Chrono pharmacokinetics


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Chrono pharmacokinetics

  1. 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. 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. 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
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. 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.
  12. 12. • 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
  13. 13. 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
  14. 14. Pulsincap®
  15. 15. • 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
  16. 16. 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
  17. 17. Lag-phaseof 5 hrs
  18. 18. 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
  19. 19. 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 solubleand water insoluble polymers. When the multiparticulates are exposed towater, the water-soluble polymer dissolves and drug diffuses through thepores present in the coating
  20. 20. 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
  21. 21. • Egalet®• A tablet in capsule device• Core-in-cup tablet technology• A bi-layered tabletPharmaceutical Development and Technology, 2009; 14(6): 602–612Drug delivery technologies for chronotherapeutic applicationsZaheeda Khan, Viness Pillay, Yahya E. Choonara, and Lisa C. du Toit
  22. 22. 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.
  23. 23. • 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
  24. 24. • 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
  25. 25. Teratogen• Result in malformations• Exert its effect in particular stage of fetal development• Dose dependent incidence