A Review on Pulsatile Drug Delivery System

Rupali V. Khankari, Sneha M. Umale

Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule

*Corresponding Author E-mail: snehaumale912@gmail.com

ABSTRACT:

Pulsatile Drug Delivery Systems are gaining a lot of interest as they deliver the drug at the right place, at the right time and in the right amount, thus providing spatial, temporal and smart delivery and increasing patient compliance. The use of pulsatile release of the drugs is desirable where constant drug release is not desired. PDDS can be classified into time controlled systems wherein the drug release is controlled primarily by the delivery system; stimuli induced PDDS in which release is controlled by the stimuli, like the pH or enzymes present in the intestinal tract or enzymes present in the drug delivery system and externally regulated system where release is programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation. The current article focuses on the diseases requiring PDDS, methodologies involved for the existing systems, current situation and future scope, recent advances in PDDS and PDDS product currently available in the market.

KEYWORDS: Drug delivery system, PDDS.

INTRODUCTION:

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^1,2.

Methodologies for PDDS:

From technological point of view pulsatile drug release system are further divided to single and multiple units system.

Single unit system:

1 Capsule Based:

Amidon and Leesman described a drug delivery system for administering a drug in controlled pulse doses to an aqueous environment in the body of a living being. The formulation comprises of one or more, and preferably less than ten, individual drug-containing subunits in a unitary drug depot, such as a tablet or capsule. The individual subunits are designed to dissolve at different sites and/or times in the gastrointestinal tract to release pulse doses of drug into the portal system in an analogous manner to the rate of release from an immediate release dosage form administered according to an appropriate dosing schedule. The dissolution time of the individual subunits can be controlled by several methods including the provision of pH sensitive enteric coatings and permeability-controlled coatings. The drug delivery system has significant advantages for the oral administration of first-pass metabolized drugs which exhibit a non-linear relationship between input rate of the drug into the portal system and bioavailability.

Fig. 1: Schematic diagram of capsular system

Percel and coworkers described a capsule capable of delivering therapeutic agents in the body in a time controlled or position-controlled pulsatile release fashion, composed of one or more populations of multicoated particulates (beads, pellets, granules, etc.). Each bead has been prepared by coating an inert particle such as a nonpareil seed (sugar sphere), with a drug and a polymeric binder or by preparing a drug containing particle by granulation and/or extrusion- spheronization, coating the active drug particle with a plasticized enteric coating, and coating plasticized enteric coated drug particle with a mixture of a water insoluble polymer and an enteric polymer. One of the membrane barriers is composed of an enteric polymer while the second membrane barrier is composed of a mixture of water insoluble polymer and an enteric polymer. The composition and the thickness of the polymeric membrane barriers determine the lag time and duration of drug release from each of the bead populations. Optionally, an organic acid containing intermediate membrane may be applied for further modifying the lag time and/or the duration of drug release. Jenkins described a Multiparticulate modified release composition in an erodable, diffusion controlled or osmotic form designed to release the active ingredients at about six to twelve hours so that the resulting plasma profile is substantially similar to the plasma profile produced by the administration of the two or more immediate release dosage forms given sequentially. The composition can be in the form of an erodable formulation in which the structural integrity of the particulates deteriorates within the body over time, in the form of a diffusion controlled formulation in which the particulates are dispersed in a liquid medium or in the form of an osmotic controlled formulation in which the release of the active ingredient from the composition is controlled by osmosis.

2 Osmotic based pump capsule:

Osmotic delivery capsules ("osmotic pumps") function by virtue of walls which selectively pass water into the capsule reservoir. Absorption of water by the capsule through these walls is driven by a water-attracting agent in the capsule interior which creates osmotic pressure across the capsule wall. The water-attracting agent may be the beneficial agent itself whose controlled release is sought, but in most cases, it is a separate agent specifical1y selected for its ability to draw water, and this separate agent is being isolated from the beneficial agent at one end of the capsule. In either case, the structure of the capsule wall does not permit the capsule to expand, and as a result, the water uptake causes discharge of the beneficial agent through an orifice in the capsule at the same rate that water enters by osmosis.

Linkwitz and coworkers proposed a drug delivery capsule where drug delivery is driven by the osmotic infusion of moisture from a physiological environment. The capsule has a delivery orifice which opens intermittently to achieve a pulsatile delivery effect. The wall in which the orifice is formed is constructed of an elastic material (elastomer) which stretches under a pressure differential caused by the pressure rise inside the capsule as the osmotic infusion progresses. The orifice is so small that when the elastic wall is relaxed, the flow rate of drug through the orifice is substantially zero, but when the elastic wall is stretched due to the pressure differential across the wall exceeding a threshold, the orifice expands sufficiently to allow the release of the drug at a physiologically beneficial rate. The selection of the materials from which the device is constructed and the configuration of the device and its dimensions controls the length of time between pulses^3,4,5

3 Erodable Barrier System:

Kim described a formulation of coated Donut Shaped Tablet (DST) and multi-layer DST so that immediate release or time-delayed release can be achieved. Both zero order or first order extended release kinetics are possible, depending on the excipients and types of drugs in the tablet formulation. The coating layer for time delay is made of high molecular weight water soluble polymers so that the dose dumping can be minimized even when the hydrated surface of the DST and MLDST peels off. Low molecular weight water soluble polymer coatings having a drug dispersed may be employed to provide a pulsatile release of a drug.

