Drug Delivery Systems: Pharmaceutical Technology Petra University. 1

Drug Delivery Systems
Pharmaceutical
technology Petra University. 1
Content
 Introduction page 3
 Oral drug delivery systems page 16
 Nasal drug delivery page 124
 Pulmonary drug delivery page 144
 Transdermal delivery page 181
 Parenteral delivery Page 200
Student Evaluation
Midterm exam 40
Homeworks and participation 20
Final Exam 40
2
Introduction
3
Drug Delivery
 Drug delivery is the method or process of
administering pharmaceutical compound to
achieve a therapeutic effect in humans or
animals.
 Most common methods of delivery include the

preferred non-invasive peroral (through the
mouth), topical (skin), transmucosal (nasal,
buccal, sublingual, vaginal, ocular and rectal)
and inhalation routes.
4
Drug Delivery
 Many medications such as peptide and protein,
antibody, vaccine and gene based drugs, in
general may not be administered using these
routes because they might be susceptible to
enzymatic degradation or can not be absorbed
into the systemic circulation efficiently due to
molecular size and charge issues to be
therapeutically effective.
 Protein and peptide drugs have to be delivered

by injection.
5
Why do we need NDDS?
 The conventional dosage forms provide drug
release immediately and it causes fluctuation
of drug level in blood depending upon dosage
form.
 Therefore to maintain the drug concentration

within therapeutically effective range need
novel drug delivery system.
6
Novel Drug Delivery System
 “Novel Drug delivery System (NDDS) refers
to the approaches, formulations, technologies,
and systems for transporting a
pharmaceutical compound in the body as needed
to safely achieve its desired therapeutic effects.
It may involve scientific site-targeting within the
body, or it might involve facilitating systemic
pharmacokinetics; in any case, it is typically
concerned with both quantity and duration of
drug presence”.
7
 Novel Drug delivery is often approached via a
drug's 1) chemical formulation, but it may also
involve 2) medical devices or 3) drug-device
combination products. Drug delivery is a concept
heavily integrated with dosage form and route of
administration.
 NDDS is advanced drug delivery system which 1)
improves drug potency, 2) control drug release
to give a sustained therapeutic effect, 3) provide
greater safety, 4) finally it is to target a drug
specifically to a desired tissue.
8
 NDDS is a system for delivery of drug other
than conventional drug delivery system.
 NDDS is a combination of advance technique

and new dosage forms which are far better
than conventional dosage forms.
9
Advantages of NDDS
 Optimum dose at the right time and right
location.
 Efficient use of expensive drugs, excipients
and reduction in production cost.
 Beneficial to patients, better therapy,
improved comfort and standard of living.
10
Modes of NDDS
 Targeted Drug Delivery System
 Controlled Drug Delivery System
 Modulated Drug Delivery System
11
Sustained Release Vs
Controlled Release
 SR – Release of initial dose & further prolonged release of
drug. Also called extended release, delayed release,
prolonged release. SR means slow release of a drug
substance from a dosage form to maintain therapeutic
response for extended period (8-12hrs). Time depends on
dosage form. e.g., Aspirin SR Tablet, Zuclopenthixol Depot
Injection etc.
 CR – Release of drug in controlled release for long

periods. In this the rate or speed at which the drug is
released is controlled. e.g., Adalat CR (Nifidipine).
12
Sustained Release Vs
Controlled Release
 Sometimes SR is called as controlled
release but all controlled release are not
sustained release.
13
Targeted Drug Delivery
System
 The drug is delivered in such a way that drug
is only active in the target area of the body
(cancerous tissues) in which drug is released
over a period of time in a controlled manner.
e.g., Colon targeted drugs.
 Delivery of drugs to their site of action is one

of the major problem facing the
pharmaceutical industries.
14
Factors affecting NDDS
 Physicochemical properties of a drug
 Route of administration
 Acute / Chronic therapy
 Target sites
 The Patient
 The disease state/level
Homework: (write summary report)
Hamid, R. A. S., Al-Akayleh, F., Shubair, M., Rashid, I., Al Remawi,
M., & Badwan, A. (2010). Evaluation of three chitin metal silicate
co-precipitates as a potential multifunctional single excipient in
tablet formulations. Marine drugs, 8(5), 1699-1715.
15
Oral Drug Delivery System
16
Contents
 Overview of Digestive system
 Introduction
 Advantages
 Disadvantages
 Dissolution
 Diffusion
 Combination of Dissolution & Diffusion
 Osmotic pressure controlled system
 Hydrodynamically balanced systems
 pH controlled
 Ion exchange controlled systems
 References
17
Concept
 Controlled drug delivery is one which delivers

the drug at a predetermined rate, for locally or
systemically, for a specified period of time.
 Continuous oral delivery of drugs at

predictable & reproducible kinetics for
predetermined period throughout the course of
GIT.
18
Controlled Release System
Matrix
Pharmaceutical
Plasma concentration time profile
Pharmaceutical
Challenges in Oral Drug Delivery
 Development of drug delivery system

Delivering a drug at therapeutically effective
rate to desirable site.
 Modulation of GI transit time

Transportation of drug to target site.
 Minimization of first pass elimination

Pharmaceutical
Advantages
 Total dose is low.
 Reduced GI side effects.
 Reduced dosing frequency.
 Better patient acceptance and compliance.
 Less fluctuation at plasma drug levels.
 More uniform drug effect
 Improved efficacy/safety ratio.

Pharmaceutical
Disadvantages
 Dose dumping.
 Reduced potential for accurate dose

adjustment.
 Need of additional patient education.
 Stability problem.
Pharmaceutical
Mechanism aspects of Oral drug
delivery formulation
1.Dissolution : 1. Matrix
2. Encapsulation
2.Diffusion : 1. Matrix
2. Reservoir
3.Combination of both dissolution & diffusion.
4.Osmotic pressure controlled system

Pharmaceutical
Dissolution Definition
 Solid substances solubilizes in a given solvent.
 Mass transfer from solid to liquid.
 Rate determining step: Diffusion from solid to

liquid.
 Several theories to explain dissolution –

Diffusion layer theory (imp)
Surface renewal theory
Pharmaceutical
Limited solvation theory.
Noyes Whitney Equation
dc/dt = kD.A (Cs – C )
dc/dt = D/h A. (Cs – C)
dc/dt = Dissolution rate.

k= Dissolution rate constant (1st order).
D = Diffusion coefficient/diffusivity
Cs = Saturation/ maximum drug solubility.
C =Con. Of drug in bulk solution.
Cs-C=concentration gradient.
h =Thickness of diffusion layer.
Pharmaceutical
Matrix Type
 Also called as Monolith dissolution
controlled system. Soluble drug
 Controlled dissolution by:

1.Altering porosity of tablet.
2.Decreasing its wettebility.
3.Dissolving at slower rate.
Slowly
dissolving
 First order drug release. matrix
 Drug release determined by

dissolution rate of polymer.
 Eg. Dimetane extencaps, Dimetapp

extentabs.
Pharmaceutical
Matrix devices
 In this system the solid drug dispersed in
to the insoluble matrix.
Pharmaceutical
Encapsulation
 Called as Coating dissolution
controlled system.
Soluble drug
 Dissolution rate of coat depends
upon stability & thickness of
coating.
Slowly
 Masks dissolving
colour,odour,taste,minimising or erodible
GI irritation. coat
 One of the microencapsulation

method is used.
 Eg. Ornade spansules,

Chlortrimeton
Pharmaceutical Repetabs
Diffusion
 Major process for absorption.
 No energy required.
 Drug molecules diffuse from a region of higher

concentration to lower concentration until equilibrium is
attainded.
 Directly proportional to the concentration gradient

across the membrane.
Pharmaceutical
Matrix Diffusion Types
 Rigid Matrix Diffusion

Materials used are insoluble plastics such as PVP & fatty
acids.
 Swellable Matrix Diffusion
1. Also called as Glassy hydrogels.Popular for sustaining

the release of highly water soluble drugs.
2. Materials used are hydrophilic gums.
Examples : Natural- Guar gum,Tragacanth.
Semisynthetic -HPMC,CMC,Xanthum gum.
Synthetic -Polyacrilamides.
Examples: Glucotrol XL, Procardia XL

Pharmaceutical
Matrix system
Rate controlling
step:
Diffusion of dissolved
drug in matrix.
Pharmaceutical
Advantage and Disadvantage of
Matrix and Reservoir system
Matrix system Reservoir system

1. Suitable for both non- 1. Degradable reservoir
degradable and degradable systems may be difficult to
system. design.
2. No danger of ‘dose 2. Rupture can result in

dumping’ in case of dangerous ‘dose dumping’
rupture.
3. Achievement of ‘zero
3. Achievement of ‘zero order’ release is easy.
order’ release is difficult
Pharmaceutical
Methods to develop the Reservoir devices
a) Press coating (slowly soluble films and coating)

b) Air suspension techniques
• The microencapsulation process is commonly used procedure
to drug particle incorporated in to tablet or capsule.
• In most cases drug is incorporated in coating film as well as in

the microcapsule.
• The care should be taken during placement into tablet or

capsule dosage forms to minimize fragmentation or fusion of
the particle both effects will alter release characteristics.
Pharmaceutical
Factor effecting constant drug release
• Polymer ratio in the coating
The increase the polymer ratio decrease in drug release due to
leaching effect.
• Film thickness
The drug release rate from an insoluble membrane is expected to
increase as the membrane thickness decreases.
• Hardness of microcapsule
The hardness of microcapsule increase, prolong the time of drug
release.
Pharmaceutical
Higuchi Equation
Q = DE/T (2A.E Cs)Cs.t)1/2
Where ,
Q=amt of drug release per unit surface area at time t.
D=diffusion coefficient of drug in the release medium.
E=porosity of matrix.
Cs=solubility of drug in release medium.
T=tortuosity of matrix.
A=concentration of drug present in matrix per unit
volume.
Pharmaceutical
Reservoir System
 Also called as Laminated matrix device.

