INTRODUCTION:

Up to now, the design of drug delivery systems has been governed by the homeostatic theory, based on the assumption of biological functions that display constancy over time¹. However, researches in chronopharmacological field have demonstrated that many functions of the human body vary considerably during a day and the effectiveness and toxicity of many drugs can vary depending on the time of drug administration in relation to circadian rhythm of biochemical, physiological and behavioural processes^{2, 3}. Optimal clinical outcome cannot be achieved if drug plasma concentration is constant with time. If symptoms of disease display circadian variation, exemplified by allergic rhinitis^4,5, asthma^6,7, ischemic hearth diseases like myocardial infraction, angina pectoris and congestive heart failure, stroke, hypertension^8-10, rheumatoid arthritis, osteoarthritis¹¹, peptic ulcer¹², haemorrhagic and perforated ulcer, epilepsy, sleep disorders, apnoea, parkinsonism, hypercholesterolemia¹³, cancer¹⁴; the drug release should also vary over time in synchrony with the pathophysiological rhythms of disease and/or biological rhythms the body¹⁵.

The concept of chronotherapy “coordination of the treatment in synchrony with biorhythms” by providing “right dose to the right person at right time” has brought a new approach to the development of drug delivery systems¹⁶. For long enough, it has been focused on the physics and chemistry of drug delivery but now it is really a time to take into account what the body needs. Until now, the emphasis has been on the formulations that maintain constant drug level throughout the day¹⁷, but now it is required to develop more biologically appropriate formulations that take account of variations in body functions. So, the matching drug release to the body’s circadian rhythms has been the ultimate goal of selecting new drug delivery technology to increase the efficacy and safety of drugs by targeting their release to the specific time of the day when there is maximum clinical manifestation of a disease¹⁵.

This can be achieved by chronotherapeutic drug delivery systems (Chrono DDS) and various dosage forms can be fabricated so as to release the drug in a time-controlled manner, which deliver the active medicament ‘when’ and ‘where’ it is required¹⁸. Chronotherapeutic DDS is defined as “a drug delivery system that matches the body’s changing needs at certain times of day or night in order to optimize therapeutic profile and to minimize side effects”¹⁵.

DISEASES AND CHRONOTHERAPEUTICS:

The 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. 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 function. 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. Epidemiological studies have documented the elevated risk of disease symptoms during the 24-hours cycle (see-Fig-1)

Figure 1: Disease Displaying Circadian Rhythm

The potential benefits of chronotherapeutic have been demonstrated in the management of a number of diseases. In particular there is a great deal of interest in how chronotherapy can particularly benefit patients suffering from allergic rhinitis, rheumatoid arthritis and related disorders, asthma, cancer, cardiovascular diseases, and peptic ulcer disease. Patients with allergic rhinitis often report that they suffer their worst symptoms when they wake up in the morning. Patients may obtain better results in controlling this morning discomfort if they were to take a long-acting antihistamine at night rather than taking the medication in the morning as is frequently recommended.

Anti-inflammatory therapy:

In the case of individuals who suffer from rheumatoid arthritis and related painful joint disorders, 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 hours 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.

Anti-asthma therapy:

It has been estimated that symptoms of asthma occur 50 to 100 times more often at night than during the day. Many circadian-dependent factors appear to contribute to the worsening of nocturnal asthmatic symptoms. For example, cortisol (an anti-inflammatory substance) levels were highest at the time of awakening and lowest in the middle of the night, and histamine (amediator of bronchoconstriction) concentrations peaked at a level that coincided with the greatest degree of bronchoconstriction at 4:00 am. A research finding also reveals that theophylline absorption is slower at night. The enhanced understanding of the chronobiological impact upon the pathology of asthma, and the pharmacology and pharmacokinetics of the drugs used in its management, have led to new approaches to disease management and enhanced patient care.¹⁶

Chemotherapy:

