INTRODUCTION:

Chronotherapy, a new approach for treating pathological conditions, is based on circadian rhythm. A Coordinating biological rhythms (chronobiology) with medical treatment is called chronotherapy. The knowledge of 24 hr rhythm in the risk of disease plus evidence of 24 hr rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy (chronotherapy). Many diseases are affected by the biological rhythm and show circadian symptoms intensity. One approach to increase the efficiency of pharmacotherapy is the administration of drugs at times at which they are most effective.

Biological rhythms:

A biological rhythm is a self-sustaining process inside the human body. It is defined as the process that occurs periodically in an organism in conjunction with and often in response to periodic changes in environmental condition.

Our bodies' rhythms, also known as our biological clocks, take their cue from the environment and the rhythms of the solar system that change night to day and lead one season into another. Our internal clocks are also dictated by our genetic makeup.

These clocks influence how our bodies change throughout the day, affecting blood pressure, blood coagulation, blood flow and other functions.

There are 4 types of rhythms in our body.

A. Ultradian, which are cycles shorter than a day (for example, the milliseconds it takes for a neuron to fire or a 90-minute sleep cycle)

B. Circadian, which last about 24 hours (such as sleeping and waking patterns)

C. Infradian, referring to cycles longer than 24 hours.

D. Seasonal, such as seasonal affective disorder (SAD), which causes depression in susceptible people during the short days of winter.

Circadian Rhythms:

Biological rhythm within a single day is termed as circadian rhythm. Here, the oscillation time is 24 hours.

Human circadian rhythm is based on sleep-activity cycle, is influenced by our genetic makeup and hence, affects the body’s functions day and night (24-hour period)¹. The dependence of bodily functions in certain disease states on circadian rhythm is well known. However, chronobiological studies have established circadian rhythm for almost all body functions, e.g., heart rate, blood pressure, body temperature, plasma concentration of various hormones, gastric pH and renal function². It has become apparent that rhythmic processes are indispensable for the treatment of human diseases. Just as physiological functions vary over time, pathological states of disease have circadian rhythms.

An inherited master clock network composed of the paired suprachiasmatic nuclei (SCN) controls circadian rhythms. These are placed in the hypothalamus and the pineal gland of the human brain³. The effectiveness and toxicity of many drugs vary depending on dosing time associated with 24 our rhythms of biochemical, physiological and behavioural processes under the control of the circadian clock. Identification of a rhythmic marker for selecting dosing time will lead to advancement in chronopharmacotherapy. To monitor the most appropriate time of day for administration of drugs that may increase their therapeutic effects and/or reduce their side effects⁴.

DISEASES AND CHRONOTHERAPEUTICS:

Up to now, design of drug delivery systems has been governed by the homeostatic theory. This theory is based on the assumption of biological functions that display constancy over time. The potential benefits of chronotherapeutics have been demonstrated in the management of a number of diseases (see table.1).

Some of the conditions, which may be significantly benefited, are given below:

1. Hypertension

2. Myocardial infarction

3. Cerebrovascular accidents

4. Bronchial asthma

5. Arthritis

6. Peptic ulcer

7. Hypercholesterolemia

Hypertension:

The first chronotherapeutic therapy for hypertension and angina pectoris has recently been developed which matches drug delivery to the circadian pattern of blood pressure and rhythm of myocardial ischemia.

Myocardial Infarction:

Onset of myocardial infarction has been shown to be more frequent in the morning with 34% events occurring between 6 A.M. and noon. Acute cardiac arrest and transient myocardial ischemia shows an increased frequency in morning. The causes for these findings have been suggested to be release of catecholamines, cortisol, increase in the platelet aggregation and vascular tone ^5,6.

Cerebrovascular accidents:

The cerebrovascular accidents have been shown to occur on the first hours of morning between 10 A.M. and 12 noons, and the incidence declines steadily during the evening and the midnight.

Bronchial asthma:

Asthma may be the most common disease with the largest circadian variation. Because asthma has such a striking circadian variation, several types of chronotherapy have been tried.

Arthritis:

The new cyclooxygenase-2 inhibitors effectively relieve osteoarthritis symptoms when taken in the morning; better results are obtained in rheumatoid arthritis when part of the dose is taken in the evening⁷.