 Hollow system containing an inner core surrounded
in water insoluble membrane.
 Polymer can be applied by coating or micro
encapsulation.
 Rate controlling mechanism - partitioning into
membrane with subsequent release into surrounding
fluid by diffusion.
 Commonly used polymers - HPC, ethyl cellulose &
polyvinyl acetate.
 Examples: Nico-400, Nitro-Bid
Pharmaceutical
Reservoir System
Rate controlling
steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.
Pharmaceutical
Dissolution & Diffusion
Controlled Release system
 Drug encased in a partially soluble
membrane. Insoluble
membrane
 Pores are created due to dissolution
of parts of membrane. Entry of
dissolution
fluid
 It permits entry of aqueous medium
into core & drug dissolution. Drug
diffusion
 Diffusion of dissolved drug out of
system. Pore created by
dissolution of
 Eg. Ethyl cellulose & PVP mixture soluble fraction of
dissolves in water & create pores of membrane
insoluble ethyl cellulose membrane.
Pharmaceutical
Osmotic Pressure Controlled
Drug Delivery System
Pharmaceutical
Introduction
 The oral drug delivery has been popular most widely
utilized route of administration among all the routes that
have been explored for the systemic delivery of drugs.
 The bioavailability of drug from these formulations may

vary significantly, depending on factors such as physico-
chemical properties of the drug, presence of excipients etc.
 The drug release can be modulated by different ways but

the most of novel drug delivery systems are prepared using
matrix, reservoir or osmotic principle.
Pharmaceutical
Introduction
 Osmotic pressure is used as driving force for these
systems to release the drug in controlled manner.
Osmotic drug delivery technique is the most interesting
and widely acceptable among all other technologies used
for the same.
 These systems can be used for both route of

administration i.e. oral and parenterals. Oral osmotic
systems are known as gastro-intestinal therapeutic
systems (GITS).
Pharmaceutical
Principle
 Here osmotic pressure is used as the power/source or energy to
activate and control the release of drug from the device. In this
system, the drug reservoir contains the drug either in the form of
solid or as solution, which is enclosed within a semipermiable
housing having controlled water permeability. The drug is activated
to release in solution form at a constant rate through a special
delivery orifice.
 The rate of drug release is modulated by controlling the gradient of

osmotic pressure.(i.e. differences in osmotic pressure b/w the drug
delivery system and the external environment)
Pharmaceutical
Oral controlled release:
Osmotic tablet technology
 Once- or twice-daily dosing regimens for crystalline and enhanced-
bioavailability drugs is often desired and needed to maximize
therapeutic effect, patient safety, and compliance.
 Bend Research has developed two proprietary tablet technologies

that provide drug release in a predictable, reliable manner. Both
dosage forms are driven by osmotic/hydrostatic pressure and
provide steady-state, zero-order release that is generally
independent of GI pH and agitation.
 These attributes minimize patient-to-patient variability and allow

accurate prediction of in vivo performance from in vitro dissolution
testing. A wide range of release rates is possible.
Pharmaceutical
Osmotic swellable-core
technology
 A bi-layer tablet
containing an insoluble,
semipermeable coating
with a delivery orifice
 Preferred API and dose:

poorly water soluble, or
bioavailability-enhanced
forms ; low to moderate
dose.
Pharmaceutical
Osmotic asymmetric membrane
technology
 A single-layer tablet containing an
insoluble, asymmetric microporous
coating produced by controlled phase
separation
 Preferred API and dose: water soluble;

low to high dose.
Pharmaceutical
Oral osmotic pumps
Pharmaceutical
Controlled porosity osmotic pump
Osmotic bursting osmotic pump
Osmotic pump for insoluble drugs
Delayed Delivery Osmotic

device
Telescopic capsule
Oros CT (Colon
Targeting)
Sandwiched oral
therapeutic system
Pharmaceutical technology Petra University. 48

Elementary osmotic pump
It is simplest possible form of osmotic pump as it does
not require special equipment and technology. It can
be mass –produced economically using ordinary
tabletting and coating machine and a facility to drill an
orifice.
The elementary osmotic pump consists of an osmotic

core containing drug, which is coated with a
semipermiable membrane, usually cellulose acetate,
with a delivery orifice.
The core may or may not contain an osmotic agent depending

on the osmotic activity of the drug. When exposed to aqueous
environment, the core imbibes water osmotically at a
controlled rate through the semipermiable membrane,
forming a saturated drug solution inside the system. The
membrane being non-extensible, internal volume of the
pump remains constant.

The system delivers, via the orifice, in
any time interval, a volume of saturated
solution of drug equal to volume of water
uptake. This process is continues at a
constant rate until all solid drug inside the
tablet has been dissolved and only a
solution filled shell remains.
The residual dissolved drug

continues to be delivered, but at a
declining rate, until the osmotic
pressure inside and outside the
pump is equal.

Acutrim tablet
 It is an oral osmotic pressure controlled G.I. DDS. this systems are
fabricated by encapsulating an osmotic drug core containing an
osmotically active drug or a combination of an osmotically inactive
drug with an osmotically active salt like Nacl, within a
semipermiable membrane made from cellulose acetate polymer.
 A delivery orifice with a controlled diameter is drilled, using a laser

beam, through the coating membrane for controlling the drug release.
 The polymer membrane is not only semipermiable in nature but is

also rigid & capable of maintaining the structural integrity of the G.I.
DDS during the course of drug release. It is permeable to the influx of
water in G.I.T. but impermeable to drug solutes.
Pharmaceutical
Acutrim tablet
Pharmaceutical
In the GIT, the GI fluid
dissolves the immediately
It is a solid tablet of releasable PPA layer,which It is designed to
water soluble and provides an initial dose of provide a controlled
osmotically active PPA, and its water delivery of PPA over
phenylpropanolamine component then penetrates a duration of 16hr for
(PPA) HCl enclosed through the semipermiable
membrane at a rate appetite suppression
within a semipermiable in a weight control
determined by PwAm/hm to
membrane made from dissolve the controlled
cellulose triacetate. The program. The same
release dose of PPA. Under
surface of the the osmotic pressure
delivery system has
semipermiable membrane differential created (πs-πe), also been utilized for
is further coated with a the PPA solution is the oral controlled
thin layer of PPA dose for delivered continuously at a delivery of
immediate release. controlled ratethrough an
orifice predrilled by a laser Indomethacin.
beam.
Pharmaceutical
Modifications
 The external surface of the semipermiable membrane can be coated with a
layer of bioerodable polymer like enteric coating, it regulate the penetration of
GI fluid through the semipermiable membrane & target the delivery of a drug
to the lower region of the GIT.
 The coating membrane of the DDS can be constructed from a laminate of two
or more semipermiable membranes with differential permeabilities.
 The osmotic pressure controlled GI delivery system can be further modified to
constitute two compartments separated by a movable partition. The
osmotically active compartment absorbs water from GI fluid to creat an
osmotic pressure that acts on the partition forces it to move upward and to
reduce the volume of the drug reservoir compartment and to release the drug
formulation through the delivery orifice .
Pharmaceutical
Modifications
Pharmaceutical
Modifications
 This system has been applied to the development of a

GI-delivery system for the oral controlled delivery of
Nifedipine .
 Further more, a two compartment GI-delivery system

has been applied to the simultaneously GI-controlled
delivery of two drugs, such as Oxprenolol sebacinate
and Hydralazine HCl, from separate compartment,
simultaneously and independently at different
delivery rates.
Pharmaceutical
Push pull osmotic pump
 Push pull osmotic pump is a modified EOP. through, which it is possible to
deliver both poorly water-soluble and highly water soluble drugs at a constant
rate.
 This system resembles a standard bilayer coated tablet. One layer (depict as the
upper layer) contains drug in a formulation of polymeric, osmotic agent and
other tablet excipients.
 This polymeric osmotic agent has the ability to form a suspension of drug in
situ. When this tablet later imbibes water, the other layer contains osmotic and
colouring agents, polymer and tablet excipients. These layer are formed and
bonded together by tablet compression to form a single bilayer core. The tablet
core is then coated with semipermeable membrane.
Pharmaceutical
Pharmaceutical
 After the coating has been applied, a small hole is drilled through
the membrane by a laser or mechanical drill on the drug layer
side of the tablet.
 When the system is placed in aqueous environment water is
attracted into the tablet by an osmotic agent in both the layers.
The osmotic attraction in the drug layer pulls water into the
compartment to form in situ a suspension of drug.
 The osmotic agent in the non-drug layer simultaneously attract
water into that compartment, causing it to expand volumetrically
and the expansion of non drug layer pushes the drug suspension
out of the delivery orifice.
Pharmaceutical
Osmotic pump with non-
expanding second chamber
 The second category of multi-chamber devices comprises system
containing a non-expanding second chamber. This group can be
divided into two sub groups, depending on the function of second
chamber.
 In one category of these devices, the second chamber is used to

dilute the drug solution leaving the devices. This is useful because
in some cases if the drug leaves the oral osmotic devices in a
saturated solution, irritation of GI tract is a risk.
Pharmaceutical
 Example: - The problem that lead to withdrawal of
osmosin, the device consist of a normal drug
containing porous tablet from which drug is released as
a saturated solution. However before the drug can
escape from the device it must pass through a second
chamber.
 Water is also drawn osmotically into this chamber
either because of osmotic pressure of drug solution or
because the second chamber contain, water soluble
diluents such as NaCl.
Pharmaceutical
 This type of devices consist of two rigid chamber, the first
chamber contains a biologically inert osmotic agent, such as sugar
or a simple salt like sodium chloride, the second chamber contains
the drug. In use water is drawn into both the chamber through the
surrounding semi permeable membrane.
 The solution of osmotic agent formed in the first chamber then

passes through the connecting hole to the drug chamber where it
mixes with the drug solution before exiting through the micro
porous membrane that form a part of wall surrounding the
chamber. The device could be used to deliver relatively insoluble
drugs.
Pharmaceutical
Osmotic bursting pump
 This system is similar to an EOP except delivery orifice is
absent and size may be smaller. When it is placed in an aqueous
environment, water is imbibed and hydraulic pressure is built up
inside until the wall rupture and the content are released to the
environment.
 Varying the thickness as well as the area the semipermeable

membrane can control release of drug. This system is useful to
provide pulsated release.

