You are hereREVIEW ON: PULSATILE DRUG DELIVERY SYSTEM

REVIEW ON: PULSATILE DRUG DELIVERY SYSTEM


CLASSIFICATION OF PDDS (TECHNOLOGY USED)
From technological point of view pulsatile drug release system are further divided to single and multiple units system.

SYSTEM UNIT SYSTEM
These are subdivided as capsule-based system, osmotic system, delivery system with soluble or erodible membranes, and delivery system with repturable coating.

CAPSULE-BASED SYSTEM
Capsule based system consists of pulsincap system, which consists of an insoluble capsule body and swellable and degradable plugs made of approved substances such as hydrophilic polymers or lipids. The lag time is controlled by plug, which pushed away by swelling or erosion and drug is released as a pulse from the insoluble capsule i.e. Pulsincap®.


Fig 1:CAPSULE-BASED SYSTEM

A swellable hydrogel plug seals the drug contents in to capsule body. When this capsule body came in to contact with dissolution medium, the hydrogel plug swells, and after the lag time the plug pushed itself outside the capsule and rapidly released the drug [12]. Various types of material used for formulation of swellable plug which include hydroxyl propyl methyl cellulose, poly vinyl acetate and poly ethylene oxide. The length of plug decides lag time. Plug material is generally made up of HPMC, polyvinyl alcohol, glyceryl mono oleate, pectin, polymethacrylates.

OSMOTIC SYSTEM
Osmotic system consists of capsule coated with the semipermeable membrane. Inside the capsule there is an insoluble plug consisting of osmotically active agent and the drug formulation [13].


Fig 2: OSMOTIC SYSTEM

Another system is also based on expendable orifice that contain capsular system in which liquid drug is absorbed on highly porous particles. Drug releases through orifice of a semi permeable capsule supported by an expending osmotic layer after the barrier layer is dissolved.

The Port® System (Port Systems, LLC) consists of a gelatin capsule coated with a semi permeable membrane (e.g., cellulose acetate) housing an insoluble plug (e.g., lipidic) and an osmotically active agent along with the drug formulation when in contact with the aqueous medium, water diffuses across the semipermeable membrane, resulting in increased inner pressure that ejects the plug after a lag time. The lag time is controlled by coating thickness [14].

DELIVERY SYSTEM WITH SOLUBLE OR ERODIBLE MEMBRANES
In such systems the drug release is controlled by the dissolution or erosion of the outer coat which is applied on the core containing drug. Time dependent release of the active ingredient can be obtained by optimizing the thickness of the outer coat. e.g chronotropic system which consists of a drug containing core layered with HPMC optionally coated with an outer enteric coating.

 Fig 3: DELIVERY SYSTEM WITH SOLUBLE OR ERODIBLE MEMBRANES

The lag time prior to drug release is controlled by the thickness and the viscosity grade of HPMC layer. Solid dosage form coated with lipid barriers such as carnauba wax & beeswax along with surfactants like polyoxyethylene sorbitan monooleate. When this system comes in contact with the aqueous medium the coat emulsifies or erodes after the lag-time depending on the thickness of coat [15].

DELIVERY SYSTEM WITH REPTURABLE COATING
These systems are based up on a reservoir system coated with a rupturable membrane. The outer membrane ruptures due to the pressure developed by effervescent agents (or) swelling agent. Citric acid & sodium bicarbonate is incorporated as effervescent mixture in tablet core coated with ethyl cellulose, when system comes in contact with water it produces carbon dioxide gas which exerts pressure & after lag time rupture the membrane & rapid release of drug occurs. A reservoir system with a semi permeable coating is proposed especially with drugs with high first pass effect in order to obtain in-vivo drug pattern similar to the administration of several immediate release doses croscarmellose sodium starch.


Fig 4:DELIVERY SYSTEM WITH REPTURABLE COATING

glycollate or low substituted hydroxy propyl cellulose were used as swelling substances, which resulted in complete film rupture followed by rapid drug release. The lag time is controlled by composition of outer polymeric membrane [1, 2].Sungthongjeen et al developed a tablet system consisting of core coated with two layers of swelling  and  rupturable  coatings  wherein  they  used spray  dried  lactose  and  microcrystalline  cellulose  in drug  core  and  then  core  was  coated  with  swelling polymer   croscarmellose   sodium   and   an   outer rupturable  layer  of  ethylcellulose[16].

II. Multiple Units

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 therapeutical 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 therapeutical plasmatic level is reached only at the desired moment, i.e. during sleep or at the moment of awakening.

Chen described a system composed of a large number of pellets made up of two or more populations of pellets or particles. Each pellet contains a drug containing core, and a water soluble osmotic agent enclosed in a water permeable, water-insoluble polymer film. Incorporated into the polymer film is a hydrophobic, water insoluble agent which alters the permeability of the polymer film. The film coating of each population of pellets differs from the coating of every other population of pellets in the dosage form in the rate at which water passes through to the core and the rate at which drug diffuses out of the core. The osmotic agent dissolves in the water, causing the pellet to swell and regulating the rate of diffusion of drug into the environment of use. As each population of pellets releases drug into the environment sequentially, a series of pulsatile administrations of the drug from a single dosage form is achieved [17].

