Advanced Drug Delivery

Systems
The term “drug delivery systems” refers to the
technology utilized to present the drug to the
desired body site for drug release and absorption.
The first drug delivery system developed was the
syringe, invented in 1855, used to deliver medicine
by injection. The modern transdermal patch is an
example of advanced drug delivery system.
The goal of any drug delivery system is to provide a
therapeutic amount of drug to the proper site in the
body to promptly achieve and then maintain the
desired drug concentration.
This idealized objective points to the two aspects most
important to the drug delivery, namely:
*Spatial placement: relates to targeting of a drug
to a specific organ or tissue.
*Temporal delivery of a drug: refers to controlling
the rate of drug delivery to the target tissue.
Dosage Forms
There are numerous dosage form into which a drug substance
can be incorporated for the convenient and efficacious treatment
of a disease. Dosage forms can be designed for administration by
all possible delivery routes to maximize therapeutic response.

Dosage Forms Available For Different Administration Routs:

Oral- Solutions, syrups, elixirs, suspensions, emulsions,

gels, powders, granules, capsules, tablets.
Topical- Ointments, creams, pastes, lotions, gels, solutions,
topical aerosols.
Parenteral- Injections (solutions, suspensions, emulsions forms),
implants, irrigation and dialysis solutions.
Rectal- Suppositories, ointments, creams, solutions, powders.
Lungs- Aerosols (solutions, suspensions, emulsions, powder
forms), inhalation, sprays, gases.
Nasal- Solutions, inhalations.
Eye- Solutions, ointments.
Ear- Solutions, suspensions, ointments.
Conventional Dosage Form or Immediate – Release
Dosage Form
Conventional / Immediate – release dosage form is a dosage form
which is formulated / designed to give rapid and complete release
of the drug contained therein immediately after administration.

Kinetic scheme for the extra vascular administration the

conventional dosage form of a drug that follows one –
compartment open model for disposition:
Kr Ka
Dosage Absorption Pool Body Compartment
Form
Drug Absorption
Release ( INPUT )

Ke
Urine
Elimination
( OUTPUT )
Kr, Ka and Ke : first order rate constants for drug release, absorption and overall elimination
respectively.
Immediate release from a convenient dosage form implies that
Kr >>> Ka. This means that absorption of a drug across a
biological membrane (e.g. GI epithelium) is the rate–timing
step in delivery of the drug to the body compartment.
For non–immediate–release dosage forms Kr <<< Ka.
i.e. release of drug from the dosage form is the rate limiting
step. Therefore the above scheme reduces to the following:

Kr Ke
Dosage Body Compartment
Urine
Form
Drug Elimination
Release

Essentially, the absorptive phase of the kinetic scheme

becomes insignificant compared to the drug release. Thus the
effort to develop a non–immediate–release dosage form must
be primarily directed at altering the release rate by affecting the
value of Kr.
Typical drug blood level vs. time curve / profile for
extra vascular administration of a single dose of the
conventional dosage form of a drug following one –
compartment open model for disposition:
Absorption
phase Toxic range

IV rout
MTC /
MSC
Rate of drug input
= Rate of drug output Therapeutic
range

MEC

Ineffective
range

Time
Typical drug blood level – time profile for multiple dosage
(non–immediate–release) regimen (equal doses of the
drug at fixed intervals) of a conventional dosage form:

A) For time intervals allowing complete elimination of the

previous dose: A series of isolated single dose profiles
are obtained

MSC

MEC

Dose Dose Dose

Time
B) For the dosing time intervals shorter than the time required
for complete elimination of the previous dose:
MSC

MEC

D D D D D D D D
Time

At the start of the multiple dosage regimen, the blood levels of drug tends
to increase in successive doses. But the rate of drug elimination will
increase as the average blood level of drug rises (first order kinetics) and a
situation is eventually reached when the overall rate of elimination of drug
becomes equal to the overall rate of supply. This situation is called “Steady
State”.
For a drug administered at equal time intervals, the time required
for the average blood levels to reach the 95% of the steady state value is
4.3 times the biological half–life (t½) of the drug. The corresponding figure
for 99% is 6.6 times.
Advantages of Conventional Dosage Form:

1. Per unit cost of conventional dosage form is less

than non-immediate release dosage form.
2. More flexibility for the physician for adjusting
dosage form in conventional dosage form.
3. Conventional dosage form can accommodate the
patient variation.
4. No problems with drug having too small half life.
5. Potent drugs can’t be formulated as sustained
release dosage form.
Limitations of Conventional Drug Therapy:

1. Unable to maintain therapeutic blood level for a prolonged

period of time.
2. Fluctuation of blood level over successive dosing intervals
(giving peak and valley pattern).
3. Risk of over medication or under-medication because of
drug blood level fluctuation.
4. Require frequent dosing Patient inconvenience + Poor
patient compliance Therapeutic failure / Inefficiency.