Antineoplastic drugs cause cytotoxic effects on healthy and diseased tissues. As would be expected, the biological rhythms of both healthy and tumor cells may influence the susceptibility of normal and malignant cells to these agents. It has been demonstrated that "susceptibility rhythms" to drugs may differ between healthy tissue and cancerous tissue. Therefore, the "correct" timing of drug treatment may reduce host toxicity, increase maximum drug tolerance, and ultimately result in better tumor management. The pharmacologic and pharmacokinetic properties of the drug, rhythmic changes in DNA and RNA synthesis, RNA translational activity and mitotic activity may influence tumor cell susceptibility. It appears that the timing of drug administration in the treatment of cancer can have a significant impact upon treatment success.

Cardiovascular therapy:

The differences in patterns of illness between day and night for cardiovascular disorders such as hypertension, angina, heart attack, sudden cardiac death and stroke have been documented¹⁷. Medications have been formulated, and dosing schedules established, in an attempt to provide appropriate concentration of a drug in the target area of the body when the drug is most needed. ¹⁶

Figure 2: Blood Pressure Graph for 24 hours

For example,(fig-2), it has often been found that the blood pressure of a hypertensive patient increases rapidly in the morning after awakening, typically peaks in the middle to late time of the day, decreases in the evening, and is lowest while the patient sleeps at night. It may also be important to recognize that the risk of heart attack appears to be greatest during the early morning hours after awakening. Currently, there are antihypertensive products in the market that are chronotherapeutic medications with novel drug delivery systems, releasing drug during the vulnerable period of 6 am to noon upon administration of medications at 10 pm. Some of these are listed in Table-1.

Table 1: Some Chronotherapeutic Antihypertensive Products

Product

Generic name

Manufacturer

InnoPran

Propranolol

GlaxoSmithKline

USA

Cardizem

Diltiazem

Biovail Corporation

Mississauga, ON Canada

Verelan

Verapamil

Schwars Pharma

Monheim, Germany

Covera

Verapamil

Schwars Pharma

Monheim, Germany

Covera

Verapamil

G. D. Searle

(a division of Pfizer), NY, USA

Anti-ulcer therapy:

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.

CHRONOPHARMACOKINETICS:

Chronopharmacokinetics entails the study of temporal changes in drug absorption, distribution, metabolism and excretion. Pharmacokinetic parameters, which are conventionally considered to be constant in time, are influenced by various physiological functions displaying circadian rhythm¹⁶. Circadian changes in gastric acid secretion, gastrointestinal motility, gastrointestinal blood flow, drug protein binding, liver enzyme activity, renal blood flow and urinary pH may play a role in time-dependent variation of drug plasma concentration. Numerous chronopharmacokinetic studies have been conducted over the last 20 years. The results of these studies demonstrate that time of administration affects drug kinetics. Studies in man have been reported, particularly in relation to cardiovascular active drugs, non-steroidal anti-inflammatory drugs (NSAIDs), local anaesthetics, anticancer drugs, psychotropic drugs, antibiotics and anti-asthmatic drugs. Most of the drugs seem to have a higher rate or extent of bioavailability when they are taken in the morning than when they are taken in the evening.

ADVANTAGES OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS¹⁵:

 Optimize drug availability at the specific time when disease symptoms are most severe

 Optimize drug efficacy by determining the timing and amount of medication

 By reducing dosing frequency, 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

Table2 shows potential drug candidates that have been developed or are under development for Chrono DDS. It can be formulated by utilizing different technologies, based on the concept of time-controlled release, pulsed release, triggered and programmed drug delivery systems and devices, commonly called as chronopharmaceuticals¹⁹.

