The mammalian circadian pacemaker resides in the suprachiasmatic nuclei(SCN) and influence a multitude of biological processes, including the sleep wake rhythm. The circadian clock acts like a multifunction timer to regulate homeostatic systems such as sleep and activity, hormone levels, appetite, and other bodily functions with 24h cycles. Diseases such as hypertension, asthma, peptic ulcer, arthritis, etc, follow the body’s circadian rhythm. This means that many diseases have rhythmic changes with time. Such diseases include osteoporosis, cardiovascular diseases and peptic ulcer. In osteoporosis severe during day and becomes bothersome in the evening and in the rhythmic arthritis, peaks in the morning and decrease as day progresses^1,3.

The goal in drug delivery research is to develop formulations to meet therapeutic needs relating to particular pathological conditions. Research in the chronopharmacological field has demonstrated the importance of biological rhythm in drug therapy, and this has brought a new approach to the drug delivery systems. Most physiological, biochemical, and molecular processes in healthy organisms display predictable changes on a 24 hour schedule. chronotherapeutic products can synchronize drug delivery with circadian rhythms in order to optimize efficacy and/ or minimize side effects. Also problem occurs with the diseases of heart such as cardiovascular diseases such hypertension and angina pectoris. By taking advantage of known biological patterns in disease manifestation, the goal of developing chronopharmaceutic products to optimize the desired effects of drug and minimize its undesired ones, can be obtained.

DEFINITION AND CONCEPT OF CHRONOPHARMACEUTICS:

The term “circadian” was coined by Franz Halberg from the Latin word “circa”, meaning about and dies meaning day. Pharmaceutics is an area of biomedical and pharmaceutical sciences that deals with the design and evaluation of pharmaceutical dosage forms to assure their safety, effectiveness, quality and reliability. chronopharmaceutics has been described as a branch of pharmaceutics devoted to the design and evaluation of drug delivery system that release a bioactive agent at a rhythm that ideally matches in real time the biological requirement of a given disease therapy or prevention. Ideally, chronopharmaceutical drug delivery systems (ChrDDS) should embody time-controlled and site-specific drug delivery systems regardless of the route of administration^1,3,4.

MOLECULAR BASIS FOR CHRONOPHARMACEUTICS

The circadian pacemaker of mammals resides in the paired suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep-wake rhythm. Clock genes are the genes that control the circadian rhythms in physiology and behavior. Twenty-four hour rhythm has been demonstrated for the function of physiology and the pathophysiology of diseases. Clock controls several diseases such as metabolic syndrome, cancer, and so on. CLOCK mutation influences the expression of both rhythmic and nonrhythmic genes in wild‐type tissues. These genotypic changes lead to phenotypic changes, affecting the drug pharmacokinetic and pharmacodynamic parameters The effectiveness and toxicity of many drugs vary depending on dosing time. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also the pharmacokinetics of medications. Thus, knowledge of the 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy. One approach to increasing the efficiency of pharmacotherapy is the administration of drugs at times at which they are most effective and/or best tolerated. Drugs for several diseases are still given without regard to the time of day. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. The mechanisms underlying chronopharmacological findings should be clarified from the viewpoint of clock genes. On the other hand, several drugs have an effect on the circadian clock^3-4.

RHYTHMS IN PHYSIOLOGICAL FUNCTIONS AND DISEASES:

Physiological functions:

Chronobiological approach has clarified the presence of 24 h rhythms in physiological functions and diseases. The examples described below show the approximate peak time of 24 h rhythms relative to the diurnally active human The rhythms of serum cortisol, aldosterone, testosterone, platelet adhesiveness, blood viscosity, and NK-cell activity show a peak during the initial hours of daytime. The peaks in insulin cholesterol, triglycerides, platelet numbers, and uric acid occur later during the day and evening. The rhythms of basal gastric acid secretion, white blood cells (WBC), lymphocytes, prolactin, melatonin, eosinophils, adrenal corticotrophic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) shows peaks at specific times during the nighttime. Human circadian time structure; shown in the approximate peak time of the circadian (24-hour) rhythms of selected biological variables in persons adhering to a normal routine of daytime activity (6-7 a.m to 10-11 p.m) alternating with night time sleep^1-4.

