Orodispersible drug delivery systems

Disintegrate and/or dissolve rapidly in the saliva without the need for water.

Tablets Films

Fast-dissolving Fast- disintegrating

tablets are designed to dissolve in saliva remarkably

fast, within a few seconds

contain agents to enhance the rate of tablet disintegration in

the oral cavity

Orodispersible drug delivery systems

European Pharmacopoeia adopted the term “Orodispersible Tablet” as a tablet that to be placed

in oral cavity where it disperses rapidly before swallowing.

There are multiple fast-dissolving OTC and Rx products on the market worldwide

There is increases in the number of new chemical entities under development using a fast-dissolving

drug delivery technology. Anti-ulcer (e.g. Omeprazole), antiasthamatics

(salbutamol sulphate), antitussives, expectorants, antihistaminics, NSAID’S (e.g. paracetamol,

meloxicam, valdecoxib).

•Ease of administration for patients who are mentally ill, disabled and uncooperative. •Requires no water •Self administration. •Overcomes unacceptable taste of the drugs and could provide a pleasant mouth feel. •Allows high drug loading. •Provide advantages of liquid medication in the form of solid preparation. •Adaptable to existing processing and packaging machinery. •Increased bioavailability (pre-gastric absorption ).

Advantages of orodispersible dosage forms

While the claimed increase in bioavailability is

disputable, it is clear that the major advantage of

these formulations is convenience

Advantages of orodispersible dosage forms

The fast-dissolving property of the tablet is attributable to a quick ingress of water into the tablet matrix resulting in its rapid disintegration.

Approaches for orodispersible Tablets

The basic approaches to developing orodispersible dosage forms tablets are: •Maximizing the porous structure of the tablet matrix •Incorporating the appropriate disintegrating agent •Using highly water-soluble excipients

Lyophilization

Tablet Molding

Direct compression

Spray drying

Sublimation

Mass extrusion

Conventional Techniques Used in the Preparation of Orodispersible Tablets

Freeze drying or Lyophilization

A process in which water is sublimated from the product after

freezing.

Scanning electron images of orodispersible tablets prepared by lyophilization

Freeze drying or Lyophilization

Advantages: Tablets are highly porous, with a very high specific surface area, which dissolve rapidly and show improved absorption and bioavailability. Disadvantages: Tablets are fragile with low mechanical strength, which make them difficult to handle and require special packaging. They are hygroscopic and exhibit poor stability on storage under stressed conditions.

Freeze drying or Lyophilization

Molding

moistening the powder blend with a suitable solvent followed by putting into mold plates.

The solvent is then removed.

Molding

Compression molding

Heat molding

No-vacuum lyophilization

Drying solidified agar at -300C under

vacuum

Evaporate a frozen mixture containing a

gum at standard pressure

Air drying of a hydroalcoholic

solvent

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.

The formulations contained: •Gelatin as a support agent for the matrix •Mannitol as a bulking agent •Na starch glycolate or crosscarmellose as a disintegrant. The formulation was spray dried to yield a porous free flowing powder. Tablets manufactured from this powder disintegrated in less than 20 s in an aqueous medium.

Spray drying

Drug solution or slurry is sprayed

Steam of hot gas

Drug powder

Solvent evaporation

Spray drying

Sublimation

Conventional compressed tablets containing highly

water-soluble ingredients and volatile ingredients. The

volatile material is removed by sublimation, leaving

behind a porous matrix.

Sublimation

Inert solid ingredients that displayed high volatility :

ammonium bicarbonate ammonium carbonate

benzoic acid Camphor

hexamethonium tetramine Naphthalene

phthalic anhydride Urea

Urethane cyclohexane & benzene

water

Sublimation

Advantages: •Easy •Conventional equipment •Commonly available excipients •Limited number of processing steps •High doses can be accommodated

Direct compression

Direct compression

Disintegrants Sugar-based excipients dextrose, fructose, isomalt, maltitok, maltose,

mannitol, sorbitol, starch hydrolyse, polydextrose, and xylitol

Effervescent disintegrating

agents

Superdisintegrants

Microcrystalline cellulose crospovidone croscarmellose Na

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.

Mass extrusion

Mass extrusion

Patented Technologies for orodispersible Tablets

Some patented technologies are available. Each technology has a different mechanism, and each fast-dissolving/disintegrating dosage form varies regarding the following: -Mechanical strength of final product; -Drug and dosage form stability; -Mouth feel; -Taste; -Rate of dissolution of drug formulation in saliva; -Swallowability; -Rate of absorption from the saliva solution; and -Overall bioavailability.

Zydis Technology

The first marketed fast dissolving tablet.

Produced by lyophilizing

Usually consisting of gelatin

Tablet properties: •Dissolves in the mouth within seconds. •Very lightweigh, fragile, and must be dispensed in a special blister pack. •Self-preserving because the final water concentration in the freeze-dried product is too low to allow for microbial growth. •The drug amount is less than 60 mg for soluble drugs. •Particle size of insoluble drugs between 50-200mm to prevent sedimentation during processing. •Has poor stability at higher temperatures and humidities.

