Controlled drug

delivery systems

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 Learning Objectives
At the end of the lecture you will be able to
• Describe the types of drug delivery systems.
• List the various polymers used in drug delivery systems.
• Explain the criteria for selection of polymers for drug delivery.
• List the factors to be considered in sustained/controlled release
formulations.
• Describe the physicochemical and biological properties which
influence the drug delivery.

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 ManyApplicationhavepolymer

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 Classification of Drug Delivery
Systems
• Diffusion Controlled Release D
• Dissolution Controlled Release
• Diffusion & Dissolution Controlled Release
System
• Ion- exchange Resins
• pH- Independent Formulations
• Osmotically Controlled Release
• Altered Density Formulations
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 sautenomore

Drug diffusion (‫ )انتشار‬through the

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putsomenanianeamesman
dissolve
gotmacular
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polymer membrane or matrix
•
on The process of diffusion is generally described by Fick’s first
it law of diffusion. J = -D (dc/ dt)
• Where J : is the flux of drug across the membrane given in
units of amount / area time (Flux is the amount of drug
sonnavearnsunecureinson passing across unit area in unit time).
•
oneomanitienstuanittime
t.gyutenoveeromrant.ca D : is diffusion coefficient of drug in membrane in units of
area / time.
• dc/ dt : represents rate of change in concentration C
zeroorder
pitinconstant
be
relative to a distance X in the membrane.
The law states that amount of drug passing across a unit
area in unit time, is proportional to the concentration
difference across that plane. conc sina.im
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 Abbreviations in Delivery Systems
order
perunittime zero
• CD - Controlled Diffusion identityitsustainedor
release
contra

• CR - Controlled Release
• CRT - Controlled-Release Tablet
• DR - Delayed Release
• ER - Extended Release
• ter
In mid GITS - Gastrointestinal therapeutic system
• LA - Long Acting
• SA - Sustained-Action
• SR - Sustained (/slow) release
• TD - Time Delay
• TR - Time Release
• XL- Extra Long
• XR- Extended-Release
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 win
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ensure navewater
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patchrelease
otneedwaterithas Classification based on drug diffusion
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• Based on the drug diffusion through the

release

polymer membrane or matrix , the drug

delivery systems are primarily divided into
two classes:
s
1. Monolithic (Matrix) : where the drug is is
unite

distributed throughout a polymer matrix

power

2. Reservoir: where the drug is surrounded by

a polymer membrane in d rowme
miingt pasme

Depending on the molecular structure of the polymer, these systems may be classified as
microporous or nonporous.
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 Monolithic Systems

Regular
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Monolithic Systems no
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• Consists of drug dispersed homogeneously

earoneirstrass one.am
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throughout a polymer matrix. Entry of water

Dissolution of drug
• Release Diffusion of drug
• diffusion of drug through the polymer
• diffusion through pores in the polymer structure
• For the drug to get released, it has to be first dissolved
in surrounding polymer and then diffuse through the
polymer structure.
• Polymers used are : polyalkyls, polyvinyls, etc.
• Example – Nitroglycerine releasing system for
prophylaxis or treatment of angina pectoris.
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 Monolithic Systems sure.ae
x
a aieeuisioneam

● In this model, drug in the out side layer exposed to the bathing
solution is dissolved first and then diffuses out of the matrix.

● So for this system to be diffusion-controlled, the rate of

dissolution of drug particles with in the matrix must be much

matrix.
e
faster than the diffusion rate of dissolved drug leaving the
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polymer
Drug dispersed in polymer
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Drag hasdissolve fast
s

Monolithic Systems

Marketed products:
Procan SR (PROCAINAMIDE HCl)-ventricular
tachycardia
Desoxyn-Gradumet (methamphetamine)- CNS Stimulant
Choledyl SA (Oxtriphylline)-cough

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 Characteristics: Monolithic Systems
• Advantages
◦ Easier to produce than reservoir devices
◦ Can deliver high molecular-weight
compounds
• Disadvantages release
notgivecontrol
◦ Cannot obtain zero-order release Sr s d
dosage

◦ Removal of remaining matrix is necessary

whygofornon
biotic for implanted systems (For non
mm
biodegradable polymers)

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 order
whyitiszero
weusepoigmerwnerenray
Reservoir devices

