These systems are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic efficacy, and/or targeting the delivery of drug to a tissue. Depending upon the technical sophistication, these rate-control drug delivery systems can be classified into three major categories: (i) pre-programmed drug delivery, (ii) activation-controlled drug delivery, and (iii) feedback-regulated drug delivery.

1. RATE CONTROLLED
DRUG DELIVERY
SYSTEM
PRESENTED BY,
SUFAIRATH
M.PHARM PHARMACEUTICS .

2. INTRODUCTION
 Sustained release , sustained action , controlled release , extended action , time
released dosage forms are the terms used to identify drug delivery system that
are designed to achieve a prolonged therapeutic effect by continuously releasing
medication over an extended period of time after the administration of single dose.
 The term “CONTROLLED RELEASE” has become associated with those systems
from which therapeutic agents may be automatically delivered at predefined rates
over a long period of time .
 But there are some confusion in terminology between “controlled release” and
“sustained release” .

3.  SUSTAINED RELEASE
 The term sustained release has been constantly used to describe a
pharmaceutical dosage form formulated to retard the release of a therapeutic
agent such that its appearance in the systemic circulation is delayed and or
prolonged and its plasma profile is sustained in duration .
 CONTROLLED RELEASE
 It implies a predictability and reproducibility in the drug release kinetics , which
means that the release of drug ingredient from a controlled delivery system
proceeds at a rate profile that is not only predictable kinetically , but also
reproducible from one unit to another.

5. TYPES OF RATE CONTROLLED DRUG DELIVERY
SYSTEM
The rate controlled drug delivery system is classified as:
 Rate –preprogrammed drug delivery system.
 Activation modulated drug delivery system.
 Feed back regulated drug delivery system.
 Site targeting drug delivery system.

6. I. RATE PREPROGRAMMED DRUG
DELIVERY SYSTEM
• In this the release of drug molecules from the delivery
system has been pre-programmed at specific rate profile.
• In this the Ficks law of diffusion is followed .
Rate preprogrammed DDS
Polymer membrane Polymer matrix Micro reservoir
permeation controlled diffusion controlled partition controlled
DDS DDS DDS

7. Rate controlling
surface
Drug
Drug reservoir
Figure representing rate pre-programmed drug delivery system

8. 1. POLYMER MEMBRANE PERMEATION
CONTROLLED DDS
• In this, a drug formulation is either totally or partially encapsulated in
a reservoir compartment whose drug – releasing surface is covered
by rate controlled polymeric membrane .
• The drug reservoir can be solid particle, dispersion drug solid
particle or concentrated drug solution in a liquid or solid type
medium and the polymeric membrane can be homogenous or
Heterogeneous non porous polymeric material or micro porous or
semi permeable membrane .
• The release of drug from the CrDDS should be at a constant rate
(Q/T) and given by the equation :
Q/T= Km/r Ka/m Dd Dm
Km/r Dmhd + Ka/m Dd hm
Km/r ---- Partition coefficients for interfacial partitioning of drug
molecule from reservoir

9. Ka/m----- Partition coefficient for interfacial partitioning of molecule from
membrane to aqueous dissolution layer .
Dm and Dr ----- Diffusion coefficient in rate controlling membrane and aqueous
diffusion layer .
hm ----- thickness of rate controlling membrane .
hd ------ thickness of aqueous diffusion layer .
For micro porous membrane CrDDS , the release of drug at pre programmed
rate is modulated by partition coefficient , diffusitivity of drug molecule and rate
controlling membrane and the thickness of the medium.

10. a) Sphere
b) Cylinder
Polymer coating
Drug reservoir
Non porous membrane
Figure representing
types of polymer
membrane
permeation controlled
drug delivery system.
Drug release

11. EXAMPLES :
1. PROGESTASERT IUD
2. NORPLANT SUBDERMAL IMPLANT
3. OCCUSERT SYSTEM

12. 2. POLYMER MATRIX DIFFUSION CONTROLLED
DRUG DELIVERY SYSTEM
• In this the drug reservoir is produced from the homogenous dispersion
of drug particles in either a lipophilic or a hydrophilic polymer matrix.
• The drug dispersion in polymer matrix is accomplished by either
(i) Blending a dose of finely ground drug particles with a viscous
liquid (or a semi solid) polymer followed by a cross linking of polymer
chains
OR
(ii) Mixing drug solids with a melted polymer at an elevated
temperature.
• The resultant drug polymer dispersion is then molded to form DD
devices of various shapes and sizes , designed for specific
application.
• The rate of drug release is given by :
Q/t1/2 = (2𝐴CR DP )
1/2

