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1,2The oral administration of drugs has been the most common and preferred route for delivery of most therapeutic agents. It remains the preferred route of administration investigated in the discovery and development of new drug candidates and formulations. The popularity of the oral route is attributed to patient acceptance, ease of administration, accurate dosing, cost-effective manufacturing methods. 3The conventional tablets are usually administered frequently which will lead to the fluctuation of drug plasma concentration which may cause an inefficient treatment and side effects.
4The manufacture of bilayer tablet has recently become of increased interest within the pharmaceutical industry due to the tailored release profile of active ingredients. Such a tablet has fast releasing layer and a layer to sustain the drug release. These formulations are designed to deliver the drug at a predetermined rate, thus maintaining their therapeutically effective concentration in systemic circulation for prolonged period of time.
1. Tablets5,6 :
Pharmaceutical tablets are the dominant dosage forms for drug delivery, occupying two thirds of the global market. Generally they are manufactured by compressing dry powder blends consisting number of components with different functionalities in a die. With advancement in technology and increase in awareness towards the modification in standard tablet to achieve better acceptability and bioavailability, newer and more efficient tablet dosage forms are being developed. The main purpose behind formulation of different types of tablets is to create a delivery system that is relatively simpler and in expensive 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.
1.1. Various types of tablets6
a) Oral tablets for ingestion:
These tablets are meant to be swallowed intact along with a sufficient quantity of potable water. Exception is chewable tablet. Over 90% of the tablets manufactured today are ingested orally. This shows that this class of formulation is the most popular worldwide and the major attention of the researchers is towards this direction.
1. Standard compressed tablets
2. Multiple compressed tablets
a. Compression coated tablets
b. Layered tablets
c. Inlay tablets
3. Modified Release tablets
4. Delayed Release tablets
5. Targeted tablets
a. Floating tablets
b. Colon targeting tablets
6. Chewable tablets
7. Dispersible tablets
b) Tablets used in the oral cavity:
The tablets under this group are aimed to 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.
1. Lozenges and troches
2. Sublingual tablets
3. Buccal tablets
4. Dental cones
5. Mouth dissolving tablets
c) Tablets administered by other routes
These are the tablets 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.
1. Vaginal tablets
d) Tablets used to prepare solution
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 route of administration.
1. Effervescent tablets
2. Hypodermic tablets
2. Sustained release drug delivery system6,7
Fig :1 Drug release profile
Sustained release drug delivery system 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 sustained.
The goal in designing delayed release sustained or controlled delivery system is to
â€¢ Reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required, or providing uniform drug delivery.
â€¢ It should deliver the active entity directly to the site of action, minimizing or eliminating side effects.
â€¢ This may necessitate delivery to specific receptors or to localization to cells or to specific areas of the body
â€¢ The safety margin of high potency drug can be increase and the incidence of both local and systemic adverse side effects can be reduced in sensitive patient
2.1. Mechanism of drug release for sustained release drug delivery system7,8
On exposure to gastric aqueous fluid, hydrophilic matrices take up water, and polymer starts hydrating to form a gel layer. Drug release is controlled by diffusions barriers or by surface erosion. An initial burst of soluble drug may occur due to surface leaching when a matrix containing a swellable glassy polymer. Then the second layer becomes fully hydrated and states dissolving or eroding. When water reaches the center of the system then the concentration of drug falls below the solubility value, the release rate of drug begins to reduce. At the same time, an increase in thickness of the barrier layer with time increases the diffusion path length, reducing the rate of drug release. Drug release kinetic associated with these gel - layer dynamic, range initially from Fickian to annomalous (Non - Fickian) and subsequently from quasi - Constant ( near Zero order ) to constant. In general, two major factors control the drug release from swelling controlled matrix system. They include
1. The rate of aqueous medium infiltration into the matrix, followed by a relaxation process (hydration, gelation or swelling)
2. The rate of matrix erosion
2.2. Advantages and Disadvantages of sustained release dosage form9,10:
1. It improves patient compliance
2. It may improve the patho-physiology of the disease
a. It minimizes or eliminates local side effects.
b. It minimizes or eliminates systemic side effects
c. It obtains less potentiation or reduction in drug activity with chronic use
d. It minimizes drug accumulation with chronic dosing
3. It improves the efficiency in treatment
a. It cure or controls the condition more promptly
b. It improves bioavailability of some drugs
c. Reduction in fluctuation in steady-state levels and therefore better control of disease condition.
d. Make use of special effects e.g. sustained release aspirin for morning relief of arthritis by dosing before bedtimes
4. Improved therapy
a. Sustained blood level- the dosage form provided uniform drug availability or blood levels unlike peak and valley pattern obtained by intermittent administration.
b. Attenuation of adverse effects- the incidence and intensity of undesirable side effects caused by excessively high peak drug concentration resulting from the administration of conventional dosage forms is reduced.
