Oral route is a most common route of administration, about 90 per cent of drugs are administered via oral route for systemic effects. Among the drugs that are administered orally, solid oral dosage form represent the preferred choice of class of product. Most common solid oral dosage forms are tablet and capsules. Tablets and capsules account for well over half the total number and cost of all prescriptions issued. (Jain N.K et al., 2006)
The British Pharmacopoeia defines tablets as, circular in shape with either flat or convex faces and prepared by compressing the medicament or mixture of medicaments usually with the added excipients. Tablets are now the most popular dosage form, accounting for some 70 % of all ethical pharmaceutical preparations produced. Tablets remain popular as a dosage form because of the advantages afforded both to the manufacturer (e.g. Simplicity, economy) preparation, stability, convenience in packing, shipping, and dispensing etc.) as well as patient (e.g. accuracy of dosage, compactness, portability, blandness of taste, and ease of administration etc.)
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The oral route of drug delivery is typically considered the preferred and most patient-convenient means of drug administration. Consequently, much effort is directed during drug discovery to identify orally active candidates that will produce reproducible and effective plasma concentration in vivo. Many compounds are ineffectively or incompletely absorbed after oral administration and hence require frequent dosing. Modified release formulation technologies offer an effective means to optimize the bioavailability and resulting blood concentration time profiles of drugs in therapeutic window. Significant advances have been made in the development of elegant systems to modify the oral drug delivery, but the basic approaches have remained greatly unchanged with the major systems being:
Insoluble, slowly eroding, or swelling matrices,
Polymer-coated tablets, or swelling matices,
Osmotically driven systems.
Systems controlled by ion exchange mechanisms, and
Various combination of these approaches.
Advantages of Tablet Medication (Jain N.K et al., 2006)
Ease of administration of accurate dose ,Easy handling
They are lightest in weight per dosage unit and hence ,cheapest to package
in strip packing
They are convenient for the ambulatory patients
Most stable dosage form with regard to any chemical change during its
longer expiry period
Stringent environmental conditions is not required
Easily identified by their shape, size and logo compressed on their surface
They can designed to provide controlled drug dissolution
Disadvantages of Tablet Medication
Slow onset of action
Large amount of liquid cannot be incorporated
Difficulty in swallowing for geriatric and pediatric patients
They require number of adjuncts which may affect the bioavailability of
Time consume for manufacturing , as they require number of steps
Tablet Manufacturing Methods - Advantages & Disadvantages
Simple, economical process
No heat or moisture, so good for unstable compounds
Not suitable for all API generally limited to lower dose compounds.
Robust process suitable for most compounds
Imparts flowability to a formulation
Can reduce elasticity problems
Coating surface with hydrophilic polymer can improve wettability
Binds API with excipient, thus reducing segregation potential.
Expensive, time and energy consuming process
Specialized equipment required
Stability issues for moisture sensitive and thermolabile API with aqueous granulation.
Wet granulation (non aqueous)
Suitable for moisture sensitive API
Vacuum drying techniques can remove/reduce need for heat
Needs organic facility
Solvent recovery issues
Health and environment issues.
Dry granulation (slugging or roll compaction)
Eliminates exposure to moisture and drying
Not suitablet for all compounds
Conventional drug products such as tablets and capsules are formulated to release the active drug immediately to obtain rapid and complete systemic absorption of the drug. Controlled release dosage forms cover a wide range of prolonged action. It provides continuous release of active ingredient at a predetermined rate and predetermined time. The basic goal of the therapy is to achieve a steady state blood or tissue level that is therapeutically effective and non-toxic for an extended period of time. A variety of oral controlled release dosage forms has been developed over a last four decades and the types of controlled release products are as follows
Types of Products
Always on Time
Marked to Standard
Matrix erodes or drug leaches from matrix
Different pellets (colors) have different release properties
Coated ion exchange
Insoluble coat with small hole. Osmotic pressure pushes the drug out at a controlled rate.
Matrix type or osmotic pumps type sustained release oral drug delivery system has risk of erratic performance due to variable stomach emptying and GI transit time.
