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The main aim of research of drug delivery is to development of new formulations which helps to acheive therapeutic efficacy related to particular pathological conditions. Up to late 1980s the homeostatic theory governing design of drug delivery systems, the homeostatic theory is totally based on the assumption of biological functions which display constancy over time. The significance of biological rhythms in drug treatment can be demonstrated by chronopharmacological research. If drug plasma concentrations are constant then it is difficult to achieve optimal clinical outcomes. If symptoms of disease display circadian variations, drug release should also vary over time. Formulations be supposed to be reasonable by biopharmaceutical and pharmacokinetic study in arrange to decide the best hour for management. Another point raise by circadian difference of physiological purpose is that drug pharmacokinetics preserve be time dependent. Variables in physiological and pathophysiological functions in time, also need for variations of drug plasma concentration having a approach for the development of new drug delivery system i. e. chronopharmaceutical drug delivery.
In chronopharmacotherapy, drug administration is synchronized with circadian rhythms. If the peak of symptoms occurs at day, a usual dosage form can be administrated just before the symptoms are worsening. If symptoms of the disease become poorer throughout the night time or in the early on morning, the time of drug administration and the character of the drug delivery system require cautious consideration. In this case, modified release dosage forms must be used.1
The human body has many built in rhythms known as biological clocks. Broadly, these can be classified as Ultradian, Circadian, Infradian and Seasonal. Ultradian cycles are shorter than a day, e.g. time taken for a nerve impulse to be transmitted. Circadian cycles last about 24 hours, e.g. sleeping and waking patterns. Infradian cycles are longer than a day, e.g. menstrual cycle. Recently, the role of these rhythms in fighting disease and responding to medication has come under study by researchers and scientists. The coordination of medical treatment and drug delivery with such biological clocks and rhythms is termed Chronotherapy.
To initiate the concept of chronopharmaceutics, it is significant to describe the concept of pharmaceutics and chronobiology. The biological rhythms and their mechanisms can be studied with the help of Chronobiology. Biological rhythms are definite by a quantity of character. The term "circadian" was coin by Franz Halberg starting the Latin circa, meaning regarding, and dies, meaning day. Oscillations of shorter period are term ''ultradian'' (additional than one cycle per 24 hours). The oscillations that are longer than 24 hours are ''infradian'' (less than one cycle per 24 hours) rhythms. Ultradian, circadian, and infradian rhythms coexist on all level of biologic association.3
Chronobiological studies haing good corelationship with a circadian rhythm of all body functions. They are in synchrony with sleep activity cycle of the individual. The rhythms tend to fall into two groups. In the first are those that peak during the daytime and are associated with the activity phase of the individual: body temperature, mental, physical and gastrointestinal activities, blood pressure, heart rate, secretion of adrenaline etc. The second group, where rhythms show a peak during nocturnal sleep, includes secretion of several hormones, among which are growth hormone, cortisol and melatonin. Beside the physiological functions, the pathological states of disease have also circadian rhythms. Results of several epidemiological studies demonstrate the elevated risk of different pathology during a 24 hour cycle.1
Pharmaceutics is the branch of pharmaceutical sciences as well as biomedical sciences which deals with the study of designing and evaluation parameters of different drug delivery systems to promise their security, efficiency, excellence and consistency. Traditionally, drug delivery has meant receiving a simple chemical absorbed as expected from the gut or from the site of inoculation. A second generation drug delivery syatem having goal of the perfection of continuous release, zero order rate constant delivery of different bioactive agents. However, living organisms does not show zero order rate constant in their requirement or response to drugs. This is the predictable resonating dynamic system. This system requires a different amounts of drug at variable times within the circadian cycle to maximize the desired as well as minimizes undesired drug effects.4
Based on the previous definitions "chronopharmaceutics is defined as the designing and evaluation of different drug delivery systems that releases a bioactive agent at a rhythm when it requires and match the biological prerequisite of a known disease therapy."5
Preferably, chronopharmaceutical drug delivery systems (ChrDDS) should represent time controlled and site specific drug delivery systems. Advantages are secure, more efficient and consistent therapeutic effect taking into account advance in chronobiology and chronopharmacology, systems biology and Nanomedicine. Evidence suggests that an ideal ChrDDS should:
Be nontoxic within approved limits of use,
Have a real time and a specific triggered biomarkers for that disease state,
Having feedback control system (e.g. Self regulated and adaptive capability with respect to circadian rhythm and to differentiate between awake sleep status of individual patient),
Be biocompatible and recyclable, especially for parenteral administration,
Be easy to manufacture at an economic cost, and
Be easy to administered in the patients in order to increase the compliance to dosage regimen.
