There are many conditions that demand pulsatile release like

a) Many body functions that follow circadian rhythm. e.g.: Secretion of hormones, acid secretion in stomach, gastric emptying, and gastrointestinal blood transfusion.

b) Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology like bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer, and hypertension.

c) Drugs that produce biological tolerance demand for a system that will prevent their continuous presence at the biophase as this tends to reduce their therapeutic effect.

d) The lag time is essential for the drugs that undergo degradation in gastric acidic medium (e.g.: peptide drugs) and irritate the gastric mucosa or induce nausea and vomiting.

e) Targeting a drug to distal organs of gastro-intestinal tract (GIT) like the colon requires that the drug release is prevented in the upper two-third portion of the GIT.

f) The drugs that undergo first-pass metabolism resulting in reduced bioavailability, altered steady state levels of drug and metabolite, and potential food drug interactions require delayed release of the drug to the extent possible.

All of these conditions demand for a time controlled therapeutic scheme releasing the right amount of drug at the right time. This requirement is fulfilled by Pulsatile Drug Delivery Systems (PDDS). The following figures (Fig 2 and Fig 3) are showing the release profiles of drug from pulsatile drug delivery systems.

Advantages of PDDS ⁷:

ü Predictable, reproducible and short gastric residence time

ü Less inter- and intra-subject variability

ü Improve bioavailability

ü No risk of dose dumping

ü Flexibility in designing of dosage form

ü Improve stability

ü Reduced side effects

ü Reduced dosage frequency

ü Reduction in dose size

ü Lower daily cost to patient due to fewer dosage units are required by the patient in therapy.

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

ü Drug targeting to specific site like colon.

ü Protection of mucosa from irritating drugs

ü Drug loss is prevented by extensive first pass metabolism.

ü Patient comfort and compliance: Oral drug delivery is the most common and convenient for patients, and a reduction in dosing frequency enhances compliance.

Limitation of PDDS ⁷:

ü Lack of manufacturing reproducibility and efficacy due to multiple manufacturing steps

ü Large number of process variables

ü Batch manufacturing process

ü Higher cost of production

ü Trained/skilled personal needed for manufacturing

ü Low drug load

ü Incomplete release

Diseases Requiring Pulsatile Delivery ⁸:

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

Table 1: Diseases required pulsatile delivery

Diseases	Chronological behavior	Drugs used
Peptic ulcer	Acid secretion is high in the Afternoon and at night	H2 blockers
Asthma	Precipitation of attacks during night or at early morning	β2 agonist, Antihistamines
Cardiovascular diseases	BP is at its lowest during the sleep cycle and rises steeply during the early morning	Nitroglycerin, calcium channel blocker, ACE inhibitors
Arthritis	Pain in the morning and more pain at night	NSAIDs, Glucocorticoids
Diabetes mellitus	Increase in the blood sugar level after meal	Sulfonylurea, Insulin
Hypercholesterolemia	Cholesterol synthesis is generally higher during night than day time	HMG CoA reductase inhibitors
Attention Deficit Syndrome	Increase in DOPA level in afternoon	Methyl phenidate

Marketed technologies of pulsatile drug delivery ⁹:

Some of the marketed technologies of pulsatile drug delivery system are given in below table.

Classification of pulsatile drug delivery systems:

Pulsatile drug delivery system can be broadly classified into three classes:
I. Time controlled pulsatile drug delivery
II. Stimuli induced pulsatile drug delivery
III. Externally regulated pulsatile drug delivery

I. Time controlled pulsatile drug delivery
A. Single unit pulsatile systems
1. Capsule based systems
         E.g. Pulsincap system
2. Capsular system based on Osmosis
         a. ‘PORT’ System
         b. System based on expandable orifice
         c. Delivery by series of stops
         d. Pulsatile delivery by solubility modulation
3. Pulsatile system with Erodible or soluble barrier coatings

         a. The chronotropic system
         b. ‘TIME CLOCK’ System
         c. Compressed tablets
         d. Multilayered tablets
4. Pulsatile system with rupturable coating

B. Multiparticulate / Multiple unit systems:
1. Pulsatile system with rupturable coating
           E.g. Time –controlled Explosion system (TCES)
2. Osmotic based rupturable coating system
           E.g. Permeability controlled system
3. Pulsatile delivery by change in membrane permeability
           E.g.Sigmoidal release system.

