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Oral delivery is the oldest and the most extensively used and preferred route of administration effective in achieving local and systemic effects. Tablets and capsules are preferred over other dosage forms in the oral drug delivery system itself. This is due to its better patient compliance, accurate dosing, physical and chemical stability, portability, elegant distinctive appearance and competitive unit production cost. ( Lachman Lieberman)
Absorption of an orally administered drug from the GIT depends on the various factors like gastric emptying time, intestinal transit time, gastro intestinal pH, disease states, mucosal surface area, blood flow through the GIT and pre-systemic metabolism and therefore formulations should be developed within the intrinsic characteristics of the gastro intestinal physiology. Also the absorption rate of the drug varies from the stomach to the intestine due to the various factors like surface area (stomach 0.1-0.2 sq.mt, intestine 200 sq.mt), blood flow (stomach 0.15/min, intestine 1l/min), intestinal mucosa and transit time. (Brahmankar) Apart from this, basic drugs are unstable in stomach pH and acidic drugs are unstable in the intestine and therefore their absorption is greatly compromised in these environments. So various techniques like oral site specific drug delivery system have been employed for improving the absorption of these drugs and also for the local treatment of various diseases of GIT. The therapeutic agents can be enteric coated for its effective delivery to the intestinal region. (7)
CONTROLLED RELEASE DRUG DELIVERY SYSTEMS
The basic rationale of a controlled drug delivery system is to optimize the biopharmaceutic, pharmacokinetic and pharmacodynamic properties of a drug in such a way as to deliver the drug to a particular site in the body (spatial control) to promptly achieve and then maintain the desired drug concentration for a predetermined period (temporal control).(bhramanger and chein)
Drug targeting is the phenomenon of directing a drug moiety to the desired site of action with little or no interaction with the non target tissues. (1)
The rationale for drug targeting includes
The ability to reach the diseased site in the body with reduced dose and side effects.
To access previously inaccessible sites and to protect the body and drug from one another until the desired site is reached.
To control the frequency and rate of dosing to the receptor.(1)
Drug targeting is classified based on the level of selectivity.
First order of targeting or organ targeting
Second order of targeting or cellular targeting
In this the drug is targeted to a specific cell type within an organ or tissue.
Third order of targeting or sub cellular targeting. (1)
In this the drug is targeted to the intracellular components in the cell.
PULSATILE DRUG DELIVERY SYSTEM
Oral controlled release drug delivery system releases the drug with constant or variable release rates. In conventional dosage forms and in controlled drug delivery systems the drug release commences as soon as the dosage form is administered (Fig 1).
In certain conditions it is required that the drug should not be released during the initial phase of dosage form administration and that it be released only after a lag time. Such a release pattern is known as Pulsatile release.
A Pulsatile drug release is characterized by a lag time that is an interval of no drug release which is independent of the environmental factors like pH, enzymes, gastro intestinal motility and is then followed by rapid drug release.
The conditions that demand a Pulsatile release are
Body functions that follow a circadian rhythm eg. Hormones like rennin, aldosterone and cortisol which show daily fluctuations in their blood levels, acid secretion in the stomach, gastric emptying and gastro intestinal blood transfusion.
Diseases like bronchial asthma, myocardial infarction, angina pectoris, ulcer and hypertension which shows time dependence.
Asthmatic attacks which shows an increased incidence during early morning hours (Dethlefsan and Repges)
Morning stiffness typical of arthritis
The lag time is essential for the drugs that undergo degradation in the gastric medium (peptide drugs) or which can irritate the gastric mucosa or can induce nausea or vomiting.
Targeting of the drugs to the distal organs of the GIT like the colon requires the release to be prevented in the upper two-third portion of the GIT.
For the drugs that undergo extensive first pass metabolism eg ÎÂ²-blockers.
After the lag phase, according to the formulation characteristics, the Pulsatile delivery system may give a prompt and quantitative, repeated or prolonged release pattern. (pdf 1)
The major challenge in the development of pulsatile drug delivery system is to achieve a rapid drug release after the lag time. Often, the drug is released over an extended period of time.( b & c in fig 1 buk)
Recently, pulsatile release has been recognized as a potential tool for meeting the chrono pharmaceutical demands.(art 1 pg1 Maroni et al). Also for formulating a repeated release system for drugs which cannot be formulated as a prolonged release form due to the drugs pharmacological tolerance or strong first pass metabolism, a multiple daily dosing regimen can be applied.
One of the significant advantages of oral pulsatile delivery is its ability in limiting the bacterial resistant strains by controlling the delivery of antibiotics through multi-pulse delivery system. (pdf 1pg2 line 85).
Pulsatile delivery system is also used for achieving an oral colon delivery.(pdf 1 pg2 line 93). This colonic delivery is highly beneficial for drugs with poor gastro intestinal stability and permeability like proteins, peptides, oligonucleotides and nucleic acids.