For short half-life drugs, sustained release can mean less frequent dosing
and thus better compliance.
Reduce variations in plasma/blood levels for more consistent results.
More complicated formulation may be more erratic in results.
A failure of the controlled release mechanism may results of a large toxic
More expensive technology.
A sustained release product may contain a larger dose, i.e. the dose for two
or three (or more) 'normal' dosing intervals.
With advancement in technology and increase in awareness towards modification in standard tablet to achieve better acceptability as well as bioavailability, newer and more efficient tablet dosage forms are being developed. The main reasons behind formulation of different types of tablets are to create a delivery system that is relatively simple and inexpensive to manufacture, provide the dosage form that is convenient from patient's perspective and utilize an approach that is unlikely to add complexity during regulatory approval process. To understand each dosage form, tablet here are classified by their route of administration and by the type of drug delivery system they represent within their route.
Various Types of Tablets
Tablets Delivered into GIT
Standard compressed tablets
Multiple compressed tablets
Compression coated tablets
Enteric coated tablets
Sugar coated tablets
Film coated tablets
Sustained release tablets
Modified release tablet
Delayed action tablet
Colon targeting tablet
Tablets Used in Oral Cavity
Buccal and sublingual tablets
Lozenges or troches
Tablets for Miscellaneous
Multiple Compressed Tablets
The tablets in this category are prepared for two reasons:
To separate physically or chemically incompatible ingredients and
To produce repeat action/prolong action tablet.
The tablet manufacturing machine is generally operated at relatively lower speed than for standard compression tablet. There are three categories under this class:
Layered tablets - two to three component systems.
Compression coated tablets - tablet within a tablet.
Inlay tablet - coat partially surrounding the core.
The layered tablet is preferred over compression coated tablet as the surface contact is less and the production is simple and more rapid.
The tablets in this category are prepared for two reasons: to separate physically or chemically incompatible ingredients and to produce repeat action/ prolonged action tablet.
The tablet manufacturing machine is generally operated at relatively lower speed than for standard compression tablet.
There are three categories under this class:
Coat partially surrounding the core.
The layered tablet is preferred over compression coated tablet as the surface contact is less and the production is simple and more rapid.
When two or more active pharmaceutical ingredients are needed to be administered simultaneously and they are incompatible, the best option for the formulation pharmacist would be to formulate multilayered tablet. It consists of several different granulations that are compressed to form a single tablet composed of two or more layers and usually each layer is of different color to produce a distinctive looking tablet. Each layer is fed from separate feed frame with individual weight control. Dust extraction is essential during compression to avoid contamination. Therefore, each layer undergoes light compression as each component is laid down. This avoids granules intermixing if the machine vibrates.
II. Compression Coated Tablets
This type of tablet has two parts, internal core and surrounding coat. The core is small porous tablet and prepared on one turret. For preparing final tablet, a bigger die cavity in another turret is used in which first the coat material is filled to half and then core tablet is mechanically transferred, again the remaining space is filled with coat material and finally compression force is applied. This tablet readily lend itself in to a repeat action tablet as the outer layer provides the initial dose while the inner core release the drug later on. But, when the core quickly releases the drug, entirely different blood level is achieved with the risk of over dose toxicity. To avoid immediate release of both the layers, the core tablet is coated with enteric polymer so that it will not release the drug in stomach while, the first dose is added in outer sugar coating. Even so, coating operation requires interpretation while manufacturing and dawdling the manufacturing process. Sometimes, inner core may be of liquid formulation to provide immediate release of core after the coat gets dissolved.
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III. Inlay Tablets (Vaya Navin Karen et al., 2004)
A type of layered tablet in which instead the core tablet being completely surrounded by coating, top surface is completely exposed. While preparation, only the bottom of the die cavity is filled with coating material and core is placed upon it. When compression force is applied, some coating material is displaced to form the sides and compress the whole tablet. It has some advantages over compression coated tablets:
i) Less coating material is required, so cost effective.
ii) Core is visible, so coreless tablets can be easily detected.
iii) Reduction in coating forms a thinner tablet and thus freedom from capping of top coating.
