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A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted into a solid. The excipients can include diluents, binders or granulating agents, glidants and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment by extending its shelf life or to enhance the tablet's appearance.
The solubility and compression characteristics of diluents affect both rate and mechanism of disintegration of tablet. If soluble diluents are used then it may cause increase in viscosity of the penetrating fluid which tends to reduce effectiveness of strongly swelling disintegrating agents and as they are water soluble, they are likely to dissolve rather than disintegrate. Insoluble diluents produce rapid disintegration with adequate amount of disintegrants
A binder is added to a drug - filler mixture to ensure that granules and tablets can be formed with the required mechanical strength. As binding capacity of the binder increases, disintegrating time of tablet increases and this counteract the rapid disintegration.
A disintegrant is included in the formulation to ensure that the tablet when in contact with a liquid breaks up into small fragments, which promotes rapid drug dissolution. The objectives behind addition of disintegrants are to increase surface area of the tablet fragments and to overcome cohesive forces that keep particles together in a tablet. Disintegrating agent can be added either prior to granulation or prior to compression or at the both processing steps.
The function of the lubricant is to ensure that tablet formation and ejection can occur with low friction between the solid and the die wall.Mostly lubricants are hydrophobic and they are usually used in smaller size than any other ingredient in the tablet formulation. When the mixture is mixed, lubricant particles may adhere to the surface of the other particles. This hydrophobic coating inhibits the wetting and consequently tablet disintegration.
The role of the glidant is to improve the flowability of the powder. Glidants are used in formulations for direct compaction but are often also added to a granulation before tableting to ensure that sufficient flowability of the tablet mass is achieved for high production speeds.Glidants is used in the tablet formulations at the concentration of about 1-2%.
Wetting agents in tablet formulation aid water uptake and thereby enhancing disintegration and assisting in drug dissolution. Wetting agents are mainly added when hydrophobic drug is to be formulated into tablet. SLS, Sodium diisobutyl sulfosuccinate are used as wetting agent in tablet formulation.
Dissolution Retardants are incorporated into tablet formulation only when controlled release of drug is required. Waxy materials like stearic acid and their esters can be used as dissolution retardants.
They are the agents that alter the molecular forces between ingredients to enhance the dissolution of solute in the solvent. Fructose, Povidone, Surfactants are used as dissolution enhancer.
Adsorbents are the agents that can retain large quantities of liquids. Therefore liquids like Vitamin E can be incorporated into tablets by addition of adsorbents .Most commonly used adsorbents in pharmaceuticals are anhydrous calcium phosphate, starch, magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and silicon dioxide. Generally the liquid to be adsorbed is first mixed with the adsorbent prior to incorporation into the formulation. Silicon dioxide when added can play as both glidants and an adsorbent role in the formula.
Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Antioxidants undergo oxidation in place of drug or they block the oxidation reaction or they act as synergists to other antioxidants. Chelators may also act as antioxidant. Most commonly used antioxidants include ascorbic acid and their esters , alpha-tocopherol , ethylene diamine tetra acetic acid , sodium metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene , Butylated Hydroxy Anisole , citric acid , and tartaric acid .
Chelating agents tend to form complexes with trace amount of heavy metal ions inactivating their catalytic activity in the oxidation of medicaments. Ethylenediamine tetracetic acid and its salts, Dihydroxy Ethyl Glycine, Citric Acid and Tartaric Acid are most commonly used Chelators.
Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms in tablet formulation. Parabens like methyl, propyl, benzyl, butyl p-hydroxy benzoate are used as preservatives.
Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability but are incorporated into tablets for purposes like to facilitate identification of similar looking products with in a product line to avoid mix ups, to facilitate identification of products of similar appearance that exist in the lines of different manufacturers, to overcome colour change on aging, disguising of
off-colour drugs, for brand image in the market, to enhance the aesthetic appearance of the product to have better patient acceptance. In any coloured tablet, the formulation should be checked for resistance to colour changes on exposure to light.
Flavors are commonly used to improve the taste of chewable tablets as well as mouth dissolved tablets. Flavors are incorporated either as solids or oils or aqueous flavors.
