1

Pharmaceutical Technology-II
CH SHARJEEL ADNAN (PHD- BZU)
Department of Pharmaceutics
Faculty of Pharmacy
 2

Pharmaceutical Technology-II

Topic:

 ACTIVE AND PASSIVE DRUG DELIVERY SYSTEM.

 3
Key Points:

 Drug delivery system.

 Types of drug delivery system.
 Active drug delivery sytem.
 Passive drug delivery system.
 Types of active drug delivery system.
 Active vs Passive drug delivery system.
 Advantages and disadvantages of active and passive drug delivery
system.
 4

What are the Strategies of Drug Delivery System?

 Drug targeting to an area of interest within the body increases the therapeutic effectiveness as well as it
reduces the toxicity that may arise otherwise. Two strategies are widely used for drug targeting to the
desired organ/tissue.
 This ability for nanoparticles to concentrate in areas of solely diseased tissue is accomplished through either one
or both means of targeting: passive or active.
 An ideal targeted drug delivery approach would not only increase therapeutic efficacy of drugs but also decrease
the toxicity associated with drug to allow lower doses of the drug to be used in therapy. Two approaches are used
passive targeting and active targeting.
 5

Drug delivery sytem.

 6

Drug delivery system:

Characteristics of active and passive drug delivery system.

 Such products are prepared by considering- Specific properties of target cells.

 Nature of markers or transport carriers or vehicles, which convey drug to specific receptors.
 Ligands and physically modulated components.
 7

Types of drug delivery system:

Drug
delivery
system

Active drug Passive drug

delivery delivery
system system

Second
First order Third order
order
 8

Passive drug delivery system:

 This is based on the accumulation of drug at areas around the site of interest, such as in
case of tumor tissues. This is called Enhanced Permeability Retention (EPR) effect.
Such a types of targeting occurs with almost all types of drug delivery carriers.
Passive targeting is actually a misnomer because it cannot really be described as a
form of selective targeting. Although the EPR effect applies for nanoparticle
administered, the majority (>95%) of these nanoparticles tend to accumulate in
organs other than those of interest such as liver, lungs and spleen. Thus, it is the
distribution of drug by blood circulation. Examples include the use of anti-malarial
drugs being targeted for the treatment of microbial infections such as
leishmaniasis, candidiasis and brucellosis.
 9

Passive drug delivery system:

 10

Active drug delivery system:

 Through the use of ligand-receptor interactions, active targeting describes the drug
targeting interactions. However, interactions between a ligand and a receptor are
possible only when the two are in close propinquity, (i.e. less than about 0.5mm) 5. The
currently available drug delivery systems are able to reach the target by the virtue of
blood circulation and extravasation. Therefore, we can conclude that active receptor
targeting actually means ligand-receptor interaction but that takes place only after blood
circulation and extravasation. Active targeting can further be divided into three different
targeting levels.
 11

Active drug delivery system:

 12
Types of active drug delivery system:

First Second Third

order order order
 13
First order active drug delivery system:

 This is the distribution of drug to capillary beds of target sites- organ or

tissue, for example, in case of lymphatic tissue, peritoneal cavity, pleural
cavity, cerebral ventricles, eyes, joints, etc.
 14
Second order active drug delivery system:

 This is the targeting of drugs to specific sites such as the tumor cells, for example, to kupffer cells
in liver.
 15
Third order active drug delivery system:

 It is the type of drug targeting wherein the drug is intracellularly localized at the target site via
endocytosis or through receptor-based ligand mediated entry.
 17
Active vs Passive drug delivery system:
 18
Active vs Passive drug delivery system:
 41

PHARMACEUTICAL TECHNOLOGY-II
 42

PHARMACEUTICAL TECHNOLOGY-II
 43

PHARMACEUTICAL TECHNOLOGY-II
 44

PHARMACEUTICAL TECHNOLOGY-II
GASTRORETENTIVE
DRUG DELIVERY
SYSTEMS

Ch. Sherjeel Adnan

The University of Lahore.

1
 Oral route is the most convenient
and extensively used route in drug
administration , due to ;
high patient acceptability.

