Pulsatile Drug Delivery: A Leading Advent to Chronopharmacotherapy
Dr. N.Kanaka Durga Devi, Assistant Professor, K.V.S.R Siddhartha, College of Pharmaceutical Sciences
B.Sai Mrudula, Research Associate,K.V.S.R Siddhartha, College of Pharmaceutical Sciences

Unlike controlled drug delivery systems that provide constant drug levels over an extended period of time, Pulsatile Drug Delivery System (PDDS) releases the drug rapidly and completely after a lag time. The main advantage of PDDS is that it can be used to treat diseases that mainly follow circadian rhythms.

Pulsatile Drug Delivery System(PDDS) is defined as the rapid and transient release of drug molecules within a short time period immediately after a predetermined off-release period, i.e., lag time. It can show an ideal sigmoidal curve or delayed release after initial lag time. The term Chronopharmacotherapy can be split in to chronopharmacology and chronokinetics. Chronopharmacology involves the study of the effects of the drugs as a function of biological timing whereas chronokinetics refers to rhythmic changes in bioavailability, absorption, distribution, metabolism and excretion of drug. The diseases that can be justified by the PDDS include Asthma, Allergic rhinitis, Rheumatoid arthritis, Osteoarthritis, ulcers, myocardial infraction, hypercholesrolemia.

Conditions that Demand PDDS:
  1. During the cases of bronchial asthma, myocardial infraction, angina pectoris, rheumatic disease, ulcer, and hypertension where they usually display time dependence.
  2. PDDS can give a promising platform for those drugs which produce biological tolerance where usually demands the prevention of drugs continues presence in at the biophase which cause decrease in the therapeutic effect.
  3. For those drugs which undergo degradation in gastric acidic medium and those drugs which irritate gastric mucosa and showing side effects like nausea and vomiting.
  4. For targeting a drug to distal organs of GIT, where the prevention of the drug release in the upper two third portions is the basic requirement .
  5. PDDS will comfort those drugs that undergo extensive first pass metabolism.
Various Approaches of PDDS:
PDDS are generally classified in to time controlled and site specific delivery systems.

The release from the first group is primarily controlled by the system while the release from the next one is by the biological environment in the gastro intestinal tract such as pH or enzymes.

PDDS methodologies can be broadly classified in to three classes. Time controlled, Stimuli controlled and Externally regulated systems.

A) Time Controlled Systems:
Here the drug will be released only after a specified predetermined time. These include single unit and multiple unit pulsatile systems.

a) Single unit pulsatile systems:
In these systems the drug is released at a time following a predetermined lag period consisting of capsular and tablet based systems and implants.

