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Oral route of drug administration is the most important method of administering drugs for systemic effects. Nevertheless, it is probable that at least 90% of all drugs used to produce systemic effects are administered by the oral route. When a new drug is discovered, one of the first questions a Pharmaceutical company asks is whether or not the drug can be effectively administered for its intended effect by the oral route. If patient self-administration cannot be achieved, the sale of the drug constitutes only a small fraction of what the market would be otherwise. Of drugs that are administered orally, solid oral dosage forms represent the preferred class of products. Tablets and capsules represent unit dosage form in which one usual dose of the drug has been accurately placed (Lachman L et al.,1987).
1.1.2 CLASSIFICATION OF TABLETS
a) Classification Based On Mode of Administration
Tablets to be swallowed
Tablets used in oral cavity
a) Buccal tablets
b) Sublingual tablets
c) Troches and lozenges
4) Tablets administered other than oral route
b) Vaginal tablets / suppositories
b) Classification Based On Manufacturing Process
1) Standard compressed tablets
2) Multiple compressed tablets
a) Compression - coated tablets
b) Layered tablets
c) Inlay Tablets
3) Coated tablets
4) Moulded tablets (Tablet triturates)
c) Classification Based On Drug Release Profile
1) Fast dissolving tablets
2) Immediate release tablets
3) Controlled release tablets (Sustained release tablets)
4) Delayed release tablets (Enteric coated tablets)
d) Tablets Used To Prepare Solutions
a) Effervescent tablets
b) Dispersible tablets
1.2 COMBINATION THERAPY
When two or more drugs are used together to treat any disease, treatment is called as combination therapy. Now a day's various developed and developing countries move towards combination therapy for treatment of various diseases and disorders requiring long term therapy (John A et al.,2006& Michael J et al 2004).
Advantages of Combination therapy over monotherapy such as
Problem of dose dependent side effects is minimized.
A low dose combination of two different agents reduces the dose related risk.
The addition of one agent may counteract some deleterious effects of the other.
Dosage form of two or more active ingredients in combination can show
Synergistic cumulative effect and /or decreased side effects (Pujari S et al.,2003).
But at the same time, there also exist some problems in the process of preparing such combination solid dosage forms, such as incompatibility between the active ingredients or between active ingredients and excipient (Wang X et al,.2003)
1.2.1. COMMONLY USED APPROACHES FOR DEVELOPING FORMULATION OF COMBINATION THERAPY
Pellets: Pellets are round and uniform in size. This type of dosage forms are generally used to deliver the combination of drugs or to extend the release pattern or to feed in the capsule (Campen LV et al,.2002&Schimdt PC et al,.2002)
Compressed Tablets: Compressed tablets are prepared by a single compression, occur in various shapes and sizes and usually contain in addition to the medicinal substances, a number of pharmaceutical adjuvant including,
Binders, which help powders fuse or link particles to one another.
Fillers, which bulk up a tablet.
Lubricants, which prevent powders from sticking to the metal components of the tablet press and tablet-press tooling.
Disintegrants breaks the tablet after being ingested.
Multiple Compressed Tablets: The tablet-manufacturing machine is generally operated at relatively lower speeds than for standard compression tablet.
There are three categories under this class:
Layered Tablets - two to three component systems (Bilayer or Trilayer Tablet) (KrishnaiahY.S.R et al,.2002)
Compression Coated Tablets - tablet within a tablet ( Tab In Tab )
Inlay Tablets- coat partially surrounding the core
They are prepared for one of the two reasons,
To separate physically or chemically incompatible ingredients.
To produce repeat action or prolonged action products.
(A)Multilayer Tablets (Bilayer Tablet):
Fig. No 1.1. Pictorial Representation of Bilayer tablet
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 a multilayer tablet.
Bilayer tablets require fewer material than compression coated tablets, weight, and may be thinner. Monograms and other distinctive marking may be compressed on the surface of the bilayer tablets (Lachman L et al 1987).
Advantages of Bilayer Tablets over Conventional Tablets (Li SP et al,.1995)
Patient convenience is improved because fewer daily doses are required compared to traditional drug delivery systems.(Kulkarni et al,.2000)
Incompatable drugs can be easily formulated in one dosage form by Bilayer tablet technology (Vogeleer J et al,.2009)
Patient compliance is enhanced leading to improved drug regimen efficacy.
Preventing cross-contamination between two layers.
Producing a clear visual separation between two layers.
Accurate and individual weight control of two layers.
Bilayer tablets readily lend themselves to repeat action products, where in one layer on layered tablet provides the initial dose, rapidly disintegrate in the stomach. The other layer is insoluble in gastric media but is released in the intestinal environment.(William C et al ,.1989&Jitendra R et al,.2009)
The widths of each layer can be accurately controlled (Chinam NP et al,.2007)
In bilayer tablets where in one layer on layered tablets provides an immediate release and other layer act as sustained release (Sale V et al,.2001)
Limitations of layered tablets (Vogeleer J et al,.2009)
Bi-layer tablets: Quality and GMP-Requirements (Vogeleer J et al,.2009)
To produce a quality Bi-layer tablet, in a validated and GMP-way, it is important that the selected press is capable of
Preventing capping and separation of the two individual layers that constitute the bi-layer tablet.
