Physiological functions showing circadian

rhythm
Diseases known to display circadian Rhythm
Peak time of selected circadian
rhythms
Rhythms for various diseases
 S.No Disease Chronological behavior & symptoms

1. Asthma Precipitation of attacks after mid night or at wee

hours of morning

2. CVD’s B.P lowers during sleep cycle; rises steeply at

morning hours

3. Arthritis Increased concentration of c-reactive protein and

interleukin-6 in plasma. Pain in early mornings

4. Diabetes Mellitus Increase in blood sugar level after meals; in the

morning hours

5. Peptic Ulcer Gastric acid secretion is highest during the night as

well as at afternoon

6. Hyperchloesterimia Increased cholesterol synthesis in night time

compare to day time
WHY CHRONOPHARMACEUTICS
?????
 APPROACHES

Capsule
Single

Tablets

Chrono p’eutic
systems Changes in
membrane
permeability
Multiple
Reservoir systems
 CAPSULE BASED SYSTEMS
• Systems with swellable plug
1.

• Systems based on osmosis

2.

• Systems based on expandable orifice

3.

• Delivery by series of stops

4.
 Systems with swellable plug
System consist of insoluble
capsule body, housing a drug and
a plug
Example is Pulsincap systems
Plug consist of permeable and
swellable polymers like
polymethylacrlates or erodible
compressed polymers like HPMC,
PEO etc, or enzymatically erodible
polymers like pectins.
 Systems based on osmosis
System consist of capsule enclosed in semi permeable membrane.

Capsule contains insoluble plug, osmogen and drug

Example: PORT SYSTEM

Capsule comes in contact with body fluid

Semi permeable membrane allows the entry of fluid

Pressure develops inside capsule shell

Insoluble plug expels and release the drug

 Systems based on osmosis
• Designed to deliver the
drugs as liquid
formulations
• Example:
Liquid OROS Softcap
• Contains liquid drug
layer, Osmogen, push
layer and semi-
permeable membrane
 Delivery by series of stops

• Contains drug, osmogens separated by

slider partitions to deliver the drug
through orifice
 TABLET BASED SYSTEMS
• Systems with erodible or soluble coating
i. Time clock systems
1. ii. Chronotropic Systems

• System with rupturable barrier coating

2
 Systems with erodible or
soluble coating
TIME CLOCK SYSTEM
Tablet is coated with lipidic barriers
containing hydrophobic-surfactant
layer.
This coat is followed by water
soluble coat
As coated tablet comes in contact
with gastric environment the film
rehydrates and redisperse after
certain lag time.
Systems with erodible or
soluble coating
Chronotropic System
Core tablet is coated
with hydrophilic
swellable polymer
(HPMC)
Additional enteric
coating can be given
Systems with erodible or
soluble coating
Multi layered Tablets
A release pattern with
two pulses was obtained
from a three-layered
tablet containing two
drug containing layers
separated by a drug free
gellable polymeric
barrier layer.
 System with rupturable barrier
coating
These systems consist of
an outer release
controlling water
insoluble but permeable
coating subject to
mechanically induced
rupture phenomenon.
a) Initial tablet
b) Gel formation
c) Erosion
d) Extended erosion
e) Rupture of coating layer and initiation of core
dissolution
f) Extended Felo release
 MULTI UNIT SYSTEMS
• Offers more reliability when compared to single unit
systems
• Potential benefits:
 Predictable, reproducible and generally short
gastric residence time
 No dose dumping
 Reduced risk of local irritation
 Increased bioavailability with reduced variability
• Types: Pellets, Microspheres, Nanoparticles,
Granules, Beads etc.
 STIMULI INDUCED SYSTEMS
• Chemical Induced systems
Systems that releases the drug in presence of
specific enzyme or protein.
 TEMPERATURE INDUCED
SYSTEMS
• Thermo responsive hydrogel systems
• In these systems the polymer undergoes
swelling or deswelling phase in response to
temperature which modulate the drug
release in swollen state.
• Thermosenstive polymeric micelles were
developed to treat cancer. Polymer like N
isopropylacrylamide is used.
MARKETED FORMULATIONS
ADVANTAGES
 LIMITATION
• Not suitable for patients working working in
shifts
• Time consuming and technical skill is required
• Dependance human action to trigger drug
release
• Variability of drug release
DIFFERENT MECHANICAL RHYTHMS IN OUR BODY

 Circadian (Oscillation completed in 24hr)

 Ultradian (More than 1 cycle per day )
 Infradian ( Less than 1 cycle per day )
SL. No Circadian rhythmicity Disease

1 Exacerbation more common during the sleep Asthma

period & attacks after midnight or at early
morning hr

2 Worse in the morning/upon rising Allergic Rhinitis

3 Morning pain and more in night Rheumatoid Arthritis
4 Chest pain and ECG changes more common in Angina Pectoris
early morning
5 Increased blood sugar level after meal Diabetes mellitus

6 Incidence higher in the early morning Myocardial Infraction

7 Cholesterol synthesis is generally higher during Hypercholesterolemia
night than day time
8 Incidence higher in the morning after Sudden cardiac death
awakening
9 Acid secretion high in afternoon and at night Peptic ulcer disease
 REASONS FOR DESIGNING OF
CHRONOTROPIC SYSTEMS
• First pass metabolism
• Biological tolerance
• Special chronopharmalogical need
• Local therapeutic need
• Gastric irritation or drug instability in gastric
fluid
• Drug absorption differences in various
gastrointestinal segments
PULSATILE DRUG RELEASE
PATTERN
 REFERENCES:
1. Davis SS, Illum L. Drug delivery systems for challenging molecules. International
Journal of Pharmaceutics 1998;176:1-8.

2. Gennaro AR, ed. Remington. The Science and Practice of Pharmacy 20th ed.
USA:Lippincott, Williams & Wilkins; 2000; P. 903-905.

3. Burnside BA, GO X, Fiske K, Couch RA, Treacy DJ, Chang RK, Mc Guinness
CM, Rudnic EM : US20036605300 2003.

4. Bussemer T, Otto I, Bodmeier R. Pulsatile drug delivery systems Crit

Rev.Therapeutic Drug Carrier Systems 2001;18(5):433-458.

5. Yoshida R, Sakai K, Okano T, Sakurai Y. Pulsatile drug delivery systems using

hydrogels. Advanced Drug Delivery Reviews 1993;11:85-108.

6. Kikuchi A, Okano T. Pulsatile drug release control using hydrogels.

Advanced Drug Delivery Reviews 2002;54:53-77.