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Methods to enhance patient's compliance have always interested scientists towards the development of impressive oral drug delivery systems. Among them, mouth dissolving drug delivery systems have achieved a specific place in the market by overcoming previously encountered administration problems and attributing to the extension of patient's life. The requirement of water for administration of drug was avoided in mouth dissolving drug delivery systems as it have the unique property of rapidly disintegrating, dissolving and releasing the drug as they come in contact with saliva . Therefore, these dosage forms have lured the market for a certain section of the patient population which includes dysphagia, bed ridden, psychic, geriatric and pediatric patients. Several techniques have been developed in the recent past, to improve the disintegration quality of these delicate dosage forms without affecting their integrity.
The concept of the system emerged with an objective to improve patient's compliance. These dosage forms release the drug when they rapidly disintegrate and/or dissolve as they come in contact with saliva, which is an attribute that makes them highly attractive for pediatric and geriatric patients. Difficulty in swallowing conventional tablets and capsules is common among all age groups, especially in geriatric and dysphagia patients.1 This disorder of dysphagia is associated with many medical conditions including stroke, Parkinson's disease, AIDS, thyroidectomy, head and neck radiation therapy and other neurological disorders including cerebral palsy. 2
One study showed that 26% out of 1576 patients experienced difficulty in swallowing tablets due to their large size, followed by their surface, shape and taste.3 Elderly patients may find the administration of the conventional oral dosage forms difficult as they regularly require medicines to maintain a healthy life.4 Children may also have difficulty in ingesting because of their underdeveloped muscular and nervous systems. 5
The problem of swallowing tablets is also prominent in traveling patients who do not have availability for water. Aforementioned problems can be resolved by means of Mouth Dissolving Tablets (MDTs). MDTs disintegrate and/or dissolve rapidly in saliva; therefore, water is not required during administration. True fast-dissolving tablets are tablets which are designed to dissolve within seconds in saliva. Fast-disintegrating tablets are tablets which contain agents that would enhance the rate of disintegration in the oral cavity and they may take about one minute to disintegrate completely. MDTs offer several advantages over other dosage forms and are commonly used to increase the patient's compliance. The examples of the dosage forms are effervescent tablets, dry syrups and chewing gums or chewable tablets. Water is required for the administration of dry syrups and effervescent tablets or effervescent granules. During mastication by an elderly patient if the taste masking coat ruptures the bitter or unpleasant taste is experienced as they cannot chew large pieces of tablets or gums.
ADVANTAGES OF MDTs6, 7
ï‚·Â Â Â Â Â Ease of administration to patients who cannot swallow, such as the elderly, stroke victims and bedridden patients; patients who have been prohibited from swallowing, such as renal failure patients; and for psychiatric and paediatric patients for whom the drug administering is difficult.
ï‚·Â Â Â Â Â The basic concept of medication as "bitter pill" is changed due to its good mouth feel property of MDTs especially for the paediatric patients.
ï‚·Â Â Â Â Â In comparison to liquid formulations accurate dosing and convenience of administration was enabled.
ï‚·Â Â Â Â Â Solid preparation having the benefits of a liquid medication.
ï‚·Â Â Â Â Â From the pre-gastric area such as mouth, pharynx and oesophagus rapid drug absorption takes place which may produce quick onset of action.
ï‚·Â Â Â Â Â Pregastric absorption of MDTs results in advantages like enhanced bioavailability, reduced dose, improved clinical efficiency and reduced side effects.
ï‚·Â Â Â Â Â New business opportunities: product differentiation, line extension and life-cycle management, exclusivity of product promotion and patent-life extension.
IDEAL PROPERTIES OF MDTs
ï‚·Â Â Â Â Â Within a few seconds the tablet should dissolve or disintegrate in the mouth and there is no requirement of water to swallow
ï‚·Â Â Â Â Â Allow high drug loading.
