Unit – I Controlled release drug delivery

system

Subject : Novel Drug Delivery System - Sem- VII

STES’s Smt. Kashibai Navale College of Pharmacy, Kondhwa.

 Content
 Unit-I
 Controlled drug delivery systems: Introduction,
terminology/definitions and rationale, advantages,
disadvantages, selection of drug candidates. Approaches to
design controlled release formulations based on diffusion,
dissolution and ion exchange principles. Physicochemical
and biological properties of drugs relevant to controlled
release formulations.
 Polymers: Introduction, classification, properties,
advantages and application of polymers in formulation of
controlled release drug delivery systems.
 Introduction
 Oral administration of drugs has been the most common
and preferred route for delivery of most therapeutic agents.

 It remains the preferred route of administration investigated

in the discovery and development of new drug candidates
and formulations.

 The popularity of oral route is attributed to patient

acceptance, ease of administration, accurate dosing, cost-
effective manufacturing methods and generally improved
shelf-life of the product.
 For many drugs and therapeutic agents, conventional,
multiple dosing of immediate release formulations provides
satisfactory clinical performance with an appropriate balance
of efficacy and safety.

 The rationale for development of an extended release

formulation of a drug is to enhance its therapeutic benefits,
minimizing its side effects while improving the management
of the diseased condition.
 Besides its clinical advantages, an innovative extended-
release formulation provides an opportunity for a
pharmaceutical company to manage its product life-cycle.

 Now a days new chemical entities is forcing many

pharmaceutical companies to reformulate an existing
conventional formulation to an extended-release product as
a strategy of life-cycle management and retaining market
share.

 To imagine the ideal drug- delivery system, two

prerequisites would be required:
1. It would be a single dose for the duration of treatment.

2. It should deliver the active entity directly to the site of

action, thereby minimizing or eliminating side effects.
Thus, the goal of sustained/controlled release dosage
form is to maintain therapeutic blood or tissue levels of
the drug over an extended period of time.
 Figure 1.1 shows comparative blood drug level profiles
obtained from administration of conventional, controlled
as well as sustained release dosage forms.
 Thus, the conventional tablet provides only a single and
transient burst of drug.

 A Pharmacological affect is seen as long as the amount of

drug is within the therapeutic range.

 Pharmacological effect is altered when the peak

concentration is above or below the therapeutic range.

 The main purposes of controlled release is to improve

safety and minimize side effects of the drug by reducing
fluctuation in drug level.
Different Terms Used Under Novel Drug Delivery Systems

1. Delayed Release
2. Extended Release
3. Sustained Release
4. Controlled Release
5. Site Specific Targeting
6. Receptor Targeting
7. Fast Dissolve Drug Delivery System (Flash)
1. Delayed Release:
 A dosage form that releases a discrete fraction of drug at a
time or times other than administration, although one
portion may be released immediately after administration.

 Examples include; enteric coated tablets, where a timed

release is achieved by barrier coating repeated action
tablets or spansules.
2. Extended Release:
 When absorption of drug is greater than its elimination,
the release is known as extended release.

 A dosage form should allow at least a twofold reduction

in dosage frequency as compared to that drug presented as
an immediate release dosage form.

 These include; any dosage form that maintains therapeutic

blood or tissue level of drug for prolong time.
3. Sustained Release:

 It includes the drug delivery systems that achieve and ensure

slow release of drugs over an extended/prolonged period of
time or at a constant release rate to attain and maintain
therapeutically effective levels of drug concentration in the
circulation.

 Here the absorption rate is equal to the elimination rate over

an extended period of time.
4. Controlled Release:

 It includes any drug delivery system from which the drug is

delivered at a predetermined rate over a prolong period of
time.

5. Site Specific Targeting:

 It is a dosage form that releases drug at or near the intended

physiologic site of action.
 Targeted release dosage forms may have either immediate
or extended release characteristics.

 Targeted drug delivery is implicated by using carriers

either meant for passive preprogrammed or active
preprogrammed or self-programmed drug release
approach.

 Thus, they are usually appended with suitable site directing

molecules, which recognize their receptor or molecular
determinants at the target.
6. Receptor Targeting:

 In such system, the target is a particular receptor within an

organ or tissue.
7. Fast Dissolve Drug Delivery System (Flash):

 It is type of solid dosage form that dissolves or

disintegrate in the oral cavity without the help of water or
chewing.

 Fast dissolution is achieved by forming loose network

(Zydis, Eli Lilly), or by effervescent agent (Oraslav, Cima)
or with mixture of disintegrating agent and swelling (Flash
Tab, Prographarm).
 Rationale Of Controlled Drug Delivery

 The basic rationale of controlled drug delivery is to alter

the pharmacokinetics and pharmacodynamics of
pharmacologically active moieties by using novel drug
delivery systems or by modifying the molecular structure
and/or physiological parameters inherent in a selected route
of administration.

 The primary objectives of controlled drug delivery are to

ensure safety and to improve efficacy of drugs as well as
patient compliance.
 For conventional dosage forms only the dose and dosing
interval can vary and for each drug, there exists a
therapeutic window of plasma concentration below which
therapeutic effect is insufficient and above which
undesirable or toxic side effects are elicited. This is often
defined as, "the ratio of median lethal dose (LDs) to
median effective dose (EDs)".
 Advantages Of Controlled Drug Delivery

 Maintenance of drug levels within a desired range.

 Delivery of "difficult" drugs: slow release of water-soluble

drugs, fast release of low solubility drugs.

 Less dosing and increased patient compliance.

 Eliminate overdosing or underdosing.

 Prevention of side effects.

 Reduction in health care cost.

