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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
INTRODUCTION
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
INTRODUCTION
Biological rhythms are an adaptive phenomena relating to predictable changes in
environmental factors that regulate many body functions like metabolism, sleep pattern,
hormone production, hormone production and physiology .Variation in body function cause
changes both in diseases state and in plasma drug concentration. Many functions of the
human body vary considerably in a day. These variations cause changes both in disease state
and in plasma drug concentrations. Human circadian rhythm is based on sleep activity cycle,
is influenced by our genetic makeup and hence, affects the body’s functions day and night
(24-hour period) 1. The dependence of bodily functions in certain disease states on circadian
rhythm is well known. A number of hormones are released by the brain in the morning, while
others are released during sleep. Blood pressure and heart rate are highest during the hours of
6.00 a.m. to 12.00 noon 2. Diseases, such as hypertension, asthma, peptic ulcer, arthritis, etc,
follow the body's circadian rhythm . Many systems in the human body such as
cardiovascular, pulmonary, hepatic and renal systems show variation in their function
throughout a typical day. They are naturally synchronized by the internal body clocks and are
controlled by the sleep wake cycle. Each bodily system exhibits a peak time of functionality
that is in accordance with these rhythmical cycles. Similarly, disease states affect the function
of some of these systems in the body and therefore, they too exhibit a peak time of activity
within a circadian rhythm .
CHRONOBIOLOGY 3:
The term "Chrono" pertains to time and "Biology" is the science of life, thus,
chronobiology concerns with the observation of every metabolic event goes through rhythmic
changes in time that can be measured from seconds to seasons . Typical examples are levels
of plasma testosterone and cortisol, which typically peak in the early morning, and the
secretion of growth hormone, which peaks during sleep.
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
CHRONOPHARMACOKINETICS 3:
Studies show that time of drug administration especially with reference to circadian rhythm
can impact the kinetics and dynamics of various classes of medicines studies have been
reported that the time of administration of many drugs is a possible factor in variation of the
pharmacokinetics of a drug. . Different pharmacokinetics constraints of time like elimination
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
rate, peak concentration, volume of distribution, and AUC of a number of drugs are affected
by circadian rhythms relates to the dosing-time, which could be expressed as rhythm-
dependent, under the divergences in the effects of drugs.
CHRONOTHERAPEUTICS 3:
It refers to the clinical practice of harmonizing delivery of the drug in accordance with
body's circadian rhythm including ailment states to create maximum benefit and minimizing
harm .
CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 3:
ChrDDs refers to a treatment method in which in vivo drug availability is timed to match
circadian rhythms of disease in order to optimize therapeutic outcomes and minimize side
effects.
OBJECTIVES OF WORK:
The aim of project work is to study in general about various pharmaceutical aspect
of chronotherapeutic drug delivery system in solving many formulation problem and to
conduct literature survey and characterisation ,to summarise the further scope as well as in
application in pharmacy
IDEAL CHARACTERISTICS OF CHRONOTHERAPEUTIC DRUG DELIVERY
SYSTEM 4:
Ideal ChrDDS should:
be non-toxic within approved limits of use,
have a real-time and specific triggering biomarker for a given disease state,
have a feed- back control system (e.g. self -regulated and adaptative capability to
circadian rhythm and individual patient to differentiate between awake – sleep status).
be biocompatible and biodegradable, especially for parenteral administration,
be easy to manufacture at economic cost.
be easy to administer in to patients in order to enhance compliance to dosage
regimen.
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ADVANTAGES OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 5 :
1. Extended day time activity or night time activity.
2. Reduced side effect.
3. Reduced dosage frequency.
4. Reduction in dose size.
5. Improved patients compliance.
6. Lower daily cost to patient due to fewer dosage unit are required by the patients
7. Drug adapt to suit circadian rhythm of body function or diseases.
8. Drug targeting to specific site. e .g colon
9. Avoids degradation of in upper gastrointestinal tract.(proteins and peptides) .
10. Drug loss is prevented by extensive first pass metabolism.
11. Extended release of drug in pulsatile manner .
12. Right timing and the amount of medication optimizes the drug's desired effects and
minimize the undesired ones.
DISADVANTAGES OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM5:
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. Person become less productive during
chronotherapy and staying awake till the other schedule will be bit uncomfortable.
3. Medical supervision is mandatory for this therapy. And regular consulting of sleep
speacitists is recommended.
4. 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.
5. Person going through the therapy may feel unusually hot or cold sometimes.
6. Have to consult the doctor regularly to avoid side effect.
7. Major drawbacks of existing oral chronotropic systems are their dependence human
action to trigger the drug release.