Controlled Porosity Osmotic
Pumps
 In this type two layers of membrane are applied on pumps .
 The inner is microporous membrane, which is made up of

cellulosic material containing some pore forming agents. A
semipermeable membrane cover this layer.
 When the system is placed in an aqueous environment the

soluble components of first layer of coating dissolve, resulting
in a microporous , which provides greater flux of water into the
system.
Pharmaceutical
Pumps for insoluble drugs
 In this system particles of osmotic agents are coated with an
elastic semipermeable membrane.
 These coated particles are then mixed with the relatively

insoluble drug and tableted and coated with the rigid
semipermeable membrane in usual way.
 When this system is placed in an aqueous environment, water is

drawn through the two membranes in-turn into the osmotic
agent particles, which swell and hydrostatic force delivers the
insoluble drug out of the pump.
Pharmaceutical
Sandwiched osmotic tablets
 It is composed of polymeric push layer sandwiched

between two drug layers with two delivery orifices.
 When placed in the aqueous environment the middle

push layer containing the swelling agents swells and the
drug is released from the two orifices situated on
opposite sides of the tablet and thus SOTS can be
suitable for drugs prone to cause local irritation of the
gastric mucosa.
Pharmaceutical
Sandwiched osmotic tablets
Pharmaceutical
System
Pharmaceutical
System
Pharmaceutical
Advantages
Osmotic drug delivery system for oral and parenteral use offer
distinct and practical advantage over other means of delivery. The
following advantages contributed to the popularity of osmotic drug
delivery system.
 They typically give a zero order release profile after an initial lag.
 Deliveries may be delayed or pulsed if desired.
 Drug release is independent of gastric pH and hydrodynamic
condition.
 They are well characterized and understood.
 The release mechanisms are not dependent on drug.
 A high degree of in-vitro and in vivo correlation .
Pharmaceutical
Advantages & Disadvantages
 The rationale for this approach is that the presence of water in
GIT is relatively constant, at least in terms of the amount
required for activation and controlling osmotically base
technologies.
Disadvantages
 Costly .
 If the coating process is not well controlled there is a risk of

film defects, which results in dose dumping.
 Size hole is critical .
Pharmaceutical
Marketed products
Product name Active Design Dose
Acutrim Phenylpropanola Elementary pump 75 mg

mine
Alpress LP Prazosin Push-pull 2.5-5 mg

Cardura XL Doxazosin Push-pull 4.8 mg
Ditropan XL Oxybutinine Push-pull 5, 10 mg
chloride
Efidac 24 Pseudoephedrine Elementary pump 60 mg , 180 mg

Glucotrol XL Glipizide Push-pull 5, 10 mg
Pharmaceutical
Pharmaceutical
Introduction
 This system is either capsule or tablet form is designed to prolong GI
residence time in an area of the GIT to maximize drug reaching its
absorption site in solution state & hence ready for absorption.
 Hydrodynamically balanced system are also known as floating drug

delivery system. HBS have a bulk density lower than gastric fluid &
hence remain floating in the stomach.
 This is a hydration activated drug delivery system depends on the

hydration induced swelling process to activate the release of drug. In
this system the reservior is homogenously dispersed in a swellable
polymer matrix fabricated from a hydrophilic polymer.
Pharmaceutical
Principle
• In GIT the laminate absorb GI fluids & become
increasingly swollen , which generate hydrodynamic
pressure in the system,the hydrodynamic pressure thus
created forces the drug reservior compartment to reduce in
volume and causes the liquid drug formulation to release
through the delivery orifice at a rate defined by :-
• Q / t=Pf Am/ hm ( qs - qe)
• Where, Pf = Fluid permeability, Am = Effective surface

area , hm= Thickness of wall with annular openings,
( qs - qe)= Difference in the hydrodynamic pressure
between the drug delivery system( qs ) & the environment
(qe).
Petra University. 76
Principle
 Hydrodynamic pressure activated drug delivery system

can be fabricated by enclosing a collapsible,
impermeable container, which contains a liquid drug
formulation to form a drug reservoir compartment inside
a rigid shape retaining housing a composite laminate of
an absorbent layer and a swellable, hydrophilic polymer
layer is sandwiched between the drug reservoir
compartment and the housing.
Pharmaceutical
Principle
Pharmaceutical
 Rate controlling factors:
 Fluid permeability ,
 Effective area of wall with openings ,
 Hydrodynamic pressure gradient.
Pharmaceutical
Formulation and development of
Hydrodynamically balanced system (HBS)
or Floating drug delivery system(FDDS)
Selection of drug
candidate: Three major requirements for
FDDS formulation:
1.Drugs which are 1. It must form a cohesive gel
predominantly absorbed from barrier.
upper part of GIT.
2.Specific gravity lower than
2. drugs which are acting locally gastric content(1.004-1.010).
on stomach.
3. drugs those are poorly soluble 3. Release content slowly to
at alkaline pH. serve as a reservoir.
4.drugs that degrade in the colon.
Pharmaceutical
FORMULATION
20-75% w/w of one or more gel forming hydrocolloid are

incorporated into the formulation and then compressing
these granules into a tablet (or encapsulating into
capsules).
e.g., Hydroxy ethyl cellulose,

Hydroxy propyl cellulose,
Hydroxy propyl methyl cellulose &
Sodium carboxy methyl cellulose.
Pharmaceutical
Classification of FDDS
Types of FDDS
depending on the use
of 2 formulation
variables
EFFERVESCENT NON-
FLOATING EFFERVESCENT
DOSAGE FLOATING
FORMS DOSAGE FORMS
Pharmaceutical
EFFERVESCENT FLOATING
DOSAGE FORMS
 These floating drug delivery system employ matrices from swellable polymers like
Methocel or Chitosan & effervescent components such as Sodium bicarbonate &
Tartaric or Citric acid or matrices having chambers of liquid components that
gasify at body temperature.
 The matrices are prepared in such a manner that when they come in contact with
stomach fluid , CO2 is generated, & retained entrapped in hydrocolloid gel.
 This leads to an upward flow of the dosage form and maintains it in a floating
condition.
 A single layered tablet can be prepared by initially mixing the CO2 generating
component in tablet matrix. A bilayered tablet may be compressed in which gas
liberating component is present in hydrocolloid layer and the drug is compressed
in other layer of sustain release
Pharmaceutical
Multiple type of floating dosage
system
 Multiple type of floating dosage system composed of effervescent layers and
swellable membrane layers coated on sustained release pills.
 The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid
was divided into 2 sublayers to avoid direct contact between the 2 agents. These
sublayers were surrounded by a swellable polymer membrane containing polyvinyl
acetate and purified shellac.
 When this system was immersed in the buffer at 37ºC, it settled down and the solution
permeated into the effervescent layer through the outer swellable membrane. CO2 was
generated by the neutralization reaction between the 2 effervescent agents, producing
swollen pills (like balloons) with a density less than 1.0 g/mL.
 It was found that the system had good floating ability independent of pH and
viscosity and the drug (para-amino benzoic acid) released in a sustained
manner(Figure ,A and B).
Pharmaceutical
Multiple type of floating dosage
system
Figure . (A) Multiple-unit oral floating drug delivery system. (B)

