DEFINITION:

Pulsatile drug delivery is a specialized system designed to release a specific amount of drug rapidly and completely after a predetermined lag phase, during which no drug is released. This mechanism allows for time-controlled drug administration aligning with the body`s biological rhythms or specific disease conditions. The distinct pulsatile release pattern is beneficial for treating conditions requiring drug release at particular times, such as asthma, arthritis, cardiovascular diseases, and diabetes.

INTRODUCTION:

Pulsatile drug delivery systems (PDDS) are advanced formulations designed to release drugs at predetermined times, aligning with the body`s biological rhythms. These systems are particularly beneficial for diseases with circadian variations, such as asthma, hypertension, and arthritis, where symptoms peak at specific times. Unlike conventional sustained-release systems, PDDS ensures drug release in a controlled, time-dependent manner, improving therapeutic efficacy and reducing side effects.

Pulsatile drug delivery systems (PDDS) can be classified into time-controlled, stimuli-induced, and externally regulated systems, utilizing mechanisms like polymeric coatings, osmotic pumps, and enzymatic triggers. These technologies ensure precise drug release, enhancing patient compliance and treatment outcomes.

Despite challenges in formulation stability and scalability, advancements in nanotechnology and polymer engineering continue to refine PDDS. The review explores the mechanisms, applications, and future prospects of pulsatile drug delivery in optimizing disease management.^{1, 3}

Biological Rhythms:

Biological rhythms are natural cycles of physical, mental, and behavioral changes in living organisms that occur in response to environmental factors, such as light and temperature. These rhythms are regulated by internal biological clocks and include daily cycles like the circadian rhythm, which controls sleep-wake patterns, as well as seasonal or annual cycles seen in reproduction or migration in animals. The synchronization of these rhythms ensures the optimal functioning of an organism by aligning physiochemical activities with external environmental cues, contributing to overall health and adaptation. Disruptions to these rhythms, such as those caused by shift work or jet lag, can lead to various physical and mental health issues.

There are 4 types of rhythms in our body

1. Circadian Rhythms:

These are roughly 24-hour cycles, such as the sleep-wake cycle, body temperature regulation, and hormone secretion. They are influenced by light and darkness in the environment.

2. Ultradian Rhythms:

These are cycles shorter than 24 hours, such as the stages of sleep (like REM and non-REM) or the regular patterns of heartbeat and digestion.

3. Infradian Rhythms:

These are cycles longer than 24 hours, including menstrual cycles in humans, seasonal breeding patterns in animals, and hibernation.

4. Tidal Rhythms:

Found in marine organisms, these are synchronized with tidal movements, often occurring every 12.4 hours in response to changes in water levels.

5. Annual Rhythms:

These occur on a yearly basis, such as migration, reproduction, or shedding for certain animals, aligning with seasonal changes.

Generation of Circadian Rhythms:

Circadian rhythms are biological cycles that follow a roughly 24-hour pattern, regulating various physiological processes such as sleep-wake cycles, hormone secretion, body temperature, and metabolism. These rhythms are primarily controlled by the suprachiasmatic nucleus (SCN), a group of neurons located in the hypothalamus, which acts as the body's master clock. The SCN receives signals from the retina, using light as the primary zeitgeber (time cue) to synchronize the internal clock with the external environment. At the molecular level, clock genes such as CLOCK, BMAL1, PER, and CRY generate rhythmic patterns through a self-regulating feedback loop. The pineal gland plays a key role in this process by secreting melatonin, a hormone that induces sleep and is influenced by darkness. Additionally, circadian rhythms regulate the secretion of other hormones like cortisol, which peaks in the morning to promote wakefulness, and growth hormone, which is released at night. Apart from the SCN, peripheral clocks exist in organs like the liver, heart, and kidneys, which respond to other cues such as food intake, temperature, and physical activity. However, factors like shift work, jet lag, and irregular lifestyle patterns can disrupt circadian rhythms, potentially leading to health disorders such as sleep disturbances, metabolic issues, and cardiovascular diseases. Understanding the generation of circadian rhythms is crucial for optimizing therapies, including pulsatile drug delivery systems, which align drug release with the body's natural cycles for maximum efficacy and minimal side effects.

