UNIT-I

CONTROLLED DRUGDELIVERY
SYSTEM

Pointsto be covered in this topic

’O INTRODUCTION
’ODEFINITIONS
’ORATIONAL
OADVANTAGES
ODISADVANTAGES
OSELECTION OF DRUG CANDIDATES
0APPROACHES

>O PHYSIOLOGICAL ANDBIOLOGICAL

PROPERTIES OF DRUGS
 CONTROLLED DRUG DELIVERY
SYSTEM
OINTRODUCTION
Every drug molecule needs a delivery system to carry the drug to the
site of action upon administration to the patient.
Delivery of the drugs can be achieved using various type of dosage
forms like tablets, capsules, creams, liquids, ointments etc.
Most of these conventional drug delivery systems are known to
provide immediate release of the drug with little or no controlover
delivery rate
To achieve &maintain therapeutically effective plasma
Several doses are needed daily which may cause significant
fluctuations in plasma.
Because of these fluctuations in plasma levels the drug level could fall
below the MEC. Such fluctuations result in unwanted side effects

lack of intended therapeutic benefit.

Sustained-release & controlled release drug delivery systems can
reduce the undesired fluctuations of drug levels, reduce side
effects,while improving the therapeutic outcome of the drug.
Controlled drug delivery Immediate versus controlled release

systems can include the Imaediate

relcase
level
1Drug
plasma
maintenance of drug levels MTC

within a desired range, the

need for fewer administrations,
4
MEC
optimal use of the drug in Next dose
Next dose
question, and increased patient Next dose (osolk
Time
compliance.
O DEFINITIONS
º CONTROLLED DRUG DELIEVRY SYSTEM: This drug systems are More
advanced& are designed to deliver the drug at specific release rate within
a predetermined time period
SUSTAINED-RELEASE DRUG SYSTEM-This system prolong the duration
of action by slowing the release of drug usually at the cost of delayed
onset &its pharmacological action.
ORATIONAL
The basic idea behind cDDSconcept isto alter the pharmacokinetics &
pharmacodynamics of bioactivities either by modifying the molecule
structure or physiological parameters.
By using NDDS, the primary objective of CRDDS is to safety &enhance
efficacy of drug with improved patient compliance.
OADVANTAGES
" Improvement in bioavailability of some drugs
Improved patient compliance
Reduction in drug level fluctuation in blood
Reduction in total drug usage ,compared to conventional therapy
Reduction in drug accumulation with chronic therapy
Reduction in drug toxicity (local/systemic)
Reduction in frequency of drug administration
ODISADVANTAGES
" Delay in onset of drug action
Possibility of dose dumping in the case of a poor formulation strategy
" Increased potential for first pass metabolism
Possibility of less accurate dose adjustment in some cases
Not alldrugs are suitable for formulating into ER dosage form
 OSELECTION OFDRUG CANDIDATES
Characteristics that may make a drug unsuitable for CDDR
/ Short elimination half-life / Active absorption
Longelimination half-life Low or slow absorption
Narrow therapeutic index Extensive first pass effect
Poor absorption
Parameters for drug selection parameter: Preferred value
Molecular weight/ size: < 1000
Solubility: >0.1 ug/ml for pH 1-7.8
Pka Non ionized moiety: > 0.1% at pH 1- 7.8
Apparent partition coefficient: High
Absorption mechanism: Diffusion
General absorbability: From all GI segments
Release: Should not be influenced by pH and enzymes
OAPPROACHES TO DESIGN CONTROLLED RELEASE
FORMULATIONS
1. Dissolution controlled release
Encapsulation Dissolution control
Seed or granule coated
Micro encapsulation
/ Matrix Dissolution control