To our information, such perfect ChrDDS is not up till now available on the market. The popular of these functions may be found at the edge of Chronobiology, chronopharmacology, systems biology and Nanomedicine. Figure 1 presents the overview of most serious diseases displaying significant daily variations.
Figure 1: Disease Displaying Circadian Rhythm.
Many of circadian dependent diseases displays acute symptoms in the early morning hours or in the morning at awaken6 most asthma attack occur at 04:00 to 06:00 hours. Nocturnal asthma is a multifaceted relations of several coincident circadian rhythms e.g. discharge of hydrocortisone and adrenaline. Ischemic heart diseases, such as angina pectoris, myocardial infraction and stroke manifests more frequently during the night or in the morning before breakfast. Rapid increase in blood Pressure is mostly responsible for these attacks. In hypertensive and also in normotensive individuals, the blood pressure rises notably before awakening. Symptoms of rheumatoid arthritis and osteoarthritis have significant circadian rhythm. Stiffness and pain are greatest on awakening or in the early morning. Circadian rhythm of level of interleukin 6 is in good correlation with the rhythm of symptoms of rheumatoid arthritis. Dyspnoea and peak of expiratory flow values have been establish to develop into poorer during the night.1
Pharmacokinetics deals with absorption, distribution, metabolism and elimination of drugs. The different steps in pharmacokinetics are determined and influenced by physiological functions of the body. Pharmacokinetic parameters such as peak drug concentration (Cmax), time to Cmax (Tmax), and volume of distribution, area under the curve, bioavailability, and plasma protein binding and elimination half life are conventionally not considered to be influenced by the time of day. However, this paradigm can no longer be justified as it has been convincingly demonstrated that bodily functions, including those influencing pharmacokinetics, are not constant in time. Numerous studies in man and in experimental animals have provided convincing evidence for the existence of daily or circadian (driven by an internal clock) rhythms. In nearly every physiological function such as blood flow, stroke volume, peripheral resistance, parameters monitored by ECG recordings, in the plasma concentrations of hormones such as cortisol, melatonin, insulin, prolactin, nor adrenaline, renin, angiotensin, aldosterone, in atrial Natriuretic hormone and plasma cAMP concentration, in blood viscosity, aggregability and fibrinolytic activity, plasma concentration of glucose, electrolytes, plasma proteins, enzymes, and in the number of circulating red and white blood cells and blood platelets. Moreover, various functions of the lung of the liver and of the kidneys can vary pronounced with time of day. Also gastric acid secretion exhibits a circadian variation with peak values in the late afternoon in normal subjects as well as in patients suffering from peptic ulcer disease. Moreover, the onset and symptoms of certain diseases do not occur at random within the 24 hour cycle. As early as 1698 John Floyer (1698, 1761) reported that asthma attacks are more frequent during the night time hours than at other times of the day, an observation which has nicely been confirmed in modern epidemiological studies in asthmatic patients. Similarly, the occurrence of coronary infarction, sudden cardiac death as well as of angina pectoris attacks and of pathological ECG recordings is unevenly distributed over the 24 hours. In animal experiments significant circadian rhythms have been demonstrated at the cellular and sub cellular level of various neurotransmitter receptors, signal transduction processes and enzyme activities. Moreover, the genetics of the circadian clock have been demonstrated in Drosophila melongaster, Neurospora, the golden hamster and the mouse.
