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Methods to improve patient's compliance have always attracted scientists towards the development of fancy oral drug delivery systems. Among them, mouth dissolving drug delivery systems have acquired an important position in the market by overcoming previously encountered administration problems and contributing to extension of patient's life. Mouth dissolving drug delivery systems have the unique property of rapidly disintegrating and/or dissolving and releasing the drug as soon as they come in contact with saliva, thus obviating the requirement of water during administration. 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 rapidly disintegrate and/or dissolve to release the drug as soon 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 elderly 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 evident in traveling patients who may not have ready access to 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. Some tablets are designed to dissolve in saliva within few seconds, and are true fast-dissolving tablets. Others contain agents to enhance the rate of tablet disintegration in the oral cavity and are more appropriately termed as fast-disintegrating tablets, as they may take about one minute to disintegrate completely. MDTs offer several advantages over other dosage forms like effervescent tablets, dry syrups and chewing gums/tablets, which are commonly used to enhance patient's compliance. Administering effervescent tablets/granules and dry syrups require intake of water. Elderly patients cannot chew large pieces of tablets or gums and sometimes experience the bitter or unpleasant taste of the drug in the dosage form if the taste masking coat ruptures during mastication.
ADVANTAGES OF MDTs6, 7
· Ease of administration to patients who cannot swallow, such as the elderly, stroke victims and bedridden patients; patients who should not swallow, such as renal failure patients; and who refuse to swallow, such as paediatrics, geriatric and psychiatric patients.
· Patient's compliance for disabled bedridden patients and for traveling and busy people who do not have ready access to water.
· Good mouth feel property of MDTs helps to change the basic view of medication as "bitter pill", particularly for paediatric patients due to improved taste of bitter drugs.
· Convenience of administration and accurate dosing as compared to liquid formulations.
· Provides benefit of a liquid medication in the form of solid preparation.
· More rapid drug absorption from the pre-gastric area i.e. mouth, pharynx and oesophagus which may produce rapid onset of action.
· Pregastric absorption can result in improved bioavailability, reduced dose and improved clinical performance by reducing side effects.
· New business opportunities: product differentiation, line extension and life-cycle management, exclusivity of product promotion and patent-life extension.
IDEAL PROPERTIES OF MDTs
· Water is not required to swallow and should dissolve or disintegrate in the mouth within a few seconds.
· Allow high drug loading.
· Should be compatible with taste masking and other excipients.
· Have a pleasing mouth feel.
· Leave minimal or no residue in the mouth after oral administration.
· Have sufficient strength to withstand the rigors of the manufacturing process and post manufacturing handling.
· Exhibit low sensitivity to environmental conditions such as humidity and temperature.
· Should be adaptable and amendable to existing processing and packaging machinery.
· Allow the manufacturing of tablets using conventional processing and packaging equipments with low cost.
METHOD OF ADDITION OF DISINTEGRANTS
Disintegrants are substances or mixtures of substances added to the drug formulation that facilitates the break up or disintegration of tablet or capsule content into smaller particles that dissolve more rapidly than in the absence of disintegrants.
Ideal characteristics of disintegrants are:
Good hydration capacity
Good moulding and flow property
Very poor gel formation tendency
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 mixed with other powders before wetting the powder mixtures with the granulating fluid. In external method, the disintegrant is added to the sized granulation with mixing prior to compression. Part of disintegrant can also be added internally and externally. This leads to immediate disruption of the tablet into previously compressed granules while disintegrating agent within the granule produce further erosion of the granules to the original powder particles. This method usually produces better and most complete disintegration than the addition of disintegrant to the granulation surface only.
