INTRODUCTION:

Oral administration has been one of the most frequently used routes for drug delivery due to its obvious advantages of ease of administration, superior patient compliance compared to other routes, less sterility constraints and various designed dosage forms. Delayed pulsatile drug delivery is a treatment approach where in medication delivery is increased in one or few body parts in comparison to other body parts, offering an improved efficacy of treatment and a reduced side effects¹. The principle grounds for the use of pulsatile release is where a constant drug release is not desired. Pulsatile systems are beneficial for the drugs showing chronopharmacological nature². Pulsatile drug release dosage forms delivers the maximum drug concentration at the body part when symptoms are observed after a specified off-release lag time and/or in a specific site in the gastrointestinal tract. The release profile of such a delivery is characterized by a lag time followed by rapid and complete drug release³.

The pulsatile delivery is desirable as i) For drugs with an extensive first pass metabolism, e.g. Beta-blockers ii) For drugs acting locally or having an absorption window in specific the gastrointestinal tract, iii) For peptides and proteins that are sensitive to gastric fluid iv) It decreases the side effects commonly associated with the treatment of colon diseases^4–7. The term “chrono” mentions to the observation that rhythmic changes in time is shown by every metabolic events⁸. Chronobiology infers to the study of biological rhythms and their mechanisms. Three types of mechanical rhythm in our body are: Circadian, Ultradian and Infradian⁹

Fig. 1: Schematic representation of pulsatile drug delivery system

Necessity of pulsatile drug delivery system:

There are many conditions and diseases where sustained release formulations do not show good efficacy. In such cases Pulsatile DDS is applicable.

1. First pass metabolism:

Some drugs undergo extensive first pass metabolism and thus fast drug input to saturate metabolizing enzymes is required. In such cases, a constant/sustained oral delivery of drug would result in reduced oral bioavailability.

2. Biological tolerance:

A decline in the pharmacotherapeutic effect of the drug is seen with the drug plasma profiles e.g., biological tolerance of transdermal nitroglycerin.

3. Special chronopharmacological needs:

Circadian rhythms in certain physiological functions are well established e.g., asthma and angina pectoris attacks are most frequently in the morning hours.

4. Local therapeutic needs:

For the treatment of local disorders such as inflammatory bowel disease, 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 (e.g.: peptide drugs), irritate the gastric mucosa (NSAIDS) or induce nausea and vomiting

Advantages:

· They can be used for extended day time or night time activity.

· These systems reduce the dosing frequency, dose size and cost, reduces side effects, and thereby improves patient compliance.

· Drug adapts to suit circadian rhythms of diseases.

· Site specific targeting like colon can be achieved(eg:In Ulcerative colitis)

· They protect gastric mucosa from irritating drugs(eg: NSAIDS)¹⁰

· Drug loss by extensive first pass metabolism is prevented¹¹

Drawbacks:

· Low drug loading

· Proportionally higher need for excipients

· Lack of manufacturing reproducibility and efficacy

· Large number of process variables

· Multiple formulation steps

· Higher cost of production

· Need of advanced technology

· Trained/skilled personal needed for manufacturing^[12]

Table 1: Diseases that require pulsatile drug delivery

Diseases	Chronological behaviour	Drugs used
Cancer	During each daily activity phase of the circadian cycle the blood flow to tumours is threefold greater than during the daily rest phase	Vinca alkaloids, Taxanes^13,14
Neurological disorders	The underlying mechanisms of epilepsy in the brain may have circadian patterns	MAO-B inhibitor
Asthma	Exacerbates during sleep period	Β2 agonist, Antihistamines
Arthritis	Level of pain increases at night.	NSAIDs, Glucocorticoids
Hypercholesterolemia	Cholesterol synthesis is generally higher during night than daylight.	HMG CoA reductase, Inhibitors
Diabetes mellitus	Blood sugar level peaks after meal.	Sulfonylurea, Insulin
Cardiovascular diseases	Capillary resistance and vascular reactivity are higher in the morning and decreases later in the day	Nitroglycerin, calcium channel, blocker, ACE inhibitors
Peptic ulcer	Acid secretion is high during the afternoon and at night.	H2 blockers
Attention deficit syndrome	High DOPA level in afternoon.	Methylphenidate

