Controlled release drug delivery system2

CONTROLLED
RELEASE DRUG
DELIVERY SYSTEM
Prepared By :
Ms. Bansari B. Patel
Mpharm sem-1
Department of pharmaceutics
Bhagwan Mahavir College of Pharmacy ,Surat.
Gujarat technological university
Guided By :
Mr. Vinod D. Ramani
Associate Professor
Department of Pharmaceutics
Bhagwan Mahavir College of Pharmacy

 CONTENTS
• Introduction
• Advantages
• Disadvantages
• Factors affecting
• Approaches to CRDDS
• References

 WHAT IS CRDDS?
Controlled drug delivery system refers to system that provides some
control to either temporal or spatial or both nature of the drug release.
Temporal :- refers to controlling the rate of specific time of drug delivery
to targeted tissue .
Spatial :- refers to targeting a drug to a specific organ or tissue.
Ideal condition for DDS :-
i. It should deliver drug at a rate that is required by the body over a
period of treatment.
ii. It should deliver drug solely to the site of action.

Hence , CRDDS attempts to :-
i. sustain drug action at a predetermined rate by maintaining effective
drug level in body and thereby minimizing undesirable side effects of
drug.
ii. Localize drug action by spatial placement of controlled release
system in diseased tissue or organ.
Generally , very few systems fulfil the above principles .
In most cases , the release system creates constant conc. of drug
within body over extended period of time.
Ideally , it is desirable to place drug at site of target , be it a tissue
,organ or receptor, leaving rest of the body drug free , but it would be
quiet difficult if the target is covered by some barriers.
 WHAT IS CRDDS?

As shown , conventional
tablet or capsule provides
single burst of drug . As long
as amount of drug is above
MEC , pharmacological
response is observed,. But as
it rises above MSC , toxicity or
side effects may occur.
Whereas , in CR , drug is
released at a constant rate.
Hence it will not rise above
MSC and thereby minimizing
toxicity or side effects.
SR also decreases side effect
but the rate of release varies
over period of time.

 ADVANTAGES OF CRDDS
CR formulation release drug at a required rate for prolonged time
,thereby decreasing frequency of drug administration and also side
effects.
• E.g. : Nifedipine in conventional formulation causes hypotension
in patients.CR Nifedipine product avoids high initial blood conc
which causes sudden hypotension .
As frequency of dosing decreases , patient compliance improves.
Maximum utilization of drug enabling reduction in total amount of
drug dose administered.

Decreased side effect
• Eg:-CR product of paroxetine delays release of paroxetine until tablet
has passed through stomach . As a result , side effect like nausea is less
as compared to immediate release.
Increase in safety margin of high potency drug due to better control of
plasma level.
Decrease in health care cost with CR products due to :-
i. Short term therapy
ii. Decrease in frequency of dosing
iii. Improved therapy
 ADVANTAGES OF CRDDS

 DISADVANTAGES OF CRDDS
Higher cost of formulation .
Poor in -vivo in-vitro co-relation.
Failure of controlled release mechanism may result in release of a large
toxic dose.
Reduced potential for drug adjustment of drug normally administered in
varying strengths.
Retrieval of drug is difficult in case of toxicity , poisoning or
hypersensitivity reaction.

 FACTORS AFFECTING CRDDS
Factors affecting CRDDS
Physiochemical Pharmacokinetic Pharmacodynamic
properties properties properties
a. Molecular Size a. Absorption rate a. Drug dose
b. Aqueous solubility b. Elimination half life b. Therapeutic range
c. Partition co-efficient c. Metabolism rate c. Therapeutic Index
d. Dissociation constant d. Dosage form index d. Plasma conc
e. Ionization at physiological response
pH relationship
f. Stability in GI milieu
g. Route of administration

