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Oral route of drug administration is most appealing route for delivery of drugs of various dosage forms. The tablets is one of the most preferred dosage form because of its ease of administration, accurate dosing and stability as compared to oral liquid dosage forms and when compared to capsules, tablets are more temper evident.
Tablets may be defined as solid unit pharmaceutical dosage forms containing drug substance with or without suitable Excipients and prepared by either compression or molding mehtods1. The first step in the development of dosage form is Preformulation, which can be defined as investigation of physicochemical properties of drug substance alone and when combined with Excipients. The main objective of Preformulation studies, is to develop stable and bioavilabel dosage form and study of factors affecting such stability, bioavailability and to optimize so as to formulate the best dosage form, here optimization of formulation means finding the best possible composition2. compressed tablets are formed by applying pressure, for which compression machines (tablet presses) are used and they are made from powdered crystalline or granular material, alone or in combination with binder, disintegrants, release polymers, lubricants and diluents and in some cases colorant.
These tablets are meant to be swallowed intact along with a sufficient quantity of Â Â potable water. Exception is chewable tablet. Over 90% of the tablets manufactured today are ingested orally. This shows that this class of formulationÂ is the most popular worldwide and the major attention of the researcher is towardsÂ this direction.
The tablets under this group are aimed release active pharmaceutical ingredient in oral cavity or to provide local action in this region. The tablets under this category avoids first-pass metabolism, decomposition in gastric environment, nauseatic sensations and gives rapid onset of action. The tablets formulated for this region are designed to fit in proper region of oral cavity.
These tablets are administered by other route except for the oral cavity and so the drugs are avoided from passing through gastro intestinal tract. These tablets may be inserted into other body cavities or directly placed below the skin to be absorbed into systemic circulation from the site of application.
The tablets under this category are required to be dissolved first in water or other solvents before administration or application. This solution may be for ingestion or parentral application or for topical use depending upon type of medicament used.
1. Effervescent tablet
2. Hypodermic tablet
1.2 FORMULATION OF TABLETS:
In addition to active pharmaceutical agent (API), the tablets contain non drug substances called as Excipients, which include:
When the dosage of active pharmaceutical agent is inadequate to produce the bulk some inert substance are added to make the tablet and to make the bulk. Example are lactose (USP), direct compressible starches (Sta-Rx-1500), microcrystalline cellulose (NF), sucrose, hydrolysable starches (Emdex, Cellutab)
They are added in dry or liquid form during wet granulation to form granules or to promote cohesive compacts for directly compressed tablets. Commonly used binders are acacia, pregelatinised starch, starch paste, sodium alginate, gelatin, poyvinylpyrolidine. The method of introducing the binder depends on its solubility, thus when small quantity of solvent is to be used, the binder is blended with dry powder. With large quantity the binder is usually dissolved in the liquid.
These are added to cause break up or disintegration of tablet when tablet comes in contact with water. The active pharmaceutical agent should be release from tablet matrix as effectively as possible to allow rapid dissolution. The classed of disintegrants called as super disintegrants are used in much less concentration and more effective than conventional disintegrants.
These include agents, flavours and sweeteners. They are used to enhance patient compliance, product identification, taste masking and in chewable tablets
Anti adherents, Glidants, Lubricants- These promote flow from hopper to die cavity, prevent sticking to punches and promote ejection of tablet from die cavity.
It is the process of converting a powder mass into small aggregates called granules. The main purpose of granulation is:
â€¢ Improve of flow characteristics
â€¢ Improve of compressibility
Flow properties can be determined by measuring angle of repose
Granules can be produced by following process
In this method, solution, suspension or slurry containing binder is added to powder mass to blend the powder particles, so that aggregates are formed. These aggregates are called as granules. The granules are formed due to formulation of liquid bridges between particles due to capillary and surface tension forces. The steps involved in wet granulation are as follows:
It involves compression of granules by means of tablet presses followed by milling and screening, prior to final compression into tablet. For dry granulation large capacity presses are used. The compacted masses formed are called slugs and the process as slugging. On large scale dry granulation is performed using roller compacter.
Industrial scale equipment used for wet granulation and mixing:
Mixing:- Little ford mixer, diosna mixer
Granulation:- Rapid-Mixer-Granulator, Topo-Granulator, Little-Ford-MGT-Mixer Granulator, The Gral Mixer Granulator.
Drying:- Fluidized bed dryer, Double cone nmixer-dryer process, Nauta process.
Compression is the process of applying pressure to a material. The appropriate volume of granules in a die cavity is compressed between an upper and lower punch to consolidate the material into solid matrix, which is subsequently ejected from die cavity as an intact tablet4. The subsequent events that occur in the process of compression are follows:-
tablet formulation is compressed on stamping machine called presses, which can either be single punch or multi station rotary punch.