Figure no:1 Human circadian time structure

RHYTHM IN DISEASES

The sneezing, runny nose, and stuffy nose in allergic and infectious rhinitis are worst in the morning upon getting out of bed. The onset of migraine headaches is most frequent in the morning around the time of awakening. The symptoms of rheumatoid arthritis are the worst first thing in the morning, while those of osteoarthritis are the worst later in the day. The morbidity and mortality associated with myocardial infarction are greatest during the initial hours of daytime. The incidences of thrombotic and hemorrhagic stroke are the greatest in the morning around the time diurnal activity is commenced. The ischemic events, chest pain, and ST-segment depression of angina are the strongest during the initial three to five hours of daytime. The pain and gastric distress experienced at the onset of peptic ulcer disease and its acute exacerbation are most prevalent in the late evening and early morning. The seizures of epilepsy are common around sleep onset at night and offset in the morning. The symptoms of congestive heart failure are worse nocturnally. The manifestation of ST-segment elevation in Prinzmetal’s angina is most frequent during the middle to later half of the night. The risk of an asthma attack is greatest during nighttime.

Twenty-four hour rhythms in the processes that make up the pathophysiology of diseases cause prominent day–night patterns in the manifestation and severity of many medical conditions as shown in Fig 2.^1-5.

Figure no:2 Effect of circadian rhythms in pathophysiology of diseases

CHRONOTHERAPY:

The knowledge of 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics pharmacodynamics, effects, and safety constitutes the rationale for pharmacotherapy (chronotherapy).Then treatment of an illness or disorder by administering a drug at a time of day believed to be in harmony with the body’s natural rhythms is called chronotherapy. One approach for increasing the efficiency of chronotherapy is the administration of drugs at times at which they are most effective and/or best tolerated. Chronotherapy is especially relevant in the following cases. The risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease.

Several examples for chronopharmacotherapy are described below:

1. The morning daily or alternate-day dosing strategy for methylprednisolone constitutes the first chronotherapy to be incorporated into clinical practice.

2. Evening, once-daily dosing of specially formulated theophylline tablets for the treatment of nocturnal asthma.

3. Before-bedtime administration of verapamil HCL as a unique controlled onset extended-release 24 h dosage form to optimize the treatment of patients with ischemic heart disease and/or essential hypertension.

4. Evening administration of hydroxymethylglutaryl (HMG)-CoA-reductase antagonists for the management of hyperlipidemia.

5. Evening, once-daily dosing of conventional H2-receptor antagonists or morning once-daily administration of proton- pump antagonist tablet medications for the management of peptic ulcer disease.

6. Before-bedtime administration of hypnotics for sleep induction and maintenance.

Programmed-in-time infusion of antitumor medications according to biological rhythms to moderate toxicity and enhance dose-intensity in cancer treatment^1-3.

Advantages of chropharmaceutics:

Through chronopharmaceutics, appropriate delivery of drug can be achieved.

(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. This can be avoided be Chronopharmaceutics. For such drug Chronopharmaceutics is useful

(2) Biological tolerance: Continuous release drug plasma profiles are often accompanied by a decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal nitroglycerin

(3) Special chronopharmacological needs: It has been recognized that many symptoms and onset of disease occur during specific time periods of the 24 h 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 bowel 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: For compounds with gastric irritation or chemical instability in gastric fluid, the use of a sustained release preparation may exacerbate gastric irritation and chemical instability in gastric fluid

(6) Drug absorption differences in various gastrointestinal segments: In general, drug absorption is moderately slow in the stomach, rapid in the small intestine, and sharply declining in the large intestine. Compensation for changing absorption characteristics in the gastrointestinal tract may be important for some drugs.^1-6

Disadvantages of Chronopharmaceutics:

(1) It develops a non 24 hours sleep wake syndrome after the treatment as the person sleeps for over 24 hours during the treatment. It’s not quite common but the degree of risk is not known.