I. Physio Chemical Proprerties:-
a. Molecular size and weight of drug :-
Lower the molecular weight or size , faster and complete the absorption
For drugs absorbed by pore mechanism , the molecular size threshold is
150 Daltons for spherical compound and 400 Daltons for linear
compound.
But 95% of drugs are absorbed by passive diffusion. Diffusivity , i.e. , the
ability of a drug to diffuse to a membrane is inversely proportional to
molecular size. So larger the molecular size , lower will be the diffusivity
and hence the absorption. It can be expressed as :
logD = -Sv logV + Kv
= -Sm logM +Km
Where , D=diffusivity , V = molecular volume
M= molecular weight or mass
Sv , Sm , Kv , Km =constant

b. Aqueous Solubility :-
Drug must be in solution form before they can be absorbed. Hence
compounds having lower aqueous solubility suffers oral bioavailability
problems. Eg : Warfarin , Digoxin , Griesofulvin
Aqueous solubility plays an important role in selecting mechanism for
CR.
Eg : For slightly soluble drug , diffusion systems are poor choice as the
driving force in such system is conc in aqueous solution. On other hand ,
such drug can be effectively incorporated in matrix system.
In selecting polymer coatings for CR system , dissolution rate of drug
must be considered.
Aqueous solubility limits the loading efficiency of drug in carriers such
as liposome .Most water soluble drug tends to leak from such carriers

c. Partition co-efficient / Lipophilicity of drug :-
Partition co efficient influence not only the permeation of drug through
biological membrane but also diffusion across the rate controlling
membrane or matrix .
Drugs with extremely high partition co-efficient readily penetrate the
membranes but are unable to proceed further. Such drugs have
increased tendency to cross even the more selective barriers like BBB.
Whereas drugs having high aqueous solubility cannot penetrate
through the membranes.
Hence a balance in partition co-efficient is necessary to give an
optimum flux for permeation through the biological and rate controlling
membranes.

d. Drug dissociation and ionization at physiological pH :-
For optimum absorption , drug should be unionized at the site .
Acidic drugs remains unionized in acidic pH (3.0 -7.5) and basic drug
remains unionized in basic pH (7.0-11.0).
Drugs existing mostly in ionized form are poor candidates for CRDDS.
Eg : Hexamethonium.

e. Protein Binding :-
It is well known that many drugs bind to plasma protein with the
influence on duration of action.
Drug-protein binding serve as a depot for drug producing a
prolonged release profile, especially it is high degree of drug binding
occurs.
Extensive binding to plasma proteins will be evidenced by a long half
life of elimination for drugs and such drugs generally most require a
sustained release dosage form. However drugs that exhibit high
degree of binding to plasma proteins also might bind to biopolymers
in GI tract which could have influence on sustained drug delivery. The
presence of hydrophobic moiety on drug molecule also increases the
binding potential.

f. Drug stability :-
Drugs unstable in GI environment cannot be administered as oral CR
formulation . E.g. Nitroglycerine . For such drugs a different route of
administration should be used.
Drugs unstable at gastric pH can be designed as sustained release in
intestine with limited or no delivery in stomach . Eg , Propantheline.
On the other hand , drug unstable in intestine can be designed as
gastroretentive dosage form . Eg, Probanthine .

g. Route of administration :-
 Different route of administration are selected based on various physical
parameters of drugs . Various commonly used routes for CRDDS are :-
i. Oral route :-
The drug whose administration is pH dependent , destabilized by gastric
fluid or enzymes , undergoes extensive presystemic metabolism
(nitroglycerine) , has an absorption window and / or absorbed actively
(riboflavin) are poor candidates for this route .
For a drug to be successful as oral controlled release formulation , it
should be absorbed through the entire length of GIT.
The main limitation of this route is the transit time . The duration of
action can be extended for 12 to 24 hrs.
This route is suitable for drug given in dose as high as 1000mg .

ii. Intramuscular / subcutaneous route :-
This route is suitable when duration of action is to be prolonged for 24
hrs to 12 months.
Only a small dose of drug , about 2ml or 2 grams can be administered
by this route.
Factors affecting drug release and selection are solubility of drug in
surrounding tissues , molecular weight ,partition co efficient and pKa of
drug and contact surface between the drug and surrounding tissues .
iii. Transdermal route :-
This route is used for drugs showing extensive first pass metabolism
upon oral administration or drugs with low dose such as nitroglycerine.
Factors affecting are partition co-efficient , contact area , skin condition
skin permeability rate ,etc.