All functions involved in the pharmacokinetic steps from drug absorption in drug elimination can be circadian phase dependent. Thus, gastric emptying time of solids is faster in the morning than in the afternoon. Also, the perfusion of the gastrointestinal tract varies with time of day, being more pronounced at midnight and the early morning hours than around noon and in the late afternoon. Since drugs are mainly absorbed by passive diffusion these rhythmic patterns must have implications for the pharmacokinetics. These observations would nicely explain why, in general, drugs are more rapidly absorbed and more rapidly reach the systemic circulation when taken in the morning. Accordingly, clinical studies showed mainly for lipophilic drugs that tmax can be shorter and Cmax can be higher after morning than evening drug dosing. Some data are compiled in Table 1.
As mentioned above, the onset and the degree of certain diseases can be circadian phase dependent as shown for bronchial asthma, myocardial infarction, angina pectoris (including silent ischemia), rheumatic disease, ulcer disease, and for the 24 hours blood pressure profile in essential hypertension (dippers) and the disturbed pattern in forms of secondary hypertension (non dippers, e.g. in renal and endocrine diseases, gestation).
Since both the need for an adequate drug concentration and the dose response relationship can be dependent on the time of day, it is conceivable that the pharmacokinetic profile at the given time of day has implications for drug treatment. Thus, it has been nicely shown that in nocturnal asthma, evening dosing of theophylline or Î² agonists can be of advantage in treating the asthma attacks. Histamine2 receptor antagonists for ulcer disease are recommended for evening dosing. In dippers, antihypertensive drugs are in general dosed in the morning, whereas in the non dippers evening dosing might not only reduce high blood pressure.
Finally, non steroidal anti inflammatory drugs (NSAIDs) (Table 1) may be better given in the evening when treating rheumatic patients.
Table 1: Chronokinetics after morning (AM) Vs evening (PM) dosing.
Cmax (Âµg L-1)
IS 5 MN i. r.
IS 5 MN s. r.
Nifedipine i. r.
Nifedipine s. r.
Verapamil i. r.
Verapamil s. r.
A. M. â‰¥ P. M.
A. M. â‰¤ P. M.
A. M. â‰¥ P. M.
A. M. < P. M.
*P<0.05, a significant difference in half life.
IS 5 MN = isosorbide dinitrate,
i. r. = immediate release,
s. r. = sustained release.
TIME CONTROLLED RELEASE DOSAGE FORMS
Oral drug delivery is the most popular and convenient form of the drug administration. Evaluation of oral solid dosage forms on the basis of dissolution profile:
From 1950s. Conventional (immediate release) dosage forms
From 1960s. Prolonged release (sustained release) dosage forms
From late 1980s. Pulsatile or prolonged release dosage forms following a lag period.
There are different advantages of modified release formulations over immediate release formulations. With these formulations at less frequent drug administration is a possible, lower peak concentration can be obtained to keep away from unfavorable effects and patient fulfillment can be improved. The modified release dosage forms can be separated into subgroups of rate controlled release, tardy release and pulse release formulations. Retarded release formulations includes site specific dosage forms and time controlled release. Time delayed delivery system (time controlled release formulations and pulsed release formulations) is the best approach to deliver drugs in accordance with the circadian rhythms of the disease. The mentioned approach serves a purpose particularly in the treatment of in the early hours symptoms. By time the drug management, at an optimal time plasma peak can be ontained. Per day dose frequency can be condensed. When there are no symptom, there is no require intended for drugs. Saturable presystemic metabolism and development of tolerance can also be avoided.8
When sampled with sufficient frequency over 24 hours the physiological and pathological rhythms a sigmoidal curve can be observed. The main goal of the scientists working on the evaluation of chronopharmaceutical drug delivery systems is to work out the formulations which plasma level and by extrapolation the concentration of drug at the receptor exactly parallels this sigmoidal pattern. Realism in the near future the scientists have to concentrate on methods of timing the pulsatile delivery of drugs to coincide with the peak time of clinical need or of receptor sensitivity. Today the investigations are focused on the identification of partial triggers that can be used to provoke the drug release from the formulations in a time dependent manner.