Fig. 01: Circadian Rhythms

Fig. 02: Circadian Rhythms cycle

CLASSIFICATION:

Figure 03: Classification of pulsatile drug delivery.

A. Time-controlled Pulsatile release:

1. Single unit system

Capsular system:

A capsular system is an advanced drug delivery method where a water-insoluble capsule encloses the drug and is sealed with a swellable hydrogel plug. When exposed to bodily fluids, the plug absorbs liquid, swells, and is eventually expelled after a predetermined lag time, allowing for rapid drug release. The lag time can be controlled by adjusting the plug`s material, size, and position.

The system such as the Pulsincap developed by R.P. Scherer, is particularly useful for chronotherapy, where medication needs to be released at specific times (e.g., for nocturnal asthma or arthritis). It also helps minimize gastrointestinal irritation by delaying drug release until it reaches the desired site. Additionally, customizable lag times and the ability to incorporate effervescent agents for poorly soluble drugs make this system highly versatile. By improving drug effectiveness and patient compliance, capsular systems offer a significant advantage in controlled drug delivery.

Figure 04: Capsular system

Port System (programmable oral release technology):

PORT System (Programmable Oral Release Technology) is an osmotic drug delivery system designed for controlled, pulsatile drug release. It consists of a gelatin capsule coated with a semi-permeable membrane, an insoluble plug, and an osmotically active agent. Upon contact with an aqueous medium, water diffuses in, creating internal pressure that ejects the plug after a predetermined lag time, which is controlled by the membrane thickness. This system is classified into expandable delivery orifices, where osmotic pressure forces drug release in liquid form, and delivery by series of stops, used in implantable capsules with compartments separated by movable partitions for pulsatile release. The PORT system is especially beneficial for conditions like ADHD, as it ensures timed drug release, reducing the need for multiple daily doses. Its ability to mimic natural biological rhythms, improve patient compliance, and allow lag time customization makes it a valuable advancement in controlled drug delivery.

Fig. 05: PORT System

Solubility Modulation:

Magruder`s pulsatile drug delivery system utilizes solubility modulation to achieve controlled drug release, particularly for anti-histaminic drugs like salbutamol sulfate. The formulation consists of salbutamol sulfate as the active ingredient and sodium chloride used is kept below the saturation level, ensuring controlled osmotic pressure when gastrointestinal fluids enter the osmotic devices. This mechanism enables a pulsatile release of the drug, delivering the medication in a timed manner to enhance therapeutic efficacy.

Fig. 06: Solubility Modulation

The figure shows Step 1: Caps dissolve immediately, and a modified release dose is released. Step 2: The energy source is activated by controlled permeation of GI fluid. Step 3: The time-release plug is expelled. Step 4: Administer the second dose via pulse or sustained release.

Reservoir System:

A reservoir system in pulsatile drug delivery is a controlled-release system designed to release drugs at specific time intervals, aligning with biological rhythms (chronotherapy). It consists of a drug core surrounded by a rate-controlling membrane that delays release through mechanisms like osmotic pressure, enzymatic degradation, or polymer swelling and rupture. This system is used in conditions like asthma, cardiovascular diseases, and diabetes, ensuring optimal drug efficacy with reduced side effects and improved patient compliance.

Fig. 07: Reservoir System

2. Multiple unit system:

I. Rupturable coating system:

These systems depend on the disintegration of the coating for the release of drugs. The pressure 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 was incorporated in a tablet core coated with ethyl cellulose. The carbon dioxide developed after the penetration of water into the core resulted in a pulsatile release of the drug after the rupture of the coating. The release may depend on the mechanical properties of the coating layer.

II. Time-Controlled Expulsion System:

The time-controlled expulsion system is a drug delivery approach that combines osmotic and swelling effects to achieve controlled drug release. The drug core consists of a low bulk density solid and or liquid lipid material, along with disintegrants, which facilitate drug release. The core is coated with cellulose acetate, a semi-permeable polymer. Upon contact with an aqueous medium, water penetrates the core, gradually displacing the lipid material. Once the lipid material is depleted, the internal pressure builds up until it reaches a critical stress point, leading to the rupture of the coating and subsequent drug release. Another variation of this system includes capsules or tablets composed of multiple pellets, where different pellet compositions enable controlled, sequential drug release. This system ensures precise timing of drug expulsion, making it suitable for pulsatile drug delivery and chronotherapeutic applications.