Classification of pulsatile drug delivery system:

1. Time controlled

2. Stimuli induced

3. Externally regulated

1. Time controlled pulsatile drug delivery

1.1 Single unit pulsatile systems:

· Capsule based systems:

Pulsincap system:

Single-unit systems have been mostly developed in capsule form. The lag time is controlled by a plug. Plug gets pushed away by swelling or erosion, and the rug is released Pulsincap. In this system, the water insoluble capsule encloses the drug reservoir. The capsule swells when comes in contact with the dissolution fluid, and after a lag time, the plug pushes itself outside the capsule, rapidly releasing the drug

Fig. 2: Design of pulsincap system

1.2 Capsular system based on Osmosis:

(a) ‘PORT’ System:

The system comprises semi permeable membrane enclosing a capsule. Within the capsule is an insoluble plug of osmotically active agent and the drug formulation. Pressure is developed when the capsule comes in contact with the dissolution fluid resulting in expelling of the insoluble plug after a lag time

(b) System based on expandable orifice:

An osmotically driven capsular system was developed to deliver the drug in liquid form. After the barrier layer is dissolved, the liquid drug absorbed into highly porous particles is released through an orifice of a semipermeable capsule.

Fig. 3: System based on expandable orifice

(c) Delivery by series of stops:

This particular system is designed for implantable capsules. The capsule includes a drug and water-absorptive osmotic engine. These are positioned in compartments segregated by a movable slider. Series of stops block the movement of drug and provides lag time.

(d) Pulsatile delivery by solubility modulation:

Solubility modulation system provides pulsed delivery of variety of drugs. It was particularly developed for delivery of salbutamol sulphate containing sodium chloride as modulating agent.

1.3 Pulsatile system with soluble/erodible barrier coatings:

These systems are reservoir devices coated with a barrier layer. After a fixed lag period the barrier erodes/ dissolves releasing the drug rapidly from reservoir core. The thickness of the coating layer determines the lag time.¹⁵

(a) The chronotropic system:

The system comprises a drug containing core coated by hydrophilic swellable HPMC producing a lag phase (Gazzaniga et al., 1994). The variable gastric emptying time can be overcome by an outer enteric film, and a colon-specific release can be achieved, assuming that small intestinal transit time is unchanged (Poli et al., 1993). Thickness and the viscosity grades of HPMC controls the lag time.

(b) ‘TIME CLOCK’ System:

A delivery device based on solid dosage form coated by an aqueous dispersion. An aqueous dispersion of a hydrophobic surfactant layer at 75°c (Beeswax, carnauba wax, poly {oxyethylene}-sorbitan monooleate) is used to coat the core (Wilding et al., 1994). The thickness of the film controls the lag time.

(c) Compressed tablets:

Compression coating implies direct compression of both the core and the coat. The rapidly disintegrating outer tablet of the compression-coated tablet provides the initial dose, in the stomach and the inner layer is formulated with components so as to release in the intestinal environment.Example: Cellulose derivatives

1.4 Pulsatile system with rupturable coating:

The system requires disintegration of the coat for the release of drug¹⁶. By effervescent excipients, swelling agents, or osmotic pressure the required pressure for coat rupture is achieved¹⁷. After penetration of water into the core, carbon dioxide is produced by effervescent mixture of citric acid and sodium bicarbonate incorporated in a tablet core coated with ethyl cellulose resulting in pulsatile release of drug by rupture of the coat. With increasing coating thickness and hardness of the core tablet the lag time increases.

2. Multiparticulate / Multiple unit systems:

2.1 Pulsatile system with rupturable coating:¹⁸

· Time–controlled Explosion system (TCES):

The drug is coated on non-pareil sugar seeds and subsequently with a swellable layer and finally an insoluble top layer coating (Ueda et al., 1994). The swellable layer expands on penetration of water resulting in rupture of film with subsequent rapid drug release. Varying coating thickness or addition of high amounts of lipophilic plasticizer in the outermost layer results in variable lag time. Increased concentration of osmotic agent provides rapid release after the lag phase.

