PULSATILE DRUG DELIVERY SYSTEM AND RECENT ADVANCES: A REVIEW

ABOUT AUTHORS:
Bhaskar Ingole, Shradha Tiwari*
SSS. Indira College of pharmacy,
Vishnupuri, Nanded
*Shraddha.life10@gmail.com

ABSTRACT:
Pulsatile drug delivery aims to release drugs on a programmed pattern means at appropriate time and/or at appropriate site of action. Pulsatile Drug Delivery Systems are gaining a lot of interest as they deliver the drug at the right place at the right time and in the right amount, thus providing spatial and temporal delivery and increasing patient compliance These systems are designed according to the circadian rhythm of the body. Pulsatile release of the drugs is used where a constant drug release is not desired.Gastric retentive systems, systems where the drug is released following a programmed lag phase, chronopharmaceutical drug delivery systems matching human circadian rhythms, multiunit or multilayer systems with various combinations of immediate and sustained-release preparation, are all classified under pulsatile drug delivery systems. On the other hand, site-controlled release is usually controlled by factors such as the pH of the target site, the enzymes present in the intestinal tract and the transit time/pressure of various parts of the intestine. In this review, recent patents on pulsatile drug delivery of oral dosage forms are summarized and discussed.

REFERENCE ID: PHARMATUTOR-ART-1766

INTRODUCTION:
Pulsatile delivery is defined as the transient and fast release of certain amounts of drug molecules within a short time period immediately after a predetermined off-release period, i.e, lag time. This system provides spatial and temporal delivery of the drug. Pulsatile Drug Delivery Systems are gaining a lot of interest as they deliver the drug at the right place at the right time and in the right amount, thus providing spatial and temporal delivery and increasing patient compliance. A pulse has to be designed in such a way that a complete and rapid drug release is achieved after the lag time. Various systems like single- and multiple-unit systems and capsular systems, osmotic systems based on the use of soluble or erodible polymer coating and use of rupturable membranes have been dealt with in the article. It summarizes the latest technological developments, formulation parameters, and release profiles of these systems. These systems are beneficial for the drugs having chronopharmacological behavior where night time dosing is required, such as anti-arhythmic and anti-asthmatic. Current review article discussed the reasons for development of pulsatile drug delivery system, types of the disease in which pulsatile release is required, classification, advantages, limitation, and future aspects of pulsatile drug delivery system.

Pulsatile delivery is defined as the rapid and transient release of certain amounts of drug molecules within a short time period immediately after a predetermined off-release period, i.e, lag time. These deliver the drug at the right time and at the right place and in the right amount thus increasing patient compliance. Pulsatile systems are beneficial for drugs where night time dosing is required, such as anti-asthmatic and anti-arrhythmic drugs where the disease severity is time dependent. Some of the disease conditions wherein PDDS are promising include duodenal ulcer, cardiovascular diseases, arthritis, asthma, diabetes, neurological disorder, cancer, hypertension and hypercholesterolemia. These are modified release dosage forms which offer control over the release pattern of drug and provide better control over drug regimen. These dosage forms release the drug in a pulsatile manner and maintain plasma drug level within therapeutic range. Some examples for the recent advances in oral pulsatile drug delivery technology are ACCU-BREAK Technology, SODAS Technology, Diffucaps, PulsincapTM, IPDAS Technology, CODAS Technology, GEOCLOCK Technology, PULSYS Technology, OSDrC Technology, Intelli Matrix Technology, Eurand’s pulsatile and chrono release system and Versetrol Technology. Diseases wherein PDDS are promising include asthma, peptic ulcers, cardiovascular ailments, arthritis and attention deficit syndrome in children and hypercholesterolemia. This review focuses on recent developments in oral pulsatile delivery systems. As already mentioned, these systems can be classified either according to their target release profile (i.e. time or site specific) or according to the technology used (i.e. single unit or multi unit). The contents of each group are further divided to several subgroups. Given the two classification schemes and the fact that the boundaries between the subgroups are not sharply defined, the majority of the systems discussed in each paragraph are only indicative, as each invention in reality belongs to more than one subgroups. Oral drug delivery is the largest segment of the total drug delivery market. It is the most preferred route for drug administration. The oral controlled-release systems show a typical pattern of drug release in which the drug concentration is maintained in the therapeutic window for a prolonged period of time, thereby ensuring sustained therapeutic action. There are certain conditions for which such a release pattern is not suitable that demand release of a drug after a lag time. In other words, they require pulsatile drug delivery system (PDDS). The pulsatile system is gaining a lot of interest, as the drug is released completely after defined lag time.. Pulsatile drug delivery is defined as the rapid and transient release of certain amount of molecules within a short time period immediately after a predetermined off-released period, i.e., lag time, or these systems have a peculiar mechanism of delivering the drug rapidly and completely after a lag time, i.e., a period of no drug release. Over the last 30 years the pharmaceutical market has been demonstrated increasing preferably for controlled and targeted drug delivery system. Such systems have been focused on constant, variable; sustain drug release and/or targeting the therapeutic agent to a specific site/tissue/ organ. However, recently there are certain conditions for which such release pattern is not suitable. Such conditions that lead to the requirements of a time programmed therapeutic system, which is capable of releasing drug after predetermined time delay and maintain constant drug levels through the day. To introduce the concept of chronotherapeutics, it is important to define the following concepts.

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Chronotherapeutics is the discipline concerned with the delivery of drugs according to inherent activities of a disease over a certain period of time. It is becoming increasingly more evident that the specific time that patients take their medication may be even more significant than was recognized in the past. Co-ordination of biological rhythms and medical treatment is called chronotherapy. Interestingly, the term circadian is derived from the Latin circa which means “about” and dies which can be defined as “a day”. Normally, circadian rhythms are synchronized according to internal biologic clocks related to the sleep-wake cycle. The potential benefits of chronotherapeutics have been demonstrated in the management of a number of diseases.

