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NOVEL DRUG
DELIVERY SYSTEMS

Dr. Talib Hussain, PhD

Lecturer, IPS, UVAS,
Lahore.
 01
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SUSTAINED/
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CONTROLLED
RELEASE DDS

Developmental aspects of
Matrix
and
Reservoir Systems
CONTENTS 02
❑ Introduction
❑ Terminologies
❑ Types.
❑ Importance.
❑ New Paradigms.
❑ Conclusion.
 INTRODUCTION
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❖Conventional (immediate-release, IR) oral drug
products, such as tablets and capsules, are formulated
to release the active pharmaceutical ingredient (API)
immediately after oral administration.
❖No deliberate effort is made to modify the drug
release rate
❖Rapid drug absorption and onset of associated
pharmacodynamic (PD) effects
❖Poorly soluble (lipophilic) drugs show gradual
absorption due to slow dissolution or selective
absorption across the GI tract.
 MODIFIED RELEASE 04
❖ To achieve a desired therapeutic objective or better
patient compliance, the pattern of drug release is
deliberately changed to develop modified release (MR) drug
delivery systems.
❖The objective of MR DDS for oral administration is to
control the release of the therapeutic agent and thus
control drug absorption from GIT.
❖ It alters the timing and rate of release of the drug
substance in the formulation.
❖The drug-release characteristics of time course and/or
location are chosen to accomplish therapeutic goals
 TERMINOLOGIES 05
1. Extended-release drug products: allows at
least a twofold reduction in dosage frequency as
compared to IR. These include controlled-release,
sustained-release, and long-acting, prolonged
release, timed release etc.
2. Delayed-release drug products: releases a
discrete portion of drug at a time other than the
promptly release after administration. An initial
portion may be released promptly after
administration. E.g. enteric-coated dosage forms.
3. Targeted-release drug products: releases drug
at or near the intended physiologic site of action.
 DIFFERENCE B/W CONTROLLED,
SUSTAINED AND IMMEDIATE RELEASE 06
SUSTAINED RELEASE DDS 07
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❖Sustained-release drug delivery system releases drug at a
predetermined rate Template
(concentration dependent) for a
prolonged period of time.
❖The drug may be delivered in an initial therapeutic
dose (burst release), followed by a slower and
prolonged release.
❖The purpose of a loading dose is to provide
immediate or fast drug release to quickly provide
therapeutic drug concentrations in the plasma.
❖The system follows pseudo first order kinetics.
CONTROLLED RELEASE DDS
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❖Controlled-release drug delivery system releases constant
amount of drug at a predetermined rate for the a specified
period of time Template
❖The rate of release of drug is designed so that amount of
drug loss from the body by elimination is constantly
replaced
❖Rate in = Rate out = kelim x Cd x Vd
❖A constant plasma drug concentration is maintained with
minimal fluctuations
❖Controlled release systems are able to provide actual
therapeutic control or attempts to control drug
concentration in target tissues
❖These systems follows zero order drug release (independent
of concentration present in system)
 DELAYED RELEASE DDS
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❖An enteric-coated tablet is one kind of delayed release
Template dosage family
type within the modified-release
designed to release drug in small intestine.
❖The enteric-coating materials are polymer-based
barrier applied. This coating may delay release of
the medicine until after it leaves the stomach, either
for the purpose of drug protection under harsh pH
circumstance or for alleviation of irritation on cell
membrane from the drug itself. For example,
aspirin irritates the gastric mucosal cells of the
stomach so are designed to release drug in intestine.
 OTHER MODIFIED
RELEASE SYSTEMS 10
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❖A repeat-action tablet is a type of modified-release drug
product that is designed to release one dose of drug
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initially, followed by a second or more doses of drug at a
later time. It provides the required dosage initially and
then maintains or repeats it at desired intervals.
❖A prolonged-action drug product is a formulation whose drug
activity can continue for a longer time than conventional. It
is analogous to sustained release drug delivery system.
❖The prolonged release drug product prevents very rapid
absorption of the drug by slowing dissolution of drug.