MECHANISM INVOLVED IN MOUTH DISSOLVING TABLET TECHNOLOGIES
To ensure the tablet's fast dissolving attribute, water must quickly egress into the tablet matrix to cause rapid disintegration and instantaneous dissolution of the tablet. Maximizing the porous structure of the tablet matrix and incorporating an appropriate disintegrating agents or highly water soluble excipients in the tablet formulation are the basic approaches used in current fast dissolving tablet technologies. Basically, the disintegrant's major function is to oppose the efficacy of the tablet binder and the physical forces that act under compression to form the tablet. The mechanism by which tablet is broken down into smaller particles and then produces a homogeneous suspension or solution is based on:
High swellabilty of disintegrants
Capillary action and high swellability
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 / lyophilization
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 is the process in which water is sublimed from the product after it is frozen. This technique creates an amorphous porous structure that can dissolve rapidly. A typical procedure involved in the manufacturing of oral disintegrating tablet (ODT) using this technique is mentioned here. The active drug is dissolved or dispersed in an aqueous solution of a carrier/polymer. The mixture is done by weight and poured in the walls of the preformed blister packs. The trays holding the blister packs are passed through liquid nitrogen freezing tunnel to freeze the drug solution or dispersion. Then the frozen blister packs are placed in refrigerated cabinets to continue the freeze-drying. After freeze-drying the aluminium foil backing is applied on a blister-sealing machine. Finally the blisters are packaged and shipped. The freeze-drying technique has demonstrated improved absorption and increase in bioavailability. The major disadvantages of lyophilisation technique are that it is expensive and time consuming; fragility makes conventional packaging unsuitable for these products and poor stability under stressed conditions.
Moulding process is of two types i.e. solvent method and heat method. Solvent method involves moistening the powder blend with a hydro alcoholic solvent followed by compression at low pressures in moulded plates to form a wetted mass (compression moulding). The solvent is then removed by air-drying. The tablets manufactured in this manner are less compact than compressed tablets and posses a porous structure that hastens dissolution. The heat moulding process involves preparation of a suspension that contains a drug, agar and sugar (e.g. mannitol or lactose) and pouring the suspension in the blister packaging wells, solidifying the agar at the room temperature to form a jelly and drying at 30â-‹C under vacuum. The mechanical strength of moulded tablets is a matter of great concern. Binding agents, which increase the mechanical strength of the tablets, need to be incorporated. Taste masking is an added problem to this technology.The taste masked drug particles were prepared by spray congealing a molten mixture of hydrogenated cottonseed oil, sodium carbonate, lecithin, polyethylene glycol and an active ingredient into a lactose based tablet triturate form. Compared to the lyophilisation technique, tablets produced by the moulding technique are easier to scale up for industrial manufacture.
In this technique, gelatin can be used as a supporting agent and as a matrix, mannitol as a bulking agent and sodium starch glycolate or crosscarmellose or crospovidone are used as superdisintegrants. Tablets manufactured from the spray-dried powder have been reported to disintegrate in less than 20 seconds in aqueous medium. The formulation contained bulking agent like mannitol and lactose, a superdisintegrant like sodium starch glycolate & croscarmellose sodium and acidic ingredient (citric acid) and/or alkaline ingredients (e.g. sodium bicarbonate). This spray-dried powder, which compressed into tablets showed rapid disintegration and enhanced dissolution.
To generate a porous matrix, volatile ingredients are incorporated in the formulation that is later subjected to a process of sublimation. Highly volatile ingredients like ammonium bicarbonate, ammonium carbonate, benzoic acid, camphor, naphthalene, urea, urethane and phthalic anhydride may be compressed along with other excipients into a tablet. This volatile material is then removed by sublimation leaving behind a highly porous matrix. Tablets manufactured by this technique have reported to usually disintegrate in 10-20 sec. Even solvents like cyclohexane; benzene can be used as pore forming agents.
Direct compression represents the simplest and most cost effective tablet manufacturing technique. This technique can now be applied to preparation of ODT because of the availability of improved excipients especially superdisintegrants and sugar based excipients.
In many orally disintegrating tablet technologies based on direct compression, the addition of superdisintegrants principally affects the rate of disintegration and hence the dissolution. The presence of other formulation ingredients such as water-soluble excipients and effervescent agents further hastens the process of disintegration.
SUGAR BASED EXCIPIENTS
This is another approach to manufacture ODT by direct compression. The use of sugar based excipients especially bulking agents like dextrose, fructose, isomalt, lactilol, maltilol, maltose, mannitol, sorbitol, starch hydrolysate, polydextrose and xylitol, which display high aqueous solubility and sweetness, and hence impart taste masking property and a pleasing mouth feel. Mizumito et al have classified sugar-based excipients into two types on the basis of moulding and Dissolution rate.
Type 1 saccharides (lactose and mannitol) exhibit low mould ability but high dissolution rate.
Type 2 saccharides (maltose and maltilol) exhibit high mould ability and low dissolution rate.