• In this system, a water-insoluble polymeric material

(Hydroxypropyl cellulose, ethyl cellulose and polyvinyl
acetate) encases a core of drug.
• First process is the swelling of polymer ‫تضخم‬
• Drug will partition into the membrane and exchange
with the fluid surrounding the particle or tablet.
• Additional drug will enter the membrane, diffuse to
the periphery, and exchange with the surrounding
media. Swelling of polymer whenputPolymertosolution
polymerswelling
then Partition of drug polymer notdissolve
beforediffusion itwin
partition
pggeeqq.fiiIonticenttorosmer

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Diffusion of drug
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 sa s

Reservoir devices
• The partition coefficient describes thermodynamic rather
than structural characteristics of the solute/polymer/solvent
system.
• Transport governed by Fick’s Law
• i.e., when the concentration within the diffusion volume does not
change with respect to time.

• Eg. Ocusert System, Progestasert system, Transdermal

Patches
• Marketed products: Nico-400 (Niacin-oral), Nitro-Bid
(Nitroglycerin-transdermal), Nitrospan (Nitroglycerin-oral)
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Reservoir devices

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 generator
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haneusion

Characteristics of a Reservoir
Diffusional Systems
• Advantages
◦ Zero-order delivery is possible
◦ Release rate variable with polymer type
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• Disadvantages
canoniorgima
◦ Removal of system from implants (if non sooodalton
skat
or
unitotensuin

see
biodegradable)
T
◦ É Not preferred for high-molecular weight
causetheydon'thavepartition
compounds
◦ Expensive
◦ Potential toxicity if system fails.
Teressvoirsystemiseainananguinraeaseatsumetime

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 aero order

IgGer An Ideal Drug Delivery System

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• Inert shouldn'treactwith
• Biocompatible
• Mechanically strong n
• Comfortable for the patient
Taken.sn amount.esnoneaosaseeorm
• Capable of achieving high drug loading limitedpolymertakedruginside
• Readily processable
• Safe from accidental release
• Simple to administer and remove
• Easy to fabricate and sterilize causmostofthemuseasinjection
socnemicaencontainrsn.mneometorroana
container
wenavenanomactensiass
sometime

• Free of leachable impurities

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 Polymers in drug delivery
• A natural or synthetic compound consisting of large molecules made
up of a linked series of repeated simple monomers.
• The monomers can be linked together to generate a linear polymer.

Molecularweightveryhigh

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 CLASSIFICATION OF POLYMERS
Based on origin :
Natural Polymers
Anime
s ource
Proteins based polymers – Collagen, Casein, Gelatin, Keratin, Albumin
plant
source
Polysaccharides- Starch, cellulose, agarose, carrageenan, dextran, chitosan,
hyaluronic acid, alginate, glycogen, cyclodextrins etc.

2) Synthetic Polymers
d. Biodegradable WehareIn but itJoing it togother
I acid whichMake it polymer
Polyesters- poly lactic acid, poly glycolic ourbody
Polyanhydrides- poly adipic acid, poly terphthalic acid

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 Biodegradable cont….
III) Poly amides- poly imino carbonates, poly amino acids
IV) Phosphorous based polymers- poly phosphates, polyphosphonates
V) Others- poly cyano acrylates, poly urethanes

b. Non biodegradable use Inoral causetheydegrade anddispread

Cellulose derivatives- Carboxymethyl cellulose(CMC), ethyl cellulose(EC),

cellulose acetate, cellulose acetate propionate, hydroxypropyl methyl
cellulose(HPMC)
Silicones-Poly dimethyl siloxane, colloidal silica
wehavemorethan20
Acrylic polymers- polymethacrylates, polymethyl methacrylates,
Others- Polyvinylpyrrolidones(PVP), poloxamers Atroomtem some
reegertc o it liquid

exampletoImplant

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‫التعرية‬
Erosion???

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 Biodegradable and Bioerodible Controlled Release
Polymers
mediawill breakdown andeleminate
Byenzyme orbyAqueous
These materials degrade within the body as a result of natural biological
processes, eliminating the need to remove a drug delivery system after release of
the active agent has been completed a iwi

Bulk erosion - the polymer degrades in a fairly uniform manner throughout the
matrix
Surface Eroding - degradation occurs only at the surface of the polymer,
resulting in a release rate that is proportional to the surface area of the drug
delivery system

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CHARACTERISTICS OF IDEAL POLYMER