2. Diffusion controlled release

Reservoir type devices

VMatrix type devices
3. Diffusion and Dissolution controlled systems
4. lon exchange resins
5. Osmotically controlled release
 Dissolution controlledrelease
It is a rate determining step when liquid is diffusing from solid. Several
theories explain dissolution:
/ Diffusion layer theory,
Surface renewal theory, dc/dt = Dissolution rate,
K= Dissolution rate constant (1st order),
/ Limited solvation theory. D = Diffusion coefficient/diffusivity,
Noyes Whitney Equation Cs =Saturation/maximum drug solubility.
C= Conc. Of drug in bulk solution
dc/dt= kD.A (Cs -C)
Cs-C= Concentration gradient,
dc/dt= D/h A. (Cs -) h =Thickness of diffusion layer:
> Encapsulated dissolution system
This is also known as coating dissolution controlled system.
Dissolution rate of coat depends upon stability & thickness of coating.
Controlled release by decreasing the dissolution
Slayly
rate of drugs which are highly water soluble can diasolving
or erodible
Coat
be formulated by preparing appropriate salt.
Soluble drug
º Matrix dissolution system
It is also known as monolithic dissolution controlled system.
In this dissolution iscontrolled by: Altering porosity of tablet, decreasing
its wet ability, dissolving at slower rate.
Slowly
" It follows first order drug release. dissolving
matrix
Diffusion controlled system
(Soluble drug)
" Itis a major process for absorption inwhich no energy required.
Inthis drug molecules diffuse from a region of higher concentration to
lower concentration until equilibrium is attained and it is directly
"oportionalto the concentration gradient across the membrane.
In this system release rate is determined by its diffusion through a
water-insoluble polymer.
> Reservoir diffusion system
It isalso called as laminated matrix device.
" It is a hollow system containing an inner core surrounded by water
insoluble membrane and polymer can be applied by coating
encapsulation.
The Rate controlling mechanism is that drug will partition into membrane
and exchange with the fluid surrounding the drug by diffusion. Commonly
used polymers are HPC, ethyl cellulose & polyvinyl acetate.
Examples: Nico-400, Nitro-Bid.
Matrix dissolution system
" Rigid Matrix Diffusion: Materials used are insoluble plastics such as PVP.
Swellable Matrix Diffusion: it is also called as Glassy hydro gels and
popular for sustaining the release of highly water soluble drugs. Materials
used are hydrophilic gums.
C
Examples:
Natural- Guar gum, Tragacanth.
Semi synthetic -HPMC, CMC, Xanthum gum.
Synthetic -Polyacrilamides.
Examples: Glucotrol XL, Procardia XL
Tlme 0 TIne t1 Tlne t2

ResevoiE
systemns

Non-constent drug source

reseotr

DWfuslon
ystem
Gonstat drug ource -
Drug
Menoithde eelutien
matrix

Monolthie
systems

--
Monolithie disperson
Dissotved drug moleeues
Nendiesolved druge (dispersed aggregates)
 Dissolution & Diffusion Controlled Release system
" Inthis drug is encased in a partially soluble membrane and pores are
created due to dissolution of parts of membrane. It permits entry of
Insoluble
membrane
aqueous medium into core & drug is
Entry of
dissolved or diffused out of the system. dissolution
fluid
. Drug
Ex- Ethyl cellulose & PVP mixture diffusion

dissolves in water &creates pores Pore created by

dissolution of
of insoluble ethyl cellulose soluble fraction of
membrane

lon exchange resins controlled release system

" lon exchange resins are cross-linked water insoluble polymers carrying
ionizable functional groups.
These resins are used for taste masking and controlled release system.
The formulations are developed by embedding the drug molecules in
the ion-exchange resin matrix and this core is then coated with a semi
permeable coating material such as Ethyl Cellulose.
" In tablet formulations ion-exchange resins have been used as
disintegrant.
Principle:
lsbased on preparation of totally insoluble ionic material
V Resins are insoluble in acjdic and alkaline media
They contain ionizable groups which exchanged for drug molecules
IER are capable of exchanging positively
or negatively charged Cation Eehange Vs Anion Exchange

drug molecules to
form insoluble poly
OResinO
salt resinates.

Catlon Rchanger Anlen Rhanges

 OPHYSIOLOGICAL AND BIOLOGICAL PROPERTIESOF DRUGS
* Physiological properties
>Aqueous Solubility's:
Weak water soluble drugs are difficult to design the controlled release
formulations.