III. Sigmoidal Release System:

A sigmoidal release system provides a controlled drug release pattern with an initial lag phase, a rapid release phase, and a plateau, making it ideal for timed and colonic drug delivery. This release profile is influenced by the permeability and water uptake of polymers like Eudragit RS or RL, which respond to counter-ions in the medium. The system enables pulse release by altering diffusion properties, sometimes forming a core-shell layer on hydrogels for on-off drug regulation. Such systems are beneficial in chronotherapy, targeted drug delivery, and colonic treatments, ensuring precise drug release at the right time and site.

Fig. 08: Sigmoidal Release System

IV. Modified Permeation System:

A modified permeation system is a drug delivery approach that controls the rate and extent of drug permeation through a barrier, such as a polymer membrane or biological tissue. This system regulates drug release by modifying factors like polymer composition, membrane thickness, pH sensitivity, or external stimuli (e.g., temperature, ions, enzymes). Polymers like Eudragit, ethyl cellulose, and hydrogels are commonly used to achieve sustained, pulsatile, or targeted release. This system enhances bioavailability, reduces dosing frequency, and improves therapeutic efficacy, making them useful in transdermal patches, colonic drug delivery, and chronotherapy.

V.Floating Delivery Based System:

Floating delivery-based systems are a type of oral drug delivery technology designed to remain in the stomach for extended periods, allowing for prolonged drug release. These systems are buoyant and typically composed of materials that can float on gastric fluids, such as hydrogels or pH- sensitive polymers. By staying in the stomach longer, the floating system can provide a controlled release of drugs, enhancing bioavailability and improving therapeutic outcomes.

B. Stimuli Induced:

1. Thermo-Responsive:

Thermo-responsive drug delivery systems are designed to release drugs in response to temperature changes. These systems typically use thermoresponsive polymers that undergo physical or chemical changes (e.g., phase transition, swelling, or gelation) when exposed to specific temperature thresholds. The change in the polymer`s properties allows for controlled drug release.

2. Chemical stimuli induced:

Chemical stimuli-induced drug delivery systems are designed to release drugs in response to specific chemical signals, such as changes in pH, ionic strength, or the presence of particular enzymes or molecules. These systems often use pH-sensitive polymers, enzyme-responsive materials, or redox-sensitive agents that react to the chemical environment in the body. For instance, pH-sensitive systems can release drugs in areas like the stomach (low pH) or the intestines (neutral pH). Similarly, enzyme-responsive systems release drugs when they encounter specific enzymes at targeted sites., such as in the colon or tumors. These systems are useful for site-specific drug delivery, enhancing therapeutic effectiveness while reducing side effects.

I. Glucose sensitive system:

A glucose-sensitive system refers to a mechanism or a biological design that responds to changes in glucose levels. Such systems are commonly studied in the context of medical technology, such as glucose-sensitive insulin delivery methods or biosensors for diabetes management. These systems rely on components like enzymes, materials, or nanoparticles that detect glucose concentrations and trigger a corresponding action. For example, glucose-sensitive insulin pumps release insulin in proportion to detected glucose levels, aiming to mimic the body's natural regulation of blood sugar. The development of such systems is an active area of research, as they offer the potential for more precise and automated glucose management, reducing the burden on individuals with diabetes.

II. Inflation-induced systems:

Inflammation-induced pulsatile release systems respond to inflammatory conditions at injury sites, where hydroxyl radicals (OH) are generated. These systems, such as those based on hyaluronic acid (HA), degrade rapidly in the presence of hydroxyl radicals, offering targeted drug release at the site of inflammation. This approach can be used to treat conditions like rheumatoid arthritis, where anti-inflammatory drugs incorporated into HA gels can be delivered specifically to areas of inflammation, enhancing therapeutic effects.