Diseases for which pulsatile drug delivery preferred :

Sr.No.	Disease Name	Disease precipitate at
I.	Peptic ulcer:	Acid secretion is high in the afternoon and at night
II.	Asthma:	Precipitation of attacks during night or at early morning hour
III.	Migraine	at early morning hour
IV.	Diabetes mellitus:	Increase in the blood sugar level after meal
V.	Attention deficit syndrome:	Increase in DOPA level in afternoon
VI.	Cardiovascular diseases:	BP is at its lowest during the sleep cycle and rises steeply during the early morning period.
VII.	Arthritis:	Pain in the morning and more pain at night
VIII.	Myocardial Infarction:	Onset of myocardial infarction has been shown to be more frequent in the morning with 34% events occurring between 6 A.M. and noon.
IX.	Hypertension:	Heart rate and blood pressure are increased in the early morning hours (morning or A.M. surge). The blood pressure declines form mid afternoon and is minimum at midnight

There are numerous advantages of the pulsatile drug delivery systems. Some of them are enlisted as below:

1.      These systems can be used for extended day time or night time activity.

2.      They reduce the dose frequency, dose size and cost, which ultimately reduces side effects, thereby improving patient compliance.

3.      Drug adapts to suit circadian rhythms of body functions or diseases.

4.      Drug targeting to a specific site, like the colon, can be achived.

5.      Provides controlled delivery of active agent at a predetermined rate.

6.      Maintenance of optimal and effective drug level for prolonged duration.

7.      More effective utilization of active ingredient.

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Disadvantage
1. Low drug loading capacity and incomplete release of drug.
2. Multiple manufacturing steps.

CLASSIFICATION OF PULSATILE SYSTEM ACCORDING TO TARGET RELEASE:
a. Time Controlled Delivery Systems
b. Site Specific Delivery Systems

CLASSIFICATION OF PULSATILE SYSTEMS ACCORDING TO THE TECHNOLOGY USED:
a. Single unit systems
b. Multiple unit systems

Classification of Pulsatile Drug Delivery Systems

Time-controlled pulsatile release systems :
The principle of time controlled drug delivery systems is that the release of the drug happens according to a predetermined rate so to achieve maximum therapeutic and minimum toxic effect. Systems having a lag phase (delayed release systems) and systems where the release is following a biological/circadian rhythm are the most commonly used controlled release systems. As already mentioned the delayed drug release for meeting chronotherapeutical needs provides optimum drug delivery for a number of widespread chronic pathologies. Most delayed release delivery systems are reservoir devices covered with a barrier coating, which dissolves, erodes or ruptures after a lag phase. Well known coating techniques are applied to pellets and tablets to delay drug’s release. Conventional coatings dissolve slowly to release drugs into the intestine. Another well-known coating technique employs a water-permeable but insoluble film which encloses the active ingredient and an osmotic agent. As water from the gut slowly diffuses through the film into the core, the core swells until the film bursts, releasing the drug. The film coating may be adjusted for selecting suitable rates of water permeation, and thereby, release time. Alternatively, the tablet coating may be impermeable, and water enters through a controlled aperture in the coating until the core bursts. When the tablet bursts, the content is released immediately or over a longer period of time. These and other techniques may be employed to formulate tablets or capsules with the requisite time interval before drug release. An excellent example of a time controlled delivery system is a three pellet pulsatile delivery system of diltiazem consisting of a fast release fraction, a medium release fraction and a slow release fraction, patented by Sharma and coworkers in 2003 .  The fast release membrane composition includes an anionic surface active agent which assures complete drug release after providing a desired lag time. The medium and slow release fractions are plasticized with decreased concentration of triethyl citrate and increased concentrations of silicone dioxide powder for improved process performance. Dltiazem is release from the system in three well defined pulses over 30 hours.

Delivery systems containing erodible coating layer:
Bulk-eroding system: Bulk erosionmeans that the ingress of water is faster than the rate of degradation. In this case, degradation take places throughout the polymersample and proceeds until a critical molecular weight is reached. At this point, degradation products become small enough to be solubilized, and the structure starts to become significantly more porous and hydrated. Hence, there is a time lag before the drug can be released corresponding to the time required for critical molecular weight to be reached.

Surface eroding system:. In this type of system, the reservoir device is coated with a soluble or erodible layer, which dissolves with time and releases the drug after a specified lag period, as in case of  a chronotropic system, where the drug is entrapped in the core layer with hydroxyl propyl methyl cellulose (HPMC) and with an additional layer of enteric-coated film outside it. The time clock system is another example of a surface eroding system and consists of solid dosage form coated with lipid barriers like carnauba wax and beeswax along with surfactants. When both these systems come in contact with aqueous medium, the coat emulsifies or erodes after the lag time. It is independent of the gastrointestinal motility, pH, enzyme and gastric residence. The lag time and onset of action are controlled by thickness and the viscosity grade of the polymer used.

Delivery system with rupturable coating layer:
These systems depend on the disintegration of the coating layer for the release of a drug. The pressure necessary for the rupture of the coating can be achieved by effervescent excipients, swelling agents or osmotic pressure. An effervescent mixture of citric acid and sodium bicarbonate has been reported, wherein the mixture was incorporated in a tablet core coated with ethyl cellulose. The carbon dioxide developed after penetration of water into the core resulted in a pulsatile release of the drug after rupture of the coating. The release may depend on the mechanical properties of the coating layer. It is reported that the weak and non-flexible ethyl cellulose film ruptured adequately as compared with more flexible films. The lag time increases with increasing coating thickness and hardness of tablet. Bai et al. invented a pulsatile drug delivery system comprising a plurality of particles that were divided into several individual delivery units, each having its own distinct composition. The individual particles had the same composition as the internal core, but the thickness of the external coating layer varied. Drug delivery was controlled by the rupture of the membrane. The timing of release was controlled by the thickness of the coating and the amount of water-soluble polymer needed to achieve the pulsed release.