2
CONTROLLED RELEASE
 CRDDS release drug at a predetermined rate, as
determined by drug’s pharmacokinetics and
desired therapeutic concentration. This help in
achieving predictable drug plasma concentration
required for therapeutic effect.
CRDDS is determined by-
1. Physicochemical properties of the drug
molecule like, the aqueous solubility, intestinal
permeability, pH- solubility profile, etc.
2. Pharmacokinetic profile of the drug
3. The interaction of these properties with the
anatomy and physiology of the GI tract 3
Dosage Transit time(hr)
form
Gastric Small Total
intestine
Tablets 2.7±1.5 3.1±0.4 5.8

Pellets 1.2±1.3 3.4±1.0 4.6

Capsules 0.8±1.2 3.2±0.8 4.0

Oral solutions 0.3±0.07 4.1±0.5 4.4

4
REGIONAL VARIABILITY IN INTESTINAL
ABSORPTION__CONCEPT OF ABSORPTION
WINDOW

A. Physiochemical factors
1. pH dependent solubility(1-8)
2. pH dependent stability(degradation)
3. Enzymatic degradation
B. Physiological factors
1. Mechanism of absorption(active/facilitated)
2. Microbial degradation(400 species)
C. Biochemical factors
1. Intestinal metabolic enzymes(cytochrome p450)
2. Multidrug efflux pump(p-gp in villus tip)

5
6
Absorption
window
No absorption of drug
Released in region
Preceding the window
7
DEFINITION
 These are the drug delivery
systems which possess the
ability of retaining the drug
in the GIT particularly in
the stomach for prolonged
period of time, and release
the drug in controlled
amount.
 After the drug release for
required time period the
dosage form should get
degraded without causing
any gastric disturbances. 8
INTRODUCTION
❑ The control of gastrointestinal transit of orally
administered dosage forms using gastro retentive
drug delivery systems (GRDDS) can improve the
bioavailability of drugs that exhibit site-specific
absorption.
❑ To overcome physiological adversities, such as short
gastric residence times (GRT) and unpredictable
gastric emptying times (GET).
❑ This dosage forms will be very much useful to deliver
‘narrow absorption window’ drugs.

9
REVIEW OF STOMACH AND GIT
A tube about nine meters long that runs through
the middle of the body from the mouth to the
anus and includes ;
 throat (pharynx),
 esophagus,
 stomach,
 small intestine (consisting of the duodenum, jejunum
and ileum) and
 large intestine (consisting of the cecum, appendix,
colon and rectum).
The wall of the gastrointestinal tract has the
same general structure throughout most of its
length from the esophagus to the anus, with some 10
local variations for each region.
IMPORTANT IN GIT FOR GRDDS:
 Throat(to determine size of dosage unit)
 Stomach & upper small intestine(chemical
environment to determine drug absorption)

11
SALIENT FEATURES OF UPPER
GASTROINTESTINAL TRACT
Length Transit pH Absorbing Absorption
(m) time surface pathway
(hr) area (m2)

Stomach 0.2 Variable 1-4 0.1 P,C,A

Small P,C,A
Intestine 6-10 3±1 5-7.5 120-200 F,I,E,CM

P – Passive diffusion C – Aqueous channel transport

A – Active transport F – Facilitated transport
I – Ion-pair transport E – Entero-or pinocytosis
12
CM – Carrier mediated transport
GASTRIC EMPTYING

The process of gastric emptying occurs both during fasting

and fed state.
❑ In fasted state,

• the process of gastric emptying is characterized by an

inter digestive motility pattern that is commonly called
migrating motor complex (MMC)(migrating myloelectric
cycle)
• This is a series of events
that cycle through the
stomach and small
intestine every
1.2 to 2hrs. 13
❑ In fed state,
• the gastric emptying rate slowed down because
the onset of Migration Motor Complex (MMC) is
delayed
• the feeding state results in a lag time prior to
the onset of gastric emptying
• It is thought that the sieving efficiency of the
stomach is enhanced by the fed pattern or by the
presence of food.

14
REQUIREMENTS FOR GASTRIC RETENTION

 Dosage form must be able to withstand the forces

caused by peristaltic waves in the stomach.

 It must resist premature gastric emptying.

 Once its purpose has been served, the device

should be removed from the stomach with ease.