Commonly Utilized Chronotherapeutic Drug Release Systems With Their Basic Mechanistic Enteric-coated systems¹:

In addition with site-specific delivery mainly, this system can also be utilized in time-

controlled drug administration, when a lag time is needed. Enteric coating provides time-delayed release.(fig-3)

Example: Chronotopic® drug delivery system^20,21

Figure 3: Enteric-coated system

Capsule based systems:

It is single-unit system in which, the lag time is controlled by a plug, which gets pushed away by swelling or erosion and the drug is released as a ‘Pulse’ from the insoluble capsule body.(fig-4)

Example: Pulsincap® system^{22, 23,24}

Figure 4: Pulsincap system

Layered systems:

Include three or four layers system providing biphasic drug release. Outer layer provides immediate release of drug, followed by layer(s) of swellable polymer or impermeable polymer on both the side of core, controlling / delaying the release rate of the drug present in central core layer²⁵.(fig-5)

Examples: Geomatrix®²⁶, Qtrol™ coating technology²⁷, Geminex ^TMtechnology²⁸

Figure 5: Layered systems

Press-coated systems¹:

The inner core (swellable or containing disintigrants) contains the drug and the outer release-controlling compression coat is made of different types of (swellable or erodible) polymers. Most such formulations release drug after a lag phase, which can be controlled by changing the barrier formulation or the coating thickness and are followed by rapid core dissolution. (fig-6)

Examples:SyncroDose™technology²⁸,TIMERx®technology²⁸,GeoClock technology²⁹

Figure 6: Press-coated systems

Membrane diffusion controlled systems:

Partially soluble membrane comprises of water insoluble, erodable or swellable polymer coat encloses a drug core. The polymer membrane acts as a barrier, allows the diffusion of the drug through it, maintaining the controlled release.(fig-7)

Examples: CODAS^Tm -Chronotherapeutic Oral Drug Absorption System technology^31,32, Time Clock® system³³

Figure 7: Membrane diffusion controlled systems

Systems based on osmosis¹:

Elementary osmotic pumps, which contain osmotically active core with drug, a push layer and rate controlling semi permeable polymer layer can provide 5-6 h lag-time and if taken bedtime, could provides optimal drug concentrations when the patient wakes up and during daytime. (fig-8)

Examples: COER-24 TM 33, Port®29 (Programmable Oral Release Technology) system

Figure 8: Systems based on Osmosis

Multiparticulate / Granular Systems:

Granules or beads with drug containing core are coated by enteric and water insoluble or swellable polymers, which provides delayed release and some beads are coated with immediate release coating. Finally they are either compressed in a tablet of filled in a gelatin capsular shell, resulted in multiple unite dosage forms.

Examples: Diffucaps® technology³⁵, Time controlled explosion systems(fig-9) (TES)^36,37, Sigmoidal release systems (SRS) ³⁸, Micropump® Technology³⁹.

Figure 9: Time controlled explosion systems

RECENT ADVANCEMENTS IN CHRONO DRUG DELIVERY SYSTEM:

Controlled Onset and Extended Release - COER-24^TM:

Most established one is OROS technology developed and marketed by Alza (1996) and used for Controlled Onset and Extended Release (COER-24^TM), verapamil HCl tablet (Covera-HS, Pharmacia, USA) which is the first commercial chronotherapeutic system for treatment for hypertension and angina pectoris, registered in USA.

COER-24^TM is an osmotically controlled single unit system (fig-10). The outermost component is a semi permeable membrane that regulates absorption of water into the tablet. Water is absorbed from the gastrointestinal tract at a fixed rate, until a second layer is reached. The second layer or delay coat then absorbs water and temporarily prevents the passage of water into the inner core of the tablet, which contains verapamil. This process delays drug release for approximately 4 to 5 h. When sufficient moisture has been absorbed, a third layer, consisting of osmogen, expands osmotically, pushing verapamil out of the tablet through laser-drilled holes at outer layer at a consistent rate. Continued absorption of water and ongoing osmotic expansion of the third layer provides for extended release of drug and 24 h control of blood pressure.

Figure 10: Schematic Presentation of Covera-HS in the CORE-24 System

Chronotherapeutic Oral Drug Absorption System -CODAS^TM technology:

Second chronotherapeutic drug delivery approach developed by Elan, (approved by FDA in 1998) is Chronotherapeutic Oral Drug Absorption System (CODAS^TM) technology for formulation of verapamil HCl capsule (Veleran PM, Schwarz Pharma, USA).