5. No therapeutic action during overnight no dose period

Risk of symptom break through in chronic disease.
6. Total amount of drug required is higher over the entire
course of therapy. (compared to SRDF)
7. Local/systemic side effect + overall health care cost is high.
Non-Immediate Release Dosage Form
Non-immediate release dosage form is those which do not
release whole amount of drugs contained, immediately after
administration.

Why Non-Immediate Release Dosage Form?

a) Delayed release of an immediate release unit. Ex: Enteric
coated tablet or capsule.
b) Repetitive intermittent release of two or more immediate
release unit incorporated into a single dosage form. Ex:
Repeat action tablet or capsule.

***Although a repeat action dosage form exhibits the same

“peak and valley” pattern as associated with conventional
dosage forms, but it improves patient compliance by reducing
dosing frequency.
Types of Non-Immediate Release
Dosage Form :

1. Delayed release dosage form

2. Sustained release dosage form
a) Control release
b) Prolonged release
3. Site specific release dosage form
4. Receptor release dosage form
Site–Specific Release and Receptor–
Release Dosage Forms

Site–specific and receptor release dosage

forms offer targeted delivery of a drug directly
to a certain biological location.

In case of site–specific release dosage

forms, the target is the specific receptor for
the drug within an organ or tissue.
Sustained Release Dosage
Forms
Sustained release dosage
forms are those dosage forms
which are designed to release
drug continuously at sufficiently
slow or controlled rate over an
extended period of time to provide
prolonged therapeutic effect.
In case of oral dosage forms, this
period is usually measured in
hours. But in case of injectable
dosage forms, the period may
range from days to months or even
years.
Sustained release dosage forms can further
be categorized as:
a) Controlled release dosage forms: those
sustained–release dosage forms which are
designed to release drug at a sufficiently
controlled rate to maintain a constant blood
level over an extended period of time.
b) Prolonged release dosage forms: which
cannot maintain a constant blood level, but the
blood level declines at such a sufficiently slow
rate that it remains within the therapeutic
range for a satisfactory prolonged period of
time.
 MSC

MEC
A
B

Time (hrs)

Fig: The blood level–time profile of (A) Controlled–

release (B) Prolonged–release dosage form
Criteria of a Drug Required for Designing as
Sustained Released Dosage Form:
• They exhibits neither very slow nor very fast
rates (t½<2hrs) of absorption and excretion.
[Drugs having biological half lives of between 4 &
6 hours make good candidates in sustained –
release formulations.]
• They are uniformly absorbed from the GIT.
• They are administered in relatively low dose.
• They are used in the treatment of chronic rather
than acute conditions.
• They possess a good margin of safety.
[Accidental dose dumping from potent drugs may
be strongly hazardous.]
 Formulation Methods for Oral SRDF
Common methods used in the design of orally
administered SDRF include three general principles:
A. Barrier principle
1. Reservoir systems or devices
2. Osmotic Pumps or Systems
B. Embedded matrix principle
1. Matrix Systems or Devices
C. Physico-chemical Modification
1. Ion–Exchange Resin Complexes
2. Other Drug Complexes
3. Drug Adsorbates
4. Prodrugs
1. Reservoir Systems or Devices (Barrier Principle)
These systems or devices consists of a core of drug
material is surrounded by a coat of retardant
barrier (polymeric membrane). The layer of
retardant material separates the drug and the
elution medium.

AD
C

Drug
Reservoir
B A
Mechanism of drug release from a reservoir device:
The release of drug from the reservoir can occur by four
mechanisms:
• i. Diffusion of drug present in the reservoir as a solution or
suspension through the barrier. Here the barrier is
impermeable to the elution medium. For the case of
solution , the release is first order. For suspensions,
release is zero order if membrane diffusion is slower than
dissolution. This principle has been successfully applied in
the development of ophthalmic , intra–vaginal and
transdermal controlled release devices.
• ii. Penetration / permeation of elution medium through the
barrier occurs followed by dissolution of the drug in the
reservoir. Later diffusion of the dissolved drug through the
barrier results in availability of drug for absorption.
• iii. Timed erosion of the barrier after sufficient moisture /
elution medium has permeated the membrane.
• IV. Rupture of the barrier after sufficient moisture has
permeated the membrane.
Common methods employed to develop
reservoir systems/devices Include:
A. Coating
B. Microencapsulation
A. Coating: A number of reservoir devices
can be prepared by applying the
technology of coating which includes:
a. Mixed release coated granules/ pellets
b. Uniform release coated granules/ pellets
c. Microdialysis cells
d. Drug coat of retardant material over
placebo pellets
a. Mixed release coated granules
Drug pellets/ granules are divided into 3 to 4
groups. One group is left uncoated to provide
the initial loading dose and the other groups of
pellets/ granules are coated to different
thicknesses. The various groups are mixed
together and placed in capsules or compressed
into tablets.

