dose of water soluble drugs.

2.

Moulding

Very rapid dissolution (5-15s)

High dose.

High cost of production.

Weak mechanical strength.

Possible limitations in stability.

3.

Tabletting

(standard)

Low cost of production.

Use of standard equipment/materials.

High dose.

Good physical resistance.

Disintegration capacity markedly limit by the size and hardness of the tablets.

4.

Tabletting (effervescent)

Use of standard equipment.

High dose.

Good physical resistance.

Pleasant effervescent mouth feel.

Operating in controlled low humidity.

Need of totally impermeable blister.

Table 4: Advantages and Disadvantages of Patented technologies

S.N.

Technique

Novelty

Advantage(s)

Disadvantage(s)

1.

Zydis

First market, Freeze dried.

Quick dissolution, self-preserving, increased bioavailability

Expensive process, poor stability at higher temperature and humidity

2.

Orasolv

Unique taste-masking, lightly compressed.

Taste-masking is two-fold, quick dissolution .

Low mechanical strength

3.

Durasolv

Compressed dosage form, Proprietary taste masking.

High mechanical strength than Orasolv, good rigidity.

Inappropriate with larger doses.

4.

Flash Dose

Unique spinning mechanism to produce floss-like crystalline structure, much like cotton candy.

Higher surface area for dissolution.

High temperature required to melt the matrix can limit the use of heat sensitive drugs, sensitive to moisture and humidity.

5.

Flashtab

Compressed dosage form containing drug as microcrystals.

Only conventional tableting technology is required.

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6.

Wowtab

Combination of low-mouldability and high mouldability saccharides.

Smooth melt action gives superior mouth feel.

Adequate dissolution rate and hardness.

No significant change in bioavailability.

7.

Oraquick

Uses patented taste-masking technology.

Faster and efficient production appropriate for heat-sensitive drugs.

----

8.

Ziplet

Incorporation of water-insoluble inorganic excipients for excellent physical performance.

Good mechanical strength, handling problems during manufacturing are avoided, satisfactory properties can be obtained at high dose (450mg) and high weight (850 mg).

As soluble component dissolve, rate of water diffusion in to tablet is decreased because of formation of viscous concentrated solution.

EVALUATION STUDIES OF ODTS

General Appearance

This includes evaluation of tablet's visual identity, size, shape, color, odour, taste, surface texture, physical flaws, consistency and legibility.(Anand et al., 2007).

Size and Shape

It is evaluated using vernier caliper.

Tablet thickness

10 tablets are selected randomly from each batch and measured its thickness using micrometer.

Weight variation

20 tablets are randomly selected and individually weighed to check for weight variation.

Weight variation specification as per I.P (table 5)

Table 5: Weight Variation table

Average Weight of Tablet

% Deviation

80 mg or less

± 10

80 mg to 250 mg

± 7.5

> 250 mg

± 5

Tablet Breaking Resistance and Friability

Tablet breaking resistance is determined by means of a hardness assessment device used to measure the force required to break the tablets under certain conditions. Tablet friability device is made up of polished transparent synthetic polymer inside with an apparent diameter and depth. Accurately weighed tablets are placed in this plastic chambered friabilator and rotated at 25 rpm/min for 4 min. After 100 rotations, tablets are taken out, their powder is removed and they are weighed again In general, friability is required to remain below 1%. For hygroscopic tablets, it is necessary to work in a humidity controlled environment (EU Pharmacopoeia, 2007).

These tests are more convenient for the tablets prepared by means of molding or direct compressing methods. Molded tablets are usually prepared with compressing force less than conventional tablets (Dobetti, 2001; Gupta, 2010). These tests cannot be applied to ODTs prepared by means of the lyophilization method as they are very fragile. In the lyophilization method, the active substance is dissolved or dispersed in a vehicle/polymer aqueous solution (Gupta, 2010; Sznitowska, 2005). After being poured into blister pockets, it is frozen under liquid nitrogen and following lyophilization, blister is closed.

Porosity Measurement

As tablet porosity relatively indicates degree of water penetration to formulation, therefore, it is relevant to disintegration time. ODT porosity measurement can be conducted using a mercury porosimeter (Kuno, 2008; Corveleyn and Remon, 1997; Bi et al., 1996; Sunada and Bi, 2002).

The porosity (∈) can also be calculated based on actual density of tablet (ρactual) determined by means of a pycnometer, mass (m) and volume (V) measured (Schiermeier and Schmidt, 2002; Bi et al., 1999a; Sugimoto et al., 2006b; Bi et al., 1999b), using the following equation.