 Improved efficiency in treatment.

 Reduction in adverse side effects and improvement in

tolerability.
 Disadvantages Of Controlled Drug Delivery
 Dumping is a major disadvantage of CRDDS, which refers
to the rapid release of a relatively large quantity of drug
from a controlled release formulation. This phenomenon
becomes hazardous with potent drugs.

 Poor in-vivo and in-vitro correlations.

 Difficult to optimize the accurate dose and dosing interval.

 Patient variability affects the release rate like GI emptying

rate, residential time, fasting or non-fasting condition, etc.
 Factors Influencing The Design And Act Of Controlled
Release Products/Physicochemical consideration

1. Physiological Properties:

(1) Aqueous solubility:

 Most of the active pharmaceutical moiety (API) are weakly

acidic or basic in nature that affect the water solubility of
API.
 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.

 These types of drugs are a good candidate for CRDDS.

The pH dependent solubility also creates a problem in
formulating CRDDS.

 BCS class-III and IV drugs are not a suitable candidate

for this type of formulations.
 Determination of Solubility:
1. Semi-quantitative method.
2. Accurate-quantitative method.
3. pH change method.

 Absorption of poorly soluble drugs is often dissolution rate-

limited.

 Such drugs do not require any further control over their

dissolution rate and thus may not seem to be good
candidates for oral controlled release formulations.
 Controlled release formulations of such drugs may be
aimed at making their dissolution more uniform rather
than reducing it.
(2) Partition coefficient (P-value):
 P-value denotes the fraction of the drug into oil and
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.

 The partition coefficient is defined as "the concentration

ratio of unionized drug distributed between two phases at
equilibrium".
3) Drug pKa:
 pKa is the factor that determine the ionization of drug at
physiological pH in GIT. Generally, the high ionized drugs
are poor candidates for CRDDS.

 The absorption of the unionized drug occurs rapidly as

compared to ionized drugs from the biological membranes.

 The pKa range for an acidic drug that ionization depends

on the pH is 3.0 to 7.5 and for a basic drug it lay between 7
and 11.
(4) Drug stability:
 Drugs that are stable in acid/base, enzymatic degradation,
and other gastric fluids are good candidates for
CRDDS.

 If drug is degraded in the stomach and small intestine, it

is not suitable for controlled release formulations because
it will decrease in bioavailability of concern drug.
(5) Molecular size and molecular weight:

 The molecular size and molecular weight are two

important factors which affect the molecular diffusibility
across a biological membrane.

 The molecular size less than 400D is easily diffused but

greater than 400D create a problem in drug diffusion.
(i) The ability of drug to pass through membranes is called
as diffusivity.
(ii) An important influence upon the value of diffusivity-D,
in polymers is the molecular size of the diffusing
species.
(iii) The value of D thus, is related to the size and shape of
the cavities as well as size and shape of the drugs.
(iv) Molecular size of the drug plays a major role when it
comes to diffusion of the drug through a biological
membrane.
(6) Protein binding:

 The drug-protein complex act as a reservoir in plasma for

the drug.

 Drugs showing high plasma protein binding are not a

good candidate for CRDDS because the protein binding
increases the biological half-life. So, there is no need to
sustain the drug release.
This complex leads to:
 Inhibition of therapeutic effect of such amount.

 Half-life is increased (compared to in vitro studies).

 Toxicity profiles elevated.

 Thus, in most of the cases, protein binding is

undesirable. Many drugs are highly protein bound (may
be 95%), thus the need of formulating a modified drug or
drug delivery system starts.
 Biological Properties
(1) Absorption:

 Uniformity in rate and extent of absorption is an important

factor in formulating the CRDDS. However, the rate
limiting step is drug release from the dosage form.

 The absorption rate should rapid the release rate to prevent

the dose dumping.

 The various factors like, aqueous solubility, log P, acid

hydrolysis, which affect the absorption of drugs.
(2) Distribution:
 Distribution of drug from the conventional dosage form
directly gets distributed throughout the body, and gets
accumulated to some of the off-sites, which may lead to
toxicity.

 Such thing can be prevented by CRDDS, which can be

site-targeted and specific towards the diseases condition
area and thus preventing accumulation in other sites.

 It also enables the complete drug to be reached to the

required site, unlike the conventional forms.
(3) Elimination:

 There are so many drugs available, which accumulates in

the organs like; liver, pancreas, etc. and becomes fatal
sometimes. Removal of such unwanted accumulated
portion is quite hectic for the system due to slow
elimination rate.

 In such cases, CRRDS again plays a major role as the

accumulation in off-sites are comparatively negligible, and
also the released drug easily expresses the action and then
gets eliminated safely.
(1) Biological half-life (t):

 In general, the drug having short half-life requires frequent

dosing and suitable candidate for controlled release system.

 A drug with long half-life requires dosing after a long-time

interval.

 Ideally, the drugs having t1/2 2-3 hours, are a suitable

candidate for CRDDS. Drugs having t1/2 more than 7-8
hours are not used for controlled release system.
5) Dose size:

 The CRDDS are formulated to eliminate the repetitive

dosing, so it must contain the large dose than conventional
dosage form. But the dose used in conventional dosage
form give an indication of the dose to be used in CRDDS.

 The volume of sustained dose should be as large as it

comes under acceptance criteria.
 Size of the drug plays a major role in determining the size
of the final finished product.

 In case, the dose is already high, then formulating the

same into controlled release will further increase the
overall dosage size and thereby reduce 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 may need to carry a
prohibitively large quantity of drug.
(6) Therapeutic window:

 The drugs with narrow therapeutic index are not suitable

for CRDDS. If the delivery system failed to control
release, it would cause dose dumping and ultimate toxicity.
(7) Absorption window:

 The drugs which show absorption from the specific

segment in GIT, are a poor candidate for CRDDS.