Various technologies to develop time controlled per oral drug delivery systems have been extensively studied during last 15 years. Innovative time dependent mechanisms have been described for tablets, pellets and capsules utilizing different physicochemical and physicomechanical strategies. The active substance is released at a predetermined time after activation by fluid of organism. The Chrono pharmacokinetic clock starts after the formulations come into contact with gastric fluid. Using of this strategy is possible when it is known that the active substance is effectively absorbed from the enteric length of the gastrointestinal tract. However, where an active substance is known to be variably absorbed as a function of gastrointestinal tract site, such a drug may be not a good candidate for chronopharmaceutical drug delivery. Time dependent changes in the pharmacokinetics after oral administration can be found in many classes of drugs. Most of the drugs appear to have higher rates or extent of bioavailability when they are administrated in the morning than when they are in use in the evening. For example, by means of cardiovascular drugs such as Nifedipine, oral nitrates and Propranolol a plasma peak concentrations are double as high and times to climax concentrations are shorter after morning dose as following evening administration.
Such tendency was not detected when prolonged release dosage forms were used. The underlying mechanisms if they chronopharmacokinetic pattern involves a faster gastric emptying time and greater gastrointestinal perfusion in the morning. Atenolol, in difference to propranolol, is not immersed more quickly after morning administration compare with evening administration.9
This confirm to facilitate the absorption rate of a lipophilic drug after morning dosing is faster than the same characteristic of hydrophilic drugs.
The influence on chronokinetic of the route of administration must also be considered. For example, there are studies showing that chronopharmacokinetic variation is not found when the drug is administrated rectally. Circadian variation in the activity of many gastrointestinal, hepatic and renal processes could explain why the absorption of drug, distribution, biotransformation and excretion of drugs change as a function of the time of administration. The drug absorption process can be altered by factors as the structure of the membrane, the physicochemical properties of drugs, the pH, the rate of gastric emptying and the motility the blood flow to the gastrointestinal tract. No study is available presently on temporal variations in the structure of membranes or on the effect of circadian changes of pH on drug absorption.
However, circadian rhythm in gastric emptying time and blood flow could explain the differences in absorption and chronopharmacokinetic behavior.
Very few investigations have been carried out on circadian variation in the process of distribution of a drug to its site of action. The factors influencing drug distribution are body size and composition, blood flow to the various organs, binding of drugs to plasma proteins, and membrane permeability of drugs. In the first study, Naranjo et al. (1980) looked the protein binding of diazepam and found that the free drug fraction was largest during the night (23:00 to 08:00) and smallest at 09:00. Significant time dependent variation of valproic acid binding was found (Patel et al. 1982). Maximal free ratio was obtained between 02:00 and 08:00 but the minimal binding occurred in the afternoon between 16:00 and 20:00.
The changes in free plasma levels of drugs could explain some chronopharmacokinetic data because it is general that the free drug in plasma is the fraction absorbed and metabolized. Any increase or decrease in the free concentration could lead to parallel changes in plasma or serum levels of the drug. Time dependent variation in drug binding has clinically important consequences only for drugs that are highly protein bound (more than 90%) and have a small volume of distribution.1
CHRONOPHARMACEUTICAL DRUG DELIVERY SYSTEM
Controlled drug delivery systems contain acquire a center stage in the area of pharmaceutical reaearch and development department. Such systems always offers temperory or spatial control greater than the release of drug. So in terms of petentability he granted a new lease of life to a drug molecule.
Figure 2: Plasma drug concentration profile for conventional tablet or capsule and zero order formulation.
There are certain conditions for which continuous conventional controlled release pattern is not suitable. These certain conditions demanded the release of drug after a lag time. Therefore pulsatile drug delivery syatem is best suited for it. This drug delivery system is a characteristics of a lag time means there is no any drug release followed by rapid drug release. In the early 1990s the first pulsatile drug delivery formulation was developed and released the vigorous substance at a accurately distinct time point. In this manner, the aim of the research was to achieved and the release pattern is called as sigmoidal release pattern. The characteristic features of the formulation was defined by lag time which followed by a drug pulse with containing active quantity being released as a burst release.12
Figure 3: Drug release profile of pulsatile drug delivery system.
Thus, the major role while developing the pulsatile drug delivery system is to attain a rupture release after the lag phase. Moreover the drug is released over an extensive period of time.
CURRENTLY REPORTED SYSTEMS
Pulsatile drug delivery systems are based on time controlled drug delivery system; in which the system control the delay time independent of environmental factors like enzymes, pH, gastrointestinal motility, etc. This drug delivery system can be classified as a single unit (e.g., tablets or capsule) or multiple unit (e.g., pellets) systems.