1. Cost is very high.
2. Unpredictable and often poor In vitro in vivo correlation.
3. Dose dumping.
4. Reduce potential for dosage adjustment of drugs normally administered in varying strengths
5. For oral SR dosage forms there is an additional disadvantage that the effective drug release period is influenced and limited by GI residence time.
6. Retrieval of the drug is difficult in case of toxicity, poisoning or hypersensitivity reactions.
2.3. Criteria to be met by drug proposed to be formulated in sustained release dosage forms:
a) Desirable half-life8,9,11,12:
The half life of a drug is an index of its residence time in the body. Short half life(2 hours) indicates higher content of the drug for absorbtion. On the other hand, drug with elimination half life of eight hours is effectively sustained in the body. So, short half life drugs are syuitable candidates for sustained release. Ideally, the drug should have half-life of three to four hours.
b) High therapeutic index:
Drugs with low therapeutic index are not for controlled release formulations. Dose dumping may occure as in the case of Digitoxin.
c) Small dose:
If the dose of a drug in the conventional dosage form is high, its suitablea candidate for controlled release. This is chiefly due to the size of a unit dose controlled release formulation would become too big, to administer without difficulty.
d) Desirable absorption and solubility characteristics:
Absorption of poorly water soluble drug is often dissolution rate limited. Incorporating such compounds into controlled release formulations is not suitable and may reduce overall absorption efficiency.
e) Desirable absorption window:
Certain drugs when administered orally are absorbed only from aGIT. This part is referred to as the 'absorption window'. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if formulated as controlled release dosage form are unsuitable.
f) First pass clearance:
Delivery of the drug to the body in desired concentrations is seriously hampered in case of drugs undergoing extensive hepatic first pass metabolism, when administered in controlled release forms.
3. Matrix tablets 13,14,15
One of the simplest approaches to the manufacture of extended release dosage forms involves the direct compression or granulation of blends of drug, dissolution retardant material and additives to form a tablet in which drug is embedded in a matrix of the retardant Alternately, retardant drug blends may be granulated prior to compression.
There are three different types of matrix tablets, hydrophilic matrices, fat-wax materials and plastic matrices.
3.1. Hydrophilic Matrix Tablets:
Sodium carboxymethylcellulose, Methylcellulose, Hydroxypropylcellulose, Hydroxyethylcellulose, Polyethylene oxide, Polyvinyl pyrollidone, Polyvinyl acetate, Carboxypolyethylene, Alginic Acid, Gelatin and natural gums are used as matrix materials.
The hydrophilic matrix requires water to activate the release mechanism. Upon immersion in water, the hydrophilic matrix quickly forms a gel around the tablet. Drug release is controlled by a gel diffusion barrier that is formed and / or tablet erosion.
3.2. Fat-wax Matrix Tablets
The primary constituents of a fat-wax matrix are fatty acids and / or fatty esters. The drug can be incorporated into fat-wax granulations by spray congealing in air, blend congealing in an aqueous media with or without the aid of surfactants and spray drying techniques.
The drug embedded into a melt of fats and waxes is released by leaching and / or hydrolysis as well as dissolution of fats under the influence of enzymes and pH changes in the gastro intestinal tract.
Fatty acids are more soluble in an alkaline rather than acidic medium. Fatty esters are more susceptible to alkali catalyzed hydrolysis than to acid catalyzed hydrolysis. Polyethylene, ethyl cellulose and glycerin esters of hydrogenated resins have been added to modify release pattern.
3.3. Plastic Matrix Tablets
Commonly used plastic matrix materials are Polyvinyl chloride, Polyethylene, vinyl acetate / vinyl chloride co-polymer, vinylidene chloride, acrylonitile co-polymer, acrylate / methyl methacrylate co-polymer, Ethyl cellulose, cellulose acetate and polystyrene.
Plastic matrix tablets can be prepared by direct compression of drug with plastic materials provided the plastic material can be comminuted or granulated to desired particle size to facilitate mixing with drug particle.
The process may be accomplished by
ïƒ˜ Mixing the solid drug, and the plastic powder and kneading with a solution of the same plastic material or other binding agent in an organic solvent and then granulating.
ïƒ˜ Dissolving the drug and the plastic in a common organic solvent and then a granulating upon evaporation of the solvent.
ïƒ˜ Using latex or pseudo latex as granulation fluid to granulate the drug and plastic masses.
3.4. Material used as retardants in matrix tablet formulation:
Hydrophilic : Methylcellulose (400CPs, 4000CPs), Hydroxy ethylcellulose, Hydroxypropylmethylcellulose (60HG, 90HG, 25CPs, 40000CPs, 150000CPs), Sodium Carboxymethylcellulose, Carboxy polymethylene, Galactomannose , Sodium alginate.