High aqueous solubility drug show burst release followed by a rapid

increment in plasma drug concentration.
BCS class-lII & IV drugs are not a suitable candidate for this type of
formulations.
> Partition coefficient (P-value):
P-value denotes the fraction of the drug into oil & aqueous phase that is a
significant factor that affects the passive diffusion of the drug across the
biological membrane.
The drugs are having high or low P value not suitable for CR, it should be
appropriate to dissolve in both phases.
º DrugpKa:
pka is the factor that determined the ionization of drug at physiological
pH inGIT.
Generally, the high ionized drugs are poor candidates for CRDDS.
º Drugstability:
" Drugs that are stable in acid/base, enzymatic degradation, and other
gastric fluids are good candidates for CRDDS.
º Molecular size & molecular weight:
The molecular size &molecular weight are two important factors which
affect the molecular diffusibility across a biological membrane.
The molecular size less than 400D is easily diffuse but greater than 400D
create a problem in drug diffusion.
> Protein binding:
The drug-protein complex act asa reservoir inplasma for the drug
Drug showing high plasma protein binding are not agood candidate for
CRDDS because Protein binding increases the biological half-life.

Biological factors
º Absorption:
The absorption rate should rapid then release rate to prevent the dose
dumping.
The various factors like aqueous solubility, log P, acid hydrolysis, which
affect the absorption of drugs.
Biological half-life (y2):
Ideally, the drugs having ty/2 2-3 hrs are a suitable candidate for CRDDS.
Drugs have t1/2 more than 7-8 hrs not used for controlled release system.
º Dose size:
The CRDDS formulated to eliminate the repetitive dosing, so it must
contain the large dose than conventional dosage form.
7Therapeutic window:
" The drugs with narrowtherapeuticindex are not suitable for CRDDS.
" If the delivery system failed to control release, it would cause dose
dumping and ultimate toxicity.
r Absorption window:
The drugswhich show absorption from the specific segment in GIT, are a
poor candidate for CRDDS.
Drugs which absorbed throughout the GIT are good candidates for
controlled release.
 UNIT-I
POLYMERS
Points to be covered in this topic
OINTRODUCTION

OSIGNIFICANCE

’ 0CLASSIFICATION

OPROPERTIES

OADVANTAGES OF POLYMERS IN

CRDDS

OAPPLICATION OF POLYMERS IN

FORMULATION OF CDDS
 POLYMERS Polymers
OINTRODUCTION
" The word "polymer means "many parts.
A polymer is a large molecule made up of
many small repeating units.
Polymers are considered to be a subset of Monomers

macromnolecules. Macromolecule refers to any Polymerization

large molecule.
" A monomer is a small molecule that combines
Polymer
with other molecules of the same or different

types to form a polymer.

OSIGNIFICANCE
In the field of drug delivery, polymers are becoming increasingly
significant.
Polymers are the major tool for controlling the medication release rate
from the formulatión.

Polymers can be used to conceal the flavor of a medicine, improve its

stability, and change its release properties.
O CLASSIFICATION
Natural Polymer Synthetic Polymers
Synthetic Polymers
Biodegradable Polymer
Non-biodegradable Polymer
 Natural Polymer
Protein based polymer: Collagen Albumin ,Gelatin
Polysaccharides: Alginate, Cyclodextrin, Chitosan, Dextran, Agarose,
Hyaluronic acid, Starch,Cellulose
Synthetic Polymers
Biodegradable Polymer
Polyester: Poly lactic acid, Poly glycolic acid, Poly hydroxyl butyrate,
Polyester, Polycaprolactone, Poly lactide-co-glycolide (PLGA), Poly
diaxonone
" Polyanhydride: Poly adepic acid, Poly sebacic acid, Poly terpthalic acid
"Polyamides: Poly amino acid, Poly imino carbonate
" Phosphorous based polymer: Polyphosphates, Polyphosphonates, Poly
Phosphazenes
V Non-Biodegradable polymers
Cellulose derivative: Carboxy methyl cellulose, Ethyl cellulose, Cellulose
acetate, hydroxylpropyl methyl cellulose.
" Silicons: Polydimethyl siloxane, Colloidal silica, Polymethacrylate,
Polymethyl methacrylate
Others:Poly vinyl pyrolidine, Ethyl vinyl acetate, Poloxamine etc.
Biodegradable Polymer
Natural polymers and their modified derivatives (e.g. starch,
cellulose) as well as synthetic polymers (e.g. polyacrylamides,
polyacrylates,and polyethylene glycol) are utilised in the technology of
prolonged release medication formulation.
In order to build a good medication delivery system, the polymer
matrix must be chosen carefully.
 Degradable polymers are favoured for medication delivery applications
since they do not require surgical removal.
They disintegrate into smaller, mnore absorbable
molecules, therefore it's crucialto ensure sure the
monomers are not hazardous.