 Drugs which are absorbed throughout the GIT are good

candidates for controlled release.
(8) Patient physiology:

 The physiological condition of the patient like gastric

emptying rate, residential time, and GI diseases influence
the release of the drug from the dosage form directly or
indirectly.

 Pharmacokinetic parameters considered during the drug

selection are listed as follow:
 Formulation Aspects Influencing The Design Of Oral
Controlled Release Drug Delivery
Systems/Pharmaceutical consideration

1. Drug Properties:

 Drug solubility and dose are the most important factors to

be considered in the design of ER matrices.

 In general, extended-release formulation of extreme drug

solubility's coupled with a high dose is challenging.
 Drugs with very low solubility (e.g. <0.01 mg/ml) may
dissolve slowly and have slow diffusion through the gel layer
of a hydrophilic matrix.

 Therefore, the main mechanism of release would be through

erosion of the surface of the hydrated matrix. In these cases,
the control over matrix erosion to achieve consistent extended
release throughout the GI tract is critical.

 For drugs with very high-water solubility, the drug dissolves

within the gel layer (even with small amount of free water)
and diffuses out into the media.
 Therefore, it is important to control the factors that affect
drug diffusivity (e.g. pH, gel strength and availability of
free water) within the gel layer and parameters that ensure
integrity of the gel layer after the drug has been dissolved
and released from the gel layer.

 For poorly soluble drugs, particle size of the drug has a

major influence on its release profile.

 A decrease in particle size of the drug causes increase in

solubility and hence faster drug release rate.
2. Polymer Considerations:
 Depending on dosage size and desired release rate, the
typical use level can vary from 20 to 50% (w/w). For drugs
with high water solubility, there is a threshold level of
polymer for achieving controlled release, and further
increase in polymer level may not decrease the drug release
rate.

 However, for obtaining a robust formulation with consistent

performance and insensitivity to minor variations in raw
materials or manufacturing processes, a usage level of 30%
(w/w) has been recommended.
 Particle size of the polymer is also an important factor.

 The finer the particle size, the faster the rate of hydration of
the polymer and hence better the control of drug release.

 Coarser polymer particles used in a direct compression

formulation have been reported to result in faster drug
release than finer particles.

 The coarser the particle size, the slower the hydration rate
and gel layer formation.
3. Presence of Other Excipients:

 Fillers:
 Soluble fillers (e.g. lactose), insoluble fillers (e.g.
microcrystalline cellulose, dicalcium phosphate) and/or
partially soluble (e.g. partially pregelatinized starch).

 Fillers are generally used in hydrophilic matrices to enhance

pharmaco-technical properties of tablets (improve
compressibility, flow and mechanical strength) or to modify
the drug release profile.
 The inclusion of fillers affects the dissolution performance
of a matrix by a "dilution effect" on the polymer.

 The magnitude of the effect on the performance of matrices

is dependent on the drug, the polymer level and the level of
excipient itself.

 The presence of water-soluble fillers in high concentrations

in the matrix leads to faster and greater water uptake by the
matrix, resulting in weaker gel strength, higher erosion of
the gel layer and therefore faster drug release.
 Insoluble but weakly swellable fillers such as;
microcrystalline cellulose remains within the gel structure
and generally result in decreased release rate.

 The presence of partially pregelatinized starch such as;

Starch 1500Ⓡ in HPMC matrices has been reported to
decrease the drug release rate.

 For a highly soluble or sparingly soluble drug, the rank

order of release rate was as follows:
 Lactose Microcrystalline cellulose > Partially
pregelatinized starch.
4. Release Modifiers and Stabilizers:

 Drugs with pH-dependent aqueous solubility (weak acids or

bases) are formulated in HPMC matrices, they may exhibit
pH-dependent drug release.

 Formulating CR matrices of such drugs may lead to lower

drug release due to exposure of the dosage form to
increasing pH media of the GI tract (from pH 1.2 to 7).
 Formulating pH-independent CR matrices for such drugs
would not only ensure adequate release throughout the
physiological pH, but also lower intra- and inter-patient
variability.

 Development of such pH-independent matrices for weakly

basic drugs has been shown with the incorporation of
acidic excipients (weak acids or salts of strong acids) that
lower the micro-environmental pH within the gel layer and
thus maintain high local solubility of the drug independent
of the external release media.
5. Effect of Salts and Electrolytes:

 In general, as the concentration of ions in a polymer

solution increases, polymer hydration or solubility
decreases.

 The amount of water available to hydrate the polymer is

reduced because more water molecules are required to keep
the ions in solution.

 Moreover, the types of ions in solution affect the polymer

hydration to varying degrees.
 The susceptibility of cellulose ethers to ionic effects follows
the lyo-tropic series of the ions (chloride < tartrate <
phosphates and potassium < sodium).

 Changes in the hydration state of a polymer in solution are

manifested primarily by changes in solution viscosity and
turbidity or cloud point.

 At low ionic strengths, the polymer hydration is unaffected,

but higher ionic strengths may lead to a loss of gel integrity
of the matrix.
 The extent of this influence depends on the polymer type
and lyotropic series of the ions.

 The effect of electrolytes or salts is important only in cases

where high concentrations of salts or electrolytes are
present as tablet components or as constituents of
dissolution media.

 In vivo conditions, however, have fairly low ionic strength

(ionic strength of gastrointestinal fluids, (0.01-0.15)) to
affect the polymer hydration and have significant impact on
release rate.
6. Characteristics of Dosage Form:

 Variation in tablet shape and size may cause changes in

surface area available for drug release and hence influences
drug release profiles from HPMC matrices.