Capsular based systems:
  1. Capsular system with a swellable plug: It consists of an insoluble capsule body with drug and swellable plug. Usually the outer capsule body is coated with ethyl cellulose in order to render it impermeable. The moulded hydrogel plug seals the drug contents within the capsular body.
  2. Capsular system based on osmosis: It contains a gelatin capsule coated with a semi permeable membrane, an insoluble plug or a non swellable slider partition and an osmotic charge with in the capsule shell. On contact with aqueous media, water diffuses across the semi permeable membrane resulting in an increased inner pressure and causes ejection of the plug or slider partition after a certain lag time. The lag time can be altered by modifying the thickness of the semi permeable layer and use of different non swellable separators.
  3. Capsular systems based on expandable orifice: This is mostly recommended for liquid formulations and these liquid formulations mostly favour delivery of insoluble drugs and certain macromolecules such as polypeptides and polysaccharides.
  4. Delivery by a Series of Stops: This system is described for implantable capsules. The capsule contains a drug and a water-absorptive osmotic engine that are placed in compartments separated by a movable partition. The pulsatile delivery is achieved by a series of stops along the inner wall of the capsule. These stops obstruct the movement of the partition but are overcome in succession as the osmotic pressure rises above a threshold level . The number of stops and the longitudinal placements of the stops along the length of the capsule dictate the number and frequency of the pulses, and configuration of the partition controls the pulse intensity.
  5. Pulsatile delivery by Solubility modulation: The pulsed delivery can be based on drug solubility for any of the drug candidates. Some drugs are freely soluble where as some are sparingly soluble and can even be insoluble . Depending on the requirement for pulsatile drug delivery the solubility of the drug candidates can be modified.
Tablet based systems:
  1. Systems with erodible or soluble coatings: In these systems the drug release is controlled by the dissolution or erosion of the outer coat which is applied on the core containing the drug. The lag time can be varied by varying the thickness of the outer coat. In this system two subtypes are included. They are time clock system and chronotropic system.
  2. Systems with rupturable barrier coatings: Here the core is coated with a rupturable membrane and it usually ruptures due to the pressure developed by the swelling agents or osmotic agents or effervescents that are present within the core.
Implants:
These are drug delivery systems that are usually placed subcutaneously by a large bore needle, pellet injectors or minor surgery.
  1. Bulk-eroding systems: An example would be an implant of an antigen consisting of a compressed core of antigen in Emcompress® coated with a Eudragit S100(enteric coated polymer) then a blend of PLGA: ethylcellulose (EC). Penetration of water through the coating is dependent on the degradation of the PLGA and subsequent formation of pores, which delay it by 60–90 days before the release of a model antigen (vitamin B12).
  2. Surface-eroding systems: Poly (ortho) ester and polyanhydride polymers are used in these systems as they show surface eroding property. Pulsatile release of a model protein (lysozyme, molecular weight 14 000) has been described by incorporation into poly (ortho ester) matrices. The in vitro release of model low-molecular weight dyes, brilliant blue and carboxyfluorescein, in two pulses, one immediately and the second after 2 weeks was also demonstrated. The release took place through a device that was cylindrical in shape and consisted of a compressed core of drug in a fast-eroding polyanhyride.
b) Multiple unit pulsatile systems:
These releases the drug in more pulses and these are more advantageous than the single pulse systems as they involve no risk of dose dumping. They also offer advantages such as decreased intra and inter subject variability showing flexible release patterns.

B) Stimuli Controlled Systems:
These are intelligent drug delivery systems, demonstrating an ability to sense external environmental changes, judge the degree of external signal, and release appropriate amounts of drug. These systems show release of the drug after stimulation by a biological factor like temperature or any chemical stimuli. These are said to be closed loop delivery systems that means they respond to changes in local environment such as presence or absence of a specific molecule and there fore self regulating.

a) Thermo responsive hydrogel systems:
These follow the principle of the temperature induced systems. They show swelling and deswelling phases in response to the temperature modulations .

b) Chemical stimuli induced pulsatile systems:
In case of 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 causes a change in the pH of the system.

c) Inflammation - induced pulsatile systems:
On receiving any physical or chemical stress, such as injury, fracture etc., inflammation takes place at the injured sites. During inflammation, hydroxyl radicals are produced from these inflammationresponsive cells. In pH sensitive drug delivery systems such type of pulsatile drug delivery system contains two components one is of immediate release type and other one is pulsed release which releases the drug in response to change in pH.

C) Externally Regulated Systems:
These are said to be open loop systems which are not self regulating and require externally generated changes like magnetic fields, ultrasound, electric field, light and mechanical forces to initiate drug delivery.

There are many drug carriers that work on the principle of stimuli controlled and externally regulated systems. These drug carriers are mainly Nanomaterials. Nanomaterials have a relatively larger surface area which can make materials more chemically reactive and they show increased quantum effects like optical, electrical and magnetic behavior of materials.
Other targeting drug carriers:
• Dendrimers
• Liquid crystals
• Nanoparticles
• Nanoclinics
• Nanoshells
• Cantilevers
• Quantam dots

Micelles:
Micelles are nanomaterials formed by self assembly of amphiphilic block copolymers of size range of 5-50 nm in aqueous solutions. Here the drugs are physically entrapped in the core of block copolymer micelles.

