Pulsatile Drug Delivery Systems for Chrono therapeutic Applications: Current Approaches and Future Perspectives

Today, a vast amount of Literature reports that biological processes are not Constant but vary according to time. Although Much of drug delivery research has focused on Constant drug release rate due to limitations of Delivering drug according to disease rhythmicity, Clinical studies show that magnitude of rhythmic Differences can be to a great extent and a strong Determinant of when during 24 hour most morbid and mortal event will occur. For many drugs Constant release system is not suitable. Drugs not Suitable for constant release are used in disease Condition that exhibit rhythmic variation within a Circadian cycle. For, drugs with decrease Bioavailability due to first pass metabolism, gradual Release of drug from constant release systems can Result in greater degradation.^[1] The New devlopment delivery systems works on various principle by providing variable /constant drug amount over a particular time period and physiological factors however the body Circadian rhytm and chronotherapy.  Oral controlled drug delivery systems are the most common form of controlled drug delivery Systems which release the ydrug with constant or variable release rates. Indeed, these systems Optimize drug efficacy and reduce adverse effects. Indeed, reduced dosing frequency and Improved patient compliance can be achieved using controlled drug delivery systems, Compared to immediate release preparations.^[2]Conventionally, in oral controlled drug delivery systems, the release of the drug commences, as soon as the dosage form is administered. In addition, there are some specific conditions for Which conventional release pattern is not suitable as it requires some sort of timed release of Therapeutic agents at specific sites. Therefore, there is a need to develop a system which is Capable of releasing drugs after predetermined time delay or lag time and maintain constant Drug release for specified time. These drug deliveries are generally known as pulsatile drug Delivery systems (PDDS), sigmoidal release systems or time-controlled systems.^[3]

There are many conditions that demand pulsatile Release like,

• Many body functions that follow circadian rhythm. E.g: Secretion of hormones, acid secretion in stomach and Gastric emptying.
• Chrono pharmacotherapy of diseases which shows Circadian rhythms in their pathophysiology like Bronchial asthma, myocardial infarction, angina Pectoris ,rheumatic disease, ulcer, and hypertension
• The lag time is essential for the drugs that undergo Degradation in gastric acidic medium (e.g: peptide Drugs) and irritate the gastric mucosa or induce nausea  And vomiting.^[3]

       The drugs that undergo first-pass metabolism Resulting in reduced bioavailability, altered steady state Levels of drug and metabolite, and potential Fooddruginteractions require delayed release of the drug to The extent possible.^[4]

Pulsatile Drug Delivery Systems:

 The pulsatile effect, i.e., the release of drug as a “pulse” after a lag time has to be designed in Such a way that a complete and rapid drug release should follow the lag time. Such systems Are also called time-controlled as the drug released is independent of the environment. These systems are designed in a manner that the drug is available at the site of action at the right Time in the right concentration.[2] Pulsatile drug delivery system is most intresting time and site specific system as per Pathophysiological need of the disease. Pulsatile drug delivery system is characterized by Time of period of no release(lagtime) fallowed by a rapid and complete drug release. The drug Release was influenced by type of pulsatile delivery system there was employed in Formulation(capsular system, osmatic system, rupturable polymeric coating). The lag time Was reduced by replacing the swelling agents and disintegrating agents. By reducing the lag Time the drug release was done before the actual time of release.^[3,4]

Circadian Rhythms :

It is defined as Self-Sustaining, Endogenous oscillations that occur with a periodicity of about 24Hours. Interestingly, the term circadian is derived from the latin circa which means About and Dies Which Can Be defined as?A Day. Normally, circadian Rhythms Are Synchronized According to Internal Biologic Clocks Related to the Sleep-Wake cycle. Circadian rhythms are self-sustaining endogenous, exhibiting periodicities of about one day or 24 h. normally circadian rhythms are synchronized according to the body’s pacemaker clock located in suprachiasmic nucleus of hypothalamus. The physiology and biochemistry of a human body is not same everyday but variable in a predictable manner as defined by the timing of the peak and trough of each of the body’s circadian processes and functions. There are many documents that verify that more chances of heart attacks occur during the early morning time, as levels of cortisol and blood pressure are high in early morning and low in the night. Indeed, nocturnal asthma increased responsiveness in early morning and there is a sudden surge of gastric acidity in the mid night. Moreover, high cholesterol synthesis occurs at night than in the daytime. All these events associated with the circadian rhythms, gives the importance for designing time specific drug delivery which is very important.^[5] 