 A constant surface area to volume ratio (S/V) of different

size and shape tablets for a HPMC formulation would lead
to similar drug release profiles.

 The size of the tablet may also dictate the polymer level
requirement.
 Smaller tablets have been reported to require higher
polymer content because of their higher surface area to
volume ratio and thus shorter diffusion pathways.

 One technology proposed for modifying the matrix

surface area to volume ratio was by physical restriction of
the swelling of hydrophilic matrix by partially coating the
matrix with insoluble polymers or multi-layered tablets
(Geomatrix® technology).

 08+Application of film coatings to tablet formulations is

a common practice in the pharmaceutical industry.
 Tablets are coated for a variety of reasons such as
improving the stability of the formulation, taste masking,
enhancing the aesthetic appearance, identification and
branding, improving the packaging process or modifying
drug release profile.

 Coating of hydrophilic matrices with water-soluble

polymers such as; OpadryⓇ or low-viscosity HPMC
generally does not alter drug release profiles.
 Coating with water- insoluble polymers such as ethyl
cellulose with or without permeability modifiers (e.g., low
viscosity grades of HPMC or Opadry) may be used for
modulating the drug release profile from HPMC matrices.
 Approaches/Types/Classification Of Oral Controlled Drug
Delivery System
1. Dissolution controlled systems

2. Diffusional systems
(a) Reservoir devices
(b) Matrix devices

3.Bio erodible and combination of diffusion and dissolution

systems

4. Osmotically controlled systems

5. Ion-exchange systems

6. pH-independent formulations

7. Altered density formulations

(a) High density approach
(b) Low density approach

 The majority of oral controlled release systems rely on

dissolution, diffusion or a combination of both mechanisms,
to generate slow release of drug to the gastro-intestinal tract.
 1. Dissolution-Controlled Systems

 Controlled release preparations of drugs could be made by

decreasing their rate of dissolution.

 The approaches to achieve this include preparation of

appropriate salts or derivatives, coating the drug with a
slowly dissolving material or incorporating it into a tablet
with a slowly dissolving carrier.
 Dissolution controlled systems can be made in several
different ways: By alternating layers of drug with rate
controlling coats, a pulsed delivery can be achieved.

 If the outer layer is a quickly releasing bolus of drug, initial

levels of drug in the body can be quickly established with
pulsed intervals following.

 An alternative method is to administer the drug as a group of

beads that have coatings of different thicknesses. Since the
beads have different coating thicknesses, their release will
occur in a progressive manner.
 Those with the thinnest layers will provide the initial dose.
The maintenance of drug levels at later times will be
achieved from those with thicker coatings. This is the
principle of the spansule technology or
microencapsulation.
 Based on the technical sophistication, it is classified as:

a. Matrix type

b. Encapsulation type
a. Matrix Type:

 Dissolution devices are prepared by compressing the drug

with slowly dissolving carrier into tablet.

Controlled dissolution by:

1. Altering porosity of tablet
2. Dissolving at slower rate
3. Decreasing its wettability

 The drug release is determined by dissolution of the

polymer.
Examples: Dimetane extencaps, Dimetapp extentabs.
b. Encapsulation Type:

 The drug particles are coated or encapsulated by

microencapsulation technique.

 The pellets are filled in hard gelatin capsule, popularly

called as 'spansules’.

 Once the coating material dissolves, the entire drug inside

the microcapsule is immediately available for dissolution
and absorption.
 Here the drug release is determined by dissolution rate and
thickness of polymer membrane which may range from 1 to
200μ.

 Dissolution rate of coat depends upon stability and

thickness of coating.

 Examples:
1. Ornade spansules.
2. Chlortrimeton repetabs.
2. Diffusional Systems:

 Diffusion systems are characterized by the release rate of a

drug being dependent on its diffusion through an inert
membrane barrier. Usually, this barrier is an insoluble
polymer. In general, two types of diffusional systems are
recognized. They are reservoir device and matrix devices.
a. Reservoir Devices:

 Reservoir devices are characterized by a core of drug, the

reservoir, surrounded by a polymeric membrane.

 The nature of the membrane determines the rate of release

of drug from the system.
 The advantages of reservoir diffusional systems are, zero-
order delivery are possible and release rate will vary with
polymer type.

 The disadvantages of reservoir diffusional systems are,

system must be physically plant site, difficult to deliver
high-molecular weight compounds, rupture can result in
dangerous dose dumping.
b. Matrix Devices:

 A matrix device consists of drug dispersed homogeneously

throughout a polymer matrix.

 In this model, drug in the outside layer exposed to the

bathing solution is dissolved first and then diffuses out of
the matrix.
 This process continues with the interface between the
bathing solution and the solid drug moving towards the
interior.

 Obviously, for this system to be diffusion controlled, the

rate of dissolution of drug particles within the matrix must
be much faster than the diffusion rate of dissolved drug
leaving the matrix.
3. Bio Erodible and Combination of Diffusion and
Dissolution Systems:

 These systems can combine diffusion and dissolution of

both the matrix material and the drug.

 Drug not only can diffuse out of the dosage form, as with
some previously described matrix systems but the matrix
itself undergoes a dissolution process.
 The complexity of the system varies from the fact that, as
the polymer dissolves the diffusional path length for the
drug may change. This usually results in a moving
boundary diffusion system.

 Zero-order release can occur only if surface erosion

occurs and surface area does not change with time.

