e.g. - Thermoregulation, Hormonal secretions, Heart rate, Urination, Bowel activity, Appetite.

Ultradian rhythm:

Oscillation that is shorter than 24 hrs (more than one cycle per day)

e.g. - Sleep cycle (90-110min),

Growth hormone production cycle (3hrs),

Nasal cycle (4 hrs)

Infradian rhythm:

Oscillation that is longer than 24 hrs (less than one cycle per day)

e.g. - Menstrual cycle

Why Chronotherapy?

There are certain conditions for development of chronotherapy, which demands release of drug after lag time. In other words, it is prime necessities that the drug should not be released at all during the initial phase of dosage form administration. Such a release pattern is known as pulsatile release. The conditions that demand such release include:

§ A number of hormones shows chronological behavior causing 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, rennin and angiotensin are secreted in the morning.

§ Normal physiological body functions shows circadian effects, 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 like heart rate, blood pressure, body temperature, plasma concentrations, intraocular pressure, stroke volume and platelet aggregation also demonstrate time consistent patterns of chronology.⁸

§ Diseases like bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer, and hypertension display time dependence.⁹

§ Some drugs are undergoes extensively first-pass metabolism like β-blockers and those that are characterized by idiosyncratic pharmacokinetics or pharmacodynamics resulting in reduced bioavailability, altered drug/metabolite ratios, altered steady state levels of drug and metabolite, and potential food-drug interactions which can be overcome by use of chronotherapy which delivers drug when there is need to the body to reduce side effects and increase therapeutic efficacy of the drug.

§ Drugs having short half life need to repeatedly administered which results in patient incompliance and also continuous exposure of the drug to the body may lead to adverse effects which can be overcome by chronotherapy.¹⁹ (Table: 1)

Advantages of chronotherapy

1. Extended day or night time activity.

2. Reduced side effects.

3. Reduced dosage frequency.

4. Reduction in dose size.

5. Improved patient compliance.

6. Lower daily cost to patient due to fewer dosage units are required by the patient in therapy.

7. Drug adapts to suit circadian rhythms of body functions or diseases.

8. Drug targeting to specific site like colon.

9. Protection of mucosa from irritating drugs.

10. Drug loss is prevented by extensive first pass metabolism.

Methodologies for chronotherapy:

Methodologies for the chronotherapeutic drug delivery system can be broadly classified into three classes;

1. Time controlled

2. Stimuli induced

3. Externally regulated

1. Time controlled system:

In time controlled drug delivery systems, release is obtained after a specific time interval in order to mimic the circadian rhythm. Such type of drug delivery system contains two components: one is of immediate release type and other one is a pulsed release type. Various methodologies that can be used for time controlled release system are discussed in following section.

A. Single unit systems:

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

A.1. Capsule based system :

Several single unit pulsatile dosage forms with a capsular design have been developed. Most of them consist of an insoluble capsule body, which contains the drug and a plug, which prevents drug release during the lag phase. Mechanisms of plug removal include dissolution, erosion, or induced pushing-out of the plug by swelling or osmotic pressure.

A.1.1 Pulsincap system:

Pulsincap was developed by R.P. Scherer International Corporation, Michigan, USA. Such system consisted of a water-insoluble body (hard gelatin capsule coated with polyvinyl Chloride or ethyl cellulose) filled with the drug formulation.²⁰ The capsule half was closed at the open end with a swellable hydrogel plug. Polyemers used for designing of the hydrogel plug were various viscosity grades hydroxy propyl methyl cellulose, poly methyl methyacrylates, poly vinyl acetate, poly ethylene oxide. Upon contact with dissolution media or gastrointestinal fluids, the plug swelled and pushed itself out of the capsule after a lag time, followed by a rapid release of the capsule content. The lag time prior to the drug release was controlled by the dimension and the position of the plug. In order to assure a rapid release of the drug content, effervescent agents or disintegrants could be included in the drug formulation, in particular with water insoluble drugs. Studies in animals and healthy volunteers proved the tolerability of the formulation (e.g., absence of gastrointestinal irritation). In order to overcome the potential problem of variable gastric residence time of a single unit dosage form, the pulsincap system was coated with an enteric layer, which dissolved upon reaching the higher pH regions of the small intestine. This allowed a more precise control of the drug release after passage of the stomach, because the transit time in the intestinal tract is less variable. Krogel and Bodmeier studied the release of chlorpheniramine utilizing the erodible plugs fitted in the capsules. Stevens et al. designed a hydrophilic sandwich capsule that was based on a system where a capsule was enclosed within a capsule and the space in between was a gel barrier layer composed of HPMC. When the outer capsule dissolved, the delay in the second pulse was provided by the barrier gel layer.²¹

