Thursday, June 4, 2009

Chronotherapeutic Drug Delivery System is an Optimizing Approach to Emerging Drug Delivery



Circadian biological rhythms give rise to prominent day-night patterns in the dependence and patho-physiological functions of a large number of human diseases and symptoms-either their activity waxes or wanes with time. Therefore, matching drug release to the biological rhythm has been the ultimate goal of a selecting new drug delivery technology. Such chronotherapeutic DDS match the body's changing needs at certain times of day or night in order to optimize therapeutic profile and to minimize side effects.

SOME ANTIHYPERTENSIVE MEDICATIONS for time-controlled release include Covera HS, Verelan PM and Cardizem LA. Further research is also in progress for a number of commonly used drugs having circadian patterns and fall under the categories of anti-asthmatic, anti-arthritis and anti-cancer. Thus, this article focuses on the emerging role of chronotherapeutic drug delivery systems (DDS) in optimizing the treatment of several diseases. Along with chronotherapeutics, key words for this article include circadian biological rhythm and disease conditions.


Over the past two decades, the pharmaceutical market has been demonstrating an increasing preference for controlled and targeted DDS. Such systems have been focused on constant, variable, sustaining and/or targeting the therapeutic agent to a specific site, tissue or organ. However, there are certain conditions for release patterns that are not suitable. Such conditions lead to the requirements of a time-programmed, therapeutic system, which is capable of releasing a drug after predetermined time delay and maintaining constant drug levels throughout the day.

Matching drug release to the body's circadian rhythms has been a fundamental strategy for selecting a new drug delivery system to increase the efficacy and safety of drugs by proportioning peak plasma concentrations during the 24 hours in synchrony with biological rhythm. Such circadian biological rhythms give rise to prominent day-night patterns in the dependence and pathophysiological functions of a large number of human diseases and symptoms with activity waxing or waning with time.

Chronotherapeutic DDS is a relatively new concept in the emerging drug delivery technology. The term "chrono" refers to every biological event undergoing rhythmic changes in time, while the term "chronotherapy" refers to the coordination of biological rhythms with treatment. Thus, the chronotherapeutics DDS is defined as a level that the drug delivery system matches the body's changing needs at certain times of day or night in order to optimize therapeutic profile and to minimize side effects. Chronotherapeutic DDS offers certain advantages over other DDS, including the ability to:

  • Optimize drug availability at the specific time when disease symptoms and complications are most severe;

  • Optimize drug efficacy by determining the timing and amount of medication;

  • Reduce dosing frequency and hence improved patient compliance and provide a most cost-effective therapy;

  • Avoid adverse effects and thus outcomes of toxicity;

  • Delivery of drugs exhibiting a chronobiological behavior.

What Chronotherapeutic DDS Needs

However, there are number of considerations for the development of chronotherapeutic drug delivery system.

For example, a number of hormones, which show distinct daily fluctuations, e.g. growth hormone, melatonin gastric acid, prolactin, luteinizing hormone etc., are released in the evening or during sleep, while aldesterone, cortisol, renin and angiotensin are secreted in the morning.

Circadian effects observed in normal physiological body functions, including gastrointestinal motility, gastric acid secretion, gastrointestinal blood flow, renal blood flow, hepatic blood flow, urinary pH, cardiac output, drug-protein binding and liver enzymatic activity, all play a prominent role in time-dependent variation of drug plasma concentrations. Circadian changes in biological functions-heart rate, blood pressure, body temperature, plasma concentrations, intraocular pressure, stroke volume and platelet aggregation-also demonstrate time-consistent patterns.

Other factors are the onset and extent of several diseases and the symptoms, which also can vary in body circadian rhythms and display time dependence (Table 1).

Applications for Chronotherapeutics DDS

The potential benefit of chronotherapeutic pharmaceuticals has been demonstrated by a number of DDS developed for timed release of drugs having a chronobiological behavior or when symptoms of the diseases are circadian dependent. Table 2 lists the various drugs for which daily variations in effects have been reported or are under study in clinical trials.

1) Cardiovascular Diseases

Chronopharmaceuticals for cardiovascular diseases have been studied extensively. Presently, four drugs have been successfully incorporated into chronopharmaceuticals for clinical use. The first established chronotherapeutics DDS for timed-release of antihypertensive /antianginal agent is OROS technology developed and marketed by Alza in 1996 for controlled onset and extended release (COER) formulation of verapamil hydrochloride tablet (Covera HS, Pharmacia, USA) to reduce the peak morning of cardiovascular events.