 The inherent advantage of such a system is that, the bio

erodible property of the matrix does not result in a ghost
matrix and removal from implant sites is not necessary.
 The disadvantages of this system include, difficulty to
control kinetics owing to multiple processes of release,
potential toxicity of degraded polymer must be considered.

 Another method of bio erodible system is to attach the drug

directly to the polymer by a chemical bond.

 Generally, the drug is released from the polymer by

hydrolysis or enzymatic reaction. A third type, which in this
case utilizes a combination of diffusion and dissolution, is
that of a swelling-controlled matrix.
 Here the drug is dissolved in the polymer, but instead of an
insoluble or eroding polymer, as in previous systems,
swelling of the polymer occurs.

 This allows entrance of water, which causes dissolution of

the drug and diffusion out of the swollen matrix.

 In these systems, the release rate is highly dependent on the

polymer swelling rate, drug solubility and the amount of
soluble fraction in the matrix. This system usually
minimizes burst effects, since polymer swelling must occur
before drug release.
4. Osmotically Controlled Systems:

 In these systems, osmotic pressure provides the driving

force to generate controlled release of drug.

 Consider a semi-permeable membrane that is permeable

to water, but not to drug.

 A tablet containing a core of drug surrounded by such a

membrane and when this device is exposed to water or
any other body fluid, water will flow into the tablet
owing to the osmotic pressure difference.
 These systems generally appear in two different forms. The
first one contains the drug as a solid core together with
electrolyte, which is dissolved by the incoming water.

 The electrolyte provides the high osmotic pressure

difference.

 The second system contains the drug in solution in an

impermeable membrane within the device.
 The electrolyte surrounds the bag. Both systems have
single or multiple holes bored through the membrane to
allow drug release.

 In the first example, high osmotic pressure can be relieved

only by pumping solution, containing drug, out of the hole.

 Similarly in the second example, the high osmotic pressure

causes compression of the inner membrane and drug is
pumped out through the hole.
 The advantages of osmotically controlled devices are,
zero-order release is obtainable.

 Reformulation is not required for different drugs and

release of drug independent of the environment of the
system.

 The disadvantages of these systems include, systems can

be much more expensive than conventional counterparts
and quality control is more extensive than conventional
tablets.
5. lon-Exchange Systems:

 Ion-exchange systems generally use resins composed of

water-insoluble, cross-linked polymers.

 These polymers contain salt-forming functional groups in

repeating positions on the polymer chain.

 The drug is bound to the resin and released by exchanging

with appropriately charged ions in contact with the ion-
exchange groups.
 Resin - Drug + X-resin-X + Drug

Conversely,

Resin - Drug + Y Resin - Y + Drug

*Where, X and Y are ions in the GI tract. The free drug then
diffuses out of the resin.
 The drug-resin complex is prepared by mixing the resin
with drug solution either by repeated exposure of the resin
to the drug in a chromatography column or by prolonged
contact in solution.
 The date of drug diffusing out of the resin is controlled by the
area of diffusion, diffusional path length and rigidity of the
resin, which is a function of the amount of cross- linking
agent used to prepare the resin.

 This system is advantageous for drugs that are highly

susceptible to degradation by enzymatic processes, since it
offers a protective mechanism by temporarily altering the
substrate.
 This approach to controlled release, however, has the
limitation that the release rate is proportional to the
concentration of the ions present in the area of administration.
 Although the ionic concentration of the GI tract remains
rather constant with limits, the release rate of the drug can
be affected by variability in diet, water intake and
individual intestinal content.

 An improvement in this system is to coat the ion-exchange

resin with a hydrophobic rate-limiting polymer, such as
ethyl cellulose or waxes.

 These systems rely on the polymer coat to govern the rate

of drug availability.
 POLYMERS

 Polymers are compounds with high molecular masses

formed by monomers.

 In Greek, the word poly means 'many and meros means

'units or parts.

 Polymers play a major role in the development of drug

delivery technology by release of two types of drugs like,
hydrophilic and hydrophobic in a synchronized manner
and constant release of formulations over extended periods.
 There are numerous advantages of polymers acting as an inert
carrier to which a drug can be conjugated, for example the
polymer improves the pharmacokinetic and
pharmacodynamic properties of biopharmaceuticals through
various ways like; plasma half-life, decreases the
immunogenicity, build ups the stability of biopharmaceuticals,
improves the solubility of low molecular weight drugs, and
has a potential of targeted drug delivery.

 However, they have their own limitations, such as; the natural
polymers are most abundant and biodegradable but are
difficult to reproduce and purify.
 Synthetic polymers have high immunogenicity, which
prevent their long term usage.

 Non-biodegradable polymers are needed to be sugary after

they release the drug at the targeted site.

 The general characteristic features that makes the polymer a

potential candidate for drug delivery include; safety,
efficacy, hydrophilicity, absence immunogenicity biological
inactivity, sufficient pharmacokinetics and presence of
functional groups for covalent conjugation of drugs,
targeting moieties or formation of copolymer.
 Characteristics of Ideal Polymer
1. Low density.
2. Low coefficient of friction.
3. Good corrosion resistance
4. Good mould ability.
5. Excellent surface finish can be obtained.
6. Can be produced with close dimensional tolerances.
7. Economical.
8. Poor tensile strength.
9. Low mechanical properties.
10. Poor temperature resistance.
11. Can be produced transparent or in different colours.
 Advantages of Ideal Polymer

1.Polymers used in colloidal drug carrier systems, consisting

of small particles, show great advantage in drug delivery
systems because of optimized drug loading and releasing
property.

2.A polymer (natural or synthetic) is aggregated with a drug

in controlled drug delivery and hence it gives an effective
and controlled dose of drug, avoiding overdose.
3.The degradable polymers are ruptured into biologically
suitable molecules that are assimilated and discarded from the
body through normal route.