Insoluble inert : Polyethylene, Polyvinylchloride, Methyl-methacrylate copolymer, Ethylcellulose.
Insoluble Erodable : Carnauba wax, Stearyl alcohol, Stearic acid, Polyethylene glycol monostearate, Triglycerides, Castor wax.
4. Novel dual release tablets16,17
Synonyms: Bilayer tablet, multi-layer matrix tablet , bilayer caplets.
Dual release tablet is a unit compressed tablet dosage form intended for oral application. It contains two parts in which one part having conventional or immediate release part another one is sustained or controlled release part.
4.1. Bilayer tablets
Several pharmaceutical companies are currently developing bilayer tablets for a variety of reasons, patient extension, therapeutic marketing to name a few.
4.1.1 Ideal properties for bilayer tablets press
â€¢ Preventing capping and separation of the two individual layers that constitute the bilayer tablet.
â€¢ Providing sufficient tablet hardness.
â€¢ Preventing cross contamination between the two layers.
â€¢ Producing a clear visual separation between the two layers.
â€¢ High yield.
â€¢ Accurate and individual weight control of the two layers.
4.1.2 Manufacturing of bilayer tablets:
Bilayer tablets were manufactured as shown in the by removal of the upper punch after the initial layer decompression and refilling the die for the final compaction. After the second compaction and decompression the lower punch was removed and the tablet was ejected by the application of a force to the upper punch driving the tablet out of the die.
Fig: 2 The schematic representation of the uni-axial die compaction method: A-Die filling, B-Compaction, C-Decompression, D- Ejection, E-Green body. 1 refers to the final compaction of a bilayer tablet
4.1.3 Types of bilayer tablet press :
(a) Single sided tablet press.
(b) Double sided tablet press.
(c) Bilayer tablet press with displacement monitoring.
(a) Single sided tablet press:
â€¢ The simplest design is the single sided press with both chambers of the doublet feeder separated from each other.
â€¢ Each chamber is gravity or forced fed with different powder, thus producing the two individual layers of the tablets.
â€¢ When the die passes under the feeder, it is first loaded with the first layer powder followed by the second layer powder.
â€¢ Then the entire tablet is compressed in one or two steps.
Limitations of the single sided press:
â€¢ No weight monitoring / control of the individual layers.
â€¢ No distinct visual separation between the two layers.
â€¢ Very short first layer dwell time due to the small compression roller, possibly resulting in poor de-aeration, capping and hardness problems.
â€¢ This may be corrected by reducing the turett-rotation speed (to extend the dwell time) but with the consequence of lower tablet output.
Dwell time is defined as the time during which compression force is above 90% of its peak value. Longer dwell times are a major factor in producing a quality tablet, especially when compressing a difficult formulation.
Separation of the two individual layers is the consequence of insufficient bonding between the two layers during final compression of the bilayer tablet. Correct bonding is only obtained when the first layer is compressed at a low compression force so that this can still interact with the second layer during final compression of the tablet. Bonding is severely restricted if the first layer is compressed at a too-high compression force. However, many bilayer formulations requires a first layer compression force of less than 100 daN in order to retain the ability to bond with the second layer. Above 100 daN, this ability may be lost, bonding between both layers may not be sufficient, resulting in low hardness of the bilayer tablet and separation of the two layers.
(b) Double sided tablet press
â€¢ A double sided press offers an individual fill station, pre-compression and main compression for each layer. In fact the bilayer tablet will go through four compression stages before being ejected from the press.
â€¢ In most double sided tablet presses with automated production control use compression force to monitor and control tablet weight.
â€¢ The effective peak compression force exerted on each individual tablet or layer is measured by the control system at main compression of the layer.
â€¢ This measured peak compression force is the signal used by the control system to reject out of tolerance tablets and correct the die fill depth when required.
(c) Bilayer tablet press with displacement
The displacement tablet weight control principle is fundamentally different from the principle based upon compression force.
When measuring displacement, the control system sensitivity does not depend on the tablet weight but depends on the applied pre-compression force.
â€¢ Weight monitoring/control for accurate and independent weight control of the individual layers.
â€¢ Low compression force exerted on the first layer to avoid capping and separation of the two individual layers.
â€¢ Independence from the machine stiffness.
â€¢ Increased dwell time at pre-compression of both first and second layer to provide sufficient hardness at maximum turett speed.
â€¢ Maximum prevention of cross contamination between the two layers.
â€¢ Clear visual separation between the two layers and maximized yield.