  1. Thermo sensitive micelles: A very elegant approach to improve temporal control involves the use cross linked of block copolymers where one of the segments possesses a lower-critical solution temperature (LCST). Below their LCST, polymers such as poly(N-isopropylacrylamide) (PNIPAAm) are water -soluble, while raising the temperature of an aqueous solution above the LCST results in phase separation. These are said to be thermo sensitive micelles.
  2. Ultrasound-responsive micelles:Another approach to improve temporal control was ultra sound - responsive micelles. One of the examples is the PLAb-PEG copolymer micelles prepared by Hongji Zhang et al. The release behavior of these micelles is based on the applied High intensity focused ultrasound (HIFU). They prepared biodegradable PLA-b-PEG copolymers and self -assembled them into spherical micelle in aqueous solution. They used hydrophobic Nile Red, as a payload model to examine the release behavior of the micelles. They found that the release behavior of encapsulated Nile Red was triggered by HIFU.
Liposomes:
Liposomes are small artificial vesicles of spherical shape that can be produced from natural nontoxic phospholipids and cholesterol. Because of their size, hydrophobic and hydrophilic characters and biocompatibility, liposomes are promising systems for drug delivery.
  1. Enzyme sensitive liposomes: The hydrogel matrix which is hydrophilic was designed to protect the liposomes from degradation. To achieve a pulsatile release of drug molecules the liposomes inside the microcapsules are coated with phospholipase A2. Phospholipase A2 is known to gather at the water/liposome interfaces and remove an acyl group from the phospholipid in the liposome, resulting in the destabilization of the liposome which results in release of the drug molecules from the interior, thus allowing drug release to be regulated by the rate determining microcapsule membrane.
  2. Ultrasound-responsive liposomes: Echogenic targeted liposomal complex can incorporate drugs and deliver them directly to cells. Rhodamine-labeled echogenic liposomes (Rh-ELIP) containing nanobubbles are delivered to the arterial wall, to check whether 1-MHz continuous wave ultrasound enhances the delivery profile.
LIMs:
Liposomes-in-micro sphere (LIM) made of biodegradable polymers, is conceived from a combination of the polymer and the lipidbased delivery systems and can integrate the advantages and avoid the drawbacks of the two systems. They demonstrated that a decrease in the particle size of liposomes and increase in the pore size of the polymeric matrix shortened the initial offrelease period and increased the liposome release rate.

Dendrimers:
Dendrimers are nanometre-sized, polymer macromolecules. They consist of a central core, branching units and terminal functional groups. The core chemistry determines the solubilizing properties of the cavity within the core, whereas external chemical groups determine the solubility and chemical behavior of the dendrimer itself. Targeting is achieved by attaching specific linkers to the external surface of the dendrimer which enable it to bind to a disease site, while its stability and protection from phagocytes is achieved by decorating the dendrimers with polyethylene glycol chains.

Liquid Crystals:
Liquid Crystals combine the properties of both liquid and solid states. Liquid crystals can be made to form into different geometries, with alternate polar and non-polar layers (i.e., lamellar phases), within which aqueous drug solutions can be incorporated.

Hydrogels:
Hydrogels are three-dimensional polymer networks that swell but do not dissolve in aqueous media. They are said to be carriers of swelling -controlled based.
  1. Thermo sensitive hydrogels: PIPAAm cross-linked gels are one of the examples of hydrogels that have shown thermoresponsive, discontinuous swelling and deswelling phases. Further a similarly rapid deswelling phase was achieved by incorporating poly ethylene glycol (PEG) graft chains into PIPAAm cross-linked hydrogels.
  2. Enzyme sensitive hydrogels: Yui et al. recently reported the development of a new drug delivery device based on hydrogel. They tested the drug release form PEG-grafted dextran gel combined with an ungrafted dextran gel in a multi-layer structure located within an impermeable silicone tube exhibiting an open end at both sides.
Nanoparticles:
These include nanoclinics, nanoshells, cantilevers, polymeric nanoparticles, nanocrystals.
  1. Nanoclinics: These are one of the multifunctional Nanodevices, which mostly help in targeted drug delivery. Until now these were used as a successful approach in killing malignant cells.
  2. Nanoshell: These are nanodevices that consist of core of silica and a metallic outer layer of usually gold. By manipulating the thickness of the layers making up the nanoshells, the beads can be designed that absorb specific wavelength of light and mostly they absorb near infrared region light that can easily penetrate several centimeters in human tissues. Absorption of light by nanoshell creates an intense heat that is lethal to cells. Because of their size nanoshells will preferentially concentrate in cancer lesion sites due to the EPR (Enhanced permeability and Retention effect).
  3. Cantilevers: They are microfabricated drug delivery devices that consist of tiny bars usually made of silicon built by the semiconductor lithographic techniques. These can be targeted toward specifically expressed proteins of the tumor cells. As cancer cells secrete its molecular products, the antibodies coated on the Cantilever fingers selectively binds to these secreted proteins. Thus the selectivity of these cantilevers is more and the drug can be easily administered to the targeted cells.
Hydrogel nanoparticles:
Hydrogel nanoparticles have gained considerable attention in recent years as one of the most promising nanoparticulate drug delivery systems owing to their unique potentials via combining the characteristics of a hydrogel system with a nanoparticle.