❖A prolonged action tablet is similar to a first-order-release
product except that the peak is delayed differently.
 DRUG PROPERTIES RELEVANT TO
SUSTAINED RELEASE FORMULATION 11
❖ The design of sustained release delivery
system is subjected to several variables and
each of variables are inter-related.
❖ For the purpose of discussion it is
convenient to describe the properties of the
drugs as being either physico-chemical or
biological, these may be divided in two
types.
❖ 1. Biological properties
❖ 2. Physicochemical properties
 BIOLOGICAL FACTORS INFLUENCING
MODIFIED RELEASE DDS 12
1. BIOLOGICAL HALF LIFE
❖The goal of sustained release is to maintain therapeutic
blood level over an extended period, so drug must enter the
circulation at approximately the same rate at which it is
eliminated. Elimination rate is described by the half-life (t1/2)
❖Therapeutic compounds with short half life are excellent
candidates for sustained release preparation since these can
reduce dosing frequency.
❖Drugs with half-life shorter than 2 hours, e.g. Furosemide,
levodopa are poor candidate for sustained release formulation
because it requires large amount of drug in DDS to
maintain sustained effects. More than 8 hours half-life is also
generally not suitable for sustaining forms, since their effect is
already sustained. E.g.; Digoxin, Warfarin, Phenytoin etc.
 2. ABSORPTION 13
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❖ Absorption plays a major role in the delivery of drugs to
the systemic circulation
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❖ An ideal sustained-controlled release system should release
the drug at a rate lower than absorption rate Kr<<Ka
❖ Considering the absorption time of a drug as 8-12h based
on GI retention time, the absorption half life should be 3-
4h so for a delivery system to absorb completely.
❖ Otherwise system will pass out of the potential absorptive
phase before complete drug release.
❖ Absorption rate constant should be 0.17-0.23h-1 to give 80-
95% absorption.
❖ This should be the release rate constant for delivery system.
 ABSORPTION CONT… 14
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❖Compounds with true low absorption rate
constant are inherently controlled release
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❖So for drugs having limited absorption phase, the
system should remain in the absorption window
through out the delivery period.
❖Gastro-retentive drug delivery systems are
designed for this purpose
❖Low density systems and bioadhesive systems are
means of delivering drug through this process.
❖The utility of penetration enhancers to increase the
absorption of drug can also be utilized but can
cause toxicity.
 METABOLISM 15
❖There are two areas of concern relative to
metabolism that significantly restrict sustained
release formulation.
❖1. If drug upon chronic administration is
capable of either inducing or inhibition
enzyme synthesis it will be poor candidate for
sustained release DDS because of difficulty of
maintaining uniform blood levels of drugs.
❖2. If there is a variable blood level of drug
through a first-pass effect, this also will make
preparation of sustained release product
difficult.
METABOLISM CONT…
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❖Drug that are significantly metabolized before
absorption, either in lumen of intestine, can
show decreased bio-availability 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 during a specific period,
allowing more complete conversion of the drug
to its metabolite.
 PHYSICOCHEMICAL
FACTORS 17
1. DOSE SIZE
❖In general a single dose of 0.5 - 1.0 gm is
considered for a conventional dosage form this
also holds for sustained release dosage forms.
❖If an oral product has a dose size greater that
500mg it is a poor candidate for sustained release
system, Since addition of sustaining dose and
possibly the sustaining mechanism will, in most
cases generates a substantial volume product that
unacceptably large.
 2. PARTITION COEFFICIENT
AND MOLECULAR SIZE 18
❖When a drug is administered to the GIT, it must
cross a variety of biological membranes to produce
therapeutic effects in another area of the body.
❖The membranes are lipidic, so partition coefficient
of drugs becomes important in determining
effectiveness of membranes barrier penetration.
❖Compounds having very low partition coefficient
will have difficulty penetrating membranes this also
applies to partitioning through polymeric membrane
❖So the choice of diffusion membrane will be
dependent on partition characteristics of drug.
 2. CONT….
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❖ The ability of drug to diffuse through membranes
its so called diffusivity & diffusion coefficient is
function of molecular size (or molecular weight).