II. Stimuli induced pulsatile drug delivery
1. Temperature-induced pulsatile release

2. Chemical stimuli-induced pulsatile release

a) Glucose-responsive insulin release devices

b) Inflammation-induced pulsatile release

c) Drug release from intelligent gels responding to antibody concentration

d) Electric stimuli-responsive pulsatile release

e) pH sensitive drug delivery system

III. Externally regulated pulsatile drug delivery

1. Magnetic induces release

2 Ultrasound induces release

3. Electric field induces release

4. Light induces release ¹⁰

I. Time controlled pulsatile drug delivery:

A. Single unit pulsatile systems:
1. Capsule based systems:
Single-unit systems are mostly developed in capsule form. The lag time is controlled by a plug, which gets pushed away by swelling or erosion, and the drug is released as a “Pulse” from the insoluble capsule body ¹¹.

c) Pulsatile delivery by change in membrane permeability:

The permeability and water uptake of acrylic polymers with quaternary ammonium groups can be influenced by the presence of different counter-ions in the medium ⁴⁰. Several delivery systems based on this ion exchange have been developed. Eudragit RS 30D is reported to be a polymer of choice for this purpose. It typically contains positively polarized quaternary ammonium group in the polymer side chain, which is always accompanied by negative hydrochloride counter-ions. The ammonium group being hydrophilic facilitates the interaction of polymer with water, thereby changing its permeability and allowing water to permeate the active core in a controlled manner. This property is essential to achieve a precisely defined lag time ⁴¹.

II. Stimuli induced pulsatile drug delivery:

1. Temperature-induced pulsatile release:

Thermo-responsive hydrogel systems have been developed for pulsatile release. In these systems the polymer undergoes swelling or deswelling phase in response to the temperature which modulate drug release in swollen state. Y.H. Bae et al developed indomethacin pulsatile release pattern in the temperature ranges between 20⁰C and 30⁰C by using reversible swelling properties of copolymers of N-isopropyl acrylamide and butyryl acrylamide ⁴². Kataoka et al developed the thermosensitive polymeric micelles as drug carrier to treat the cancer. They used end functionalized poly (N isopropyl acrylamide) (PIPAAm) to prepare corona of the micelle which showed hydration and dehydration behavior with changing temperature ⁴³.

2. Chemical stimuli-induced pulsatile release:

a) Glucose-responsive insulin release devices:

In case of diabetes mellitus there is rhythmic increase in the levels of glucose in the body requiring injection of the insulin at proper time. Several systems have been developed which are able to respond to changes in glucose concentration. One such system includes pH sensitive hydrogel containing glucose oxidase immobilized in the hydrogel. When glucose concentration in the blood increases glucose oxidase converts glucose into gluconic acid which changes the pH of the system. 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 release. Examples of the pH sensitive polymers include N, N dimethyl aminoethyl methacrylate, chitosan, polyol etc. Obaidat and Park prepared a copolymer of acrylamide and allyl glucose. The side chain glucose units in the copolymer were bound to concanavalin A ⁴⁴. These hydrogels showed a glucose-responsive, sol–gel phase transition dependent upon the external glucose concentration. Okano et al developed the system based upon the fact that boronic acid moiety forms reversible bonds with polyol compounds including glucose. They used water-soluble copolymers, containing phenyl boronic acid side chains which showed formation of a reversible complex gels with polyol compounds such as polyvinyl alcohol (PVA) ⁴⁵. Such complexes dissociated after the addition of glucose in a concentration dependent manner.

b) Inflammation-induced pulsatile release:

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 polymorphonuclear cells play a role in the healing process of the injury. During inflammation, hydroxyl radicals (OH^-) are produced from these inflammation-responsive cells. Yui and co-workers used hyaluronic acid (HA), a linear mucopolysaccharide composed of repeating disaccharide subunits of N-acetyl-D-glucosamine and D-glucuronic acid ^{46, 47}. In the body, HA is mainly degraded either by a specific enzyme, hyaluronidase, or hydroxyl radicals. Degradation of HA via the hyaluronidase is very low in a normal state of health. Degradation via hydroxyl radicals however, is usually dominant and rapid when HA is injected at inflammatory sites. Thus, Yui and co-workers prepared cross-linked HA with ethylene glycol diglycidyl ether or polyglycerol polyglycidyl ether. These HA gels degraded only when the hydroxyl radicals were generated through the Fenton reaction between Fe⁺² ions and hydrogen peroxide in vitro. Thus, a surface erosion type of degradation was achieved. When microspheres were incorporated in the HA hydrogels as a model drug, these microspheres were released only when hydroxyl radicals induced HA gel degradation. The microsphere release was regulated by the surface erosion type of degradation.