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APPROACHES FOR CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM
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APPROACHES FOR CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 6:
Controlled release formulations can be divided into subgroups of rate-controlled
release, delayed-release and pulsed-release formulations. Delayed-release formulations
include time controlled release and site specific dosage forms .When constant drug plasma
levels need to be avoided, as in chronotherapy, time-controlled or pulsed-release formulations
are preferable, especially in the treatment of early morning symptoms. By timing drug
administration, plasma peak is obtained at an optimal time and the number of doses per day
can be reduced. Saturable first-pass metabolism and tolerance development can also be
avoided .
ENTERIC COATED SYSTEM 6:
Enteric coatings have traditionally been used to prevent the release of a drug in the
stomach Enteric coatings are pH sensitive and drug is released when pH is raised above 5 in
the intestinal fluid. These formulations can be utilised in time-controlled drug administration
when a lag time is needed. Because of the unpredictability of gastric residence, such systems
cannot be the first choice when a time-controlled release is required. In the treatment of
nocturnal asthma, as albutamol formulation containing a barrier coating which is dissolved in
intestinal pH level above about 6, has been successfully used. The system contains a core
which is film coated with two polymers, first with HPMC and then with a gastro-resistant
polymer (Eudragit),cellulose acetate phthalate, hydroxyl propylmethylcellulose are used for
coating which protects the dosage forms from the acidic environment of the GIT and allows
delivery of the drug to the small or large intestine based on solubility, pH and coating
thickness of the polymeric layer .In this system the duration of the lag phase in absorption
can be controlled by the thickness of the HPMC layer. Enteric coated systems are used for
site specific and time controlled drug delivery.
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2 .LAYERD SYSTEM 6:
These 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 was 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. Multi-layer tablet system it consists
of a matrix core containing the drug dose. This kind of three layer device has been used in
the treatment of Parkinsonian patients using L-- dopa/ benserazide. Night time problems and
early-morning symptoms of Parkinsonism can be avoided by using a dual release
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
3.TIME-CONTROLLED EXPLOSION SYSTEM(TES) 7:
These have been developed for both single and multiple unit dosage forms . In both
cases, the core contains the drug, an inert osmotic agent and suitable disintegrates. Individual
units can be coated with a protective layer and then with 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 the formulation can also be achieved through the use of swelling
agents. Lag time is controllable by varying the thickness of the outer polymer coating .
4.SIGMOID RELEASE SYSTEM(SES) 7:
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 .
By applying different coating thicknesses, lag times in vivo of up to 5 hours can be achieved.
Release rates from SRS, beyond the lag time, has been found to be independent of coating
thickness.
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6.PRESS-COATED SYSTEM 8:
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. On the other
hand, for large-scale manufacture, special equipment is needed. The major drawbacks of the
technique are that relatively large amounts of coating materials are needed and it is difficult
to position the cores correctly for the coating process .In recent years, various controlled
release, especially time-controlled release, drug delivery systems based on compression
coating technology have been studied. Most of such formulations release drug after a lag
phase, followed by a rapid dissolution of the core. a press coated device in which the inner
core contains the drug and the outer coat is made of different types of polymers. The outer
barrier, which controls drug release, can be either swellable or erodible. Lag times can be
varied by changing the barrier formulation or the coating thickness . Hydrophilic polymers
such as hydroxypropyl methylcellulose and sodium alginate have been used in the coat to
control drug release.
7.PULSINCAP 8:
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It is a single unit system comprised of a water insoluble capsule body enclosing the
drug reservoir. The capsule body is closed at one end with a swellable hydro gel plug.
Various hydro gels such as hydroxypropyl methylcellulose, hydroxypropyl,polyvinyl
pyrrolidone are used as plug materials. Enzymatically controlled erodible polymers such as
pectin can also be used as plugging material. When the capsule comes in contact with water it
absorbs water and swells. After a lag time the plug gets pushed out and the drug gets release
rapidly in the form of a pulse. The total length of the plug, its position of the insertion into the
capsule and the polymer used for making the plug controls the lag time of the system. Rapid
release of the drug can be ensured by the inclusion of effervescent agents, super disintegratnts
and osmotic agents.
8.SWELLING AND ERODIDLE SYSTEM 9:
Swelling and erodible systems released after the lag time. The coating layer is made up
of various hydrophilic polymers .In addition to this enteric coating can be applied outside to
overcome the gastric pH effect on the drug. The lag time of the system can be controlled by
thickness of the polymeric coat and the viscosity grade of the polymer used.
9.MULTIPARTICULATE SYSTEM 9:
More reliable gastric emptying pattern is observed for multiparticulate systems and is
based on changes in membrane permeability and rupture of the coating. The drug is coated on
non-peril sugar seeds followed by coating with swellable polymeric layer. The swelling
agents include super disintegrates, effervescent agents and osmotic agents. Upon ingress of
water, the swellable layer expands resulting in rupture of the film and rapid drug release.