The CODAS^TM delivery system incorporates a 4 to 5 h delay in drug delivery followed by an extended drug release with a peak concentration occurring approximately 11 h after administration. Each capsule contains numerous pellets that consist of an inert core surrounded by active drug and rate-controlling membranes that combine water-soluble and water-insoluble polymers. As the pellets lie in the gastrointestinal tract, water washes over the polymer-coated pellets, slowly dissolving the water-soluble polymer and allowing the drug to diffuse through the resultant pores in the coating. The water insoluble polymer continues to provide a barrier and maintains the controlled release of the drug throughout the remainder of the 24 h dosing interval(fig-11).

Figure 11: Cross section of an individual bead in the verapamil -CODAS^TMdelivery system

Diffucaps® technology:

Italian drug delivery company, Eurand uses a polymer layer for timed release from drug containing particles in its Diffucaps® technology which is a multiparticulate system that provides optimal release profiles for either single drugs or for a combination of drugs. Customized drug release profiles are created by first layering active drug either from aqueous or solvent based drug solutions onto a neutral core (such as cellulose spheres) followed by the application of one or more rate-controlling, functional membranes(fig-12).

Figure 12: Diffucaps® technology

By using Diffucaps® technology, Eurand has developed a timed and sustained release dosage form which is a combination of controlled and delayed release membrane system and the uses multiple-release profile beads in a capsule system of the beta-blocker propranolol, for Reliant Pharmaceuticals and it is currently marketed in the US as Innopran XL®³⁵

Pulsincap® system:

Pulsincap® (developed by R.P. Scherer International Corporation, Michigan, US), comprises of a water-insoluble capsule body filled with drug formulation. The body is closed at the open end with a swellable hydrogel plug. Upon contact with gastro-intestinal fluids, the plug swells, pushing itself out of the capsule after a lag time followed by a rapid drug release. The lag time is controlled by dimension and position (the length and point of insertion into the capsule) of the plug, which gets pushed away by swelling or erosion and the drug is released as a ‘Pulse’ from the insoluble capsule body(fig-13).

Figure 13: Pulsincap® system

The plug material consists of insoluble but permeable and swellable polymers (polymethacrylates)^42,43, erodible compressed polymers (hydroxypropylmethylcellulose, polyvinylalcohol, polyethyleneoxide), congealed melted polymers (saturated polyglycolatedglycerides, glycerylmonooleate), and enzymatically controlled erodible polymer (pectin).

Port® -Programmable Oral Delivery Technology system:

The Port® (Programmable Oral Delivery Technology) system (fig-14), developed by Therapeutic system research laboratory Ann Arbor, Michigan, USA, consists of a capsule coated with a semi permeable membrane. Inside the capsule is an insoluble plug consisting of osmotically active agent and the drug formulation. When this capsule comes in contact with the dissolution fluid, the semi permeable membrane allows the entry of water, which causes the pressure to develop and the insoluble plug is expelled after a lag time, which is controlled by coating thickness. Such a system is utilized to deliver methylphenidate, used in the treatment of attention deficit hyperactivity disorder (ADHD) in school-age children.

Figure14: The Port® system

Egalet® technology:

Egalet® technology (Egalet a/s, Denmark) shows promising chronotherapeutic release by its delayed burst release form. Egalet® uses erosion rather than diffusion as the method for drug delivery⁴⁴. The system consists of an impermeable shell with two lag plugs, enclosing a plug of active drug in the middle of the unit. The time of release can then be modulated by the length and composition of the plugs along with the diameter of the Egalet. The matrix is designed to erode when comes in contact with water. The shells are made of ethylcellulose and cetostearyl alcohol while the matrix of the plugs comprises a mixture of polyethyleneglycol monostearates and polyethylene oxides. The advantage is that the surface area, which is exposed to water, remains constant with time, resulting in zero-order performance after certain lag-time⁴⁵. Egalet® is very nearer to get US FDA approval for chronotherapeutic labeling (fig-15).