(2) Person may also be sleep deprived sometimes.

(3) Person become less productive during chronotherapy and staying awake till the other schedule will be bit uncomfortable.

(4) You will have to take some time off from your busy normal schedule as its time taking therapy.

(4) Medical supervision is mandatory for this therapy. And regular consulting of sleep specialists is recommended.

(5) One has to keep himself awake till the next sleep schedule, so he have to get himself busy so that he stay awake till the other schedule.

(6) Person going through the therapy may feel unusually hot or cold sometimes.

(7) Have to consult the doctor regularly to avoid side effects^1-6

Biological Rhythms, Age, Race, Gender, and Socioeconomic Factors:

The connection between these rhythms and age, race, gender, demographic, socioeconomic, and work factors may be important to the concept of effective and safe systems for chronotherapy and the prevention of diseases based on recent discussions on personalized medicine^1-6

BIOLOGICAL RHYTHMS, HEALTH, AND DISEASES:

Table no:1 Circadian stage dependent diseases

Cardiovascular diseases	Angina pectoris, myocardial infraction, hypertension, heart attack, stroke, cardiac ischemia, sudden cardiac death
Respiratory diseases	Asthma, allergic rhinitis
Gastrointestinal disorders	Peptic ulcer and duodenal ulcer
Inflammatory diseases	Rheumatic arthritis and related painful joint disorders such as osteoarthritis gout,
Neurological diseases	Epilepsy, migraine, parkinsonism and sleep disorders
Mammalian diseases	Various types of cancer
Others	Hypercholesterolemia, diabetes etc

Biological Rhythms and Sleep Disorders:

The hypothalamus is recognized as a key center for sleep regulation, with hypothalamic neurotransmitter systems providing the framework for therapeutic advances. Human sleep, its duration, and organization depend on its circadian phase . Melatonin is a hormone secreted by the pineal gland in the brain. It helps to regulate other hormones and maintains the body's circadian rhythm. Melatonin plays a critical role in when we fall asleep and when we wake up. When it is dark, body produces more melatonin; when it is light, the production of melatonin drops. Being exposed to bright lights in the evening or too little light during the day can disrupt the body' s normal melatonin cycles. For example, jet lag, shift work, and poor vision can disrupt melatonin cycles. In such conditions it was suggested that prior knowledge of the subject’s type of circadian rhythm, and timing of treatment in relation to the individual’s circadian phase, may improve the efficacy of melatonin. Other drugs such as theophylline and pentobarbital, in addition to having a number of already established pharmacological properties, have been further identified as chronobiotics; or drugs that may be used to alter the biological time structure by rephasing a circadian rhythm.

Biological Rhythms and Respiratory Disorders:

Basically, the symptoms of allergic asthmatic patients typically worsen during the night, especially during the early morning hours. The severity of asthma during the night represents the changing status of biological functioning due to circadian rhythms in bronchial patency; airways hyper reactivity to acetylcholine, histamine, and house dust; and plasma cortisol, epinephrine, histamine, and cyclic AMP. The studies has proved that the symptoms of allergic rhinitis was severe in the month of January to April In addition, the elevated severity of symptoms in the morning experienced by 60–70% of patients was recommended as a guide to individually optimize dosing time(s) of medications, such as antihistamines. These observations provide a strong rationale for the chronotherapy of respiratory diseases. For example, the effects of antihistamine and anti-inflammatory medicines may be enhanced by timing them to the day–night temporal pattern in symptom manifestation and intensity to achieve optimization of their beneficial effects with control of toxicity, that is, as a chronotherapy.