II. Pharmacokinetic characteristics of drug :
a. Absorption rate :-
For a drug to be administered as controlled release formulation ,
absorption must be efficient .
Rate of release Kr > rate of absorption Ka.
A drug with slow absorption rate is poor candidate as continuous
release of such drug results in pool of unabsorbed drug . E.g. , Iron ,
decamethonium.
b. Elimination half life :
Ideally , rate of absorption = rate of elimination
Smaller the t½, larger the amount of drug to be incorporated in
controlled release dosage form .
Drugs with t½ 2 to 4 hrs are suitable for such system . E.g. Propranolol.

c. Rate of metabolism :-
A drug which is extensively metabolized is a suitable candidate for such system
unless the metabolism is too rapid.
A drug capable of inducing or inhibiting metabolism is poor candidate since
state levels would be difficult to maintain.
d. Dosage form index :-
DI =Css max/ Css min
where , DI=dosage form index , Css max = maximum conc of drug at time t,
Css min = minimum conc of drug at time t.
The drug release rate should be monitored so that a steady plasma conc is
by reducing DI ratio , while maintaining the drug level within the therapeutic
window.
Ideally the rate of drug release from the formulation should be greater then rate
absorption.
Ideally it should be close to one.

III. Pharmacodynamic characteristics of drug :
a. Drug Dose : -
In general a single dose of 1.0 gm is considered for a conventional
dosage form this also holds for controlled release dosage forms.
In case, the dose already high, then formulating the same into
controlled release will further increase the overall dosage size &
reduced patient compliance.
 For drugs with an elimination half-life of less than 2 hours as well as
those administered in large doses, a controlled release dosage form
need to carry a prohibitively large quantity of drug.
b. Therapeutic Range :-
The ideal drug for CRDDS should have therapeutic range wide enough
such that variation in release rate do not result in concentration
the level.

c. Therapeutic index :-
In general the larger the volume of therapeutic index safer the drug.
Drug with very small values of therapeutic index usually are poor
candidates for CRDDS due to pharmacological limitation of control over
release rate .e.g.- induced digoxin, Phenobarbital, phenytoin.
Here , TI = Therapeutic index , TD50 =median toxic drugs ,
ED50=median effective dose
d. Plasma Concentration Response (PK/PD) Relationship :-
Drugs such as Reserpine whose pharmacological activity is independent
of its concentration are poor candidates for controlled release system.

FACTORS AFFECTING CRDDS
SR NO PROPERTIES DESIRED FEATURES
A Biopharmaceutics Properties
1Molecular Size Less than 600 Daltons
2Aqueous solubility More than 0.1 mg / ml
3Partition Co-efficient 1 to 2
4Dissociation constant pKa Acidic drugs, pKa >2.5 , and Basic Drugs , pka<11.0
5Ionisation at Physiological pH Not more than 95%
6Stability in GI milieu Stable at both Gastric and intestinal pH
7Absorption mechanism Passive but not through a window
B Pharmacokinetic Properties
1Absorption Rate High
2Elimination Half-Life 2-6 hrs
3Metabolism Rate Not Too High
4Dosage Form Index (DI) 1
C Pharmacodynamic Properties
1Drug Dose Maximum 1 gm
2Therapeutic Index (TI) Wide
3Therapeutic Range Wide
4PK/PD relationship Good

APPROACHES FOR CRDDS
 Chemical approach
 Biological approach
 Pharmaceutical approach

APPROACHES FOR CRDDS
Chemical
approach
• pH- activated
• Ion- activated
• Hydrolysis- activated
Biological
approach
• Enzyme- activated
• Biochemical-
activated
Pharmaceutical
approach
• Dissolution controlled
• Diffusion Controlled
• Diffusion-dissolution
Controlled