Several delivery systems based on ion exchange principle have been developed. Other used
polymers such as Eudragits RS30D. It contains positively charged quaternary ammonium
groups in the side chain accompanied by negative hydrocolloid counter ions. The ammonium
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groups interact with water, change the permeability and allow water to penetrate in to the
core layer in a controlled manner.
10.ULTRASOUND DRUG DELIVERY SYSTEM 9:
Ultrasound is an enhancer for improvement of drug penetration through biological
barriers such as skin, blood vessels etc. The ultrasound effect enhances degradation of the
polymer in which the drug molecules are incorporated. The drug can be released by repeated
ultrasound exposure. Pulse delivery is achieved by on off application of ultrasound.
.
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CHRONOPHARMACEUTICAL TECHNOLOGIES
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CHRONOPHARMACEUTICAL TECHNOLOGIES 10:
Currently key technologies in chronopharmaceutics includes:
CONTINR
PHYSICO- CHEMICAL MODIFICATION OF A.P.I:
OROSR
CODASR
CEFORMR,
DIFFUCAPSR
CHRONOTOPIC TECHNOLOGY:
EGALET TECHNOLOGY:
GEOCLOCK TECHNOLOGY:
CHRONOMODULATING INFUSION PUMPS
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CHRONODOSE SYSTEM:
CRYSTAL RESERVOIR SYSTEM:
TIMERxR
CONTROLLED-REALSE MICROCHIPS
PORT TECHNOLOGY
THREE DIMENSIONAL PRINTING(3DP) TECHNOLOGY
1.CONTINR TECHNOLOGY 10:
In this technology, molecular coordination complexes are formed between a cellulose
polymer and a non-polar solid aliphatic alcohol optionally substituted with an aliphatic group
by solvating the polymer with a volatile polar solvent and reacting the solvated cellulose
polymer directly with the aliphatic alcohol, preferably as a melt. This constitutes the complex
having utility as a matrix in controlled release formulations since it has a uniform porosity
(semi permeable matrixes) which may be varied . This technology has concretely enabled the
development of tablet forms of sustained-release aminophylline, theophylline, morphine, and
other drugs. Research suggested that evening administration of UniphylR (anhydrous
theophylline) tablets represented a rational dosing schedule for patients with asthma who
often exhibit increased broncho constriction in the morning. CONTINR technology provides
for closer control over the amount of drug released to the bloodstream, and benefits patients
in terms of reducing the number of doses they need to take every day, providing more
effective control of their disease (particularly at night), and reducing unwanted side effects .
2.PHYSICO- CHEMICAL MODIFICATION OF A.P.I 10:
Method is used to modify the physicochemical properties (e.g. .solubility, partition
coefficient, membrane permeability, etc.) of the API to achieve the Chronopharmaceuticals
objective. The rationale for such approach is based on the solubility and permeability are
critical factors governing drug bioavailability. Typical examples of the use of this strategy in
chronotherapy are those of antihyperlipidemic statins (HMG-Co A reductase inhibitors) and
ant ulcerative agents(histamine H2 receptor-antagonists) . Basically, the introduction a
methyl group in the chemical structure of lovastatin leads to the production of simvastatin.
Such modifications change the melting point (m.p.) of these compounds from 174.5 to 135–
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138 jC for lovastatin and simvastatin, respectively .Molecular weight and m.p. of compounds
are related to their solubility. Physicochemical modifications affect the time to reach the
maximum plasma concentration (Tmax) for these compounds. The Tmax varies from 2 to 4
h for lovastatin and simvastatin, respectively. Prodrug approach may also be used to obtain a
ChrDDS. For example, lovastatin and simvastatin are lactone prodrugs that are modified in
the liver to active hydroxyl acid forms. Since, they are lactones, they are less water soluble
than other statins .
3.OROS TECHNOLOGY 11:
OROSR technology uses an osmotic mechanism to provide pre-programmed,
controlled drug delivery to the gastrointestinal tract. The dosage form comprises a wall
compartment. The active drug is housed in a reservoir, surrounded by a semi-permeable
membrane/wall (e.g. cellulose esters, cellulose ethers and cellulose ester–ethers) and
formulated into a tablet. The tablet is divided into two layers, an active drug layer and a layer
of osmotically active agents (e.g. polyethylene oxide)) comprising means for changing from a
non-dispensable viscosity to a dispensable viscosity when contacted by fluid that enters the
dosage form. while the cap is made of proprietary water‐permeable blends of
polycaprolactone and flux enhancers For example, water from the gastrointestinal tract
diffuses through the membrane at a controlled rate into the tablet core, causing the drug to be
released in solution or suspension at a pre determined rate. This creates a ‘pump’ effect that
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pushes the active drug through a hole in the tablet. This technology, especially the OROSR
Delayed Push– Pull System, also known as controlled on extended release (COER) was used
to design Covera-HSR, a novel antihypertensive product. It actually enabled delayed,
overnight release of verapamil to help prevent the potentially dangerous surge in BP that can
occur in the early morning .