Capsule-shaped system provided with release controlling plug:
R.P. Scherer International Corporation, Michigan developed the pulsincap system, in which the lag time is continued by a plug that gets pushed away by swelling or erosion, releasing the drug as a pulse from the insoluble capsule body. The system is comprised of a water insoluble capsule enclosing the drug reservoir. A swellable hydrogel plug was used to seal the drug contents into the capsule body. When the capsule comes in contact with dissolution fluid, the plug gets swells, and after a lag time, the plug pushes itself outside the capsule and rapidly releases the drug. The length of the plug and its point of insertion into the capsule controlled the lag time.

Stimuli-induced pulsatile release system:
Stimuli-based drug delivery systems release the drug in response to stimuli that are induced by the biological environment. Release of the drug in response to those systems results from stimuli-induced changes in the gels or in the micelles, which may deswell, swell or erode in response to the respective stimuli. In these systems, the drug is released after stimulation by any biological factor, like temperature or any other chemical stimuli.The mechanisms of drug release include ejection of the drug from the gel as the fluid phase syneresis out, drug diffusion along a concentration gradient, electrophoresis of charged drugs toward an oppositely charged electrode and liberation of the entrapped drug as the gel or micelle complex erodes. There has been much interest in the development of a stimuli-sensitive delivery system that releases therapeutic agents in the presence of a specific enzyme or protein.

These systems are considered excellent delivery candidates, since they can be modified according to the task to be achieved. They are further classified into:

Thermoresponsive pulsatile release:
Hydrogels that undergo reversible volume changes in response to changes in temperature are known as thermosensitive gels. Thermosensitive hydrogels have been investigated as possible drug delivery carriers for stimuli-responsive drug delivery. Hydrogels are crosslinked networks of biological, synthetic or semi-synthetic polymers. These gels shrink at a transition temperature that is related to the lower critical solution temperature (LCST) of the linear polymer from which the gel is made. One of the common characteristics of temperature-sensitive polymers is the presence of hydrophobic groups, such as methyl, ethyl and propyl groups. From the many temperature-sensitive polymers, poly(N-isopropylacrylamide) (PINPA) is probably the most extensively used. PINPA crosslinked gels have shown thermoresponsive, discontinuous swelling/ deswelling phases, swelling, for example, at temperatures below 32°C and shrinking above this temperature. Krezanoski et al. describe the use of the reversed thermal gelation (RTG) system, consisting of a polyol polymer, such as Pluronic®. Gels of this type of polymer display low viscosity at ambient temperature, and exhibit a sharp increase in viscosity as the temperature rises. Yuk et al. developed temperature-sensitive drug delivery systems utilizing an admixture of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer (F-68) and poly vinyl alcohol (PVA). pulsatile release of acetaminophen occurred due to pulsatile change in temperature between 35°C and 40°C.

Chemical stimuli-induced pulsatile release:
The development of stimuli-sensitive delivery systems has been the latest topic of interest. These systems release therapeutic agents in the presence of any biological factor, like enzyme, pH or any other chemical stimuli. One prominent application of this technology has been the development of a system that can automatically release insulin in response to elevated blood glucose levels. Kazunori et al.developed a gel composed of PNIPA with phenyl boronic acid moieties that showed a remarkable change in the swelling induced by glucose. This type of glyco-sensitive gel may have potential utilitiy in self-regulated drug releasing systems as well as in other applications, such as actuators, regulators and separation systems with glyco-sensitivity. pH-dependent systems for glucose-stimulated drug delivery are based on the oxidation reaction of glucose to gluconic acid, catalyzed by glucose oxidase, which can lower pH to approximately 5.8 in a glucose-rich environment, such as the bloodstream after a meal. This reaction can be used to drive the swelling of a pH-dependent membrane. A dual membrane system was formed, with the first membrane referred to as the glucose sensing membrane, in which glucose oxidase was immobilized on cross-linked polyacrylamide. The second membrane worked as an interface between the insulin reservoir and the sensing membrane. Composed of N, N-diethylaminoethyl methacrylate and 2-hydroxypropyl methacrylate (DEA-HPMA), it formed the barrier membrane.

Externally regulated pulsatile release system:

Electroresponsive pulsatile release:
An electric field as an external stimulus has advantages,such as availability of equipment that allows precise controlwith regard to the magnitude of the current, duration of electricpulses, interval between pulses, etc. Electrically responsive deliverysystems are prepared from polyelectrolytes and are thus pHresponsive as well as electroresponsive. Under the influence of the electric field, electroresponsive hydrogels generally deswell, swell or erode. Poly(2-acrlamide-2-methylpropanesulfonic acid-cobutyl methacrylate) [P(AMPS-co-BMA)] hydrogels were used for electric stimuli-induced drug delivery systems. Kwon et al.
exploited cross-linked poly(2-acrylamide-2-methylpropanesulfonic acid-co-butyl methacrylate) (P(AMPS-co-BMA)) hydrogels for electric stimuli-induced drug delivery.The mechanisms of drug release include expulsion of a drug from the gel as the fluid phase syneresis out, drug diffusion along a concentration gradient and electrophoresis of a charged drug toward an oppositely charged electrode and release of the entrapped drug as the gel complex erodes with regards to the magnitude of the current, duration of electric pulses, interval between pulses, etc. Electrically responsive delivery systems are prepared from polyelectrolytes and are thus pH responsive as well as electroresponsive. Under the influence of an electric field, electroresponsive hydrogels generally deswell, swell or erode. Poly(2-acrlamide-2- methylpropanesulfonic acid-co-butyl methacrylate) P(AMPSco- BMA) hydrogels were used for electric stimuli-induced drug delivery system.