It has following advantages over compression coated tablets (Vaya Navin Karen et al., 2004)
A new platform technology for decreasing the mechanical shear on double compressed products which can lead to decrease in unknown process related Impurities.
Incompatible drugs can also be designed.
Release of both drugs start immediately.
Lack of proper bonding of two layers is avoided in inlay tablet.
Minimize the stress due to high compression force which degrades certain active ingredients in multilayered tablet.
Core is visible, so coreless tablets can be easily detected.
Reduction in coating from a thinner tablet and thus freedom from capping of top coating.
The release of immediate release layer is not hindered by modified release layer.
The present invention also teaches the use of dual retard technique to effectively control the release rate of modified release active ingredient by using small quantity of release controlling agents. This dual retard technique thus sufficiently reduces the size of the dosage form, which is convenient for swallowing.
A further object of the present invention is a formulation, which gives accurate dosing and is prepared by conventional and simple processes.
A further object of the present invention is to provide a dosage form, containing one active ingredient in an immediate release form and another active ingredient as modified release and the release or disintegration of the immediate release active ingredient is not hindered by the modified release ingredient.
Another object of the present invention is to provide a dosage form, which effectively avoids the problem of separation of layers of multilayered tablets.
Accordingly a need exists for a dosage form providing combination of immediate release and modified release active ingredients and providing solution to problems associated with dosage forms described in prior art. Further, the dosage form should be simple and economical to produce.
Current guidelines for combination therapy advise the use of agents with differing and complementary mechanisms of action in order to maximize therapeutic activity and reduce toxicity.
To reduce this disparity in the duration of action, a novel strategy would be to combine a sustained release formulation of one active ingredient (shorter duration of action) with conventional formulation (long duration of action) of another active ingredient. This would make it possible to give the active ingredients in same dosing frequency.
This type of combination will give better compliance and a relative freedom from mealtime drug administration, thus, improving the quality of life. More importantly, because of prolonged duration of action, it shall produce a stricter control of blood glucose and consequently less diabetic complications.
The term "modified release" used herein in relation to the composition according to the invention or a rate controlling polymer or used in any other context means release, which is not immediate release and is taken to encompass controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release. The term "modified release dosage form" as used herein can be described as dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended release drug products (as per US FDA guideline for 'SUPAC-MR: Modified Release Solid Oral Dosage Forms').
The term "immediate release" used herein in relation to composition according to the invention or used in any other context means release which is not modified release and releases more than 70% of the active ingredient within 60 minutes. The term "immediate release dosage form" as used herein can be described as dosage form which allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug (as per US FDA guideline for 'SUPAC-MR: Modified Release Solid Oral Dosage Forms').
Further advantages of present invention include the disintegration of inner portion is not hindered as nonswellable release controlling agents are used which do not swell and maintain the shape during operation and it effectively prevents the separation of the layers of the multilayered tablets which is normally associated with normal multilayered table.
The future trend in control release tablets can be in
Multilaminated sustained release tablets
pH-independent controlled release granules
Thixotropic bilayer tablets.
Most drugs today are still prescribed in dosage forms date back to the earliest records of pharmacy for instance the pill (1500 Bc), the coated pill (c900 AD), the tablet (10th century) and the capsule 1833. For the past two decades investigations on pharmacokinetics and pharmacology have clearly demonstrated that the rate and extent of systemic drug availability determined, the therapeutic response and not the dose. The focuses of research and development in pharmaceutical sciences, technology in particular have shifted from to dose the rate determining components of the dosage forms.
The interest in sustained release type of dosage forms during the past decade, had prohibitive costs of developing new drug entitles the expiration of patents. The discovery of novel polymer systems and devices suitable for rate controlled drug delivery of sustain release drug delivery units. The team sustain or controlled drug release or matrix tablets incorporates the element of prolongation of duration of drug action as well as the drug predictability & reproducibility in drug release kinetics.