15
NEED OF GASTRO RETENTIVE
DRUG DELIVERY SYSTEM
A controlled drug delivery system with prolonged
residence time in the stomach is of particular interest
for drugs that;
❑ Are locally active in the stomach (misoprostol,
antacids antibiotics against H.pylori).
❑ Have an absorption window in stomach or in the
upper small intestine (L-dopa, P-aminobenzoic acid,
furosemide).
❑ Are unstable in the intestine or colonic environment
(captopril).
❑ Exhibit low solubility at high pH values (diazepam,
verapamil).
❑ Alter normal flora of the colon (antibiotics).
❑ Absorbed by transporter mechanism (paclitaxel). 16
FACTORS CONTROLLING THE
GASTRIC RETENTION TIME OF
DOSAGE FORM

1.Density: GRT is a function of dosage form buoyancy.

2. Size
3. Shape of dosage form:Tetrahedron and ring shaped
devices.
4. Fed or unfed state:If the timing of administration of the
formulation coincides with MMC, the GRT of the unit
can be expected to be very short. However, in the fed state,
MMC is delayed and GRT is considerably longer.
5. Caloric content:GRT can be increased by 4 to 10 hours
with a meal that is high in proteins and fats. 15
6. Frequency of feed: The GRT can increase by
over 400 minutes, when successive meals are
given compared with a single meal due to the low
frequency of MMC.

7. Gender: Mean ambulatory GRT in males

(3.4±0.6 hours) is less compared with their age
and race matched female counterparts (4.6±1.2
hours), regardless of the weight, height and body
surface.

8. Age: Elderly people, especially those over 70,

have a significantly longer GRT.

9. Posture: GRT can vary between supine and

upright ambulatory states of the patient. 18
Advantages

❖ Improved drug absorption, because of increased GRT and more

time spent by the dosage form at its absorption site.

❖ Controlled delivery of drugs.

❖ Minimizing mucosal irritation by releasing drugs slowly at a

controlled rate.

❖ Treatment of gastrointestinal disorders such as gastro-

esophageal reflux, providing local action.

❖ Ease of administration and better patient compliance.

19
LIMITATIONS

 Retention in the stomach is not desirable for

drugs that cause gastric lesions (e.g. Non-
steroidal anti-inflammatory drugs NSAIDs).
 Drugs that are degraded in acidic environment of
stomach (e.g. Insulin).
 Drugs that undergo a significant first-pass
metabolism (e.g. Nifedipine).
 Drugs that have very limited acid solubility (e.g.
Phenytoin).
20
 APPROACHES FOR PROLONGING
THE GASTRIC RESIDENCE TIME
HD
S
F
1. High-density systems. S
(HDS) S
S
2. Floating systems. (FS)
3. Swelling and
expanding systems.
(SS)
4. Mucoadhesive &
Bioadhesive systems.
(AS)
5. Magnetic systems(MS)
6. Superporous 21
hydrogels(SH)
HIGH DENSITY SYSTEMS

❑ Gastric contents have a density close

to water (~1.004).
❑ A density 2.6-2.8g cm-3 is necessary
for significant prolongation of gastric
residence time(threshold value).
❑ When the patient take high-density pellets ,
they sink to the bottom of the stomach where
they become entrapped in the folds of the
antrum and withstand the peristaltic waves of
the stomach wall.

22
HIGH DENSITY MATERIALS:
The commonly used excipients in high density
system includes high density compounds
such as;
 barium sulphate, (4.9g/cm3)

 zinc oxide,

 iron powder,

 titanium dioxide.

Drug release follows

simple diffusion through
Polymer membrane.
23
DRAWBACKS OF HIGH DENSITY SYSTEM
 The major drawback with such systems is that it
is technically difficult to manufacture them with
a large amount of drug (>50%) and to achieve the
required density.
 It is unpredictable;whether the dosage form will
stand peristaltic movement or not.

24
EXPANDABLE SYSTEMS
Expandable systems are also called as plug type
systems. They achieve larger size in stomach.
Based on three configurations:
 A small collapsed configuration which enables
sufficient oral intake
 Expanded form that is achieved in the stomach and
thus prevents passage through the pyloric sphincter.
 A smaller form that is achieved in the stomach when
the retention is no longer required i.e. after the
system has released its active ingredient, thereby
enabling evacuation.
These systems include;
 Unfold able systems
 Swelling systems 25
UNFOLDABLE SYSTEM:
 Unfolding systems are systems which are
actually of larger size but they are folded to
decrease size and kept in capsules. In
stomach these systems comes out of
capsules and unfolds to larger size.
 Made of biodegradable polymers
(gelatin). The concept is to make a carrier,
such as a capsule, incorporating a
compressed system which extends in the
stomach.
 shape memory 26
 Different geometric forms of unfoldable
systems
27
SWELLABLE SYSTEMS

❑ Swelling system are generally matrix system

containing hydrocolloids which by action of
hydration and osmosis get swelled.
❑ The dosage form is small enough to be
swallowed, and swells in gastric liquids.
❑ The bulk enables gastric retention and maintain
the stomach in fed state, suppressing
housekeeper waves.