III. pH based systems:

pH-based systems in pulsatile drug delivery are innovative approaches designed to release drugs at specific times or conditions, often to mimic the body's natural rhythms or target specific sites. These systems rely on materials sensitive to pH changes, which trigger the release of drugs when they encounter environments with particular pH levels. For example, the gastrointestinal tract has varying pH levels, and a pH-sensitive system can ensure that the drug is released in the desired part of the digestive system, such as the stomach (acidic pH) or the intestines (alkaline pH). This mechanism is particularly beneficial for drugs that require timed or site-specific delivery, enhancing therapeutic efficacy and reducing side effects. The technology holds promise for treating conditions like diabetes, cancer, or inflammatory diseases, where precise drug delivery is crucial.

Fig 09: Pulsincap release

C. External Stimuli:

External stimuli-induced drug delivery systems are open-loop systems that rely on external factors like electric fields, magnetic fields, or light to control drug release in a programmed pattern. These systems are not self-regulated but offer precise control over the release timing, making them ideal for pulsatile drug delivery.

I. Electro-responsive:

Electro-responsive pulsatile release systems use an applied electric field to influence drug release by altering the rate-limiting membrane or directly affecting the solute. These systems often involve polymers with two redox states, which bind drug ions in one state and release them in another. The electric field can induce swelling of the membrane, changing its permeability and pore size, and enhancing solute transport through electrophoretic or electroosmotic effects.

II. Magnetically induced:

Magnetically stimulated pulsatile systems involve embedding magnetic beads in a polymer matrix containing the drug. When exposed to a magnetic field, the beads oscillate, creating compressive and tensile forces that push the drug out of the matrix. Magnetic particles like magnetite or iron are commonly used. For example, Langer's system used ethylene-vinyl acetate copolymer with magnetic beads, while Saslawski applied an oscillating magnetic field to release insulin from alginate microspheres, demonstrating enhanced drug release with the magnetic field.

Table 01: Advanced technologies and marketed formulations of Pulsatile drug delivery system

Technology	Mechanism	API	Disease	Proprietary Name	Make
COER-24 ^™	Single-unit system	Verapamil	Hypertension	Covera HS	Alza
Diffucaps ^™	Multiparticulate system	Propranolol	Hypertension	InnoPran ® XL	Reliant Pharmaceuticals
Pulsicap ^™	Rupturable system	Dofetilide	Hypertension	-	RPSIC, Michigan, US
Port® System	Programmable system.	Methylphenidate	Hyperactivity Disorder (ADHD)	-	TSRL, Michigan USA
Egalet ®Technology	Delayed Burst Release system	-	Pain relief	Egalet®	Egalet Denmark
SyncroDose ™Technology	Agglomerated Hydrophilic Matrix System	-	Alzheimer's Disease	TIMERx ™	Penvest Pharmaceutical
Qtrol ^™Technology	Multi-Layer Coating Technology	Cortisol	Asthma and COPD	-	-
TES ^™	Time-controlled explosion system	-	-	-	Fujisawa pharmaceutical
Smartcoat^™Technology	controlled release system	-	-	chronotabs	Biovail
CEFORM technology	Pulse release system	Diltiazem HCl	Hypertension	Cardizem®L A	-
API modification	Physico-chemical modification	Famotidine	Gastroesophageal reflux disease (GERD)	Pepcid®	-
API modification	Physico-chemical modification	Simvastatin	Cardiovascular diseases	Lipovas®	-
Three-dimensional printing	Externally regulated system	Diclofenac sodium	Inflammation	Their form*	Ratiopharm
CONTIN technology
OROS™	Osmotic mechanism	Verapamil HCL	Hypertension	Covera -H5*; XL Tablet	Alza

Technolog Ies in Pulsatile Drug Delivery Systems:

1. Pulsincap Technology:

Pulsincap technology is a pulsatile drug delivery system that uses a capsule with a hydrogel plug to control drug release after a preset lag time. It aligns medication timing with biological rhythms or specific site targeting, improving therapeutic effectiveness. They ensure the site-specific release of drugs, making it ideal for conditions where targeted or delayed delivery enhances therapeutic outcomes, such as in treating colon-related diseases.

