Chronopharmaceutics : A relevant approach to drug delivery


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Chronopharmaceutics : A relevant approach to drug delivery

  1. 1. CHRONOPHARMACEUTICS: RELEVANT APPROACH TO DRUG DELIVERY Presented by Gurubas T. Shelke M. Pharm Sem-1 Pharmaceutics Guided By Mrs. Shilpa ShotriyaEmail
  2. 2. CONTENTS Introduction Circadian rhythm Disease with established circadian rhythms Modeling approach different disease Design and developmentChronopharmaceutical drug delivery system Hurdles in chronopharmaceutical drug research and development
  3. 3. Cont… Chronopharmacodynamic Chronopharmacokinetics Chronopharmaceutical technologies Examples of Chronop’cal drug delivery system Conclusion References
  4. 4. INTRODUCTION Chronopharmaceutics is a branch of pharmaceutics devoted to the design and evaluation of drug delivery systems that release a bioactive agent at a rhythm that ideally matches the biological requirement of a given disease therapy. Includes the fundamentals and research into various aspects of chronophysiology, chronopathology, chronogenetics, chronoph armacology, chronopharmacokinetics, chronopharmacodynami cs, chronotherapeutics, and chronotoxicology.
  5. 5. Cont… Combination of chronobiology and pharmaceutics To release a drug at a rhythm to match the biological requirement for a given disease therapy To design and evaluate ChrDDS To improve of therapeutic efficacy and patient-compliance. Chronobiology : Study of biological rhythm and mechanism in biological system
  6. 6. Circadian rhythm Human biological functions are represented on a 24-hour clock, called circadian rhythm Related to the sleep-wake cycle It can alter the sleep-wake cycles, hormone release, body temperature and other biochemical, phsiological process
  7. 7. Circadian rhythm influences on physiologicalprocess Physiological functions Changes Body temperature Sleep ↓ wakefulness ↑ Breathing Sleep Sleep ↓ wakefulness ↑ Blood pressure Sleep ↓ wakefulness ↑ Growth hormone pm 11:00 secretion ↑ Adrenaline pm 11:00 secretion ↑ Heart rate Sleep ↓ wakefulness ↑ Plasma catecholamines Increase in morning Plasma aggregability Increase in morning Fibrinolytic activity Decrease in morning Gastric acid secretion Highest in evening Gastric emptying More rapid in morning
  8. 8. Disease with established circadian rhythms Fig1.24 h clock diagram of the approximate time, in human following the diurnal activity/nocturnal sleep routine, when symptoms or events of diseases are worst or most frequent
  9. 9. Cont…. Fig2: The day/night patterns of disease severity.
  10. 10. Diseases Asthma : 1.airway resistance increases progressively at night 2.lung function reaches at low pt in the early morning 3. Because of bronchoconstriction and exacerbation symptom vary in circadian fashion 4. Chronotherapies have been studied for asthma with oral corticosteroids, theophylline,and β2 agonist Arthritis: 1.Circadian rhythm in the plasma concentration of c-reactive protein and interleukin-6 of patients with rheumatoid arhritis 2. Chronotherapy for NSAID’s studied
  11. 11. Cont.. Duodenal ulcer 1.gastric acid secretion is highest during the night. 2.Histamine blockers are developed by ChrDDS Cancer: Blood flow to tumors and tumor growth rate are each up to threefold greater during each daily activity phase of the circadian cycle than during the daily rest phase
  12. 12. Modeling approach for different disease: Modeling cardiovascular diseases : 1.linear models 2.nonlinear model 3.multiple linear models Harmonic regression equations for the frequency of onset of myocardial infarction according to plasma creatine -kinase MB = number of myocardial infarctions (CK-MB) activity per hour t = time of day in hour
  13. 13. Modeling cancer chemotherapy Two major models: Differential equation of each cell cycle 1. lumped parameter models (e.g. Gompertz model): Describe tumour growth Diff. tumour type Behavior heterogeneity2. Cellcycle models Xi: number of cells in a particular stage is Describe cancer tumor behavior Ti: transition rate between stages based on the number of cells in di: death rate for cells in a particular stage r : enter the resting stage a given phase of the cell cycle (1-r): return to the RNA/protein synthesis stage
  14. 14. Modeling glucose insulin interaction To estimate glucose and insulin in diabetic patient G(t),: plasma glucose,I(t): plasma insulin X(t): insulin concentration in a remote compartment E(t): exogenous insulin, Pi: parameters, Gb: Basal glucose concentration
  15. 15. Modeling other diseases Biochemical marker require for other diseaes f(t): pharmacokinetic/pharmacodynamic (PK/PD) M: mesor (midline,value about which oscillation occur) A: amplitude (half the difference between the highest and lowest values) w: the angular frequency
  16. 16. Design and development of ChrDDS:
  17. 17. Hurdles in ChrDDS1. Rhythmic biomaterials and system design Biomaterial would biocompatible or biodegradable overcome by microchip based drug delivery system, nanofabrication biomaterial responsive to light , temparature ,pH,2. Rhythm engineering and modeling models required to elucidate the biological rhythm age-structured partial differential equation (PDE) with time-periodic coefficients was used to compare the growth rate of the models3. Regulatory guidance related to these types of modified dosage forms: bioavailability requirements for CR products are covered in the US Code of Federal Regulations under 21 CFR 320.25 IR formulation of the same drug ingredient or activemoiety, are covered under 21 CFR 314.54
  18. 18. Chronopharmaceutical technologies: 1. CONTIN technology 2. Physico-chemical modification of the API 3. OROS technology 4. CODAS technology 5. CEFORM technology 6. DIFFUCAPS technology 7. Chronomodulating infusion pumps 8. TIMERx technology 9. Other CR erodible polymers 10. Controlled-release microchip
  19. 19. CONTIN technology1.Complex formed between cellulose polymer andnon polar solid aliphatic alcohol which act asamatrix2.Used for aminophylline,theophylline,morphine3. Uniphyl(anhydrous theoforphylline) forastmatic patient broncoconstriction incresed4. More effective controll of disease and reduesunwanted side effects
  20. 20. OROS technology OROS Delayed Push– Pullk System, also known as controlled onset extendedrelease (COER) To design Covera HSR, a novel anti-hypertensive product Overnight release of Fig. Outline of the COER-24/OROS verapamil delivery system: (a) drug formulation, (b) swelling To control BP early in the polymeric compartment, (c) hydrophilic morning polymeric coating, (d) osmotic membrane and (e) laser-drilled orifices.
  21. 21. Physico-chemical modification of the API Physicochemical properties (e.g. solubility, partition coefficient, membrane permeability, etc) altered Solubility and permeability are critical factors governing drug bioavailability Ex. 1.Antihyperlipidemic statins (HMG-CoA reductase inhibitors) Introduction of methyl group in lovastatin produces simvastatin results in increase in Tmax from 2 to 4 hr
  22. 22. CODAS technology The Chronotherapeutic Oral Drug Absorption System (CODASR) is a multiparticular system. To designed for bedtime drug dosing, incorporating a 4–5 h delay in drug delivery Introduced by the non-enteric release-controlling polymer applied to drug loaded beads Ex. CODAS-verapamil extended release capsules (Verelan PM)
  23. 23. CEFORM technology Production of uniformly sized and shaped microspheres Based on melt- spinning To subject solid feedstock i.e. biodegradable polymer/bioactive agents combinations to the combination of temperature,thermal gradients, mechanical forces, flow, and flow rates during processing
  24. 24. Cont.. Microsphere produced spherical of diameter 150–180 µm Microspheres used in a wide variety of dosage forms, including tablets, capsules, suspensions, effervescent tablets, and sachets Ex Cardizem LA, 1-day diltiazem formulation as ChrDDS
  25. 25. Chronomodulating infusion pumps Include pre-programed system as well as system sensitive to magnetic fields, ultrasound, electric fields, temperature, light and mechanical stimulation Infusion pump in the market: 1. Melodie 2. Programmable Synchromed 3. Panomat V5 infusion 4.The Rhythmic pumps Ex. Insulin therapy
  26. 26. TIMERx technology combines primarily xanthan and locust bean gums mixed with dextrose Drug release from TIMERx: Water penetration from Gi to TIMERx gum matrix Expand to form agel Active drug substance released Ex. oral CR opioid analgesic oxymorphone
  27. 27. Three-dimensional printing A novel technique based on solid free form fabrication methods. Basis of the TheriForm R technology Complex oral drug delivery devices have been fabricated using the 3DP process :- 1.Immediate-extended release tablets, 2.Pulse release, 3.Breakaway tablets, and 4.Dual pulsatory tablets.
  28. 28. CR erodible polymers Erodable polymer designed for different formulation: 1.tablets 2.capsules 3.microparticles Insoluble excipient Gel forming excipient (e.g. dibasic calcium (e.g.Hydroxypropylmethy- phosphate) lcellulose) Erodible Tablet
  29. 29. Controlled-release microchip Produced by microfabrication technology Solid-state silicon microchip :- Provide controlled release of single or multiple chemical substances on demand. Release mechanism : electrochemical dissolution of thin anode membranes Microreservoirs filled with chemicals in solid, liquid or gel form
  30. 30. Chronopharmacodynamics At the cellular and subcellular level biological rhythm can give rise to significant dosing-time differences ths phenomenon called as chronesthesy Rhythms in receptor number or conformation, second messengers, metabolic pathways,and/or free-to-bound fraction of medications impt in chronopharmacodynamic
  31. 31. Cont… Ex.1. antitumor effect of IFN-β and the antiviral effect of IFN-α in more efficient during the early rest phase than during the early active phase 2.Imatinib mesylate inhibit the tyrosine kinase acts on receptor Abl, the bcr-abl chimeric product, KIT, PDGF receptors Efficacy of imatinib is more when PDGF receptor activity is more
  32. 32. Chropharmcokinetics Chropharmcokinetics consist of ADME of drug
  33. 33. MARKETED DRUGSFDA approval API Propriatory Chronopharmaceuti Indication date name; cal tchnology dosage formSept. 01, 1982 Theophylline Uniphyl CONTIN ASTHMAOct. 15, 1986 Famotidine PepcidR; Physico-chemical Ulcer tablets modification of APIDec. 23, 1991 Simvastatin ZocorR; Tablets Physico-chemical Hypercholest modification of API erolemiaFeb. 26, 1996 Verapamil HCl Covera-HSR OROS Hypertension TabletNov. 25, 1998 Verapamil HCl VerelanRPM; CODAS Hypertension CapsuleFeb. 06, 2003 Diltiazem HCl CardizemR LA; CEFORM Hypertension verapamil HCl TabletMar. 12, 2003 Propranolol HCl InnoPranR XL DIFFUCAPS Hypertension verapamil HCl Capsule
  34. 34. MARKETED DRUGS IN JAPAN API Proprietary name Chronopharmaceutical Disease dosages form technologyFamotidine Gaster® tablets Physico-chemical Ulcer modification of APISimvastatin Lipovas® Physico-chemical Hyperlipidemia tablets modification of APITheophylline Uniphyl® CONTIN® Asthma extended release tabletsTulobuterol Hokunalin® Transdermal chronodelivery Asthma tape system
  35. 35. Conclusion Chronopharmaceutics will certainly improve patient outcome and optimize disease management in the future Selection of the appropriate chronopharmaceutical technology should take into considerations the application range (e.g. targeted drugs of different physico-chemical properties), the ease of manufacturing, the cost- effectiveness, and the flexibility in the pharmacokinetic profile
  36. 36. Cont… Major drawback of existing oral ChrDDS on the market it depend on human action to trigger the drug administration for example on daily basis Ideal ChrDDS should be self regulating, in future it may possible to develop Ideal ChrDDS when taken any time of the day and should take environmental factors in account (e.g. awake–sleep, light–dark, activity–rest status)
  37. 37. References1.Bi-Botti C. Youan* Chronopharmaceutics: new approach, Journal of Controlled Release 98 (2004) 337– 3532. S. Leslie, in: Euroceltique, SA, United States, 1982, p. 203. W. Hoffman, R. Smith, A. Willard, in: Merck & Co., United States, 1984, p. 26.4. FDA, in: Electronic Orange Book (Administration, F. a. D.,Ed.), Electronic Orange Book, Washington, DC, 20035. S. Leslie, The Contin delivery system: dosing considerations J. Allergy Clin. Immunol. 78 (1986) 768– 773
  38. 38. Cont..6. Bi-Botti C. Youan, Chronopharmaceutical drug delivery systems: Hurdles, hype or hope? Advanced Drug Delivery Reviews 62 (2010) 898–9037. Shigehiro Ohdo, Chronotherapeutic strategy: Rhythm monitoring, manipulation and disruption; Advanced Drug Delivery Reviews 62 (2010) 859–8758. Asim Sattwa Mandal, Nikhil Biswas, Kazi Masud Karim, Arijit Guha, Sugata Chatterjee,Mamata Behera, Ketousetuo Kuotsu, Drug delivery system based on chronobiology—A review; Journal of Controlled Release 147 (2010) 314–325