Peptic ulcer:

In the past, histamine2 antagonists were administered at regular intervals around the clock, on the basis of pharmacokinetic properties. However, because maximal acid secretion, peptic ulcer disease pain, and perforation of gastric and duodenal ulcers are more common at night, administration of these drugs at bedtime is more effective. Nocturnal administration not only reduces acid secretion more effectively but also promotes ulcer healing and reduces ulcer recurrence⁸.

Hypercholesterolemia:

When the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were first introduced, morning dosing was recommended. This strategy was re-evaluated after the discovery of the circadian rhythm of cholesterol biosynthesis, in which higher rates of cholesterol intake and hepatic cholesterogenesis occur during the evening hours, even in the fasting state.

Epidemiological studies have documented the physiological or biochemical function shows a peak (see Fig.1)⁹and elevated risk of disease symptoms during the 24-hour cycle (see Fig. 2)⁹

Figure 1: Display in the form of a 24 hr clock diagram of the approximate time in humans following diurnal activity/ nocturnal sleep, when physiological or biochemical function shows a peak.

Figure 2: Display in the form of a 24 hr clock diagram of the approximate time in humans following the diurnal activity/nocturnal sleep routine, when symptoms or events of diseases are worst or most frequent

Table 1: Target diseases in chronotherapy

Disease	Chronological behavior and symptoms
Asthma	Precipitation of attacks after midnight or at early morning hours.
Cardiovascular diseases	BP lowers during sleep cycle but rises steeply at early morning hours.
Arthritis	Increased conc. of c-reactive protein and interleukin-6 in blood. Pain in early morning compared to day time for rheumatoid arthritis and vice versa for osteoarthritis.
Diabetes mellitus	Increase in blood sugar level after meal.
Attention deficit syndrome	Increase in DOPA level in afternoon.
Hypercholestemia	Increased cholesterol synthesis during night w.r.t day time.
Peptic ulcer	Acid secretion increases in night as well as in afternoon.

PULSATILE DRUG DELIVERY SYSTEM:

Pulsatile drug delivery system is that system which releases the drug rapidly and completely after a lag time at the right place at the right time and in the right amount, thus providing spatial and temporal delivery and increasing patient compliance¹⁰. These systems are designed according to the circadian rhythm of the body. The principle rationale for the use of pulsatile release of the drugs is where a constant drug release is not desired. A pulse has to be designed in such a way that a complete and rapid drug release is achieved after the lag time. Advances in chronobiology, chronopharmacology and requirement of an appropriate technology to deliver the drug at specific time and site resulted into novel drug delivery systems, chronotropic or pulsatile drug delivery systems. The principle rational behind designing these delivery systems is to release the drug at desired time as per the pathophysiological need of disease, resulting in improved patient therapeutic efficacy and compliance. These systems are developed when zero order drug release is not desired. Pulsatile drug delivery systems are designed to release certain amount of drug within a short period of time, immediately after a predetermined lag time (see Fig. 3).

There are many conditions that demand pulsatile release like

a) Many body functions that follow circadian rhythm. e.g.: Secretion of hormones, acid secretion in stomach, gastric emptying, and gastrointestinal blood transfusion.

b) Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology like bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer, and hypertension.

c) Drugs that produce biological tolerance demand for a system that will prevent their continuous presence at the biophase as this tends to reduce their therapeutic effect.

d) Avoiding degradation of upper gastrointestinal tract, e.g. proteins and peptides¹¹.

e) Targeting a drug to distal organs of gastro-intestinal tract (GIT) like the colon requires that the drug release is prevented in the upper two-third portion of the GIT.

f) The drugs that undergo first-pass metabolism resulting in reduced bioavailability, altered steady state levels of drug and metabolite, and potential food drug interactions require delayed release of the drug to the extent possible.

Figure 3: Drug Release Profile Of Pulsatile Drug Delivery Systems

Classification of pulsatile drug delivery systems:

Pulsatile systems can be classified into single- and multiple-unit systems. Single-unit systems are formulated either as capsule-based or osmosis-based systems. Single-unit systems are designed by coating the system either with eroding/soluble or rupturable coating. In multiple-unit systems, however, the pulsatile release is induced by changing membrane permeability or by coating with a rupturable membrane.