c) Drug release from intelligent gels responding to antibody concentration:

There are numerous kinds of bioactive compounds which exist in the body. Recently, novel gels were developed which responded to the change in concentration of bioactive compounds to alter their swelling/ deswelling characteristics. Miyata and co-workers focused on the introduction of stimuli-responsive cross-linking structures into hydrogels ^{48, 49}. Special attention was given to antigen antibody complex formation as the cross-linking units in the gel, because specific antigen recognition of an antibody can provide the basis for a new device fabrication.

d) Electric stimuli-responsive pulsatile release:

The combination of developments in several technologies, such as microelectronics and micromachining, as well as the potential need for chronotherapy, have currently assisted the development of electronically assisted drug delivery technologies. These technologies include iontophoresis, infusion pumps, and sonophoresis ⁵⁰. Several approaches have also been presented in the literature describing the preparation of electric stimuli-responsive drug delivery systems using hydrogels. Kishi et al. developed an electric stimuli induced drug release system using the electrically stimulated swelling /deswelling characteristics of polyelectrolyte hydrogels ⁵¹. They utilized a chemo mechanical system, which contained a drug model within the polyelectrolyte gel structure. These gels exhibited reversible swelling / shrinking behavior in response to on–off switching of an electric stimulus. Thus, drug molecules within the polyelectrolyte gels might be squeezed out from the electric stimuli-induced gel contraction along with the solvent flow. To realize this mechanism, poly (sodium acrylate) microparticulate gels containing pilocarpine as a model drug were prepared ⁵².

e) pH sensitive drug delivery system:

Such type of pulsatile drug delivery system contains two components one is of immediate release type and other one is pulsed release which releases the drug in response to change in pH. In case of pH dependent system advantage has been taken of the fact that there exists different pH environment at different parts of the gastrointestinal tract. By selecting the pH dependent polymers drug release at specific location can be obtained. Examples of pH dependent polymers include cellulose acetate phthalate, polyacrylates, sodium carboxy methyl cellulose. These polymers are used as enteric coating materials so as to provide release of drug in the small intestine. Yang et al developed pH-dependent delivery system of nitrendipine in which they have mixed three kinds of pH dependent microspheres made up of acrylic resins Eudragit E-100, Hydroxy propyl methyl cellulose phthalate and Hydroxy propyl methyl cellulose acetate succinate as pH dependent polymers. In one of the study carried out by Mastiholimath et al attempt was made to deliver theophylline into colon by taking the advantage of the fact that colon has a lower pH value (6.8) than that of the small intestine (7.0–7.8). So, by using the mixture of the polymers, i.e. Eudragit L and Eudragit S in proper proportion, pH dependent release in the colon was obtained ⁵³.

III. Externally regulated pulsatile drug delivery:

For releasing the drug in a pulsatile manner, another way can be the externally regulated systems in which drug release is programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation.

1. Magnetic induces release:

Magnetically regulated system contains magnetic beads in the implant. On application of the magnetic field, drug release occurs because of magnetic beads. Saslawski et al. developed different formulation for in vitro magnetically triggered delivery of insulin based on alginate spheres. Magnetic carriers receive their magnetic response to a magnetic field from incorporated materials such as magnetite, iron, nickel, cobalt etc. Magnetic-sensitive behavior of intelligent ferrogels for controlled release of drug was studied by Tingyu Liu, et al. An intelligent magnetic hydrogel (ferrogel) was fabricated by mixing poly (vinyl alcohol) (PVA) hydrogels and Fe₃O₄ magnetic particles through freezing-thawing Cycles ⁵⁴. Although the external direct current magnetic field was applied to the ferrogel, the drug got 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 ⁵⁵. Tingyu Liu, et al developed the magnetic hydrogels which was successfully fabricated by chemically crosslinking of gelatin hydrogels and Fe₃O₄ nanoparticles (40–60 nm) through genipin (GP) as cross-linking agent ⁵⁶.