Figure 1: Release profiles of dosage forms

A.2. Systems based on osmosis:

The Port^®system was developed by Therapeutic system research laboratory Ann Arbor, Michigan, USA, and consists of a gelatin capsule coated with a semipermeable membrane (e.g. cellulose acetate) housing an insoluble plug (e.g. lipidic) and an osmotically active agent along with the drug formulation.²² When in contact with the aqueous medium, water diffuses across the semipermeable membrane, resulting in increased inner pressure that ejects the plug after a lag time. The lag time is controlled by coating thickness. Such a system was utilized to deliver methylphenidate used in the treatment of attention deficit hyperactivity disorder as the pulsatile port system. This system avoided second time dosing, which was beneficial for school children during daytime. ¹⁶

A.3. System with eroding or soluble coating:

In such system barrier dissolves or erodes after a specified lag time, after which the drug is released rapidly from the reservoir core. In general, the lag time prior to drug release can be controlled by the thickness of the coating layer. Various lag times have been achieved with press-coated tablets, where the press-coated barrier layer consisted of a mixture of a soluble polymer, hydroxy propyl methyl cellulose (HPMC) and different water-insoluble polymers, such as ethyl cellulose, Eudragit RS or polylactic acid in different ratios. The release medium permeates through the coating and then results in disintegration of the tablet, whereby the lag time prior to disintegration decreases with increasing proportion of the water-soluble polymer.

A.3.1 Chronotropic^®system:

Chronotropic^®system consists of a core containing drug reservoir coated by a hydrophilic polymer HPMC. An additional enteric-coated film is given outside this layer to overcome intra-subject variability in gastric emptying rates. The lag time and the onset of action are controlled by the thickness and the viscosity grade of HPMC. ^23,24Gazzaniga et al. prepared insulin loaded chronotropic system using HPMC.²⁵

A.3.2 Time Clock^® system:

The Time Clock^® system was developed by West Pharmaceutical Services Drug Delivery and Clinical Research Centre consists of a solid dosage form coated with lipidic barriers containing carnauba wax and beeswax along with surfactants, such as polyoxyethylene sorbitan monooleate.²⁶ 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. Midha et al. invented a pulsatile delivery system for d-threomethyl phenidate, an additional CNS stimulant in a dosage form comprising at least two individual drugs containing dosage limit housed in a closed capsule. The dosage units are designed in the form of compressed tablets which provide delayed release.²⁷

A.3.3 Multilayered Tablet:

A release pattern with two pulses was obtained from a three-layered tablet containing two drug containing layers separated by a drug-free gellable polymeric barrier layer.²⁸ This three layered tablet was coated on three sides with in impermeable ethyl cellulose, and the top portion was left uncoated. Upon contact with dissolution medium, the initial dose incorporated into the top layer was released rapidly from the non-coated surface. The second pulse was obtained from the bottom layer after the gelling barrier layer of HPMC was eroded and dissolved. The rate of gelling and/or dissolution of the barrier layer control the appearance of the second pulse.^28,29The gelling polymers reported include cellulose derivatives like HPMC, methyl cellulose or polyvinyl alcohols of various molecular weights and the coating materials include ethyl cellulose, cellulose-acetate-propionate, methacrylic polymers, acrylic and methacrylic co-polymers, and polyalcohols.³⁰

A.3.4 Eroding system with hollow cylinder with coated surfaces:

Another dosage form with an erosion-controlled lag time had a drug-containing core, which was incorporated into a compressed, hollow cylinder consisting of hydroxy propyl cellulose (HPC).³¹ The flat surfaces of the tablet were coated with an impermeable polymer, poly (ethylene vinyl acetate). The delivery system was prepared by hand; a hole was drilled into a tablet to obtain the hollow matrix, the inner drug core was placed into this hole and the system was coated by hand on the two flat base surfaces. Lag times between 6 and 11 hr were achieved with either a fast drug release after the lag time (using microcrystalline cellulose or lactose in the core) or sustained release (with HPC in the core). The lag time increased with increasing thickness of the matrix cylinder or by increasing viscosity of HPMC.³²The complete erosion of the matrix was necessary to release the drug.