4.CODASR TECHNOLOGY 11:
The Chronotherapeutic Oral Drug Absorption System (CODASR) is a
multiparticular system which is designed for bedtime drug dosing, incorporating a 4–5 h
delay in drug delivery. This delay is introduced by the level of non-enteric release-controlling
polymer applied to drug loaded beads. The release controlling polymer is a combination of
water soluble and water insoluble polymers. As water from the gastrointestinal tract comes
into contact with the polymer coated beads, the water soluble polymer slowly dissolves and
the drug diffuses through the resulting pores in the coating. The water insoluble polymer
continues to act as a barrier, maintaining the controlled release of verapamil . The rate of
release is essentially independent of pH, posture and food. The night time dosing regimen of
(CODASR-Verapamil)was not associated with excessive BP reductions during the sleeping
hours. The CODASR verapamil extended release capsules (VerelanR PM) as ChrDDS
actually provided enhanced BP reduction during the morning period when compared with
other time intervals of the 24-h dosing period .
5.CEFORMR TECHNOLOGY 11:
The CEFORMR technology allows the production of uniformly sized and shaped
microspheres of pharmaceutical compounds. This ChrDDS approach is based on
‘‘meltspinning’’,which means subjecting solid feedstock i.e. biodegradable polymer/bioactive
agents combinations to the 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 Am, 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 either with an enteric coating or combined into a fast/ slow release combination. This
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technology has been actually used to develop CardizemR LA, 1-day diltiazem formulation as
ChrDDS .
6.DIFFUCAPSR TECHNOLOGY 12:
In the DIFFUCAPSR technology, a unit dosage form, such as a capsule for
delivering drugs into the body in a circadian release fashion, comprises of one or more
populations of drug containing particles (beads, pellets, granules, etc.). Each bead population
exhibits a pre-designed rapid or sustained release profile with or without a predetermined lag
time of 3–5 h. The active core of the dosage form may comprise an inert particle or an acidic
or alkaline buffer crystal (e.g. cellulose ethers), which is coated with an API-containing film-
forming formulation and preferably a water-soluble film forming composition (e.g. hydroxyl
propylmethylcellulose,polyvinyl pyrrolidone) to form a water-soluble/dispersible particle.
The active core may be prepared by granulating and milling and/or by extrusion and
spheronization of a polymer composition containing the API. Such a ChrDDS is designed to
provide a plasma concentration–time profile, which varies according to physiological need
during the day, i.e. mimicking the circadian rhythm and severity/manifestation of a
cardiovascular disease, predicted based on pharmacokinetic and pharmacodynamic
considerations and in vitro/in vivo correlations. This technology has been used to formulate
the first and recently FDA approved propranolol containing ChrDDS (InnopranR XL) for the
management of hypertension. Diffucaps beads are <1.5 mm in diameter and can be filled into
capsules or compressed into orally disintegrating tablets.
Advantages of Diffucaps
• Ideal for drugs exhibiting poor solubility in lower intestinal pH, in environments with pH
above 8.0, or in physiological fluids
• Can combine multiple drugs and/or multiple release profiles in
the same dosage form
• Simple formulation of dose‐proportional strengths.
• Can minimize food effect
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Cross section of Diffucaps
7.CHRONOTOPIC TECHNOLOGY 13:
It consists of a core containing drug reservoir coated by a
hydrophilic polymer hydroxylpropyl methylcellulose (HPMC). An additional enteric‐coated
film is given outside this layer to over come 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.
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8.EGALET TECHNOLOGY 13:
It offers a delayed release. System consists of an impermeable shell with two lag plugs,
active drug after the inert plugs have eroded, the drug is released, thus a lag time occurs.
Time of release can 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 made up of a mixture of
pharmaceutical excipients including polymers like polyethylene oxide (PEO). g is
sandwiched between the plugs.
: Egalet: (a) Intact Unit (b) Erosion of the time delay insert plugs, and (c) Drug release
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9.GEOCLOCK TECHNOLOGY 14:
Geoclock tablets have an active drug 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. developed to achieve an on–off switching
drug delivery for transdermal application via the externally repeated cycle of temperature
change.
X ray of Geoclock tablets
10.CHRONOMODULATING INFUSION PUMPS 14:
The portable pumps are usually characterized by a light weigh (300–500 g) for easy
portability and precision in drug delivery. For example portable programmable multi-channel
pumps allowed demonstration of the clinical relevance of the chronotherapy principle in a
sufficiently large patient population. Specifically, a clinical phase III trial involving several
patients with metastatic gastrointestinal malignancies compared a flat versus the
chronomodulated three-drug regimen, and demonstrated large, simultaneous improvements in
both tolerability and response rates in patients with metastatic colorectal cancer receiving
chronotherapy.