Working principle of effervescent floating drug delivery system.
Pharmaceutical
Triple-layer tablet floating
dosage system
 Swellable asymmetric triple-layer tablet with floating ability to prolong the
gastric residence time of triple drug regimen (tetracycline, metronidazole,
and clarithromycin) in Helicobacter pylori–associated peptic ulcers using
hydroxy propyl methyl cellulose (HPMC) and poly ethylene oxide (PEO) as
the rate-controlling polymeric membrane excipients.
 The design of the delivery system was based on the swellable asymmetric
triple-layer tablet approach. HPMC and PEO were the major rate-controlling
polymeric excipients.
 Tetracycline and metronidazole were incorporated into the core layer of the
triple-layer matrix for controlled delivery, while bismuth salt was included in
one of the outer layers for instant release.
Pharmaceutical
dosage system
 The floatation was accomplished by incorporating a gas-generating layer
consisting of sodium bicarbonate: calcium carbonate (1:2 ratios) along with
the polymers.
 The in vitro results revealed that the sustained delivery of tetracycline and
metronidazole over 6 to 8 hours could be achieved while the tablet remained
afloat.
 The floating feature aided in prolonging the gastric residence time of this
system to maintain high-localized concentration of tetracycline and
metronidazole.
Pharmaceutical
dosage system
Figure- Schematic presentation of working of a triple-layer system. (A) Initial

configuration of triple-layer tablet. (B) On contact with the dissolution medium the
bismuth layer rapidly dissolves and matrix starts swelling. (C) Tablet swells and erodes.
(D) and (E)Pharmaceutical
Tablet erodes completely.
NON -EFFERVESCENT
FLOATING DOSAGE FORMS
FORMULATION:
It includes;
 Gel forming or swellable cellulose type of
hydrocolloids & polysaccharides.
 Matrix forming polymers (polycarbonate,
polyacrylate, polymethacrylate & polystyrene).
Pharmaceutical
MECHANISM
 Gel forming hydrocolloids swells in contact with gastric fluid after oral
administration and maintains a relative integrity of shape and a bulk density of
less than unity within gastric environment. The air thus trapped by the swollen
polymer imparts buoyancy to the dosage form.
 The gel barrier controls the rate of solvent penetration into the device & the rate
of drug release from the device.
 It maintains a bulk density of less than 1 and thus remains buoyant in the
gastric fluid inside the stomach for up to 6 hrs; conventional dosage forms
disintegrate completely within 60 min and are emptied totally from the stomach
shortly afterward.
Pharmaceutical
Advantages of HDDS
1. Improved drug absorption.

2. Controlled delivery of drugs. 6. Treatment of gastro intestinal
disorders such as gastro-
3. Delivery of drugs for local
esophageal reflux.
action in stomach.
7. Simple and conventional
4. Minimizing the mucosal
equipments required for
irritation due to drugs, by drug
manufacture.
releasing slowly at controlled
rate 8. Ease of administration and
better patient compliance.
5. Site specific drug delivery.
Pharmaceutical
Disadvantages of HDDS
1. Gastric retention is influenced

by many factors such as gastric 3. Not suitable for drugs with
motility, pH and presence of stability or solubility problems in
food. These factors are never stomach.
constant and hence the buoyancy
can not be predicted.
4. Drugs with irritant effect on
gastric mucosa are not suitable.
2. Require sufficiently high level
of fluids in the stomach.
Pharmaceutical
Marketed products
PRODUCT ACTIVE INGREDIENT
MADOPAR LEVODOPA & BENSERZIDE
VALRELEASE DIAZEPAM
TOPALKAN ALUMINIUM MAGNESIUM
ANTACID
ALMAGATE FLAT COAT ANTACID
LIQUID GAVISON ALGINIC ACID & NaHCO3
Pharmaceutical
CONCLUSION
 HBS system can remain in the stomach for longer period hence can release
the drug over a prolong period of time.
 These systems are particularly advantageous for drugs that are specifically
absorbed from stomach or proximal part of small intestine ( e.g., Riboflavin &
Furosemide).
 Drugs that have poor bioavailability because of site specific absorption from
the upper part of GIT are potential candidates to be formulated as floating
drug delivery systems, thereby maximizing their absorption.
 FDDS also serves as an excellent drug delivery system for the eradication of
Helicobacter pylori, which can cause chronic gastritis & peptic ulcers.
Pharmaceutical
pH controlled GI delivery
systems
 This type of GI delivery system is designed for
the controlled release of acidic or basic drugs in
GIT, at a rate independent of the variation in GI
pH.
Pharmaceutical
Formulation
 This system is prepared by first blending acidic or basic
drug with one or more buffering agents,
Eg. Pri, sec, ter salt of citric acid.
 Then granulating with excipients, to form small granules

and then coating the granules with GI fluid permeable
film-forming polymer.
Eg. Cellulose derivatives.
Pharmaceutical
Mechanism
 Polymer coating controls the permeation of GI fluid.
 The GI fluid permeating into the device is adjusted by

the buffering agents to an appropriate constant pH.
 This is the pH where drugs dissolve and is delivered

through the membrane at the constant rate, regardless
of the location of device in the alimentary canal.
Pharmaceutical
pH controlled GI Drug Delivery
Pharmaceutical
pH responsive hydrogels
 This system have been targeted for per-oral controlled
drug delivery, taste masking of bitter drugs and
intravascular drug release during elevated blood pH in
certain CVS defects.
 It includes the ionic polymers, for eg. Polyacrylamide,

poly acrylic acid, poly methacrylic acid, etc.
Pharmaceutical
Mechanism
 In aqueous media of appropriate pH and ionic
strength, pendant groups, ionised and
developed fixed charges on the fixed charges
generating electrostatic repulsive forces
responsible for pH dependent swelling or
deswelling of the hydrogel, thereby controlling
the drug release.
Pharmaceutical
Drug release pattern
 This system is designed in a monobasic or pulsatile
pattern.
 Peroral controlled drug delivery requires uniform drug
delivery with increase in drug pH, gradient in different
segments of GI Lumen.
 Eg. Albumin cross-linked 1-vinyl-2-pyrrolidinone
hydrogels were studied for their swelling behaviour at
different values.
 Swelling increases above pH 7, thus correlating with
the maximal transit time of the drug delivery system
through the intestine.
Pharmaceutical
Drug release pattern
 Pulsatile pattern of drug release is required in the
diseased state exhibiting a rhythmic pattern.
 For localised delivery of heparin and streptokinase

based on poly( N-isopropyl acrylamide-co-
methacrylic acid) hydrogel, were assessed for their
swelling behaviour in response to pulses in
temperature and pH.
Pharmaceutical
pH- Activated Drug Delivery System
 This system permits targeting the delivery of a drug only in the region with a
selected pH range.
 Drugs administered orally would encounter a spectrum of pH ranging from 7

in the mouth, 1 - 4 in the stomach and 5 - 7 in the intestine.
 Since most drugs are weak acids or weak bases, their release is pH dendent.
 However, buffers can be added to the formulation to help maintain a constant

pH, like salts of citric acid, tartaric acid, phosphoric acid are commonly used.
Pharmaceutical
pH- Activated Drug Delivery
System
 pH Activated Drug Delivery System is fabricated by coating the drug-
containing core with a pH–sensitive polymer combination.
 For example, a gastric fluid labile drug is protected by encapsulating it inside

a polymer membrane that resists the degradative action of gastric pH, such as
the combination of Ethyl cellulose and Hydroxylmethylcellulose phthalate.
In the stomach, coating membrane resists the action of gastric fluid (pH<3) &
the drug molecule is thus protected from acid degradation.
After gastric emptying the Dosage form reaches the small intestine and comes
in contact with intestinal fluid (pH>7.5) which activates the erosion of polymer
- Hydroxylmethylcellulose phthalate from the coating membrane.
Pharmaceutical
pH- Activated Drug Delivery
System
This leaves a microporous membrane of intestinal
fluid insoluble polymer of Ethylcellulose, which
controls the release of drug from the core tablet.
The drug solute is thus delivered at a controlled

manner in the intestine.
Pharmaceutical
Ion Exchange Resinates As
Controlled Release Drug
Delivery Systems
Pharmaceutical
Introduction
 It is an attractive method for Sustained
Release drug delivery systems.
 Drug release characteristics depend upon the

ionic environment of the resin containing drug.
 Therefore, it is less susceptible to environment

conditions such as enzyme content and pH at
the absorption site.
Pharmaceutical
Introduction
 This approach requires the presence of ions in
solution, and therefore it would not be applicable
to the skin, or other areas with limiting
quantities of eluting ions.
 Where as the Subcutaneous and Intramuscular

routes have pool of available ions, and therefore,
would be better suited for this approach.
Pharmaceutical
Principle
Resins are water-insoluble materials containing anionic or
cationic groups in repeating units on the resin chain.
A Cation Exchange Resin generally has Sulphonic and

Carboxylic functional groups as an integral part of the resin and
an equivalent amount of cationic drug molecules.
An Anion Exchange Resin generally has quaternary ammonium

groups and polyalkylamine functional groups as an integral part
of the resin and an equivalent amount of anionic drug
molecules.
Pharmaceutical
Types of Ion Exchange Resins
Resin type Chemical constitution Structure
Strongly acidic cation Sulphonic acid group attached to a R – SO3 - H +
exchanger styrene and divinylbenzene copolymer
Weakly acidic cation Carboxylic acid group attached to an R – COO - Na +

exchanger acrylic and divinylbenzene copolymer
Strongly basic anion Quaternary ammonium group attached -

R –N (CH3)3+ Cl
exchanger to a styrene and divinylbenzene
copolymer
Weakly basic anion Polyalkylamine group attached to a -

R –NH (R)2+ Cl
exchanger styrene and divinylbenzene copolymer
Pharmaceutical
Types of Ion Exchange Resins
Pharmaceutical
Mechanism
Cation exchange resin:

H+ + Resin – SO3 - Drug + Resin – SO3 - H + + Drug +
Anion exchange resin:

Cl - + Resin – N (CH3)3+ Drug - Resin – N (CH3)3 + Cl - + Drug-
Pharmaceutical
Drugs Suitable for Resinate Preparation
1. Drugs should have acidic and basic groups in their chemical

structure.
2. Biological half life should be between 2-6 hrs, drugs with t1/2 <
1 hr or > 8 hrs are difficult to formulate.
3. The drug is to be absorbed from all regions of GI tract.
4. Drugs should be stable sufficiently in the gastric juice.
Pharmaceutical
Some Important Properties of
Ion-Exchange Resins
 Particle Size and form :
The rate of ion exchange reactions depend on the size of the resin particles.
Decreasing the size of resin particle significantly decreases the time

required for the reaction to reach equilibrium with the surrounding medium.
Most of the ion exchange resins are available in the form of spherical
beads. When the beads are immersed in water, they imbibe a limited amount
of water to form a homogenous gel like structure.
Pharmaceutical
Ion-Exchange Resins
 Ion exchange resins have hydrocarbon network to which ionizable sulphonic
acid groups are attached. The hydrogen ions are completely dissociated in the
imbibed water and are free to diffuse through out the entire resin bead and
hence can be exchanged for an equivalent amount ions of like charge.
 Porosity : Porosity is defined as the ratio of the volume of the material to its
mass. The limiting size of ions which can penetrate into a resin matrix
depends strongly on the porosity.
 Swelling :The swelling behavior of the resin has a marked effect on the
release characteristics of drug resinates. The amount of swelling is inversely
proportional to the degree of divinylbenzene crosslinking present in the resin.
Pharmaceutical
Ion-Exchange Resins
 Ion exchange capacity:
It is expressed in the terms of milliequivalents per gram of ion exchange
resin.
eg. The exchange capacity of a cation exchange resin is usually found in the
laboratory by determining the number of milligram equivalents of sodium
ion which are absorbed by 1 gram of the dry resin in the hydrogen form.
 The Resin ion exchanger should be Stable, Pure and free from toxicity.
Pharmaceutical
General Preparation Of Drug Resinates
Loading of drugs is done by two ways :-
Column Process: A highly concentrated drug solution

is eluted through a bed or column of the resin until
equilibrium is established.
Batch Process: The resin particles are stirred with a

large volume of concentrated drug solution.
The drug resin is then washed to remove the contaminating ions

Pharmaceutical and dried to form particles or beads.
General Preparation Of Drug
Resinates
 The release rate can be further controlled by coating the drug resin complex using
microencapsulation .
 Coated and uncoated drug resin complexes can be mixed in certain ratios and can be
filled into capsules with excipients or suspended in a palatable flavored vehicle
containing suitable suspending agents.
 The release of drug from uncoated resin beads is expected to begin immediately while
release from the coated form would be delayed giving sustained effect.
 The drug containing resin granules are first treated with an impregnating polymer such
as PEG 6000 to retard the rate of swelling in water and further coated with a water
permeable polymer such as Ethyl Cellulose to control the rate of release.
Pharmaceutical
General Preparation Of Drug
Resinates
Pharmaceutical
Applications
 Adsorbents of Toxins
 As Antacids
 As Bile Acid binding agents
 In treatment of Liver diseases
 In Renal insufficiency
 In Ophthalmology for glaucoma

Pharmaceutical
Therapeutic applications
1. Cholestyramine  It is a quaternary ammonium anion
exchange resin with basic groups attached to a
stryne – divinyl benzene copolymer.
 Used for the reduction of elevated serum

cholestrol levels in patients with
hypercholestrolemia.
2. Colestipol Similar anion exchange resin, used as a
hypolipidemic drug. It increases the catabolic rate
of low density lipoproteins and decreases
cholestrol level.
Pharmaceutical
Therapeutic applications
3. Sod. Polystrene It is a sulphonic cation exchange resin used
in the treatment of hyperkalemia and renal
failure.
4. Phenteramine A sympathomimetic amine used for the short

term management of hypotension has also been
formulated as ion exchange resins.
5.Dextromethorphan It is used as an Antitussive that raises the

threshold of cough center in the CNS and
suppresses cough.
Pharmaceutical
Nasal Drug Delivery
123
Nasal physiology
 The nasal cavity is divided by the nasal septum
(comprised of bone and cartilage), with each half
opening at the face (via the nostrils)
 There is also a connection to the oral cavity provided

by the nasopharynx
 The lateral walls comprise a folded structure (refered to
as the nasal labial folds or conchae) providing a total
surface area of about 150 cm2 in humans
 The three main areas of the nasal cavity are:
 The anterior and the posterior vestibules
 The respiratory region
 The olfactory region
124
Nasal physiology
125
Nasal physiology
 The epithelial tissue within the nasal cavity is relatively
highly vascularized, and thus provides a potential conduit
for drug delivery
 The cellular makeup of the nasal epithelial tissue consists

mainly of ciliated columnar cells, non-ciliated columnar
cells, goblet cells and basal cells, with the proportions
varying in different regions of the nasal cavity
 Ciliated cells facilitate the transport of mucus towards the

nasopharynx. Basal cells, which are poorly differentiated,
act as stem cells to replace other epithelial cells. Goblet
cells, which contain numerous secretory granules filled
with mucin, produce the secretions that form the mucus
layer
126
Nasal delivery: Local delivery
 Intranasal administration of medicines is the natural
choice for the treatment of topical nasal disorders.
 Among the most common examples are antihistamines

and corticosteroids for rhinosinusitis, and nasal
decongestants for cold symptoms
 In these cases, intranasal route is the primary option

for drug delivery because it allows a rapid symptom
relief with a more favorable adverse-event profile than
oral or parenteral routes
127
Nasal delivery: Local delivery
 In fact, relatively low doses are effective when
administered topically, minimizing simultaneously the
potential of systemic toxic effects. Recently, for
instance, topical antibiotherapy has been considered in
chronic rhinosinusitis in an attempt to eradicate biofilm
bacteria, often resistant to systemic treatment, and still
avoiding systemic toxicity
128
Nasal delivery: Systemic
delivery
 This route is easier and more comfortable for the
patient than the parenteral route and it avoids
enterohepatic recirculation and gut enzymes
 This naturally makes it attractive for the delivery of

peptides and recombinant DNA technology
 However, absorption rates fall off sharply when the

molecular weight exceeds 1000 Daltons which probably
explains why desmopressin is delivered successfully (m.
w. 1069 Daltons), whilst insulin (m. w. 6000 Daltons
approx.) is not
129
delivery
 The nasal mucosa demonstrates typical absorption
mechanisms. Water soluble drugs enter via passive
diffusion through aqueous channels. As the diffusion
path through the nasal mucosa is short, intranasally
administered drugs demonstrate a rapid rise to peak
plasma concentrations, but the rapid clearance from
the mucosa limits available time for absorption
 Amino acids such as tyrosine and phenylalanine are

absorbed by active transport, presumably by similar
mechanisms to those observed in the blood brain
barrier
130
delivery
 Currently, commercial products which utilize this
route for systemic delivery exist for some gonadorelin
analogues, which are hypothalmic hormones
 These include buserelin for prostatic cancer,

oestradiol dependent endometriosis and infertility,
and nafarelin also for endometriosis and infertility
 Other commercial products includes desmopressin for

diabetes insipidus and primary nocturnal enuresis
and lypressin for diabetes insipidus
131
Nasal delivery: Systemic delivery
-Penetration enhancers
 The drive to increase the absorption of large molecular
weight molecules has lead to the use of penetration
enhancers
 Bile salts, e.g. sodium deoxycholate, sodium

glycocholate and sodium taurocholate, decrease the
viscosity of mucus and create transient hydrophilic
pores in the membrane bilayer
 EDTA, and fatty acid salts such as sodium caprate and

sodium laurate, increase paracellular transport by
removal of luminal calcium, thus increasing
permeability of the tight junctions
132
 Non-ionic detergents e.g. Laureth-9 alter membrane
structure and permeability
 It should be remembered that the penetration

enhancers are generally non-specific and there remains
the potential that any large molecule can enter the
systemic circulation once the epithelial barrier is
breached
 Some penetration enhancers, e.g. Laureth-9 and bile

salts, have been reported to be toxic to the nasal
mucosa
133
 Cyclodextrins have been used as solubilizers and
absorption enhancers for nasal drug delivery
 Methylated ß-cyclodextrins have been used to promote

absorption of peptides and proteins, but mainly in
animals
 Limited studies show that the cyclodextrins are well

tolerated in humans
134
Nasal delivery: vaccination
route
 Advantages include: highly vascular mucous
membranes, low enzymatic degradation compared to
oral vaccines, and greater acceptability to patients
 Disadvantages: mucociliary clearance and inefficient

uptake of soluble antigens. Therefore, nasal vaccines
require potent adjuvants and delivery systems to
enhance their immunogenicity and to protect their
antigens
 It is important to note that even for active antigens,

intranasal delivery may not elicit an immune response
in the absence of an effective adjuvant
135
route
 Presentation of a suitable antigen with an appropriate
adjuvant to the nasal-associated lymphoid tissue
(NALT) has the potential to induce humoral and cellular
immune responses
 This approach may be a particularly effective approach

to achieving rapid mass immunization, for instance in
children and/or in developing countries and disaster
areas
 Intranasal immunization may lead to development of

local, as well as systemic, immunity.
136
route
 Vaccination via the intranasal route does not require a
sterile product or a sterile dosing technique (a distinct
advantage in developing areas of the world).
 An example of an intranasal vaccine is FluMist®, a

cold-adapted live influenza virus: This product is given
as one or two doses over the influenza season via a
syringe sprayer
137
route
 Additional examples of human efficacy testing of
intranasal vaccines includes those targeted against
 adenovirus-vectored influenza
 proteosome-influenza
 influenza A
 influenza B
 meningococcal outer membrane vesicle
 a combination respiratory syncytial virus (RSV) and
parainfluenza 3 virus (PIV3) live, attenuated intranasal
vaccine
 Effective nasal immunization requires an effective