❖ Generally, values of diffusion coefficient for
intermediate molecular weight drugs, through
flexible polymer range from 10-8 cm2 / sec.
❖ Thus high molecular weight drugs or polymeric
drugs should be expected to display very slow
release kinetics in sustained release device using
diffusion through polymer membrane.
 3. AQUEOUS SOLUBILITY, pKa,
IONIZATION 20
❖ Most of drugs are weak acids or bases, since the
unchanged form of a drug preferentially permeates across
lipid membranes, drugs aqueous solubility will generally be
decreased by conversion to an unchanged form.
❖ Delivery systems that are dependent on dissolution or
diffusion will also be dependent on solubility of drug in
media.
❖ Delivery systems must function in changing pH as
stomach is acidic and small intestine neutral.
❖ A drug soluble in stomach will be uncharged in intestine
so will be absorbed (Immediate release)
❖ For drugs with low water solubility will be difficult to
incorporate into sustained release mechanism.
 CONT…
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❖ For drugs with low water solubility (<0.01mg/ml) are
inherently sustained as release will be only dependent to
dissolution of drug in GIT.
❖ The lower limit for solubility of drug to be formulated as
sustained/controlled release system is 0.1mg/ml.
❖ Diffusional systems will be poor choices for slightly soluble
drugs as driving force for diffusion is drugs solution that will
be too low for these drugs.
4. 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.
❖ Compounds that are unstable in the small intestine may
demonstrate decreased bioavailability when administered
from a sustaining dosage form.
 ORAL SUSTAINED/CONTROLLED
RELEASE PRODUCTS 22
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❖Diffusion controlled systems
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❖Dissolution controlled systems
❖Diffusion & Dissolution controlled systems
❖Chemically controlled systems
❖Ion exchange resins
❖Swelling controlled (Hydrogels) systems
❖Osmotically controlled systems
❖Magnetically controlled systems
 DISSOLUTION CONTROLLED
SYSTEMS 23
❖Sustained release products can be prepared by decreasing
the rate of dissolution. Slower the rate of dissolution of
drug, more time will be required to dissolve and absorb.
❖Three approaches are used to develop slow release
1) Preparing salts of drug or it derivatives (chemical).
2) Coating the drug with slow dissolving material
3) Incorporating (matrix) drug in slow dissolving carrier
❖ Two methods can be used to develop dissolution
controlled systems
1) Matrix dissolution controlled: The rate of penetration
of dissolution fluid in to the matrix determines the drug
dissolution and subsequent release
2) a) Alternating layers of drug with rate controlling coat, a
pulsed delivery can be achieved.
 METHODS TO DEVELOP DISSOLUTION
CONTROLLED SYSTEMS 24

❖ The outer layer release the pulse of drug first then the
inner layer after the polymeric layer dissolves
2) b) Group of drug beads with different thickness of
polymer coatings
❖ The thinnest layer will dissolve first then the thicker
resulting in progressive release and developing steady
state levels (Snapsule capsules, Fefol, GSK)
 DISSOLUTION CONTROLLED
SYSTEMS CONT… 25
❖ Dissolution process is considered diffusion layer
controlled.
❖ Rate of diffusion from solid surface to bulk solution
through a liquid film as rate determining step is described
at steady state by Noyes Whitney Equation.
𝑑𝐶 𝐷
❖ = 𝑘𝐷 𝐴 𝐶𝑆 − 𝐶 = 𝐴(𝐶𝑠 − 𝐶)
𝑑𝑡 ℎ
𝑑𝐶
❖ Where = Dissolution rate
𝑑𝑡
❖ 𝑘𝐷 = dissolution rate constant
❖ Cs = saturated solubility of drug
❖ C = concentration of drug in solution at t
❖ Here kD is equivalent to diffusion coefficient divided by
thickness of layer (D/h)
 Noyes Whitney Equation
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❖ The equation describes that rate of release can only be
constant if these parameters are constant.
a) Surface area
b) Diffusion coefficient
c) diffusion layer thickness
d) Concentration difference
❖ These are difficult to control especially surface area.