SUPER DISINTEGRANTS BLENDING
PHASE TRANSITION PROCESS
In this method combination of low and high melting point sugar alcohols, as well as a phase transition in the manufacturing process are important for making ODTs without any special apparatus. ODTs were produced by compressing erythritol (melting point:122oC) and xylitol (melting point:93.95 oC) and then heating at about 93 oC for 15 min. After heating, the median pore size of the tablets was increased and tablet hardness was also increased .The increase of tablet hardness with heating and storage did not depend on the crystal state or the lowering melting point of sugar alcohol.9
Melt Granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a meltable binder. The advantage of the technique compared to a conventional granulation is that water or organic solvents are not needed because there is no drying step .The process is less time consuming and uses less energy than wet granulation. It is a useful technique to enhance the dissolution rate of poorly water soluble drugs, such as grisiofulvin. This approach to prepare ODT with sufficient mechanical integrity, involves the use of a hydrophilic waxy binder (Superpolystate, PEG-6-stearate). Superpolystate is a waxy material which acts as a binder and also helps the disintegration of the tablets as it melts in the mouth and solubilises rapidly leaving no residues.
COTTON CANDY PROCESS
It utilizes a unique spinning mechanism to produce floss-like crystalline structure, which mimic cotton candy. Cotton candy process involves formation of matrix of polysaccharides or saccharides by simultaneous action of melting and spinning. The matrix formed is partially recrystallized to have improved flow properties .This process can accommodate high doses of drug and offers improved mechanical strength.12
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 tablet. The dried cylinder can also be used to coat granules for bitter drugs and thereby achieve taste masking.10
Patented FDTs Technologies
Flash tab technology
Yamanouchi pharma technology
The Zydis process requires the active ingredient to be dissolved or suspended in an aqueous solution of water soluble structure forming additives. Then the mixture is poured into the preformed blister pockets of a laminate film and freeze-dried .The two most commonly used structural additives are gelatin and mannitol although some other materials such as starch, gums, etc may be used depending on the properties of the active ingredient. The best physical characteristics are achieved by using a mixture of a water-soluble polymer and a crystalline sugar alcohol or amino acid at a typical combined concentration of 10%w/w in the matrix solution. The polymer gives the strength and resilience while the component gives the hardness and texture.
DESIRED CHARACTERISTICS OF ZYDIS TECHNOLOGY
Drug should be chemically stable
Particle size should be smaller than 50µm
Dose for water - soluble drugs is limited (60mg)
LYOC TECHNOLOGY (Laboratories L.Lafon, Maisons Alfort, France)
Lyoc utilizes a freeze drying process but differ from Zydis in that the product is frozen on the freeze dryer shelves. To prevent inhomogeneity by sedimentation during this process, these formulations require a large proportion of undissolved inert filler (mannitol), to increase the viscosity of the in process suspension.
FLASH TAB TECHNOLOGY
This is patented by Ethypharm France. This technology includes granulation of excipients by wet or dry granulation method followed by compression into tablets.Excepients used in this technology is of two types. Disintegrating agents include reticulated polyvinylpyrrolidine or carboxy methyl cellulose. Starch, modified starch. micro crystalline cellulose, carboxy methylated starch, etc. These tablets have satisfactory physical resistance.
Advatab tablets disintegrate rapidly in mouth, typically in less than 30 second ,to allow for convenient oral drug administration without water. These tablets are especially suited to those patients that experience difficulty in swallowing capsules and tablets. This is a critical advantage as the unpleasant taste of drugs is a significant restriction in the application of other ODT technologies.
YAMANOUCHI PHARMA TECHNOLOGY
Yamanouchi patented this technology, so it is called as WOW TAB.WOW means without water .This technology utilizes conventional granulation and tableting methods .It is used for both water-soluble and insoluble drugs, the breakthrough WOW TABTM technology provides quick, convenient and consistent dosing for patients of all ages having swallowing difficulties.
Akina patented this technology. It utilizes the concept of formulating plastic granules and compressing them at low pressure to produce strong tablets with high porosity. The process involves mixing the porous plastic material with water penetration enhancer followed by granulating with binder. The tablets obtained have excellent hardness and rapid disintegration time ranging from 15 to 30 sec depending on size of tablet.
Pharmaburst TM is a "Quick Dissolve "delivery system patented by SPI Pharma is a co-processed excipients system with specific excipients, which allows rapid disintegration and low adhesion to punch faces14