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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 ID-gurushelke356@gmail.com

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, chronoph
armacology, chronopharmacokinetics, chronopharmacodynami
cs, 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
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. 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 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. 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 = number of myocardial infarctions
(CK-MB) activity per hour
t = time of day in hour

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 heterogeneity
2. 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. 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. 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:

18. 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

19. 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

20. 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

21. 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.

22. 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

23. 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)

24. 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

25. 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

26. 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

27. 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

28. 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.

29. 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

30. 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

31. 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

32. 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

33. Chropharmcokinetics
 Chropharmcokinetics consist of ADME of drug

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

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

36. 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

37. 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)

38. 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

39. 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