28
IMPORTANT FACTORS:

 Swelling index means how much fold it can

increase in volume
 swelling time are the important factor for such
systems.
 Optimum amount of cross linking is required to
maintain balance between swelling and
dissolution of hydrogel.

29
 Gastric
Fluid

High degree
of Cross-
linking

Time
Low degree
of Cross-
linking
Gastric
Fluid
POLYMERIC ENVELOP AND TINY PILLS IN
THE MATRIX:

31
Picture of tablet in Dry and Wetted state
32
DRAWBACKS:

✓ The Dosage form must maintain a size larger

than pyloric sphincter

✓ The Dosage form must resist premature gastric

emptying

33
SUPER POROUS HYDRO GELS

• Swellable agents with pore size ranging between 10nm

and 10µm are used.
• Absorption of water by conventional hydrogel is very slow
process and several hours may be needed to reach as
equilibrium state during which premature evacuation of
the dosage form may occur.
• Superporous hydrogels swell to equilibrium size with in a
minute, due to rapid water uptake by capillary wetting
through numerous interconnected open pores.
• They swell to large size and are intended to have
sufficient mechanical strength to withstand pressure by
the gastric contraction. 34
POLYMERS:
 This is achieved by co-formulation of a
hydrophilic particulate material , and Ac-Di-Sol.
(crosscarmellose)

35
MUCOADHESIVE OR BIOADHEDIVE SYSTEM
 The technique involves coating of microcapsules with
bioadhesive or mucoadhessive polymer, which
enables them to adhere to the gastric epithelial cells
or mucin and remain for longer time period in the GI
while the active drug is released from the device
matrix.
Bioadhesion(Ab) is dependent on polymer
concentration (c),represented by quadratic equation as;
Ab=a + a1c + a2c²
o

Where a a1 a2 are constants.

o

36
MECHANISM OF BIO/MUCO-ADHESION
 Hydration – mediated adhesion
 Bonding –mediated adhesion

 Receptor – mediated adhesion

37
MUCOADHESIVE ORAL DRUG DELIVERY SYSTEMS
Drug Dosage form Mucoadhesive
polymer

Glipizide Microcapsules HPMC, Sodium

CMC,MC,Carbopol
Metoclopramide Microcapsules Chitosan

Diltiazem Hcl Tablet HPMC, Sodium CMC

Sucralfate Tablet Methocel E4M

DRAWBACKS:

 Continuous production of mucous may limit

muco adhesion.
 Bio adhesion may cause local irritation.

39
MAGNETIC SYSTEMS

• This system is based on a simple idea: the

dosage form contains a small internal magnet,
and a magnet placed on the abdomen over the
position of the stomach.
Drawbacks:
• Although these systems seem to work, the
external magnet must be positioned with a
degree of precision that might compromise
patient compliance.

40
FLOATING SYSTEMS:
 Floating drug delivery systems (FDDS) have a
bulk density less than gastric fluids and so
remain buoyant in the stomach without affecting
gastric emptying rate for a prolonged period of
time.
 While the system is floating the drug is released
slowly at the desired rate from the system.
 After release of drug, the residual system is
emptied from the stomach. This results in an
increased GRT and a better control of the
fluctuations in plasma drug concentration.
41
CLASSIFICATION:
• Noneffervescent systems
1. Single-unit floating dosage system
2. Multiple unit floating dosage system

• Effervescent (gas-generating) systems

1. Single-unit floating dosage system
2. Multiple unit floating dosage system

• Raft-forming systems

42
NON EFFERVESCENT SYSTEMS
Single unit
1. Floating tablets(MATRIX TABLET)
2. Floating capsules(HBS capsules)
3. Tablets with hollow cylinder
4. Microporous reservior
5. Multilayer flexible film

43
1.MATRIX TABLET
 Incorporating gel forming hydrocolloids HPMC,
which is the most commonly used polymer for
floating.
 Out of various grades of HPMC, low viscosity
grade are used for floating purpose.
 Mixture of alginate and HPMC also prepared for
floating tablet.