CLASSIFICATION OF PDDS BASED ON STIMULI INDUCED
1. Temperature induced system
2. Chemically induced system
3. Externally induced system

1. TEMPERATURE INDUCED SYSTEM
Thermo-responsive hydrogel systems have been developed for pulsatile release. In these systems the polymer undergoes swelling or deswelling phase in response to the temperature which modulate drug release in swollen state [16]. Y.H. Bae et al developed indomethacin pulsatile release pattern in the temperature ranges between 200C and 300C by using reversible swelling properties of copolymers of N-isopropylacrylamide and butyrylacrylamide. Kataoka et al developed the thermosensitive polymeric micelles as drug carrier to treat the cancer. They used endfunctionalized poly (N isopropylacrylamide) (PIPAAm) to prepare corona of the micelle which showed hydration and dehydration behavior with changing temperature[18,19].

2. CHEMICALLY INDUCED SYSTEM
There has been much interest in the development of stimuli-sensitive delivery systems that release a therapeutic agent in presence of specific chemical moieties like enzyme or protein. One of the good example is Glucose-responsive insulin release devices in which insulin is release on increasing of blood glucose Level. In diabetes mellitus there is rhythmic increase in the levels of glucose in the body requiring injection of the insulin at proper time. Several systems have been developed which are able to respond to changes in glucose concentration. One such system includes pH sensitive hydrogel containing glucose oxidase immobilized in the hydrogel. When glucose concentration in the blood increases glucose oxidase converts glucose into gluconic acid which changes the pH of the system. This pH change induces swelling of the polymer which results in insulin release. Insulin by virtue of its action reduces blood glucose level and consequently gluconic acid level also gets decreased and system turns to the deswelling mode thereby decreasing the insulin release [20].

Yui et al. designed drug delivery systems based on the polymers which responded to the hydroxyl radicals and degraded in a limited manner. Yui and co-workers used hyaluronic acid (HA), in the body, HA is mainly degraded either by hydroxyl radicals or a specific enzyme, hyaluronidase. Degradation through hydroxyl radicals however, is usually dominant and rapid when HA is injected at inflammatory sites. Thus, they designed crosslinked HA with ethylene glycol diglycidylether or polyglycerol polyglycidylether Thus, a surface erosion type of degradation was achieved. Patients with inflammatory diseases, such as rheumatoid arthritis, can be treated using this type of system [21, 22].

In Enzymatically- Activated liposomes, drug loaded liposomes wasincorporated into microcapsules of alginatehydrogels. Liposomes inside themicrocapsules were coated withphospholipase A2 to achieve a pulsatilerelease of drug molecules. Phospholipase A2was shown to accumulate at thewater/liposome interfaces and remove anacyl group from the phospholipids in theliposome. Destabilised liposomes releasetheir drug molecules, thus allowing drugrelease to be regulated by the ratedetermining microcapsule membrane [23].

Miyata et al. focused on the development of stimuli responsive crosslinking structures into hydrogels. Special care was given to antigen-antibody complex formation as the cross-linking units in the gel, since specific antigen recognition of an antibody can provide the foundation for a new device fabrication. Using the difference in association constants between polymerized antibodies and naturally derived antibodies towards specific antigens, reversible gel swelling/deswelling and drug permeation changes could occur. Thus, biological stimuli responsive hydrogel were created [24].

3. EXTERNALLY INDUCED SYSTEM
For releasing the drug in a pulsatile manner, another way can be the externally regulated systems in which drug release is programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation.

ELECTRICALLY STIMULATED
Electrically responsive delivery systems are prepared by polyelectrolytes (polymers which contain relatively high concentration of ionisable groups along the backbone chain) and are thus, pH-responsive as well as electro-responsive. Under the influence of electric field, electro responsive hydrogels generally bend, depending on the shape of the gel which lies parallel to the electrodes whereas deswelling occurs when the hydrogel lies perpendicular to the electrodes. An electroresponsive drug delivery system was developed by R. V. Kulkarni, et al., using poly (acrylamide-grafted-xanthan gum) (PAAm-g- XG) hydrogel for transdermal delivery of ketoprofen[25].

MAGNETICALLY STIMULATED
Magnetically regulated system contains magnetic beads in the implant. On application of the magnetic field, drug release occurs because of magnetic beads [26].Magnetic carriers receive their magnetic response to a magnetic field from incorporated materials in beads such as magnetite, iron, nickel, cobalt etc.Tingyu Liu, et al developed the magnetic hydrogels which was successfully fabricated by chemically crosslinking of gelatin hydrogels and Fe3O4 nanoparticles (ca. 40–60 nm) through genipin (GP) as cross-linking agent. Saslawski et al.[19] developed different formulations for in vitro magnetically triggered delivery of insulin based on alginate spheres. In an experiment, ferrite microparticles (1μm) and insulin powder were dispersed in sodium alginate aqueous solution. The ferrite-insulin alginate suspension was later dropped in aqueous calcium chloride solution which causes the formation of cross linked alginate spheres, which were further cross linked with aqueous solution of poly(L-lysine) or poly(ethylene imine). They described that the magnetic held characteristics due to the ferrite microparticles and the mechanical properties of the polymer matrices could play role in controlling the release rates of insulin from the system [27].

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