Figure 15: Egalet® system

SyncroDose™ technology:

SyncroDose™ (Penvest Pharmaceutical) is claiming as the first delivery technology that provide true chronotherapy delivery options that offer a variety of pre-determined lag times, followed by a variety of customized profiles to coincide with the body's circadian rhythm pattern. The SyncroDose technology utilizes the TIMERx™ agglomerated hydrophilic matrix system in the compression coating combined with the active and various other excipients in the core. Lag time is controlled by variations in the two polysaccharides, xanthan gum and locust bean gum⁴⁶(fig-16,17). This delivery system works by controlling the rate of water ingress into the coating and subsequent disintegration of the core⁴⁷.

Figure 16: SyncroDose technology (TIMERx™)

Figure 17: Mechanism of TIMERx

The TIMERx® system can precisely control the release of the active drug substance in a tablet by varying the proportion of the gums, together with the tablet coating and the tablet manufacturing process.

Geminex^TM Dual Release Technology:

Geminex^TM Dual Release Technology (Penvest Pharmaceutical), provide release of the active drug in two different release profiles (immediately release and controlled release). A customized agglomerated hydrophilic complex that forms a controlled-release matrix upon compression controls the drug release rate. The matrix consists of two polysaccharides, xanthan and locust bean gum. Interactions between these components in an aqueous environment form a tight gel with a slowly eroding core. A major advantage of the Geminex^TM technology is the ability to develop a combination drug product that has two unique release profiles⁴⁹.

Chronotropic® system:

Chronotropic® system is based upon a drug reservoir which is surrounded with a soluble barrier layer that dissolves with time and the drug releases at once after this lag time. It consists of a core containing drug reservoir, coated by a hydrophilic polymer HPMC. The lag time and the onset of action are controlled by the thickness and the viscosity grade of HPMC. The system is suitable for both tablets and capsules. Chronotopic™ system has also been attained from gelatin capsule cores suitable for conveying dispersed and multiparticulate formulations, which are described as potentially beneficial to the oral bioavailability of peptides and proteins.

Time Clock® system:

Time Clock® system (West Pharmaceutical Services Drug Delivery & Clinical Research Centre) consists of a solid dosage form coated with lipidic barriers containing carnuba wax and bees wax, along with surfactants such as polyoxyethylene sorbitan monooleate. This coat erodes or emulsifies in the aqueous environment in a time proportional to the thickness of the film, and the core is then available for dispersion. The lag time can be increased with increasing coating thickness. The major advantage of this system is its ease of manufacturing without any need of special equipment.

Qtrol™ technology:

Qtrol™, a patented coating technology by Phoqus, allows formation of tailored dosage forms and particularly its tri-layer coating for time dependent release. Phoqus is developing an innovative new product Chronocort™, claiming for the first-in-class circadian hydrocortisone therapy for the treatment of congenital adrenal hyperplasia, Addison's disease and hypo-pituitarism, by utilizing their patented Qtrol™ technology to deliver the corticosteroid hydrocortisone in a time-release profile that mimics the healthy adrenal system's circadian rhythm release of cortisol.

GeoClock technology:

GeoClock technology (by SkyePharma), allows the preparation of chronotherapy-focused press coated tablets. GeoClock tablets have an active drug loaded inside an outer tablet layer consisting of a mixture of hydrophobic wax and brittle material in order to obtain a pH-independent lag time prior to core drug delivery at a predetermined release rate. This dry coating approach is designed to allow the timed release of both slow release and immediate release of active core by releasing the inner table first after which time the surrounding outer shell gradually disintegrates. GeoClock technology has also applications for the improved release of colonic drug delivery, as well as multiple pulse drug delivery to deliver doses of the drug at specific times throughout the day. The sleep-inducing product, currently known as SKP-1041, is a non-benzodiazepine hypnotic agent formulated using SkyePharma's patented GeoClock technology.