2.2 Osmotic based rupturable coating system:

The combination of osmotic and swelling effects makes the osmotic based rupturable coating system. Drug, a low bulk density lipid material (eg, mineral oil) and a disintegrant makes up the core. Finally a cellulose acetate coating is made on the core. Water ingress into the core displaces lipid material. Rupture of coat occurs followed by the depletion of lipid material, when the internal pressure reaches the critical stress. (Amidon et al., 1993).

2.3 Pulsatile Delivery by Change in Membrane Permeability:

Several delivery systems based on ion exchange have been developed. The preferred polymer for this purpose is Eudragit.

2.4 Stimuli induced pulsatile systems:

The drug release occurs after stimulation by any biological factor like temperature, or any other chemical stimuli. Based on the stimulus, the systems are further classified into:

2.4.1 Temperature induced systems

2.4.2 Chemical stimuli induced system

2.4.3 pH Sensitive Pulsatile Release

Time-controlled release systems can only release at pre-programmed time points, whereas stimuli-induced pulsatile release systems are more easily manipulated.¹⁹

2.4.1 Temperature induced systems²⁰

Thermal stimuli-regulated pulsed drug release is established through the design of drug delivery devices such as hydrogels and micelles. Example: Poly(N-isopropyl acryl amide) PIPAAm cross-linked gels has shown thermoresponsive, discontinuous swelling / deswelling phases:

2.4.2 Chemical stimuli induced pulsatile systems:

a) Glucose-responsive insulin release devices:

To respond to changes in glucose concentration, pH sensitive hydrogel containing glucose oxidase immobilized in the hydrogel has been developed.

b) Inflammation induced pulsatile release device:

It is possible to treat patients with inflammatory diseases like rheumatoid arthritis; using anti-inflammatory drug incorporated HA gels as new implantable drug delivery systems (Kikuchi et al., 2002).

3. Externally regulated pulsatile drug delivery^21,22

The externally regulated Systems is one in which drug release is programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation. It contains magnetic beads in the implant. When magnetic field is applied, drug release occurs due to the presence of magnetic beads (Survase et al., 2007; Kikuchi et al., 2002).

3.1 Magnetic induced release

3.2 Ultrasound induced release

3.3 Electric field induced release

3.4 Light induced release

3.1 Magnetic induces release:

Magnetically regulated system contains magnetic beads in the implant. Drug release occurs in response to applied magnetic field with the help of magnetic fields.

3.2 Ultrasound induces release:

The ultrasonic waves cause the erosion of the polymeric matrix effecting the drug release.

3.3 Electric field induces release:

Electrically responsive delivery systems are both pH-responsive as well as electro-responsive

3.4 Light induces release:

Light-sensitive hydrogels uses the interaction between light and material to modulate drug delivery.

Technologies Used in Chronopharmaceutics:

Major objective of chronopharmaceutics is to deliver the drug in higher concentrations during the time of greatest need and in lesser concentrations when need is less to minimize unnecessary side effects. Few of the technologies used in chronopharmaceutical drug delivery system development are:

4. CONTIN Technology:^23,24

Technology utilises cellulosic polymer solvated with volatile polar solvent. The solvated cellulose polymer on reaction with aliphatic alcohol forms molecular coordination complex which can be used as a matrix in controlled release formulations having an uniform porosity. CONTIN technology has been used in development of sustained release tablet of aminophylline, theophylline, morphine, and other drugs.

5. OROS Technology:²⁵

This technology utilises osmotic agents to result a pre-programmed, controlled drug delivery to the gastrointestinal tract. This technology, especially the OROS® delayed push pull™ was used to design covera- HS®, a novel antihypertensive product. This enables delay, overnight release of verapamil to prevent surge in BP in morning.