13. Lipophilic polymer
Non swellable matrix
Drug
release
Hydrophilic
swellable matrix
Drug
release
Gel layer
Drug
Reservoir
(dispersion)

14. EXAMPLES
• NITRO-DUR
• COMPUDOSE SUBDERMAL IMPLANT

15. 3. Micro reservoir partition controlled drug delivery system
• In this the drug reservoir is suspension of drug solid particle in an aqueous
solution of water miscible polymer , like polyethylene glycols.
• This forms a homogenous dispersion of many discrete , un leachable and
microscopic drug reservoirs in a biocompatible polymer like silicone.
• The rate of drug release dQ/ dt is given by
dQ/dt = Dp Ddm Kp D l S l(1-n)
Dp hd + Dd hpm Kp nSp- h1
(1/Kl + 1/ Km ).
n----- ratio of drug concentration at the inner edge of interfacial barrier.
K1 ,Km , K n----- partition coefficient for interfacial partitioning of drug from the
liquid compartment to polymer matrix , from polymer matrix to polymer coating
membrane, from polymer coating membrane to elution solution.
Sl and Sp ----- solubility in compartment and polymer matrix.
h------thickness.

16. EXAMPLES :
1. TRANSDERMAL NITRODISC SYSTEM
2. TRANSDERMAL CONTRACEPTIVE DEVICE
3. SYNCRO- MATE –C IMPLANT

17. II . ACTIVATION MODULATED DRUG DELIVERY
SYSTEM
• In this , the release of drug molecules from the delivery system is
activated by some physical , chemical or biochemical processes and/ or
facilitated by an energy supplied externally.
• Rate is controlled by applied energy.
• CLASSIFICATION
Activation modulated drug delivery system is mainly classified into 3
1. PHYSICAL MEANS
 Osmotic pressure activated drug delivery system
 Hydro dynamic pressure activated drug delivery system
 Vapour pressure activated drug delivery system
 Mechanical force activated drug delivery system
 Magnetic activated drug delivery system
 Sonophorosis activated drug delivery system
 Ionotophorosis activated drug delivery system
 Hydration activated drug delivery system

18. 2.CHEMICAL MEANS
 PH activated drug delivery system.
 Ion activated drug delivery system.
 Hydrolysis activated drug delivery system.
3. BIOCHEMICAL MEANS
 Enzyme activated drug delivery system.
 Activation modulated drug delivery system.

19. Drug
Rate controlling
surface.
Energy sensorDrug reservoir

20. 1. PHYSICAL MEANS
a. OSMOTIC PRESSURE ACTIVATED DRUG DELIVERY SYSTEM
• It depends upon the osmotic pressure to activate the release of drug.
• In this the drug reservoir , which can be either solution or solid formulation , is
contained within the semipermeable housing with a controlled water
permeability.
• The drug in solution is released through a special laser
drilled delivery orifice at a constant rate under a controlled
gradient of osmotic pressure.
• For a solution type , osmotic pressure activated CrDDS , the intrinsic rate of DD
(Q/t) is defined by,
Q/t = Pw Am (πs – πe)
hm
For solid type,
Q/t = Pw Am (πs – πe) Sd
hm
Where,

21. Pw ----- Water permeability
Am ----- effective surface area
hm ------ thickness of semi permeable housing.
(πs – πe) ------Differential osmotic pressure b/n drug delivery system with osmotic
pressure of πs environment
Sd ----- Aqueous solubility.
The release of drug molecules from this type CrDDS is activated by osmotic
pressure and controlled at a rate determined by the water permeability and effective
surface area of semipermeable housing as well as osmotic pressure gradient.