4.Reservoir based polymers is advantageous in various ways

like it increase the solubility of incompetently soluble drugs and
it lowers the antagonistic side effects of drugs.

5.Magneto-optical polymer coated and targeted nanoparticles are

multimodal (optically and MRI detectable) while Quantum Dots
are only optically detectable.
6.Some Quantum dots contain Ca which is known to be toxic
to humans. Magneto/optical nanoparticles whether polymer
coated or targeted are composed of iron oxides/polymers which
are known to be safe, therefore have great future.

7.Dextran is the common polymer used for coating of iron

oxide (plasma expander and affinity for iron) and are used for
treatment of iron anaemias since 1960 and is still in operation.

8.In controlled release, some of the polymers like;

polyurethanes for elasticity, polysiloxanes for insulating ability
are used for their intended non-biological physical properties.
9.Current polymers like; Poly 2-hydroxy ethyl
methacrylate, Polyvinyl alcohol, Polyethylene glycol are
used because of their inert characteristics and also, they are
free of leachable impurities.

10.In biodegradable polymers, the system is biocompatible

and it will not show dose leaving behind at any time, and
the polymer will keep its properties until after exhaustion of
the drug.
11. In hydrogels like drug delivery systems, the properties of
polymer materials like PEG, (the easy polymer used to
design hydrogels), can be managed to enhance features like;
size of the pore, which is used to manage rate of diffusion of
the conveyer drugs. PEGylation was considered to minister
many diseases like; hepatitis B and C, neutropaenia
connected with cancer chemotherapy (PEG-GCSF) 28 and
various types of cancers [PEG] glutaminase merged with a
glutamine anti-metabolite 6-diazo-5- oxo-norleucine (DON).
12.Polymers span from their use as films or binders
covering agents in tablets to flow managing agent in liquids
or emulsions for improving drug security and to alter the
delivering characteristics. Micelles due to its smaller size
have a small circulation time in the body. Hence, it results
in an advantage of entering in the tumor cells easily.
because of the EPR effect.

13.Large importance of polymers in drug delivery has been

noticed because they give a distinctive property which so
far is not achieved by any of the materials.
14.Polymers are preferable in the fact that they habitually
show a pharmacokinetic profile as contrast to small-scale
molecule drug with lengthy circulation time and they also have
the ability for tissue targeting.

15.Gold nanoparticles are easy to prepare, good capability of

co-existence, and their capacity to attach with other
biomolecules without changing their properties.
16. Biggest benefit of utilizing polymers in drug delivery is
their control (manipulation) on their properties (e.g. linkers
and molecular weight) to modify to the need of drug delivery
systems.
 Polymer Classification

1. Classification Based on Source

1. Natural polymers: These are derived from natural sources

and can be polysaccharides and protein in chemical nature.

For example: Albumin, Cellulose, Starch, Rubber, Wool.

2. Semi-synthetic polymers: These types of polymers are
derived from naturally occurring polymers by means of
chemical modifications.

For e.g. Vulcanized rubber, Gun cotton, Cellulose

diacetate, HPMC, etc.
(i) Vulcanized rubber is used in making tyres as the
process of vulcanization increases the mechanical
strength of natural rubber.

(ii) Gun cotton which is a cellulose nitrate is used in

making explosives. Cellulose on acetylation with acetic
anhydride in the presence of sulfuric acid forms
cellulose diacetate which is used in production of treads
and materials like films, glasses, etc.
3. Synthetic polymers: Synthetic polymers are of artificial
origin which consist of fibers. This is the polymer, which was
prepared by Laboratory is known as Synthetic Polymer.

For example: Buna-S, Buna-R, Nylon, Polythene,

Polyester.
 2. Classification Based on Structure

1. Linear polymers:

 The smallest repeating unit arranged in straight line path is

known as Linear polymer. For example: PVC.

2. Branched chain polymers:

 Contain linear chains having some branches. For example:

low density polymer, Polyethylene, HPLD polyethylene.
3. Cross linked chain polymers:

 In this type, all molecules are chemically bonded together,

forming a three-dimensional network. The bonding is
usually covalent but other types such as; ionic bond is also
possible.

 Cross-linked polymers are produced from linear and

branched polymers or directly from chemical precursor.

 For e.g. Natural rubber, polyacrylamide gels, epoxies,

alkyd resins, etc
 3. Classification Based on Polymerization

1. Additional polymers:

 Additional polymers are formed by the repeated addition of

monomer molecules possessing double or triple bonds.

 n(CH2 CH2) (CH2-CH₂)- =Ethylene polyethylene, one form

of polymer is converted into another form of polymer by
loss of atoms and ions from molecule.
2. Condensation polymers:

 Condensation polymers formed by repeated condensation

reaction between two different bi-functional or tri-
functional monomeric units.

 For e.g. terylene (dacron), nylon 6, 6,

 One polymer can be converted into anther form of

polymer without loss of atoms and ionsfrom molecule.
4. Classification Based on Molecular Force

1. Nylon:

 Nylon is used as general name for all synthetic fiber

forming polyamides, having a protein like structure.

 These are the condensation polymers of diamine and

dibasic acids.
 A number is usually suffixed with the Nylon which refers
to the number of carbon atoms present in the diamine and
the dibasic acids respectively.

 For example: Nylon 6, 6. Nylon-6, 6 is obtained by the

polymerization of adipic acid with hexamethylene
diamine.
2. Thermoplastic polymers:

 These are linear or slightly branched long chain polymers,

which can be softened on heating and reversibly hardened
on cooling repeatedly.

