This document discusses chronotherapeutics and chronomodulated drug delivery systems. It explains that biological rhythms like circadian rhythms influence physiological functions and disease states over daily cycles. The suprachiasmatic nucleus acts as the body's biological clock, controlling circadian rhythms in response to hormonal variations. Chronokinetics studies how absorption, distribution, metabolism, and elimination of drugs can vary over daily cycles. Understanding a drug's chronokinetics can optimize dosing for conditions that fluctuate throughout the day and improve efficacy and safety.

1. CHRONOKINETICS
CHRONOTHERAPEUTICS AND
CHRONOMODULATED DRUG DELIVERY
SYSTEM

2. •Chronobiology is the science concerned with the
biological mechanism of the diseases according to a time
structure.
•Chronopharmacology is the science concerned with the
variations in the pharmacological actions of various drugs
over a period of time of the day.
•A biological rhythm is one or more biological events or
functions that reoccur in time in a repeated order and with
a repeated interval between occurrences .
•The biological clock is the mechanism found within living
organisms that coordinates the timing of physiological
functions and behaviors to the natural day-night cycle.

3. •The mammalian Circadian pacemaker resides in the paired
suprachiasmatic nuclei (SCN).
•When light falls on the eye, afferent nerves arising from the
retina of the eye transmit the light signals directly through
retino hypothalamic tract to the paired suprachiasmatic
nuclei situated in the hypothalamus and pineal gland.
•Biological clock since found is represented by
suprachiasmatic nuclei , which creates biological rhythms
under control of clock genes.

4. •Clock genes control vast array of circadian rhythms in
physiology and behaviour.
•The rhythmic activities of Clock genes and cyclic secretion
of melatonin from pineal gland comprise the central
timekeeping mechanism.
•These generated biological rhythms deal with the control of
biological functions including those of the autonomic nerve
system, endocrine system, and immune system, which are
fundamental in homeostasis and in protection against
various diseases .

5. Types of biological rhythms:
- Ultradian rhythms, shorter than a day .
Eg: thousandths of a second (like the pulses in neurons)
seconds (like the heartbeat)
- Circadian rhythms, which last about one day.
•Circadian rhythms are self-sustaining and endogenous
oscillations that occur with a periodicity of about 24 Hours.
Eg: the sleep-waking rhythm, the body temperature,
sensitivity to pain or alcohol, reaction time, levels of
hormones in the blood etc.

6. -Infradian rhythms, longer than a day.
Eg: monthly rhythm - menstrual cycle
Yearly rhythm – bird migration
-Tidal rhythms, commonly observed in marine life, which
follow the roughly 12-hour transition from high to low tide
and back.

7. Circadian rhythm:
•Derived from the Latin circa, meaning "around," and dies,
meaning "day”. Circadian : around a day.
•Rhythm is the measured movement, recurrence of action or
function at regular intervals.
•Circadian rhythm is the regular recurrence of certain
phenomena in cycles of approximately 24 hours.
•The best-known circadian rhythms include body
temperature , hormone secretion, metabolism, sleep or wake
cycle .

8. The suprachiasmatic nucleus controls circadian rhythms
in response to hormonal variation in the body

9. Biological Clock in Human

11. •The hormones that are secreted in the morning include
cortisol, catecholamines, plasma renin, aldosterone, and
angiotensin.
•In contrast, gastric acid, growth hormone, prolactin,
melatonin, follicle-stimulating hormone, luteinizing
hormone, and adreno-corticotrophic hormone (ACTH) peak
in the evening or during sleep.
•For instance, the increase in catecholamines in the morning
promotes platelet aggregation. This is especially important
since fibrinogen also increases, and the body’s own
endogenous t-PA decreases, promoting a procoagulant state
with increased blood viscosity.
•Cholesterol synthesis is more in the evening than in the
morning.

12. Circadian Rhythms in Occurrence and Severity of
Disease
•Sudden infant death, symptoms of allergic rhinitis, and
rheumatoid arthritis are either most intense overnight or in the
morning upon wakening.
•Migraine headache is typically triggered during rapid eyeball
movement (REM) episodes during night time sleep or in the early
morning hours after awakening.
•Angina pectoris, ventricular arrhythmia, acute myocardial
infarction, sudden cardiac death, stroke, fatal pulmonary
embolism, and hypertensive crises, all are most frequent in the
morning.