Providing sufficient tablet hardness.
Preventing cross-contamination between the two layers.
Producing a clear visual separation between the two layers.
Accurate and individual weight control of the two layers.
(B)Compression Coated Tablets
Fig. No 1.2. Pictorial Representation of Compression Coated Tablet
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 (Campen LV et al,.2002).
Centralization of the core tablets can be achieved by:
Reducing the rotational speed
By preparing relatively softer granules of core tablet which prevent the sliding of the core on the bottom layer of coating
Incompatible drugs can be formulated as compressed coated tablets,
If a drug tends to discolour or develop a mottled appearance because of the oxidation or sunlight, it can be minimized by formulating it as a compressed coated tablet.
Coating may cover:
Provide a barrier for substances irritating to stomach
Core may inactivated by gastric juice.
Fig. No 1.3. Pictorial Representations of Inlay Tablets
Inlay tablets are a type of layered tablets in which instead the core tablet being surrounded by coating, top surface is completely exposed (Li SP et al,.1995)
It has some advantages over compression-coated tablets:
Less coating material is required
Core is visible, so coreless tablets can be easily detected
Reduction in coating forms a thinner tablet and thus freedom from capping of top coating.
1.2.2 Various Approaches Used in the Bilayer Tablet (Timmin S et al,.2002)
a) Floating Drug Delivery System (Ziyaur R et al,.2006&Narendra C et al,.2006)
These are designed to have a low density and thus float on gastric contents after administration until the system either disintegrates or the device absorbs fluid to the point where its density is such that it loses buoyancy and can pass more easily from the stomach with a wave of motility responsible for gastric emptying.
The bilayer tablet is designed in such a manner that, one layer gives the immediate dosing of the drug which gives faster onset of action while other layer is designed as a floating layer which floats in the stomach (GI-fluid).
b) Polymeric Bioadhesive System.(Patel VM et al,.2007)
These are designed to imbibe fluid following administration such that the outer layer becomes a viscous, tacky material that adheres to the gastric mucosa/mucus layer. This should encourage gastric retention until the adhesive forces are weakened.
These are prepared as one layer with immediate dosing and other layer with bioadhesive property.
c) Swelling System
These are designed to be sufficiently small on administration, so as not to make ingestion of the dosage form difficult (e.g., less than approximately 23 mm long and less than 11 mm wide for an oval or capsule -shaped tablet whereas 10-12mm in diameter for round tablets). On ingestion they rapidly swell or disintegrate or unfold to a size that precludes passage through the pylorus until after drug release has progressed to a required degree. Gradual erosion of the system or its breakdown into smaller particles enables it to leave stomach. The simple bilayer tablet may contain an immediate release layer with the other layer as extended release or conventional release.
1.2.3. SINGLE SIDED PRESS (Vogeleer J et al,.2009)
Various types of Bi-layer presses have been designed over the years. The simplest design is a single-sided press with both chambers of the double feeder separated from each other. Each chamber is gravity- or forced-fed with a different powder, thus producing the two individual layers of the tablet.
Limitations of single-sided press (Vogeleer J et al,.2009)
No weight monitoring/control of the individual layers.
No distinct visual separation between the two layers.
very short first layer-dwell time
To eliminate these limitations, a double-sided tablet press is preferred over a single-sided press. A double-sided press offers an individual fill station, pre compression and main compression for each layer. In fact, the Bi-layer tablet will go through 4 compression stages before being ejected from the press.
Fig No 1.4. Bilayer Compression Machine
Compaction: To produce adequate tablet formulation, certain requirements such as sufficient mechanical strength and desired drug release profile must be met(Rudnic EM et al,.2000&GSK,UK&Cooper et al,.2003)
Compression: It is defined as reduction in bulk volume by eliminating voids and bringing particles into closer contacts (Breech AJ et al,.1998)
Consolidation: It is the property of the material in which there is increased mechanical strength due to interparticulate interaction (bonding). The compression force on layer 1 was found to be major factor influencing tablet delaminating(Li SP et al,.1995)
Fig.1.5.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
1.2.4 .General aspects regarding compression of Bilayer Tablets:
The steps involved in the manufacturing of bilayer tablet involve preparation of granules of both the layers, then compression of first layer with low hardness. The granules of second layer are introduced in the die cavity having pre compressed first layer which is then compressed using higher compression force to get the desired hardness.