2. Chronset:

A proprietary OROS system delivering drugs based on time or site-specific models in the gastrointestinal tract (GIT). Using osmosis, the drug is enclosed in a semipermeable membrane with a laser-drilled orifice. Bilayer or trilayer tablets include drug and osmotically active agents, releasing medication under pressure generated by GI fluids.

3. IPDAS36:

An oral drug delivery system for NASIDS, leveraging multi-particle systems with high-density beads. After ingestion, the tablet disintegrates, spreading drug-loaded beads through the GI tract. Controlled release occurs via diffusion layer or matrices.

4. CEFORM:

Utilizes spherical microspheres (150-180um) made through a melt-spinning process involving biodegradable polymers, temperature, and mechanical forces. These microspheres are used in capsules, tablets, suspensions, and effervescent tablets. Enteric-coated microspheres enable controlled drug release.

5. DIFFUCAPS:

A capsule system with drug particles (beads, pellets, or granules) designed for rapid or sustained release, with or without lag time. Layers of drug-release polymers and excipients regulate solubility, aided by buffers like organic acids or alkalis.

6. EGALET:

A delayed-release system with an impermeable shell and two lag plugs enclosing a drug plug. Erosion of the inert plug determines the lag time, for releasing the drug. Made from plasticizers, biodegradable polymers, and pharmaceutical additives.

NEEDS OF PDDS:

1. Aligning drug release with the body`s natural circadian rhythms optimizes treatment. For example, cortisol levels naturally peak in the morning, making morning-release medications effective for certain conditions.

2. Chronopharmacotherapy are diseases like asthma, which worsen during the night, can benefit from PDDS by ensuring medications are released exactly when symptoms are most severe, improving therapeutic outcomes.

3. The prevents drug degradation is a drugs sensitive to stomach acidity, such as peptides, can bypass the stomach with PDDS, ensuring they reach their target intact.

4. Certain drugs have gastric side effects. PDDS allows delayed release until the drug reaches safer regions of the digestive tract, reducing discomforts like nausea or vomiting.

5. Targeted drug delivery ensures that drugs meant for specific regions, such as the colon, are released only after passing through the upper gastrointestinal tract, improving treatment precision.

6. They reduce the first-pass metabolism by delivering drugs directly to the bloodstream, PDDS bypasses liver metabolism, enhancing drug bioavailability and effectiveness.

7. They prevent drug tolerance.

8. PDDS ensures medication is released at the time it is most needed, maximizing efficacy while minimizing potential side effects.

9. Improved patient compliance is simplifying dosing to a single, timed-release dose makes it easier for patients to adhere to their medication schedule.

10. Many hormonal treatments, such as insulin or growth hormone therapy, require pulsatile release. PDDS meets these specific timing needs efficiently.

FUTURE SCOPE OF PDDS:

1. Growing Popularity-

PDDS is gaining attention due to its ability to release

drugs only when needed, reducing drug resistance.

2. improved safety for toxic drugs-

ideal for anticancer and highly toxic drugs, minimizing side effects seen in conventional therapies.

3. FDA-approved chronotherapeutic drugs-

drugs many times controlled drugs are now available, proving the potential of this system.

4. Challenges in development-

Requires identifying circadian rhythms and suitable biodegradable, biocompatible, and responsive biomaterials.

5. Regulatory challenges-

Difficulties in proving chronotherapeutic advantages in preapproval phases.

1. Risk management program-

The FDA implements strategies to balance approval with safety concerns.

2. Ongoing research-

Studies focus on discovering precise circadian rhythms and developing advanced drug-delivery devices.

3. Future potential-

PDDS is expected to lead drug delivery innovations due to its advantages in site-specific and time-controlled drug release.

4. Controlled drug release-

Achieved through various polymers and coating thickness, ensuring precision in drug delivery.

CONCLUSION:

The circadian rhythm of the body plays a crucial role in determining the optimum timing for drug delivery. Understanding this natural biological cycle is essential for developing more effective treatment strategies. With the constant demand for advanced drug delivery systems, pulsatile drug delivery stands out as a promising approach. By delivering medication at the right time, in the right place, and in the right amounts, pulsatile systems have the potential to significantly benefit patients with chronic conditions like arthritis, ulcers, asthma, and hypertension.