NECESSITIES OF PULSATILE DDS :

1. First pass metabolism: Some drugs, such as beta blockers, and salicylamide, undergo extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize pre- systemic metabolism. Thus, a constant/sustained oral method of delivery would result in reduced oral bioavailability.
2.  Biological tolerance: Drug plasma profiles are explain by a decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal nitroglycerin, salbutamol sulphate.
3.  Special chrono special chrono pharmacological needs: Circadian rhythms in certain physiological functions are well established. It has been recognized that many symptoms and onset of disease occur during specific time periods of the 24 hour day, e.g., asthma and angina

pectoris attacks are most frequently in the morning hours.

4.  Local therapeutic need: For the treatment of local disorders such as inflammatory disease, the delivery of compounds to the site of inflammation with no loss due to absorption in the small intestine is highly desirable to achieve the therapeutic effect and to minimize side effects.
5.  Gastric irritation or drug instability in gastric fluid : Protection for those drugs are essential which are effected by gastric acidic environment and undergo degradation in gastric acidic medium (eg, peptide drugs), irritate the gastric mucosa (NSAIDS) or induce nausea and vomiting.^[5]

Advantages of Pulsatile Drug Delivery System.

? It extended day time or night time activity.

? Less side effects.

? Less dose size and dosing frequency.

? Good patient compliance.

? Improve bioavailability

? Drug adapts to suit circadian rhythms of body functions or diseases.

? It targets specific site like colon.

? It protects mucosa from irritating drugs.

? Drug loss is prevented by extensive first-pass metabolism.^[3]

 Disadvantages of Pulsatile Drug Delivery System:

? Lack of manufacturing reproducibility and efficacy .

? More formulation Process .

? Expensive .

? Need of advanced technology with an advance instrument.

? In-vivo variability in single unit pulsatile drug delivery system.^[4,5]

CLASSIFICATION OF PULSATILE DRUG DELIVERY SYSTEMS^[6]

 Pulsatile drug delivery system is classified into four classes:

A. Time controlled pulsatile release

1. Single unit system

    i. Capsular system

                      ii. Port system.

   iii. Delivery by solubility modulation.

   iv. Delivery by solubility modulation.

   v. Delivery by reservoir systems with erodible or soluble barrier coatings.

B. Multi-particulate system

  i. Pulsatile system based on rupturable coating.

 ii. Time controlled expulsion system.

 iii. Pulsatile delivery by change in membrane permeability.

 iv. Sigmoidal release system.

 v. Low density floating multi particulate pulsatile systems

.C. Stimuli induced

1. Chemical stimuli induced pulsatile systems

2. External stimuli pulsatile release

3. Micro electro mechanical systems (MEMS)

4. Magnetically induced pulsatile release

5. Pulsatile release systems for vaccine and hormone products

    A . TIME CONTROLLED PULSATILE DRUG DELIVERY

I. Single unit systems

1. Capsular Systems: The majority of single-unit systems are developed as capsules form. The plug is removed after the pre determined lag time due to swelling ,erosion or dissolution. Pulsincap is one such method that consists of a water insoluble capsule enclosing the drug reservoir and was developed by R. P. Scherer International Corporation in Michigan, United States. When this capsule comes into contact with the dissolution fluid, it expands, and the plug pushes itself outside the capsule after a lag time, and releasing  the drug rapidly.^[4]

Fig 2: schematic diagram of capsular system

2. Port systems: Therapeutic system research laboratory in Ann Arbor, Michigan ,USA, developed the port system . The Port System - consists of a gelatin capsule coated with a semi permeable membrane (e.g: cellulose acetate) housing an insoluble plug (e.g: lipidic) and an osmotic ally active agent along with the drug formulation. When it comes in pressure that ejects the plug after a- time lag.^[5]

Fig 3: Drug release mechanism from PORT system

3. 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.

