Traditionally, drugs are released in an immediate or extended manner. A pulsatile drug release, where the drug is released rapidly after a well defined lag-time, could be advantageous for many drugs or therapies. As the pulsatile drug delivery achieve desired therapeutic effect and reducing side effect, so patient compliance can be obtained along with lowering dose frequency. These systems are designed according to the circadian rhythm of the body and the drug is released as a pulse. Diseases like asthma, peptic ulcers, cardiovascular ailments, arthritis and attention deficit syndrome in children and hypercholesterolemia can be cured by drugs, released by PDDS.
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Traditionally, drugs are released in an immediate or extended manner. A pulsatile drug release, where the drug is released rapidly after a well defined lag-time, could be advantageous for many drugs or therapies.
As the pulsatile drug delivery achieve desired therapeutic effect and reducing side effect, so patient compliance can be obtained along with lowering dose frequency. These systems are designed according to the circadian rhythm of the body and the drug is released as a pulse. Diseases like asthma, peptic ulcers, cardiovascular ailments, arthritis and attention deficit syndrome in children and hypercholesterolemia can be cured by drugs, released by PDDS.
Recent trends include Multiparticulate drug delivery systems that are especially suitable for achieving controlled or delayed release oral formulations with low risk of dose dumping, flexibility of blending to attain different release patterns as well as reproducible and short gastric residence time.
Author Guidelines Submit Manuscript. Drug Dev. This is an open access paper distributed under thecopyright agreement with Serials Publication, whichpermits unrestricted use, distribution, andreproduction in any medium, provided the originalwork is properly cited. Related article at Pubmed , Scholar Google. Modified release dosage forms have a great importance in this regard.
Such systems control the release pattern of drug, either with constant or variable rates drug is released with predetermined release rates.
However, there are certain conditions for which such a release pattern is not suitable. These conditions demand release of drug after a lag time.
This condition can be achieved by pulsatile drug delivery system which is defined as the rapid and transient release of certain amount of molecules within a short time period immediately after a predetermined off- release period i. In this graph, it was aimed to achieve a sigmoid release pattern Figure 1. The characteristic feature of the formulation was a well defined lag time followed by a drug pulse with the enclosed active quantity being released at once.
Thus, the major challenge in the development of pulsatile drug delivery system is to achieve a rapid drug release after the lag time. A new concept of chronopharmaceutics has emerged, wherein research is devoted to the design and evaluate the drug delivery systems that release a therapeutic agent at a rhythm that ideally matches the biological requirement of a given disease therapy2.
Chronobiology is the study of biological rhythms and their mechanisms. There are three types of mechanical rhythms in our body. These are: Ultradian Rhythms Shorter duration oscillations are termed as Ultradian Rhythms more than one cycle per 24 h.
Infradian Rhythms Oscillations that are longer than 24 hours are termed as Infradian Rhythms less than one cycle per 24hours e. Monthly Menstruation. Circadian rhythms Circadian rhythms are self-sustaining, endogenous oscillations that occur with a periodicity of about 24 Hours Figure.
These rhythms allow organism to anticipate and prepare for precise and regular environment changes. There are clear patterns of core body temperature, brain wave activity, hormone production, and other biological activities linked to this cycle.
Some people function best in the morning while others have their peak in the noon or evening. If our normal rhythm is disrupted we tend to become anxious e. In sleep wake cycle, an animal will settle into a 24 hour cycle activity and sleep even if deprived of light.
Diurnal blood pressure fluctuations are super imposed by a hour rhythm with lower levels during the night and higher in the day3, Diseases requiring pulsatile drug delivery Circadian rhythm regulates many body functions in humans, viz. Asthma is one such disease where pulsatile drug delivery system can be useful. Circadian changes are seen in normal lung function, which reaches a low point in the early morning hours. In peptic ulcer acid secretion is high in the afternoon and at night. In case of cardiovascular diseases, BP is at its lowest during the sleep cycle and rises steeply during the early morning period.
Platelet agreeability is increased and fibrinolytic activity is decreased in the morning, leading to a state of relative hypercoagulability of the blood. Circadian increase in the blood sugar level after meal has been observed in Diabetes mellitus. Circadian variations seen in DOPA level in afternoon in case of Attention deficit syndrome7, 9, 10, Mechanism of drug release from pulsatile drug delivery system The mechanism of drug release from PDDS can be occurring in the following ways Diffusion Water diffuses into the interior of the particle when particle come in contact with aqueous fluids in the gastrointestinal tract and resultant drug solutions diffuse across the release coat to the exterior.
Erosion Some coatings designed to erode gradually with time, result in the release of drug contained within the particle. Osmosis An osmotic pressure can be built up within the interior of the particle when water allows entering under the right circumstances. The drug is forced out of the particle into the exterior through the coating. Time Controlled system 1. Internally stimuli induced system 2.
Externally Regulated System 3. Electric field induces release 3. The release of the active ingredient can be controlled by thickness and viscosity of the outer coat. The Time Clock system consists of a solid dosage form coated with lipid barriers containing carnauba wax and bees wax along with surfactants. Chronotropic system consists of a core containing drug reservoir coated by a hydrophilic polymer HPMC.
System is composed of a drug-containing core and swells able polymeric coating of HPMC which slow the interaction with aqueous fluids4,8,9,11,13,14,15,16, Pulsatile Delivery by Rupture of Membrane These systems consist of an outer release controlling water insoluble but permeable coating subject to mechanically induced rupture phenomenon. The rupturing effect is achieved by coating the individual units with effervescent or swelling agents Figure. Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time.