Examples : The Manesty Nova rotary press, Cadmach compression Machine, Colton rotary press, Osaka rotary press.
1.3 SUSTAINED RELEASE DOSAGE FORMS 2
The term sustained release is known to have existed in the medical and pharmaceutical literature for many decades. Sustained release has been constantly used to retard the release of therapeutic agents such that its appearances in the circulation is delayed or prolonged and its plasma profile is sustained in duration. The onset of its pharmacological action is often delayed and duration of therapeutic action is sustained1.
The objective of sustained release of drug, in a general way is to modify the normal behaviour of drug molecule in a physiological environment. It can lead to the following.
Sustained drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body with minimization of desirable side effects.
Â Â Â Â Â Â Â Â Â Â Â 1. Localization of drug action by spatial placement placement of a Controlled release Â Â Â Â Â Â system usually rate controlled adjacent to or in the diseased tissue of organ.
2. Targeting drug action by using carriers of chemicals derivatives to deliver drug to Â Â Â Â Â Â Â Â particular target cell type
1.4 NOVEL DRUG DELIVERY SYSTEMS3, CAN BE BROADLY CLASSIFIED INTO Â Â Â Â Â Â TWO GROUPS
Sustained release drug delivery system (SRDDS)
Controlled release drug delivery system (CRDDS)
SUSTAINED RELEASE DRUG DELIVERY SYSTEM (SRDDS)
SRDDS include any drug delivery system that achieves slow release of drug over an extended period of time. This leads to increase in duration of effect so that therapeutic effect is sustained.
CONTROLLED RELEASE DRUG DELIVERY SYSTEM (CRDDS)
CRDDS has a meaning goes beyond the scope of sustained action. It implies when the system is successful at maintaining constant drug levels in target tissue or cells
The ideal goal in designing a Controlled release system is to deliver drug to the desired site at a pre-determined rate according to the needs of the body, i.e. a self regulated system based on feedback control.
In general4, the siding interval may be increasing by any one of the following:
By modifying the drug molecule to decrease the rate of elimination.
By modifying the release rate of dosage form to decrease the rate of absorption.
1.4.1 SUSTAINED RELEASE DRUG DELIVERY SYSTEM:
The ideal objective of drug delivery system point to the two aspects, most namely spatial placement and temporal delivery of drug.
Spatial placement release to targeting of a drug to a specific organ or tissue, while temporal delivery refers to controlling the rate of drug delivery to the target tissue. An approximately designed sustained release drug delivery system can be major advance towards solving those two problems. It is for their reason that the science and technology responsible for development of SR pharmaceuticals have been and continue to be focus of a great deal of attention in both industrial and academic laboratories. The fact that coupled with the intrinsic inability of conventional dosage forms to achieve spatial placement is a compelling matter for investigation of SR drug delivery system4.
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 â€¦â€¦â€¦â€¦..Absorption pool â€¦â€¦â€¦â€¦.. Targetâ€¦â€¦â€¦â€¦â€¦.
Drug 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 â€¦â€¦â€¦â€¦â€¦. Target area â€¦â€¦â€¦â€¦â€¦.
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. Rescuing the dose required, or providing uniform drug delivery. If one were to imagine the ideal drug delivery system, two pre-requisites would be requested. First it would be a single dose for the duration of treatment whatever it may be for day or weeks as with infection or lifetime of the patient, as in hypertension or diabetes. Second it should deliver active entity directly to the site of action, there by minimizing of eliminating side effects6.
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.
1.6 ADVANTAGES OF SUSTAINED DRUG THERAPY7:
All sustained release product share the common goal of improving drug therapy over that achieved with their non-sustained counterparts. This improvement is drug therapy is represented by several potential advantages of the SR system, as shown below.
Avoid patient compliance problems.
Employ less total drug.
Reduce dosing frequency.
Minimize or eliminate systemic side effects.
Improve efficiency in treatment
Control condition most promptly.
Improve bioavailability of some drugs.
Make use of special effects eg: sustained release.
A smoother therapeutic response over the dosage interval.
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 SR system is to promptly achieve and maintain the desired effect. Once daily SR formulated shorter acting drug that provides a resistant therapeutic response at the end of the dosage interval can provides additional cover. Economy 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/hospitalization, less cost work time, ect8.
SR dosage forms have following disadvantages.
Cost is very high.
Unpredictable and often poor in vitro : in vivo correlation.
Reduce potential for dosage adjustment and increase potential for pass clearance and poor systemic availability in general.
For oral SR dosage forms there is an additional disadvantage that the effective drug release period is influenced and limited by gastro intestinal (G.I) residence time.
SR drug delivery system can be classified into following categories.
Rate programmed drug development system.
Activation modulated drug development system.