Mechanism of drug release: Moisture

penetration through the barrier→ swelling of the
core → rupture of the barrier.
The retardant materials used for coating
includes:
-Combination of waxes, fatty acids, alcohols and
esters.
-Enteric materials such as cellulose acetate
phthalate and formalized gelatin.
-Mixture of solid hydroxylated lipids such as
hydrogenated castor oil or glyceryl trihydroxy-
stearate mixed with modified celluloses.

Examples of drugs designed as SRDF by this

method include Erythromycin, Pancreatin etc.
b. Uniform release coated granules / pellets
In this method, drug granules / pellets are
uniformly coated by a retardant material that
slowly release drug over sufficiently prolonged
period of time.
Retardant materials employed for this purpose
include hydrolyzed styrene maleic acid
copolymer, partially hydrogenated cotton seed oil
etc.
Examples of drugs designed as SRDF by this
technique include Crystals of ascorbic acid,
Methylprednisolone etc.
c. Microdialysis cells
Drug pellets are coated with a mixture of ethyl
cellulose (a water insoluble and pH insensitive
polymer) and sodium chloride particles or some other
water soluble materials (e.g. polyethylene glycol).
Release mechanism: Ethyl cellulose when in contact
with GI fluid, the water soluble material will dissolve
and salt will leach out forming pores which acts as a
dialytic membrane. The elution media then permeates
through dialytic membrane causing dissolution of the
drug and the drug solution then diffuses through the
essentially intact membrane.
Examples of drugs designed as SRDF by this technique
are Nitroglycerin, Propoxyphene, Aspirin etc.
d. Drug coat of retardant material over placebo
pellets
The drug is suspended in the coating of retardant
material applied onto placebo pellets. The
prepared pellets are placed in capsules. The drug
is released by erosion or rupture of the barrier.
Retardant materials employed include
polyethylene glycol, modified ethyl cellulose,
shellac or cellulose acetate phthalate.
Example of drugs designed as SRDF by this
technique is theophylline.
B. Microencapsulation:
Microencapsulation means encapsulation of drug
material in microscopic size particles of a ‘wall
forming’ material.
Microencapsulation is a process by which solids,
liquids or even gases may be encapsulated into
microparticles whose size ranges from several
tenths of 1µ to 5000µ in size through the formation of
thin coating of wall material around the substance
being encapsulated.
Retardant coating materials used are gelatin,
polyvinyl alcohol, ethyl-cellulose, polyvinyl chloride.

The most common method of microencapsulation is

coacervation. Other techniques like, spray drying.
Coacervation: In this technique, the prospective
wall–forming material e.g. gelatin, is dissolved in
water. The drug material to be microencapsulated is
added to the solution and the two–phase mixture is
thoroughly stirred until the drug material is broken up
to the desired particle size.
Then a solution of a second material (usually acacia)
is added which concentrates gelatin into tiny liquid
droplets called “coacervates” that encircle drug
particles.
The particles are coated to different thicknesses,
mixed together and compressed into tablets or
placed in capsules.
The drug is released by dissolution of coating
materials.
Applications of microencapsulation:
• For masking test, (acetaminophen tab)
• To reduce gastric irritation (KCl)
• To separate the incompatible ingredients
(Aspirin tab)
• To prevent volatilization (menthol)
• To protect drugs from moisture and oxidation
(vit A palmitate)
Disadvantages:
• Incomplete or discontinuous coating
• Inadequate stability
• Economic limitations
Examples : Micro – K ( KCl )
2. Osmotic Systems / Pumps (Barrier Principle)
This is an example of membrane- controlled release
technology. These systems employ osmotic pressure as the
driving force to cause the release of drug. A constant release of
drug can be achieved if a constant osmotic pressure is
maintained and a few other features of the system are
controlled.

A number of osmotic pumps / systems have been designed by

pharmaceutical manufacturers including:
1. Oral Osmotic Systems
2. Push – Pull Osmotic System
3. Multi Directional Osmotic Drug Absorption System
Mechanism of Drug Release: GI fluid enter the
tablet core across the semi-permeable membrane →
dissolve drug→ creates an osmotic gradient across
the membrane →pumps the drug out through the
delivery orifices.
The rate of drug solution release is approximately
one to two drops per hour.
1. Matrix Devices (Embedded Principle)
• In this case, the drug is dispersed (embedded) in
a matrix of retardant material, which may be
encapsulated in particulate form or compressed
into tablets. The drug may be insoluble (Network
model) or soluble (Dispersion model) in the
retardant material.
Among the innumerable method used in controlled
release drug from pharmaceutical dosage form,
the matrix system is the most frequently applied;
it’s release system for delay and control of the
release of the drug that is dissolved or dispersed
in a resistant supports to disintegration.
 Fig. Network model (Drug is
insoluble in the retardant material)