❖ For spherical particles, the change in surface area can be
related to weight of particles under sink conditions, so
above equation can be written in cube root equation
1Τ3
❖ 𝑊0 − 𝑊 1Τ3 = 𝑘𝐷 𝑡
❖ Where W0 is initial weight and W is weight of remaining
amount at time t, 𝑘𝐷 is cube root dissolution rate constant
 DIFFUSIONAL SYSTEMS
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❖ The release of drug from inert membrane barrier

(insoluble polymer) dependent on diffusion is
characterized as diffusional system.
❖ There are two subclasses of diffusional systems
1) Reservoir Systems
2) Matrix systems
 RESERVOIR SYSTEMS
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❖ The core of drug (the reservoir) surrounded by a
polymeric membrane is called reservoir system.
❖ The nature of membrane describe rate of release of drug
from the system.

Cm(0) and Cm(d) are concentration at inside surface of membrane and C(0)
and C(d) concentration at adjacent areas
 FICK’S LAW OF DIFFUSION
29
❖ The process of diffusion can be described by series of
diffusion equations including Fick’s law of diffusion.
❖ The amount of drug passing across a unit area is
proportional to concentration difference across plane.
𝑑𝐶
❖ 𝐽 = −𝐷
𝑑𝑋
❖ Where J is flux (amount/area-time), D is diffusion
coefficient (area/time) that describe drug’s ability to
diffuse through solvent (depends on molecular size and
charge), dC/dX represent rate of change of concentration
C relative to distance X in the membrane.
 CONT…
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❖ Assume, the drug on either side of the membrane is in
equilibrium i.e. membrane surface and bathing solution.
❖ The concentration inside the membrane can be related to
concentration at adjacent layer as
𝐶𝑚(0)
❖𝐾 = at X = 0
𝐶𝑑
𝐶𝑚(𝑑)
❖𝐾 = at X = d
𝐶𝑑
❖ K is diffusion coefficient and describe ratio of drug
concentration in membrane to that in bathing solution, Cm
is concentration of drug inside surface and Cm(d) is
concentration outside surface, d is thickness of diffusional
layer (diffusional path length)
 CONT…
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written as 𝐽=
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❖Assuming D and K constants Fick’s law can be
𝐷𝐾𝑑𝐶
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−
𝑑
❖The drug release is dependent on geometry of the
system, so surface area becomes a factor
𝑑𝑀𝑡 𝐴𝐷𝐾𝑑𝐶
=
𝑑𝑡 𝑑
❖Where 𝑑𝑀𝑡 is mass of drug released after time t,
𝑑𝑀𝑡 Τ𝑑𝑡 is the steady state release rate at time t, A is
surface area of device. The same equation can be
written for all three geometries i.e. spheres, cylinders
and slabs. The system can achieve zero order release
if all the parameters on left side become constant
CHARACTERISTICS OF RESERVOIR
DIFFUSIONAL SYSTEM 32
Description Drug core surrounded by polymeric
membrane to control release rate
Advantages Zero order release is possible
Release rate is variable based on type of
polymer used
Disadvantages System must be physically removed from
the implant sites
Difficult to deliver high molecular weight
compounds
Increased cost per dosing unit (difficulties
in developing)
Potential toxicity if system fails as high
dose incorporated
 MATRIX SYSTEM
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❖ A matrix is an inert solid vehicle in which a drug is
uniformly suspended.
❖ The drug release from such matrix systems is mainly
controlled by the diffusion process, concomitant
swelling, and/or erosion processes.
❖ When an erodible or swellable polymer matrix is
involved, the drug release kinetics is further
complicated by the presence of a second moving
boundary, namely, the swelling or eroding front, which
moves either opposite to or in the same direction as the
diffusion front.
❖ The drug is present in a small percentage, so that the
matrix protects the drug from rapid dissolution and the
drug slowly diffuses out over time.
MATRIX SYSTEM
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 ASSUMPTIONS OF MATRIX SYSTEM
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❖ Drug release from matrices depends on regulation of matrix.