 Their hardness is a temporary property and varies with

temperature.

 The polymer under heating can convert from one state to

another state and after cooling, it can again convert to its
original state. For example: polyvinyl chloride.
 General Mechanism of Drug Release from Polymer

Three primary mechanisms for drug release, namely:

1. Diffusion

2. Degradation

3. Water penetration (Swelling)

1. Drug Release from Polymer by Diffusion:

 Rate limiting step is diffusion of drug through inert water

insoluble membrane barrier.

 There are of two types:

1. Reservoir

2. Matrix
1. Reservoir Diffusion System:

 In membrane-controlled reservoir devices, the drug is

contained in a core, which is surrounded by a polymer
membrane, and it is released by diffusion through this rate
controlling membrane.

 For example, Poly (N-vinyl pyrrolidone), Poly

(ethylene-co-vinyl acetate).
 Drug delivery from typical reservoir devices:

(i) Implantable or oral systems,

(ii) Transdermal systems.
2. Matrix Diffusion:

 In these devices, the drug is released either by passing

through the pores or between polymer chains, and these
are the processes that control the release rate.

 For example, polyethylene, polyvinylacetate.

2. Degradation:

 Bio degradation is the chemical changes that alter the

molecular weight or solubility of the polymers. Bio erosion
may refer to as physical process that result in weight loss of
a polymer device.

 The possibility for a polymer to degrade and to have its

degradation by products assimilated or excreted by living
system is designated as Bioresorbable.
 The erosion of polymers basically takes place by two
methods:

1. Chemical erosion
2. Physical erosion

1. Chemical Erosion:

 Bio erosions through chemical mechanisms are explained

below:
 Mechanism-I:

 It describes the degradation of water-soluble macromolecules

that are cross-linked to form three-dimensional network.

Degradation in these systems can occur by:

Type (1A):

 Degradation occur at crosslinks to form soluble backbone

polymeric chains.
 It provides high molecular weight, water soluble
fragments.

Type (1B):

 Degradation occur to form water-soluble fragments.

 Such type provide slow molecular weight, water soluble

oligomers and monomers.
 Mechanism-II:

 Describes the dissolution of water insoluble

macromolecules with side groups that are converted to
water insoluble polymers as a result of ionization,
protonation or hydrolysis of the groups.

 Materials showing this type of erosion include:

 Cellulose acetate derivatives

 Co-polymers of maleic anhydride

Mechanism-III:

 Describes the degradation of insoluble polymers with

liable bonds.

 It forms low molecular weight, water soluble molecules.

 Polymers undergoing this type of erosion include;.

Poly(lactic acids)Polylglycolic acid) and their co-polymers,
etc
2. Physical Erosion:

 The physical erosion mechanisms can be characterized

as heterogeneous or homogeneous.

 Most polymers undergo homogenous erosion that means

the hydrolysis occur at even rate throughout the polymeric
matrix.

 In homogenous erosion, there is loss of integrity of the

matrix or polymer.
 In heterogeneous erosion, also called as surface erosion,
the matrix degrades and the drug is released from the
surface.

 Highly crystalline polymers tend to undergo

heterogeneous erosion.
3. Water Penetration (Swelling):

 These types of systems are initially dry and when placed in

body, absorb water or other fluid and it swells.

 In swelling controlled release systems, an active agent is

homogenously dispersed in a glassy polymer, because
glassy polymers are essentially impermeable, the active
agent is immobilized in the matrix and the diffusion through
the solid polymer phase takes place.
 When a monolithic devices are placed in an aqueous
environment, water begins to penetrate the matrix and
swelling takes place. As a consequence of the swelling
process, chain relaxation takes place and the incorporated
active agent begins to diffuse from the swollen layer.

 In linear amorphous polymers, dissolution follows the

swelling process, but crosslinked polymers or those
containing significant chain entanglements or partial
crystallinity willremain insoluble but will be mechanically
week.
 Swelling increases aqueous solvent content within the
formulation as well as the polymer mesh size, enabling the
drug to diffuse through the swollen network into external
environment.

 For example: (N-isopropyl-acrylamide), Ethylene-vinyl

alcohol.
 Role of Polymers in Drug Delivery

1. Immediate drug release dosage form tablets:

 Polymers including: polyvinyl pyrrolidone and

hydroxypropyl methyl cellulose (HPMC) are found to be a
good binder which increases the formation of granules that
improves the flow and compaction properties of tablet
formulations prior to tableting.
2. Capsules:

 Many of the polymeric excipients used to "bulk out"

capsules fills are the same as those used in intermediate
release tablets.

 For hard and soft shell, gelatin is most often used. By recent
advances, HPMC has been accepted as alternative material
for hard and soft capsules.
3. Modified drug release dosage forms:

 To achieve gastro-retention, mucoadhesive and low

density polymers have been evaluated their ability to
extend gastric residence time by bonding to the mucus
lining of the stomach and floating on top of the gastric
contents respectively.
4. Extended release dosage forms:
 Extended and sustained release dosage forms prolong the
time that, systemic drug levels are within the therapeutic
range and thus reduce the number of doses the patient must
take to maintain a therapeutic effect there by increasing
compliance.

 The most commonly used water insoluble polymers for

extended release applications are, the ammonium
ethacrylate copolymers, cellulose derivatives; ethyl cellulose
and cellulose acetate, and polyvinyl derivative; polyvinyl
acetate.
5. Gastro retentive dosage forms:

 Gastro retentive dosage forms offer an alternative

strategy for achieving extended release profile, in which
the formulation will remain in the stomach for
prolonged periods, releasing the drug insitu, which will
then dissolve in the liquid contents and slowly pass into
the small intestine.
Applications of Polymers in Formulation of Controlled
Drug Delivery System
1. Osmotic Pressure-Controlled GI Delivery System:

 Semi-permeable membrane is made from biocompatible

polymers.