ï‚·Â Â Â Â Â Should be stable with taste masking and other ingredients used in tablet formulation.
ï‚·Â Â Â Â Â Have a pleasing mouth feel.
ï‚·Â Â Â Â Â Leave little or no residue in the mouth after oral administration.
ï‚·Â Â Â Â Â Should have enough strength to withstand the pressures of the manufacturing process and post manufacturing handling.
ï‚·Â Â Â Â Â To environmental conditions such as humidity and temperature low sensitivity is exhibited.
ï‚·Â Â Â Â Â Should be adaptable and amendable to existing processing and packaging machinery.
ï‚·Â Â Â Â Â Conventional processing and packaging equipments can be used for manufacturing of tablets which results in reduced cost.
METHOD OF DISINTEGRANTS ADDITION
Disintegrants are substances or mixtures of substances that are added to the drug formulation which enhance the break up or disintegration of capsule or tablet content into smaller particles.
Ideal characteristics of disintegrants are:
Good hydration capacity
Good moulding and flow property
Gel formation tendency should be very poor
No tendency to form complexes with the drugs
Three methods of incorporating disintegrating agents into the tablet:
Internal addition (Intragranular)
External addition (Extragranular)
Partial Internal and External
In internal addition method, the disintegrant is blended thoroughly with the granulating fluid before wetting the powder mixtures. In external addition method, the disintegrant is added to the sized granulation along with proper mixing which is done prior to the compression. Part of disintegrant can also be added internally and externally. Immediate disruption of the tablet into previously compressed granules will take place and the disintegrating agent within the granule will produce further erosion of the granules to the original powder particles. This method usually produces most complete disintegration when compared with the addition of disintegrant to the granulation surface only.
MECHANISM INVOLVED IN MOUTH DISSOLVING TABLET TECHNOLOGIES
The tablet's fast dissolving attribute was ensured when water quickly enter into the tablet matrix to cause quick disintegration and increased dissolution of the tablet. The basic approaches used in fast dissolving tablet technologies are increasing the porous structure of the tablet matrix and incorporating disintegrating agents or highly water soluble excipients in the tablet formulation. The basic function of a disintegrant used in the formulations of tablets are to oppose the physical forces and efficacy of the tablet binder which act during the compression of tablet. The process involved in the production of a homogeneous suspension or solution of tablet where the tablet is broken down into smaller particles is based on:
Capillary actionÂ Â
High swellabilty of disintegrantsÂ
Capillary action and high swellabilityÂ Â
Chemical reaction (Release of Gases)
TECHNIQUES FOR PREPARING FAST DISSOLVING TABLETS
Many techniques have been reported for the formulation of Fast dissolving tablets
1. Freeze drying / lyophilizationÂ Â Â Â Â Â Â Â Â Â Â Â Â
2. Tablet Moulding
3. Spray drying
5. Direct compression
6. Phase transition process
7. Melt Granulation
8. Cotton candy Process
9. Mass extrusion
FREEZE-DRYING OR LYOPHILIZATION8
Freeze drying process involves freezing of water and its subsequent sublimation from the product and this technique will create an amorphous porous structure which will dissolve quickly. The procedure involved in the manufacturing of oral disintegrating tablet (ODT) is specified here. In an aqueous solution of a carrier/polymer, the active pharmaceutical ingredient is dissolved or dispersed. Further the mixture is poured in the preformed blister packs and for freezing the mixtures, the trays holding the blister packs are made to pass through liquid nitrogen freezing tunnel. To continue the freeze-drying the frozen blister packs are placed in refrigerated cabinets. After freeze drying on a blister-sealing machine an aluminium foil backing is applied. Finally the blisters are packaged and shipped. Improved absorption and increase in bioavailability is demonstrated by the freeze-drying technique. The major disadvantages of lyophilisation technique are that it is time consuming and expensive; fragility makes conventional packaging unsuitable for these products and poor stability under stressed conditions.Â
Solvent method and heat method are the two types of moulding process. Solvent method involves moistening the powder mass with a hydro alcoholic solvent and then compressing at low pressures in moulded plates to form a wetted mass. The process is also known as compression moulding. The solvent removal is done by air drying method and thus formulated tablets are found to be less compact than compressed tablets. The heat moulding process involves preparation of a suspension containing a drug, sugar such as mannitol or lactose and agar and then pouring this formulated suspension in the blister packaging units followed by solidifying the agar at the room temperature to form a jelly and its subsequent drying at 30â-‹C under vacuum. The mechanical strength of moulded tablets is a matter of concern and the strength of the tablets was increased by binding agents, and need to be added. An additional problem to the efficiency of technology is taste masking. The drug particles which were taste masked, was formulated by spray congealing a molten mixture of hydrogenated cottonseed oil, lecithin, sodium carbonate, PEG and an active pharmaceutical ingredient into a lactose based tablet triturate form. Tablets produced by the moulding technique are effective and easier to scale up for industrial manufacture when compared to the lyophilisation technique.