Ultrasonically stimulated:
Ultrasound is mostly used as an enhancer for the improvement of drug permeation through a biological barrier, such as skin, lungs, intestinal wall and blood vessels. There are several reports describing the effect of ultrasound on controlled drug delivery. Kost and coworkers depicted an ultrasound-enhanced polymer. Miyazaki et al. used ultrasound to achieve up to a 27-fold increase in the release of 5-fluorouracil from an ethylene and vinyl acetate (EVAc) matrix. Increasing the strength of the ultrasound resulted in a proportional increase in the amount of 5-fluorouracil released

Magnetically induced pulsatile release:
Use of an oscillating magnetic to regulate the drug delivery from a polymer matrix was one of the first methodologies investigated to develop an externally controlled drug delivery system. Magnetic carriers receive a response to a magnetic field from incorporated materials, such as magnetite, iron, nickel, cobalt, etc. For biomedical applications, magnetic carriers must be water-based, biocompatible, non-toxic and non-immunogenic. Basically the mechanistic approach behind the strategy is based on slowing down the movement of oral drugs in the gastrointestinal system through magnetic attraction. This is possible by filling an additional magnetic component into capsules or tablets. The speed of travel through the stomach and intestines can then be slowed down at specific positions by an external magnet, thus changing the timing and/ or extent of drug absorption into stomach or intestines

Release Using pH at Targeted Site
The pH differential between the stomach and small  intestine has historically been exploited in oral drug delivery. Significant variations in the pH occur in the GI tract with values ranging from approximately 1.2 in the stomach, to 6.6 in the proximal small intestine and a peak of about 7.5 in the distal small intestine followed by a sharp decline in colon where the luminal pH is below 7.  Delivery of drugs to sites beyond the stomach are especially desirable for drugs that are destroyed by the acid conditions or enzymes of the stomach, or for drugs that cause adverse events by local activity in the stomach. The low stomach pH and presence of gastric enzymes have led to the development of oral drug dosage forms in which the drug is provided with an enteric coating. Enteric coating materials exhibit resistance to acidic gastric fluids yet are readily soluble or permeable in intestinal fluid. Enteric polymeric materials are primarily weak acids containing acidic functional groups, which are capable of ionization at elevated pH. In low stomach pH, the enteric polymers are protonated, and therefore, insoluble. As the pH increases in the intestinal tract, these functional groups ionize, and the polymer becomes soluble in the intestinal f1uid.thus, an enteric polymeric film coating allows the coated solid to pass through the stomach to the small intestine where the drug is then released in a pH controlled fashion and either become available for absorption or exerts a pharmacologic effects locally. Targeting drugs to specific regions along the GI tract provides the ability to locally treat GI diseases, thus reducing side effects of drugs or inconvenient and painful direct delivery of drugs. Such specific delivery also potentially increases the efficiency of the drug and enables a reduction of the minimum effective dose of the drug. Furthermore, targeted delivery to certain parts in the GI tract may be advantageous when the absorption of a drug into the systemic circulation is limited to only a part of the GI tract. In such cases, the absorption may be increased when the drug is delivered in a pulsatile and complete way within the GI absorption window, since it would increase the driving force for absorption at the site where it is specifically needed. Several coated systems that utilize the pH differential in the GI tract have been used to target various delivery sites in the intestinal lumen. A patent on a pH-controlled pulsatile delivery system has been recently published, describing a formulation were a core is surrounded by a pH sensitive coating material in which a swellable agent is embedded underneath an enteric coat. The enteric coating material erodes upon a change in pH and then GI fluid reaches the swellable agent which swells enough to accelerate the disintegration of the coating and to cause instant release of the drug at the target site. pH Controlled drug release at a specific target site can be achieved by the use of a single polymer or a combination of polymers. Such coating polymers can be selected from the group consisting of cellulose, hydroxypropyl methylcellulose, and various Eudragits. The coating layer may contain plasticizer. In another example drug delivery composition consisting of a complex between  polyvinyl pyrrolidone and other synthetic polymers like poly(maleic diacid-alkyl vinyl ether) have been proved to target the proximal part of small intestine , while dosage forms coated with the acrylic polymer Eudragit S, an excipient known to have a threshold pH for dissolution, has been successfully target distal gut.

From technological point of view pulsatile drug release system are further divided to single or multiple units system.

Single unit systems :

Capsular Systems
Different single-unit capsular PDDS have been developed, A general -design of such systems consists of an insoluble capsule body housing a drug and a plug. The plug is removed after a predetermined time lag due to swelling, erosion, or dissolution. The Pulsincap® system is an example of such a system that is made up of a water-insoluble capsule body filled with drug formulation The body is closed at the open end with a swellable hydrogel plug. Upon contact with dissolution medium or gastro-intestinal fluids, the plug swells, pushing itself out of the capsule after a time lag. This is followed by a spontaneous release of the drug (Fig 2). The time lag can be controlled by manipulating the dimension and the position of the plug. For water insoluble drugs, a spontaneous release can be ensured by inclusion of effervescent agents or disintegrants. The plug material consists of insoluble but permeable and swellable polymers (e.g.:polymethacrylates), erodible compressed polymers (e.g: hydroxypropylmethyl cellulose, polyvinyl alcohol, polyethylene oxide), congealed melted polymers (e.g: saturated polyglycolated glycerides, glycerylmonoole and enzymatically controlled erodible polymer e.g:pectin). These formulations are well tolerated in animals and healthy volunteers, and there have been no reports of gastro-intestinal irritation. However, there was a potential problem of variable gastric residence time, which was overcome by enteric coating the system to allow its dissolution only in the higher pH region of small intestine.

Port systems:
The Port System - consists of a gelatin capsule coated with a semi permeable membrane (e.g: cellulose acetate) housing an insoluble plug ( e.g: lipidic) and an osmotically active agent along with the drug formulation. When it comes in contact with the aqueous medium, water diffuses across the semi permeable membrane, resulting in increased inner pressure that ejects the plug after a – time lag. The time lag is controlled by the thickness of semi permeable membrane. The system showed good correlation in lag times of in-vitro and in-vivo experiments in humans .