Sustain release dosage forms are becoming popular as these have a number of advantages over conventional preparation viz.
Reduction of dosing frequencies
Less fluctuation in circulating blood levels
Avoid patient compliance
Minimize local and systematic side effects
Improve bioavailability of some drugs
For this sustained release system the oral route of administration have received the most attention.
Sustained release dosage forms can divide conventionally into four categories.50
Site specific release
Oral dosage forms
Ion exchange system
Classically matrix products exhibit first order (or perhaps square root of time) drug release characteristics, it's necessary to employ specially designed materials or strategies that seek to manipulate tablet structure or geometry. Combination of conventional HPMC matrix technology with upper and lower layer. This helps to moderate drug release by increase in surface area with concomitant reduction in drug concentration within the device. (Robinson et al, 1992)
Figure No: 1 Graphical Comparison of blood concentration vs. time
Release of medicament can follow various mechanisms
i) Diffusion is Rate Limiting
Diffusion is driving force where the movement of drug molecules occurs from high concentration in the tablet to lower concentration in gastro intestinal fluids. This movement depends on surface area exposed to gastric fluid, diffusion pathway, drug concentration gradient and diffusion coefficient of the system.
Figure No: 2 Diffusion release pattern
In practice, we can follow either of the two methods,
The drug is formulated in an insoluble matrix; the gastric fluid penetrates the dosage form and dissolves the medicament and release the drug through diffusion.
The drug particles are coated with polymer of defined thickness so as the portion of drug slowly diffuse through the polymer to maintain constant drug level in blood.
ii) Dissolution is Rate Limiting
The drugs with poor water solubility (BCS class 2 and 4) are inherently sustained release forms. While for water soluble drugs, it's possible to incorporate a water insoluble carrier to reduce dissolution of the drug particles are coated with this type of materials e.g. Polyethylene Glycol. One may skip the use of disintegrating agent to promote delayed release.
iii) Osmotic Pressure is Rate Limiting
Osmosis is a phenomenon in which the flow of liquid occurs from lower concentration to higher concentration through a semi permeable membrane which allows transfer of liquid only. The whole drug is coated with a semi permeable membrane with a hole on one end of tablet made by a laser beam. The gastric fluid penetrates through the membrane, solubilizes the drug and increases the internal pressure which pumps the drug solution out of the aperture and releases the drug in gastric environment. The delivery rate is constant provided that the excess of drug present inside the tablet. But, it declines to zero once the concentration drops below saturation.
Figure No: 3 Osmotic Release Pattern
iv) Release is Controlled by Ion Exchange
Ion exchangers are water insoluble resinous materials containing salt forming anionic or cationic groups. While manufacturing, the drug solution is mixed with resin and dried to form beads which are tableted. The drug release depends upon high concentration of charged ions in gastro intestinal tract where, the drug molecules are exchanged and diffused out of the resin into the surrounding fluid. This mechanism relies upon the ionic environment of resin and not pH or enzyme on absorption site.
IMMEDIATE RELEASE TABLETS
Since the initial success of the immediate release tablet (IR tablets ), they have been steadily improving for development of more patient-friendly dosage forms. To obviate the problems related to conventional dosage forms, immediate release tables have been formulated which combine the hardness, dosage uniformity, stability and other parameters, with extremely easy administration. The immediate release tablets start to disintegrate immediately in the GIT even in the absence of water. Bioavailability/rate of dissolution of the poorly soluble drug from a solid oral dosage form depends on the release of the drug substance from the drug product/dosage form i.e., disintegration of the solid oral dosage form which will increase the wettability of the drug by increasing the surface area of the drug particles. (Vasanthakumar Sekar et al., 2008).
After a tablet disintegrates or dissolves, the active ingredient in the tablet can be absorbed from the GIT resulting in the desired therapeutic effect. (Seong Hoon Jeong et al., 2007)
Advantages of Immediate Release Medication
Beneficial for pediatrics, geriatrics & shizophrenic patients who have difficulty in swallowing conventional solid dosage forms.