Feed back modulated drug development system.
Site targeting drug development system.
All categories consist of the following common structure features
i. Drug reservoir compartment.
ii. Rate-controlling element.
iii. Energy source.
1.9 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 10,11.
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:
1.10 MECHANISM OF DRUG RELEASE13,12:
Sustained release tablets are often classified according to the mechanism of drug release. The following are the most common means used to achieve a slow controlled release of the drug from tablets;
Drug transport control by diffusion.
Drug transport control by convective flow.
(Accomplished by, for example, osmotic pumping)
A) Dissolution controlled release systems
In dissolution controlled extended release systems the rate of dissolution in the gastrointestinal juices of the drug or another ingredients is the release controlling process. Sparingly water soluble drug can form a preparation of a dissolution controlled extended release type. Reduced drug solubility can be accomplished by preparing poorly soluble salts or derivatives of the drug. An alternative means to achieve extended release based on dissolution is to incorporate the drug in a slowly dissolving carrier.
Dissolution controlled extended release system can also be obtained by covering drug particles with a slowly dissolving coating. The release of the drug from such units occurs in two steps,
The liquid that surrounded the release unit dissolves the coating
(rate liming dissolution step )
The solid drug is exposed to the liquid and subsequently dissolves
Sustained release oral products employing dissolution as the rate limiting step are in principle the simplest to prepare. A drug with a slow dissolution rate is inherently sustained. Some example of these drugs includes digoxin, griseofulvin, and salilcylamide. Others, such as aluminum aspirin, ferrous sulfate, and benzphetamine paomate, produce such forms when in contact with the absorption pool contents. Steroids have been reports to undergo transformation into less soluble polymorphs during dissolution in the absorption pool14.
For those drugs with high water solubility and therefore high dissolution rate, one can decrease solubility through appropriate salt of derivative formation. Unfortunately, forms such as these do not meet the criterion of constant availability tate because can be achieved by coating drug particles or granules with materials of varying thickness or by dispersing them in a polymeric matrix.
The basic principle of dissolution control is as follows. If the dissolution process is diffusion layer controlled, where the rate of diffusion from the solid surface through an unstirred liquid film to the bulk solution is rate limiting, the flux J is given by:
J= -D (dc/dx) (3)
Where D is the diffusion coefficient and dc/dx is the concentration gradient from the solid surface to the bulk solution. The flux can also be defined as the flow rate to material (dm/dt) through a unit area (A), thus one has the equation:
J= (1/A) dm/dt (4)
If the concentration gradient is linear and the thickness of the diffusion layer is h,
Dc/dx = (Cb-Cs)/h (5)
Where Cs is the concentration at the solid surface and Cb is the concentration in the bulk solution. By combing the above equation, the flow rate of material is given by
Dm/dt = - (DA/h) (Cb-Cs) = KA (Cs-Cb) (6)
Where K is the intrinsic dissolution rate constant.
The above equation predict constant dissolution rate. If the surface area, diffusion co-efficient, diffusion layer thickness, and concentration difference are kept constant. However, as dissolution proceeds, all of the, parameters the surface area especially, may change.
Dissolution control of drug release via thickness and dissolution rate of the Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â membrane barrier coat15
Most suitable dosage forms for this mechanism is compressed tablets containing coated particles E.g. ethyl cellulose, Nylon, Acrylic resins. Release depends on drug solubility and pore structure membrane .constant release resulted when GI fluid passes through barrier to dissolve drug.
B) Diffusion controlled release systems
There are two types of diffusion controlled systems which have been developed over the past two decades: reservoir devices and matrix devices .In diffusion controlled extended release systems the transport by diffusion of dissolved of drug in pores filled with gastric or intestinal juice or in a solid phase is the release controlling process.
Depending on the part of the release unit in which the drug diffusion takes place, diffusion controlled release systems are divided into matrix systems and reservoir systems .the release unit can be tablet or a nearly spherical particle of about 1 mm or less intact during course of the release process
In matrix systems diffusion occurs in pores located within the bulk of the release unit ,and in reservoir systems diffusion takes place in a thin water soluble film or membrane ,often about 5-20 um thick ,which surrounds the release unit ,diffusion through the membrane can occur in pores filled with fluid or in the solid phase that forms the membrane .
Drug is release form a diffusion controlled realest unit in to two steps:
Â Â Â Â Â Â Â Â 1. The liquid that surrounds the dosage form penetrates the release unit and dissolves the Â Â Â Â Â Â Â drug . A concentration gradient of dissolved drug is thus established between the Â Â Â Â Â Â Â interior and the exterior of the release unit
Â Â Â Â Â Â Â Â Â 2. The dissolved drug will diffuse will diffuse in the pores of the release unit or the Â Â Â Â Â Â Â surrounding membrane and thus be released, or alternatively, the dissolved drug will Â Â Â Â Â Â Â partition into the membrane surrounding the dose unit and diffuse in the membrane.