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11.CHRONODOSE SYSTEM 14 :
The ChronoDose system is a revolutionary drug delivery device, worn like a wristwatch,
which can be pre-programmed to administer drug doses into the body automatically, at
different times of the day and with varying dose sizes.
12..CRYSTAL RESERVOIR SYSTEM 14:
A transdermal system for chronotherapy of asthma. A thermo responsive membrane was
developed to achieve an on–off switching drug delivery for transdermal application via the
externally repeated cycle of temperature change.
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13.TIMERxR TRCHNOLOGY 15:
The TIMERxR technology (hydrophilic system) combines primarily xanthan and locust
bean gums mixed with dextrose. The physical interaction between these components works to
form a strong, binding gel in the presence of water. Drug release is controlled by the rate of
water penetration from the gastrointestinal tract into the TIMERxR gum matrix, which
expands to form a gel and subsequently releases the active drug substance. This system can
precisely control the release of the active drug substance in a tablet by varying the proportion
of the gums, together with the third component, the tablet coating and the tablet
manufacturing process. Potential application of this technology is the development of an oral,
CR opioid analgesic oxymorphone .
14.CONTROLLED-REALSE MICROCHIPS 15:
An alternative method to achieve pulsatile or Chronopharmaceuticals drug release
involves using micro fabrication technology. A solid-state silicon microchip that can provide
controlled release of single or multiple chemical substances on demand. The release
mechanism was based on the electrochemical dissolution of thin anode membranes covering
micro reservoirs filled with chemicals in solid, liquid or gel form. Initially conducted
proof-of-principle release studies with a prototype microchip using gold and saline solution
as a model electrode material and release medium, and demonstrated controlled, pulsatile
release of ch poly(L-lactic acid) and had poly(D,L-lacticco- glycolic acid) membranes were
fabricated that released four pulses of radio labelled dextran, human growth hormone or
heparin. This technology has the potential to be used in the design of ChrDDS with a better
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control over drug release kinetic in order to match biological requirement over a versatile
period of time.
15.PORT TECHNOLOGY 16:
The Programmable Oral Release Technologies (PORT) system is a uniquely coated,
encapsulated system that can provide multiple programmed release of the drug. It contains a
polymeric core coated with a semipermeable, rate-controlling polymer. Poorly soluble drugs
can be coated with solubilising agents, to ensure a uniform controlled release from the dosage
form. In the capsule form, the gelatine capsule is coated with a semi permeable, rate-
controlling polymer. Active medicament mixed with an osmotic agent is kept inside the
capsule shell. A water-insoluble plug is used to seal the capsule shell. Immediate release
compartment can be added according.
The Port System - consists of a gelatine capsule coated with a semi permeable
membrane (e.g.: cellulose acetate) housing an insoluble plug ( e.g.: lipidic) and an
osmotically active agent along with the drug formulation . When it comes in contact with the
aqueous medium, water diffuses across the semi permeable membrane, resulting in increased
inner pressure that ejects the plug after a – time lag. The time lag is controlled by the
thickness of semi permeable membrane. In order to deliver drug in liquid form, an
osmotically driven capsular system was developed. In this system, liquid drug is absorbed
into highly porous particles, which release the drug through an orifice of a semi permeable
capsule supported by an expanding osmotic layer after the barrier layer is dissolved. The
capsular system delivers drug by the capsule's osmotic infusion of moisture from the body.
The capsule wall is made up of an elastic material and possesses an orifice. As the osmosis
proceeds, the pressure within the capsule rises, causing the wall to stretch. The orifice is
small enough so that when the elastic wall relaxes, the flow of the drug through the orifice
essentially stops, but when the elastic wall is distended beyond threshold value, the orifice
expands sufficiently to allow drug release at a required rate. Elastomers, such as styrene-
butadiene copolymer have been suggested .
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16.THREE –DIMENTIONAL PRINTING (3DP) TECHNOLOGY 16:
Three-dimensional printing (3DP) is a novel technique used in the fabrication of complex
oral dosage delivery pharmaceuticals, based on solid freeform 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 pulsatory 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 during in vitro
with a lag time between the pulses of about four hours. This technology is the basis of the
Therefore technology.