13. •Perforated and bleeding ulcer is reported to be most
common in the afternoon.
•Some seizure disorders are triggered during specific sleep
stages and / or by transitions between sleep and
wakefulness.
•Symptoms of osteoarthritis worsen during the course of
daily activity, being typically most intense in the late
afternoon and evening.
•Depression is most severe in the morning.
•Gout, gall bladder and peptic ulcer attacks are most frequent
at night.
•Acute pulmonary edema, congestive heart failure, and
asthma worsen nocturnally

14. Diseases known to display circadian Rhythm

15. CIRCADIAN RHYTHMS OF DISEASES
Peak Time of Event/Variable

16. CHRONOKINETICS
•Chronopharmacokinetics deals with the study of the temporal
changes in absorption, distribution, metabolism and
elimination and thus takes into account the influence of time of
administration on these different steps.
•All physiological functions oscillate rhythmically in time, the
activity, toxicity, and kinetics of a medication may depend on its
administration time.
•The main aim of chronokinetic studies is to control the time of
administration which can be responsible for variations of drug
kinetics but also may explain chronopharmacological effects
observed with certain drugs.

17. NEED OF CHRONOKINETIC STUDY
•When possible daily variations in pharmacokinetics may be
responsible for time dependent variations in drug effects
(e.g. some antimicrobial agents are more effective at a specific
time of day),
•When drugs have a narrow therapeutic range .
•When symptoms of a disease are clearly circadian phase-
dependent (e.g. nocturnal asthma, angina pectoris, myocardial
infarction, ulcer disease).
•When drug plasma concentrations are well correlated to the
therapeutic effect in case the latter is circadian phase
dependant.

18. Drug Absorption :
•Several factors, such as the physico-chemical properties of
the drug ( lipophilicity or hydrophilicity ), the area and the
structure of the biomembrane , gastric emptying, pH and
motility, and gastrointestinal blood flow, may influence the
absorption process after oral drug administration.
•Most lipophilic drugs seem to be absorbed faster when the
drug is taken in the morning compared with the evening
because of faster gastric emptying time and a higher GI
perfusion in the morning.
•Such changes may contribute to the dosing time dependent
difference of drug absorption.

19. Drug Distribution:
•Blood flow depends on several regulatory factors, including
sympathetic and parasympathetic systems which activities are
known to be circadian time dependent with a predominant
diurnal effect of the sympathetic system..
•A diurnal increase and nocturnal decrease of blood flow and
local tissue blood flows may explain a possible difference in
drug distribution depending on the dosing time.
•Plasma proteins such as albumin or alpha 1 glycoprotein acid
have been documented to be circadian time dependent. The
plasma concentrations of albumin and alpha 1 glycoprotein
acid show peak around noon.

20. Drug metabolism :
•Hepatic drug metabolism seems to depend on liver enzyme
activity and / or hepatic blood flow.
•Both factors show a circadian time-dependent difference.
Enzyme activities show a circadian time-dependent
difference in many tissues such as brain, kidney, and liver.
•Conjugation, hydrolysis, and oxidation show a circadian
time-dependent difference.

21. Drug elimination:
•Renal physiological functions such as glomerular filtration,
renal blood flow, urinary pH, and tubular resorption show a
circadian time-dependent difference with higher values during
daytime.

22. DRUGS UNDERGOING CHRONOKINETICS:
1. Antibiotics :
•Important aspect of chronokinetics in antibiotics is that not
only the efficacy of the drug may increase but also the toxicity
of certain drugs may decrease at different time of day.
Aminoglycosides:
•Renal toxicity of aminoglycosides can be reduced by giving
the drug as a single daily injection when patients are active (at
day time or in other words in the activity period)
Eg: gentamycin, tobramycin, amikacin

23. 2. Antihypertensive drugs:
•Blood pressure, stroke volume, cardiac output, blood flow
are higher in morning and decrease later in the day.
• Cmax was higher and/or tmax shorter after morning than
evening dosing of the lipophilic drugs (nifedipine, oral
nitrates, propranolol) .
•Atenolol (hydrophilic drug ) is not absorbed rapidly after
morning administration.
•ACE inhibitors were found to be safe and effective when
administered at bed time when compared to morning.