A dissolution step is thus normally involved in the release process but the diffusion step is the rate controlling step.
The rate at which diffusion will occur depends on four variables:
â- The concentration gradient over the diffusion distance.
â- The area.
â- The distance over which diffusion occurs.
â- The diffusion co-efficient off the drug in the diffusion medium.
Some of these variables are used to modulate the release rate in the formulation.
C) Erosion controlled release systems:
In erosion controlled extended release systems that rate of drug release is controlled by the erosion of a matrix in which drug is dispersed. The matrix is normally a tablet, I.e. the matrix is formed by a tab letting operation, and the system can thus be described as a single unit system. The erosion in its simplest form can be described as a continuous liberation of matrix material (both drug and Excipients) from the surface of the tablet, i.e. surface erosion. The consequence will be a continuous reduction in tablet weight during the course of the release process.
Schematic illustration of the mechanism of drug release from a erosion based matrix tablet (t=time)
mtx img 2
Drug release from an erosion system can thus be described in two steps.
1. Matrix material, in which the drug is dissolved or dispersed, is liberated from the Â Â Â Â Â Â Â Â surface of the tablet.
2. The drug is subsequently exposed to the gastrointestinal fluids and mixed with (if the Â Â Â Â Â Â Â drug is dissolved in the matrix) or dissolved in (if the drug is suspending in the matrix) Â Â Â Â Â Â Â the fluid.
The erode matrix can be formed from different substances. One Â Â Â Â Â Â Â example is lipids or waxes, in which the drug is dispersed. Another example is Â Â Â Â Â Â Â polymers that gel in contact with water (Hydroxyl ethyl cellulose). The gel will subsequently erode and release the drug dissolved or dispersed in the gel. Diffusion of the drug in the gel may occur in parallel.
D) Osmotically controlled release systems.
Osmotic controlled oral drug delivery systems utilize osmotic pressure for controlled delivery of active agents. Drug delivery from these systems to a large extent is independent of the physiological factors of the gastrointestinal tract and these systems can be utilize for systemic as well as targeted delivery of drugs. The release of drug(s) from osmotic systems is governed by various formulation factors such as solubility and osmotic pressure of the core components(s), size of the delivery orifice and nature of the rate controlling membrane. Drug release from this system is independent of pH and other physiological parameters to a large extent and it is possible to modulate the release characteristics 11.
1.11 MATRIX TABLET,16,17,18
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
There are three classed of material used as release retardants in matrix tablet formulations.
a) Insoluble inert polymers
Tablets prepared from these materials are designed to be ingested intact and not break a part in GI tract. Ingested tablets contain unreleased drug in the core. For example polyethylene, poly vinyl chloride, Ethyl cellulose, Methyl acrylate - methacrylate copolymer.
b) Insoluble, erodable polymers
These form matrices that control release through both pore diffusion and erosion. Release characteristics are therefore more sensitive to digestive fluid composition than to the totally insoluble polymer matrix. Total release of drug from wax-lipid matrices is not possible , since a certain fraction of the dose is coated with impermeable wax films. For example carnuba wax in combination with stearic acid, stearyl alcohol, Castor wax and Triglycerides.
c) Hydrophilic polymers
This group represents non-digestible materials that form gels in situ. Drug release is controlled by penetration of water through a gel layer produced by hydration of the polymer and diffusion of drug through the swollen, hydrated matrix, in addition to erosion of the gelled layer. The extent to which diffusion or erosion controls release depends on the polymer elected for formulation as well as on drug polymer ratio. For example methyl cellulose, hydroxyl ethyl cellulose, hydroxypropyl methylcellulose,Sodium alginate.
1.12 TYPES OF MATRIX TABLET19
a)Hydrophilic Matrix Tablet
For example sodium carboxymehylcellulose, methylcellulose, hydroxypropyl-methylcellulose, hydroxyethylcellulose, polyethylene oxide, poly vinyl pyrrolidine, poly vinyl acetate, gelatin, natural gums etc. several commercial patented hydrophilic matrix systems are currently in use, such as synchron technology and hydrodynamically balanced system. Main advantages of hydrophilic matrix systems are ease of manufacture and excellent uniformity of matrix tablet.
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) Plastic matrix tablets
For example polyvinyl chloride, polyethylene, polyvinyl acetate, vinyl chloride copolymer, vinyllidine chloride, acrylate or methyl methacrylate polymer, ethyl cellulose, Cellulose acetate, Polystyrene.
With plastic material(s) tablets can be easily prepared by direct compression of drug provided the plastic material can be comminuted or granulated to desired particle size to facilitate mixing with drug particles.