INTRODUCTION:(1,2)

Pulsatile systems are gaining a lot of interest as they deliver the drug at the right site of action at the right time and in the right amount, thus providing spatial and temporal delivery and increasing patient compliance. The release of the drug as a pulse after a lag time has to be designed in such a way that a complete and rapid drug release follows the lag time. These systems are designed according to the circadian rhythm of the body. The principle rationale for the use of pulsatile release is for the drugs where a constant drug release, i.e., a zero-order release is not desired.

Fig. 1: Release pattern of Sustained (A) and Pulsatile Release (B).

Chronopharmacotherapy

Recent studies show that diseased have predictable cyclic rhythms and the timing of medication regimens can improve outcome in selected chronic conditions. “Chronopharmaceutics” consist of two words chronobiology and Pharmaceutics. Chronobiology is the study of biological rhythms and their mechanisms. There are three types of mechanical rhythms in our body, they are -

-Circadian

-Ultradian

-Infradian

Circadian :

“Circa” means about and “dies” means day

Ultradian:

Oscillation of shorter duration are termed as ultradian (more than one cycle per 24 h)

Infradian:

Oscillations that are longer than 24 h (less than one cycle per day).

Chronopharmacology:

Chronopharmacology is the science concerned with the variations in the pharmacological actions of various drugs over a period of time of the day. Chronopharmacokinetics: Chronopharmacokinetics involves study of temporal changes in drug absorption, distribution, metabolism and excretion. Pharmacokinetic parameters, which are conventionally considered to be constant in time, are influenced by different physiological functions displaying circadian rhythm. Circadian changes in gastric acid secretion, gastrointestinal motility, gastrointestinal blood flow, drug protein binding, liver enzyme activity, renal blood flow and urinary pH can play role in time dependent variation of drug plasma concentrations.

Chronotherapy:

Co-ordination of biological rhythms and medical treatment is called chronotherapy. Chronotherapeutics: 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.

Fig. 2: Schematic diagram of circadian rhythm showing diseases require PDDS.

Necessities of pulsatile Drug delivery system: (3,4)

1. First pass metabolism:

Some drugs, such as beta blockers, and salicylamide, undergo extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize pre-systemic metabolism. Thus, a constant/ sustained oral method of delivery would result in reduced oral bioavailability.

2. Biological tolerance:

Drug plasma profiles are often accompanied by a decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal nitroglycerin, salbutamol sulphate.

3. Special chronopharmacological needs:

Circadian rhythms in certain physiological functions are well established. It has been recognized that many symptoms and onset of disease occur during specific time periods of the 24 hour day, e.g., asthma and angina pectoris attacks are most frequently in the morning hours.

4. Local therapeutic need:

For the treatment of local disorders such as inflammatory bowel disease, the delivery of compounds to the site of inflammation with no loss due to absorption in the small intestine is highly desirable to achieve the therapeutic effect and to minimize side effects.

5. Gastric irritation or drug instability in gastric fluid:

Protection from gastric environment is essential for the drugs that undergo degradation in gastric acidic medium (eg, peptide drugs), irritate the gastric mucosa (NSAIDS) or induce nausea and vomiting.

Merits:(5,6,7)

1. Predictable, reproducible and short gastric residence time

2. Less inter- and intra-subject variability

3. Improve bioavailability

4. Limited risk of local irritation

5. No risk of dose dumping

6. Flexibility in design

7. Improve stability

Demerits:

1. Lack of manufacturing reproducibility and efficacy

2. Large number of process variables

3. Batch manufacturing process

4. Higher cost of production

5. Trained/skilled personal needed for Manufacturing.

T able 1. Diseases required pulsatile delivery(8,9)

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

Formulation consideration: (10,11,12)

Different approaches of pulsatile system are

broadly divided as follows:

1. Time controlled,

2. Internal stimuli induced,

3. Externally regulated,

4. Multiparticulate.

1.Time controlled system:

In time controlled drug delivery system, drug is released in pulsatile manner after specific time interval in order to coincide the drug with proper site, thus mimic the circadian rhythm.

Pulsatile Delivery by Solubilisation or Erosion of layer:

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 2. Time dependent release of the drug can be obtained by optimizing the thickness of the outer coat as shown in Fig.