Polylactide (PLA) and Poly Lactide co Glycolide

Biodegradable
(PLGA) are the most commonly utilised polymers for
this application.
These polymers have been utilised in biomedical applications for over 20
years and are biodegradable, biocompatible, and non-toxic.
Non-Biodegradable Polymers
Non-degradable polymers have
have the primary
disadvantage of requiring surgery to remove them
Non
from the body once the medication has been Biodegradable
depleted.
As a result, non-biodegradable polymers can only be
used if the implant can be easily removed.
OPROPERTIES
The following properties are used to classify the polymers for
medication delivery:
V Source: Apolymer might be synthetic, natural, or a mix of two.
Chemical nature: polyester, polyanhydride, protein-based,
cellulose derivatives, and so oncan all beused.
Backbone stability: either biodegradable or non biodegradable
polymers exist.
VSolubility: The polymer can be either hydrophilicor hydrophobic
in nature.
 However, each of the above characteristics has its own set of constraints,
such as the fact that natural polymers,while abundant and biodegradable,
difficult tocopy and purify.
C
Synthetic polymers have a high immunogenicity, which prevents them
from being used for lengthy periods of time.
OADVANTAGES OF POLYMERS IN CRDDS
Polymers are the most promising option for controlled drug
administration because of their attractive, flexible features and ease of
production at industrial scale, and potential for further modification.
Polymer therapeutics include linear or branched polymer chains that
act as a bioactive molecule, such as polymeric drugs, or as an inert carrier
for a drug
Polymers play an important part in the advancement of drug delivery
technology by offering long repetitive dose and coordinated release of
medicines.

There are several advantages to using a polymer as an inert carrier to

which a drug can be conjugated.
Rheumatoid arthritis, diabetes, hepatitis B and C, cancer, and ischemia
have all been targeted with polymer conjugates.
This is a critical for the persistent growth of this field and will continue to
harvest accomplishment in the synthesis of novel biopharmaceuticals.
O APPLICATION OF POLYMERS IN FORMULATION OF CDDS
The Ocuserts System:
The use of conventional drug delivery systems, such as drops and
ointments, to transport therapeutic agents to the eye for the treatment
eye problems (eg, glaucoma), is an inefficient process.
 The use of polymeric implants
inserted under the lower cul
Drug release
de-sac of the eye improves the Controling polymer
membrane
efficiengy of ocular medication
Whie margin for
delivery. positioning system
ineye
Pilocarpine is distributed within Drug reservoir
an alginic acid matrix in this
Poymer membrane
system, which is sandwiched
between two polymer layers
(ethylene-co-vinyl acetate).
Transdermal Patches:
Transdernmal medication delivery entails the drug diffusing through the
skin and eventually being absorbed into the systemic circulation.
" The drug delivery system is made up of many layers, including a metallic
backing layer that prevents drug loss by being resistant to drug
diffusion,a drug containing reservoir, arate controlling membrane, and
an adhesive layer.
" Membrane controlling drug diffusion Adhesive layer. The medicine is
dissolved or disseminated in the matrix using solid polymer (acrylate co
polymer).
Matrix Reservoir

Multilaminate
Drug-in-Adhesive

Bacing Drug Membrane AdhesiveinerSiün