• Should be inert and compatible with the

environment.
• Should be non-toxic.
• Should be easily administered.
• Should be easy and inexpensive to fabricate.
• Should have good mechanical strength.
makeyourdrugstrong
polymershould
DrughasNo
escapedrugeromexposetoliverce
polymer
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 Criteria
sa
for selection of Polymer
Hydrophilic
1. Surface properties
PVP
– Hydrophilicity ofpolymerprusreleasfast somethin
p needle
someeasingeniectern

– Lubricity (reduction in friction)/Smoothness must

tone
present
eoresnteractwitnbiogiamemnane oetetanrata.neeecua.ge
–Tanewatersieit
Surface energy/charge Butpartramerenocuary neutral
sweneastsarsree.se
winneeast

– Water sorption capacity (swelling)

– Desorption (water repellent) Surface charges on polymers
s a
Dragreenseslowen
caseofthis
option
t
nottanewater

Surface properties can be improved by chemical, physical and biological

cannemouity
Surface properties can be improved by chemical, physical and biological means.
means.
2. Physical properties
– mustforpolymer(Ability to withstand damage)
Durability
– Permeability
– WHDegradability
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t.si
nerdegradationnignarusresease

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some
degree
 Selection of Polymer……….
BBB surroundBloodvesseln assenreat

3. Bulk properties iagerstranspor

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gyensienrng

– Molecular Weight Brain

stick
– Adhesion
transdermal'ncasputnotnededforer

– Solubilitymm ungreleaseccauseweusenatine me
–
lymedissolves
Release mechanism (diffusion/dissolution) risen pray
n– Film forming ability likefilmcoatingchasetaste out control
come
notdissolve
polymer pea
–
solute
Mechanical stability (sustain effect)
– Morphololgywhichgood Smith rough
ornot dependonproduct
– ErosionzeitfustPorus
snrugnee.sebefast
– Leaching (extraction)
l shouldn'thappen y's

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 Applications in Controlled Drug Delivery
• Reservoir Systems
- Ocusert System
- Progestasert System
- Reservoir Transdermal Patches
• Matrix Systems
• Swelling Controlled Release Systems
• Biodegradable Systems
• Osmotically controlled Drug Delivery

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 a Factors Influencing the Design and Performance of
Controlled Release Dosage forms 2m y't m
1. Drug Physicochemical properties in for
onsoon
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excretion
arson
a. Solubility goodskinbasalsubzu astof haslowersalubrityDrug
Drug not
saunaabsorb

wneed
cause e
b. Dose size
c. pKa
d. Partition coefficient
e. Drug stability
f. Molecular size and diffusivity
g. Protein binding
2. Route of drug delivery
h. Drug physico-chemical properties
i. Solubility in aqueous solution
j. Drug biological interactions
k. Desired pharmacological effect
3. Biological Factors
12. Biological Half life
13. Therapeutic index
14. Absorption
15. Distribution
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16. Metabolism
 1. Physicochemical Properties-Solubility
If the drug is in the solid state, it must dissolve before it
aienrasenosetostomantassectnemostaragaissavenere
piece
can be therapeutically active. tempsistempresananganemmaintaineromses
saunas penmasingneson cannon
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nosaideormanareserssti
amormosomisnavegoasaunity

Factors affecting Solubility

particesiessamity
wecanusecommeasentnostiginparatranisationsemarousanning

• pH, Temperature, Hydrophobicity, solid form of the drug,

Particle size, and presence of complexing agents in 231
solution.
rate no
Solubility can be increased by
• Making its corresponding salt acid reactwithstrongbase
weak's saltcrainmanga
Bioavaliabats a Basic iii acid salt
chawitratessuitate
• Prodrugs (Valcyclovir a prodrug of acyclovir) nisi
weanbase

sureaeareansuasion
• Decreasing particle size base
causstronsacinmas

Iranian
across
• Using amorphous form
mannnn
amrn.my
winsome e
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mm i amanagerseaman
• Complexing agents e.g. Cyclodextrin antenna s

• Solubilizing agents (surfactants), buffers etc.