The lag time can be varied by varying coating thickness or adding high amounts of lipophilic plasticizer in the outermost layer4, 8, 9,11,13,14,15,16, Capsule Shaped Pulsatile Drug Delivery System This dosage form consists of an insoluble capsule body containing drug and a release controlling plug Soluble is fitted between immediate release compartment and pulsed release compartment Figure.
The length of plug decides lag time. When it comes in contact with aqueous fluids, the cap rapidly dissolves thereby releasing the immediate release component followed by pulsed release component. Here the plug decides lag time which is inserted in to the body. A hydrostatic pressure generate inside the capsule that is why pulsatile drug delivery achieved4, 8, 9,11,13,14,15,16, There is an insoluble plug consisting of osmotically active agent and the drug formulation inside the capsule.
This system divides the capsule interior into two compartments- one for the beneficial agent and the other for the osmotically active agent. Water diffuses across the semi permeable membrane when this cap comes into contact with GI fluids and it results in increased pressure inside that ejects the plug after a predetermined lag time. Thickness of the coating decides the lag time. Ritalin methyl phenidate used in the treatment of attention deficit hyper active disorder ADHD in children4,8,9,11,13,14,15,16, Internally stimuli induced system Temperature—induced pulsatile release: Temperature is the most widely applied triggering signal for a variety of triggered or pulsatile drug delivery systems.
The body temperature often deviates from the physiological temperature C in the presence of pathogens or pyrogens. This deviation from normal range acts as a stimulus that triggers the release of therapeutic agents from several temperature-responsive drug delivery systems. Thermo responsive hydro gel systems: Hydro gels that undergo reversible volume changes in response to changes in temperature are known as thermo sensitive gels.
In thermo-responsive hydro gel systems, hydro gels undergo reversible volume changes in response to changes in temperature. These gels shrink at a transition temperature that is referred to the lower critical solution temperature LCST of the linear polymer.
As it undergo volume change, this property can be utilised to obtain a squeezing hydro gel device by positioning hydro gel within a rigid capsule.
The reversible volume change of temperature-sensitive hydro gels accomplish onoff release e. In aqueous solution, block copolymers formed micellar structure with core shell structure below PIPAAm's transition temperature. In this system, drug is released when polymer undergoes swelling or deswelling phase in response to chemical reaction with membrane, alteration of pH and Inflammation induce3, 4, The shell was constructed from thermo responsive PIPAAm, while the core comprised of hydrophobic polymer aggregates.
Chemical stimuli induced pulsatile release: Glucose-responsive insulin release devices These devices have been developed to respond with changes in glucose concentration in the blood. The hydro gels showed a glucose-responsive, sol—gel phase transition dependent upon the external glucose concentration.
These devices also have pH sensitive hydro gel containing glucose oxidase immobilized in the hydro gel. When glucose concentration in the blood increases glucose oxidase converts glucose into gluconic acid which changes the pH of the system. This swelling of the polymer induced by this pH change 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. Examples of the pH sensitive polymers include N, N- dimethylaminoethyl methacrylate, chitosan, polyol etc3, 7, 15, PH sensitive drug delivery system This system contains two components- one is of immediate release type and second is pulsed release which releases the drug in response to change in pH.
As different pH environment exist at different parts of the gastrointestinal tract so this advantage is utilised by pH dependent system. By selecting the appropriate pH dependent polymers, desired drug release can be achieved at specific location. Examples of pH dependent polymers are cellulose acetate phthalate, polyacrylates, and sodium carboxymethylcellulose.
These polymers are used as enteric coating materials so as to provide release of drug in the small intestine3, 7, 15, Inflammation-induced pulsatile release Any physical or chemical stress, such as injury, fracture etc. The inflamed responsive cells produce hydroxyl radicals.
Yui and co-workers focused on the inflammatory induced hydroxyl radicals and designed drug delivery systems, which responded to the hydroxyl radicals and degraded in a limited manner.
They used hyaluronic acid HA which is specifically degraded by the hyaluronidase or free radicals. Degradation of HA via the hyaluronidase is very low in a normal state of health. Degradation via hydroxyl radicals however, is usually dominant and rapid when HA is injected at inflammatory sites. Thus, it is possible to treat patients with inflammatory diseases like rheumatoid arthritis; using anti inflammatory drug incorporated HA gels as new implantable drug delivery systems5, 7,10,11, Drug release from intelligent gels responding to antibody concentration In the human body numerous kinds of bioactive compounds are exist.
Antigenantibody complex formation is of great importance as the cross-linking units in the gel due to such specific interaction. Externally Regulated System Magnetic induces release Magnetically regulated system contains magnetic beads in the implant. Magnetic steel beads were engrafted in an ethylene and vinyl acetate EVAc copolymer matrix that was loaded with bovine serum albumin as a model drug.
9. Pulsatile Drug Delivery System: Method and Technology Review
Control drug delivery and optimize release profiles with a sophisticated multiparticulate system. One or more functional polymer membranes are applied to a drug core granulated or layered onto a neutral surface through either aqueous or organic solvent-based drug solutions or suspensions. This results in a small, multi-layered bead. Depending on drug pH levels of solubility, either an organic acid or an alkaline buffer layer is incorporated to create an optimal pH. The organic acid layer is placed underneath the drug layer, while the alkaline buffer is placed over the drug layer. Either is coated with one or more functional polymers to ensure that the individual layers are not depleted until release of the drug is complete.
Recent technologies in pulsatile drug delivery systems