Fig. Dispersion model (Drug is

soluble in the retardant material)
To define matrix, it is necessary to know the characters
that differentiate it from other controlled release
dosage forms. Hence the following must be
considered:
• The chemical nature of support (generally, the
support are formed by polymeric net)
• The physical state of drug (dispersed under
molecular or particulate form or both)
• The matrix shape and alteration in volume as a
function of time.
• The route of administration (oral administration
remains the most widely used but other route are
adaptable)
• The release kinetic model.
 Types of matrix material/devices:
On the basis of the solubility of the materials matrix
devices can be classified into two:
1. Matrix may be soluble: Hydrophilic polymers
2. Matrix may be insoluble:
a. Insoluble polymer matrix (plastic matrix)
b. Lipid matrix
c. Insoluble but potentially erodable matrix
1. Soluble Matrix: (Hydrophillic Matrix)
Drug can be dispersed in soluble matrix and drug
release depends on slow dissolution of the matrix by
elution media. This delivery system is also called
swellable soluble matrix.
In general they comprise a compressed mixture of
drugs and water swellable hydrophilic polymer. The
systems are capable of swelling, followed by gel
formation, erosion and dissolution in aqueous media.
Hydrated matrix layer on contact of water further
controls the diffusion of water. When outer layer is
fully hydrated, it erodes and drug contained is
released. Thus, drug diffusion and tablet erosion
controls the rate of drug release.
Hydrophilic materials: e.g. Hydroxy propyl
methyl cellulose, sodium CMC,
methylcellulose, Hydroxy ethyl cellulose.
Natural gums: Galactomannose (guargum),
chitosan, gum acacia, locust bean gum,
sodium alginate, karaya gum, pectins, xanthan
gum.
Examples of Drugs:
Sodium diclofenac
Oramorph SR tablets (Morphin sulfate)
 2. Insoluble matrix
a. Plastic or “Skeleton” matrix: These are insoluble
inert polymers such as polyethylene, polyvinyl
chloride, methyl acrylate-methacylate copolymer
and ethyl cellulose. The mixture of drug and ground
polymer may be directly compressed into tablets.
• Release mechanism: Drug is slowly released from
the inert matrix by diffusion following liquid
penetration. If channeling agent is used, diffusion
occurs through channels. Release rate can be
modified by changes in the porosity (pore-forming
salts) and compression force of the matrix.
This occurs when the matrix is insoluble in water, and
the drug is insoluble in the matrix but soluble in water.
• b. Lipid matrix: These are also water
insoluble matrix. Here drug delivered by
diffusion or by surface erosion.
Release mechanism: In this model, it is
assumed that drug is released by primarily
diffusion of drug through the matrix and
secondarily partition between matrix and water.
This occurs when the matrix is insoluble in
water, but the drug is soluble in the matrix and
has a high solubility in water/elution media.
c. Insoluble erodable matrix: This matrix is water
insoluble but potentially erodable. The matrix
includes waxes, lipids and related materials.
Examples include carnauba wax, castor wax
(hydrogenated castor oil) and triglycerides.
• The drug and additives are generally depressed in
molted wax, which is then congealed, granulated
and placed into capsules and compressed into
tablets. The loading dose is provided as untreated
granules or as an outer core.

Release mechanism: In this model, it is assumed

that solid drug dissolves from the surface layer of
the device first; when this layer completes
delivering drug, the next layer begins to be
depleted by dissolution and diffusion through the
matrix to the external solution.
 Factors influencing the drug release from
matrix
• Choice of matrix material.
• Amount of drug incorporated in the matrix.
• Viscosity of the hydrophilic material in aqueous
system at a fixed concentration.
• Drug: matrix ratio.
• Tablet hardness, porosity, and density variation.
• Tablet shape and size.
• Solubility of drug in aqueous phase.
• Surfactants and other additives.
 Advantages of matrix devices
1. With proper control of the manufacturing process, reproducible
release profiles are possible. The variability associated with them
is slightly less than coated release form.
2. Structure allows an immediate release of small amount of active
principle, there is no risk of dose dumping.
3. Their capacity to incorporate active principle is large, which suits
them to delivery of large doses.
4. The manufacturing processes are notably simple. Tablet
formulation can be done via direct compression or by wet
granulation techniques.
5. Large variety of non-expensives gelling agents is approved for
oral use by the competent official organization.
6. The safety margin of high-potency drugs can be increased.
7. The drug release from hydrophilic matrices show a typical time
dependent profile i.e. decreased drug release with time because
of increased diffusion path length.
4. Ion – Exchange Resin Complexes
Ion – exchange resins are water insoluble polymers
containing salt forming groups on the polymer chain.

Resins used are special grades of styrene / divinyl

benzene copolymers that contain substituted acidic
groups (carboxylic and sulfonic for cation
exchanges) or basic groups (quaternary ammonium
for anion exchanges).