Biological Rhythms and Cardiovascular Diseases:

The blood pressure and heart rate in normotensives and essential (primary) hypertensive patients display highest values during daytime followed by a nightly drop and an early morning rise. It was also suggested that predictable changes in responsiveness of the hematopoietic and immune system provide an opportunity to improve the effects of growth factors and cytokines and decrease their undesirable side effects .Moreover, a relatively recent study of the differences in the pharmacokinetic patterns of metoprolol between a pulsatile drug delivery system using a pulsatile capsule, an immediate release tablet, and a controlled release tablet suggested that pulsatile drug delivery offers a promising way for chronopharmacotherapy Based on these observations, several chronotherapeutic agents for hypertension and angina pectoris, controlled onset, extended release had been developed and are being marketed These observations call for a circadian time-specified drug dosage form design and delivery treatment for heart disease as well.

Biological Rhythms and Cancer:

The toxicity and/or efficacy of several anticancer agents has been shown in various experimental systems to be dependent on the circadian timing of their bolus administration or the circadian shaping of their continuous infusion. One of the cellular processes that are regulated by circadian rhythm is cell proliferation, which often shows asynchrony between normal and malignant tissues. This asynchrony highlights the importance of the circadian clock in tumor suppression in vivo and is one of the theoretical foundations for cancer chronotherapy which might lead to new therapeutic targets.

Biological Rhythms and Infectious Diseases:

The non-steroidal anti-inflammatory agents (NSAIDs) such as ibuprofen may be more effective at relieving pain, if the drug is administered at least 4 to 6 h before the pain reaches its peak. It will be more helpful if arthritis patients take the NSAIDs before bed time if they experience a particularly high level of discomfort in the morning

Biological rhythms and ulcer:

It is well established that patients with peptic ulcer disease often experience the greatest degree of pain near the time that they go to bed, as the rate of stomach acid secretion is highest at night. The timing of administration of ulcer medications has a significant impact on their therapeutic effect.

Biological rhythms and Hypercholesterolemia:

The morning doses were recommended at first for HMG CO-A inhibitors but after the discovery of circadian rhythms the profile was reevaluated and the evening doses were recommended as the cholesterol intake and cholesterol biosynthesis is more in the evening hours even in fasting state

Biological Rhythms and Neurodegenerative Diseases:

Important brain diseases that may benefit from chronopharmaceutical systems include anxiety, insomnia, epilepsy, and Alzheimer and Parkinson diseases. The circadian variability in hemorrhagic stroke has also been reported Chronobiology makes possible the discovery of new regulation processes regarding the central mechanisms of epilepsy. For example, the electroencephalogram (EEG) in an animal model for generalized absence epilepsy showed that a circadian pattern emerged for the number of spike-wave discharges.

Biological Rhythms and Metabolic Disorders:

Metabolic status varies predictably on a daily and seasonal basis in order to adapt to the cyclical environment. The hypothalamic circadian pacemaker of the suprachiasmatic nuclei (SCN) coordinates these metabolic cycles. Disturbances of this coordination, as occur in long-term shift work, have a major impact on health including metabolic disorders such as obesity, diabetes, and hypercholesterolemia. Moreover, recent studies revealed that sleep loss in humans leads to metabolic disorders and an intriguing question would be the relation between a healthy biological clock and normal appetite and weight regulation More recent studies have shown that processes ranging from glucose transport to gluconeogenesis, lipolysis, adipogenesis, and mitochondrial oxidative phosphorylation are controlled through biological clock. Cholesterol synthesis is generally higher during the night than during daylight, and diurnal synthesis may represent up to 30–40% of daily cholesterol synthesis. Chronopharmaceutics also offer the perspective of improved therapy for metabolic disorders such as obesity, diabetes, and hypercholesterolemia.

