Ø No risk of dose dumping

Ø Flexibility in design

Ø Improve stability

Ø Improve patient comfort and compliance

Ø Achieve a unique release pattern

Ø Extend patent protection, globalize product, and overcome competition.

Drawbacks³:

Ø Lack of manufacturing reproducibility and efficacy

Ø Large number of process variables

Ø Multiple formulation steps

Ø Higher cost of production

Ø Need of advanced technology

Ø Trained/skilled personal needed for manufacturing.

Fig 1: Drug release profile of pulsatile drug delivery system

2. Diseases Requiring Pulsatile Delivery:

Recent studies have revealed that diseases have predictable cyclic rhythms and that the timing of medication regimens can improve outcome in selected chronic conditions ⁴.The list of diseases which are required pulsatile release given in table 1.

Table 1.Diseases required pulsatile delivery:

Chronological behavior	Drugs used	Diseases
Acid secretion is high in theafternoon and at night	H₂ blockers	Peptic ulcer
Precipitation of attacks during night or at early morning	β₂ agonist, Antihistamines	Asthma
BP isat its lowest during the Sleep cycle and rises steeply during the early morning	Nitroglycerin, ACE inhibitors Calcium channel blockers	Cardio vascular diseases
Pain in the morning and more pain at night	NSAIDs, glucocorticoids	Arthritis
Increase in the blood sugarlevel after meal	Sulfonylurea, Insulin	Diabetes mellitus
Cholesterol synthesis isgenerally higher during nightthan day time	HMG CoA reductase inhibitors	Hyper Cholesterolemia
Increase in DOPA level in afternoon	Methylphenidate	Attention deficit syndrome

3. Methods for pulsatile drug delivery:

Methodologies for the pulsatile drug delivery system can be broadly classified into four classes;

1. Time controlled

2. Stimuli induced

3. Externally regulated

4. Multi particulate

3.1. Time controlled pulsatile release system:

In time controlled drug delivery systems pulsatile release is obtained after a specific time interval in order to mimic the circadian rhythm. Such type of pulsatile drug delivery system contains two components: one is of immediate release type and other one is a pulsed release type.

3.1.1. Delivery systems with rupturable coating layer:

Most pulsatile delivery systems are reservoir devices coated with a rupturable polymeric layer. Upon medium ingress, drug is released from the core after rupturing of the surrounding polymer layer, due to pressure buildup within the system. The pressure necessary to rupture the coating can be achieved with swelling agents, gas producing effervescent excipients or increased osmotic pressure. Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time⁵.

Fig:2-Schematic diagram of drug delivery with rupturable coating layer

3.1.2 Delivery system with erodible coating layers:

In such systems, the core containing drug is coated with the soluble or erodible polymer as outer coat and drug release is controlled by the dissolution or erosion of the outer coat. Time dependent release of the drug can be obtained by optimizing the thickness of the outer coat⁶.

Fig:3 Schematic diagram of drug delivery with erodible coating layer

3.1.3 Capsule shaped system provided with release controlling plug:

This dosage form consists of an insoluble capsule body containing a drug and swellable and degradable plugs made of approved substances such as hydrophilic polymers or lipids and release controlling plug between immediate release compartment and pulsed release compartment. On contact with aqueous fluids, the cap rapidly dissolves thereby releasing the immediate release component followed by pulsed release component. The length of plug decides lag time ^7,8.

Fig:4 Schematic diagram of release of drug from capsule.

3.1.4. Pulsatile system based on Osmosis:

Osmotic system consists of capsule coated with the semipermeable membrane.Insidethe capsule there is an insoluble plug consisting of osmotically active agent and thedrug formulation⁹.

Fig.5 Schematic diagram of osmosis system

3.2. Stimuli induced pulsatile systems:

In these systems there is release of the drug after stimulation by any biological factor like temperature, or any other chemical stimuli. These systems are further classified in to temperature induced systems and chemical stimuli induced system, on the basis of stimulus¹⁰.