Drug is bound to the resin by repeated exposure of

the resin to the drug in a chromatographic column or
by prolonged contact of the resin with the drug
solution.
For example, drug-resin salts may be prepared by percolation of
the sodium salt of the resin with a concentrated solution of a drug
hydrochloride salt. The following equation represents the drug
release in-vivo:
Resin – SO3Na + Drug HCl → NaCl + Resin-SO3. Drug H

Similarly drug-resinates are prepared by reaction of sodium salts

of acidic drugs with resin chloride.
Resin – NH4Cl + Drug Na → NaCl + Resin-NH4. Drug

The resin.drug complex is then washed with ion-free water and

dried. The resulting product can be encapsulated, tabletted or
suspended in ion-free vehicles.

Release in-vivo :
Resin – NH4.Drug + NaCl (body fluid) → Drug Na + Resin-NH4Cl
5. Other Drug Complexes
Certain drug substances that are only slowly soluble in the body
fluids are inherently long acting (Griseofulvin).
Thus drugs that are, high water soluble may be bound to
suitable complexing agents to form complexes which are poorly
water soluble and consequently give sustained action.
The steps or mechanism involved in controlling the
release of drug from drug complexes in GI fluid can be
illustrated as follows:
Dissolution Dissociation
DC . solid DC . solution D
Examples include:
Tannic acid complexes of basic drugs like amphetamine and
antihistamines.
Other complexing agents to prepare complexes of basic drugs
include polygalacturonic acid, algenic acid and arabogalactose
sulfate.
6. Drug Adsorbate
Drug adsorbates represent a special case of complex
formation in which the product is essentially insoluble.

Drug availability is determined only by the rate of dissociation

(desorption) and access of the adsorbent surface to water as
well as the effective surface area of the adsorbate.

The mechanism involved in controlling the release of drug from

adsorbates can be illustrated as follows:

Desorption
AD. Solid D

The adsorbate, can be formulated as liquid suspensions,

tablets or capsules.
7. Prodrugs
Prodrugs are therapeutically inactive drug derivatives
that regenerate the parent drug in-vivo by enzymatic or non-
enzymatic hydrolysis.
The steps or mechanisms involved in controlling release of
drug from a prodrug can be depicted by the following scheme:

Desorption Absorption
PD. Solid PD. Solution PD. Plasma

Metabolism

Elimination
 PARENTERAL SUSTAINED RELEASE
PARENTERALS
Para: outside
Enteron: intestine (i.e. beside the intestine)
These are the preparations which are given other
than oral routes.

For a variety of reasons, the most notable being

physiological and anatomical constraints, not all of
these are useful as routes for controlled drug
delivery.
Up to the present, efforts in developing controlled
release parenteral dosage forms seems to have
concentrated the subcutaneous and intramuscular
routes, resulting in such products as aqueous and
oil solutions, and implants.
There are currently a number of injectable depot
formulations on the market.
• Penicillin G procaine suspensions
• Fluphenazine enanthate and decanoate in oil
solution
• Insulin-zinc suspensions
 Mechanism of drug release
 When these formulations are injected into
subcutaneous or muscular tissues, A depot is formed at
the site of injection which acts as a reservoir for drug.
 Drug Molecules will be released continuously from the
reservoir at a rate determined by the characteristics of
each formulation.
 This continuous release of drug molecules will result in
a prolonged drug blood level.
The rate of drug absorption and hence duration of
therapeutic activities will be determined by:
• The nature of the vehicle
• The physicochemical characteristics of the drug
• The interaction of drug with vehicles and tissues/fluid
 Significance
• The scientists are leaned towards depot formulations
because of the advantages these delivery system possess
which include :
– Ease of application,
– Localized delivery for a site-specific action in the body,
e.g. in local anesthesia/analgesia
– Reduced dosing frequency without compromising the
effectiveness of the treatment
– Increased dosing compliance,
• Examples of applications for prolonged release parenteral
delivery include: fertility treatment, hormone therapy, protein
therapy, infection treatments (antibiotics and antifungals), cancer
therapy, chronic and postoperative pain treatment, vaccination/
immunization, treatment of CNS disorders, and immunosupression.
 Types of depot formulation
Ø Dissolution controlled depot preparation:
 In this type of formulation the rate of drug absorption

controlled by slow dissolution of drug particle in the

formulation or in the tissue fluid.
 There are two approaches that can be utilized to control the

dissolution of solid drug to prolong absorption.