To manufacture bilayer tablets, materials should have good compressibility and have bonding capacity. Hence, while choosing the excipients, one should investigate which excipients show plastic deformation and which show elastic recovery nature
The precompression parameters can be controlled separately to allow precise control of the deaeration during die filling, which in turn could minimize the capping tendency
Layer tablets usually undergo a light compression as each component is laid down, with the main compression being the last one. The slug (layer 1) should be compressed as soft as possible during the compression. The function of the layer 1 compression force is to tamp the material to make room in the die for the second layer of material(Ilgaz A et al,.)
The physical characteristics of tablet components can affect the formation of multilayer tablets. For materials undergoing volume reduction, mainly by plastic deformation (materials consolidating mainly by plastic deformation), a decrease in surface roughness of the first layer of the bilayer tablet, obtained by an increase in compaction load, results in marked decrease in interparticulate attraction between the two layers(Chokshi R et al,.)
Fig No1. 6. Problems associated with Bilayer tableting, Capping (A), Lamination (B) and possible causes of Capping/Lamination (C).
1.3 .Tablet Manufacturing Methods (Remington et al,.1660-1675)
Table No.1.1. Processing Steps Commonly Required in Various Tablet Granulation Techniques:
Ã- = Step used
X= Step not used
1.4 .Human immunodeficiency virus (HIV): is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections(Eric S et al,.&Weiss RA et al,.1993)
The four major routes of transmission are unsafe sex, contaminated needles, breast milk, and transmission from an infected mother to her baby at birth (perinatal transmission). Screening of blood products for HIV has largely eliminated transmission through blood transfusions or infected blood products in the developed world.
Fig.1.7. Diagram of human immunodeficiency virus
1.4.1. Classification(Grabar S et al,.2009)
There are two species of HIV known to exist: fl1V-1 and HIV-2. HIV-1 is the virus that was initially discovered and it is more virulent, more infective, and is the cause of the majority of HIV infections globally.
Table. No 1.2.classification
1.4.2 sign and sympotms(Piatak M et al,.1993&Pantaleo G et al,.1997)
Infection with HIV-1 is associated with a progressive decrease of the CD4+ T cell count and an increase in viral load. The stage of infection can be determined by measuring the patient's CD4+ T cell count, and the level of HIV in the blood.
1.5 .HIV Life Cycle(Chan D et al,.1998&Wyatt R et al,.1998)
Binding and Fusion:
HIV begins its life cycle when it binds to a CD4 receptor and one of two co-receptors on the surface of a CD4+ T- lymphocyte. The virus then fuses with the host cell. After fusion, the virus releases RNA, its genetic material, into the host cell.
An HIV enzyme called reverse transcriptase converts the single- stranded HIV RNA to double-stranded HIV DNA.
The newly formed HIV DNA enters the host cell's nucleus, where an HIV enzyme called integrase "hides" the HIV DNA within the host cell's own DNA.
Fig.1.8. HIV life cycle
When the host cell receives a signal to become active, the provirus uses a host enzyme called RNA polymerase to create copies of the HIV genomic material, as well as shorter strands of RNA called messenger RNA (mRNA). The mRNA is used as a blueprint to make long chains of HIV proteins.
An HIV enzyme called protease cuts the long chains of HIV proteins into smaller individual proteins. As the smaller HIV proteins come together with copies of HIV's RNA genetic material, a new virus particle is assembled.
The newly assembled virus pushes out ("buds") from the host cell. During budding, the new virus steals part of the cell's outer envelope. This envelope, which acts as a covering, is studded with protein/sugar combinations called HIV glycoproteins. These HIV glycoproteins are necessary for the virus to bind CD4 and co- receptors. The new copies of HIV can now move on to infect other cells.
1.6 ANTI -RETROVIRAL THERAPY(Michael A et al,.2006)
Antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) infection has improved steadily since the advent of potent combination therapy in 1996.
Discuss the goals of treatment for human immunodeficiency virus (HIV) infection.
Present the basic principles of antiretroviral therapy (ART).
Review the ARV medicines currently being used around the world to treat HIV infection.
Discuss barriers to effective ART and some ways to overcome them.
The goals of ARV therapy (ART) include the following:
Maximal and durable suppression of HIV replication
Restoration and preservation of immune function
Improvement in quality of life
Reduction in HIV-related morbidity and mortality
Types of Antiretroviral therapy (Michael A et al,.2006)
Monotherapy: This is the use of only one anti-retroviral drug. Monotherapy is no longer recommended for use in the treatment of HIV infection except in prevention of motherÂ to child transmission of HIV where Zidovudine (AZT) or Nevirapine can be used35.
Combination Therapy: Combination therapy is the use of more than one antiretroviral drug. It has been demonstrated that combination therapy is more effective and has less chances of developing resistance than Monotherapy.
Haart:-Highly Aggressive Anti-Retroviral Therapy(Shafer R et al,.1999&Martin C et al,.2007&Zuckermam M et al,.2005)
Fixed dose combinations: are multiple antiretroviral drugs combined into a single pill.
abacavir+ zidovudine+ lamivudine
Table.no1.3 Different brands available in market