Single unit systems: These are sub-classified as capsule-based systems, osmotic systems. Delivery systems with soluble or erodible membranes, and delivery systems with rupturable coating.

Capsule based systems:

Single-unit systems are mostly developed in capsule form. The lag time is controlled by a plug, which gets pushed away by a plug, swelling or erosion, and the drug is released as a “Pulse” from the insoluble capsule body.

Systems based on osmosis:

The Port system was developed by Therapeutic system research laboratory Ann Arbor, Michigan, USA, and consists of a capsule coated with a semi permeable membrane. Capsule insoluble plug of Osmotically active agent and the drug formulation¹². As soon as the capsule came in contact with the dissolution fluid, the semi permeable membrane allowed the entry of water, develop the pressure and the insoluble plug expelled after a lag time. Such a system was utilized to deliver methylphenidate.

Drug delivery system with eroding or soluble barrier coating:

In this systems drug reservoir surrounded a soluble barrier layer that dissolves with time, and the drug releases at once after this lag time. Chronotropic system consists of a core containing drug reservoir coated by a hydrophilic polymer HPMC^13-15. The lag time and the onset of action are controlled by the thickness and the viscosity grade of HPMC. The time clock system is a delivery device based on solid dosage form that is coated by an aqueous dispersion¹⁶. This coating is a hydrophobic- surfactant layer which a water-soluble polymer is added to improve adhesion to the core.

Drug delivery systems with rupturable layers/membranes:

These systems are based upon a reservoir system coated with a rupturable membrane. The outer membrane ruptures due to the pressure developed by effervescent agent or swelling agents.

Multiple Unit Systems:

The units of multiparticulate systems are distributed freely throughout the gastrointestinal systems and their gastrointestinal transport is affected to a lesser extent than sniffle-unit formulations by the transit time of food¹⁷Multiparticulate systems are further classified as systems based upon change in membrane permeability and systems based upon rupturable coating.

Pulsatile system based on change in membrane permeability:

A Sigmoid release system (SRS) is reported which is based upon the interaction of acrylic polymers with quaternary ammonium groups in the presence of different counter ions. SRS system consists of pellet cores having drug and succinic acid coated with ammonio-methacrylate copolymer USP / NF type (B). The water in the medium dissolves succinic acid. The drug inside and the acid solution increase the permeability of the polymer film. This system was used to design an acid – containing core.

Pulsatile systems with rupturable coating:

The rupturing effect is achieved by coating the individual units with effervescent or swelling agents. Bai et al. invented a pulsatile drug delivery system comprising of a plurality of particles that are divided into servra; individual delivery units, each having its own distinct composition. Drug delivery was controlled by the rupture of the membrane. The timing of release was controlled by the thickness of coating and the amount of water-soluble polymer to achieve the pulsed release. The individual particles had the same compositing of internal core. But the thickness of the external coating layer varied ¹⁸.

CHRONOTHERAPEUTIC FLOATING PULSATILE DRUG DELIVERY SYSTEM:

Chronotherapeutics refers to a treatment method in which in vivo drug availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. It is based on the observation that there is an interdependent relationship between the peak-to-trough rhythmic activity in disease symptoms and risk factors, pharmacologic sensitivity, and pharmacokinetics of many drugs¹⁹. As more continues to be learned about chronobiology and chronotherapeutics, it is becoming increasingly more evident that the specific time that patients take their medication may be even more significant than was recognized in the past.

The tradition of prescribing medication at evenly spaced time intervals throughout the day, in an attempt to maintain constant drug levels throughout a 24- hour period, may be changing as researchers’ report that some medications may work better if their administration is coordinated with day-night patterns and biological rhythms in which there is a specificity in delivering higher amount of drug in a burst at circadian timings correlated with specific pathological disorder to achieve maximum drug effect. In these systems there is a transient release of certain amount of drug within a short period of time immediately after a predetermined off-release period.

Floating pulsatile concept is applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. This delivery system is used for the time and site specific release of drugs acting as per chronotherapy of disease.