antigen and/or a potent mucosal adjuvant or carrier
138
Mechanisms to increase nasal residence
time of formulations
 Two basic approaches have been used to increase the
nasal residence times of drugs:
 to use viscosity enhancers such as
hydroxypropylmethylcellulose and methylcellulose
 to use a “bioadhesive” excepients such as albumin,
Sephadex, starch, dextran, hyaluronan, and chitosan
 Chitosan has been shown to exhibit advantages as a

vaccine carrier due to its immune stimulating activity
and bioadhesive properties that enhance cellular
uptake, permeation and antigen protection, as well as
being well tolerated by humans
139
Intranasal drug delivery to the central
nervous system
 Drugs delivered intranasally are transported along
olfactory sensory neurons to yield significant
concentrations in the CSF and olfactory bulb
 Small molecules such as cocaine and cephalexin can be

transported directly to the CNS from the nasal cavity
 Cephalexin preferentially entered the CSF after nasal

administration compared to intravenous (IV) and
intraduodenal administration in rats. The levels of
cephalexin in CSF were 166-fold higher 15 minutes
after nasal administration than those of the other two
routes
140
nervous system
 The ratio of the methotrexate AUCCSF value between
the intranasal route and the IV injection was over 13-
fold
 A number of protein therapeutic agents, such as

neurotrophic factors and insulin, have been successfully
delivered to the CNS using intranasal delivery in a
variety of species
 Insulin-like growth factor I (IGF-I) could be delivered to

the brain directly from the nasal cavity, even though
IGF-I did not cross the BBB efficiently by itself. As a
consequence, intranasal IGF-I markedly reduced infarct
volume and improved neurological function following
focal cerebral ischemia 141
nervous system
 Research in humans has also provided evidence for
direct delivery of therapeutic agents to the CNS from
the nasal cavity.
 CNS effects of intranasal insulin in humans was

demonstrated without altering plasma glucose or insulin
level
 Intranasal administration is a promising approach for

rapid-onset delivery of medications to the CNS
bypassing the BBB.
142
Intranasal drug delivery : limitations
 One of the biggest limitations is insufficient drug
absorption through the nasal mucosa. Many drug
candidates cannot be developed for the nasal route
because they are not absorbed well enough to produce
therapeutic effects
 Another limitation concerning nasal administration is

that a small administration volume is required, beyond
which the formulation will be drained out into the
pharynx and swallowed
143
Pulmonary Drug Delivery
144
Pulmonary Drug Delivery
 Anatomy and Physiology of the Respiratory System
 Advantages of Pulmonary Delivery
 Lung epithelium at different sites within the lungs
 Pulmonary absorptive surfaces
 Systemic delivery of:
 Small hydrophobic drugs
 Small hydrophilic drugs
 Macromolecules drugs
 Pulmonary Drug Delivery Devices
145
Anatomy and Physiology of the
Respiratory System
 The human respiratory system is divided into upper and
lower respiratory tracts
 The upper respiratory system consists of the nose,

nasal cavities, nasopharynx, and oropharynx
 The lower respiratory tract consists of the larynx,

trachea, bronchi, and alveoli, which are composed of
respiratory tissues
 The left and right lungs are unequal in size. The right
lung is composed of three lobes: the superior, middle,
and inferior lobes. The smaller left lung has two lobes
146
Respiratory System
147
Respiratory System
 The nasopharynx is a passageway from the nose to the
oral pharynx
 The larynx controls the airflow to the lungs and aids in

phonation
 The larynx leads into the cartilaginous and

fibromuscular tube, the trachea, which bifurcates into
the right and left bronchi
 The bronchi, in turn, divide into bronchioles and finally

into alveoli
148
Respiratory System
 The respiratory tree can be differentiated into the
conducting zone and the respiratory zone.
 The conducting zone consists of the bronchi, which are

lined by ciliated cells secreting mucus and terminal
bronchioles.
 The respiratory zone is composed of respiratory

bronchioles, alveolar ducts, atria, and alveoli
149
Respiratory System
150
Respiratory System
 The epithelium in the conducting zone gets thinner as it
changes from pseudostratified columnar to columnar
epithelium and finally to cuboidal epithelium in the
terminal bronchioles
 The upper part of the conducting zone (from the

trachea to the bronchi) consists of ciliated and goblet
cells (which secrete mucus)
 These cells are absent in the bronchioles. Alveoli are

covered predominantly with a monolayer of squamous
epithelial cells (type I cells) overlying a thin basal
lamina
151
Respiratory System
 Cuboidal type II cells present at the junctions of alveoli
secrete a fluid containing a surfactant
(dipalmitoylphosphatidylcholine), apoproteins, and calcium
ions
 The lungs are covered extensively by a vast network of

blood vessels, and almost all the blood in circulation flows
through the lungs. Deoxygenated blood is supplied to the
lungs by the pulmonary artery
 The pulmonary veins are similar to the arteries in

branching, and their tissue structure is similar to that of
systemic circulation. The total blood volume of the lungs
is about 450 mL, which is about 10 percent of total body
blood volume
152
Comparison of the lung epithelium at
different sites within the lungs
153
Types of epithelium
154
Advantages of Pulmonary Delivery of
Drugs To Treat Respiratory Disease
 Deliver high drug concentrations directly to the disease site
 Minimizes risk of systemic side effects
 Rapid clinical response
 Bypass the barriers to therapeutic efficacy, such as poor

gastrointestinal absorption and first-pass metabolism in the
liver
 Achieve a similar or superior therapeutic effect at a fraction

of the systemic dose, (for example, oral salbutamol 2–4 mg
is therapeutically equivalent to 100–200 μg by metered dose
inhaler)
155
Drugs To Treat Systemic Disease
 A non-invasive, needle-free delivery system
 Suitable for a wide range of substances from small

molecules to very large proteins
 Enormous absorptive surface area (140 m2) and a

highly permeable membrane (0.2–0.7 μm thickness) in
the alveolar region
 Large molecules with very low absorption rates can be

absorbed in significant quantities; the slow mucociliary
clearance in the lung periphery results in prolonged
residency in the lung
156
Drugs To Treat Systemic Disease
 A less harsh, low enzymatic environment
 Avoids first-pass metabolism
 Reproducible absorption kinetics
 Pulmonary delivery is independent of dietary

complications, extracellular enzymes, and inter-patient
metabolic differences that affect gastrointestinal
absorption
157
Pulmonary absorptive
surfaces
 The airways (the trachea, bronchi and bronchioles) are
composed of a gradually thinning columnar epithelium
populated by many mucus and ciliated cells that
collectively form the mucociliary escalator
 The airways bifurcate roughly 16–17 times before the

alveoli are reached
 Inhaled insoluble particles that deposit in the airways

are efficiently swept up and out of the lungs in moving
patches of mucus, and for those deposited in the
deepest airways this can be over a time period of about
24 hour
158
surfaces
 The monolayer that makes up the alveolar epithelium is
completely different. The tall columnar mucus and cilia
cells are replaced primarily (>95% of surface) by the very
broad and extremely thin (<0.1 µm in places) type 1 cells
 Distributed in the corners of the alveolar sacs are also the

progenitor cells for the type 1 cells and the producers of
lung surfactant, the type 2 cells
 The air-side surface of each of the 500 million alveoli in

human lungs is routinely 'patrolled' by 12–14 alveolar
macrophages, which engulf and try to digest any insoluble
particles that deposit in the alveoli
159
surfaces
 An excess of 90% of alveolar macrophages are located
at or near alveolar septal junctional zones
 Insoluble, non-digestible particles that deposit in the

alveoli can reside in the lungs for years, usually
sequestered within macrophages
 Molecules such as insulin are formulated either as

liquids or in highly water-soluble aerosol particles that
dissolve rapidly in the lungs and thereby largely avoid
macrophage degradation
160
surfaces
 Protein therapeutics that are taken up by macrophages
can be rapidly destroyed in the lysosomal 'guts' of the
phagocytic cells
161
The effect of particle size on the deposition of aerosol
particles in the human respiratory tract following a slow
inhalation and a 5-second breath hold
Alveolar region
Mouth and throat
Airways
162
Systemic delivery of small
hydrophobic molecules
 Small, mildly hydrophobic molecules can show extremely
rapid absorption kinetics from the lungs
 However, as hydrophobicity increases, molecules can

become too insoluble for rapid absorption and can persist in
the lungs for hours, days or weeks
 Typical drug molecules with log octanol–water partition

coefficients greater than 1 can be expected to be absorbed,
with absorption half-lives (the time it takes half of the
molecules deposited into the lungs to disappear from the
tissue) of approximately 1 minute or so; decreasing the log
octanol–water partition coefficient to –1 or lower can
increase the half-life to around 60 minutes
163
hydrophobic molecules
 Examples of rapidly absorbed inhaled hydrophobic drugs
include nicotine, 9-tetrahydrocannabinol (THC), morphine
and fentanyl
164
Inhaled morphine (dose = 8.8 mg)
compared with intravenous injection
(dose = 4 mg) in human volunteers
165
hydrophilic molecules
 In general, neutral or negatively charged hydrophilic
small molecules are absorbed rapidly and with high
bioavailabilities from the lungs
 This class of molecules has an average absorption half-