6. CODAS Technology:²⁶

CODAS® (chronotherapeutic oral drug absorption system). In certain cases, immediate release of drug is undesirable while a delayed drug action may be required for a variety of reasons. By use of chronotherapy drug release may be programmed to occur after a prolonged interval following administration. Verelan® PM utilises the proprietary CODASTM technology.

7. CEFORM^® Technology:²⁷

This technique finds use in development of microspheres of uniform size and shape. It is based on –melt spinning in which biodegradable polymer or bioactive agents combination is subjected to combination of temperature, thermal gradients, mechanical forces, flow, and flow rates during processing. Cardiazem® LA, 1 Day diltiazem chronotherapeutic drug delivery system has been developed using this technology.

8. Smartcoat™ Technology ( Biovail):²⁸

Bioavail technology is used to develop very high potency, controlled-release tablets with drug release over a 24 h period.‘Chronotabs’ are developed for bedtime administration.

CONCLUSION:

Both experimental and theoretical backgrounds, and market constraints demonstrate the clinical relevance of chronopharmaceutics. If drug release is designed in a time controlled manner so that maximum drug is made available at peak time, optimization of the therapy can be achieved for diseases that follows the circadian rhythm. Dependence of response over human action to trigger the drug release is the major drawback associated with these systems. Hence, an ideal chronotropic system should be self regulating, taken any time and should take environmental factors in account (e.g. awake– sleep, light–dark, activity–rest status). The overall success of chronopharmaceutics will depend on the successful integration of knowledge from future advances in development timing, system biology and nanomedicine. The selection of the chronopharmaceutical technology should take into considerations the application range, the ease of manufacturing, the cost-effectiveness, and the flexibility in the pharmacokinetic profile. In near future due to more advancement of technology, the hurdles in manufacturing and processing steps will be overcome and a number of patients will be greatly benefited by these systems.

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Received on 04.01.2021 Modified on 19.04.2021

Research J. Pharm.and Tech 2022; 15(3):1359-1364.

DOI: 10.52711/0974-360X.2022.00227

Diffucaps®	The active drug is layered onto a neutral core (such as cellulose spheres) and then one or more rate-controlling, functional membranes are applied.
Orbexa®	This technology produces beads that are of controlled size and density using granulation, spheronization and extrusion techniques.
Oros® Push Pull^TM	A bilayer / trilayer tablet core consisting of one or more drug layers, surrounded by a semipermeable membrane with a drilled orifice
CODAS^TM	Drug delivery system enables a delayed onset of drug release, resulting in a drug release profile that more accurately compliments circadian patterns This delay in release is introduced by the level of release controlling polymer applied to the drug loaded beads.The release controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes in contact with the polymer coat beads, the water soluble polymer slowly dissolves and the drug diffuses through the resulting pores in the coating.
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. Lag time is controlled by variations in the two polysaccharides, xanthan gum and locust bean gum.
Geoclock®	Chronotherapy-focused press-coated tablets, have an active drug inside an outer tablet layer consisting of a mixture of hydrophobic wax and brittle material is prepared. It provides a pH-independent lag time prior to core drug delivery at a predetermined release rate.
Geomatrix^TM	Constructing a multilayered tablet for controlled drug delivery. It has two basic key components; 1) hydrophilic polymers such as hydroxypropyl methycellulose (HPMC) and 2) surface controlling barrier layers.
Pulsincap®	A water impermeable capsule body with hydro gel plug. Plug length and insertion depth controls lag time.
Port®	A water permeable coated gelatin capsule with n osmotic core that swells and is sealed with an insoluble wax plug. The contents swells to remove the plug.
EGALET®	The Egalet® Time Release consists of three compartments: a coat, a drug release matrix and a lag component.
oSDrC®	Any number of cores of any shape can be placed into the tablet just where they need to be positioned for optimum delivery of active pharmaceutical ingredients(API).
PULSYS^TM	The typical PULSYS drug delivery format is a tablet containing multiple pellets with different release profiles
COLAL®	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^.[29,30]