A.4. Drug delivery system with rupturable layers/membranes:

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

An effervescent mixture of citric acid and sodium bicarbonate was incorporated in a tablet core coated with ethyl cellulose.³³ The carbon dioxide developed after penetration of water into the core resulted in a pulsatile release of drug after rupture of the coating. The release may depend on the mechanical properties of the coating layer. It is reported that the weak and non-flexible ethyl cellulose film ruptured sufficiently as compared to more flexible films. The lag time increases with increasing coating thickness and increasing hardness of the core tablet.

The highly swellable agents, also called superdisintegrants, were used to design a capsule-based system comprising a drug, swelling agent, and rupturable polymer layer. Superdisintegrants like cros-carmellose, sodium starch glycollate and low substituted hydroxy propyl cellulose.³⁴ The swelling of these materials resulted in a complete film rupture followed by rapid drug release. The lag time is function of the composition of the outer polymer layer. The presence of hydrophilic polymer like HPMC reduced the lag time. Sungthongjeen et al. designed a system where the tablets of buflomedil HCl prepared by direct compression with varying amounts of spray-dried lactose and microcrystalline cellulose were coated with an inner swelling layer using cros- carmellose sodium and an outer rupturable layer using ethyl cellulose. It was observed that by increasing the amount of ethyl cellulose coating, the lag time could be prolonged. Ethyl cellulose, being water insoluble, retarded the water uptake. Similar results were obtained with cros-carmellose sodium. Increasing the amount of microcrystalline cellulose decreased the lag time substantially.³⁵ Bussemer et al. worked on a system with rupturable coating on drug present in hard gelatin capsules. These capsules were first coated with a swelling layer and then with an insoluble but water-permeable outer coating. These coated capsules when immersed in the release media could take up the media at a constant rate up to a point when the outer coating would rupture because of the pressure caused by the swelling layer. It could be concluded that by increasing the swelling layer, the lag time could be shortened. However, by increasing the outer coating, the lag time could be prolonged. It was also observed that addition of HPMC to the outer coating shortens the lag time.³⁶

B. MULTIPARTICULATE SYSTEMS (multiple unit system):

Multiparticulate systems (e.g., pellets) offer various advantages over single-unit systems.³⁷These include no risk of dose dumping, flexibility of blending units with different release patterns, reproducible and short gastric residence time. But the drug-carrying capacity of multiparticulate systems is lower due to presence of higher quantity of excipients.^37,38 Such systems are invariably a reservoir type with either rupturable or altered permeability coating.

Advantages:

· Short gastric residence time

· Reproducible gastric residence time

· No risk of dose dumping

· Flexible to blend pellets with different composition or release pattern

· Lowest transit time variability

· Unique profiles

· Amenable to capsule and tablets

· Capable of pulsatile release

Disadvantages:

· Multiple manufacturing steps

· Low drug load

· Incomplete release

B.1. Reservoir systems with soluble or eroding polymer coatings:

Reservoir type multiparticulate pulsatile systems are based on soluble/erodible layers in place of rupturable coatings.³⁹ The barrier dissolves or erodes after a specific lag time followed by burst release of drug from the reservoir core. In general, for this kind of systems, the lag time prior to drug release can be controlled by the thickness of the coating layer. Gazzaniga et al. shows slow dissolution behaviour of high viscosity polymers. It consists of mini-tablets with there in dispersed a drug substance which is coated with a high viscosity polymer (HPMC 4000) and an outer enteric coating. The outer film protects the system from the fluids in the stomach and dissolves on entering the small intestine. HPMC layer delays the release of drug for 3-4 hrs. when the system is transported through small intestine.⁴⁰ A pH sensitive multi-particulate system, comprising of Eudragit S-100 coated pellets was designed for chronotherapeutics delivery of diltiazem hydrochloride for treating angina pectoris.⁴¹

B.2. Low density floating multiparticulate systems:

Conventional multiparticulate release dosage forms having longer residence time in the gastrointestinal tract and due to highly variable nature of gastric emptying process, may resulted in in-vivo variability and bioavailability problems. In contrary, low density floating multiparticulate dosage forms reside in stomach only and not affected by variability of pH, local environment or gastric emptying rate. These dosage forms are also specifically advantageous for drugs either absorbed from the stomach or requiring local delivery in stomach. Overall, these considerations led to the development of multiparticulate pulsatile release dosage forms possessing gastric retention capabilities. A multiparticulate floating-pulsatile drug delivery system was developed using porous calcium silicate (Florite RE) and sodium alginate, for time and site specific drug release of meloxicam for chronotherapy of rheumatoid arthritis.⁴² Badve et al developed hollow calcium pectinate beads for floating-pulsatile release of diclofenac sodium intended for chronotherapy. ⁴³

B.3. System Based on Rupturable Coating:

Drug is released from the core after rupturing of the surrounding polymer layer after incorporated in dissolution medium, due to pressure build-up within the system. The pressure necessary to rupture the coating can be achieved with swelling agents, gas-producing effervescent excipients or increased osmotic pressure. Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time.

Time-Controlled Explosion System developed by Fujisawa Pharmaceutical Co., Ltd. This is a multiparticulate system in which drug is coated on non-pareil sugar seeds followed by a swellable layer and an insoluble top layer. The swelling agents used include superdisintegrants like sodium carboxy methyl cellulose, sodium starch glycollate, L-hydroxy propyl cellulose, polymers like polyvinyl acetate, polyacrylic acid, polyethylene glycol, etc. Alternatively, an effervescent system comprising a mixture of tartaric acid and sodium bicarbonate may also be used. Upon ingress of water, the swellable layer expands, resulting in rupture of film with subsequent rapid drug release.^44,45 In-vivo studies of time-controlled explosion system (TCES) with an in-vitro lag time of 3 hours showed appearance of drug in blood after 3 hours and maximum blood levels after 5 hours.⁴⁵

B.4. System based on change in membrane permeability:

The permeability and water uptake of acrylic polymers with quaternary ammonium groups can be influenced by the presence of different counter-ions in the medium.⁴⁶ Eudragit RS 30D is used for the purpose of developing ion exchange delivery system using theophylline as a model drug with sodium acetate.^47,48 It typically contains positively polarized quaternary ammonium group in the polymer side chain, which is always accompanied by negative hydrochloride counter-ions. The ammonium group being hydrophilic facilitates the interaction of polymer with water, thereby changing its permeability and allowing water to permeate the active core in a controlled manner. This property is essential to achieve a precisely defined lag time. It was found that even a small amount of sodium acetate in the pellet core had a dramatic effect on the drug permeability of the Eudragit film.⁴⁹

Sigmoidal Release System: This consists of pellet cores comprising drug and succinic acid coated with ammonio-methacrylate copolymer.⁵⁰ The lag time is controlled by the rate of water influx through the polymer membrane. The water dissolves succinic acid, the drug in the core and the acid solution in turn increases permeability of the hydrated polymer film. In addition to succinic acid, acetic acid, glutaric acid, tartaric acid, malic acid or citric acid can be used. The increased permeability can be explained by improved hydration of film, which increases free volume. These findings were used to design a coated delivery system with an acid-containing core. Stevens et al. have used extrusion/spheronisation technology to produce a novel pellet formulation containing diltiazem that was coated with a mixed film coat comprising ethyl cellulose as a diffusion barrier retarding release and Eudragit RS polymers use to increase permeability causing sigmoidal release profile.⁵¹

2. Stimuli induced systems:

In these systems there is release of the drug after stimulation by any biological factor like temperature or any other chemical stimuli. These systems are further classified in to temperature induced systems and chemical stimuli induced system, on the basis of stimulus.

2.1. Temperature induced systems:

Thermo-responsive hydrogel systems have been developed for chronotherapeutics purpose. Thermo-responsive polymer undergoes swelling or deswelling phase in response to the temperature which modulate drug release in swollen state.⁵² Y.H. Bae et al developed indomethacin pulsatile release pattern in the temperature ranges between 20⁰C and 30⁰C by using reversible swelling properties of copolymers of N-isopropylacrylamide and butyrylacrylamide.⁵³ Kataoka et al developed the thermosensitive polymeric micelles as drug carrier to treat the cancer.⁵⁴