life of about 60 minutes, in contrast to some of the
lipophilic molecules that are absorbed in seconds to
minutes
166
Systemic delivery of macromolecules
 The use of the lungs for the delivery of peptides and
proteins, which otherwise must be injected, is one of
the most exciting new areas in pulmonary delivery
 For reasons that are not completely understood, the

lungs provide higher bioavailabilities for
macromolecules than any other non-invasive route of
delivery
 However, unlike the situation with small molecules, for

which lung metabolism is minimal, enzymatic hydrolysis
of small natural peptides can be very high unless they
are chemically engineered (blocked) to inhibit
peptidases
167
 Small natural peptides make poor drugs by any route of
delivery because of peptidase sensitivity, whereas
blocked peptides show high pulmonary bioavailabilities
 As molecular mass increases and peptides become

proteins with greater tertiary and quaternary structure,
peptidase hydrolysis is inhibited or even eliminated and
bioavailabilities of natural proteins can be high
 Insulin can be considered to be a large peptide (or

small protein), with enough size to avoid much of the
metabolism seen with smaller peptides
168
 The rate of macromolecule absorption is primarily
dictated by size — the larger the size the slower the
absorption
 Molecules such as insulin, growth hormone and many

cytokines typically peak in blood following aerosol
inhalation in 30–90 minutes, whereas smaller blocked
peptides can be absorbed faster
 After a 15-year development effort, inhaled human

insulin (IHI) applied regularly at meal time has been
approved both in the US and the European Union for
the treatment of adults with diabetes (Exubera)
169
 Conjugation of molecules such as interferons, follicle
stimulating hormone (FSH) and erythropoietin (EPO) to
the constant (Fc) region of antibodies has been shown to
prolong the systemic duration
 Interestingly, the optimal pulmonary site of absorption of

these conjugates seems to be the conducting airways, in
contrast to the major site for insulin, which is in the deep
lung
 The airways are enriched with antibody transcytosis

receptor mechanisms. Fc conjugates of proteins have
serum half-lives >1 day and are believed to be absorbed
with high bioavailabilities (20–50%) from the lungs
170
Pulmonary Drug Delivery Devices
 Dry Powder Inhalation (DPI) Devices
 The Pressurized Metered-Dose Inhalation (pMDI)

Device
 Nebulizers
171
Dry Powder Inhalation (DPI)
Devices
 DPIs are used to treat respiratory diseases such as
asthma and COPD, systemic disorders such as diabetes,
cancer, neurological diseases (including pain), and
other pulmonary diseases such as cystic fibrosis and
pulmonary infectious diseases
 Devices requiring the patient's inspiration effort to

aerosolize the powder aliquot are called passive devices
because as they do not provide an internal energy
source
 Active devices provide different kinds of energy for

aerosolization: kinetic energy by a loaded spring and
compressed air or electric energy by a battery
172
Dry Powder Inhalation (DPI)
Devices
 Most DPIs contain micronized drug blended with larger
carrier particles, which prevents aggregation and
promotes flow
173
Principle of dry powder inhaler
design
174
The Pressurized Metered-Dose
Inhalation (pMDI) Device
 The pressurized metered-dose inhalation (pMDI) device
was introduced to deliver asthma medications in a
convenient and reliable multi-dose presentation
 The key components of the pMDI device are: container,

propellants, formulation, metering valve, and actuator
 The pMDI container must withstand high pressure

generated by the propellant. Stainless steel has been used
as a pMDI container material. Aluminum is now preferred
because, compared to glass, it is lighter, more compact,
less fragile, and light-proof
175
 Coatings on the internal container surfaces may be
useful to prevent adhesion of drug particles and
chemical degradation of drug
 Propellants in pMDIs are liquefied, compressed gases

that are in the gaseous phase at atmospheric pressure
but form liquids when compressed
 They are required to be nontoxic, nonflammable,

compatible with drugs formulated either as suspensions
or solutions, and to have appropriate boiling points and
densities
176
177
Nebulizers
 A nebulizer is a device used to administer medication to
patient in the form of a mist inhaled into the lungs
 It is commonly used in treating cystic fibrosis, asthma, and

other respiratory diseases
 There are two basic types of nebulizers:

 The jet nebulizer functions by the Bernoulli principle by which
compressed gas (air or oxygen) passes through a narrow orifice,
creating an area of low pressure at the outlet of the adjacent liquid
feed tube. This results in the drug solution being drawn up from
the fluid reservoir and shattering into droplets in the gas stream
 The ultrasonic nebulizer uses a piezoelectric crystal, vibrating at a
high frequency (usually 1–3 MHz), to generate a fountain of liquid
in the nebulizer chamber; the higher the frequency, the smaller the
droplets produced
178
Jet nebulizer
179
Ultrasonic nebulizer
180
Transdermal drug delivery
system
Transdermal drug delivery system
• Definition:
Transdermal drug delivery is defined as a self
contained discrete dosage form, which when applied to
the intact skin, will deliver the drug at a controlled rate to
the systemic circulation.
POTENTIAL BENEFITS OF
TRANSDERMAL DRUG DELIVERY
(ADVANTAGES)
• Easy to use.
• Avoid GIT absorption problems for drugs.
• Avoids FP hepatic metabolism of drugs.
• More improved and convenient patient compliance.
• Rapid termination in case of toxicity is possible.
• Self medication is possible.
• Reduces frequency of dosing.
• Maintains therapeutic level for 1 to 7 days.
• Controlled delivery resulting in more reliable and
predictable blood levels.
DISADVANTAGES
• Daily dose of more than 10mg is not possible.
• Local irritation is a major problem.
• Drug requiring high blood levels are unsuitable.
• Drug with long half life can not be formulated in TDDS.
• Uncomfortable to wear.
• May not be economical.
• Barrier function changes from person to person and within the
same person.
• Heat, cold, sweating (perspiring) and showering prevent the
patch from sticking to the surface of the skin for more than one
day. A new patch has to be applied daily.
Routes of drug absorption through skin
FACTORS AFFECTING
TRANSDERMAL PERMEABILITY
 Physico chemical properties of parent molecule
 Physico chemical properties of drug delivery system
Physiological and pathological condition of skin
Biological factors
BASIC COMPONENTS OF TRANSDERMAL
DRUG DELIVERY SYSTEM
COMPONENT OF TRANSDERMAL DEVICE INCLUDE:
1) POLYMER MATRIX
2) THE DRUG
3) PERMEATION ENHANCER
4) OTHER EXCEPIENTS
Basic components of Transdermal
drug delivery
188
Topical application-absorption & action
of drugs
LOCALIZED
DRUG IN DELIVERY DRUG IN TARGET TISSUE PHARMACOLOGICAL
SYSTEM RESPONSE
TOPICAL
RELEASE
DRUG IN SKIN SECRETION

FLUIDS, SWEAT, SEBUM, DISTRIBUTION
pH 4.5--5.5
TRANSDERMAL
ABSORPTION
DRUG IN BLOOD CIRCULATION

ELIMINATION
SYSTEMIC
FORMULATION APPROACHES
FOR DEVELOPMENT OF
TRANSDERMAL DRUG
DELIVERY SYSTEM
1. POLYMER MEMBRANE PERMEATION
CONTROLLED SYSTEM
2. POLYMER MATRIX DIFFUSION
CONTROLLED TDDS SYSTEM
3. ADHESIVE DISPERSION-TYPE
SYSTEM
4. GRADIENT CONTROLLED TDDS
Drug – impermeable metallic
plastic laminate
}
R11 Drug reservoir
R2 gradient layers
R1>R2>R3
R3
5. MICRORESERVIOR TYPE OR
MICROSEALED DISSOLUTION CONTROLLED
SYSTEM
rim
ADVANCED RESEARCHES
MICROARRAY NEEDLE
 Advanced micro-needle Patch transdermal system
allowing continuous delivery through the skin of
proteins and water-soluble drugs.
ADVANCED RESEARCHES
 The device create painlessly micropores in the S.C.

known as microstructered arrays or microneedles.
 These devices have about 400 microneedles.
 The solid silicone needles (coated with drug) or
hollow metal needles (filled with drug solution)
penetrate the horny layer without breaking it or
stimulating nerves in deeper tissues.
 Flux increase up to 1,00,000 fold are reported.
MICRONEEDLE ARRAY
Find an appropriate place to put the
patch
Parenteral Drug Delivery
200
201
Parenteral Drug Delivery
 Intravenous delivery
 Intramuscular delivery
 Subcutaneous delivery
202
Advantages of intravenous
delivery
 Rapidity of action which results from the drug
being presented directly to the circulation without
the need for release from a formulation or
absorption through an epithelium
 A much more predictable response than is obtained

from other routes. The uncertainty of poor or
incomplete absorption and its variability is
eliminated
203
Advantages of intravenous
delivery
 Intravenous delivery can be used when the patient
cannot be fed orally (for example they may be
comatose or have had gastric resection) or un-
cooperative, as in the case of psychiatric patients
 the intravenous route is paradoxically one of the

safest for the testing of new drugs. If the drug
under test is infused over a period of several
minutes, delivery can be stopped instantly should
any adverse reaction develop
204
Disadvantages of intravenous delivery
 The need for extensive training of

medical staff so that the correct amount
of drug goes into the right place with
the right technique
 Sterility must be maintained, so the

formulation must be prepared and
handled in a sterile fashion
205
Complications associated with intravenous
delivery
1. Air embolism, or the injection of air into a vessel. Small air bubbles
may be absorbed in the blood but larger amounts (a few ml) of air
can prove fatal, particularly if it reaches the brain
2. Thrombosis, the formation of a clot in a blood vessel, can be