2 Ultrasound induces release:

In case of ultrasonically modulated systems, ultrasonic waves cause the erosion of the polymeric matrix thereby modulating drug release. Miyazaki et al evaluated the effect of ultrasound (1 MHz) on the release rates of bovine insulin from ethylene vinyl alcohol copolymer matrices and reservoir-type drug delivery systems in which they found sharp drop in blood glucose levels after application of ultrasonic waves. 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 are 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 streaming ⁵⁷.

3. Electric field induces release:

Electrically responsive delivery systems are prepared by 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 bend, depending on the shape of the gel which lies parallel to the electrodes whereas deswelling occurs when the hydrogel lies perpendicular to the electrodes. An electroresponsive drug delivery system was developed by R. V. Kulkarni, et al., using poly (acrylamide-grafted-xanthan gum) (PAAm-g- XG) hydrogel for transdermal delivery of ketoprofen ⁵⁸.

4. Light induces release:

Light-sensitive hydrogels have potential applications in developing optical switches, display units, and opthalmic drug delivery devices ⁵⁹. 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 lower critical solution temperature (LCST), hydrogel collapses and result in an increased rate of release of soluble drug held within the matrix. Mathiowitz et al developed photochemically controlled delivery systems prepared by interfacial polymerization of polyamide microcapsules. For this purpose, azobisisobutyronitrile (AIBN), a substance that photochemically emanates nitrogen gas, was incorporated. Due to exposure of azobisisobutyronitrile to light causing release of nitrogen and an increase in the pressure which ruptures the capsules thereby releasing the drug ⁶⁰.

Recent advances in the pulsatile drug delivery:

Nowadays pulsatile drug delivery systems are gaining importance in various disease conditions specifically in diabetes where dose is required at different time intervals. Among these systems, multi-particulate systems (e.g. pellets) offer various advantages over single unit which include no risk of dose dumping, flexibility of blending units with different release patterns, as well as short and reproducible gastric residence time ⁶¹. Multiparticulate systems consists pellets of different release profile which can be of any type like time dependent, pH dependent, micro flora activated system as discussed in the previous sections. Site and time specific oral drug delivery have recently been of great interest in pharmaceutical field to achieve improved therapeutic efficacy. Gastroretentive drug delivery system is an approach to prolong gastric residence time, thereby targeting site specific drug release in upper gastrointestinal (GI) tract. Floating drug delivery system (FDDS) and bioadhesive drug delivery are widely used techniques for gastro retention. Low density porous multiparticulate systems have been used by researchers for formulation of FDDS. Sharma and Pawar developed multiparticulate floating pulsatile drug delivery system using porous calcium silicate and sodium alginate for time and site specific drug release of meloxicam ⁶².

Various pulsatile technologies have been developed on the basis of methodologies as discussed previously. Some of them are as follows.

SODAS® Technology: SODAS® (Spheroidal Oral Drug Absorption System) is Elan’s Multiparticulate drug delivery system. Based on the production of controlled release beads, the SODAS® technology is characterized by its inherent flexibility, enabling the production of customized dosage forms that respond directly to individual drug candidate needs. Elan’s SODAS® Technology is 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. The most recent regulatory approvals for SODAS® based system occurring with the launch of once-daily oral dosage forms of Avinza™, Ritalin® LA and Focalin® XR ⁶³.

IPDAS® Technology: The Intestinal Protective Drug Absorption System (IPDAS® Technology) is a high density multiparticulate tablet technology, intended for use with GI irritant compounds. 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 through the polymeric membrane. Micromatrix of polymer/active ingredient formed in the extruded/spheronized multiparticulates. Naprelan®, which is marketed in the United States and Canada, employs the IPDAS® technology. This was innovative formulation of naproxen sodium ⁶³.

CODAS™ Technology: Elan’s drug delivery technology can be tailored to release drug after a predetermined delay. The CODAS™ drug delivery system enables a delayed onset of drug release, resulting in a drug release profile that more accurately compliments circadian patterns. Elan’s Verelan® PM represents a commercialized product using the CODAS™ technology. The Verelan® PM formulation was designed to begin releasing Verapamil approximately four to five hours post ingestion. This delay is introduced by the level of release-controlling polymer applied to the drug-loaded beads ⁶³.