SUSTAINED RELEASE DOSAGE FORMS
The system that designed to achieve a prolonged therapeutic effect by continuously releasing medication and maintaining effective concentration in blood over extended period of time after administration of a single dose.
Sustained Release drug Therapy:
Conventional dosage forms include Solutions, Suspension. Capsules, Tablet, Emulsion, Aerosol, Foams and Suppositories which can be considered to release their ingredients into and absorption pool immediately. This is illustrated in the following simple kinetic scheme.
Kr ka ke
Dosage form Absorption pool Target area
Drug release Absorption Elimination
The absorption pool represent a solution of the drug at the site of absorption, and the terms kr, ka& ke first order rate constant for drug release, absorption and overall elimination respectively. Immediate release form a conventional dosage form implies that Kr >>> Ka that is release of drug from the dosage form is the rate limiting step. This cause the above kinetic scheme to reduce to the following.
Dosage form Target area
Drug release Elimination
Essentially, the drug absorption phase of the kinetic scheme become insignificant compared to the drug release phase. Thus the effort to develop a release delivery system is primarily direct at altering the release rate by affecting the value of Kr.
Non-immediate release delivery system may be conveniently divided into the 3 categories.
b. prolonged release
Site specific targeting
1. Delayed release
These systems are those that use repetitive, intermittent dosing of a drug from one or more immediate release units incorporated into a single dosage form. Examples of delayed release system include repeat action tablet and capsules and enteric-coated tablets where time release achieved by barrier coating.
2. Sustained release:
Sustained release system includes any delivery system that achieves release of drug over an extended period of time.
If the system at maintaining constant drug level in the blood of target time. It is considered a controlled release system, if it is unsuccessful at this but never the less extends the donation of action over that achieved by conventional delivery, it is considered a prolonged release system.
a) Controlled release:
These system also provide a low release of drug over an extended period of time and also can provide some control, whether this be of a temporal or spatial nature, or both, of drug release in the body, or in other words, the system is successful at maintaining constant drug levels in the target tissue or cells.
The goal in designed sustained or controlled delivery systems is to reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action. Many terms used to refer to therapeutic systems of controlled and sustained release have been used although describe terms such as ''Timed release'' and ''Prolonged release'' gives excellent manufacture identification. Sustained release constitutes any dosage form that provides medication over an extended time. Controlled release however denotes that the system is able to provide you actual therapeutic control.
b) Extended release:
Pharmaceutical dosage forms that release the drug slowed than normal manner at predetermined rate and necessarily reduce the dosage frequency by two folds.
3) Targeted release:
Site Specific Targeting :
These systems refer to targeting of a drug directly to a certain biological location. In this case the target is adjacent to or in the diseased organ.
2) Receptor Targeting:
These systems refer to targeting of a drug directly to a certain biological location. In this case the targeting and receptor targeting system specify the spatial
aspect of drug delivery and are also considered to be controlled drug delivery systems.
ADVANTAGES OF SUSTAINED DRUG THERAPY
All sustained release product share the common goal of improving drug therapy over that achieved with their non-sustained counterparts. This improvement in drug therapy is represented by several potential advantages of the SR system, as shown below.
Avoid patient compliance problems.
Improve efficiency in treatment
Control condition most promptly.
Employ less total drug.
Reduce dosing frequency.
Minimize or eliminate systemic side effects
Improve bioavailability of some drugs.
A smoother therapeutic response over the dosage interval.
Obtain less potentiation or reduction in drug activity with chronic use.
Minimize drug accumulation with chronic dosing.
Minimizing or eliminating patient compliance problems is an obvious advantage of sustained - release therapy. Because of the nature of its release kinetics a sustained release system should be able to utilize less total drug over the course of therapy than a conventional preparation. Unquestionably the most important reason for sustained drug therapy is improved deficiency in treatment i.e. optimized therapy. The result of obtaining constant drug blood level from a sustained release system is to achieve promptly the desired effect and
maintain it for an extended period of time. Reduction or elimination of fluctuations in the drug blood level allows better disease state management. In addition the method by which sustained release is achieved can improve the bioavailability of some drugs. Economy of sustained drug therapy can be examined from two points of view. Although the initial cost of most sustained drug delivery system is usually greater than that of conventional dosage form because of the special nature of these products the average cost of treatment over an extended period may be less. Economy may also result from a decrease in nursing time or hospitalization, less cost work time.