particularly dangerous if the clot circulates in the bloodstream.
Certain disease states, or old age, can predispose to thrombosis,
but it can also be caused by irritant formulations which are injected
too rapidly.
3. Haemolysis, the breakdown of red cells with the release of

haemoglobin, can cause kidney damage if severe. This is normally
a problem with strongly hypotonic injections, although certain
membrane-active drugs such as amphotericin B can also cause this
problem
206
Complications associated with intravenous
delivery
4. Phlebitis is the inflammation of the vein wall due to irritation
from the formulation; it can be caused by the formulation
itself, or may be due to precipitation of the drug if injection
is too rapid
5. Extravasation, or the leakage of the injection from the vein

into the surrounding tissue, can lead to extensive damage
since there may be no mechanism to rapidly clear it from
the injection site. This is a particular problem for cytotoxic
materials, (e.g. methotrexate or mitomycin) as it can lead to
ulceration and necrosis which is slow to heal
207
Intravenous delivery: Formulation
considerations
 intravenous formulations must be sterile in order to avoid
causing an infection
 Particulate material, such as small fragments of dust, glass,

or pieces of rubber closures, must also be rigorously
excluded
 Small volume parenterals, defined as those below 100 ml in

volume, can be formulated at a pH ranging from 4 to 10,
and be considerably hypotonic or hypertonic. Large volume
parenterals must be more closely matched to the properties
of the blood, and the pH is rarely outside the limits 6–8.
208
considerations
 IV parenterals to be infused through a peripheral vein are
closely matched in tonicity:
 Plasma extenders, which are often infused through a
peripheral vein, are closely matched in tonicity
 parenteral nutrition mixtures may have a tonicity up to around
twice that of blood (infused into subclavian vein) In this case
the infusion is very rapidly diluted, so that variations in its
properties are of lesser importance
209
considerations
 Ideally all injections would be formulated at pH 7.4 and be
isotonic with blood; however it is often necessary to use less
physiologically acceptable solvents, especially to aid the
solubility of a drug which may be poorly soluble near neutral
pH, or to control stability.
 In certain cases it may also be necessary to add cosolvents
such as ethanol or propylene glycol, or surfactant-based
solubilizing agents (for example deoxycholate, which is used
to solubilize amphotericin B in the injectable Fungizone®).
 These injections are far from physiological and it is wise to
infuse them slowly over several minutes, or ideally with an
infusion pump, to ensure that they are rapidly diluted as
they enter the blood.
210
Intramuscular delivery
 The most significant advantage of
intramuscular delivery is the ease with
which a wide range of drugs can be
administered in a variety of dosage
forms, which not only provide rapid
absorption, but can also be used for
sustained therapy
211
Steps involved in intramuscular delivery
I) release of the drug from the dosage form into the
intercellular fluid (ICF)
II) absorption from the ICF into the blood and lymphatics
III) transport from the local blood volume into the general
circulation
IV) metabolism
 The concentration of drug is determined by the relative

rates of these processes, and we should note that the
capillary membrane is highly permeable and in general
will not be rate limiting, but perfusion of the muscle by
the blood may be significantly slower.
212
Perfusion limited absorption of drugs from
intramuscular injections
 Injection of a bolus of soluble drug. In this case the drug is
immediately available in the ICF and is rapidly absorbed into
the capillaries
 In this case the rate-limiting absorption step is the perfusion
of the muscle by the blood. Any factor which influences
muscle perfusion (such as movement or exercise) will
change the rate of absorption
 In particular, if cardiac failure has occurred, absorption will
be extremely low since the muscle perfusion rate will be
small. For this reason intramuscular delivery is contra-
indicated if cardiac function is poor
213
Perfusion limited absorption of drugs from
214
Device limited absorption of drugs from
 Injection of the drug in sustained-release form (e.g. a
solid depot or crystal suspension). In this case release
from the formulation is slower than absorption or
perfusion, and so the behavior of the device becomes
the rate-limiting step, and the effects of muscle
perfusion are not evident
 Under these conditions the concentration of drug in the

plasma remains approximately constant until the
delivery device is exhausted, a period which can be
designed to last from several hours to several months.
215
Absorption of drugs from intramuscular
injections
216
Intramuscular injections: Formulation
considerations
 Since the formulation does not have to be miscible
with water, it is possible to inject a much wider
range of materials than those which can be
administered intravenously. The possible
formulations include (in order of release rate):
 aqueous solutions
 aqueous suspensions
 oily solutions
 oil in water emulsions
 water in oil emulsions
 oily suspensions
 dispersions in polymer or solid implants
217
considerations
 If the drug is extremely hydrophobic it will not
dissolve in the ICF
 If it is strongly ionized or extremely water soluble

it will not be able to cross the capillary membrane
 Drugs which are strongly protein-bound will also

be slowly absorbed since their activity in solution
will be reduced
218
considerations
 A number of drugs administered in solutions may
be absorbed slowly if the composition of the
formulation changes after injection
 For example, phenytoin is formulated as an

injection at pH 12 due to its low solubility. On
injection the ICF quickly reduces the pH to normal
levels, and the drug precipitates. As a result it may
then take several days for the dose to be fully
absorbed.
219
Subcutaneous delivery
 A subcutaneous injection (SC) is made into the
connective tissue beneath the dermis, and should
be contrasted with an intradermal injection which
is made into the dermal layer, often between the
dermis and the epidermis
 This is a critical distinction because the

subcutaneous tissues have a significant volume of
interstitial fluid into which the drug can diffuse,
while the epidermal tissue has relatively little
available fluid, nor is it well perfused by blood
220
 As a result an intradermal injection persists at the
site for a long period and the available volume for
injection is small; it is normally used for antigens
(e.g. tuberculin) and vaccines (smallpox)
221
222
 Drugs injected subcutaneously dissolve in the
interstitial fluid and gain entry to the bloodstream
by two routes:
1. They may be absorbed directly into blood vessels, but
the subcutaneous tissues are often adipose and poorly
perfused
2. the interstitial fluid is collected by lymphatic capillaries
and these drain into the regional lymph nodes and then
into the bloodstream
 These pathways are both relatively slow and

depend on the local vasculature, so absorption
from subcutaneous sites can be slow and
unpredictable.
223
 A strategy to deal with variability in absorption is
to make the release from the dose form rate-
limiting (as is the case for intramuscular depot
delivery systems) so that biological variation then
has little influence on the drug pharmacokinetics.
 A large number of delivery systems have been
devised which work in this way; probably the best
known being Zoladex® (AstraZeneca) which
releases the hormone goserelin, a drug used in
the treatment of androgen-dependent tumors. A
single injection lasts for 28 days.
224
 Technology of this type is particularly suited to
peptide hormones in which the dose is small and
the size of the device can be minimized. A number
of other interesting examples of this depot
technique can be found in the literature, including
the use of emulsion depots for methotrexate,
hydrogels and block copolymer gels.
225

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Drug Delivery Systems

 Most common methods of delivery include the

 Protein and peptide drugs have to be delivered

 Therefore to maintain the drug concentration

 NDDS is a combination of advance technique

 CR – Release of drug in controlled release for long

 Delivery of drugs to their site of action is one

 Controlled drug delivery is one which delivers

 Continuous oral delivery of drugs at

 Development of drug delivery system

 Modulation of GI transit time

 Minimization of first pass elimination

 Reduced GI side effects.

 Reduced dosing frequency.

 Better patient acceptance and compliance.

 Less fluctuation at plasma drug levels.

 More uniform drug effect

 Improved efficacy/safety ratio.

 Reduced potential for accurate dose

 Need of additional patient education.

3.Combination of both dissolution & diffusion.

4.Osmotic pressure controlled system

 Mass transfer from solid to liquid.

 Rate determining step: Diffusion from solid to

 Several theories to explain dissolution –

dc/dt = Dissolution rate.

 Controlled dissolution by:

 Drug release determined by

 Eg. Dimetane extencaps, Dimetapp

 One of the microencapsulation

 Eg. Ornade spansules,

 Drug molecules diffuse from a region of higher

 Directly proportional to the concentration gradient

 Rigid Matrix Diffusion

1. Also called as Glassy hydrogels.Popular for sustaining

Examples: Glucotrol XL, Procardia XL

Matrix system Reservoir system

2. No danger of ‘dose 2. Rupture can result in

a) Press coating (slowly soluble films and coating)

• In most cases drug is incorporated in coating film as well as in

• The care should be taken during placement into tablet or

Q = DE/T (2A.E Cs)Cs.t)1/2

 Also called as Laminated matrix device.

 The bioavailability of drug from these formulations may

 The drug release can be modulated by different ways but

 These systems can be used for both route of

 The rate of drug release is modulated by controlling the gradient of

 Bend Research has developed two proprietary tablet technologies

 These attributes minimize patient-to-patient variability and allow

 Preferred API and dose:

 Preferred API and dose: water soluble;

Osmotic bursting osmotic pump

Osmotic pump for insoluble drugs

Delayed Delivery Osmotic

Pharmaceutical technology Petra University. 48

The elementary osmotic pump consists of an osmotic

The core may or may not contain an osmotic agent depending

Pharmaceutical technology Petra University. 50

The residual dissolved drug

Pharmaceutical technology Petra University. 51

 A delivery orifice with a controlled diameter is drilled, using a laser

 The polymer membrane is not only semipermiable in nature but is

 This system has been applied to the development of a