In order to deliver drug in liquid form, an osmotically driven capsular system was developed. In this system, liquid drug is absorbed into highly porous particles, which release the drug through an orifice of a semi permeable capsule supported by an expanding osmotic layer after the barrier layer is dissolved. The capsular system delivers drug by the capsule's osmotic infusion of moisture from the body. The capsule wall is made up of an elastic material and possesses an orifice. As the osmosis proceeds, the pressurethin the capsule rises, causing the wall to stretch. The orifice is small enough so that when the elastic wall relaxes, the flow of the drug through the orifice essentially stops, but when the elastic wall is distended beyond threshold value, the orifice expands  sufficiently to allow drug release at a required rate. Elastomers, such as styrene-butadiene copolymer have been suggested

Delivery by solubility modulation:
These systems contain a solubility modulator for pulsed delivery of variety of drugs. The system was especially developed for delivery of salbutamol sulphate. The compositions contain the drug (salbutamol sulphate) and a modulating agent, sodium chloride (NaCl). The amount of NaCl was such that it was less than the amount needed to maintain saturation in a fluid that enters the osmotic device. The pulsed delivery is based on drug solubility. Salbutamol has solubility of 275 mg/ml in water and 16 mg/ml in saturated solution of NaCl, while NaCl has solubility of 321 mg/ml in water, and its saturation solubility is 320 mg/ml. These values show that the solubility of the drug is a function of the modulator concentration, while the modulators solubility is largely independent of drug concentration. The modulating agent can be a solid organic acid, inorganic salt, or organic salt.

Delivery by reservoir systems with erodible or soluble barrier coatings
Most of the pulsatile drug delivery systems are reservoir devices coated with a barrier layer. Thisbarrier erodes or dissolves after a specific lag period, and the drug is subsequently released rapidly. The time lag depends on the thickness of the coating layer.

The Time Clock® system consists of a solid dosage form coated with lipid barriers containing carnauba wax and bees wax along with surfactants, such as polyoxyethylene sorbitan monooleate This coat erodes or emulsifies in the aqueous environment in a time proportional to the thickness of the film, and the core is then available for dispersion. The major advantage of this system is its ease of manufacture without any need of special equipment. The disadvantage of this system is a premature drug release when the penetrating water dissolves the drug.

The Chronotropic® system consists of a drug-containing core coated by hydrophilic swellable hydroxypropylmethyl cellulose (HPMC), which is responsible for a lag phase in the onset of drug release Time lag is controlled by the thickness and the viscosity grades of HPMC used in coating the drug core. The system is suitable for both tablets and capsule formulations.

Multi unit pulsatile system:
Multiparticulate dosage forms offer more reliability when compared to single-unit dosage forms. The potential benefits offered such as predictable gastric emptying, no risk of dose dumping, flexible release patterns, and increase bioavailability with less intra and inter subject variability. Multiparticulate systems are further classified as systems based upon change in membrane permiablity and system is based on rupturable coating.

Reservoir system with rupturable coating:
Multiparticulate drug dosage forms are composed of small beads, each small bead further comprised many layers. Some layers contain drug substance, while others are rate-controlling polymers. With the multiparticulate system, customized drug release profiles are created by first layering active drug onto an inert core (such as a cellulose sphere), then applying one or more rate-controlling, functional polymers, to produce spherical, multi-layered particles. The drug-layering process can be conducted either from aqueous or solvent-based drug solutions. Many release profiles can be achieved using this approach-including sustained release, time-delayed release, and pulsatile release of active pharmaceutical ingredients for absorption throughout the GI tract. Time-delayed release of the drug as either a burst or sustained release profile can be achieved over a period of 1-12 h, with a lag time of 4-10 h. The duration of drug release following the lag-time depends on the composition and thickness of the polymer barrier and the lag-time coating itself. The multiparticulate system provides optimal release profiles for either single or combination .Ueda et al. developed a time-controlled explosion systems (TES), where drug is released by explosion of the outer membrane. TES was developed for multiple-unit dosage forms consists of a core drug plus an inert osmotic agent and suitable disintegrants. The osmotic pressure build up by water ingress causes the core to explode, with an immediate release of the drug. The explosion of formulation can also be achieved through use of swelling agents.

Reservoir Systems with soluble coating:
Another class of reservoir-type multiparticulate pulsatile systems is in which the barrier dissolves or erodes after a specific lag time followed by burst release of drug from the reservoir core. The lag time in such systems is controlled by the thickness of the coating layer. The basic principle employed in these systems is that of pH-sensitive polymers complimenting to their large increase in solubility at some point in the GI tract.

Gazzaniga  et al. developed a multi-unit system with a reservoir drug coated with a high viscosity polymer (HPMC 4000) and an outer enteric coating. The outer film protects the system from the fiuids in the stomach and dissolves on entering the small intestine. HPMC layer delays the release of drug for 3-4 h when the system is transported through small intestine. Another system was developed containing multicoated multiparticulates for time controlled pulsatile release. One of the coating membranes is an enteric polymer and the second membrane barrier is a mixture of a water-insoluble polymer and an enteric polymer. An organic acid, such as fumaric acid, citric acid, succinic acid, tartaric acid, or malic acid, may be provided between the first and second membrane layers to provide for the time-separated pulses. The acids in between the membranes may delay the dissolution of the enteric polymer in the inner layer, thereby increasing the lag time as well as decreasing the rate of release of the active ingredient from the coated microparticulates

Systems with changed membrane permeability:
The release profile in this system depends on physic-chemical properties of drug and its interaction with the membrane. A sigmoidal release pattern obtained in this system is based on the permeability and water uptake of  eg: Eudragit RS or RL and is influenced by the presence of different counter-ions in the release medium. Narisawa et al has developed a device capable of pulse release depending on the change in diffusion properties of Eudragit RS. They found that a core of theophylline coated with Eudragit RS showed very slow release rates in pure water but a significant increase in the release rate was found when the microcapsules were immersed in an organic acid solution containing succinic, acetic, glutaric, tartaric, malic, or citric acid. This was due to higher hydration of the film containing quaternary ammonium groups on interaction with the acids. Another such system was reported in which theophylline and sodium acetate acting as permeability modifiers were layered on the pellets followed by a coat of Eudragit RS30D. The lag time was increase with increasing thickness of the outer membrane.