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 Dose size / pKa Soomydayfor use
orancan
forsustaincontrolrelease

• If an oral product has a dose size greater that 0.5 g it is

considered as a poor candidate for sustained release system.
• Why the dose of drug should be low in selecting controlled
release formulations? itwillincrease sizeofnose Bettetogotomultipledose
• The addition of sustaining dose and possibly the sustaining
mechanism will, in most cases generates a substantial volume
product that is likely to be very large.
• pKa : tnevainemeansoi.otnmgtnatson.ee

so
manana coma
• and
The relationship between pKa of compound and absorptive
outer
summoned

environment. Presenting drug in an uncharged form is

advantageous for drug permeation but solubility decrease as the
drug is in uncharged form. This is well explained by Henderson-
Hasselbalch equation. pitanalogtiffin Y g 2 ios o acidicmedia morean
wearily Pha 4.12 o completly maximum
Acigggburrofen
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2 a completelyunionized
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weaklybasic metoproto
Pr a r zoned
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unionized
lionize acidicmedia
 Good partitions coef ent and solubility will be good drug

Partition coefficient
◦ Partition coefficient = Fraction of drug in an oil phase
a in r
Fraction of drug in aqueous phase. 1 25
y
Accordingly compounds with relatively high partition coefficient are
predominantly lipid soluble and consequently have very low aqueous
solubility.

Compounds with very low partition coefficients will have difficulty in

penetrating membranes resulting in poor bioavailability.

• The higher the lipid/water partition coefficient , the greater the rate
of transfer across the membrane

• Increasing polarity of a drug, by increasing ionization will decrease

the lipid/ water partition coefficient and vice versa.

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 unstabletotakeorally
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dissolve acidic
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i polymer intestinal
onlydissolvean
Esa Drug Stability
• Orally administered drugs can be subject to both acid base
hydrolysis and enzymatic degradation.
• Degradation will proceed at the reduced rate for drugs in
the solid state.
• For drugs that are unstable in stomach, systems that
prolong delivery over the entire course of transit in GI tract
are beneficial.
• Compounds that are unstable in the small intestine may
demonstrate decreased bioavailability when administered
from a sustaining dosage from. This is because more drug
is delivered in small intestine and hence subject to
degradation.
Yastrontestinal

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 1Drughavenighnownooowhatbestroute
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highmolecularweightthe
reinswinbeslowditension
per
mession
Molecular size and diffusivity
• The ability of drug to diffuse through membranes by itself
is called diffusivity while diffusion coefficient is the
function of molecular size (or molecular weight).
• Generally, values of diffusion coefficient for intermediate
molecular weight drugs, through flexible polymer, range
from 10-8 to 10-9 cm2/sec.
• The diffusion coefficient in many polymers frequently are
so small that they are difficult to quantify i.e. less than 10-
12 cm2/sec.
• Thus high molecular weight drugs should be expected to
display very slow release kinetics in sustained release
device using diffusion through polymer membrane.

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 Protein Binding valueast
bindalong
soprotein
than
more name

• It is well known that many drugs bind to plasma proteins and

influence the duration of drug action.
• Since blood proteins are for the most part re-circulated and not
eliminated, drug Protein binding can serve as a depot for
drug.
• Producing a prolonged release profile, especially if a high
degree of drug binding occurs.
308
Inactive
ngbindtoprotein Drug
conga
itlife
native
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• Extensive binding to plasma proteins will be evidenced
by a long half life of elimination for drugs and such
drugs mostly do not require a sustained release dosage
form.
• However drugs that exhibit high degree of binding to
plasma proteins also might bind to bio-polymers in GI
tract which could have influence on sustained drug
O
delivery.
onsurface
• The presence of hydrophobic moiety on drug molecule
also increases the binding potential.
surface easingexcretedinbody
hydrophilicon

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knowledge
Interesting fact about a human body
● Absorbing surface area of skin: 2 m2
● Absorbing surface area of the lung: 70 m2
● Absorbing surface area of GI tract: ~200 m2
(1/2 basket ball court)
is
Absorb high
here very
● Small intestine is ~5 cm around and 6.7 meter long
● Total length of capillaries is ~60, 000 KM

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 What is the top selling pharmaceutical drug?

● Adalimumab – $19.9bn. (Arthritis)

● Apixaban – $9.8bn. (Anticoagulant)
● Lenalidomide – $9.7bn. (Myeloma)
● Pembrolizumab – $7.1bn. (Immunotherapy)

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 2. Factors Influencing the Selection of
the Delivery Route
A. Drug physico-chemical properties
– Drug molecular size (molecular weight) thantmiss
oowe
moregiven
paratra

Éu
– Half-life notsiveoral Emora or
nasi 38 not
stare
stomam
entestinutsive
air
– Chemical stability
– Loss of biological activity in aqueous
solution
• Proteins
– Denaturation, degradation

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Factors Influencing the Selection of the
Delivery Route
lowso
unitParti
na