Molecularly Imprinted Polymers (MIP):
Molecularly imprinted polymers have an enormous potential for drug delivery systems. By following the MIP technology the drug delivery can be modulated to rate programmed drug delivery, where drug diffusion from the system has to follow a specific rate profile or activation modulated drug delivery. The release is either activated by some physical, chemical or biochemical processes or is due to feedback regulated drug delivery, where the rate of drug release is regulated by the concentration of a triggering agent, which is activated by the drug concentration in the body.

Microelectromechanical Systems(MEMS) :
The delivery systems under this category work either on the basis of implantable technology or are oral delivery systems or injectable. Microfabrication techniques are used to produce these MEMS.
  1. Neural implants: These are used for neural stimulation, recording of neural activities. The system consists of the surgically implanted module, an external computer system that is used by the physician to program the module through induction, and an external switch that the patient uses to activate the device.
  2. Drug-coated stents: Stents are one method by which the size of arteries can be increased in patients with heart disease and narrowing of the arteries. These are also implantables. But these have certain disadvantages like hyperplasia and restenosis. One novel approach that has been suggested for improving the performance of stents and decreasing the incidence of restenosis is to use microfabricated silicon microprobes to deliver therapeutic agents to the arterial wall.
  3. Micro reservoirs: These devices could be used for oral drug delivery , with release of the drug triggered by binding of a surface -functionalized molecule to cells in the digestive tract, or the devices could be injected for intravenous distribution.
  4. Mini and micropumps: Minipumps offer greater temporal dosing flexibility and reduction of instability and hypoglycemia to patients who are poorly controlled with subcutaneous insulin injections or have recurrent hypoglycemia.
  5. Biosensors: Sensors are implantables and one of the components of MEMS based integrated drug delivery systems. Sensors are mainly used for monitoring pH, analytes, and pressure of tissues, blood, and body fluids where as Immunosensors are used in a variety of medical diagnostic tests to analyze clinically important analytes that are often present in very low concentrations. The main principle involved with these immunosensors was binding interactions between an antibody and antigen which results in detectable signals.
Meshes:
These are multilayered drug loaded biodegradable nanofiber meshes that enable time-programmed dual release in a single formulation using sequential electrospinning. It consists of first drug loaded mesh (top), barrier mesh, second drug loaded mesh and basement mesh(bottom). They have some unique features such as a high surface-area-to-volume ratio, flexibility of morphological designability, and an extra cellular matrix-like structure. They demonstrate the time programmed drug release by using these multilayered electro spun nanofiber meshes.

Conclusion
In the present review, we described the various approaches for pulsed drug delivery systems. Various drug carriers can be modulated to better disease markers and immunological and toxicological screeners by flexible engineering of various polymers and hydrogels which help in passive and active targeting of the disease sites and also nourish pulse drug delivery pursuing Stimuli and External regulated concepts. Thus combined approach of drug carriers with sigmoidal and controlled release concepts of PDDS put together the benefit of targeting as well as pulse release.