Such systems can help align drug release with the body's natural rhythms, ensuring better therapeutic outcomes. This approach not only enhances patient compliance but also optimizes drug delivery to the targeted site, reducing the risk of side effects. In conclusion, well-designed pulsatile drug delivery systems offer a more personalized and efficient way to treat chronic diseases, ultimately improving the quality of life for patients.

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34. A Review on Pulsatile Drug Delivery System Dr. D. Rama Brahma Reddy, D. Tejaswi, K. Anand, M. Bhaskar, M. SaiVenkata Reddy, M. Naveen Kumar, M. Narendra.

35. A Review on Novel Approach Pulsatile Drug Delivery System Nayana D. Patil, M.M. Bari, S.D.Barhate.

Received on 14.04.2025 Revised on 19.05.2025

Accepted on 18.06.2025 Published on 25.07.2025

Available online from July 31, 2025

Res. J. Pharma. Dosage Forms and Tech.2025; 17(3):212-220.

DOI: 10.52711/0975-4377.2025.00030

This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 International License. Creative Commons License.

Diseases	Chronological behavior	Drug used
Peptic ulcer	Acid secretion is high in the afternoon and at night.	H₂ blockers
Cancer	The blood flow to tumors is 3-fold greater during each daily activity phase of the circadian cycle than during the daily rest phase.	Vinca alkaloids, Taxanes
Duodenal ulcer	Gastric acid secretion is highest at night while gastric and small bowel motility and gastric emptying are all slower at night.	Proton pump inhibitors
Neurological disorders	The central pathophysiology of epilepsy and the behavioral classification of convulsive events.	MAO-B inhibitor
Hypercholesterolemia	Cholesterol synthesis is generally higher during the night than in the daytime.	HMG CoA reductase inhibitors
Diabetes mellitus	Increase in the blood sugar level after meal.	Sulfonylurea, Insulin
Arthritis	The level of pain increases at night.	NSAIDs, Glucocorticoids
Cardiovascular diseases	BP is at its lowest during the sleep cycle and rises steeply during the early morning.	Nitroglycerine, calcium channel blockers, ACE inhibitors
Asthma	Precipitation of attacks during the night or in the early morning.	B₂ agonist, Antihistamines
Attention deficit syndrome	Increase in DOPA level in the afternoon	Methylphenidate

ASPECT	ADVANTAGES	DISADVANTAGES
Bioavailability and absorption	Shows better and increased Bioavailability and absorption than conventional dosage forms due to burst release and site-specific targeting.	Complex formulation may affect uniform absorption.
Drug dose Optimization	Allows a reduced drug dose without affecting therapeutic activity.	Low drug loading capacity may limit effectiveness for high-dose drugs.
Side effect reduction	Minimizes adverse effects by avoiding unnecessary drug exposure.	If the release mechanism fails, overdose or inefficacy may occur.
Patient Compliance	Improves patient adherence due to reduced dosing frequency.	Requires precise patient administration to ensure effectiveness.
Multiple Dosing in One System	Enables multiple drug-release pulses within a single dose.	Requires sophisticated formulation techniques.
Reduced local irritation	Less risk of local irritation compared to conventional dosage forms.	Environmental factors (e.g., pH)
Dosing Stability	Provides greater stability in controlled drug release.	Variability in individual patient metabolism may impact effectiveness.
Specific Release	Targeted release at specific sites enhances therapeutic efficacy.	Difficult to achieve for all types of drugs.
Prevention of First-Pass Metabolism	Avoids drug degradation in the liver, improving the bioavailability.	Not suitable for drugs requiring continuous systemic levels.
Complex Manufacture	Advanced formulation techniques ensure precise drug delivery.	Requires a large number of manufacturing steps, making it complex.
High Production Cost	Innovative technology improves drug delivery effectiveness.	Involves high costs due to specialized production methods.
Limited Manufacturing Units	Specialized technology ensures accuracy in drug release.	The lack of widespread manufacturing units limits availability.