PRODAS® Technology: Programmable Oral Drug Absorption System (PRODAS® Technology) is a multiparticulate technology, which is unique in that it combines the benefits of tabletting technology within a capsule. The PRODAS® delivery system is presented as a number of minitablets combined in a hard gelatin capsule. Very flexible, the PRODAS® technology can be used to pre-program the release rate of a drug. It is possible to incorporate many different minitablets, each one formulated individually and programmed to release drug at different sites within the gastro-intestinal tract. It is also possible to incorporate minitablets of different sizes so that high drug loading is possible ⁶³.

PULSYS™ Technology: MiddleBrook™ (Earlier known as Advancis Pharmaceuticals) Pharmaceuticals developed PULSYS™, 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. PULSYS™ Technology’s Moxatag™ tablet contain Amoxicillin is designed to deliver amoxicillin at lower dose over a short duration therapy in once daily formulation. Advancis have also demonstrated that by preclinical studies which improved bactericidal effect for amoxicillin when deliver in pulsatile manner as compared to standard dosing regimen even against resistant bacteria ⁶³.

Current scenario and future prospects:

Now a day's pulsatile drug delivery is gaining popularity. The prime advantage in this drug delivery is that drug is released when necessity comes. As a result chances of development of drug resistance which is seen in conventional and sustained release formulations can be reduced. Furthermore, some anticancer drugs are very toxic. These drugs give hazardous problems in conventional and sustained release therapies. Now many FDA approved chronotherapeutic drugs are available in the market. This therapy is mainly applicable where sustained action is not required and drugs are toxic. Key point of development of this formulation is to find out circadian rhythm i.e. suitable indicator which will trigger the release of drug from the device. Another point is absence of suitable rhythmic biomaterial which should be biodegradable, biocompatible and reversibly responsive to specific biomarkers in rhythmic manner. Regulatory is another big question. In preapproval phase it is sometimes difficult to show chronotherapeutic advantage in clinical settings. In post approval phase causal recreational drug abuse along with on a much larger scale, by the criminal diversion of these modified formulations for profit have arisen problems. The FDA has now heavily relied on the development and implementation of risk management programs as a strategy to allow an approval of a drug to go forward while exercising some restrictions. Many researches are going on the pulsatile drug delivery to discover circadian rhythm with suitable device in the world. In future this delivery will be a leading way to deliver therapeutic agents due to its some unique characters like low chance of dose dumping, patient compliance and the above factors ⁶⁴.

CONCLUSION:

Sustained release formulations are not efficient in treating diseases especially diseases with chronological pathophysiology, for which pulsatile drug delivery is beneficial. Circadian rhythm of the body is an important concept for understanding the optimum need of drug in the body. There is a constant need for new delivery systems that can provide increased therapeutic benefits to the patients. Pulsatile drug delivery is one such system that, by delivering drug at the right time, right place, and in right amounts, holds good promises of benefit to the patients suffering from chronic problems like arthritis, asthma, hypertension, etc. Thus designing of proper pulsatile drug delivery will enhances the patient compliance, optimum drug delivery to the target site and minimizes the undesired effects.

ACKNOWLEDGEMENTS:

Authors are thankful to Bharati Vidyapeeth’s College of Pharmacy, Sector-8, C.B.D., Belapur, Navi Mumbai for providing the necessary facilities.

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Research J. Pharm. and Tech. 5(4): April 2012; Page 449-461

Technology	Mechanism	API	Disease
OROS®	Osmotic Mechanism	Verapamil HCL	Hypertension
Three Dimensional printing®	Externally regulated system	Diclofenac Sodium	Inflammation
DIFFUCAPS®	Multiparticulate System	Verapamil HCl, propranolol HCl	Hypertension
Pulsincap TM	Rupturable system	Dofetilide	Hypertension
Pulsys®	Time controlled system	Amoxycillin	Bacterial infections
Uniphyl®	Externally regulated system	Theophyllin	Asthma
Retalina®	Osmotically regulated	Methyl phenidate	Attention Deficit Syndrome
CODAS®	Multiparticular pH dependent system	Verapamil HCL	Hypertension