(∈) = 1− [m/ (ρ actual Ã- V)]

Porosities of ODTs prepared by means of spray-drying, lyophilization, sublimation and cotton-candy methods are more in comparison with those prepared by means of other methods. In the spray-drying method, aqueous mixture containing excipient is spray-dried to obtain a highly porous structure, active substance is added to this porous powder mixture and tablet is then compressed (Gupta et al., 2010; Wagh et al., 2010). In the sublimation method, inert solid materials (such as urea and camphor) that are rapidly sublimated are mixed with other tablet excipients and the mixture is compressed as tablet, sublimated material is then disassociated by sublimation to obtain tablet with porous structure (Bharawaj et al., 2010; Rao et al., 2010). In the cotton-candy method, the polysaccharide or saccharides make up the matrix called floss by rapid melting and rotation. Tablets prepared by means of this process are highly porous and they leave a nice taste in the mouth because of rapid dispersion of sugar with saliva (Gupta et al., 2010).

Dissolution Test

Usually USP Apparatus II (paddle) method and 50 rpm of paddle speed are recommended for the ODT dissolution test. However, a better discrimination between in vitro dissolution profiles can be made at low paddle speeds. Additionally, it has been reported that when the basket method is used, pieces of tablet from its rapid dispersion may accumulate at the inner top side of the basket and may not mix up adequately and hence reproducible results may not be obtained (Siewert et al., 2003; Klancke, 2003).

Determination of Water Absorption Capacity/Wetting Time

In this test, a circular tissue paper is placed in a petridish and tablet is placed on the paper. A certain volume of distilled water is added, and the time required to cover the entire tablet surface is recorded as the wetting time (Bi et al., 1996; Sunada and Bi, 2002; Schiermeier and Schmidt, 2002; Rawas et al., 2006).

As for the water absorption capacity, ODT is first weighed when dry (W first) and after it has become entirely wet, it is weighed again (W last), and water absorption capacity is calculated using the equation given below.

Water Absorption Capacity = 100(W last−W first) / W first

Determination of ODT Disintegration Time

ODTs must be hard enough to withstand the mechanics of production, storage and transportation yet must be sufficiently friable to dissolve or disperse to small pieces for the patient to swallow comfortably (Fu et al., 2004). Determination of disintegration time is important for the development of ODT formulation.

9.1. In-Vivo Determination of Disintegration Time

In vivo determination of disintegration time may be carried out with healthy volunteers picked up on a random basis. After tablet is put on the tongue, the period of time until disintegration of the last granule will be measured. It is recommended that the volunteers should wash their mouths at the end of the test. The requirement for permission from the Board of Ethics and application of tablets that contain active substances which have many side effects on healthy volunteers are the restrictions of this test (Bi et al., 1996; Sunada and Bi, 2002; Abdelbary et al., 2005; Que et al., 2006; Okuda et al., 2009; Shu et al., 2002; Sugimoto et al., 2006a; Fukami et al., 2006).

9.2. In-Vitro Determination Methods of Disintegration Time

9.2.1. Determination of Disintegration Time with Modified Dissolution Test Device

USP Apparatus II method at 100 rpm of paddle speed in 900 mL of distilled water (37°C) has been used in this test (Bi et al., 1996; Sunada and Bi, 2002). Tablet is placed in a sinker, which is then suspended in the middle of a glass container, and dispersion time is determined as the period of time the tablet has been disintegrated entirely and has passed through sieve of the sinker to the modified dissolution test apparatus. Que et al., (2006) prepared rizatriptan benzoate containing ODTs and used the modified dissolution test device. They found that the paddle stirring rate, diameter of the sinker sieve and tablet hardness were effective on disintegration time, whereas, temperature of dispersion medium and position of the sinker were not very effective on disintegration time and this method was well correlated with in vivo disintegration time at a mixing speed of 50 rpm.

9.2.2. Texture Analysis Method

In this method, texture analysis device is used in order to determine the beginning and ending points of disintegration. Tablet adhered under a probe is pressed by means of applying a stable pressure towards base of the beaker containing distilled water and extent of penetration is measured. As the tablet begin to disperse, probe functions at a certain distance to gain a stable force and extent of compression increases. Beginning and ending time of disintegration is determined from the time-extent graphics composed by the device (Abdelbary et al., 2005; El-Arini and Clas, 2002).

9.2.3. CCD Camera Method

This method utilizes disintegration device made up of a steel disintegration container containing 200 mL of distilled water at a temperature of 37 ± 2°C and an external container with thermostat containing water. Images taken by the CCD camera during the period of disintegration are transferred to a computer. Disintegration time is calculated using the graphics obtained with regard to the wear on the tablet surface area as a function of time (Morita et al., 2002).