Lip’ral™ SSR - Lip’ral™ Synchronised Solubilizer Release:

Lip’ral™ Synchronised Solubilizer Release called as Lip’ral™-SSR (by Lipocine, Inc.) synchronizes the release of the insoluble drug and solubilizers and is ideally suited for drugs that require solubilization and controlled release. The release profiles can be modulated for delayed, pulsatile, or sustained release for targeted site absorption or chronotherapeutics without compromising therapeutic bioavailability. Other advantages of Lip’ral-SSR technologies are the use of bioacceptable excipients and the use of conventional manufacturing processes that are easy to scale-up⁵⁰.

Geomatrix® system:

Geomatrix®, a multi-layer tablet system consists of a hydrophilic matrix core containing the drug dose. One or two impermeable or semi permeable polymeric coatings (films or compressed) applied on both sides of the core⁵¹. This kind of three-layer device has been used in the L-dopa/benserazide treatment of Parkinsonism patients⁵². Night-time problems and early-morning symptoms of Parkinsonism can be avoided by using dual-release Geomatrix® formulation, which allows daily doses of drug to be reduced and leads to extent of bioavailability 40% greater than when a traditional controlled release formulation is employed.

Time-Controlled Explosion System (TES):

Time-Controlled Explosion System (TES),by Fujisawa Pharmaceutical Co. Ltd. has been developed for both single and multiple unit dosage forms. In both cases, a core contains drug plus an inert osmotic agent and suitable disintegrants. Individual units can be coated by a protective layer and then by a semi permeable layer, which is the rate controlling membrane for the influx of water into the osmotic core. As water reaches the core, osmotic pressure is built up; the core ultimately explodes with immediate release of the drug. The explosion of formulation can also be achieved through use of swelling agents, including superdisintegrants like sodium carboxymethyl cellulose, sodium starch glycollate, L-hydroxypropyl cellulose, polymers like polyvinyl acetate, polyacrylic acid, polyethylene glycol⁵³.

Sigmoidal Release System (SRS):

Sigmoidal Release System (SRS), a pellet type multiple unit preparations, containing an osmotically active organic acid have been coated with insoluble polymer to achieve different lag-times. Release rates from SRS after the lag time has found to be independent of the film thickness.In study, a good in vitro in vivo correlation with beagle dogs has been observed at early stage of drug (teophylline or propranolol hydrochloride) release⁵⁴.

Ticking Capsule⁵⁵:

Psivida expects to design ticking capsule, a chronotherapeutic device that employs some electrical means of controlling pulsatile drug release coupled with electronic timing.(fig-18)

Figure 18: Ticking Capsule

ChronoDose™ system:

Chrono Therapeutics, Inc. has developed a miniaturized drug delivery system ChronoDose™ for the precise, automated, time and dosage-controlled administration of drugs, non-invasively through the skin⁵⁶. It is worn like a wristwatch (fig-19), can be pre-programmed to administer drug doses into the body automatically, at different times of the day, and with varying dose sizes. The purpose of this technology is to deliver drugs during 24 to 72 h in an on/off fashion compliant with the circadian rhythm or pursuant of time and/or rate dependent pharmacological effects (fig-20). The ChronoDose™ system is claimed to represent the first true non-invasive chronopharmacological drug delivery device⁵⁷and can be programmed for a variety of drug delivery patterns to achieve customized patient dosing regiments for optimal therapy. These laboratory tests have shown that ChronoDose™ system has achieved all the initial objectives, which includes:

 Accurately and precisely vary each and every dose (adjust delivery rates to predefined values)

 Start and stop drug delivery accurately and with precision at predefined time points (accurate ‘on and off’ dosing)

 Achieve all of the above repeatedly and with the same degree of accuracy each time (multiple starts and stops to achieve any pre-programmed and optimized drug delivery profile)⁵⁸