B. Solubility in aqueous solution

(hydrophobicity/hydrophilicity)
• pH
• pKa - ionization
• Temperature
• Concentration
• Crystallinity
• Particle size
• State of hydration

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Factors Influencing the Selection of the
Delivery Route
C. Drug biological interactions
– Sensitive to First pass metabolism (FPM) Olomgnetanaingliver

– act Low membrane permeabilitybenicaiglow cnet.mn

sing 215
transdermal

– Enzymatic degradation some or

– Bacterial degradation a asooo

– Half-life
– Side effects
• Irritation (e.g. Transdermal)

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 Factors Influencing the Selection of the
Delivery Route
D. Desired pharmacological effect
– Local
• topical, vaginal
– Systemic
• oral, buccal, IV, SC, IM, rectal, nasal
– Immediate response
• IV, SC, IM, nasal
– maximum
Dose size
Smc

mis in Y's of 86 I
tot is at y y y

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 3. Biological Factors
1. Half-life short pray east
ereminal

•The usual goal of an oral SR product is to maintain therapeutic

blood levels over an extended period.
•So the drug must enter in the circulation of approximately the
same rate of which it is eliminated.
• The elimination rate is quantitatively described by half-life
(t1/2).
•Therapeutic compounds with short half lives (3-8 h) are
excellent candidates for sustained/controlled release oral
preparations. Since this can reduce dosing frequency.
•In general drugs with half-lives shorter than 3 h are poor
candidates for SR/CR as dose size will increase.
•Compounds with long half lives, more than 8 h are not used in
sustained release forms because their effect is already sustained.

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 Twodiffrenformmma
foranimehuman
2. Therapeutic index (TI)
• In animals, TI=LD50/ED50, where LD50 is the lethal dose of a drug for
50 % of the population and ED50 is the minimum effective dose for 50
% of the population. In human; TI=TD50/ED50 where TD50 is the
toxic dose.
• In many instances, the conventional method is more preferred to deliver
the drug, but some drugs are unstable and toxic by frequently dosing.
These kinds of the drug have the narrow therapeutic range and face
solubility difficulties. In such cases, CR is used, which maintain the
drug plasma level in the therapeutic index .
• Drugs with narrow therapeutic index are not suitable for oral delivery
systems.
varAnson
smallchang
leadto level
toxic

or
i exnotsu
theraputiand
narrow oralcameman
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 than
more atraugareabsorbmydiffusionfor
aoi turncarrier
example

ecan'tweuse
3. Absorption
nano

• Drugs with low oral absorption and bioavailability can be

made CR formulations.
• CR drug delivery systems are not preferred if the
pharmacological activity of the drug is not related to its
blood levels (e.g. vancomycin) or if the absorption of drug
is by active transport.need or e nergy carrier

forme
good inin inwin
test whatever absorb

• The rate, extent and uniformity of absorption of a drug

are important factors when considered its formulation into
a controlled release system.
• The rate limiting step in drug delivery from a CR system
is its release from a dosage form, rather than absorption.
• Rapid rate of absorption of drug, relative to its release is
Mz c ssercontent essential if the system is to be successful.
the
erect 0
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 4. Distribution good
Aboveno distrainvery
enbody
Less
thant

some can
roamer cross
barrier

• The distribution of drugs into tissues can be important

factor in the overall drug elimination kinetics.
• Since it not only lowers the conc. of circulating drug but
it also can be rate limiting in its equilibrium with blood
and extra vascular tissue.
• Consequently apparent Vd assumes different values
depending on time course of drug disposition.
• For design of SR products, one must have information of
disposition of drug.

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 5. Metabolism almostan has
organ enzyme

• Drugs that are significantly metabolized before absorption,

either in lumen or the tissue of the intestine, can show
decreased bioavailability from slower-releasing dosage
forms. Most intestinal wall enzymes systems are
saturable.

• As drug is released at a slower rate to these regions less

total drug is presented to the enzymatic process allowing
more complete conversion of the drug to its metabolite.
• Give reason why drugs undergoing extensive hepatic
metabolism are not suitable for oral controlled drug
delivery systems.
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• References

• The Theory and Practice of Industrial Pharmacy,

Lachman L, and Liberman H. A, Publisher; CBS
Publishers & Distributors, 2009.
• http://sustainrelease.com/
• http://www.pharmainfo.net/reviews/controlled-
released-system-review
• http://www.pharmainfo.net/pppc08/fundamentals-
controlled-release-systems

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Questions?