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

e.g. The Time Clock® system11,12 and the Chronotropic® system.

Pulsatile Delivery by Rupture of Membrane:(13)

In place of swelling or eroding, these systems are dependent on the disintegration of the coating for the release of drug. The pressure necessary for the rupture of the coating can be achieved by the swelling, disintegrants, effervescent excipients, or osmotic pressure. Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time.

Fig. 4: Schematic diagram of drug delivery with rupturable coating layer.

Capsule Shaped Pulsatile Drug Delivery System:(14)

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.

Pulsatile System Based On Osmosis:(15)

Osmotic system consists of capsule coated with the semipermeable membrane. Inside the capsule there is an insoluble plug consisting of osmotically active agent and the drug formulation.

e.g. The Port® System

Fig.6: Schematic diagram of osmosis system

2. Internal stimuli induced system:(16)

In these systems, the release of the drug takes place after stimulation by any biological factor like temperature, or any other chemical stimuli. Many of the polymeric delivery systems experience phase transitions and demonstrate marked swelling deswelling changes in response to environmental changes including solvent composition ionic strength, temperature, electric fields, and light.

Temperature–induced pulsatile release:(17)

This deviation sometimes can act as a stimulus that triggers the release of therapeutic agents from several temperature responsive drug delivery systems for diseases accompanying fever. The temperature induced pulsatile/ triggered drug delivery systems utilize various polymer properties, including the thermally reversible coil/globule transition of polymer molecules, swelling change of networks, glass transition and crystalline melting.

Thermoresponsive hydrogel systems:(18)

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 hydrosensitive 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 delivery.

Thermoresponsive polymeric micelle systems:(19)

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 beam. Jianxiang Zhang, et al synthesized thermally responsive amphiphilic poly(N isopropylacrylamide) (PNIPAm)-grafted polyphosphazene (PNIPAm-g- PPP) by stepwise cosubstitution of chlorine atoms on polymer backbones with amino-terminated NIPAm oligomers and ethyl glycinate (GlyEt). Diflunisal (DIF)-loaded micelles were prepared by dialysis method. In vitro release test at various temperatures was also performed to study the effect of temperature on the drug release profiles.

Chemical stimuli induced pulsatile systems:(20)

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.

Glucose-responsive insulin release devices:(21)

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 approximately. 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 release. Kazunori Kataoka, et al reported remarkable change in the swelling induced by glucose demonstrated for the gel composed of PNIPAAm with phenylboronic acid moieties. On-off regulation of insulin release from the gel achieved through a drastic change in the solute transport property as a result of the formation and disruption of the surface barrier layer of the gel.

pH sensitive drug delivery system:(22)

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, polyacrylates, sodium carboxy methyl cellulose.

Inflammation-induced pulsatile release:(23)

Physical or chemical stress, such as injury, broken bones, etc., initiates inflammation reactions, because of which hydroxyl radicals ('OH) are produced from these inflammation-responsive cells. Yui et al. designed drug delivery systems based on the polymers which responded to the hydroxyl radicals and degraded in a limited manner. Yui and coworkers used hyaluronic acid (HA), in the body, HA is mainly degraded either by hydroxyl radicals or a specific enzyme, hyaluronidase. Degradation through hydroxyl radicals however, is usually dominant and rapid when HA is injected at inflammatory sites. Thus, they designed crosslinked HA with ethylene glycol diglycidyl ether or polyglycerol polyglycidyl ether Thus, a surface erosion type of degradation was achieved. Patients with inflammatory diseases, such as rheumatoid arthritis, can be treated using this type of system.

Drug release from intelligent gels responding to antibody concentration:(24)

Miyata et al. focused on the development of stimuli responsive crosslinking structures into hydrogels. Special care was given to antigen-antibody complex formation as the cross-linking units in the gel, since specific antigen recognition of an antibody can provide the foundation for a new device fabrication. Using the difference in association constants between polymerized antibodies and naturally derived antibodies towards specific antigens, reversible gel swelling/deswelling and drug permeation changes could occur. Thus, biological stimuli responsive hydrogels were created.