4. Delivery by solubility modulation: These systems contain a solubility modulator for pulsed delivery of variety of drugs. The system was especially developed for delivery of salbutamol sulphate. The compositions contain the drug (salbutamol sulphate) and a modulating agent, sodium chloride (NaCl). The amount of NaCl was such that it was less than the amount needed to maintain saturation in a fluid that enters the osmotic device. 

5. Delivery by reservoir systems with erodible or soluble barrier coatings: Most of the pulsatile drug delivery systems are reservoir devices coated with a barrier layer. This barrier erodes or dissolves after a specific lag period, and the drug is subsequently released rapidly. The time lag depends on the thickness of the coating layer.^[5]

B. Multi particulate Systems: Multi-particulate drug delivery systems are mainly oral dosage forms consisting of a multiplicity of small discrete units, in which the active substance is present as a number of small independent subunits. There are different types of multi particulate systems and these are enumerated and explained below.

1. Pulsatile System Based on Rupturable Coating: This is a multi particulate system in which drug is coated on non-pareil sugar seeds followed by a swellable layer and an insoluble top layer.
2. Time controlled expulsion system: This system is based on a combination of osmotic and swelling effects. The core contains the drug, a low bulk density solid and/or liquid lipid material (e.g., mineral oil) and a disintegrant. The core is further coated with cellulose acetate. Upon immersion in aqueous medium, water penetrates the core displacing the lipid material. After the depletion of lipid material, internal pressure increases until a critical stress is reached, which results in rupture of the coating material Another system is based on a capsule or tablet composed of a large number of pellets.
3. Pulsatile Delivery by Change in Membrane Permeability: The presence of different counter-ions in the medium can influence the permeability and water uptake of acrylic polymers containing quaternary.
4. Sigmoidal Release System: This consists of pellet cores comprising drug and succinic acid coated with methacrylate copolymer USP/NF type B. The time lag is controlled by the rate of water influx through the polymer membrane. The water dissolves acid and the drug in the core. The acid solution in turn increases permeability of the hydrated polymer film ammonium groups. On the basis of this ion exchange, several delivery systems have been developed.
5. Low density floating multi particulate pulsatile systems : Conventional multi particulate pulsatile release dosage forms mentioned above are having longer residence time in the gastrointestinal tract and due to highly variable nature of gastric emptying process may result in in vivo variability and bioavailability problems.^[6]

 C. Stimuli Induced

1. Chemical stimuli induced pulsatile systems: Glucose-responsive insulin release devices: 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.

I. Inflammation-induced pulsatile release During inflammation ,hydroxyl radicals are produced from these inflammation-responsive cells. Degradation via hydroxyl radicals however, is usually dominant and rapid when Hyaluronic Acid gel is injected at inflammatory sites.

II. Temperature induced systems: 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.^[6]

2. External stimuli pulsatile release: Electrically responsive delivery systems are prepared from polyelectrolytes (polymers which contain relatively high concentration of ionizable groups along the backbone chain) and are thus, pH responsive as well as electro-responsive.

3. Micro electro mechanical systems (MEMS): A micro fabricated device has the ability to store and release multiple chemical substances on demand by a mechanism devoid of moving its parts. The microchip consists of an array of reservoirs that extend through an electrolyte-impermeable substrate.^[7]

4. Magnetically stimulated pulsatile system: In this system magnetic steel beads can be embedded in a polymer matrix with model drug. During exposure to the magnetic field, the beads oscillate within the matrix, alternatively creating compressive and tensile forces.^[8]

MARKETED TECHNOLOGIES OF PULSATILE DRUG ^[9]

Table:  Marketed Products of Pulsatile Drug Delivery