 PHARMACEUTICAL APPROACH
A. Dissolution controlled Release:
Matrix dissolution control
 Encapsulation or Reservoir dissolution control
B. Diffusion Controlled Release:
Reservoir devices
Matrix devices
C. Dissolution-Diffusion Controlled (Combination)

DISSOLUTION CONTROLLED RELEASE:
Controlled release oral products employing dissolution as the rate-
limiting step are in principle the simplest to prepare.
1. Encapsulation or reservoir dissolution control:
These methods generally involve coating individual particles or
of drug with a slowly dissolving material.
The coated particles can be compressed directly into tablets as in
Spacetabs or placed in capsules as in the Spansule Products.

Since the time required for dissolution of the coat is a function of its
thickness and aqueous solubility, one can obtain repeat or sustained
action by employing a narrow or a wide spectrum of coated particles of
varying thicknesses respectively.
There are several ways for coating. A common method is to coat the
seeds with the drug , followed by a coat of slow dissolving materials
such as carbohydrate sugar, cellulose, polyethylene glycol, polymeric
material and wax.
Marketed:- Progestasert_ IUD, Occusert_ system, Transderm-Nitro_
system, Norplant_ subdermal implant

II. Matrix or Monolithic system:-
An alternative approach is to compress the drug with a slowly dissolving
carrier of some sort into a tablet form.
 Here, the rate of drug availability is controlled by the rate of
penetration of the dissolution fluid into the matrix.
The carrier used are bees wax, carnauba wax, castor oil ,etc.

Controlled dissolution by:
1.Altering porosity of tablet.
2.Decreasing its wettability.
3.Dissolving at slower rate.
The drug release is determined by dissolution rate of the polymer.
• Examples:
1. Dimetane extencaps,
2. Dimetapp extentabs.

DIFFUSION CONTROLLED RELEASE:
 This system is hollow containing an inner core of drug.
 The water insoluble polymeric material surrounds drug reservoir.
The drug partitions into the membrane and exchanges with the
surrounding fluid by diffusion.
There are basically two types of diffusion controlled systems which
been developed over the past two decades, reservoir devices and
devices.

Reservoir systems are hollow devices in which an inner core of the drug
is surrounded by a polymer membrane.
 In this device, the drug core is encapsulated in a water-insoluble
polymeric membrane.
The mesh (i.e., the space between macromolecular chains) of these
polymers , through which drug penetrates or diffuses after partitioning,
is of MOLECULAR LEVEL.
 The rate of drug release is dependent on the rate of drug diffusion but
not on the rate of dissolution.
 In short, mass transport phenomena at molecular level occurs.
Examples: Nico-400, Nitro-Bid.

The drug release rate is dependent on the type of polymer. High
molecular weight compounds are difficult to deliver through the device.
Delivery systems designed on this principle can be administered by
different routes: intrauterine such as Progestasert , implants such as
Norplant, transdermal such as Transderm-Nitro, and ocular such as
Occusert.

II. Matrix Device :
A matrix or monolithic device consists of an inert polymeric matrix in
which a drug is uniformly distributed.
Drugs can be dissolved in the matrix or the drugs can be present as a
dispersion.

Matrix may be HOMOGENEOUS or POROUS with water filled pores.
The rate of drug release is dependent on the rate of drug diffusion but
not on the rate of solid dissolution.
A matrix (or monolith) device is easy to formulate and gives a higher
initial release rate than a reservoir device and can be made to release at
a nearly constant rate.
High molecule weight compounds are delivered through the matrix
devices.
Matrix devices are favored over other design for their simplicity, low
manufacturing costs, and lack of accidental dose dumping, which may
occur with reservoir systems when the rate controlling membrane
ruptures.
Marketed:- Nitro-Dur_ system , Compudose_ implant

o Types of Matrix :
 Rigid Matrix Diffusion
 Materials used are insoluble plastics such as PVP & fatty acids.
 Swellable Matrix Diffusion
 Also called as Glassy hydrogels . Popular for sustaining the release of
highly water soluble drugs.
 Materials used are hydrophilic gums.
Examples :
Natural- Guar gum, Tragacanth.
Semisynthetic -HPMC, CMC, Xanthum gum.
Synthetic -Polyacrilamides.
Examples: Glucotrol XL, Procardia XL