Biological Rhythms and Pain:

Chronopharmaceutics also plays a major role at pain control therapies. Many scientists are convinced that pain intensity is rarely constant over a 24 hours period. The daily pain profile must be used to determine the best time to administer an analgesic drug to a patient. The time dependent rhythms in pain intensity depend on the medical conditions present. Morning pain is found in patients with angina pectoris, myocardial infarction, migraine, tooth ache and arthritis rheumatoid whereas nighttime’s pain is more common in arthritic pain, gastro-oesophageal reflux and renal colic. The onset of migraine headache is most frequent in the morning around the time of awakening from nighttime .The symptoms of rheumatoid arthritis are worst when awaking from nighttime, while those of osteoarthritis are worst later in the day .Patients with osteoarthritis tend to have less pain in the morning and more at night; while those with rheumatoid arthritis have pain that usually peaks in the morning and decreases throughout the day a number of drugs used to treat rheumatic diseases have varying therapeutic and toxic effects based on the timing of administration .chronopharmaceutics using the appropriate drug should ensure that the highest blood levels of the drug coincide with peak pain^1-7.

INFLUENCE OF BIOLOGICAL RHYTHMS ON PHARMACODYNAMICS AND PHARMACOKINETICS

Biological rhythms not only impact the pathophysiology of diseases, but also the pharmacokinetics and pharmacodynamics of medications. Chronopharmacology is the investigative science that elucidates the biological rhythm dependencies of medications.

Chronopharmacodynamics:

Biological rhythms at the cellular and sub cellular levels can give rise to significant dosing- time differences in the pharmacodynamics of medications that are unrelated to their pharmacokinetics. This phenomenon is termed chronesthesy. Rhythms in receptor number or conformation, second messengers, metabolic pathways, and/or free-to-bound fraction of medications help explain this phenomenon. The anti- tumor efficacy of imatinib is enhanced by administering the drug when PDGF receptor activity is increased. The potent therapeutic efficacy of the drug could be expected by optimizing the dosing schedule.

Chronopharmacokinetics:

Chronopharmacokinetics deals with the study of the temporal changes in absorption, distribution, metabolism, and elimination and thus takes into account the influence of time of administration on these different steps Many physiological factors such as gastrointestinal, cardiovascular, hepatic, and renal changes vary according to time of day as shown in Table2 Possible Physiological Factors Influencing Circadian Stage-Dependent Pharmacokinetics of Drugs (e.g., Absorption, Distribution, Metabolism, and Elimination)

Table no:2 Physiological Factors Influencing Circadian Stage-Dependent Pharmacokinetics of Drugs

ABSORPTION:

(Oral)

Gastric pH, gastric motility, gastric emptying time, gastrointestinal blood flow, transporter

(Parenteral)

Transdermal permeability, ocular permeability, pulmonary permeability

DISTRIBUTION:

Blood flow, albumin.α-1 acid glycoprotein, red blood cells, transporter

METABOLISM:

Liver enzyme activity, hepatic blood flow, gastro intestinal enzyme

ELIMINATION:

(Renal, biliary, intestinal)

Glomerular filtration, renal blood flow, urinary pH, electrolytes, tubular resorption, transporter

Drug Absorption:

Circadian changes in drug absorption have been demonstrated for several orally administered drugs in humans. Gastric acid secretion and pH, motility, gastric emptying time, and gastrointestinal blood flow vary according to the time of day. Such changes may contribute to the dosing time-dependent difference of drug absorption the dosing time-dependent difference of drug absorption is influenced by the physicochemical properties of a drug (lipophilicity or hydrophilicity) The circadian changes in drug absorption are significant for lipophilic drugs, while such changes have not been demonstrated for hydrophilic drugs. Such variations may be related to the physicochemical properties of a drug, since most lipophilic drugs seem to be absorbed faster in the morning as compared to evening. To the contrary, the absorption processes of highly water-soluble drugs do not change depending on dosing time. The mechanisms underlying the Chronopharmacokinetics of lipophilic drugs involve a faster gastric emptying time and a higher gastrointestinal perfusion in the morning.

Drug absorption by route of administration other than oral is also influenced by biological rhythms. For example, skin permeability shows circadian time-dependent differences in drug absorption. The temporal variation in drug penetration has previously been demonstrated for local anesthetic agents. Such phenomena should be considered in specific drug penetration through the skin using patches, since transdermal devices are applied 24 h a day.