EnzymaticaIIy-activated Liposome:(25)

Drug loaded liposomes was incorporated into microcapsules of alginate hydrogels. Liposomes inside the microcapsules were coated with phospholipase A2 to achieve a pulsatile release of drug molecules. Phospholipase A2 was shown to accumulate at the water/liposome interfaces and remove an acyl group from the phospholipids in the liposome. Destabilised liposomes release their drug molecules, thus allowing drug release to be regulated by the rate determining microcapsule membrane.

3. Externally regulated pulsatile release system:(26)

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.

Magnetic induces release:(27)

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. 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. Tingyu Liu, et al developed the magnetic hydrogels which was successfully fabricated by chemically crosslinking of gelatin hydrogels and Fe3O4 nanoparticles (ca. 40–60 nm) through genipin (GP) as cross-linking agent.

Ultrasound induces release:(28)

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 nonthermal 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 noncavitation effects such as radiation pressure, radiation torque, and acoustic streaming.

Electric field induces release:(29)

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.

Light induces release:(30)

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 Andrei Dashevsky, et al. developed a pulsatile multiparticulate drug delivery system (DDS), coated with aqueous dispersion of Aquacoat® ECD. A rupturable pulsatile drug delivery system consists of (i) a drug core; (ii) a swelling layer, comprising a superdisintegrant and a binder; and (iii) an insoluble, water-permeable polymeric coating. Upon water ingress, the swellable layer expands, resulting in the rupturing of outer membrane with subsequent rapid drug release. Regarding the cores, the lag time was shorter; theophylline was layered on of composite hydrogel above its LCST41, hydrogel collapses and result in an increased rate of release of soluble drug held within the matrix.

4. Multipaticulate system:(31)

Recent trends indicate that multiparticulate drug delivery systems are especially suitable for achieving controlled or delayed release oral formulations with lowrisk of dose dumping, flexibility of blending to attain different release patterns as well as reproducible and short gastric residence time. Such systems are reservoir type with either rupturable or altered permeability coating and generally housed in capsular body.

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 behaviour due to unit to unit variation. Sugar cores compared with cores consisting of theophylline. Regarding swelling layer, the release after lag time was fast and complete. Drug release was achieved after the lag time, when low-substituted hydroxypropyl cellulose (L-HPC) and sodium starch glycolate (Explotab®) were used as swelling agents. Outer membrane, formed using aqueous dispersion Aquacoat® ECD was brittle and ruptured sufficiently to ensure fast drug release, compared to ethylcellulose membrane formed using organic solution. The addition of talc led to increase brittleness of membrane and was very advantageous. Drug release starts only after rupturing of outer membrane. C. Sun, et al. developed novel pH sensitive copolymer microspheres containing methylacrylic acid and styrene cross-linking with divinylbenzene were synthesized by free radical polymerization. The copolymer microspheres showed pulsatile swelling behavior when the pH of the media changed. The pH sensitive microspheres were loaded with diltiazem hydrochloride (DH). The release characteristics of the free drug and the drug-loaded microspheres were studied under both simulated gastric conditions and intestinal pH conditions. The in vivo evaluation of the pulsatile preparation was subsequently carried out using beagle dogs independent of the gastrointestinal motility, PH, enzyme and gastric residence.

CONCLUSION:

The literature review relating to this formulation strongly recommending 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 a drug at 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. Extended release formulations and immediate release formulation are not efficient in treating the diseases especially diseases with chronological pathopysiology, for which, pulsatile drug delivery is beneficial. The drug is delivering in this system when its actual concentration is needed as per chronological need, so pulsatile release systems should be promising in the future.

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Received on 12.05.2016 Modified on 21.05.2016

Res. J. Pharm. Dosage Form. & Tech. 2016; 8(3): 221-227.

DOI: 10.5958/0975-4377.2016.00031.8

Technology	Mechanism	Proprietary name and dosage form	API	Disease
OROS*	Osmotic mechanism	Covera-H5*; XL tablet	Verapamil HCL	Hypertension
Three dimentional printing*	Externally regulated system	Their Form*	Diclofenac sodium	Inflammation
DIFFUCAPS*	Multiparticulate system	Innopran*; XL tablets	Verapamil HCL, Propranolol HCL	Hypertension
PulsincapTM	Rupturable system	PulsincapTM	Dofetilide	Hypertension