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MARKETED PRODUCTS 17:
A.P.I Product Manufacturer Chr.technology Indication
VerapamilHCL Covera HS Pfizer OROS Hypertension
VerapamilHCL VerelanPM Schwarz CODAS Hypertension
Famotidine Pepcid Merk PMAPI Ulcer
Theophyllin Uniphyl ER Purduepharma. CONTIN Asthma
Simvastatin Zocor Merck PMAPI Hyperlipedimia
DiltiazemHCL Cardiazem LA Biovail CFFORMR Hypertension
Propranolol InnopranXL Glaxo DIFFUCAPSR Hypertension
Simvastatin Lopovas Merk PMAPI Hyperlipedimia
Famotidine Gaster Astellas PMAPI Ulcer
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EVALUATION TECHNIQUES
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EVALUATION TECHNIQUES 18:
1)STABILITY STUDY 18:
A short term stability test was conducted by storing tablets in glass bottles at 25°C and
40°C for three months. Then product evaluated for, buoyancy, drug content and invitro
dissolution test and appropriate results obtained.
2)DRUG CONTENT 19:
To evaluate a tablet potential for efficacy, the amount of drug per tablet needs to be
monitored from tablet to tablet, and batch to batch. To perform the test, 10 tablets were
crushed using mortar pestle. Quantity equivalent to 100 mg of drug was dissolved in 100 ml
phosphate buffer pH 6.8, filtered and diluted up to 50μg/ml, and analyzed
spectrophotometrically. The concentration of drug was determined using standard calibration
curve.
3)PARTICLE SIZE ANALYSIS 19:
The core pellets were subjected to sieve analysis using a set of standard sieves (1700,
1400, 1000, 710, and 600 mm) in a vibratory sieve shaker for a period of 10 min. The weight
distribution data were fitted into log-normal distribution and the geometric mean diameter
was computed from the log probability plots
4)BUNOYANCY DETERMINATION 19:
The buoyancy test of triple layer tablet and floating pulsatile release 25 tablets was studied
by placing them in 500 ml beaker containing 0.1 N HCl, then tablet from same batches were
placed in dissolution test apparatus containing 0.1N HCl, maintained at 37+-0.1◦C and
agitated at 100 rpm. The floating onset time (time period between placing tablet in the
medium and buoyancy beginning) and floating duration of tablet was determined by visual
observation.
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5) INVITRO DISSOLUTION STUDY 20:
Invitro dissolution test was performed using USP type II dissolution test apparatus. The
drug release study was carried out in 0.1 N HCl for 2 h, mixed phosphate buffer of pH 5.5 for
1 hour, phosphate buffer of pH 6.8 for 2 hour followed by mixed phosphate buffer of pH 7.5
till the end of the test. The temperature of the dissolution fluid was maintained at 37±0.5°
with a stirring speed of 100 rpm. The samples withdrawn every hour were filtered (0.22 µm,
Millipore) and assayed spectrophotometrically dissolution data was analyzed to calculate the
amount of drug released and percentage cumulative drug released at different time intervals.
6)STUDY OF IN- PROCESS QUALITY CONTROL(IPQC) PARAMETERS 20:
The Weight Variation of the tablets was evaluated on 20 tablets using a Digital Balance
–Sartorius CP124S. Friability test was performed at the speed of 25rpm with tablets dropping
from height of six inches with each revolution for 4minutes on automated Friabilator EF-2
USP .Hardness was evaluated curves (n = 6). All dissolution studies were performed in
triplicate.
9)SWELLING CHARACTERISTICS 21:
To evaluate the water penetration characteristics, the tablets were exposed to 500 ml
distilled water in three different beakers for 6 h, and then evolution of tablet surface area was
carried out by recording the change in diameter and thickness of the tablets. Change in
surface area of the tablets was calculated by using following formula.
SA =2
Where, SA = Surface area and r = Radius of tablet
10)SCANNING ELECTRON MICROSCOPY (SEM) 21:
Morphology and surface topography of the core and the coated pellets were studied by
scanning electron microscopy. The samples were mounted on the SEM sample stab, using a
double-sided sticking tape and coated with gold (200A°) under reduced pressure (0.001 torr)
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
for 5 min using an Ion sputtering device The gold-coated samples were observed under the
SEM and photomicrographs of suitable magnifications obtained.
APPLICATIONS OF CHRONOTHERAPEUTIC DRUG
DELIVERY SYSTEM
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
APPLICATIONS OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 22:
The potential benefit of chronotherapeutic pharmaceuticals has been demonstrated by a
number of DDS developed for timed release of drugs having a chronobiological behaviour or
when symptoms of the diseases are circadian dependent.
1) CARDIOVASCULAR DISEASES 22:
Increase in risk of myocardial infarction between 6 am and noon was found. Blood pressure
was soaring in the morning, with a rise at about 6 am and increasing further from 7 am. Blood
pressure reaching its lowest point around 3 am by gradual declination throughout the day and
especially during sleep .The time of awakening, an increase in physical activity, serum
cortisol level and catecholamine levels which all increases blood pressure, heart rate and
myocardial contractility .cholesterol intake and hepatic cholesterogenesis takes place during
the evening hours irrespective of fed/fasting state. An evening administration of an HMG-
CoA reductase inhibitor lowered serum cholesterol levels than morning dosing .HMG-CoA
reductase inhibitors could be taken between the evening meal and bed time .