Drug Distribution:

Circadian changes in biological fluids and tissues related to drug distribution are documented to vary according to time of day. Blood flow depends on several regulatory factors, including the sympathetic and parasympathetic systems whose activities are known to be circadian time-dependent with a predominant diurnal effect of the sympathetic system. Thus, diurnal increases and nocturnal decreases in blood flow and local tissue blood flows may explain a possible difference in drug distribution depending on dosing time. Plasma proteins such as albumin or alpha 1 glycoprotein acid have been documented to be circadian time-dependent. The plasma concentrations of albumin and alpha 1 glycoprotein acid show peaks around noon. As a result, daily variations have been reported for drug protein binding. Clinically significant consequences of such temporal changes in drug binding are relevant only for drugs which are highly bound. Thus, temporal variations in plasma drug binding may have clinical implications only for drugs characterized by a high degree of protein binding and a small volume of distribution. As a particular concern in drug binding to red blood cells, circadian time-dependent changes in the passage of drug into red blood cells have been demonstrated for drugs such as local anesthetics, indomethacine, and theophylline.

Drug Metabolism:

Hepatic drug metabolism seems to depend on liver enzyme activity and/or hepatic blood flow. Both factors show circadian time-dependent differences. Enzyme activities show circadian time-dependent differences in many tissues such as brain, kidney, and liver. However, these data were obtained in animals. Such circadian changes in enzyme activity have not been reported in humans. Several chronopharmacological studies have indirectly investigated temporal variations in hepatic drug metabolism by evaluating the Chronopharmacokinetics of drugs and their metabolites. Thus, conjugation, hydrolysis and oxidation show circadian time-dependent differences.

Drug Elimination:

Renal physiological functions such as glomerular filtration, renal blood flow, urinary pH and tubular resorption show circadian time-dependent differences with higher values during daytime. These rhythmic variations in renal functions may contribute to circadian dependent changes in drug urinary excretion. The rhythmicity in urinary pH modifies drug ionization and may explain why acidic drugs are excreted faster after evening administration, as demonstrated for sodium salicylate and sulfasymazine.Such variations are obviously more pronounced for hydrophilic drugs^1-5.

CLASSIFICATION OF CHRONOPHARMACEUTICAL SYSTEMS:

Based on their physicochemical properties, different classifications have been provided for drug delivery systems. However, for practical reasons, it may be reasonable to classify ChrDDS based on the main routes of drug administration (parenteral, oral, and transdermal).

Chronopharmaceutical Drug Delivery Systems for Parenteral Route:

These include the Melodie programmable Synchromed Panomat V5 infusion and Rhythmic pumps. . The portable pumps are usually characterized by a light weight (300–500 g) for easy portability and precision in drug delivery. The Melodie pump has been used successfully in cancer chemotherapy indicating that the chronopharmaceutical systems for the parenteral route are important alternatives for effective and safe cancer therapy The concept of chemical oscillators has also been explored in the search of chronopharmaceutical systems Based on the same principle, evidence was provided that low concentrations of acidic drugs can attenuate and ultimately quench chemical pH oscillators, by a simple buffering mechanism. Moreover, taking advantage of a pH oscillator system whose periodicity is slower than that of previously considered oscillators, it was shown that multiple, periodic pulses of drug flux across a membrane could be achieved when the concentration of drug is sufficiently low. A prototype gel oscillator that functions by dissipating the chemical energy of glucose by an enzyme-mediated reaction was also proposed More recently, an alternative method to achieve pulsatile or chronopharmaceutical drug release involves using microfabrication technology.