OROS uses osmosis to release the drug contained within a semi-permeable membrane. A second chronotherapeutic drug delivery approach for hypertension was developed by Elan in 1998 using chronotherapeutic oral drug absorption system (CODAS) technology for formulation of verapamil hydrochlo-ride capsule (Verelan PM, Schwarz Pharma, USA). Cardizem LA (Diltiazem hydrochloride), which is used for hypertension and angina was approved by the FDA in 2003, is marketed by Biovail. Innopran XL (Propranolol hydrochloride) extended release capsule is used for hypertension and was approved by the FDA in 2003 and marketed by Reliant Pharmaceuticals, which utilizes the Eurand's Diffucaps technology.

2) Inflammatory Diseases

Inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout, exhibit profound circadian rhythms (variations) in the manifestation and intensity of symptoms. Chronotherapeutic-type medications increase the effectiveness and safety of treating arthritis disorders. Such drug delivery systems enhance the desired effects of drugs and minimize side effects.

The chronopharmacological studies of arthritic diseases means determining the best time to administer drugs. Long-acting NSAIDs, like flubiprofen, ketoprofen, tenoxicam and indomethacin taken at bedtime, ensure the adequate control of prominent morning symptoms of rheumatoid arthritis, while the chronotherapy of osteoarthritis involves the administration of drugs in relation to the time of day when pain is worse. If pain is worse at night or early in afternoon, an evening once-a day NSAID schedule is recommended. If pain is worse in the afternoon or night, a once-a-day morning or noontime treatment schedule is best.

"SEVERAL CHRONOTHERAPEUTIC MEDICATIONS have been proposed for treatment of nocturnal asthma. Oral steroids such as corticosteroids, glucocorticoids and methylprednisolone administered at 8 a.m. rather than 8 p.m., for example, have shown higher effectiveness in treating asthma."

3) Asthma

Circadian changes in normal lung function from alterations in pathophysiology and inflammation needs to be applied clinically. Generally the worsening of asthma occurs at night, and is often referred to as nocturnal asthma. A chronotherapeutic approach applied to nocturnal asthma is particularly important to understanding the circadian changes when choosing the dosage timing of medications.

Several chronotherapeutic medications have been proposed for treatment of nocturnal asthma. Oral steroids such as corticosteroids, glucocorticoids and methylprednisolone administered at 8 a.m. rather than 8 p.m., for example, have shown higher effectiveness in treating asthma.

Other studies have shown that oral administration of prednisolone at 3 p.m. rather than 8 a.m. improved lung function and reduced airway inflammation more effectively in the treatment of nocturnal asthma. The leukotriene active agents, including zileuton, zafirlukast and montelukast, have been proven to alleviate the symptoms and the decrement in lung function in nocturnal asthma when used chronotherapeutically.

Once daily dosing in the evening of theophylline tablets showed chronotherapeutic potential in the treatment of nocturnal asthma. Various tablet formulations of long acting -agonists (albuterol, bambuterol, salmeterol and formoterol) have been used in a chronotherapeutic approach for the treatment of asthma.

4) Oncology

Optimal drug timing (chronotherapy) in oncology resulted in allowing high-doses to be administered safely and most effectively with less toxicity, improved tumor control and patient survival. Xhronotherapeutic drugs under clinical trials have shown circadian-stage dependent anti-cancer activity, confirming and emphasizing the importance of circadian drug timing.

For that, modern oncology will demand circadian timing-stipulated, multi-drug regimens, biological therapies and hybrid chemobiotherapies. The first chronopharmacological studies of doxorubicin in 1977 for the treatment of a transplanted plasmacytoma in rats revealed that the rate of tumor shrinkage is dependent upon the time of day that the drug is given. To date, the toxicities and anti-tumor activities of at least 20 of the most commonly used chemotherapeutic agents-cisplatin, oxaliplatine, carboplatin, epirubicin, 6-mercaptopurine, methotrexate, 5-fluorouracil, vinblastine and cyclophosphamide-are documented as circadian stage-dependent both in animals and for many in humans. Circadian-dependent activity of some biological agents, most notably Interferon, and erythropoietin, have also been well documented.

5) Gastrointestinal Diseases

Circadian rhythms in the pathophysiology of the gastrointestinal tract may give rise to the administration of a time dependent drug delivery system. The symptoms of peptic ulcer are most likely to be seen in the late evening or early morning hours so the chronotherapy of peptic ulcer disease achieved by the evening dosing of H2-receptor antagonists has proven to be beneficial.


The use of chronotherapeutics drug delivery systems offers a solution for delivery of drugs exhibiting a chronobiological behavior and such DDS seems to constitute a more dependable means of matching drug level to biologic need and tolerance. Accurate timing of drug release coordinated with biological rhythms presents the opportunity to target coronary heart diseases, cancer cells, asthma and inflammatory diseases. To date, some antihypertensive medications for time-controlled release of drugs have been developed.

To date, there are several commonly used drugs having circadian patterns under categories of anti-asthmatic, anti-arthritis and anti cancer. A chronotherapeutics approach surely provides the enormous scope for research and has promise for a bright future to control diseases according to the body's physiological needs.