 E.g. cellulose acetate

 Example of such type of system include, Acutrim tablet

which contains Phenylpropanolamine as a drug.
 In this device, an osmotic agent is contained within a rigid
housing and is separated from an active agent compartment-
b, a movable partition.

 One wall of the rigid housing is a semi- permeable

membrane so that when the pump is exposed to an aqueous
environment, water will be driven osmotically across the
membrane, the increased volume within the osmotic
compartment will force the active agent out of the device
through the delivery orifice.
 Major application is for gastro intestinal drug deliveries
because delivery rate is pH independent.
2. Gel Diffusion Controlled GI Delivery System Diffusion
and Dissolution-Controlled Release System:

1. Drug is encased in a partially soluble membrane.

2. Pores are created due to dissolution parts of membrane.
3. It permits entry of aqueous medium into core and drug
dissolution.
4. Diffusion of dissolved out of system. Example: Ethyl
cellulose and PVP mixture dissolves in water and create
pores of insoluble ethyl cellulose membrane.
3. Mucoadhesive GI Delivery System:

 The new generation mucoadhesive polymers for buccal

drug delivery with advantages such as; increase in the
residence time of the polymer, penetration enhancement,
site specific adhesion and enzymatic inhibition, site
specific mucoadhesive polymers will undoubtedly be
utilized for the buccal delivery of a wide variety of
therapeutic compounds.

 The class of polymers has enormous potential for the

delivery of therapeutic macromolecules.
4. Transdermal Drug Delivery System:

 TDDS is defined as, self-contained, self-discrete dosage

forms, which when applied to the intact skin, delivers the
drug at a controlled rate to the systemic circulation.

 In this, polymer matrix plays a major role. It releases the

drug from the device to the skin.
 Advantages of Transdermal Drug Delivery System:

 They permit easy removal and termination of drug action in

situation of toxicity.
 Problems encountered with oral administration like;
degradation, gastric irritation, etc. are avoided.
5. Ocular Drug Delivery System:

 It allows prolonged contact of drug with corneal surface of

eye.

 The example for ODDS is pilocarpine in the treatment of

glaucoma. In this, muco-adhesive polymers are used as
barriers to control the drug release.

 For e.g. Polyacrylic acid, Co polymers of acetate vinyl and

ethyl.
6. Other Applications:

1. Drug Delivery and the Treatment of Diabetes:

Here the polymer will act as a barrier between blood stream
and insulin. E.g. Polyacrylamide or N,N-Dimethyl amino
ethylmetha acrylate.
2. Drug Delivery of Various Contraceptives and Hormones.
It consists of drug saturated liquid medium encapsulated in
polymeric layer which controls the concentration and
release of drugs into the blood stream. E.g. Medoxy
progesterone acetate, Progestasert, Duromine, etc
 REFERENCES

1. Y.W. Chien. Novel drug delivery system. Volume 50.

2. John C, Morten C, The Science of Dosage Form Design, Aulton: Modified release peroral
dosage forms. 2nd ed. Churchill Livingstone. 2002; 290-300.
3. Lee VHL. Controlled Drug Delivery Fundamentals and Applications: Influence of drug
properties on design. 2nd ed. Marcel Dekker, Inc. New York: 1987; 16-25.
4. Modi Kushal, Modi Monali, Mishra Durgavati, Panchal Mittal, Sorathiya Umesh, Shelat
Pragna. Oral controlled release drug delivery system: An overview. Int. Res. J. Pharm.
2013; 4(3):70-76.
5. Vyas SP, Khar RK. Controlled drug delivery: Concepts and Advances. 1st ed. Vallabh
prakashan; 2002; 156-189.
6. Brahmankar DM, Jaiswal SB. Biopharmaceutics and Pharmacokinetics:
Pharmacokinetics. 2nd ed. Vallabh Prakashan, Delhi: 2009; 399-401.
7. Allen LV, Popvich GN, Ansel HC. Ansel’s Pharmaceutical dosage form and drug delivery
system. 8th ed. 2004; 260-263.
8. Patrick JS. Martin’s Physical Pharmacy and Pharmaceutical Sciences. 3rd ed. Varghese
Publishing House. Bombay: 1991; 512-519.
9. Kar RK, Mohapatra S, Barik BB. Design and characterization of controlled release matrix
tablets of Zidovudin. Asian J Pharm Cli Res. 2009; 2:54-6
10. Lachaman L, Liberman HA, Kanig JL.The theory and practice of industrial pharmacy. 3rd
ed. Bombay: Varghese publishing house 1987.
11. Jain NK. Controlled and novel drug delivery. CBS publisher and distribution. 1997; 1-25.
12. Venkataraman DSN, Chester A, Kliener L. An overview of controlled release system.
Handbook of pharmaceutical controlled release technology. Marcel Dekker Inc. 2000; 1-30.
13. Mamidala R, Ramana V, Lingam M, Gannu R, Rao MY. Review article factors influencing
the design and performance of oral sustained/controlled release dosage form. Int. journal of
pharmaceutical science and nanotechnology. 2009; 2:583.
14. Gupta S, Singh RP, Sharma R, Kalyanwat R, Lokwani P. Osmotic pumps: A review. Int.
journal of comprehensive pharmacy. 2011; 6:1-8.
15. Robinson JR, Lee VH. Controlled drug delivery. 2nd ed. Marcel Dekker, 1987; 4-15.
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