44
Single Layer Tablet Bilayer Tablet

Loading Dose

45
2.FLOATING CAPSULES:

HBS Capsules:
➢ It is Hydrodynamically Balanced System. It is a hard
gelatin capsule containing drug with high level of one
or more highly swellable gel forming hydrocolloids
(20-75%) like HPMC, HPC, HEC, Na-CMC etc.
➢ When coming in contact with water, the hydrocolloids
at the surface of the system swell and facilitate
floating.
 Gel structure controls rate of diffusion of fluid-in and
drug- out making “Receding Boundary”.
 After exterior surface dissolves/erodes, the immediate
adjacent hydrocolloid layer is hydrated and process 46
continues to give floating for extended period of time.
1. HBS CAPSULES

47
3.TABLETS IN The device consisting of
two drug-loaded HPMC
CYLINDER matrix tablets, which are
placed within an
HPMC matrix impermeable, hollow
tablet polypropylene cylinder (open
polypropylene
at both ends). Each matrix
tablet closed one of the
cylinder’s ends so that an air-
filled space was created in
AIR between, providing a low
total system density. The
device remained floating
until at least one of the
HPMC matrix tablets is dissolved.
48
tablet
4.MICROPOROUS
RESERVIOR • Drug reservoir encapsulated
in microporous compartment
having pores on its top and
bottom walls
• Peripheral walls are sealed,to
prevent direct contact with
gastric fluid
• A floating chamber was
attached at one surface
which gives buoyancy to
entire device. Drug slowly
dissolves out via micro pores
49
5.MULTI-LAYER FLEXIBLE FILM:
The device consist of two films which are sealed
together along their periphery and in such a way
as to entrap some air between two films and so make
air pocket which imparts buoyancy.

50
MULTIPLE UNIT:
 Reduce the inter subject variability in absorption
 Lower the probability of dose dumping.

 Available as
 Beads,
 Micro-spheres,
 Micro-balloons,
 Carrier system.

51
A. Beads

1.CALCIUM ALGINATE/PECTINATE BEADS

2.ALGINATE BEADS with AIR COMPARTMENT
3.OIL ENTRAPPED GEL BEADS
4.CASEIN – GELATIN BEADS

52
 1.CALCIUM ALGINATE/PECTINATE BEADS
IONOTROPIC GELATION METHOD
porous beads with about 12 hrs buoyancy period &
residence time of 5.5 hrs

Sodium Calcium Spherical Separate,

Alginate Dropped to Freeze Dried
Chloride Gel
Solution Solution Beads(2.5 (-40oC)
mm) 24hrs

Calcium Pectinate Gel Beads

Calcium-Alginate-Pectinate Gel beads(fasten drug release)
Calcium Alginate + Chitosan Gel Beads(air entrapement53
gives Better buoyancy)
2.ALGINATE BEADS with AIR COMPARTMENT
During the preparation of calcium alginate beads before
drying process the beads are coated with the coating solution
which may be calcium alginate or mixture of calcium alginate
and PVA(water soluble additive in coating composition which
increase membrane permeability), and then they are dried
Alginate Bead
in Solution,
before Drying

Coating
before Drying
After Drying
Shrinkage of Bead 54
 3.OIL ENTRAPPED GEL BEADS

Oil – Light weight and Hydrophobic

Pectin has some Emulsification property

Aqueous
Solution of
Pectin
homogenization extruded to Calcium
Emulsion Chloride
Edible Solution
Veg. OIL

55
56
 4.CASEIN – GELATIN BEADS

• Casein has Emulsification property- Entraps Air Bubbles

• Biodegradable beads

Casein Gelatin
Solution (60oC) Rapid
Cooling
Rapidly stirred (5co ) Cooled Separated
Emulsion Acetone and
Add to
Preheated
Dried
Mineral Oil
At Reduced Pressure – NO AIR – Non Floating Beads 57
B.HOLLOW MICROSPHERE
Or MICROBALLOON
Emulsion-solvent diffusion method

• Agitate solution of PVA and thermally control at 40 degree Celsius.

• Ethanol-dichloromethane solution of drug and polymer was poured
into it.

Polymers such as polycarbonate and cellulose acetate were used in the 58

preparation of hollow microspheres.
 Mechanism of drug release:

When microspheres come in contact with gastric fluid

the polymer forms a colloidal gel barrier that controls
the rate of fluid penetration into the device and
consequent drug release.