DISADVANTAGES OF SUSTAINED DRUG THERAPY
Administration of sustained release medication dose not permits prompt termination of therapy
The physician has less flexibility in adjusting dosage regimen.
Sustained release dosage forms are designed for normal population i.e. on basis of average biologic half-life. Consequently, disease states that alter drug
Disposition, significant patient variation, and so forth are not accommodated
More costly process and equipment are involved in manufacturing many sustained release dosage form
Un predictable and poor in vitro and in vivo relationship.
Effective drug release time period is influenced and limited by GI residence
Need additional patient education.
Drugs having very short half life or very long half life are poor candidates for sustained release dosage forms.
DESIGN OF ORAL SUSTAINED RELEASE DOSAGE FORMS
The oral route of administration received the most attention for SR system. Patient acceptance and flexibility of oral rout is quite enough. It is safe rout of administration compared to most parentral routes. The present section will forces on the basic principle involved in conception and development of new approach to oral SR drug delivery system. The following classification of such system is chosen because it includes not only the conceptual approach of design, but also same element of physiology of the sustained release system as well.
1. Continuous release system:
Dissolution and diffusion control
Ion exchange resin
Osmotic ally controlled devices
Slow dissolving salts and complexes
pH independent formulation
2. Delayed-transit and Continuous Release System:
3. Delayed-release System:
A matrix is an inert solid vehicle in which a drug is uniformly suspended. A matrix may be formed by compressing or fusing the drug and the matrix material together. Generally, the drug is present in a small percentage, so that the matrix protects the drug from rapid dissolution and the drug diffuses out slowly over time. Most matrix materials are water insoluble, although some matrix materials may swell slowly in water. Hydrophobic and hydrophilic matrices are used to control the release of the drug which having different solubility properties. For water soluble drugs, the hydrophobic and hydrophilic polymeric matrices are mixed. One of the least complicated approaches to the manufacture of sustained release dosage forms involves the direct compression or granulation of blends of drug, retardant material, and additives to form a tablet in which drug is embedded in a matrix core of retardant.
Materials used as retardants in Matrix tablet
TYPES OF MATRIX TABLET
a) Polymeric Matrix Tablets
The use of polymeric material in prolonging the release rate of drug has received increased attention. Polymeric matrix tablets for oral use are generally quite safe. The use of biodegradable polymeric material for extended release has been the focus of intensive research. The number of polymers available for drug formulations is increasing and includes polyacrylate, methacrylate, polyester, ethylene-vinyl acetate copolymer (EVA), polyglycolide, polylactide, and silicone. The hydrophilic polymers, such as polylactic acid and polyglycolic acid, erode in water and release the drug gradually over time. A hydrophobic polymer such as EVA releases the drug over a longer duration time of weeks or months. The rate of release may be controlled by blending two polymers and increasing the proportion of the more hydrophilic polymer, thus increasing the rate of drug release.
b) Fat wax matrix tablet
The drug can be incorporated into fat wax granulations by spray congealing in air, blend congealing in an aqueous media with or with out the aid of surfactants and spray drying techniques. For example polyethylene, ethyl cellulose, glyceryl esters of hydrogenated resins has been added to modify the drug release pattern.
c) Gum-Type Matrix Tablets
Some excipients have a remarkable ability to swell in the presence of water and form a substance with a gel-like consistency. When this happens, the gel provides a natural barrier to drug diffusion from the tablet. Because the gel-like material is quite viscous and may not disperse for hours, this provides a means for sustaining the drug for hours until all the drug has been completely dissolved and has diffused into the intestinal fluid. A common gelling material is gelatin. The most important consideration in this type of formulation appears to be the gelling strength of the gum material and the concentration of gummy material. Modification of the release rates of the product may further be achieved with various amounts of talc or other lipophilic lubricant.