2.2. Chemical stimuli induced systems:

2.2.1. Glucose-responsive insulin release devices:

In case of diabetes mellitus, glucose level shows rhythmic changes which can be treated by chronotherapy. One such system includes pH sensitive hydrogel like N,N-dimethyl amino ethyl methacrylate, chitosan, polyol containing glucose oxidase immobilized in the hydrogel. When glucose concentration in the blood increases glucose oxidase converts glucose into gluconic acid which changes the pH of the system and induces polymer swelling and results in insulin release. Insulin by virtue of its action reduces blood glucose level and consequently gluconic acid level also gets decreased causing deswelling of polymer which decreases the insulin release. Obaidat and Park prepared a copolymer of acryl amide and allyl glucoseand bound to concanavalin A.⁵⁵ These hydrogels showed a glucose-responsive, sol–gel phase transition dependent upon the external glucose concentration. Okano et al developed the system based upon reversible complex gels of the water-soluble copolymers, containing phenylboronic acid side chains with polyol compounds such as poly(vinyl alcohol) (PVA) including glucose. ⁵⁶

2.2.2. Inflammation-induced chronotherapeutic release:

During inflammation caused by physical or chemical stress like injuries, fracture, hydroxyl radicals are produced from these inflammation-responsive cells. Yui and co-workers designed drug delivery system which responded to the hydroxyl radicals for release of drug.⁵⁷ They used hyaluronic acid (HA) which is specifically degraded by the hyaluronidase and hydroxyl radicals. HA is degraded rapidly by hydroxyl radical than hyaluronidase at inflammated site which release drugs like anti-inflammatory to treat patients with inflammatory diseases like rheumatoid arthritis.

2.2.4. pH sensitive drug delivery system:

Using pH dependent polymers includes cellulose acetate phthalate, polyacrylates, sodium carboxy methyl cellulose, we can designed chronotherapeutics system which delivers drug at specific site at specific time. Yang et al developed pH-dependent delivery system of nitrendipine using mixture of three kinds of pH dependent microspheres made up of acrylic resins Eudragit E-100, Hydroxy propyl methylcellulose phthalate and Hydroxy propyl methylcellulose acetate succinate as pH dependent polymers.⁵⁸ Mastiholimath et al deliver theophylline into colon using the mixture of the polymers, i.e. Eudragit L and Eudragit S in proper proportion.⁵⁹

3. Externally regulated systems:

Chronotherapeutics drug release is also programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation. In magnetically regulated system, on application of the magnetic field, drug release occurs because of magnetic beads. Saslawski et al. developed delivery of insulin based on magnetic alginate spheres.⁶⁰ In case of ultrasonically modulated systems, ultrasonic waves cause the erosion of the polymeric matrix thereby modulating drug release. Miyazaki et al evaluated the effect of ultrasound (1 MHz) on the release rates of bovine insulin from ethylenevinyl alcohol copolymer matrices.⁶¹ Mathiowitz et al developed photochemically controlled delivery systems prepared by interfacial polymerization of polyamide microcapsules using azobisisobutyronitrile (AIBN) which emanates nitrogen gas upon exposure of light thereby an increase in the pressure which ruptures the capsules releasing the drug.⁶²

Marketed chronotherapeutic system (Table: 2)

Conclusion:

Chronotherapy is an emerging branch of therapy which is based on chronological behaviour of human being to deliver drug at specific time and at specific site. This is advantageous to treat the diseases like Asthma, Peptic ulcer, Cardiovascular diseases, Diabetics and Rheumatoid arthritis. Various methodologies are employed for developing chronotherapeutic system like time controlled, self regulating and externally modulated and some of them are also available in market. Due to such beneficial characteristics chronotherapy should be promising in the future.

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DISEASE	CHRONOLOGICAL BEHAVIOR	DRUG USED
Peptic ulcer¹⁰	Acid secretion is high in the afternoon and at night	H₂blockers, Proton pump inhibitor
Asthma^11,12	Precipitation of attacks during night or at early morning hours	β ₂ agonist, antihistaminic
Cardiovascular diseases¹³	BP is at its lowest during the sleep cycle and rises steeply during the early morning awakening period	Nitro-glycerine, β-blocker, ACE inhibitors, Diuretics etc.
Arthritis¹⁴	Pain in the morning and more pain at night	NSAIDs, glucocorticoids
Diabetes mellitus¹⁵	Increase in the blood sugar level after meal	Sulfonylurea, insulin, bigunide
Attention deficit syndrome¹⁶	Increase in DOPA level in afternoon	Methylphenidate
Hypercholesterolemia^17,18	Cholesterol synthesis is generally higher during night than during day time	HMG CoA reductase inhibitors