3.2.1. Temperature induced systems:

Temperature is the most widely utilized triggering signal for a variety of triggered or pulsatile drug delivery systems. The use of temperature as a signal has been justified by the fact that the body temperature often deviates from the physiological temperature (37 ˚C) in the presence of pathogens or pyrogens. This deviation sometimes can be a useful stimulus that activates the release of therapeutic agents from various temperature-responsive drug delivery systems for disease accompanying fever. Thermal stimuli-regulated pulsed drug release is established through the design of drug delivery device such as hydrogels and micelles.

3.2.1.1 Thermo-responsive hydrogel systems:

Thermo-responsive hydrogel systems employ hydrogels which undergo reversible volume changes in response to changes in temperature. These gels shrink at a transition temperature that is referred to the lower critical solution temperature (LCST) of the linear polymer. Thermo-sensitive hydro sensitive hydrogels have a certain chemical attraction for water, and therefore they absorb water and swell at temperatures below the transition temperature whereas they shrink or deswell at temperatures above the transition temperature by expelling water. Thermally responsive hydrogels and membranes have been extensively exploited as platforms for the pulsatile drug delivery¹¹.

3.2.1.2 Thermo-responsive polymeric micelle systems:

In this type, the gel system tightly stores targeted drug in the micelles and rapidly releases controlled amount of the drug by switching on–off of external stimuli such as temperature or infrared laser beam¹².

3.2.2 Chemical stimuli induced pulsatile systems:

In these systems, there is release of the drug after stimulation by any biological factor like enzyme, pH or any other chemical stimuli. In these systems, the polymer undergoes swelling or deswelling phase in response to chemical reaction with membrane, alteration of pH and Inflammation induce, release of drug from polymer by swelling the polymer.

3.2.2.1 Glucose-responsive insulin release devices :

In a glucose-rich environment, such as the bloodstream after a meal, the oxidation of glucose to gluconic acid catalysed by glucose oxidase can lower the pH to approximately5.8. This enzyme is probably the most widely used in glucose sensing, and makes possible to apply different types of pH sensitive hydrogels for modulated insulin delivery. This pH change induces swelling of the polymer which results in insulin release. Insulin by virtue of its action reduces blood glucose level and consequently gluconic acid level also gets decreased and system turns to the deswelling mode thereby decreasing the insulin release¹³.

3.2.2.2 pH sensitive drug delivery system:

pH-sensitive polymers are polyelectrolytes that bear in their structure weak acidic or basic groups that either accept or release protons in response to changes in environmental pH. Examples of pH dependent polymers include cellulose acetate phthalate, poly-acrylates, sodiumcarboxy methyl cellulose.

3.2.2.3 Inflammation-induced pulsatile release:

On receiving any physical or chemical stress, such as injury, fracture etc., inflammation take place at the injured sites. During inflammation, hydroxyl radicals are produced from these inflammation-responsive cells. When human beings receive physical or chemical stress, such as injury, broken bones, etc., inflammation reactions take place at the injured sites. At the inflammatory sites, inflammation-responsive phagocytic cells, such as macrophages and poly morpho nuclear cells, play a role in the healing process of the injury. During inflammation, hydroxyl radicals (OH) are produced from these inflammation-responsive cells¹⁴.

3.3 Externally regulated pulsatile release system:

This system is not self-operated, but instead requires externally generated environmental changes to initiate drug delivery. These can include magnetic fields, ultrasound, electric field, light, and mechanical force.

3.3.1 Magnetic induces release:

Magnetic carriers receive their magnetic response to a magnetic field from incorporated materials such as magnetite, iron, nickel, cobalt etc. An intelligent magnetic hydrogel (ferrogel) was fabricated by mixing poly vinyl alcohol (PVA) hydrogels and Fe₃O₄magnetic particles through freezing-thawing Cycles. Although the external direct current magnetic field was applied to the ferrogel, the drug get accumulated around the ferrogel, but the accumulated drug spurt to the environment instantly when the magnetic fields instantly switched “off”. Furthermore, rapid slow drug release can be tunable while the magnetic field was switched from “off” to “on” mode. The drug release behavior from the ferrogel is strongly dominated by the particle size of Fe₃O₄ under a given magnetic field^15,16.

3.3.2 Ultrasound induces release:

Ultrasound is mostly used as an enhancer for the improvement of drug permeation through biological barriers, such as skin. The interactions of ultrasound with biological tissues is divided into two broad categories: thermal and non thermal effects. Thermal effects are associated with the absorption of acoustic energy by the fluids or tissues. Non-thermal bio-effects are generally associated with oscillating or cavitating bubbles, but also include non cavitation effects such as radiation pressure, radiation torque, and acoustic streaming¹⁷.

3.3.3 Eelectric field induces release:

As an external stimulus have advantages such as the availability of equipment, which allows precise control with regards to the magnitude of current, duration of electric pulses, interval between pulses etc. Electrically polyelectrolytes (polymers which contain relatively high concentration of ionisable groups along the backbone chain) and are thus, pH-responsive as well as electro-responsive. Under the influence of electric field, electro-responsive hydrogels generally deswell or bend, depending on the shape of the gel lies parallel to the electrodes whereas deswelling occurs when the hydrogel lies perpendicular to the electrodes¹⁸.

3.3.4 Light induces release:

Light-sensitive hydrogels have potential applications in developing optical switches, display units, and opthalmic drug delivery devices. The interaction between light and material can be used to modulate drug delivery. When hydrogel absorb the light and convert it to heat, raising the temperature of composite hydrogel above its LCST, hydrogel collapses and result in an increased rate of release of soluble drug held within the matrix^19,20.

3.4 Multi particulate pulsatile drug delivery system:

The purpose of designing multiparticulate dosage form is to develop a reliable formulation that has all the advantages of a single unit formulation and yet devoid of the danger of alteration in drug release profile and formulation behavior due to unit to unit variation²¹. The release of drug from microparticles depends on a variety of factors including the carrier used to form the multiparticles and the amount of drug contained in them²².

3.4.1 Reservoir systems with rupturable polymeric coatings:

Most multiparticulate systems are reservoir devices coated with a rupturable polymeric layer. Upon water ingress, drug is released from the core after rupturing of the surrounding polymer layer, due to pressure buildup within the system. The pressure necessary to rupture the coating can be achieved with swelling agents, gasproducing effervescent excipients or increased osmotic pressure. Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time²³.

3.4.2. Reservoir systems with soluble or eroding polymer coatings:

Another class of reservoir-type multiparticulate pulsatile systems is based on soluble/erodible layers in place of rupturable coatings. The barrier dissolves or erodes after a specific lag time followed by burst release of drug from the reservoir core. In general, for this kind of systems, the lag time prior to drug release can be controlled by the thickness of the coating layer. However, since from these systems release mechanism is dissolution, a higher ratio of drug solubility relative to the dosing amount is essential for rapid release of drug after the lag period²⁴.

3.4.3. Floating multiparticulate pulsatile systems:

Multiparticulate pulsatile release dosage forms mentioned above are having longer residence time in the GIT and due to highly variable nature of gastric emptying process, may resulted in in vitro-in vivo relationship was poor and bioavailability problems. In contrary, floating multiparticulate pulsatile dosage forms reside in stomach only and not affected by variability of pH, local environment or gastric emptying rate. These dosage forms are also specifically advantageous for drugs either absorbed from the stomach or requiring local delivery in stomach. Overall, these considerations led to the development of multiparticulate pulsatile release dosage forms possessing gastric retention capabilities²⁵.

CONCLUSION AND FUTURE ASPECTS:

The future of chronotherapeutics and more specifically the future of delivering drugs in a pulsatile manner seem to be quite promising as in certain disease states pulsatile release exhibit several advantages over the traditional zero or first order drug delivery mechanisms. Pulsatile drug delivery systems can be either time controlled or site-specific, single or multiple units. Delayed release formulations are not enough in treating the diseases especially diseases with chronological pathophysiology, for which, PDDS is beneficial. Thus designing of proper pulsatile drug delivery will enhances the patient compliance, optimum drug delivery to the target site and minimizes the undesired effects. PDDS are smart and efficient dosage forms satisfying needs of patients and offering interesting options for intelligent life cycle management. In near future due to more advancement of technology, the hurdles in manufacturing and processing steps will be overcome and a number of patients will be greatly benefited by these systems.

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Received on 06.06.2012

Accepted on 09.07.2012

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(4): July-Aug. 2012, 197-201