1. FORMATION OF SALT COMPLEX WITH LOW AQUEOUS SOLUBILITY
2. SUSPENSION OF MICRO CRYSTALS.
Ø Adsorption type depot preparation:
 This type of depot preparation is produced by binding of drug

molecules to adsorbents. In this case only unbound, free

species of the drug is available for absorption.
Ex. Vaccine preparation in which the antigens are bound to
highly dispersed aluminum hydroxide gel.
Ø Encapsulation type depot preparation:
 This type of preparation is formed by encapsulating drug
solids within a diffusion barriers or dispersing drug
particles in diffusion matrix.
 Release of the drug molecules is controlled by diffusion
barrier and the rate of biodegradation of microcapsules.
 e.g. Nitroxone pamoate releasing biodegradable
microcapsules.
Ø Esterification type depot preparation:
 This type of depot preparation is formed by synthesizing
the bioerodible esters of a drug and then formulating it in
an injectable formulation, which forms a drug reservoir at
the site of injection.
Ø Testosterone cypionate
Ø Fluphenazine enathate
SUSTAINED RELEASE PARENTERAL DOSAGE
FORMS
 A. AQUEOUS SOLUTION

1. HIGH VISCOSITY PRODUCTS

Increasing viscosity of the vehicle, the diffusion
coefficient of the drug will be reduced, thereby
delayed in drug transport.
Viscosity agents:
1. Methyl cellulose
2. Sodium carboxymethyl cellulose
3. Polyvinyl Pyrollidine.
2. COMPLEX FORMATION
The role of plasma protein and tissue binding in
prolonging drug action is well known. Constant
fraction of drug is complexed and that only free drug
is absorbed
 C. SUSPENSION
 They should be sterile, pyrogen free, stable, resuspendable,
syringable, injectable, isotonic & non-irritating.
 It is better for the therapeutic use of drugs that are insoluble in
conventional solvents.
 In this dosage form there is increased resistance to hydrolysis
& oxidation as drug is present in the solid form.
 Parenteral suspension also limit the formulator in what
ingredients are parenterally acceptable as suspending agent,
viscosity induce, wetting agent, stabilizers and preservative.
 Some of the official preparations are;
1) Tetanus toxoid adsorbed USP '95 - Aq. Suspension.
2) Insulin Zinc suspension USP 95 Aq. suspension.
 D. EMULSIONS
It is recommended that emulsions designed for the intravenous
(IV) route have a submicron droplet size.
i) As drug targeting systems
Emulsions are helpful to deliver drug at particular site, active
targeting may be achieved by conjugating antibodies to the
distal ends of the polyoxyethylene chain emulsifiers, provided
the emulsion droplets have a submicron droplet size.
ii) Reduces drug toxicity
Water in oil emulsion of amphotericin deoxycholate, reduces
the incidence and severity of renal impairment and chills in
patients while still maintaining the antifungal efficacy of the
drug.
MAGNETIC EMULSION: The emulsion described is a
magnetically responsive oil-in-water type emulsion with capacity
to localize the chemotherapeutic agent by application of an
electromagnet.
 E. LIPOSOMES
LIPOSOME STRUCTURE
 Bilayered structure of phospholipids and cholesterol