9.2.4. Rotary Shaft Method

In this method, ODT is placed on a perforated plate and pressure is applied by means of the rotary shaft used to produce a mechanical stress on the tablet. Located at the tip of the rotary shaft weight is a sponge circled with a conducting material. As the weight contacts the plate, the moment when disintegration ends will be determined by means of an electrical sensor (Narazaki et al., 2004; Harada et al., 2006).

Pharmacokinetic and Pharmacodynamic Considerations of ODTs

Pharmacokinetic

Absorption, distribution, metabolism and excretion of drugs are taken into considerations.

Absorption of any drug is its primary step in its kinetic profile. The rate and extent of absorption of drug determines its bioavailability. In conventional drug delivery systems, absorption is slow and often incomplete due o slow rate of dissolution and disintegration. In case of ODTs, since they rapidly dissolve and disintegrate in mouth, absorption is rapid and often complete, leads to enhanced bioavailability and better therapeutic effects.

Drug distribution depends on various factors such as drug perfusion rate, membrane permeability, plasma and tissue binding, diseased state and various dug-drug interactions.

There is a decrease in body mass and total body water in case of geriatric patients. This affects volume of distribution of lipid and water soluble drugs.

Factors such as hepatic blood flow, diseased states and age affect biotransformation as well as excretion of drugs.

Pharmacodynamic

Drug efficacy and safety are the major Pharmacodynamic considerations in formulating an ODT.

Drugs with narrow therapeutic index are usually not formulated as ODT, may pose problems of toxicity.

Drugs for emergency conditions such as ischemic heart attacks are often formulated as ODTs. Example. Nitroglycerine buccal tablet. Pediatric and geriatric populations require special attention. They have impaired drug receptor interactions die to undue development of organs.

Examples: Decreased response of adrenergic drugs to CVS.

Impaired immunity in these populations, hence taken into consideration while administering antibiotics.

Applications of ODTs

ODTs have wide range of therapeutic applications. Various ODTs have been formulated in the treatment of several ailments (table 6).

Table 6: Promising drug candidates for Mouth dissolving tablets

S.N

Category

Examples

1.

Antibacterial agents

Ciprofloxacin, Tetracycline, Erythromycin, Rifampicin, Penicillin, Doxycyclin, Nalidixic acid, Trimethoprim.

2.

Antihelminthics

Albendazole, Mebendazole, Livermectin, Praziquantel, etc

3.

Antidepressants

Trimepramine maleate, Nortryptylline HCL, Trazodone HCL, Amoxapine, etc

4.

Antidiabetics

Glibenclamide, Glipizide, Tolbutamide, Tolazamide, Gliclazide, Chlorpropamide

5.

Analgesics/anti-inflammatory Agents-

Diclofenac sodium, Ibuprofen, Ketoprofen, Mefenamic acid, Oxyphenbutazone, Indomethacin, Piroxicam, Phenylbutazone, etc

6.

Antihypertensives

Amlodipine, Carvedilol, Diltiazem, Felodipine, Minoxidil, Nifedipine, Prazosin HCl, Nimodipine, Terazosin HCl etc.

7.

Antiarrhythmics

Disopyramide, Quinidine sulphate, Amiodarone HCl, etc.

8.

Antihistamines

Acrivastine, Cetrizine, Cinnarizine, Loratadine, Fexofenadine, Triprolidine, etc

9.

Anxiolytics, sedatives hypnotics & Neuroleptics

Alprazolam, Diazepam, Clozapine, Mylobarbitone, Lorazepam, Haloperidol, Nitrazepam , Midazolam Phenobarbitone,Thioridazine, Oxazepam, etc.

10.

Diuretics

Acetazolamide, Clorthiazide, Amiloride, Furosemide, Spironolactone, Bumetanide, Ethacrynic acid, etc.

11.

Gastro-intestinal agents

Cimetidine, Ranitidine HCl, Famotidine, Domperidone, Omeprazole, Ondansetron HCl, Granisetron HCl, etc

12.

Corticosteroids

Betamethasone, Beclomethasone, Hydrocortisone, Prednisone, Prednisolone, Methyl, Prednisolone, etc.

13.

Antiprotozoal agents

Metronidazole, Tinidazole, Omidazole, Benznidazole, Clioquinol, Decoquinate etc

CONCLUSION

ODTs are more widely accepted solid dosage forms in the recent years. Compared to conventional dosage forms, ODTs have potential advantages with respect to improved patient compliance, convenience, biopharmaceutical aspects, bioavailability, safety and efficacy. Easy administration of drugs to pediatric and geriatric patients has served this form of formulation a boon for such populations. They can be easily used like the liquid dosage forms and superior to the other tablets. Also, strong market acceptance and patient demand make this dosage form a potential drug delivery system.

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