Pulsatile Drug Delivery System: A Review

Sujan Neupane^1,2*, Pramod Kharel³

¹Mallige College of Pharmacy, Silvepura-90, Bangalore, India.

²Department of Drug Administration, Bijulibajar, Kathmandu, Nepal.

³National Academy for Medical Sciences, Old Baneshwor, Kathmandu, Nepal.

*Corresponding Author E-mail: sujan.neupane93@gmail.com, kharelpramod47.pk@gmail.com

ABSTRACT:

As modern technologies advance, new methods of drug delivery systems are constantly being developed. Pulsatile drug delivery system is becoming increasingly popular because it can deliver the drug at the correct location, time, and dosage, improving patient adherence. These technologies are designed to align with the body's inherent circadian rhythm. Pulsatile drug release is mainly preferred when continuous drug release is not needed. Understanding the circadian clock's design, illness rhythm pathophysiology, and chrono pharmacology’s medication knowledge helps create and utilize chronotherapeutic dosage forms for effective disease treatment, reducing side effects, improving targeted drug delivery, and maintaining consistent dosing. Proper design of pulsatile drug delivery enhances patient adherence, targets drug distribution, and decreases side effects. Like many other medical conditions, the outlook for chronotherapy using pulsatile drug delivery seems very optimistic. Pulsatile drug delivery systems can utilize either one or multiple mechanisms to administer medication at a specific time and location. Formulation of pulsatile flow is achieved by incorporating different polymers, with the thickness of the coating layer dictating the speed of release of the active medicinal ingredient.

KEYWORDS: Pulsatile, Circadian cycle, Chronotherapeutic, Target delivery, Time controlled.

INTRODUCTION:

Due to the significant progress in technology, the pharmaceutical industry has also greatly expanded by employing modern technologies for creating different delivery systems. In spite of previous challenges faced by molecules, pharmaceutical researchers are focusing on creating a more effective method of delivering drugs instead of pursuing new drug development.^1,2 Various drug delivery systems have been developed over the last few decades to avoid fluctuations in the therapeutic window and provide sustained drug delivery. However, in certain situations, it may not be preferred for the drug to be released at the initial stage of drug delivery for controlled release from the body.³

Maintaining a steady plasma drug level may not always be beneficial because certain physiological and pathological conditions may necessitate administering the drug at specific times, especially in the early morning. In order to meet the aforementioned needs and reduce the challenges in drug discovery and development, Pulsatile Drug Delivery System (PDDS) can be effectively employed.⁴

Pulsatile Drug Delivery Systems are drug delivery systems that release the drug at a specific rate, targeting the appropriate place, time, location, and dose. PDDS are devices that control the delivery of drugs based on time and have the ability to administer drugs specifically needed during sleep, for diseases requiring a precise drug dosage, and for drugs with high first-pass metabolism and absorption in the digestive tract.^5,6 PDDS involves the quick and temporary release of a specific quantity of molecules shortly after a set delay period.⁶ These systems are created based on the body's circadian rhythm, aiming to release the drug in a way that does not follow zero order kinetics and ensures constant release. This demonstrates the benefit of offering spatial, temporal, and intelligent delivery, thereby improving patient adherence.⁷ PDDS have been discovered to offer numerous advantages compared to traditional dosage forms.

Advantages of PDDS:

· Increased absorption in the body.

· Minimal chance of irritation in the localized area.

· Enhanced design flexibility leads to increased stability.

· Enhanced patient comfort and adherence.

· Eliminate the possibility of dose dumping and decrease how often the dosage needs to be taken.

· Prolonged periods of being active during the day or night.

Disadvantages of PDDS:

· Several stages of formulation.

· Requirement for cutting-edge technology, Well-trained and skilled workforce.

· Costly.

· Minimal amount of drugs.

· Release that is not fully finished.

· Variation in drug delivery system performance within living organisms.

Prerequisite of PDDS:

1. Physiological process that adheres to the body's natural sleep-wake cycle.

2. When the circadian rhythm is disrupted by changes in hormone levels in the blood.

3. Rhythmic changes are observed in acid secretion in the stomach, gastric emptying, and gastrointestinal blood flow.

4. Illnesses like asthma, heart attacks, chest pain, arthritis, stomach ulcers, and high blood pressure are influenced by time

5. The idle time is essential for medications prone to degradation in a gastric acidic environment.

6. Just like with colon targeting, drugs can also be directed to the far end of the gastrointestinal tract.

7. Pulsatile drug delivery systems effectively deliver drugs that undergo significant first-pass metabolism. ^8-17

Figure 1: Diversity of circadian rhythms in human physiology. The peak time or acrophase of several biological processes in humans are shown relative to the sleep–wake cycle.

Mechanism of Drug Release from PDDS^18-22:

· Diffusion occurs when particles interact with aqueous fluids in the gastrointestinal tract, causing water to move into the particles and the drug solution to move out across the separation layer.

· Erosion: Certain coatings, intended to gradually degrade, lead to the release of the drug within the particle.

· Osmosis occurs when water enters particles, elevating osmotic pressure and eventually pushing the active ingredient out of the particles through the coating.

Figure 2: Drug release profiles from pulsatile drug delivery system.

Where, A: Conventional release profile, B: Burst release of drug as a after a lag time, C: Delayed release profile after a lag time, D: Constant release profile in prolonged period after a lag time, E: Extended-release profile without lag time.

Reason(s) behind Conventional sustained release approach to recent chronopharmaceutical delivery of drugs^18-19

1. Gastric irritation or medication instability in gastric liquid.

If a medication causes irritation in the stomach or is unstable in gastric fluid, an extended-release version of the drug could worsen these issues.

2. Local medical need

It is highly desired to transport chemicals directly to the site of inflammation without absorption in the small intestine to effectively treat local conditions like inflammatory bowel disease, while minimizing side effects.

3. First pass metabolism

Certain medications like beta-blockers and salicylamide undergo first-pass metabolism and need a quick drug delivery to saturate metabolizing enzymes and reduce presystemic metabolism. Hence, a continual oral dosing technique would result in decreased oral absorption.

4. Biological tolerance

Continuous release of drugs in plasma often leads to a decrease in the effectiveness of the medication's treatment. E.g., Study of tolerance to nitro-glycerine through skin.

Diseases requiring Pulsatile Delivery:^23-27

New studies suggest that diseases have recurring patterns, so it is advantageous to plan drug treatments accordingly. Solid oral pulsatile-release forms are beneficial for specific chronic conditions that do not require constant medication levels. The table includes conditions that necessitate pulsatile delivery:

Table 1: Diseases that requires pulsatile drug delivery system

Chronological Behavior	Diseases	Drugs Used
Pain intensity rises during the night.	Arthritis	NSAIDs, Glucocorticoids
Attacks that happen at night or in the early morning.	Asthma	Β₂ agonist, Antihistamines
Acid secretion levels peak during the afternoon and night.	Peptic Ulcer	H₂ blockers
Blood sugar levels increase after eating.	Diabetes mellitus	Sulfonylurea, Insulin
BP is lowest during sleep and rises significantly in the morning.	Cardiovascular diseases	Nitroglycerin, calcium channel blocker, ACE inhibitors
Cholesterol synthesis frequently increases at night compared to daytime.	Hypercholesterolemia	HMG CoA reductase Inhibitors
Gastric acid production peaks during nighttime, while gastric motility, small bowel motility, and gastric emptying rates decrease.	Duodenal ulcer	Proton pump inhibitors
The classification of convulsive events and the central mechanisms of epilepsy.	Neurological disorders	MAO-B inhibitor
Tumor’s experience three times greater blood flow during the active circadian phase than during the resting phase.	Cancer	Vinca alkaloids, Taxanes
A rise in DOPA levels during the afternoon.	Attention deficit syndrome	Methylphenidate

Capsule Based Systems: Single unit dose forms are transformed into capsule form to enhance medication delivery. The capsule body releases medication as a pulse, controlled by a plug pushed away by erosion or swelling, regulating lag time. Hydrogel and gelatin are used, along with polymers like polyvinyl alcohol, pectin, glycerol monooleate, and polyethylene oxide.

PORT Systems: This capsule design contains a non-soluble plug composed of the medication formula and an osmotic agent. As the capsule breaks down in bodily fluid, water can seep through the semipermeable barrier, building up pressure that leads to the expulsion of the insoluble blockage.

System based on Expandable Orifice: An osmotically driven capsular system is utilized for delivering liquid medication. Medicine in liquid form is soaked up by porous particles, which then release the drug through a semi-permeable opening in the capsule.

Delivery by series of Stops: The capsule includes an osmotic pump that takes in water, dividing the drug with a barrier that moves when blocked, allowing for pulsatile release.

Pulsatile delivery by Solubility Modulation: This system's solubility modulator can deliver a variety of medications in pulses. The basis of this mechanism lies in osmotic pressure and drug solubility.

The Chronotropic System: In this technology, there is a delay in action due to the coating of the hydrophilic swellable HPMC core.

TIME CLOCK Systems: When rehydrated, the medication is rapidly released using this approach, leading to reliable outcomes. Caloric intake of meals can impact the functioning of the body.

Compressed Tablets: Compression-coated tablets consist of an external layer releasing the first dose and rapidly dissolving in the stomach, and an internal layer containing ingredients released in the intestines but not soluble in gastric fluids.

Multilayered Tablets: This method involves a three-layer tablet with two drugs divided by a non-bonded polymeric barrier layer. This tablet has three layers with polymer coating on three sides and no coating on the top.

Pulsatile System with Rupturable Coating: Medicine is applied to non-toxic sugar beads in a complex system consisting of an indissoluble outer layer and an expandable layer. The film erupts as the layer expands, quickly releasing medication.

TCES - Pulsatile System with Rupturable Coating: This technique involves coating medicine onto non-toxic sugar seeds, then applying swellable and insoluble layers on top in a multilevel approach. The film tears apart when the expandable layer stretches, causing the rapid release of the medication.

Osmotic based Rupturable Coating Systems: This system integrates swelling impacts with osmotic force. The liquid substance with a disintegrant or the medication within a low bulk density core. The core had a cellulose acetate coating. Once the osmotic agents dissolve in water, the pellets swell and regulate the speed of drug diffusion. Afterward, the active ingredient in each pellet is released. This also delivers multiple drug pulses in one dose format.

Pulsatile delivery by change in Membrane Permeability: Ammonio-methacrylate copolymer coats pellet centers containing succinic acid and drugs in this syestem. Water controls the delay in the membrane by dissolving succinic acid in order to free the medication.

Temperature induced Pulsatile Release: The drug is triggered to be released through this process once biological factors like temperature and other chemical signals are activated. Thermoresponsive hydrogels made of poly-(N-isopropylacrylamide) are utilized as carriers for delivering medication in response to stimuli.

Chemical stimuli induced Pulsatile Release: Medications are delivered by stimuli-responsive drug delivery systems in response to biological cues. The medicine is discharged from those structures when the gels or micelles expand or disintegrate due to specific triggers. After receiving any biological signal, such as a chemical trigger, the medication is released within these structures.

Externally Regulated Pulsatile Drug Delivery Systems: The device's release mechanism is halted by external factors like radiation, electricity, magnetism, and ultrasonic waves on a sensitized system triggering drug discharge. It also ceases when the external stimuli are taken away from the system. Many externally controlled systems have been created as a result of recent advancements in regulation systems. It was created to accurately deliver the medication to the specific site of action, reducing the risk of side effects.

Table 2: Marketed Products of Pulsatile Drug Delivery System

Technology	API	Disease	Proprietary name
CODASÂ®	Verapamil Hcl	Hypertension	VerelanÂ® PM
CONTINÂ®	Theophylline	Asthma	UniphylÂ®
CEFORMÂ®	Diltiazem HCl	Hypertension	CardiazemÂ®
DiffucapsÂ®	Verapamil HCl, Propranolol HCl	Hypertension	InnopranÂ®
PulsincapÂ®	Metronidazole	Antihelminthic
GeoclockTM	Prednisone	Rheumatoid arthritis	Lodotra
OROSÂ®	Methylphenidate	Anti-psychotic	ConcertaÂ®
PULSYSTM	Amoxicillin	Antibiotic	MoxtagTM
Three dimensional printingÂ®	Diclofenac sodium.	Inflammation	TheirformÂ®
TIMERxÂ®	Oxymorphone	Pain management	OPANAÂ®

CONCLUSION:

Administering drugs in a pulsatile manner is beneficial for addressing diseases with time-related pathophysiology, whereas traditional drug delivery methods are not effective for treating these conditions. There has been significant work done towards creating pulsatile drug delivery systems to effectively treat conditions such as diabetes, which need therapy with non-constant dosages. In conclusion, a pulsatile drug release system offers better drug dispersion for medications with time-dependent effects, high metabolism in the liver, need for night-time dosing, or specific absorption patterns in the gastrointestinal tract. One of the primary difficulties will involve constructing uncomplicated systems using accepted excipients that have a strong correlation between in vitro and in vivo testing; achieving this will necessitate a deeper understanding of how the biological surroundings impact the release capabilities of pulsatile delivery systems.

REFERENCES:

1. V.N.L. Sirisha, M. Namrata, B. Sruthi, I. harika, K. Kiran kumar, Y. Kiran Kumar Rao, K. Pranavi. Pulsatile Drug Delivery System-A Review. Int. J. of Pharm. Res. and All. Sci. 2012; 1(3); 13-23.

2. Rupali V. Khankari, Sneha M. Umale. A Review on Pulsatile Drug Delivery System. Asian J. Pharm. Tech. 2020; 10(2): 121-124.

3. Khalifa AZ, Zyad H, Mohammed H, Ihsan K, Alrawi L, Abdullah M, et al. Recent advances in remotely controlled pulsatile drug delivery systems. J Adv Pharm Technol Res. 2022; 13: 77-82. doi: 10.4103/japtr.japtr_330_21.

4. Pal, S., Monika, M., and Singh, M. Circadian rhythms regulated pulsatile drug delivery system. International Journal of Health Sciences. 2022; 6(S4): 7944–7965. https://doi.org/10.53730/ijhs.v6nS4.10374.

5. Pragya Baghel, Amit Roy, Shashikant Chandrakar, Sanjib Bahadur. Pulsatile Drug Delivery System: A Promising Delivery System. Research J. Pharma. Dosage Forms and Tech. 2013; 5(3): 111-114.

6. Kalantzi E. Lida, Karavas Evangelos, Koutris X. Efthimios and Bikiaris N. Dimitrios, Recent Advances in Oral Pulsatile Drug Delivery, Recent Patents on Drug Delivery and Formulation 2009; 3(1). https://dx.doi.org/10.2174/187221109787158337.

7. Pandit Vinay, Kumar Ajay, Ashawat S. Mahendra, Verma P. Chander and Kumar Pravin, Recent Advancement and Technological Aspects of Pulsatile Drug Delivery System - A Laconic Review, Current Drug Targets 2017; 18(10). https://dx.doi.org/10.2174/1389450117666160208144343.

8. Survase S and Kumar N. Pulsatile drug delivery system: current scenario. CRIPS. 2007; 8(2): 106-8.

9. AD Mali and RS Bathe. An updated review on pulsatile drug delivery system. International Journal of Advances in Pharmaceutics. 2015; 4(4). DOI: 10.7439/ijap.

10. Parmar, R.D., Parikh, R.K., Vidyasagar, G.M., Patel, D.V., Patel, C.J., and Patel, B. Pulsatile Drug Delivery Systems: An Overview. 2011

11. Bhandwalkar, K., Naidu, H., and Sivakumar, T. Recent trends in pulsatile drug delivery systems: A review. 2012

12. Jain, A. A review on: Pulsatile drug delivery system. World Journal of Pharmaceutical Research, 2017; 342-357.

13. Bussemer, T., Otto, I., and Bodmeier, R. Pulsatile drug-delivery systems. Critical Reviews in Therapeutic Drug Carrier Systems. 2001; 18(5): 433–458.

14. Maroni, A., Zema, L., Cerea, M., and Sangalli, M. E. Oral pulsatile drug delivery systems. Expert Opinion on Drug Delivery. 2005; 2(5): 855–871. https://doi.org/10.1517/17425247.2.5.855.

15. Maroni, A., Zema, L., Del Curto, M. D., Loreti, G., and Gazzaniga, A. Oral pulsatile delivery: rationale and chronopharmaceutical formulations. International Journal of Pharmaceutics. 2010; 398(1-2): 1–8. https://doi.org/10.1016/j.ijpharm.2010.07.026.

16. Chirigati, F. Bringing the pulsatile release system to light. Nat Comput Sci. 2022; 2: 467. https://doi.org/10.1038/s43588-022-00307-z.

17. AL. Akilandeshwari, K. Elango, S. Daisy Chellakumari, S. Kishore Kumar. Design, Development and Evaluation of Pulsatile Drug Delivery System of Ramipril. Res. J. Pharm. Dosage Form. and Tech. 2014; 6(4): 235-242.

18. Kumar Amit and Ranga Sonam. Pulsatile Drug Delivery System: Method and Technology Review. Int. J. Drug Dev. and Res. 2012; 4(4): 95-107.

19. Ayyar, V.S., Sukumaran, S. Circadian rhythms: influence on physiology, pharmacology, and therapeutic interventions. J Pharmacokinet Pharmacodyn. 2021; 48: 321–338. https://doi.org/10.1007/s10928-021-09751-2.

20. Dubey, Harikesh. Pulsatile Drug Delivery System: an Approach of Medication according to Circadian Rhythm. Journal of Applied Pharmaceutical Science. 2018; 2: 166-176. 10.7324/JAPS. 2012. 2327.

21. Patil, N. D., Bari, M. M., and Barhate, S. D. A review on novel approach pulsatile drug delivery system. Int. J. Pharm. Sci. Rev. Res. 2013; 21(1): 209-222.

22. Librodo P, Buckley M, Luk M, Bisso A. Chronotherapeutic Drug Delivery. J Infus Nurs. 2015; 38 Suppl 6: S18-23. doi: 10.1097/NAN.0000000000000140. PMID: 26536406.

23. Haribansh Narayan Singh, Shivangi Saxena, Sunil Singh, Ajit Kumar Yadav. Pulsatile Drug Delivery System: Drugs used in the Pulsatile Formulations. Research J. Pharma. Dosage Forms and Tech. 2013; 5(3): 115-121.

24. Sanjay S. Jain, Hemanshu V. Agarwal, Pramod S. Jagtap, Neha M. Dand, Kisan R. Jadhav, Vilasrao J. Kadam. Pulsatile drug delivery system (PDDS): A Brief Overview. Research J. Pharm. and Tech. 2012; 5(4): 449-461.

25. Amritha R., Sivakumar R., Y. Haribabu. A Review on Pulsatile Drug Delivery System: Drug Scheduling based on Biological Rhythm. Research Journal of Pharmacy and Technology. 2022; 15(3):1359-4.

26. Dharmamoorthy, G., and Nandhakumar, L. Chronotherapeutics: A Range of newer drug delivery approaches for better patient compliance. International Journal of Applied Biology and P. 2011.

27. Ravikant S. Murkute, R. S. Wanare, Krishna J. Dongre. A Review: Recent Scenario on Osmotic Controlled Drug Delivery System. Research J. Pharm. and Tech. 2012; 5(5): 580-591.

28. Sunil, S. A., Srikanth, M. V., Rao, N. S., Uhumwangho, M. U., Latha, K., and Murthy, K. V. Chronotherapeutic drug delivery systems: an approach to circadian rhythms diseases. Current Drug Delivery. 2011; 8(6): 622–633. https://doi.org/10.2174/156720111797635559.

29. Jain, D., Raturi, R., Jain, V., Bansal, P., and Singh, R. Recent technologies in pulsatile drug delivery systems. Biomatter. 2011; 1(1): 57–65. https://doi.org/10.4161/biom.1.1.17717.

30. Ravichandiran V, Suba V, Senthilnathan B, Rajachandrika K, Padmapriya S, Saraswathy T. Pulsatile Drug Delivery System. Biomed Pharmacol J. 2009; 2(2).

31. Ram S Sakhare, Ashish B Roge, RL Bakal, MA Channawar, AV Chandewar. Pulsatile Drug Delivery Systems: Novel Approach on Control Drug Delivery. Research J. Pharm. and Tech. 2010; 3(1): 32-38.

32. R, V., and Nallaguntla, L. Review article on pulsatile drug delivery system. Asian Journal of Pharmaceutical and Clinical Research. 2021; 14(6): 48–59. https://doi.org/10.22159/ajpcr.2021.v14i6.4147.

33. Sheth Avani, Naman Doshi, Dipen Patel, Badmanaban R, CN Patel. Footsteps of Pulsatile Drug Delivery System in Pharmaceutical Sciences. Research J. Pharm. and Tech. 2010; 3(2): 385-389.

34. Patel Vipul P, Soniwala Moinuddin M. Pulsatile drug delivery system for treatment of various Inflammatory Disorders: A Review. Int. J. Drug Dev. and Res. 2012; 4(3): 67-87.

35. Saigal, N., Baboota, S., Ahuja, A., and Ali, J. Site specific chronotherapeutic drug delivery systems: a patent review. Recent patents on drug delivery and formulation. 2009; 3(1): 64–70. https://doi.org/10.2174/187221109787158328.

36. Anal A. K. Time-controlled pulsatile delivery systems for bioactive compounds. Recent patents on drug delivery and formulation. 2007; 1(1): 73–79. https://doi.org/10.2174/187221107779814096.

37. Giddam, Ashwin Kumar and Bhat, Amit and Lakshmi, A and Tupally, Karnaker. An Overview of Stimuli-Induced Pulsatile Drug Delivery Systems. Int. J. of Pharm Tech Research. 2010; 2.

38. Gurpreet Arora, Inderbir Singh, Manju Nagpal, Sandeep Arora. Recent Advances in Stimuli Induced Pulsatile Drug Delivery System: A Review. Research J. Pharm. and Tech. 2011; 4(5): 691-703.

39. Imanshu Agrawal, Nipa Thacker, Ambikanandan Misra. Parenteral Delivery of Peptides and Proteins, Editor(s): Ambikanandan Misra, Challenges in Delivery of Therapeutic Genomics and Proteomics, Elsevier, 2011, Pages 531-622, ISBN 9780123849649, https://doi.org/10.1016/B978-0-12-384964-9.00011-6.

40. Tahura Mahmood et al, Pulsatile Drug Delivery System- A Review. Indo Am. J. P. Sci. 2021; 8(12).

Received on 30.12.2023 Modified on 19.04.2024

Asian J. Pharm. Res. 2024; 14(3):309-314.

DOI: 10.52711/2231-5691.2024.00048