CHRONOPHARMACEUTICS: RELEVANT APPROACH TO DRUG DELIVERY

Presented by Gurubas T. Shelke

M. Pharm Sem-1Pharmaceutics

Guided ByMrs. Shilpa Shotriya

Email ID-gurushelke356@gmail.com

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

Cont…

Chronopharmacodynamic

Chronopharmacokinetics

Chronopharmaceutical technologies

Examples of Chronop’cal drug delivery system

Conclusion

References

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.

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

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

Circadian rhythm influences on physiological process Physiological functions Changes

Body temperature

Breathing Sleep

Blood pressure

Growth hormone

Adrenaline

Heart rate

Plasma catecholamines

Plasma aggregability

Fibrinolytic activity

Gastric acid secretion

Gastric emptying

Sleep ↓ wakefulness ↑

Sleep ↓ wakefulness ↑

Sleep ↓ wakefulness ↑

pm 11:00 secretion ↑

pm 11:00 secretion ↑

Sleep ↓ wakefulness ↑

Increase in morning

Increase in morning

Decrease in morning

Highest in evening

More rapid in morning

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

Cont….

Fig2: The day/night patterns of disease severity.

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

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

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

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 isTi: transition rate between stagesdi: death rate for cells in a particular stager : enter the resting stage(1-r): return to the RNA/protein synthesis stage

Modeling glucose insulin interaction

1.low order structured

To estimate glucose and insulin in

diabetic patient G(t),: plasma glucose,I(t): plasma insulinX(t): insulin concentration in a remote compartmentE(t): exogenous insulin, Pi: parameters,Gb: Basal glucose concentration

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

Design and development of ChrDDS:

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 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

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

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

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) swellingpolymeric compartment, (c) hydrophilic polymeric coating, (d) osmotic membraneand (e) laser-drilled orifices.

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

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)

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

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

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

TIMERx technology combines primarily xanthan and locust bean gums mixed

with dextrose

Drug release from TIMERx:

Water penetration from Gi to TIMERx gum matrix

Active drug substance released

Ex. oral CR opioid analgesic oxymorphone

Three-dimensional printingA 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.

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

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

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

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

Chropharmcokinetics

Chropharmcokinetics consist of ADME of drug

MARKETED DRUGSFDA approval

date API Propriatory

name;dosage form

Chronopharmaceutical tchnology

Indication

Sept. 01, 1982 Theophylline Uniphyl CONTIN ASTHMA

Oct. 15, 1986 Famotidine PepcidR; tablets

Physico-chemicalmodification of API

Ulcer

Dec. 23, 1991 Simvastatin ZocorR; Tablets Physico-chemicalmodification of API

Hypercholesterolemia

Feb. 26, 1996 Verapamil HCl Covera-HSRTablet

OROS Hypertension

Nov. 25, 1998 Verapamil HCl VerelanRPM; Capsule

CODAS Hypertension

Feb. 06, 2003 Diltiazem HClverapamil HCl

CardizemR LA;Tablet

CEFORM Hypertension

Mar. 12, 2003 Propranolol HClverapamil HCl

InnoPranR XLCapsule

DIFFUCAPS Hypertension

MARKETED DRUGS IN JAPANAPI Proprietary name

dosages formChronopharmaceutical

technologyDisease

Famotidine Gaster® tablets Physico-chemicalmodification of API

Ulcer

Simvastatin Lipovas®tablets

Physico-chemicalmodification of API

Hyperlipidemia

Theophylline Uniphyl®extended releasetablets

CONTIN® Asthma

Tulobuterol Hokunalin®tape

Transdermal chronodeliverysystem

Asthma

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

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)

References1.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

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