Marketed and patented technologies in pulsatile:

GEOCLOCK® Technology :
Geoclock® Allows the preparation of chronotherapy-focused press-coated tablets, have an active drug inside an outer tablet layer consisting of a mixture of hydrophobic wax and brittle material in order to obtain a pH-independent lag time prior to core drug delivery at a predetermined release rate.

SkyePharma developed a new oral drug delivery technology, Geoclock®, in the form of chronotherapy-focused press-coated tablets. Geoclock® tablets have an active drug inside an outer tablet layer consisting of a mixture of hydrophobic wax and brittle material in order to obtain a pH-independent lag time prior to core drug delivery at a predetermined release rate. This dry coating approach is designed to allow the timed release of both slow release and immediate release active cores by releasing the inner tablet first, after which time, the surrounding outer shell gradually disintegrates.In addition to controlled release, the Geoclock® technology also has applications for the improved release of colonic drug delivery as well as for multiple pulse drug delivery to deliver doses of a drug at specific times throughout the day. Using SkyePharma’s proprietary GeoclockTM technology, LodotraTM took the form of a specially formulated tablet, which, once ingested, did not release the active ingredient, prednisone, until approximately four hours later. LodotraTM has been designed so that maximum plasma levels are reached six hours after intake.

Geoclock® tablets have an active drug inside an outer tablet layer consisting of a mixture of hydrophobic wax and brittle material in order to obtain a pH-independent lag time prior to core drug delivery at a predetermined release rate. This dry coating approach is designed to allow the timed release of both slow release and fast release active cores by releasing the inner tablet first after which the surrounding outer shell gradually disintegrates.

PULSYS™ Technology :
The typical PULSYS drug delivery format is a tablet containing multiple pellets with different release profiles. The typical PULSYS drug delivery format is a tablet containing multiple pellets with different release profiles.

This is an oral drug delivery technology that enables once daily pulsatile dosing. The PULSYS™ dosage form is a compressed tablet that contains pellets designed to release drug at different regions in the gastro-intestinal tract in a pulsatile manner. The dosage form is made up of multiple pellet types of varying release profiles that are combined in a proportion so as to produce a constant escalation in plasma drug levels in the early portion of the dosing interval. The transit properties of pellets enhance the overall absorption-time window and offer improved bioavailability compared to tablet matrix forms.

PulsincapTM technology:
Pulsincap was developed by R.R. Scherer International Corporation (Michigan). This device consists of a non-disintegrating half capsule body sealed at the open end with a hydrogel plug that is covered by a water-soluble cap. The whole unit is coated with an enteric polymer to avoid the problem of variable gastric emptying. When this capsule comes in contact with the dissolution fluid, it swells, and after a lag time, the plug pushes itself outside the capsule and rapidly releases the drug. Another formulation approach was in the form of a bead or granule with a four-layered spherical structure, which consists of a core, a drug, swelling agent (e.g., sodium starch glycolate or carboxy methyl cellulose sodium) and an outer membrane of water-insoluble polymer (e.g., ethyl cellulose, Eudragit® RL). The penetration of GI fluids through the outer membrane causes the expansion of the swelling agent. The resulting stress due to swelling force leads to the destruction of the membrane and subsequent rapid drug release. Polymers used for designing the hydrogel plug were various viscosity grades of hydroxyl propyl methyl cellulose, polymethyl methacrylates, polyvinyl acetate and poly ethylene oxide. Another new approach was enteric-coated, timed-release, press-coated tablets (ETP tablets). These tablets were developed by coating enteric polymer on timed-released, press-coated tablets composed of an outer shell of hydroxyl propyl cellulose and core tablets containing diltiazem hydrochloride as a model drug.

OSDrC®:  technology:
OSDrC® technology allows placement of any number of cores of any shape into the tablet just where they need to be positioned for optimum delivery of active pharmaceutical ingredients (API). Precise OSDrC® positioning technology enables product development scientists to control the release of the API by altering the thickness of the outer coating. The ability to precisely position multiple cores allows the creation of tablet products with a variety of pulsatile drug release profiles.The conventional dry-coated tablet (DC) method requires core tablet preparation before, andtherefore, the complicated procedure of the conventional DCmethod increases the manufacturing cost and the chance offailure, which may lead to a rise in core tablet supply. To solvethis problem OSDRC-technology (one-step dry-coated tabletsystem, OSDRC-system) was developed that employs a double structureallowing fordry-coated tablets to be assembled in a single run. The manufacturingprocess consists of three steps: bottom layer (the 1st outerlayer) compression, core compression and whole tablet compression, which includes the upper layer and side layer (the 2nd outer layer). Because the tablets are produced in a single step while the punches make one rotation on a turntable, there is no longer any need for a separate stage to deliver the core.

The Intestinal Protective Drug Absorption System (IPDAS):
It is a new oral drug delivery approach that is applicable to gastrointestinal (GI) irritant drugs, including the nonsteroidal anti-inflammatory drug (NSAID) class. IPDAS® delivery system can also be employed to confer the advantages of multiparticulate technology in a tablet dosage form. The IPDAS® technology is composed of numerous high-density, controlled-release beads, which are compressed into a tablet form. Once an IPDAS® tablet is ingested, it disintegrates and disperses beads containing a drug in the stomach, which subsequently passes into the duodenum and along the gastrointestinal tract in a controlled and gradual manner, independent of the feeding state. Release of active ingredient is controlled by the polymer system used to coat the beads and/or the micromatrix of polymer/active ingredient formed in the extruded/spheronised multiparticulates.