A porous matrix allows rapid water penetration to diffuse drug
rapidly. Drug release from a matrix ablet is not zero order
❖ The rate of dissolution of drug particles within matrix must be
faster than the diffusion rate of dissolved drug leaving matrix.
❖ Takeru Higuchi derived mathematically matrix systems based
on following assumptions
a) A pseudo steady state is maintained during drug release
b) The diameter of drug particles is less than the average distance
of diffusion through matrix
c) Bathing solution provide sink conditions all the time
d) Diffusion coefficient of drug remains constant (no change in
characteristics of matrix)
MATRIX SYSTEM
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 Higuchi Equation
37
❖ 𝑑𝑀Τ𝑑ℎ = 𝐶0 𝑑ℎ − 𝐶𝑠 Τ2
❖ Where 𝑑𝑀 = change in amount of drug per unit area
❖ 𝑑ℎ=change in thickness of zone of matrix depleted from
drug
❖ 𝐶0 = total concentration in a unit volume of matrix
❖ 𝐶𝑠 = saturated concentration drug in the matrix
❖ From diffusion theory 𝑑𝑀 = 𝐷𝑚 𝐶𝑠ൗℎ 𝑑𝑡
❖ 𝐷𝑚 is diffusion coefficient in the matrix
❖ Equating both the equations we get
1
❖ 𝑀= [𝐷𝑠 𝐶𝑎 𝑃Τ𝑇 2𝐶0 − 𝑝𝐶𝑎 𝑡] 2

❖ Where P is porosity of matrix, T is tortuosity,

❖ 𝐶𝑎 is solubility of drug in release medium
❖ 𝐷𝑠 is diffusion coefficient in the matrix
 Higuchi Equation
38
❖ The equation can be reduced to
1Τ
❖ 𝑀 = 𝑘𝑡 2
Where k is constant
❖ A plot of amount of drug released verses square
root of time will be linear, if the release of drug
from matrix is diffusion controlled.
❖ By using the Higuchi model, one may control
release of drug from the homogenous matrix by
varying following parameters
a) Initial conc. of drug in matrix, b) Porosity, c)
Tortuosity d) Polymer system forming matrix e)
Solubility of the drug
 CHARACTERISTICS OF MATRIX
SYSTEM 39
Description Homogenous dispersion of solid drug in a
polymer mixture
Advantages Easier to produce than reservoir systems
Can deliver high molecular weight drugs
Release varies with square root of time
that allows substantial sustained release
Accidental leakage from system is less
likely as drug is dispersed in matrix system
Disadvantages Can’t obtain zero order release
System must be physically removed from
the implant sites
 BIOERODIBLE SYSTEMS
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❖ These are combined diffusion and dissolution systems.
❖ As strictly there is no system that follows diffusion or
dissolution solely, only the predominant mechanism allows
easy mathematical description.
❖ In practice dominant mechanism will overshadow other
process enough to be classified as diffusion controlled or
dissolution rate limited.
❖ Release rate is dependent on
❖ – Fraction of soluble ingredient in the coating/matrix
❖ – diffusion coefficient of drug though pore in coating
❖ – conc. of drug in dissolution media
❖ – conc. of drug in core.
 APPROACHES FOR
BIOERODIBLE SYSTEMS 41
❖The erodible matrix allows the drug to diffuse out of
matrix as diffusion system and also matrix undergoes
dissolution process
❖ The system becomes complicated by combining both
diffusion and dissolution mechanisms
❖ The polymer dissolve and the diffusion path length of the
drug decreases that result in moving boundary diffusional
system
❖ Zero order release is possible only when erosion occur but
surface area remains constant
❖ The advantage of system is that polymer ghost is dissolved
❖ Disadvantage is that release kinetics are very difficult to
control as both drug and polymer are dissolving.
 CONT…
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❖Crosslinking drug with polymers in a matrix
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allows better control of drug release as bonds can
be degraded by hydrolysis or enzymatic action.
❖The release kinetics are somewhat easier than
others
❖The system allows very high drug loading due to
presence of multiple sites on polymers for
attaching
❖System erodes as all bonds are broken and
polymer converts to monomer.