So that immediate release or time-delayed release of a drug proposed by Kim. Kohn and coworkers uses the degradation products of one polymer to trigger the release of the active compound from another polymer. The delayed release of the active compound was achieved without using a barrier system that requires complex and sophisticated formulation techniques. The proposed formulation comprises the biologically active compound having a chemical structure with hydrogen bonding sites dispersed in a biocompatible, hydrolytically degrading polyarylates. In the case of peptide drugs, interactions between the peptide and the first polymer inhibit the release of the peptide. Bonding interactions between the polymer and the active compound are used to lock the active compound into the polymeric matrix. In order to control the time of peptide release from polyarylates, a second biocompatible polymer but less hydrophobic than polyarylates is also used. The second polymer can be degraded into acidic byproducts into the matrix. This is necessary because the hydrogen bonding interactions can be weakened under conditions of low pH, resulting in the release of the peptide. Degradation products lower the pH of the matrix, causing an interruption in the interactions and the subsequent release of the peptide.^6-8

4 Rapturable Layers:

A novel formulation for once daily administration (prior to sleeping) that provides an initial delay followed by controlled release of the drug. A method for preparing a time specific delayed, controlled release formulation of dosage is also provided which method includes coating a single pellet with at least one dosage layer, which is coated by at least one seal coat and at least one outer rate controlling layer of a water-soluble polymer coat. The formulation affords excellent bioavailability while avoiding fluctuating blood levels. By that way, it is possible to maintain drug plasmatic concentrations in a desired, effective range in a circadian fashion while simplifying the administration of the drug to only once daily^9,10.

Multiple units:

1 Systems Based on Change in Membrane Permeability:

Numerous pharmaceutical forms with delayed release for oral administration are available. As already mentioned the release of the drug must be controlled according to therapeutically purpose and the pharmacological properties of the active ingredient. In consequence, it is not always desirable the blood levels to be constant. On the contrary, in order to avoid any habituation and in order to limit the side effects provoked by the active ingredient, it would be absolutely advantageous for the plasmatic rate to follow the metabolic rhythm and the specific needs of the patient during certain periods. For instance, in order to diminish the nocturnal symptoms or the symptoms upon awakening in the case of certain chronic diseases such as ischemic heart disease, asthma and arthritis, the drugs should be administered in such a way that the desired therapeutically plasmatic level is reached only at the desired moment, i.e. during sleep or at the moment of awakening Dosage form for Pulsatile release proposed by Chen containing a plurality of different pellets composed with a core and several coating layers. Chen described a dosage form for delivering drugs into the body in a series of sequential, pulsatile releasing events. The system can be used with drugs which cannot be released by diffusion through a porous coating, such as water insoluble drugs. A plurality of populations of pellets is provided within a unit dosage form such as a capsule or tablet^11,12.

Evaluation of pulsatile drug delivery system:

1. Thickness and diameters:

It is measured by using vernier calliper in mm.

2 Hardness:

The hardness of tablet was measured by using monsanto hardness tester. The unit of hardness is kg/cm^2(13,
14)

3 Friability:

Friability of tablet was found to be USP friabilator. First of all tablet batch was weighed and placed in friabilator for 100 revolution in 4 minutes. The % friability was calculated by

F = (Wi-Wf)/ Wi×100

Where, Wi = initial weight Wf = final weight^15,16.

4. Weight variation test:

The USP weight variation test was done by weighing 20 tablets individually calculating average weight and comparing the individual weight to the average.

5 Lag time and Drug release:

The lag time and drug release studies was carried out in gastric and intestinal fluids at body tem. This test is performed in USP dissolution apparatus, in this test the tablet was placed in dissolution media and the sample was withdrawn at specific time interval and after that analyzed in UV spectroscopy^17-18.

6 Rupture test:

The Rupture test on coated tablets was carried out using USP paddle apparatus. Here all other Parameters were same as In-Vitro Dissolution Method. The time at which the outer coating layer starts to rupture is called as lag time. This was determined by Rupture test¹⁹.

7 Drug content:

In this test accurately weight amount of powder was dissolved in water and filtered. After that the absorbance was measured at fixed wave length by UV spectrophotometer.

8 Water uptake study:

The % water uptake of pulsatile release tablets was determined in medium filled container placed in a horizontal shaker (100ml of 0.1 N HCl, 37.5 C, 74 rpm n=3) at predetermined time points, the tablets were removed from the dissolution medium. They were then carefully blotted with the tissue paper to remove surface water, then weighed and then placed back in the medium up to the time when the coating of the tablet ruptured. The % water uptake update was calculated as follow:

%Water uptake= [(Wt-Wo/Wo)] 100

Where, Wt- weight of tablet at time t and Wo - is weight of dry tablet²⁰.

9 Swelling index:

The individual tablets were weighed accurately and kept in 50 ml of double distilled water. Then tablets were taken out properly after 60 min., then blotted with filter paper so as to remove the water present on the surface and weighed accurately. Percentage swelling index (SI) was calculated by using the formula

SI = (Wet weight – Dry weight / Dry weight) X 100²¹.

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 03.02.2020 Modified on 07.03.2020

Asian J. Pharm. Tech. 2020; 10(2):121-124.

DOI: 10.5958/2231-5713.2020.00021.5