The intestinal protection of IPDAS® technology is inherent by virtue of the multiparticulate nature of the formulation, which ensures wide dispersion of irritant drug throughout the gastrointestinal tract. This Technology is a high density multiparticulate tablet technology, intended for gastrointestinal irritant compounds. The IPDAS® technology is composed of numerous high density controlled release beads, which are compressed into a tablet form. Once an IPDAS® tablet is ingested, it rapidly disintegrates and disperses beads containing a drug in the stomach, which subsequently pass into the duodenum and along the gastrointestinal tract in a controlled and gradual manner, independent of the feeding state. Release of active ingredient from the multiparticulates occurs through a process of diffusion either through the polymeric membrane and or the micro matrix of polymer/active ingredient formed in the extruded/spheronized multiparticulates. The intestinal protection of IPDAS® technology is by virtue of the multiparticulate nature of the formulation, which ensures wide dispersion of irritant drug throughout the gastrointestinal tract. Naprelan®, which is marketed in the United States and Canada, employs the IPDAS® technology. This innovative formulation of naproxen sodium is a novel controlled release formulation indicated for the treatment of acute and chronic pain.

Chronotherapeutic Oral Drug Absorption System (CODAS) :
CODAS® (chronotherapeutic oral drug absorption system). In certain cases, immediate release of drug is undesirable. A delay of drug action may be required for a variety of reasons. Chronotherapy is an example of when drug release may be programmed to occur after a prolonged interval following administration. Elan Drug Technology developed CODAS® technology to achieve this prolonged interval. The many advantages of the CODAS® technology include a delivery profile designed to compliment circadian pattern, controlled onset, an extended release delivery system, rate of release essentially independent of pH,and food, “sprinkle” dosing by opening the capsule and sprinkling the contents on food, reduction in effective daily dose and drug exposure, gastrointestinal tract targeting for local effect and reduced systemic exposure to achieve a target profile.63,64 Verelan® PM uses the proprietary CODASTM technology, which is designed for bedtime dosing, incorporating a 4- to 5-h delay in drug delivery. The controlled-onset delivery system results in a maximum plasma concentration (C max) of verapamil in the morning hours. These pellet-filled capsules provide for extended release of the drug in the gastrointestinal tract. The Verelan® PM formulation has been designed to initiate the release of verapamil 4–5 h after ingestion. This delay is introduced by the level of non-enteric release-controlling polymer applied to drug loaded beads.

This technology was designed to release its drug component after a prolonged period of time when administered. A good example is Verelan® PM, which was designed to release Verapamil.

help to optimize efficacy and/or minimize side-effects of a drug substance. For example, Eurand has created a circadian rhythm release (CRR) dosage form for a cardiovascular drug, Propranolol hydrochloride, with a four-hour delay in release after oral administration. When administered at bedtime, Propranolol is released after the initial delay such that maximum plasma level occurs in the early morning hours, when the patient is mostly at risk.

OROS® technology:
OROS delivery systems were adopted for poorly water soluble drugs. The push-pull system is comprised of a bilayer or trilayer tablet core consisting of one push layer and one or more drug slayers. The drug layer contains the poorly soluble drugs, osmotic agents and a suspending agent. The push layer contains among other things, an osmotic agent and water swellable polymers. A semi permeable membrane surrounds the tablet core. A variety of OROS® systems (ALZA Corp.) have been developed: Procardia XL®, Ditropan XL® and Concerta® are notable examples. The recently developed L-OROS® SOFTCAPTM delivery system combines the features of a controlled- release and bioavailability-enhanced delivery system to enhance compliance and therapeutic effect. L-OROSTM technology was developed by Alza to over come the drug solubility issue.

DIFFUCAPS® technology.:
Diffucaps® is a multiparticulate bead system comprised of multiple layers of drug, excipients and release-controlling polymers. The beads contain a layer of organic acid or alkaline buffer to control the solubility of a drug by creating an optimal pH microenvironment for drugs that exhibit poor solubility in intestinal pH, in environments with pH greater than 8.0 or in physiological fluids. Diffucaps® beads are < 1.5 mm in diameter and can be filled into capsules or compressed into orally disintegrating tablets. In addition, for patients who experience difficulty in swallowing tablets or capsules, Diffucaps® products are produced in capsules that allow the capsules to be opened and the contents used as a sprinkle on foods, providing a flexible dosage form.