 Capable of entrapping both water soluble and lipid soluble drugs

 Can alters bio-distribution; protect drug and body from each other

 Special liposomes usable for target delivery

SUSTAINED EFFECT
 Encapsulation of drug into multi-vesicular liposomes offers a

novel approach to sustained release drug delivery over several

days to weeks.
 Drug into unilamellar and multilamellar liposomes and
complexation of drug with lipids, resulted in products with better
performance, lasting several hours to a few days after
intravascular administration. 
 APPLICATION OF LIPOSOMES
Liposomes are the most widely studied modern drug delivery system
because of its amazing application for the management of following
diseases:
i) Liposomal anticancer agent - In one study it has been reported that
in patients, liposomal doxorubicin accumulates within sarcoma
lesions and produces a good therapeutic response. This formulation
is currently in clinical trials for ovarian cancer patients who have
failed to respond to paclitaxel and cisplatin
ii) Liposomes as vaccine adjuvants - Liposomal vaccines can be made
by associating microbes, soluble antigens, cytokines or
deoxyribonucleic acid (DNA) with liposomes, the latter stimulating
an immune response on expression of the antigenic protein.
iii) Liposomal anti-infective agents - It was observed in one study that
liposomal amphotericin B, by passively targeting the liver and
spleen, reduces the renal and general toxicity of the drug at normal
doses.
 F. NIOSOMES
Differs from liposomes in having surfactant in place of
phospholipid. They can be used in the treatment of cancer
and also used as vaccine adjuvant. Some of its
applications are discussed here:
i) Anticancer niosomes - Niosomal encapsulation of
methotrexate and doxorubicin increases drug delivery to
the tumour and tumoricidal activity.
ii) Niosomes at targeted site - Uptake by the liver and
spleen make niosomes ideal for targeting diseases
manifesting in these organs. Niosomal formulations of
sodium stibogluconate improve parasite suppression in the
liver, spleen and bone marrow.
iii) Niosomes as vaccine adjuvants - It was studied that
niosomal antigens are potent stimulators of the cellular and
humoral immune response.
 H. MICROSPHERES
1. Microcapsules and 2. Micromatrices
1. Microcapsules
• They are spherical particles containing drug
concentration in the center core, which is enveloped by
polymeric wall (rate controlled membrane).
2. Micromatrices
• Micromatrices are solid, spherical particles containing
dispersed drug molecules either in solution or in
crystalline form.
• The microsphere release drug in a zero order fashion
over 1 to 3 months after intramuscular or subcutaneous
injection into animals.
PREPARATION OF MAGNETIC MICROSPHERES: It is made
by preparing an aqueous mixture of water soluble drug or if
lipophilic drug, add water soluble adducting agent
(cyclodextrin), matrix material (albumin, carbohydrate and
10nm Fe3O4 particle).
INTERLEUKKIN-2 (IL-2): Inerleukin-2 is glycoprotein,
activates multiple cell types-T helper cells, Cytotoxic T-
lymphocytes, Natural killer cells, Macrophases.
It is useful in Murine tumors and human melanomas and renal
cell carcinomas. But IL-2 cleared from the plasma in 5 min.
High dose produce severe side effects - Anemia, Fever,
Hypertension, Jaundice.
Due to above reason Scientist has prepared controlled release
form of IL-2 that is adaptable for magnetic targeting to tumor.
 I. IMPLANT
Implant represents novel approach in the use of solid
dosage forms as parentral product. This method finds
particular applicability to cases where chronic
administration of drug over period ranging from days to
years.
Ø Risk Factor: Danger of toxic effect in case of leakage or
burst release of drug.
PREPARATION OF IMPLANT
Many polymers can be used to prepare rate-limiting
membrane for controlled release; few are employed for
implantation purpose.

The implantable polymers should be biocompatible and

sterilizable, such as Hydrogels, Silicones, Polyethylene
and biodegradable polymers.
 APPLICATIONS
1. CANCER - Silicone rod implants used for delivery of
levonorgestrone have been evaluated for delivery of
testosterone propionate or ethinyl estradiol in patient with
prostate cancer.
2. CONTRACEPTION - Nor plant, a subdermal implant for long
term delivery of the contraceptive agent, levonorgestrel has
recently been approved by FDA.
3. OCULAR DISEASE - Ocusert is the example of membrane
controlled system containing pilocarpine base and alginic acid
in a drug reservoir surrounded by a release rate controlling
ethylene vinyl acetate membrane.
It is designed to permit the tear fluid to penetrate the
macroporous membrane to dissolve and to carry out
pilocarpine at a constant rate of 20 to 40 µg/hr for weekly
management of glaucoma.
 FUTURE ASPECTS
Phase I pharmacokinetic-pharmacodynamic studies are
ongoing for microsphere formulation of progesterone to
establish the minimum effective dose of progesterone
microspheres suspension, for weekly intramuscular injection.
SABER is a potential parenteral in situ-forming system,
SABER-bupivacaine is designed to continuously deliver
bupivacaine up to 72 hours to treat local post-surgical pain. This
system injected at the surgical site prior to the wound closure
and is currently in Phase III clinical studies in the US.
OncoGel (BTG) is supplied as a frozen formulation of
paclitaxel in ReGel and is entering Phase II trials. OncoGel is
being injected directly into the tumor for oesophageal tumors,
and the gel disappears in four to six weeks as it releases the
paclitaxel.
 USP Requirements and FDA Guidance for
Sustained Release Dosage Forms:
The USP contains general chapters and specific tests to
determine the drug release capabilities of sustained release
tablets & capsules.
Release of Drug: The USP test for drug release for sustained
release dosage forms in based on drug dissolution from the
dosage unit against test time. According to USP the individual
monographs contain specific criteria for compliance with the test
and the apparatus and test procedures to be release tablets.

Uniformity of Dosage Units: Modified release tablets &

capsules must meet the USP standard for uniformity for
conventional dosage units. Uniformity of dosage units may be
demonstrated by either of two methods, weight variation or
content uniformity.
In vitro-In Vivo Correlations: In vitro-in vivo relationships
(IVIVRs) or in vitro-in vivo correlations (IVIVCs) one critical
to the development of oral sustained release products.
Asserting (IVIVCs) is important through out product
development, clinical evaluation, submission of an
application for FDA approval for marketing and during post
approval for any proposed formulation or manufacturing
changes.
In 1997, The FDA published a guidance document,
sustained release Oral Dosage Forms: Development,
Evaluation and Application of in-Vitro / in-Vivo
Correlations.