59
d) Carrier systems

CALCIUM SILICATE AS FLOATING CARRIER

• Granules of calcium silicate as a floating
carrier, which has a characteristically porous
structure .
• Air trapped in the pores of calcium silicate when
they were coated with polymer(HPC).

Highly Porous

Large Pore Volume

Low Inherent Density 60

EFFERVESCENT SYSTEMS:
 Gas generating system
 Matrix tablets
 Single layer tablets
 Bilayer tablets

 Multi unit floating pills

 Floating based on ion exchange resin
 Volatile liquid containing system
 Deformable unit with inflatable chamber
 Osmotically controlled DDS

61
1.GAS GENERATING SYSTEM
Effervescent reaction between carbonate/
bicarbonate salts and citric/tartaric acid to liberate
CO2,which get enrtapped in the gellified
hydrocolloid layer of the system,decreasing its bulk
density and making it float over chyme.
Matrix tablets:
 Single layer:
CO2 generating components intimately mixed
within tablet matrix.(HPMC,Chitosan,alginate)
 Bilayer tablets:
Gas generating components comprssed in one
hydrocolloid containing layer and drug in other 62
formulated for SR.
FLOATING PILLS

NaHCO3

Tartaric Acid

DRUG

Swellable Polymer
(PVA and shellac)
63
ION EXCHANGE RESIN BEADS

H+ Cl
H+ Cl

HCO3
HCO3
Resin H+ Cl

HCO3

H+ Cl H+ Cl 64
Uncoated Beads – No Floating – Escape of CO2
Volatile liquid containing system:
1.Osmotically controlled DDS
This system consists of
mainly two different part
attached with each other, one
is floating part and other is
osmotic controlled part
Floating part made up of
deformable polymeric bag
containing liquid that gasify at
body temperature.Osmotic
pressure controlling part
consists of two part, drug
reservoir & osmotically
active compartment. 65
2.Deformable unit with inflatable chamber

These type of systems consist of two chambers separated by

an impermeable, pressure-responsive,movable bladder.
• The first chamber contains the drug impregnated polymeric matrix
• and the second chamber contains the volatile liquid(ether).
• Both enclosed in gelatin shell.
The device inflates, and the drug is continuously released from
the reservoir into the gastric fluid.

66
• Raft-Forming Systems

• This system is used for delivery of antacids and drug

delivery for treatment of gastrointestinal infections and
disorders.
• These are liquid preparations having gel forming
agent(alginic acid),Na-bicarbonates and drug, which forms
foaming Na-alginate gel, while reacting with gastric acids.
• This raft floats in gastric fluids because of the low bulk
density created by the formation of CO2
• The raft has pH value higher than that of stomach contents
so that in gastric reflux the wall of oesophagus is not 67
subjected to irritation by HCl.
 Brand Name Drug (dose) Company
Levodopa (100 mg),
Madopar® (HBS) Roche, USA
Benserazide (25 mg)
Hoffman LaRoche,
Valrelease® (HBS) Diazepam (15 mg)
USA
Liquid Gaviscon® GlaxoSmithKlein,
Al(OH)3 + MgCO3
(RAFT SYSTEM) India
Pierre Fabre Drug,
Topalkan® Liquid Al – Mg antacid
France
Almagate
Al – Mg antacid
Flotcoat®
Conviron® Ferrous sulfate Ranbaxy, India
Cifran OD® Ciprofloxacin (1 g) Ranbaxy, India
68
Cytotec® Misoprostal (100/200 g) Pharmacia, USA
 EVALUATION OF GRDDS
Evaluation of a drug product is a tool to ensure-
1. Performance characteristics, and
2. Control batch to batch quality
A) IN-VITRO EVALUATION
1) Floating systems
a) Buoyancy Lag Time
It is determined in order to assess the time taken by
the dosage form to float on the top of the dissolution
medium, after it is placed in the medium.