22. orifice
Drug core
Semi permeable membraneDrug
released
water
(a)

23. orifice
Drug core
Semi permeable membrane
water
(b)
BEFORE ACTIVATION
Drug Layer
Semi permeable
membrane
Drug
released
(C)
water
DURING EXPANSION OF PUSH
LAYER

24. EXAMPLE
ACUTRIUM
 It is an oral rate controlled DDS , solid tablet water soluble and osmotically active
phenyl propyl amine HCl enclosed within a semipermeable membrane made from
cellulose triacetate .
 Semi permeable membrane surface is further coated with thin layer of PPA for
immediate release .
 It is mainly designed to provide a controlled delivery of PPA for duration of 16
hours for appetite suppression in a weight control program
Drug
reservoir
/osmotically
active
solutes
Delivery
orifice
Semi
permeable
membrane
Immediate
releasing
layer
Controlled release
dose

25. MECHANISM
 In GIT , the GI fluid dissolves the immediate release PPA layer this provides initial
dose of PPA .
 Water component penetrates through semipermeable membrane at a rate PwAm/hm
 Dissolve controlled release dose of PPA. This creates osmotic pressure differential .
 results in the continuous delivery of PPA solution at a rate through delivery orifice
predrilled by laser beam .

51. 2. HYDRODYNAMIC PRESSURE ACTIVATED DDS: in this hydrodynamic pressure is
explored as a potential source of energy to modulate the delivery of therapeutic agent .
3. VAPOUR PRESSURE ACTIVATED DDS : in this the pumping compartment contains
vaporizable fluid which vapourizes at body temperature and creates vapour pressure
and modulate the delivery of drug.
4. MAGNETIC ACTIVATED DDS: electro magnetism triggering vibration mechanism
helps in release of molecule at a low rate from polymer controlled DDS.
5. SONOPHOROSIS ACTIVATED DDS: it utilizes the ultrasonic energy to activate the
delivery of drugs from polymeric DD devices.
6.IONTOPHOROSIS ACTIVATED DDS : It uses electrical current to activate and
modulate the diffusion of charged molecule across biological membrane.
7.HYDRATION MODULATED DDS: The release of drug is modulated and activated by
hydration induced swelling of polymer matrix .

52. 8. MECHANICALLY ACTIVATED DDS :
 In this CrDDS , the drug reservoir is a solution formulation in a container equipped
with mechanically activated pumping system .
 A metered dose of drug formulation can be reproducibly delivered into body cavity .
Ex: nose , through the spray head upon manual activation of drug delivery pumping
system .
 The volume of solution delivered is controllable as small as 10-100 𝜇𝑙 and is
independent of force and duration of activation applied as well as the solution
volume in the container .
 Ex: Metered dose nebulizer – for the intranasal administration of precision dose of
leutinising hormone – releasing hormone (LHRH) and its synthetic analogue
buserelin
 ADVANTAGE : through nasal absorption , the hepatic first pass elimination can be
avoided .

54. II .CHEMICAL MEANS
1. pH ACTIVATED DRUG DELIVERY SYSTEM
 This type of CrDDS has been developed to target the delivery of drug only in the
intestinal tract and not in the stomach .
 i.e., it permits for drug liable to gastric fluid or irritating gastric mucosa .
 It is fabricated by coating a core tablet of gastric fluid sensitive drug with a
combination of intestinal fluid insoluble polymer , like ethyl cellulose and intestinal
fluid soluble polymer like hydroxyl methyl cellulose phthalate .
STOMACH
Coating of
intestinal fluid insoluble
polymer
intestinal fluid soluble
intestinal fluid polymer
GASTRIC FLUID
LIABLE DRUGS
GASTRIC FLUID
LABILE DRUGS
Micro porous membrane
of intestinal fluid insoluble
Polymer
DRUG

55.  Gastric fluid labile drug is protected by encapsulating it inside a polymer
membrane (such as combination of ethyl chloride and hydroxyl methyl cellulose
phthalate )
 That resist the degradative action of gastric pH .
 In stomach, coating membrane resist the act of gastric fluid (pH< 3) and the drug
molecules are thus protected from acid degradation .
 After gastric emptying the DDS travels to small intestine and intestinal fluid (pH<
7.5) will activate the erosion of intestinal fluid soluble hydroxy methyl cellulose
phthalate component from coating membrane .
 This leaves a micro porous membrane of intestinal fluid insoluble polymer of ethyl
cellulose .
 Which controls the release of drug from the core tablet .
 The drug solute is thus delivered at a controlled manner in intestine by
combination drug dissolution and pore channel diffusion.

56.  By adjusting the rate of intestinal fluid soluble polymer to the intestinal fluid
insoluble polymer , the membrane permeability of drug can be regulated as
desired .