SINGLE UNIT SYSTEM
There are different single unit capsular systems has be developed. A universal arrangement of such systems consists of an capsule body which is insoluble housing a drug and a plug. Then the plug is detached after a programmed lag phase owing to properties like dissolution, erosion and swelling.
PulsincapÂ® system is a system containing a water insoluble capsule body filled with formulation. Then the body is closed with open end containing a swellable hydrogel plug. When the plug having contact with the dissolution medium or gastrointestinal fluids it swells; and pushing itself out of the capsule shell after a predetermined lag phase. This is further then processed for a rapid drug release. For the control of the lag time there should be manipulations in the measurement and the location of the plug. If drugs are water insoluble, then rapid release for such type of drugs can be depends on the inclusion of effervescent agents or disintegrates.
This plug material containing a insoluble but permeable and swellable polymers like erodible compressed polymers, congealed melted polymers and enzymatically controlled erodible polymer.
Figure 4: Pulsatile release from an insoluble capsule body (coated swellable plug; and erodible plug capsular system based on osmosis)
For the study of gastro intestinal irritation such a formulations were well tolerate in animals and fit volunteers. However, there was a potential problem due to variability in gastric residence time, which was overcome by using enteric coat on the system which allows its disintegration and dissolution only in the region of higher pH of small intestine.
The PortÂ® System containing a gelatin capsule which is coated with the semi permeable membrane (e.g., PGLA, Cellulose Acetate) housing an osmotically active agents (NaHCO3, Citric acid) and an insoluble plug (e.g., lipidic) along with the drug formulation (Figure 5).
Figure 5: Drug release mechanism from PORT system.
When the formulation is in contact with the aqueous medium, water penetrates across the biological membrane, which results in increased internal pressure on the formulation that helps to ejects the plug after a lag period. Coating thickness controls the lag time. Such a system was developed to deliver a methylphenidate in the management of Attention Deficit Hyperactivity Disorder (ADHD) in the school age children. This system helps to avoids a second daily dose and if necessary then it would be administered by a nurse during childrens school hours.
A SYSTEM BASED ON EXPANDABLE ORIFICE15
The delivery of the drug in liquid dosage form. A capsular system which was driven by osmotically was residential in which the liquid drug is immersed into extremely permeable particles, and these porous particles releases the drug through an orifice of a semipermeable capsule. This semipermeable capsule was supported with an expanding osmotic layer after the dissolution of barrier layer. The delivery of the drug from the capsular system by the capsules osmotic blend of moisture from the body. An elastic material is used for the formation of casule wall and possesses an orifice. while osmosis prociding, the pressure should be increases within the capsule, which cause the wall to stretch. When the elastic wall relax the flow of the drug from side to side the orifice basically stops because the orifice is small but when the elastic wall is swollen beyond its threshold value, sufficiently expansion of orifice allows drug release at a specified rate. For that purpose elastomers like styrene butadiene copolymer has been used. The pulsatile release was achieve later than lag times of 1 to 10 hours, and it can be depends on the thickness of the outer layer and that of semipermeable membrane. For implantation when capsule was design it can delivered drugs intermittently at intervals of between 6 hours for at least 2 days.
DELIVERY BY A SERIES OF STOPS16
The implantable capsule containing a active drug molecules. And water absorptive osmotic engine is placed in compartments which is separated by a movable partition. The pulsatile drug delivery is achieve by a sequence of stops along with the internal wall of the capsule. These stops creats obstructs between the association of the separation but are overcome in sequence as the osmotic pressure increases above the threshold level. The number of stops used in it in addition to the longitudinal placement of the stops beside with the length of the capsule helps to dictate the number of pulse as well as frequency of the pulses. The configuration of the partition helps to controls the pulse intensity. For the delivery of porcine somatotropin this system was used.