 CONT…
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❖ Swelling controlled matrix actually utilize combination of
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the mechanism of diffusion and dissolution.
❖ The dispersed drug in the matrix is dissolved by
penetrating solvent in the matrix. Instead of insoluble or
eroding polymer, here the polymer swells to relax that
allows water to penetrate
❖ The release rate from the system is highly dependent on
the polymer swelling rate, drug solubility, and amount of
soluble fraction of polymeric matrix.
❖ The burst release effects are minimum as polymer require
swelling before drug release
 CHARACTERISTICS OF
BIOERODIBLE SYSTEM 44
Description Homogenous dispersion of solid drug in
an erodible polymer mixture
Advantages Easier to produce than reservoir systems
Can deliver high molecular weight drugs
Release rate is independent of conc. that
allows substantial sustained release
Accidental leakage from system is less
likely as drug is dispersed in matrix system
Removal from implant site is not necessary
Disadvantages Difficult to control kinetics as multiple
process are effecting release
Potential toxicity of polymer must be
considered
 RITGER PEPPAS EQUATION
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❖ The first ever bioerodible kinetics were resolved by a
comprehensive equation by Hopfenberg 1976.
❖ It considered release from three devices, spheres,
cylinders and slabs
𝑀 𝐾 𝑡
❖ 𝑡 = 1 − (1 − 0 )𝑛
𝑀 𝐶0 𝑎
❖ Where n=3 for a sphere, n=2 for a cylinder and n=1 for
a slab, ‘a’ is the radius of sphere or half length of
cylinder/slab, 𝑀𝑡 is mass of drug released at time t, 𝑀
is mass of drug released at infinite time.
❖ Ritger and Peppas (1987) and Korsmeyer and Peppas
(1984) developed an empirical equation to analyze both
Fickian and non-Fickian release of drug from swelling
as well as non-swelling erodible polymeric devices
 RITGER PEPPAS EQUATION
46
𝑀𝑡
❖ = 𝑘𝑡 𝑛
𝑀∞
❖ Where 𝑀𝑡 Τ𝑀∞ is fraction of drug released at time t, n is
diffusion exponent indicative of mechanism of transport
of drug through polymer, k is kinetic constant joining
structural and geometric characteristics of delivery systems.
❖ For Ritger-Peppas models, the value of release exponent ‘n’
describe four mechanisms of drug release i.e.
❖ Fickian diffusion release (Fick’s law of diffusion),
❖ Non-fickian (anomalous) release (this means that drug
release followed both diffusion and erosion controlled
mechanisms),
❖ Case II (zero order) release and
❖ Super case II release.
 RITGER PEPPAS EQUATION
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❖ The release exponent for slab (non swellable matrix) is
❖ n ≤ 0.5 for Fickian diffusion release, 0.5 < n < 1.0 for non-
Fickian release (anomalous), and n = 1 for zero order
release, where drug release is independent of time.
❖ Also, 0.45 < n < 0.9 for non-Fickian release (anomalous)
from cylinders (non swellable matrix) and
❖ 0.43 < n < 0.85 for non-Fickian release (anomalous) from
non swellable spherical samples
❖ Fickian diffusion refers to the solute transport process in
which the polymer relaxation time (tr) is much greater than
the characteristic solvent diffusion time (td). When tr ≈ td,
the macroscopic drug release becomes anomalous or non-
Fickian.
FRONTS OF SWELLING SYSTEMS
48
Whenever a bioerodible swellable tablet is placed in buffer,
the medium starts to penetrate the matrix creating sharp
boundaries (fronts) that separate various thermodynamic
States of the polymer or various phases of the matrix.
FRONTS OF SWELLING SYSTEMS
49
❖ Depending on the solubility of the
drug, three fronts can be observed,
1. A swelling front, identifying the
boundary between the glassy
polymer (A) and its rubbery gel
state (B),
2. A diffusion front, indicating the
boundary between the still un-
dissolved (solid) drug (B) and the
dissolved drug in the gel layer,
3. An erosion front, identifying the
boundary between the matrix (C)
and the dissolution medium
(water or buffer).
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