In this method, Mannitol is used as a bulking agent, gelatin as a supporting agent and also as matrix material and SSG or CCS or Crospovidone are used as superdisintegrants. In aqueous medium tablets manufactured from the spray-dried powder have been reported to disintegrate in less than 20 seconds. The formulation contained bulking agent like mannitol and lactose, acidic ingredient like citric acid, alkaline ingredients such as sodium bicarbonate and a superdisintegrant like SSG & CCS. This spray-dried powder, showed rapid disintegration and enhanced dissolution when compressed into tablets.
To generate a porous matrix, volatile ingredients are incorporated in the formulation which was further subjected to a process of sublimation. The other excipients that can be used in the compression of tablets are ammonium carbonate, benzoic acid, naphthalene, ammonium bicarbonate camphor, and phthalic anhydride. This volatile material is then removed by sublimation by leaving behind a highly porous matrix. Tablets manufactured by this technique are reported to usually disintegrate within 10-20 sec. As pore forming agents even solvents like benzene and cyclohexane can be used.
Direct compression represents the simplest and most cost effective tablet manufacturing technique. Because of the availability of improved excipients especially superdisintegrants and sugar based excipients, this technique can now be applied for the preparation of ODT.
The addition of superdisintegrants mainly affects the rate of disintegration in many ODT technologies based on direct compression and hence the dissolution is also affected by its action. The disintegration can be accelerated by the addition of ingredients like effervescent agents and water-soluble excipients.
SUGAR BASED EXCIPIENTS
This is another method to manufacture ODT using direct compression. The addition of sugar based excipients like bulking agents e.g. dextrose, maltose, mannitol, starch hydrolysate, isomalt, fructose, polydextrose and xylitol, which provide sweetness and high aqueous solubility thereby imparting a pleasant mouth feel and taste masking property. On the basis of moulding and dissolution rate, Mizumito et.al, have classified sugar-based excipients into two types
Type 1 saccharides (mannitol and lactose) which exhibit low mould ability but with high dissolution rate.
Type 2 saccharides (maltilol and maltose) which exhibit high mould ability but with low dissolution rate.
SUPER DISINTEGRANTS BLENDING
PHASE TRANSITION PROCESS
In this process the combination of low and high melting point sugar alcohols, along with a transition of phase in the manufacturing process are important for formulating ODTs. For this transition special equipments are not employed. ODTs were produced by compressing xylitol at melting point; 93.95oC and erythritol at melting point; 122oC and then heating at about 93oC for 15 min. The median pore size of the tablets along with hardness was increased after heating. The increased tablet hardness does not depend on the crystal state or the lowering melting point of sugar alcohol.9
This is a process in which with the help of a meltable binder, pharmaceutical powders are efficiently agglomerated. The advantage of the technique in comparison to the traditional granulation is that water or organic solvents are not needed as there is no drying step involved in it. Compared to wet granulation, the process is less time consuming and uses less energy. This technique can be applied for enhancing the dissolution rate of drugs with poor poorly water solubility like grisiofulvin. To prepare ODT with sufficient mechanical integrity, the approach uses the hydrophilic waxy binder such as PEG-6-stearate and Superpolystate. Superpolystate is a waxy material which helps tablet disintegration as it melts in the mouth and acts as a binder. It also solubilises rapidly without any residues.