PULSATILE DELIVERY BY SOLUBILITY MODULATION17, 18, 19
For the delivery of Salbutamol sulfate this system was specially developed. The compositions contain the Salbutamol sulfate and a modulating agent such as sodium chloride. The amount of sodium chloride was such that it was fewer than the amount needed to preserve diffusion in a fluid that enters the osmotic tool. This pulsatile drug delivery is based on solubility of drug. Salbutamol sulphate has a solubility value of 275 mg/ml in water and 16 mg/ml in a saturated solution of sodium chloride. But the sodium chloride has a solubility value of 321 mg/ml in water. These solubility value shows that the solubility of the drug is a function of the modulator concentration. The modulator's solubility is mainly free of the concentration of drug. These modulating agent in the form of a solid organic acid, inorganic salt, or organic salt. In order to manage zero order release period and beginning of the pulsatile release, ratio of drug as to modulator can be always varied. The drug can be delivered as one large pulse but after only period of zero order release.
PULSATILE SYSTEMS WITH ERODIBLE OR SOLUBLE BARRIER COATING
Almost all the pulsatile drug delivery systems are the reservoir devices and coated with a different barrier layers. These barriers erodes or dissolves after a specific lag phase, and the drug shows subsequently burst release. The lag period depending on the thickness of the outer coating layer.
TIME CLOCKÂ® SYSTEMS20
The Time ClockÂ® system contains a solid dosage form. In this system coating with lipid barriers containing different waxes like carnuba wax and bees wax beside with surface active agents like polyoxyethylene sorbitan monooleate. This coat erode or emulsifies in the aqueous surroundings in a stipulated time which is relative to the width of the film, and after that only the core formulation is available for the dispersion. This systems is better suitable for the drugs which are water soluble. For manufacturing of this system there is no required special equipment. However, such a lipid based system may be having high in vivo variability like effects of food.
CHRONOTROPICÂ® SYSTEMS21, 22
This system consists a drug containing core which is coated with hydrophilic swellable polymers like hydroxypropylmethyl cellulose. This hydrophilic swellable layer is fully responsible for a lag period in the release of drug. The differences in the gastric emptying time can be overcome through the function of an external gastric resistant enteric covering film and a colon specific discharge can be obtain. This rely on the relation reproducibility of small intestinal transit time. The interval time for such a formulations can be controlled by the thickness as well as different viscosity grades of hydroxypropylmethylcellulose.
MULTILAYERED TABLET23, 24
The release pattern from the three layered tablet with two pulses were determined. These layers containing two drugs and each layer divided by a drug free gellable polymeric barrier film. The top portion was uncoated and the three layered tablet was coated on three different sides within impermeable ethyl cellulose. Ahead contact with dissolution medium, the primary dose included into the top layer was released quickly from the non coated surface. The second pulse was obtain from the base layer after the gelling barrier layer of hydroxy propyl methyl cellulose was eroded and dissolve. The speed of gelling and dissolution of the barrier layer manage the outer shell of the second pulse. The gelling polymers report contain cellulose derivatives like hydroxy propyl methyl cellulose, methyl cellulose, or polyvinyl alcohols of various molecular weights and the outside layer materials include ethyl cellulose, methacrylic polymers, cellulose acetate propionate, acrylic and mehtacrylic co polymers, and polyalcohols.
PULSATILE SYSTEMS WITH RUPTURABLE COATING25, 26
To achieve the pressure which is necessary for the rupture of the coating the effervescent excipients, osmotic pressure, or swelling agents can be used. The tablet core coated with ethyl cellulose with incorporation of an effervescent blend of sodium bicarbonate and citric acid. The development of carbon dioxide after penetration of water into the core formulation resulted in a pulsatile discharge of drug subsequent to burst of the coating. The mechanical properties of the coating layer responsible for the release of drug. The highly swellable agents, also called superdisintegrant, are used in the designing of a capsule based system, swelling agent, and rupturable polymer layer. Examples of superdisintegrant include sodium starch glycolate, cross carmallose, and low substituted hydroxypropyl cellulose. After swelling of these materials there is a complete rupture of film which followed by burst drug release. The lag time is a function and depends on the composition of the outer coating layer. The presence of hydrophilic polymer like hydroxy propyl methyl cellulose reduces the lag time. The system can be used for delivery of both solid as well as liquid drug formulations. A reservoir system with a semipermeable membrane coating was designed for delivery of drugs which exhibited extensive presystemic metabolism. After administration of several immediate release doses the release pattern was similar.