Zydis Technology

Orasolv Technology

A fast-disintegrating tablet with drug microparticles and effervescent disintegrant.

Prepared by conventional blenders and tablet equipment using Less force of compaction.

OraSolv products disintegrate rapidly in the mouth without chewing. Drug microparticles are released and swallowed as a slurry or suspension. Complete dissolution and systemic absorption occurs in the GI tract. Typically, the pharmacokinetics are matched to the reference product.

Orasolv Technology

Tablet properties:

Their disintegration time is less than 30s.

The OraSolv formulations are not very hygroscopic.

This technology involves taste masking of active drug.

Tablets are soft and fragile

They require a special handling and packaging system.

Durasolv Technology

Produced in a fashion similar to OraSolv with much higher mechanical strength. Tablets are durable and can be packaged in traditional blister packaging, pouches or vials. This technology is best suited for formulations including relatively small doses of active compound.

This technology utilizes a unique spinning mechanism (flash heat processing)

Flash Dose Technology

Shearform technology Ceform technology

A floss-like crystalline structure to incorporate the active drug and be compressed into a tablet

Small spheres of saccharides to carry the drug

It has a very high surface area for dissolution. It disperses and dissolves quickly once placed onto the tongue.

The formed microspheres serves as a method of taste masking.

•The tablet can accommodate only up to 600 mg drug.

•Tablets produced are highly friable, soft and moisture

sensitive. Therefore specialized packing is required.

Tablet properties:

Flash Dose Technology

Wowtab Technology “With Out Water”

This process uses a combination of two different types of saccharides combined to obtain a tablet formulation with adequate hardness and fast dissolution rate.

low mouldability saccharides (rapid dissolution)

high mouldability saccharide (good binding property).

•The Wowtab product are stable •Suitable for both conventional bottle and blister packaging. •Offer superior mouth feel •Tablets dissolves quickly in 15 seconds

Wowtab Technology “With Out Water”

Tablet properties:

Flashtab Technology

Rapidly disintegrating tablet consisting of an

active ingredient in the form of microcystals

coacervation microencapsulation extrusion-spheronization

pan coating

The microcrystals of the active ingredient are added to the granulated mixture of excipients prepared by wet or dry granulation, and compressed into tablets.

Flashtab Technology

Utilize the conventional tabletting technology

Tablets have good mechanical strength

Disintegration time less than 1 min.

Taste-masking

Tablet properties:

Oraquick Technology

Fast-dissolving/disintegrating tablet

formulation utilizes a patented taste masking

microsphere technology, known as MicroMask

technology.

Oraquick Technology

•The process does not utilize solvents of any kind, this

leads to faster and more efficient production.

•Appropriate for heat-sensitive drugs.

•Good taste-masking.

•Tablets can be compressed to achieve significant

mechanical strength without disrupting taste masking.

Has quick dissolution in a matter of seconds

Tablet properties:

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 Technology

NanoCrystal colloidal dispersions of drug substance are combined with water-soluble ingredients, filled into blisters and lyophilized.

•The wafers dissolve in very small quantities of water in seconds. •Attractive for highly potent drugs because manufacturing losses are negligible •For 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.

Nanocrystal Technology

Product properties:

Evaluation tests for orodispersible tablets

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In-vitro In-vivo

Fast-dissolving films are gaining interest as an

alternative to fast-dissolving tablets to definitely

eliminate patients’ fear of chocking and

overcome patent impediments.

Fast-dissolving films

Examples for film-forming polymers: modified starches (maltodextrin), gums (xanthan & guar gum), cellulose ethers, alginates, polyvinylalcohols, polyvinylpyrrolidones or blends

They dissolve in saliva requiring no water to take.

Plasticizers •Are important factors affecting mechanical properties of films (such as tensile strength and elongation) •Variation in their concentration may affect these properties. •The commonly used plasticizers are glycerol, dibutylpthallate and polyethylene glycols

Fast-dissolving films

Manufacturing Methods 1) Solvent casting. 2) Semisolid casting. 3) Hot melt extrusion. 4) Solid dispersion extrusion. 5) Rolling.

Fast-dissolving films

Solvent casting method water soluble polymers are dissolved in water and the

drug along with other additives is dissolved in suitable solvent then both the solutions are mixed, stirred and finally casted in to the Petri plate, and dried.

Aqueous solution

Solvent

Evaluation of fast-dissolving films

•Film thickness •Film flexibility •Tensile properties •Stickiness determination •Drug content •Disintegration test •Measurement of the disintegration in the oral cavity •In vitro dissolution test

Fast-dissolving films

TECHNOLOGIES

1) SOLULEAVES™ technology

2) WAFERTAB™

3) FOAMBURST™

4) XGEL™ film

5) Quick –Dis Technology

Fast-dissolving films

Quick –Dis Technology

A thin, flexible and quick-dissolving film

•Provided in various packaging configurations, ranging from unit-dose pouches to multiple-dose blister packages. •The typical disintegration time is only 5 to 10 seconds. •The dissolving time (at which not less than 80% of the tested film is dissolved in aqueous media) is around 30 seconds •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.

Film properties: