REVIEW ON: PULSATILE DRUG DELIVERY SYSTEM

About Authors:
Bhuvnesh*1, G.Gnanarajan1, Preeti Kothiyal1
Department of Pharmacy, Shri Guru Ram Rai Institute of Technology & Science P.O. Box
80, Patel Nagar , Dehradun 248001, Uttarakhand , India1
*bhuvnesh.grg89@gmail.com

Abstract
Pulsatile drug delivery systems (PDDS) are gaining importance in the field of pharmaceutical technology as these systems deliver the right dose at specific time at a specific site. A pulsatile drug release, where the drug is released rapidly after a well defined lag-time, could be advantageous for many drugs or therapies.A pulse has to be designed in such a way that a complete and rapid drug release is achieved after the lag time so as to match body’s circadian rhythms with the release of drug which increases the efficacy and safety of drugs by proportioning their peak plasma concentrations during the 24 hours in synchrony with biological rhythm. Pulsatile release systems can be classified in multiple-pulse and single-pulse systems.  Various techniques are available for the pulsatile delivery like pH dependent systems, time dependent systems, etc. A popular class of single-pulse systems is that of rupturable dosage forms. Advantages of the pulsatile drug delivery system are reduced dose frequency; reduce side effects, drug targeting to specific site like colon and many more. Now in market varies technologies of pulsatile drug delivery system like Pulsincap, Diffucaps etc. are launched by pharmaceutical companies.

Reference Id: PHARMATUTOR-ART-1420

INTRODUCTION
Oral controlled drug delivery systems represent the most popular form of controlled drug delivery systems for the obvious advantages of oral route of drug administration. Such systems release the drug with constant or variable release rates. The oral controlled release system shows a typical pattern of drug release in which the drug concentration is maintained in the therapeutic window for a prolonged period of time (sustained release), thereby ensuring sustained therapeutic action. But there are certain conditions which demand release of drug after a lag time. i.e., Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology.[1,2]

Recent studies have revealed that diseases have predictable cyclic rhythms and that the timing of medication regimens can improve outcome in selected chronic conditions such as asthma where the crisis are mostly happening late at night, osteoarthritis where the pain is more intense again during night, rheumatoid arthritis where the pain peaks at the morning, duodenal ulcer where the highest gastric secretion is happening in the nighttimes, neurological disorders such as epilepsy where the oscillations are following melatonin secretion, hypercholesterolemia where the cholesterol synthesis is higher during the night and several cardiovascular diseases such as cardiac and/or platelet aggregation. Diseases with time structures other than circadian rhythm are also possible, for example, diabetes is following the secretion of insulin stimulated by meal, or tumour growth in cancer states that follows body changes in blood flow. Menstrual cycle and the corresponding hormonal flux are also following cyclic patterns.

Pulsatile system gaining a lot of interest as it is increasing patient compliance by means of providing time- and site-specific drug delivery system, thus providing special and temporal delivery. Pulsed or pulsatile drug release is defined as the rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off-release period. Recent studies show that diseased have predictable cyclic rhythms and the timing of medication regimens can improve outcome in selected chronic conditions [3, 4].

Drugs which exhibit tolerance should not be delivered at a constant rate, since the drug effect decreases with time at constant drug level. In addition drug toxicity increases with time when drug levels are held constant. In such cases it is preferable to opt for dosage form which will provide desired concentration of drug at particular time point only. Now, concept of chronopharmaceutics has emerged, wherein, research is devoted to the design and evaluation of drug delivery systems that release a therapeutic agent at a rhythm that ideally matches the biological requirement of a given disease therapy. “Chronopharmaceutics” consist of two words chronobiology and pharmaceutics. Chronobiology is the study of biological rhythms and their mechanisms.

MERITS:
·         Predictable, reproducible and short gastric residence time
·         Less inter- and intra-subject variability
·         Improve bioavailability
·         Limited risk of local irritation
·         No risk of dose dumping
·         Flexibility in design
·         Improve stability

DEMERITS
·         Lack of manufacturing reproducibility and efficacy
·         Large number of process variables
·         Batch manufacturing process
·         Higher cost of production
·         Trained/skilled personal needed for Manufacturing[5]

DISEASES REQUIRING PULSATILE DELIVERY
Recent studies have revealed that diseases have predictable cyclic rhythms and that the timing of medication regimens can improve outcome in selected chronic conditions. There are number of diseases which required to be formulated as PDDS as like: hypercholesterolemia, asthma, cancer, duodenal ulcer, arthritis, diabetes, neurological disorders, cardiovascular diseases and colonic delivery. A circadian rhythm occurs during hepatic cholesterol synthesis. Therefore, cholesterol synthesis is generally higher during the night than during daylight. The maximal production occurs early in the morning, i.e. 12 h after the last meal. Studies with HMG CoA reductase inhibitors have suggested that evening dosing was more effective than morning dosing [6, 7].

Disease

Chronological behaviour(category of drugs used)

Asthma

Precipitation of attacks during night or at early morning hour

Arthritis

Pain in the morning and more pain at night (NSAID, Glucocorticoids)

Cardiovascular disease

BP is at its lowest during the sleep cycle and rise steeply during the early morning awakening period (Nitroglycerine, calcium channels blockers)

Diabetes mellitus

Increase in the blood sugar level after meal(sulfonylurea,Biguanide, insulin)

Hypercholestrolemia

Cholesterol synthesis is generally higher during night than during day time (Statins)

Peptic ulcer

Acid secretion is high(H2 blockers)

Human and animal studies suggest that chemotherapy may be more effective and less toxic if cancer drugs are administered at carefully selected times that take advantage of tumour cell cycles while less toxic to normal tissue. In GI ulcer, many of the functions of the gastrointestinal tract are subject to circadian rhythms: gastric acid secretion is highest at night while gastric and small bowel motility and gastric emptying are all slower at night. During night time, when gastric motility and emptying are slower, drug disintegration, dissolution, and absorption may be slower, pulse release is curative[8.9].

Asthma is one such disease where pulsatile drug delivery system can be useful. Circadian changes are seen in normal lung function, airway resistance increases progressively at night in asthmatic patients. Chronotherapies have been studied for asthma with oral corticosteroids, theophylline, and B2- agonists [10].

The colon is also seen as the preferred absorption site for oral administration of protein and peptide drugs, because of the relatively low proteolytic enzyme activities in the colon. A colon-specific drug delivery system should prevent drug release in the stomach and small intestine, and affect an abrupt onset of drug release upon entry into the colon. Time dependent delivery has also been proposed as a means of targeting the colon [11].

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