COTTON CANDY PROCESS
The process involves the application of a spinning mechanism which results in the production of a floss-like crystalline structure. By simultaneous action of melting and spinning cotton candy process involves formation of matrix of polysaccharides or saccharides. The formed matrix is partially recrystallized for improving the flow properties. This process helps in accommodating high doses of drug and improving the mechanical strength.12
This technology using the solvent mixture of water-soluble PEG and methanol induces softening of the active powder mass. Then the simultaneous expulsion of softened mass through the extruder or syringe takes place using heated blade to develop a cylinder of the product. The product is made into even segments for the production of tablet. To achieve taste masking the dried cylinder can also be utilized for coating the granules of bitter drugs.10
Patented FDTs Technologies
Flash tab technology
Yamanouchi pharma technology
The Zydis process requires the suspension of the active pharmaceutical ingredient in an aqueous solution of water soluble structure. The prepared mixture is poured into the blister pockets which is treated by the laminated film and then kept for freeze-drying. The two most usually used structural additives are gelatin and mannitol and the additives which are used depending on the properties of the active ingredient are starch and gums. By using a mixture of crystalline sugar alcohol or amino acid and a water-soluble polymer at a specific combined concentration of 10%w/w in the matrix solution, the best physical characteristics are achieved. The component gives the hardness and texture while the polymer gives the strength and resilience.
DESIRED CHARACTERISTICS OF ZYDIS TECHNOLOGY
Drug should be chemically stable
Particle size lesser than 50Âµm
Dose for water - soluble drugs is limited (60mg)
Lyoc utilizes a freeze drying process which differs from Zydis where the product is frozen on the freeze dryer shelves. During this process, to prevent inhomogeneity by sedimentation and to enhance the viscosity of the in-process suspension, the formulated product require a large proportion of undissolved inert filler like mannitol.
FLASH TAB TECHNOLOGY
The technology is patented by Ethypharm France. This involves granulation of excipients by wet or dry granulation method followed by compression into tablets. Two types of excipients are employed in this technology. Reticulated polyvinylpyrrolidine or carboxy methyl cellulose, Starch, modified starch, micro crystalline cellulose, carboxy methylated starch, etc are some of the disintegrating agents included. Satisfactory physical resistance is present in these tablets.
Advatab tablets disintegrate within 30 second quickly in mouth and allow oral drug administration without water. This technology is most suitable for those patients that experience difficulty in swallowing capsules and tablets. This is a critical advantage over other ODT technologies as the unpleasant taste of drugs is an important restriction for other techniques.
YAMANOUCHI PHARMA TECHNOLOGY
WOW TAB is the name of the technology patented by Yamanouchi. WOW means without water. This technology is used for both water-soluble and insoluble drugs and utilizes conventional granulation and tableting methods. WOW TABTM technology provides fast, consistent and convenient dosing for patients of all ages having difficulty in swallowing.
This technology was patented by Akina. The process of preparing plastic granules and compressing them at very low pressure was utilized to produce strong tablets with high porosity. The process involves mixing the porous plastic material with water penetration enhancer and subsequent granulation using the binder. Depending on size of tablets it has very good hardness and attain rapid disintegration time ranging between 15 to 30 sec.
Pharmaburst TM is a "Quick Dissolve "delivery system. It is patented by SPI Pharma and is a co-processed excipient system with specific excipients, which provides rapid disintegration and very low adhesion to punch faces14