Variations in pH throughout the GI tract affect the solubility and absorption of certain drugs. This pH dependency can cause a problem, particularly when developing a sustained or controlled release formula. Carvedilol and dipyridamole are drugs that are soluble in the acidic conditions of the stomach but are insoluble in the neutral/slightly alkaline conditions of the intestine, where absorption of active drug is ideal. particular concern are weak, basic drug compounds that are insoluble at a pH greater than five. Eurand’s Diffucaps® technology facilitates the development and commercialization of novel, controlled-release delivery systems for once- or twice-daily dosing of single drugs or drug combinations that exhibit extreme pHdependent solubility profiles and/or are poorly soluble in physiological fluids. This proprietary technology has been developed specifically for weak, basic drugs and involves the incorporation of a pharmaceutically acceptable organic acid or a crystallization inhibiting polymer onto inert cores and coating the drug-layered beads with proprietary functional polymers. Formulations using an acid core ensure that an acidic environment surrounds the drug at all times, thereby producing a soluble drug in an in vivo environment where it would otherwise be insoluble. Three-dimensional printing®: Three-dimensional printing (3DP) is a novel solid freeform fabrication technology that has been applied to the fabrication of complex pharmaceutical drug devices, or three-dimensional printing (3DP) is a rapid prototyping (RP) technology. Prototyping involves constructing specific layers that use powder processing and liquid binding materials. Reports in the literature have highlighted the many advantages of the 3DP system over other processes in enhancing pharmaceutical applications; these include new methods in design, development, manufacture and commercialization of various types of solid dosage forms. For example, 3DP technology is flexible in that it can be used in applications linked to linear drug delivery systems, colon- targeted delivery systems, oral fast disintegrating delivery systems, floating delivery systems, time-controlled and pulse release delivery systems as well as dosage forms with multiphase release properties and implantable DDS. In addition, 3DP can also provide solutions for resolving difficulties relating to the delivery of poorly water-soluble drugs, peptides and proteins, highly toxic and potent drugs and controlled release of multidrug in a single dosage forms. Due to its flexible and highly reproducible manufacturing process, 3DP has some advantages over conventional compressing and other RP technologies in fabricating solid DDS. This enables 3DP to be further developed for use in pharmaceutics applications. However, there are some problems that limit the further applications of the system, such as the selection of suitable excipients and the pharmacotechnical properties of 3DP products. Further developments are therefore needed to overcome these issues, so that 3DP systems can be successfully combined with conventional pharmaceutics.

Diffutab®:
The active drug is layered onto a neutral core (such as cellulose spheres) and then one or more rate-controlling, functional membranes are applied. Diffutab technology enables customized release profiles and region-specific delivery. The Diffutab technology incorporates a blend of waxes and hydrophilic polymers that control drug release through diffusion and erosion of a matrix tablet. Diffutabs are particularly useful for high-dose products and drugs that require sustained release and/or once-a-day dosing. Eurand applied this technology to both soluble and insoluble products. Advantages of Diffutabs are high drug loading, supporting sustained-release and once-a-day dosing, as matrix tablets utilize a combination of water soluble particles and active drug.

Orbexa®:
This technology produces beads that are of controlled size and density using granulation, spheronization and extrusion techniques. Orbexa technology is a multiparticulate system that enables high drug loading and is suitable for products that require granulation. Eurand’s Orbexa technology produces beads of a controlled size and density using granulation spheronization and extrusion techniques. These beads provide higher drug concentration than other systems, can be coated with functional polymer membranes for additional release rate control, are flexible and are suitable for use with sensitive materials, such as enzymes. Eurand’s Orbexa technology can be used for gastric protection,delayed release, sustained release, site-specific delivery, pulsatile delivery, complex release pattern, separation of incompatibles and combination products. Orbexa beads can be filled into capsules or single-dose sachets.

Minitabs®. Eurand’s Minitabs are tiny (2 mm x 2 mm) cylindrical tablets coated with a functional membrane to control the rate of drug release. Eurand Minitabs contain gel-forming excipients that control drug release rate. Additional membranes may be added to further control release rate. The tablets are filled into capsules, allowing a combination of multiple drugs and/or multiple release profiles in the same dosage form. The Eurand Minitabs can be formulated as matrix tablets prior to further coating. Eurand Minitabs can also be used as a sprinkle on food. Eurand Minitabs combine the simplicity of tablet formulation with the sophistication of multiparticulate systems, suitable for high drug loading, and can be used as a sprinkle for pediatric and geriatric patients who have difficulty swallowing tablets.

COLAL® Alizyme Therapeutics Limited: COLAL® involves a coating for drug pellets, tablets or capsules which is composed of ethylcellulose and a form of starch called 'glassy amylose'. The glassy amylose is not digested by human enzymes as the preparation moves down the GI tract, but is digested by bacterial enzymes that are found only in the colon. When the coated product reaches the colon, the coating is degraded, allowing the drug to be released.

EGALET® TIME RELEASE : The Egalet® Time Release consists of three compartments: a coat, a drug release matrix and a lag component. The drug is contained in the inner (middle) layer of the matrix, with the outer layers providing a predetermined delay in release of the drug.

Uniphyl®:
Uniphyl (theophylline, anhydrous) tablets in a controlled- release system allow a 24-h dosing interval for patients. Uniphyl administered in the fed state is completely absorbed after oral administration. TMDS (time multiple action delivery system): This system controls release rates for multiple ingredients within a single tablet in a programmed manner. TMDS technology allows for the release of more than one active ingredient in a single tablet formulation to be released in multiple profiles over time.

SODAS® :
Based on the production of uniform spherical beads of 1-2 mm in diameter containing drug plus excipients and coated with product specific controlled release polymers. SyncroDose® Allow drugs to be delivered after predetermined lag times to coincide with the body's circadian rhythm pattern or to Allow drugs to be delivered to different sites within the gastrointestinal tract A SyncroDose tablet consists of an inner core of drug and a surrounding compression coating containing TIMERx-based materials. Lag time is controlled by variations in the two polysaccharides, xanthan gum and locust bean gum.

Conclusion:
During the last two decades, pharmaceutical technology has grown leaps and bounds and, with the advent of pulsatile drug delivery, one can remain assured of accomplishment of goal for safe and effective therapy. Oral drug delivery is the largest, oldest, and most preferred route of drug delivery. Universally sustained and controlled-release products provide a desired therapeutic effect, but fall for diseases following biological rhythms. Circadian disorders such as asthma, osteoarthritis, Rhumatoid Arthritis, cholesterol synthesis, etc., require chronopharmacotherapy. Pulsatile drug delivery can effectively crack this problem as it is modulated according to body's circadian clock giving release of drug after a specified lag time. During the last two decades, technologies to ensure time-controlled pulsatile release of bioactive compounds have been developed. A significant progress has been made toward achieving PDDS that can effectively treat diseases with non-constant dosing therapies. Various pulsatile technologies are researched and brought in the market, which surely assure a bright and promising future.

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