Figure 19: ChronoDose™ system

Figure 20: Dosage profile ChronoDose™ system

Micropump® Technology:

Micropump® Technology (Flamel Technologies Ltd.)⁵⁹, consists of a multiple-dose system containing 5,000 to 10,000 microparticles per capsule or tablet. The microparticles are released in the stomach and pass into the small intestine, where each microparticle operating as a miniature delivery system, releases the drug by osmotic pressure at an adjustable rate and over an extended period of time. COREG CR™ (carvedilol phosphate) extended-release capsules, a once-a-day beta-blocker, is marketed by GlaxoSmithKline (GSK Pharma) by using Flemel’s Micropump® Technology and it is FDA approved to treat three cardiovascular conditions⁶⁰.

Smartcoat™ Technology:

Smartcoat™ Technology⁶¹ (Biovail) is used to develop very high potency, controlled-release tablets, allowing for smaller sized tablets while controlling the release over a 24 h period. A thin, very strong molecular diffusion membrane controls the release rate, which can be adapted to a number of different profiles. ‘Chronotabs’ are developed for bedtime administration (chronotherapy) using Smartcoat™ Technology.

CONCLUSION:

The drug release pattern if designed in a time controlled manner, maximum drug can be made available at peak hours and optimization of therapy can be achieved. This could be possible by chronotherapeutic drug delivery system and so, it can be considered as the most efficient tool for successful chronotherapy without any doubt. Now a day, enormous research work is being carried out in the field of chronopharmaceuticals and as a result, many technologies and devices have been developed and marketed but still it is a challenging task to develop a perfect chronopharmaceuticals device that fulfill all requirements for chronotherapy. Though a number of chronopharmaceuticals have been developed today, Dr. Bi-Botty Youan (from the Dept. of Pharmaceutical Sciences, Texas Tech. University) believes that future chronopharmaceuticals will also have to be “smarter” than current system. This could be possible by incorporation and combined use “stimuli sensitive” or “smart polymers” along with commonly used polymers but it requires further efforts in the direction of their probable use for chronopharmaceuticals.

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Received on 26.11.2009 Modified on 24.01.2010

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 344-352

THERAPEUTIC CLASS	EXAMPLES
Cardiovascular drugs	Verapamil, diltiazem, propranolol, enalepril, nifedipine, digoxin
Non Steroidal Anti-inflammatory Agents	Flubiprofen, ibuprofen, ketoprofen, tenoxicam, indomethacin
Antiasthmatic Drugs	Methylprednisolone, prednisolone, albuterol, theophylline, bambuterol, zileuton, zafirlukast, montelukast
Anticancer Agents	Doxorubicin, cisplatin, epirubicin, 6-mercaptopurine, 5-florouracil, methotraxate, vinblastin, bleomycine,
Anti Ulcer Agents	Omeprazole, ranitidine, famotidine, cimetidine, pirenzepine, terfenadin,
Anticholesterolemic Agents	Simvastatin, lovastatin
Others	Vitamin D3, diazepam, haloperidol

Current Status of Technologies and Devices for Chronotherapeutic Drug Delivery Systems

Chronotherapeutic Oral Drug Absorption System -CODAS TM technology:

Pulsincap® system:

Port® -Programmable Oral Delivery Technology system:

Egalet® technology:

SyncroDose™ technology:

Chronotropic® system:

Qtrol™ technology:

GeoClock technology:

Lip’ral™ SSR - Lip’ral™ Synchronised Solubilizer Release:

Geomatrix® system:

ChronoDose™ system:

Micropump® Technology:

Smartcoat™ Technology:

REFERENCES:

1. Sajan J,Cinu TA,Chacko AJ, Litty J, Jaseeda J, Chronotherapeutics and Chronotherapeutic Drug Delivery Systems, Tropical Journal of Pharmaceutical Research, October 2009; 8(5):467-475

Chronotherapeutic Oral Drug Absorption System -CODAS^TM technology: