Chronopharmaceutics : A relevant approach to drug delivery

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1. CHRONOPHARMACEUTICS: RELEVANT APPROACH TO DRUG DELIVERY Presented by Gurubas T. Shelke M. Pharm Sem-1 Pharmaceutics Guided By Mrs. Shilpa Shotriya Email [email protected]

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. Cont… Chronopharmacodynamic Chronopharmacokinetics Chronopharmaceutical technologies Examples of Chronop’cal drug delivery system Conclusion References

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 , chronopharmacology , chronopharmacokinetics , chronopharmacodynamics , chronotherapeutics , and chronotoxicology .

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. 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. Circadian rhythm influences on physiological process Physiological functions Changes

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. Cont…. Fig2 : The day/night patterns of disease severity.

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 β 2 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. 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. 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 (CK-MB) activity = number of myocardial infarctions per hour t = time of day in hour

13. Modeling cancer chemotherapy Two major models: 1. lumped parameter models (e.g. Gompertz model): Describe tumour growth Diff. tumour type Behavior heterogeneity 2. Cellcycle models Describe cancer tumor behavior based on the number of cells in a given phase of the cell cycle Differential equation of each cell cycle Xi : number of cells in a particular stage is Ti: transition rate between stages di : death rate for cells in a particular stage r : enter the resting stage (1-r): return to the RNA/protein synthesis stage

14. Modeling glucose insulin interaction 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. 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. Design and development of ChrDDS :

17. Hurdles in ChrDDS 1. 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 models 3. 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. 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. CONTIN technology 1.Complex formed between cellulose polymer and non polar solid aliphatic alcohol which act as amatrix 2.Used for aminophylline,theophylline , morphine 3. Uniphyl (anhydrous theoforphylline ) for astmatic patient broncoconstriction incresed 4. More effective controll of disease and redues unwanted side effects

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 verapamil To control BP early in the morning Fig. Outline of the COER-24/OROS delivery system: (a) drug formulation, (b) swelling polymeric compartment, (c) hydrophilic polymeric coating, (d) osmotic membrane and (e) laser-drilled orifices.

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. 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. 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. 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. 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. TIMERx technology combines primarily xanthan and locust bean gums mixed with dextrose Drug release from TIMERx : Ex. oral CR opioid analgesic oxymorphone

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. CR erodible polymers Erodable polymer designed for different formulation: 1.tablets 2.capsules 3.microparticles Insoluble excipient (e.g. dibasic calcium phosphate) Gel forming excipient ( e.g.Hydroxypropylmethy-lcellulose ) Erodible Tablet

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. 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. 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. Chropharmcokinetics Chropharmcokinetics consist of ADME of drug

33. MARKETED DRUGS FDA approval date API Propriatory name; dosage form Chronopharmaceutical tchnology Indication Sept. 01, 1982 Theophylline Uniphyl CONTIN ASTHMA Oct. 15, 1986 Famotidine PepcidR ; tablets Physico -chemical modification of API Ulcer Dec. 23, 1991 Simvastatin ZocorR ; Tablets Physico -chemical modification of API Hypercholesterolemia Feb. 26, 1996 Verapamil HCl Covera -HSR Tablet OROS Hypertension Nov. 25, 1998 Verapamil HCl VerelanRPM ; Capsule CODAS Hypertension Feb. 06, 2003 Diltiazem HCl verapamil HCl CardizemR LA; Tablet CEFORM Hypertension Mar. 12, 2003 Propranolol HCl verapamil HCl InnoPranR XL Capsule DIFFUCAPS Hypertension

34. MARKETED DRUGS IN JAPAN API Proprietary name dosages form Chronopharmaceutical technology Disease Famotidine Gaster ® tablets Physico -chemical modification of API Ulcer Simvastatin Lipovas ® tablets Physico -chemical modification of API Hyperlipidemia Theophylline Uniphyl ® extended release tablets CONTIN® Asthma Tulobuterol Hokunalin ® tape Transdermal chronodelivery system Asthma

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. 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. References 1.Bi-Botti C. Youan * Chronopharmaceutics : new approach, Journal of Controlled Release 98 (2004) 337– 353 2. S. Leslie, in: Euroceltique, SA, United States, 1982, p. 20 3. 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, 2003 5. S. Leslie, The Contin delivery system: dosing considerations J. Allergy Clin. Immunol. 78 (1986) 768–773

38. Cont.. 6. Bi- Botti C. Youan , Chronopharmaceutical drug delivery systems: Hurdles, hype or hope? Advanced Drug Delivery Reviews 62 (2010) 898–903 7. Shigehiro Ohdo , Chronotherapeutic strategy: Rhythm monitoring, manipulation and disruption; Advanced Drug Delivery Reviews 62 (2010) 859–875 8. 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