Chronopharmaceuticals for cardiovascular diseases have been studied extensively.
Presently, four drugs have been successfully incorporated into Chronopharmaceuticals for
clinical use. The first established chronotherapeutic DDS for timed-release of
antihypertensive /antianginal agent is OROS technology developed and marketed by Alza for
controlled onset and extended release (COER) formulation of verapamil hydrochloride tablet
(Covera HS, Pharmacia, USA) to reduce the peak morning of cardiovascular events.. A
second chronotherapeutic drug delivery approach for hypertension was developed by Elan
using chronotherapeutic oral drug absorption system (CODAS) technology for formulation of
verapamil hydrochloride-ride capsule (Verelan PM, Schwarz Pharma, USA). Cardizem LA
(Diltiazem hydrochloride), which is used for hypertension and angina was approved by the
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
FDA is marketed by Biovail. Innopran XL (Propranolol hydrochloride) extended release
capsule is used for hypertension and was approved by the FDA and marketed by Reliant
Pharmaceuticals, which utilizes the Eurand's Diffucaps technology.
2) INFLAMMATORY DISEASES 22:
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.
Rheumatoid arthritis is characterized by morning stiffness, where as the
symptoms often are bad in the afternoon and evening with osteoarthritis. Cyclooxygenase-2
inhibitors, when taken in the morning lessen osteoarthritis symptoms. In the case of
rheumatoid arthritis, more improved results are obtained when part of the dose is taken in the
evening
3) ASTHMA 23:
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
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
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. Treatment of nocturnal asthma.
Oral steroids such as corticosteroids, glucocorticoids and methylprednisolone administered at
8 a.m. rather than 8 p.m.,
4)ONCOLOGY 23:
Optimal drug timing (chronotherapy) in oncology resulted in allowing high-doses to be
administered safely and most effectively with less toxicity, improved tumour control and
patient survival. Chronotherapeutic 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 chemo biotherapies. The first chronopharmacological studies
of doxorubicin in for the treatment of a transplanted plasmacytoma in rats revealed that the
rate of tumour shrinkage is dependent upon the time of day that the drug is given. To date, the
toxicities and anti-tumour 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)CEREBROVASCULAR ACCIDENTS24:
Cerebrovascular accidents are more common in the morning hours between 10A.M to 12
noon and it will decrease from noon to midnight. The main aim of chronotherapy in these
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
conditions is to deliver the drug in the higher doses in morning and little lower dose at noon
and in midnight times. Various ACE inhibitors like Atenolol, Nifedipine and amolodipine are
more effective when administered during night.
5) GASTROINTESTINAL DISEASES 24:
Peptic Ulcer Disease: A histamine antagonist when given at night shows the better result
unlike when given at regular intervals around the clock. This is because the more acid
secretion, more pain and perforation of gastric and duodenal ulcers are more subjective at
night rather than in day time.
6)ALLERGIC RHINITIS 24:
Early-morning hour episode of sneezing, nasal congestion and runny nose are common to
allergic rhinitis. Study also explained that a morning dose of antihistamine was not as
successful as the same dose given in the evening
7)RENAL DISEASES 24:
A repeated dosing study of high-dose active vitamin D3 in haemodialysis patients with
secondary hyperparathyroidism was conducted. A higher dose (3 mg) was given orally to 13
haemodialysis patients at 08.00 h or 20.00 h for 12 months by a randomized, cross-over
design with an 8-week washout period. Serum concentrations of calcium and inorganic
phosphate were determined by orthocresolphtalein complex method, and ammonium
molybdate method with an autoanalyser, respectively. The results indicate that a higher dose
of oral D3 is more effective and safe after dosing at evening in patients with renal
osteodystrophy .
8)DIABETICS 25:
The most widespread application of chronotherapy is insulin pump, which is used to
administer insulin for the treatment of diabetes mellitus. With the insulin pump, patients can
customize insulin delivery to meet their particular requirements. Several systems were
developed to respond the change in glucose concentration like pH sensitive hydrogel
containing glucose-oxidase enzyme immobilized in hydrogel. As the blood concentration of
glucose rises, glucose oxidase converts glucose into gluconic acid, which changes the pH of
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
system. Due to change in pH, swelling of polymer takes place and this result into insulin
release. Insulin decreases the blood glucose level and consequently the gluconic acid level
also declines and system turns to de-swelling and hence decreasing the insulin release .
LITERATURE REVIEW
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
LITERATURE REVIEW
1. Halas M et al (1998) Formulated and evaluated of press coatedCapsule Device for
Chronotherapeutic Delivery attempt was made to deliver theophylline into colon by
taking the advantage of the fact that colon has a lower pH value (6.8) than that of the
small intestine (7.0–7.8). So, by using the mixture of the polymers, i.e. Eudragit L and
Eudragit S in proper proportion, pH dependent release in the colon was obtained 2.