Dissolution-Diffusion Controlled (Combination):
The main feature of this system is that the drug is enclosed with a
partially soluble membrane. In this system, the drugs were
homogenously dispersed in a matrix.
Dissolution of part of the membrane allows for diffusion of the
contained drug through pores in the polymer coat.
The drug release from this type of matrix follows zero order kinetics.

 CHEMICAL APPROACHES :
a. pH- activated DDS
b. Ion- activated DDS
c. Hydrolysis- activated DDS

 pH- activated drug delivery system :
This type of chemically activated system permits targeting the delivery
of drug only in the region with selected pH range.

It is fabricated by coating the drug-containing core with a pH – sensitive
polymer combination.
The pH range of fluids in various segments of the gastrointestinal tract
may provide environmental stimuli for responsive drug release.
Altering the pH of the solution will cause swelling or deswelling of the
polymer. Thus, drug release from devices made from these polymers will
display release rates that are pH sensitive
Polyacidic polymers will be unswollen at low pH, because the acidic
groups will be unionized. With increasing pH, Polyacidic polymers will
swell. The opposite holds for polybasic polymers, because the ionization
of the basic groups will increase with decreasing pH.
The most commonly used pH-sensitive polymers are derivatives of
acrylic acid and cellulose.

In the stomach, coating membrane resists the action of gastric fluid
(pH<3) & the drug molecule thus protected from acid degradation.
After gastric emptying the DDS travels to the small intestine & intestinal
fluid (pH>7.5) activates the erosion of the intestinal fluid soluble
polymer from the coating membrane.
This leaves a micro porous membrane constructed from the intestinal
fluid insoluble polymer, which controls the release of drug from the core
tablet.
 The drug solute is thus delivered at a controlled manner in the intestine
by a combination of drug dissolution & pore-channel diffusion.

 Ion- activated drug delivery system:
An ionic or a charged drug can be delivered by this method & this system are
prepared by first complexing an ionic drug with an ion-exchange resin
containing a suitable counter ion.
Resins are water-insoluble materials containing anionic or cationic groups in
repeating positions on the resin chain.
The granules of drug-resin complex are first treated with an impregnating
agent & then coated with a water-insoluble but water-permeable polymeric
membrane.
This membrane serves as a rate-controlling barrier to modulate the influx of
ions as well as the release of drug from the system.
Resin- Drug+ + X+ Resin- ....X+ + Drug+ ՜
Resin- Drug+ + X+ Resin- ....X+ + Drug+
In an electrolyte medium, such as gastric fluid ions diffuse into the system
react with drug resin complex & trigger the release of ionic drug.

Since the GI fluid regularly maintains a relatively constant level of ions,
theoretically the delivery of drug from this ion activated oral drug
delivery system can be maintained at a relatively constant rate.
R-SO3 H+ + H2N-A ↔ R-SO3 – H3N-A
R-N+ H3OH- + HOOC-B ↔ R-N+ H3 –OOC-B+H2O
H2N-A → basic drug , R-SO3H+ → cation exchanger resin , HOOC-B → acidic drug
R-NH3 + OH- → anion exchanger resins.

Hydrolysis- activated drug delivery system
This type of system depends on the hydrolysis process to activate the
release of drug.
Drug reservoir is either encapsulated in microcapsules or
homogeneously dispersed in microspheres or nano particles for
injection.
It can also be fabricated as an implantable device. All these systems
prepared from bioerodible or biodegradable polymers (polyanhydride,
polyorthoesters).