Chronopharmaceutical Drug Delivery Systems for Oral Route:

Ideal oral chronopharmaceutical drug delivery systems would allow agents that previously had to be administered two to four times daily to be administered once each day. Their potential advantages include reduced dosing frequency, enhanced compliance and convenience, reduced toxicity, instantaneous drug level matching exact biological and physiological needs to treat the disease at each time point, drug effect matching body need to treat diseases, and decreased total required therapeutic or preventive dose. The key technologies in chronopharmaceutics for oral delivery include Egalet s OROSs or ChronsetTM , the ContinTM, CeformTM, , Three Dimensional Printing TM (3DP), layered systems and Sigmoidal release systems. The Egalet technology offers a delayed release form consisting of an impermeable shell with two lag plugs, enclosing a plug of active drug in the middle of the unit. After the inert plugs have eroded, the drug is released, thus a lag-time occurs. Time of release can then be modulated by the length and composition of the plugs. The shells are made of (slowly) biodegradable polymers (such as ethyl cellulose) and include plasticizers (such as cetostearyl alcohol), while the matrix of the plugs is comprises a mixture of pharmaceutical excipient including polymers like polyethylene oxide (PEO). ChronsetTM is a proprietary OROS delivery system that reproducibly delivers a bolus drug dose (>80% drug release within 15 minutes) in a time- or site-specific manner to the gastrointestinal tract (GIT). Using the Chronset technology, the drug formulation is completely protected from chemical and enzymatic degradation in the GIT before release, and the timing of release is unaffected by GIT contents. By specifically balancing the osmotic engine, the semi permeable membrane, and the other attributes of the system configuration, drug release onset times varying from 1 to 20 hours can be achieved. The CeformTM technology allows the production of uniformly sized and shaped microspheres of pharmaceutical compounds. This approach is based on ‘‘melt-spinning’’, which means subjecting solid feedstock (i.e., biodegradable polymer/bioactive agent combinations) to a combination of temperature, thermal gradients, mechanical forces, flow, and flow rates during processing. The microspheres obtained are almost perfectly spherical, having a diameter that is typically 150–180 mm, and allow for high drug content. The microspheres can be used in a wide variety of dosage forms, including tablets, capsules, suspensions, effervescent tablets, and sachets. The microspheres may be coated for controlled release with an enteric coating or may be combined into a fast/slow release combination.

Three Dimensional Printing (3DP) technology is used in the fabrication of complex oral dosage delivery pharmaceuticals based on solid free-form fabrication methods. It is possible to engineer devices with complicated internal geometries, varying densities, diffusivities, and chemicals .Different types of complex oral drug delivery devices have been fabricated using the 3DP process: immediate–extended release tablets, pulse release, breakaway tablets, and dual pulsatory tablets. The enteric dual pulsatile tablets were constructed of one continuous enteric excipient phase into which diclofenac sodium was printed into two separated areas. These samples showed two pulses of release in vitro with a lag time between pulses of about 4 hours This technology is the basis of the TheriForm technology . The latter is a microfabrication process that works in a manner very similar to an ‘‘inkjet’’ printer. It is a fully integrated computer-aided development and manufacturing process. Products may be designed on a computer screen as three-dimensional models before actual implementation of their preparation process.

Layered systems are one or two impermeable or semi permeable polymeric coatings (films or compressed) applied on both sides of the core. To allow biphasic drug release, a three-layer tablet system can also be developed. The two layers both contain a drug dose. The outer drug layer contains the immediately available dose of drug. An intermediate layer, made of swellable polymers, separates the drug layers. A film of an impermeable polymer coats the layer containing the other dose of drug. The first layer may also incorporate a drug-free hydrophilic polymer barrier providing delayed (5 h) drug absorption.

Sigmoidal release system is used for the pellet-type multiple unit preparations, SRS containing an osmotically active organic acid have been coated with insoluble polymer to achieve different lag-times.14 By applying different coating thicknesses, lag times in vivo of up to 5 h can be achieved. Release rates from SRS, beyond the lag time, has been found to be independent of coating thickness.

Press-coated systems are the delayed release and intermittent release formulations can be achieved by press-coating. Press-coating, also known as compression coating, is relatively simple and cheap, and may involve direct compression of both the core and the coat, obviating the need for a separate coating process and the use of coating solutions. Materials such as hydrophilic cellulose derivatives can be used and compression is easy on a laboratory scale.