It provides guidance to sponsors of new drug applications

(NDAs) for sustained release oral products.
Labeling:
The USP indicates labeling requirements for modified-
release dosage form in addition to general labeling
requirements. The requirements are specific to the
monograph article.
For example, the label of Aspirin Delayed
release tablets must state that, the tablets are enteric
coated.
The labeling for Theophylline extended release
capsules must indicate whether the product is
intended for every 12 or 24 hours and state with which
in vitro drug release test are described in the
monograph.
 IN VITRO EVALUATION OF SUSTAINED
RELEASE DOSAGE FORMS
The in vitro evaluation of sustained release
dosage forms is not sufficient for establishing
the efficacy of a new sustained release
dosage form.
This type of evaluation is commonly performed
for two purposes:
A. To ensure the batch-to-batch uniformity of
a proven dosage form (quality control)
B. To serve as a guide to the development of
a new formulation (prior to clinical testing)
 A. In Vitro Evaluation for the Purpose of
Quality Control
 For this purpose, USP dissolution testing
methods are usually employed using the
rotating basket, the paddle or the modified
disintegration testing apparatus.
 Simulated gastric and intestinal fluids are
used as the release media.
 Complete release profile usually is not
measured unless automated technique is
employed.
 B. In Vitro Evaluation for the Purpose of
Formulation Development
In this case, the testing methods are designed to
study the various aspects of the release profile
to verify whether the observed release profile fit
the expectations.
The various aspects of the release profile
studied include:
1. The rate and extent of release from the
maintenance dose. (Does it involve dose
dumping or insufficient drug release?)
2. Fraction of the dose released in the projected
time schedule.
3. Delay in the onset of drug release from the
maintenance dose
4. The effect of GI variables on drug release
5. The effect of process variables on drug release
6. Unit-to-unit variation (predictability of the release
profile)
7. Stability of the release profile.
(The long-term release profile of sustained
release dosage forms may change upon storage
because of their complex multi-component
nature and special types of physical changes
that may occur in some of their ingredients.)
 The analytic technique should be
automated so that the complete release
profile can directly be recorded.

 There should be provision for changing

the release medium from simulated
gastric fluid to simulated intestinal fluid
at variable programmed time intervals.
 There should be provision for controlling and
varying the hydrodynamic state in the
dissolution vessel. (For disintegrating or
erodible units, the measurements should be
made at various flow rates to generate a
release profile that will cover projected
release time in vivo.)
 Appropriate GI components should be added
to the release medium if the formulation
contains retardants whose function depends
on such components as bile salts, pancreatin,
pepsin etc.
 Testing equipment employed in this type
of evaluation include:
– USP dissolution testing apparatus
– Rotating bottle
– Stationary basket/ Rotating filter
– Sartorius absorption and solubility
simulator
– Column type flow-through assembly
Comparison between conventional and sustained-release drugs

Conventional Drug Therapy Sustained-Release Drug Therapy

1. Rapid and complete release of 1. Slow/controlled release of drug over

drug immediately after
administration.
2. Absorption is the rate-limiting
step (kr >>> ka).
3. Blood level fluctuates (Peak and
Valley).
4. There is risk of overmedication
or under medication at periods
of time.
5. Frequent dosing.
6. Patient non compliance.
Therapeutic inefficiency / failure.
7. Inconvenience of patient.
an extended period of time.
2. Drug release from the dosage form is
the rate-limiting step (ka >>> kr ).
3. Constant blood level is maintained
over a prolonged period (Reduced
fluctuation).
4. Reliable therapy as the risk is
minimized.
5. Reduced frequency of dosing.
6. Improved patient compliance.
7. Enhanced patient convenience with
day-time and night-time medication.
8. No therapeutic action during
overnight no dose period.
9. Risk of symptom breakthrough.
10. Incidence and severity of
untoward effects related to high
-peak plasma concentration .
11. More total dose over the entire
course of therapy.
12. More side effects.
13. Health care cost .
14. Permits prompt testing of
therapy.
15. Incidence of severity of GI side
effects due to dose dumping of
irritant drugs .
16. More flexibility for physician in
adjusting dosage required.
8. Maintains therapeutic action during
overnight no dose period.
9. Improved treatment of many chronic
diseases (minimizing symptom
breakthrough).
10. Incidence and severity of untoward
effects related to high – peak plasma
concentration .
11. Less total dose over the entire
course of therapy.
12. Minimize/eliminate incidence of
local/systemic side effects.
13. Health care cost .
14. Does not prompt.
15. Incidence of severity of GI side
effects due to dose dumping of irritant
drugs .
16. Less flexibility.
17. Can accommodate abnormal
cases of disease safety offering
drug disposition etc.
18.  Chance of at any site of GIT
(local irritation ).
19. No problems for drugs with too
short half lives.
20. Per unit cost is less. 
21.
Time
17. Can not accommodate.
18.  Chance of at any site of GIT (local
irritation).
19. Not suitable for drugs with too short
half lives, drugs needing specific
requirements for absorption from GIT.
20. Per unit cost is more. 
21.
Time