It is activated by hydrolysis-induced degradation of polymer chain & is controlled by
rate of polymer degradation.
E.g. LHRH – releasing biodegradable subdermal implant, which is designed to deliver
goserline, a synthetic LHRH analog for once a month treatment of prostate carcinoma.

 BIOLOGICAL APPROACH
a. Enzyme- activated DDS
b. Biochemical- activated DDS

Enzyme - activated drug delivery system
This type of biochemical system depends on the enzymatic process to
activate the release of drug.
Drug reservoir is either physically entrapped in microspheres or
chemically bound to polymer chains from biopolymers (albumins or
polypeptides).
The release of drug is activated by enzymatic hydrolysis of biopolymers
(albumins or polypeptides) by specific enzyme in target tissue.
Another approach in enzyme activated DDS is use of pH change . They
include :
i. GLUCOSE-RESPONSIVE INSULIN RELEASE DEVICES
ii. UREA-RESPONSIVE DELIVERY SYSTEM

i. GLUCOSE-RESPONSIVE INSULIN RELEASE DEVICES
In case of Diabetes mellitus there is rhythmic increase in the levels of
glucose in the body, requiring injection of the insulin at proper time.
Several systems have been developed which are able to respond to
changes in glucose concentration.
One such system includes pH sensitive hydrogel containing glucose
oxidase, immobilized in the hydrogel encapsulating saturated insulin
solution.
When glucose concentration in the blood increases, glucose oxidase
converts glucose into gluconic acid which changes the pH of the system.
This pH change induces swelling of the polymer which results in insulin
release. Insulin by virtue of its action reduces blood glucose level and
consequently gluconic acid level also gets decreased.

ii. UREA-RESPONSIVE DELIVERY SYSTEM :
 Heller and Trescony firstly reported the alteration in local pH by
immobilization of enzymes that lead to change in polymer erosion
rate.
The proposed system is based on the conversion of urea to
and NH4OH by the action of urease.
 As this reaction causes a pH increase, a polymer that is subjected
increased erosion at high pH is required.
 A partially esterified copolymer of methyl vinyl ether and maleic
anhydride was developed that displays pH dependent drug
 This polymer dissolves by ionization of the carboxylic acid group.

 This pH sensitive polymer containing dispersed drug is surrounded
by a hydrogel, containing urease, immobilized by crosslinking of
urease and bovine serum albumin with glutaraldehyde.
Diffusion of urea into hydrogel and its subsequent interaction with
urease lead to increase in pH which causes erosion of polymer with
concomitant drug release.

 ANTIBODY INTERACTIONS ACTIVATED DDS :
This approach has been proposed for antibody mediated release of
contraceptive agent.
The β- subunit of human chorionic gonadotropin (HCG) is grafted to the
surface of the polymer, which is then exposed to antibodies to β-HCG.
After implantation, this delivery system remains quiescent until
triggered by the first biochemical indication of pregnancy, i.e
appearance of HCG in the circulatory system.
 The HCG competes for the polymer bound antibodies to HCG and
initiates release of the contraceptive drug.
This approach to contraception serves to minimize the frequency of
drug administration and the side effects associated with contraceptive
drugs.

REFERENCES:
1. Y.W.CHIEN;NOVEL DRUG DELIVERY SYSTEM ;FUNDAMENTALS
DEVELOPMENT CONCEPTS AND BIOMEDICAL ASSESMENTS.SECOND
EDITION,
2. ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY;VOLUME 2
3. CONTROLLED DRUG DELIVERY: FUNDAMENTALS AND APPLICATIONS,
Second Edition, Revised and Expanded, Joseph R. Robinson and Vincent H. L.
Lee
4. DESIGN OF CONTROLLEDRELEASE DRUG DELIVERY SYSTEMS
Steve I. Shen, Bhaskara R. Jasti, and Xiaoling Li
5. Controlled Release Drug Delivery Systems Debjit Bhowmik, Harish Gopinath,
B. Pragati Kumar , S. Duraivel , K. P. Sampath Kumar

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