58. 2.ION ACTIVATED DRUG DELIVERY SYSTEM
 To maintain in gastrointestinal fluid a relatively constant level of ions ,this type of
CrDDS has been used .
3.HYDROLYSIS ACTIVATED DRUG DELIVERY SYSTEM
 This type of CrDDS depends on the hydrolysis process to activate the release of
drug molecules .
III BIOLOGICAL MEANS
1.ENZYME ACTIVATED DRUG DELIVERY SYSTEM
 In this type of CrDDS , the drug reservoir is either physically entrapped in
microsphere chemically bound to polymer chains fabricated from biopolymers such
as albumin or polypeptides .
 The release of drug is made possible by enzymatic hydrolysis biopolymers by a
specific enzyme in the target tissue .

59. Example
Development of albumin microsphere
Which release 5-fluro uracil
In a controlled manner , by
Protease activated biodegradation.
3.FEEDBACK REGULATED DRUG DELIVERY SYSTEM
 The release of drug from delivery system is activated by a triggering agent such as
a biochemical substance in the body via some feedback mechanisms .
 Rate of drug release is controlled by the concentration of triggering agent detected
by a built into the CrDDS .

60. Drug reservoir
Drug
Biochemical
responsive /
Energy sensor
Rate controlling
surface.
FEED BACK
REGULATED DDS
BIO EROSION
REGULATED
DDS
BIO
RESPONSIVE
DDS
SELF
REGULATING
DDS

61. 1. BIOEROSION REGULATED DDS
 The system consist of drug dispersed biodegradable matrix fabricated from ( poly
vinyl methyl ether ) half ester , which was coated with a layer of immobilized
urease.
 In solution which near neutral pH , the polymer only erodes very slowly .
 In presence of urea , urease at the surface of DDS metabolizes urea to ammonia .
 This causes the pH to increase and activates a rapid degradation of polymer matrix
as well as the release of drug molecules .

62. 2.BIORESPONSIVE DDS
 In this system, the drug reservoir is contained in a device enclosed by a bio
responsive polymeric membrane whose drug permeability is controlled by
concentration of biochemical agent in the tissue where CrDDS is located .
 E.g.: development of glucose triggered insulin delivery system .
 In this the insulin reservoir is encapsulated within a hydrogel membrane having
pendent –NR2 groups exist at neutral state and membrane is unswollen and thus
impermeable to insulin .
 As glucose (triggering agent) penetrates into the membrane , it oxidized
enzymatically by glucose oxidase entrapped in the membrane to form gluconic acid .
 This process triggers the protonation of –NR2 group to form -NR𝐻+
and hydrogel
membrane then becomes swollen and thus permeable to insulin molecules .
 The amount of insulin delivered is thus bio-responsive to the concentration of glucose
penetrating into CrDDS.

64. 3.SELF REGULATING DDS
 This type of feedback regulated DDS depends on a reversible and competitive
binding mechanism to activate and to regulate the release of drug.
 In this system the drug reservoir is a drug complex encapsulated within
semipermeable polymeric membrane .
 The release of drug from the delivery system is activated by the membrane
permeation of a biochemical agent from the tissue in which the system is located .
 E.X: reversible binding of sugar molecules by lectin in the design of self regulating
DDS.
 It first involves the preparation of biologically active insulin derivative in which insulin
is coupled with a sugar E.g.: maltose
Conjugated with lectin
An insulin - sugar- lectin complex formed

65. Encapsulated within a semipermeable membrane to produce CrDDs
As a blood glucose diffuses into the device and competitively binds at the sugar
binding sites in the lectin molecules.
This activates the release of insulin – sugar derivatives from binding sites
The released insulin – sugar derivatives then diffuses out of the device ( the amount
of insulin – sugar derivatives depends upon the glucose concentration ).
The self regulating delivery is achieved .
DEMERIT:
Release of insulin is non linear in response to changes in glucose level .

66. 4. SITE TARGETING DRUG DELIVERY SYSTEM
 Delivery of a drug to a target tissue that needs medication consist of multiple
steps of
(i) Diffusion &
(ii) Partitioning
 It is a complex process .
 These CrDDS has been designed to control the rate of drug release from the
delivery system , but the path for the transport of drug molecule from delivery
system to the target tissue remains uncontrollable .

67.  Optimal treatment with maximal safety is ultimate goal.
Drug reservoir
Drug
Rate controlling
surface.
Energy sensor
Site targeting
moiety