Chronopharmaceutical Drug Delivery Systems for Transdermal Route:

The transdermal route is a potential alternative for drug administration for chronotherapy. For that goal, the technologies that have been or are being investigated include crystal reservoir, automated transdermal drug delivery (ChronoDose system), and other advanced transdermal drug delivery technologies. crystal reservoir system. is a transdermal system for chronotherapy that was expected to provide more effective and safe treatment of asthma and related diseases not only in adults but also in children. The superiority of the transdermal formulation of tulobuterol over the oral formulations was indicated by its excellent pharmacokinetic profile A thermoresponsive membrane was also developed by entrapping a single or binary liquid crystal to achieve an on–off switching drug delivery for transdermal application via the externally repeated cycle of temperature change, which may simulate the dosing time of therapeutic needs for the human body Specifically in this case, a thermoresponsive membrane embedded with the binary mixture of 36% cholesteryl oleyl carbonate and 64% cholesteryl nonanoate was developed to achieve a rate-controlled and time-controlled drug release in response to the skin temperature of the human body.

The ChronoDose system is a revolutionary drug delivery device, worn like a wristwatch, which can be preprogrammed to administer drug doses into the body automatically, at different times of the day and with varying dose sizes. It automatically turns on and off to release drugs at preset times in preset amounts while the person is asleep or awake. The system is capable of precisely tailoring drug delivery where noninvasive, automated ‘‘time and dose precise’’ drug administration was previously impossible Basically, the system is a device for delivering a medicament, which has a membrane with at least one area permeable to the medicament and a reservoir space that contains a solvent and the medicament at least partially dissolved therein. An adjustable and/or deformable control element is disposed on the side of the membrane facing the reservoir space; access of the medicament from the reservoir space to at least one permeable area of the membrane can be changed. In addition an electronic device is provided whose control element can automatically be activated via a motor. The device permits the periodic alteration of the delivery rate of medicament, which is advantageous in many cases, including chronopharmaceutical applications^1-7.

CONCLUSION:

Compared to conventional dosage forms, ChrDDS can easily mimic circadian rhythm of several diseases. The application of biological rhythm to pharmacotherapy may be correlated by the appropriate timing of dosing of these drug delivery systems to synchronize drug concentrations to rhythms in disease state. ChrDDS are now better understood for selected disease such as cancer, peptic ulcer, sleep disorder, hypertension, glaucoma etc. ChrDDS appear to have choice of future as many pharmaceutical companies are developing such systems and already a number of chronotherapeutic products. Development of some more technologies for the large scale production and research at academia of chronotherapetuic systems needs to be initiated.

REFERENCES:

1. Youan C.B. Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery. Journal of Controlled Release. 98(3); 2004:337-353.

2. Sajan J, Cinu TA, Chacko AJ, Litty J and Jaseeda T. Chronotherapeutics and chronotherapeutic drug delivery systems. Trop J Pharm Res. 8(2); 2009: 467-475.

3. Smolensky MH and Labreque G. Chronotherapeutics. Pharm. News. 2(1); 1997:10-16.

4. Vyas SP, Sood A and Venugoplan P. Circadian rhythm and drug delivery design. Pharmazie.52(4); 1997: 815-820.

5. Belanger P, Bruguerolle B and Labrecque G. “Physiology and Pharmacologyof Biological Rhythms,” ed. by Redfern P. H, Lemmer B, Springer-Verlag, Heidelberg, 1997:177—204.

6. Ali J, Saiqal N, Qureshi M J, Baboota S and Ahuja A. Chronopharmaceutics: a promising drug delivery finding of the last two decades.Recent pat Drug Deliv Formul. 4(2); 2010:129-44.

7. Vivek Kumar Pawar and Rajendra Awasthi. Chronotherapy: an approach to synchronize Drug delivery with circadian rhythm. Journal of Chronotherapy and Drug Delivery. 1(1); 2010:1-8.

Received on 21.03.2012

Modified on 17.07.2012

Accepted on 09.10.2012

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(6): November–December, 2012, 309-317