2. Evans RMet al(1996 ) Formulated and evaluated Chronotherapeutic drug delivery for
in vitro multiparticulate system of insulin based on alginate spheres. In an
experiment, ferrite microparticles (1μm) and insulin powder were dispersed in sodium
alginate aqueous solution. The ferrite-insulin alginate suspension was later dropped in
aqueous calcium chloride solution which causes the formation of cross linked alginate
spheres, which were further cross linked with aqueous solution of poly(L-lysine) or
poly(ethylene imine) 6.
3. Kato H et al (2002) Formulated and evaluated Chronotherapeutic drug delivery for
ultrasound-enhanced polymer degradation system. During polymer degradation
incorporated drug as drug molecule within negatively charged P(AMPS-co-BMA)
hydrogels. By applying an electric field ion exchange between
transdermalTulobuterol ions and protons commenced at cathode, resulting in rapid
drug release from hydrogels. This rapid drug release was attributed to the electrostatic
force, squeezing effect, and electro-osmosis of the gel. Complete on-off drug release
was achieved, as no drug release was apparent without the application of electric
current 15.
4. Gupta et al (2003) Formulated and evaluated Chronopharmaceutical drug delivery
system of Theophylline and its pharmacokinetics in vivo and compaired
hardness ,friability, weight variation,drug content in-vivostudies in rabbit 20.
5. Michael et al (2009) Formulated and evaluated Chronotherapeutic drug delivery
system for Timed release film‐coated Felodipine tablets for chronotherapeutic
application in heart disease using guar gum and in combination with other
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
polymers.Tablets were subjected for the evaluation of particle size, encapsulation
efficiency ,swellable and in-vitro release27.
FUTURE PROSPECTS
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
FUTURE PROSPECTS26,27:
The medical and pharmaceutical scientists should now focus profoundly over the
importance of triggered/pulsed release of drugs. chronotherapeutic drug delivery system for
the treatment of primary open-angle glaucoma. Dual-action, chronotherapeutic drug delivery
system Controls intraocular pressure over 24 hours, reducing nocturnal pressure spikes
Increases patient compliance by easy, once-a-day insertion.PH-enzyme dependent
chronotherapeutic drug delivery system of theophylline for nocturnal asthma. . Biological
and chronobiological activities of synthetic or natural compounds. Chronotherapy in Indian,
Chinese, and other such traditional herbal medicine systems. Design and development of drug
delivery systems for treatment of diseases on chronopharmacologicalbasis . Development of
Drug targeting systems, protein and peptide delivery systems, sustained and controlled
release systems. Ability of the brain to repair DNA damage was at a minimum in the early
morning and reached a maximum in the evening due to the effects of an enzyme called XPA,
which is linked to skin cancer, it could suggest specific times of the day to avoid cancer-
causing sunrays.
Laminate ophthalmic insert that is administered once-a-day, at night, improving patient
compliance. The insert is produced from materials suitable for ophthalmic use, and is capable
of releasing two drugs at different rates. The first drug is released at a slow, continuous rate.
The second has a delayed onset and rapid release, to prevent possible IOP spikes during the
early morning. This innovative treatment represents the first chronotherapeutic
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
SUMMARY AND CONCLUSION
St Joseph’s College of Pharmacy ,Cherthala . 38
A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
SUMMARY AND CONCLUSION
The effectiveness and toxicity of certain drugs depends on dosing time associated with
24hr rhythms under control of circadian clock. The application of biological rhythm to
pharmacotherapy can be correlated by approximate timing of dosing of drugs to synchronise
drug concentration to rhythms in diseases state. Advance in chronobiology and
chronopharmacology has demonstrated the importance of biological rhythms in the treatment
of diseases and this has led to a new approach to the development novel drug delivery
system-chronotherapeutic drug delivery systems.
Chronotherapeutic drug delivery systems is useful in the treatment of
diseases in which drug availability is the timed to match rhythms of diseases, in order to
optimise therapeutic effect and minimize side effect.Variouus technologies such as time
controlled,pulsed,triggered,programmed drug delivery devices have been developed and
extensively studied in recent years for chronotherapeutical drug delivery. Some of the
disease conditions where in chronotherapeutics are promising include duodenal ulcer,
cardiovascular diseases asthma, diabetics, neurological disorder, cancer, hypertension, hyper
cholestremia.
The use of chr.DDS offer a solution for delivery of drugs exhibiting a
chronobiological behaviour and such as DDS seems to constitute more dependable means of
matching drug level to biologic need and tolerance 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.
St Joseph’s College of Pharmacy ,Cherthala . 39
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