1. Chrono-pharmacokinetics
• Chronobiology
– Science that studies the biological rythms
• Chrono-Pharmacokinetics
– Deals with study of temporal changes in ADME- due to
time of administration
• Chronokinetics
– Time dependent changes in ADME
• Chronesthesy
– Changes in susceptibility or sensitivity of a target system
• Chrono-therapeutics
– Application of chrono-biological principles to the treatment
of diseases

2. Why study Chrono-P’kinetics??
• PK-PD vary with time
– Gastric motility: is double in day time than in night
– Plasma protein concentrations are higher in day than in
night
– Hepatic blood flow has been shown to be greatest at 8 am
and metabolism to be reduced during the night
• Symptoms of a disease are circadian phase dependent e.g.
asthma, angina pectoris, myocardial infarction, ulcer diseases
• Drug toxicity can be avoided/ Minimized by administering at a
particular time

3. Body Rythms
• Cyclic variations over time
• Ultradian rythms: < 20 hrs
• Circadian rythms: 20-28 h
• Infradian rythms: > 28 h
• Circaseptan: 7 days
• Circamensual: ~ 30 days
• Circa-annual rythms: ~ 1 year

5. Circadian Rythm
• 24 hour cycle
• “Circa” meaning around “diem” meaning day
• Biological clock Supra-chiasmatic centre SCN in
hypothalamus
• Eyes > Retina (photoreceptors> photoresponsive ganglion
cells)> retino hypothalamic tract> SCN)
• SCN passes the information to Pineal gland >> Melatonin
hormone
• Exposure of light can change endogenous circadian pace Time
of light, duration wavelength, intensity, all determine circadian
patterns of body

6. Examples of circadian rythm
• Sleep cycle
• Basal gastric acid secretion
• WBC count peak at late night
• Serum cholesterol and triglycerides concentrations are highest
early in the evening
• Haemoglobin and insulin are highest in the afternoon
• Intra ocular pressure is highest between 2-4 pm and lowest in
late evening
• BP increases in morning after night sleep, peaks afternoon and
decreases during sleep
• Potassium efflux from cells is lowest around 3. pm

7. PK- Absorption
• Gastric motility, secretions, pH emptying time,
blood flow
• Lipophilic drugs better absorbed in morning
• Valproic acid, Indomethacin, Ketoprofen
better absorbed in the morning
• Skin penetration of lidocaine and prilocaine in
evening

8. PK- Distribution
• Body size, composition, Protien binding,
volume of distribution, blood flow to various
organs
• Maximum protein binding of antineoplastics
like cisplatin, carbamazepine, diazepam,
phenytoin, valproic acid, is found in afternoon
and minimum in morning

9. PK- Metabolism
• Liver enzyme activity, Hepatic blood flow
• High extraction ratio: metabolism depends on blood flow
• Low extraction ratio: metabolism depends on enzyme activity
• Hepatic blood flow high in morning
• Metabolism reduces in night

10. Asthma
• Airway resistance increase during nights
• E. g. Uniphyl a long acting theophylline preparation in the
evening  improvement in lung function in the morning
Arthritis
• Osteo-arthritis: Less pain in morning and more at night
• Rheumatoid arthritis: pain peaks in morning and
decreases as the day progresses.
• NSAID’s for RA after evening meal

11. Chrono-therapeutic drug delivery
systems
• Chronotopic DDs
• Contin
• Pulsincap system
• Ceform
• Time Rx
• Synchrodose
• OROS
• CODAS
• Diffucaps
• Pulsatile drug delivery systems
• Erosion based monolithic tables
• Multi particulate systems
• Physicochemical modification of API
• Chronomodulating infusion pumps
• Microchip strategies

12. Chronotopic® Technology
• Delayed, time-dependant pulsatile drug
delivery as well as colon specific drug release.
• HPMC coating undergoes a glassy-rubbery
transition when in contact with aqueous fluid.

13. • Diffusion and/or erosion mediated release
• The tablet matrix is prepared by firstly granulating
the drug with a range of excipients which is then
compressed.
• A mixture of HPMC and PEG solutions are then
spray-coated onto the core and allowed to dry.
Thereafter a coating of Eudragit® is applied onto the
outer surface of the tablet matrix

14. Contin® Technology
• Molecular co-ordination complexes between
cellulose polymers and non polar solid aliphatic
alcohol
• Drug + hydrophilic polymer-> Hydration and
fixation by alcohol
• Uniform porosity matrices
• E.g. Uniphyl (Anhydrous Theophylline tablets) for
asthma Evening administration

15. Pulsincap®

16. • A water insoluble drug-loaded capsule
• The capsule is sealed with a swellable hydrogel plug
comprising polymers such as the poly(methacrylates),
HPMC, PVA, PVAc, PEO, Pectin, Saturated polyglycolate d-
glycerides
• An enteric layer that dissolves upon reaching the small
intestine where the polymeric plug begins to swell resulting
in a lag-phase prior to drug release.
• The plug then expands and is pushed outward to affect drug
release.
• The variation in dimensions of the plug and its point/depth of
insertion into the capsule determines the lag-time produced
prior to drug release
• Pulsincaps® technology has the versatility of allowing one or
more minitablets, coated tablets, solutions, or
multiparticulates to be loaded within the capsule for delivery
of drug in a chrono-therapeutic manner

17. CEFORM® Technology
• Uniform size and shaped microspheres
• 150-180 microns biodegradable polymers
• Capsules, suspensions, tablets, effervescent tablets and sachets
• Cardizem® LA which is a once-daily Diltiazem formulation

18. Lag-phase
of 5 hrs

19. Oros® Technology
Drug and poly(ethylene
oxide) (PEO) granulated with a solution of poly(vinyl
pyrolidine) (PVP).
The push compartment comprises
PEO, hydroxypropylmethylcellulose (HPMC),
sodium chloride
• Covera-HS® (verapamil), antihypertensive
• Overnight drug release to prevent the surge in blood pressure that occurs in
patients during the early morning
• Manufacturing the system has proven to be complicated with the need for a
laser-drilled hole in the semi-permeable coating.
• In addition, clogging of the hole may limit drug release. Drying time also
posesa challenge as the drug delivery system requires a fairly extensive
drying period of four days

20. CODAS® technology
Verelan® PM (verapamil). This formulation
is designed to release verapamil 4–5 hours
after ingestion.
Chronotherapeutic Oral Drug Absorption System
delayed onset of drug release,
Both the core and the multilayered membrane comprise water soluble
and water insoluble polymers. When the multiparticulates are exposed to
water, the water-soluble polymer dissolves and drug diffuses through the
pores present in the coating

21. Diffucaps ®
Inert particle such as sugar spheres,
crystals or granules.
Inert binder is used to bind the drug
particles to the inert core
The drug-loaded core is then coated with a
plasticized enteric coating and thereafter
coated with a mixture of water insoluble
and enteric polymers
Size < 1 mm

22. • Egalet®
• A tablet in capsule device
• Core-in-cup tablet technology
• A bi-layered tablet
Pharmaceutical Development and Technology, 2009; 14(6): 602–612
Drug delivery technologies for chronotherapeutic applications
Zaheeda Khan, Viness Pillay, Yahya E. Choonara, and Lisa C. du Toit

23. Placental Transfer
• Placental transfer is a concern because certain drugs
may induce congenital abnormalities.
• If administered immediately prior to delivery, drugs may
directly adversely affect the infant.
– Mechanism: typically simple diffusion
– lipid-soluble,non-ionized drugs are more likely to pass
from the maternal blood into the fetal circulation.
• By contrast, ionized drugs with low lipid-solubility
are less likely to pass through the placental
"barrier".
• The fetus is exposed to some extent to all drugs
taken by the mother.

24. • Physicochemical properties of drugs
– Lipid solubility: Thiopental: apnea and sedation of fetus, Succinyl
choline, and tubocurarine cross placenta very slowly
– Molecular weight:
» 250-500 Dalton easily pass through
» Above 1000 Dalton difficult to pass: eg. Heparin
• Rate at which drug crosses the placenta and amount
reaching fetus
• Duration of exposure
• Distribution characteristics in different fetal development
• Placenta contains drug transporters e.g. Maternal
antibodies cross the placenta and provide fetus immunity
• Eg. Glyburide is pumped out by BCRP transporter and
MRP 3 transporter from the placenta >> so no glyburide
reaches the fetal circulation

25. • Protein binding
– Drugs show greater proteins binding in
plasma than in fetal proteins
• Drug Metabolism in placenta also prevents
several drugs from getting in
– Several aromatic oxidation reactions
– Drug metabolites can cause toxicity

26. Teratogen
• Result in malformations
• Exert its effect in particular stage of fetal
development
• Dose dependent incidence