• 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

Chrono-pharmacokinetics

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

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

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

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

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

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

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

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

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

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.

• 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

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

Pulsincap®

• 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

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

Lag-phaseof 5 hrs

Oros® Technology

• 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

The push compartment comprisesPEO, hydroxypropylmethylcellulose (HPMC), sodium chloride

Drug and poly(ethyleneoxide) (PEO) granulated with a solution of poly(vinyl pyrolidine) (PVP).

CODAS® technology

Chronotherapeutic Oral Drug Absorption System

delayed onset of drug release,Both the core and the multilayered membrane comprise water solubleand 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

Verelan® PM (verapamil). This formulationis designed to release verapamil 4–5 hours after ingestion.

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

• Egalet®

• A tablet in capsule device

• Core-in-cup tablet technology

• A bi-layered tablet

Pharmaceutical Development and Technology, 2009; 14(6): 602–612Drug delivery technologies for chronotherapeutic applicationsZaheeda Khan, Viness Pillay, Yahya E. Choonara, and Lisa C. du Toit

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.

• 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

• 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

Teratogen

• Result in malformations

• Exert its effect in particular stage of fetal development

• Dose dependent incidence