24. 3. Valproic acid(antiepileptic):
•Cmax tended to be higher, tmax was shorter and absorption
rate constant (ka) tended to be larger for VPA in the morning
than in evening.
4. Anti-inflammatory drugs :
•They have greater rates and extents of bioavailability when
administered in the morning than evening.
Eg. Indomethacin, Ketoprofen

25. 5. AntiAsthmatic drugs :
•Asthma is attacked more frequently in night hours.
•Lungs are more sensitive to bronchoconstrictor substances
such as Acetylcholine, Histamine, house mite dust, grass
propellers, at night time than day time. It is treated by
antiasthmatic drugs.Ex:-Theophylline, beta sympathomimetics.
•Theophylline must be given in higher doses during the night
time than day time.
6. Antiulcer drugs :
•Gastric acid secretion is highest at early night or late afternoon.
•H2 blockers like Ranitidine ,cimetidine ,famotidine should be
taken once a day in the late afternoon or early night when acid
secretion is more.

26. 7. Anticancer drugs :
•The blood flow to tumors and tumor growth rate are each up
to three fold greater during each daily activity phase of the
circadian cycle than during the daily rest phase.
•Normal human bone marrow DNA synthesis peaks around
noon, DNA synthesis in malignant lymphoma cells peaks near
midnight.
• By treatment at mid night, more tumor cell kill could be
achieved with same dose of S-phase active cytotoxic therapy
and with relatively little bone marrow damage.

27. •The activity of dehydropyrimidine dehydrogenase in human
mononuclear cells increases by 40% around midnight.
• This enzyme brings about the intracellular catabolism of
5-FU and contributes to improved tolerability of this drug
between 00:00 and 04:00.
•One approach to increasing the efficiency of the
pharmacotherapy is by administering drugs at times during
which they are best tolerated.

28. 8. Arthritis :
•Patients with osteoarthritis tend to have less pain in the
morning and more at night; while those with rheumatoid
arthritis, have pain that usually peaks in the morning and
decreases throughout the day.
•Chronotherapy for all forms of arthritis using NSAID’s such as
ibuprofen should be timed to ensure that the highest blood
levels of the drug coincide with peak pain.
•For osteoarthritis sufferers, the optimal time for a non-
steroidal anti-inflammatory drug such as ibuprofen would be
around noon or mid-afternoon.
•The same drug would be more effective for people with
rheumatoid arthritis when taken after the evening meal.

29. 9. Anti hyperlipidemic drugs
•More Cholesterol systhesis takes place in the evening than in
the morning.
•The enzyme HMG Co-A Reductase is required to reduce
hydroxy 3-methyl glutaryl Co-A to mevalonate in the synthesis
of cholesterol.
•This enzyme is competitively inhibited by HMG Co-A
Reductase inhibitors (Statins)
•Hence statins should be administered at evening rather than at
morning for increased efficacy.

30. 10. Opiod analgesics
•Stronger analgesic effects were observed when tramadol and
dihydrocodeine were applied in the evening to relieve painful
stimuli.
•Peak morphine use occurred at 9 a.m. and least use at 3 a.m.
•A recent study of meperidine reveals a circadian variation of
meperidine-induced analgesia in sickle cell anemia patients,
with maximal analgesic effect occurring with the morning
dose.

31. 11. Anti-Migraine drugs
•Sumatriptan is a drug of choice in migraine treatment.
•The mean peak serum concentration, AUC and AUMC were
significantly higher following the 07:00 h administration than
after the 19:00 h administration.
12. Immunosupressants
•A slightly increased AUC and AUMC resulting from
decreased apparent clearance during the resting (PM) versus
activity (AM) period were observed for cyclosporine.

32. 13. Local anesthetics
•The duration of local anesthesia was longest when amide-
type local anesthetic agents (lidocaine, ropivacaine,
mepivacaine and betoxycaine) were applied around 3 p.m.
• Area under the lidocaine plasma concentration curves (AUC)
was largest in the afternoon.
•The plasma levels of lidocaine were significantly higher in the
evening than at any other time of day.

33. 14. General anesthetics
Barbiturates
Higher brain pentobarbital or hexobarbital concentrations
occurred when injected during the dark phase. Postsynaptic
type A GABAergic activity is increased during nocturnal
hours, corresponding to the duration of the maximal efficacy
of barbiturates.
Benzodiazepines
The elimination half-life of midazolam was found to be at its
shortest at 14:00 h and at its longest at 02:00 h
Ketamine, Etomidate, Propofol, and Halogenated Agents
Action longer during the night than during the day.
Halothane
Greatest efficacy of halothane occurred between 24:00 and
06:00 h.

34. CHRONOTHERAPEUTICS :
•Chronotherapeutics refers to a treatment method in which in
vivo drug availability is timed to match rhythms of disease in
order to optimize therapeutic outcomes and minimize the
side effects.
•Chronotherapeutics is the discipline concerned with the
delivery of drugs according to inherent activities of a disease
over a certain period of time.
•The chronotherapy of a medication may be accomplished by
the appropriate timing of conventionally formulated tablets
and capsules, and the special drug delivery system to
synchronize drug concentrations to rhythms in disease activity.

35. CHRONOMODULATED DRUG DELIVERY SYSTEMS
1. The pulsatile drug delivery system
• Pulsatile drug release is a system where the drug is released
suddenly after a well-defined lag time or time gap according
to the circadian rhythm of disease states.
• No drug is released from the device within this lag time.
• This delivery system is suitable in cases where drugs
including proteins and peptides undergo great metabolic
degradation.
• In case of chronic treatment, the drug resistance may grow
and an adverse effect may be seen.
• Here chances are less because the desired concentration of
the drug at a certain time point is available.

36. • This method is good for drugs with extensive first pass
metabolism and those targeted to specific sites in the
intestinal tract.
• Therefore, by developing the pulsatile device for specific
colonic delivery, the plasma peak is obtained at an optimal
time, the number of doses per day can be reduced, it is with
saturable first pass metabolism, and tolerance development
can also be avoided.

37. Advantages
•Predictable, reproducible, and short gastric residence time
•Less inter- and intra-subject variability
•Improves bioavailability
•Reduced adverse effects and improved tolerability
•Limited risk of local irritation
•No risk of dose dumping
•Flexibility in design
•Ease of combining pellets with different compositions or
release patterns
•Improves stability
•Improves patient comfort and compliance
•Achieves a unique release pattern
•Extends patent protection, globalizes the product, and
overcomes competition

38. Disadvantages
•Low drug loading
•Proportionally higher need for excipients
•Lack of manufacturing reproducibility and efficacy
•Large number of process variables
•Multiple formulation steps
•Higher cost of production
•Need of advanced technology
•Trained / skilled personnel needed for manufacturing

39. 2. Enteric-coated systems :
•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.
•The system contains a core which is film coated with two
polymers, first with HPMC and then with a gastro-resistant
polymer (Eudragit® L30D).
• In this system the duration of the lag phase in absorption can
be controlled by the thickness of the HPMC layer.

40. Schematic representation of enteric coated system
Disadvantage :
•Because of the unpredictability of gastric residence, such
systems cannot be the first choice when a time-controlled
release is required

41. 3. Osmotic systems
•In the case of the osmotic system, osmotic pressure acts as a
driving force for the pulsatile drug release. The system consists
of application of a semipermeable membrane around the core
of an osmotically active drug or a drug combined with an
osmotic agent.
• The delivery orifice is drilled in to the system by laser
technique or a high speed mechanical drill.
•When the system comes in contact with fluid, due to the
differences in the osmotic pressure, the drug inside the system
is pumped out at controlled rate.

42. •A lag time of 1-10 hr can be achieved depending on the
thickness, orifice diameter and concentration of an osmotic
agent. e.g. Port system.
•This system consists of a capsule coated with a semi
permeable membrane.
•The capsule acts as a reservoir of the drug and osmotic
agent.
•Water enters into the system through the semi permeable
membrane and leads to the development of osmotic pressure
and expulsion of the drug after a desired lag time.

43. 4. Swelling and erodible systems
•In this system the drug reservoir is surrounded by a polymeric
barrier layer that swells and gets dissolved when it is in contact
of dissolution media and drug is 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.

44. 5. Press-coated systems
•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.
•The limitation of the system is that central position of the
core layer cannot be assured.
•The system can be two or three component, that is two or
three layered tablet.
•One layer provides the initial dose of the drug while other
layers are formulated with the components that are insoluble
in gastric media but dissolves in intestine. The tablet can be
coated with a semi permeable polymeric coating layer that
controls drug release.

45. 6 . Pulsincap
•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 hydrogel
plug.
•Various hydrogels such as hydroxypropylmethyl cellulose,
hydroxypropyl, polyvinylpyrrolidone 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.

46. •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.

47. 7. Ultrasound drug delivery systems
•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.

48. 8. Multiparticulate systems
•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 beads followed by
coating with swellable polymeric layer.
•The swelling agents include super disintegrants, effervescent
agents and osmotic agents.
•Upon ingress of water, the swellable layer expands resulting
in rupture of the film and rapid drug release.

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50. THANK YOU