A chronotherapeutic drug delivery system may be classified as per the function of the dosage form into single pulse system and multiple pulse system. The former as the name suggests releases whole drug from the formulation at one go in a conventional immediate release manner after a well defined lag time which is optimized depending on the peak symptom manifestation of the disease condition such as hypertension, asthma, osteo-and rheumatoid arthritis etc. A single pulse system after a lag time releases majority of the drug in a specific part of the GIT, which may be distal part of the small intestine or the colon depending on the prearranged lag time. A multiple pulse system delivers the drug in divided doses in concomitant pulses to provide advantages such as reduced dose, reduced drug related side effects, improved patient compliance and most importantly as in case of antibiotics better or improved accomplishment of the objective of effectively killing bacteria by not allowing them to develop biological tolerance by switching over to a dormant and more resistant state. A multiple pulse system may be programmed to release fractions of drug in different parts of the GIT viz. stomach, distal jejunum and transverse colon as in case of a three pulse system.

The floating beads provide two- phase release pattern with initial lag time during floating in acidic medium followed by rapid pulse release in phosphate buffer. These drug delivery systems show distinct behavior from other approaches in chronotherapy with desired low drug release in acidic medium, reduced time consumption due to single step process and also overcame the limitations of process variable caused by multiple formulation steps.

To overcome limitations of various approaches for imparting buoyancy hollow/porous calcium pectinate beads were prepared by simple process of acid base reaction during ionotropic cross linking.

RECENT TRENDS IN CHRONOTHERAPEUTIC FLOATING PULSATILE DELIVERY:

Badve et al²⁰ developed hollow calcium pectinate beads for floating-pulsatile release of diclofenac sodium intended for chronopharmacotherapy. Floating pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. This approach suggested the use of hollow calcium pectinate microparticles as promising floating- pulsatile drug delivery system for site- and time-specific release of drugs for chronotherapy of diseases.

Sharma et al²¹ developed a multiparticulate floating pulsatile drug delivery system using porous calcium silicate and sodium alginate, for time- and site-specific drug release of meloxicam. Prepared beads were spherical with crushing strength ranging from 182 to 1073g.

El-Kamel et al²² prepared floating microparticles of ketoprofen, by emulsion solvent diffusion technique. Four different ratios of Eudragit S 100 with Eudragit RL were used. The formulation containing 1:1 ratio of the 2 above mentioned polymers exhibited high percentage of floating particles in all the examined media as evidenced by the percentage of particles floated at different time intervals. This can be attributed to the low bulk density, high packing velocity, and high packing factor.

V G Somani et al²³ developed a floating pulsatile drug delivery system based on hollow calcium pectinate beads of aceclofenac intended for chronopharmacotherapy. Floating pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. This approach suggested the use of hollow calcium pectinate microparticles as promising floating- pulsatile drug delivery system for site- and time-specific release of drugs for chronotherapy of diseases.

Praveen Sher et al²⁴ developed a specific technology, based on combining floating and pulsatile principles to develop drug delivery system, intended for chronotherapy in arthritis. This approach was achieved by using low density microporous polypropylene, Accurel MP 1000^®, as a multiparticulate carrier along with drug of choice ibuprofen.

Huskisson discovered that an evening once-a-day treatment schedule of the NSAID, indomethacin, was much more effective in controlling the prominent morning symptoms of rheumatoid arthritis than a morning one²⁵. Moreover, he found people much better tolerated the medicine and with less complaint of side effects when administered as a single daily dose in the evening than morning.

Akhgari et al studied on the optimum ratio of eudragitl100 and Eudragit S1000 for colonic delivery of indomethacin pellets for chronotherapy of rheumatoid arthritis²⁶.

YH Bae. et al developed indomethacin pulsatile drug delivery system in temperature range of 20°C-30°C by using reversible swelling properties of copolymers of N-isopropyl acrylamide and butyrylacrylamide²⁷.

CONCLUSION:

There is a constant need for new delivery systems that can provide increased therapeutic benefits to the patients. Floating Pulsatile drug delivery is one such system which is intended for chronotherapy of diseases, uses floating principles to deliver the drug at the right time, right place, and in right amounts, holds good promises of benefit to the patients suffering from chronic problems like arthritis, asthma, hypertension. Hence it can be concluded that chronotherapeutic floating pulsatile drug delivery is one of the most suitable drug delivery for the time specific and site specific delivery of drugs.

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Received on 17.12.2010 Modified on 09.01.2011

Research J. Pharm. and Tech. 4(5): May 2011; Page 685-690