Pulsatile systems are basically time controlled systems and can be classified as single unit (eg. Tablets, capsules) and multiple unit (eg. Pellet) systems.
SINGLE UNIT SYSTEMS
The general make up of these systems contains an insoluble capsule body which houses a drug and a plug. After a predetermined lag time, generated due to swelling, erosion or dissolution, the plug will be removed.
The Pulsincap system is made up of a water insoluble capsule body which is closed at the open end with a molded swellable hydro-gel plug and filled with the drug and excipients. Upon contact with the gastro intestinal fluids, the plug swells and pushes itself out at a controlled rate independent of the nature and pH of the medium. The plug is usually made up of insoluble but permeable and swellable polymers.
Capsular Systems Based On Osmosis
The Port system consists of a semi-permeable membrane coated gelatin capsule with an insoluble plug (lipid) and an osmotically active agent along with the drug formulation. When placed in an aqueous medium, water diffuses across the semi-permeable membrane and the pressure inside the capsule increases resulting in the ejection of the plug after a lag time. The lag time depends on the coating thickness.
A System Based On Expandable Orifice
This system is mainly used to deliver the drug in the liquid form. The general architecture consists of a push layer, an osmotically active agent, a semi-permeable membrane coating and the liquid drug layer. When the system comes in contact with the aqueous environment, water permeates through the semi-permeable membrane and results in the expansion of the osmotic layer which in turn results in the development of the hydrostatic pressure inside the capsule and forces the liquid drug through the delivery orifice. Depending on the permeability and thickness of the barrier layer, the lag time can vary from 1-10 hrs.
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Delivery By A Series Of Stops
The system consists of a therapeutic agent and water absorptive osmotic engine that is placed in compartments separated by a movable partition. The Pulsatile delivery is achieved by a series of stops along the inner wall of the capsule, which acts by initially obstructing the movement of the partition but later on releasing the drug upon being overcome by the osmotic pressure. The number of stops and its longitudinal placement along the length of the capsule decides the number and the frequency of the pulses.
Pulsatile Systems With Erodible Or Soluble Barrier Coating
In these systems, the reservoir device is coated with a barrier layer which erodes or dissolves after a lag time, releasing the drug rapidly. The coating layer thickness determines the lag time.
The Time Clock System consists of a coating of a lipidic barrier (carnauba wax and beeswax) along with surfactants (poly oxy ethylene sorbitan mono oleate), over the drug core. This coating is followed by another water soluble coating. The coating erodes in the aqueous environment in a time proportional to the thickness of the film and the core is available for dispersion.
The Chronotropic System consists of a swellable hydrophilic HPMC coated drug core, which is responsible for the lag phase. Also the application of an outer enteric film helps in the colon specific release.
Pulsatile System With Rupturable Coating
In this system the drug is released upon the disintegration of the coating, resulting from an inside pressure developed by effervescent excipients, swelling agents (super-disintegrants like cross carmellose, sodium starch glycolate and low substituted hydroxy propyl cellulose) or osmotic agents
surrounded by a release control polymer. An immediate release layer follows this layer and which is further coated by an enteric polymer. Compared to single unit dosage forms, multi particulate system offers many advantages like increased bioavailability, predictable gastric emptying with flexible release patterns, no risk of dose dumping and less inter subject variability.The general architecture consists of a drug layer applied on core granules which is
Pulsatile System Based On Rupturable Coating
In the time controlled explosion system, swelling agents, effervescent excipients or osmotic agents are used, which upon contact with water will produce a pressure sufficient for rupturing the polymer layer coating the drug core. It is mainly employed for the delivery of insoluble drugs. Usually a lag time of 4-10 hrs is obtained with this system.
Reservoir System With Soluble Or Eroding Polymer Coating
From these systems a burst release of drug is obtained after the barrier layer erodes or dissolves.
Gazzaniga et al. formulated a system where drug containing mini tablets were coated with high viscosity polymers and then by an enteric polymer. The enteric coating dissolves in the intestine and then the HPMC layer which is exposed protects the drug tablets from releasing in the small intestine by delaying the release for 3-4 hrs.
Pulsatile Delivery By Change In Membrane Permeability.
The permeability and water uptake of acrylic polymers containing quaternary ammonium groups is influenced by the different counter ions present in the medium. Based on this ion exchange principle many drug delivery systems have been formulated and Eudragit RS 30 D is considered as the polymer of choice. The polymer side chain of Eudragit RS 30 D contains a positively polarized quaternary ammonium group which is accompanied by the negative hydrochloride counter ions. The ammonium group which is hydrophilic facilitates the interaction of the polymer with water and thereby changes its permeability and allows the water to permeate the drug core in a controlled manner.