4.1.4. Advantages of Bilayer tablets:
â€¢ Bilayer tablet is suitable for preventing direct contact of two drugs and thus to maximize the efficacy of combination of two drugs.
â€¢ Bilayer tablets can be designed in such a manner as to modified release as either of the layers can be kept as extended and the other as immediate release.
â€¢ Extension of a conventional technology.
â€¢ Potential use of single entity feed granules.
â€¢ Separation of incompatible components.
â€¢ Patient compliance is enhanced leading to improve drug regimen efficiency.
â€¢ Patient compliance is improved because fewer daily dose are required compared to traditional delivery system.
â€¢ Maintain physical and chemical stability.
â€¢ Retain potency and ensure dose accuracy.
4.1.5.Disadvantages of Bilayer tablets:
â€¢ Adds complexity and bilayer rotary presses are expensive.
â€¢ Insufficient hardness, layer separation, reduced yield.
â€¢ Inaccurate individual layer weight control.
â€¢ Cross contamination between the layers.
â€¢ Used in the combination therapy
â€¢ Used to deliver the loading dose and sustained dose of the same or different drugs.
â€¢ Used for bilayer floating tablet in which one layer is floating layer another one is release layer of the drug.
â€¢ Used to deliver the two different drugs having different release profiles.
High blood pressure (HBP) or hypertension means high pressure (tension) in the arteries. Arteries are vessels that carry blood from heart to all the tissues and organs of the body. High blood pressure does not mean excessive emotional tension, and stress can temporarily increase blood pressure. Normal blood pressure is below 120/80; blood pressure between 120/80 and 139/89 is called "pre-hypertension", and a blood pressure of 140/90 or above is considered high.
5.2Classification of Antihypertensive drugs
1. ACE Inhibitors: Captopril, Enalapril, Lisinopril, Ramapril, Perindopril
2. Angiotensin (AT1) Antagonists: Losarton, Candesartan, Irbesartan, Valsartan
3. Calcium Channel Blockers: Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine
Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide
High ceiling: Furasemide
K+ Sparing: Spirinolactone, Triamterene, Amiloride
5. ß Adrenergic Blockers: Propranolol, Metoprolol, Atenolol
6. Î± Adrenergic Blockers: Prazosin, Terazosin, Doxazosin, Phentolamine
7. ß+ Î± Adrenergic Blockers: Labetalol, Carvedilol
8. Central Sympatholytics: Clonidine, Methyldopa
Arteriolar: Hydralazine, Minoxidil, Diazoxide
Arteriolar + Venous: Sodium Nitropruside
5.3Angiotensin (AT1) Antagonists
AT1 receptor antagonists have been developed as alternatives to ACE inhibitors . Losarton, Candesartan, Irbesartan, Valsartan are currently marketed .
Pharmacologically Angiotensin (AT1) Antagonists differ from ACE inhibitors in the following ways
ïƒ˜ They donot interfere with degradation of Bradykinin and other ACE substrates .
ïƒ˜ They result in more complete inhibition of AT1 receptor activation .
ïƒ˜ They result in indirect AT2 receptor activation.
5.3.1Uses of AT1 antagonists
ïƒ˜ They used as alternatives to first line antihypertensives drugs as alternatives to ACE inhibitors.
ïƒ˜ It does not cause cough and angiodema.
ïƒ˜ It is also effective against portal hypertension.
ïƒ˜ It can also be used in the treatment of Mycardial Infraction.
Valsartan is a oral medication that belongs to the class of drugs called angiotensin receptor blockers. Angiotensin formed in the blood by the action of angiotensin converting enzyme(ACE), is a powerful chemical that attaches to angiotensin receptor found in many tissues but primarily on smooth muscle cells of blood vessels . Angiotensin attaches to the blood vessels causes the blood vessels to contract which leads to an increase in blood pressure . Valsartan blocks the angiotensin receptor by blocking the action of angiotensin, Valsartan dilates the blood vessels and reduces the blood pressure.
5.4 THIAZIDE DIURETICS
ïƒ˜ Initially the dieresis reduces plasma and extra cellular fluid volume by about 15% leading to decreased cardiac output.
ïƒ˜ Subsequently compensatory mechanisms operate to almost regain Na+ balance and plasma volume; cardiac output is restored , but the fall in BP is maintained by a slowly developing reduction in total peripheral resistance.
ïƒ˜ The fall in BP develops gradually over 2-4 weeks. During long term treatment with thiazides, the heart rate and cardiac output are unaffected while total peripheral resistance is reduces despite compensatory increase in plasma rennin activity .
Hydrochlorothiazide is a diuretic. It increases the amount of urine passed , which causes the body to loose salt and water. This medicine is used to treat high blood pressures. It also reduces the swelling and water retention caused by various medicinal conditions such as heart, liver, kidney diseases .