69
b) Floating Time
Test for buoyancy is usually performed in
SGF(Simulated Gastric Fluid) maintained at 370C.
“The time for which the dosage form continuously
floats on the dissolution media is termed as
floating time”
c) Specific Gravity / Density
Density can be determined by the displacement
method using Benzene as displacement
medium
70
d)Resultant Weight
The magnitude and direction of force/resultant weight (up or down) is
corresponding to its buoyancy force (Fbuoy) and gravity force (Fgrav)
acting on dosage form.
F = Fbuoy – Fgrav
F = Df g V – Ds g V
F = (Df – Ds) g V
F = (Df – M/V) g V
Where,
F = resultant weight of object
Df = Density of Fluid
DS = Density of Solid object
g = Gravitational force
M = Mass of dosage form
V = Volume of dosage form
So when Ds is lower, F force is positive gives buoyancy and when it is Ds
is higher, F will negative shows sinking. 71
72
2)Swelling system

1)Swelling Index

2)Water Uptake / Weight Gain

WU = (Wt – Wo) * 100 / Wo

3)Penetration Rate

Water Uptake 2 r 2
PR =
Per Unit TimeX Water Density

73
3)Bio/Mucoadhesive system:
Bioadhesion strength measurement
Force measuring device
(modified precision balance
Or automated texture
analyzer.
Upper jaw

Polymer
Membrane

Lower jaw
• Methods to measure
gastroretentivity of GRDFs

• Magnetic Resonance Imaging

• It is a noninvasive technique and allow observation of total
anatomical structure in relatively high resolution.
• The visualization of GI tract by MRI has to be further improved
by the administration of contrast media.
• For solid DFs, the incorporation of a superparamagnetic
compound such as ferrous oxide enables their visualization by
MRI.

• Radiology (X-Ray)
• In this technique a radio-opaque material has to be incorporated
in the DF, and its location is tracked by X-ray picture.
75
• ɣ-Scintigraphy

• Gamma scintigraphy relies on the administration of a

DF containing a small amount of radioisotope,
e.g.,152Sm,which is a gamma ray emitter with a
relatively short half life.

• Gastroscopy

• Gastroscopy is commonly used for the diagnosis and

monitoring of the GI tract.
• This technique utilizes a fiber optic or video system
and can be easily applied for monitoring and locating
GRDFs in the stomach. 76
ULTRASONOGRAPHY
Used sometimes, not used generally because it is
not traceable at intestine.

13 C octanoic acid breath test

Type equation here.
After ingestion of the dosage form, the time
duration after which 13 CO 2 gas is observed in
the breath indicates the transfer of the dosage
form from the stomach to the upper part of the
small intestine, which may be considered as the
gastric retention time of the dosage form.
77
• Limitations
Floating system
▪ They require a sufficiently high level of fluids in the
stomach for the drug delivery buoyancy, to float
therein and to work efficiently.

▪ Drugs which are well absorbed along the entire GI

tract and which undergoes significant first- pass
metabolism, may not be desirable candidates for
GRDDS since the slow gastric emptying may lead to
reduced systemic bioavailability.

78/5
9
Drugs
Unstable in Stomach / Acidic pH
Very Low Soluble / insoluble
Causes irritation
Adhesive
High Turn Over Rate of MUCUS LAYER
Thick Mucus Layer
Presence of Soluble Mucin
Swelling
Exit before Swells – Slow Swelling Rate
Capable to Resist House Keeper Waves 79
REFERENCES
• Viney Kumar et al.,Int.J.Rev.Life.Sci.,1(2),2011,62-67
• International Journal of Research in Pharmaceutical
and Biomedical Sciences ISSN: 2229-3701
• Bardonnet PL, Faivre V, Pugh WJ, Piffaretti JC,
Falson F. Gatroretentive dosage forms: Overview and
special case of Helicobacter pylori. J Control Release.
2006;111:1-18.
• Ecyclopedia of Pharmaceutical Technology.
• Hari Vardhan Reddy L and Murthy RSR. Floating
Dosage Systems in Drug Delivery. Critical Revises in
Therapeutic Drug Carrier Systems. 2002;19(6):553-
585.
80
• Rouge N, Buri P, Doelker E. Drug absorption
sites in the gastrointestinal tract and dosage
forms for site specific delivery. Int J Pharm.
1996; 136:117-139.
• Julan UD. Floating Drug Delivery Dystem: An
Approach to Gastroretension. Latest Reviews.
2007;5(1).
• Shweta A, Javed A, Alka A, Roop K, and Sanjula
B. Floating drug delivery systems: a review.
AAPS PharmSciTech. 2005;6 (3) Article 47.

81
82
83/5
9
 LIPOSOMES
A Novel Drug Delivery System

Ch. Sherjeel Adnan

DEPARTMENT OF PHARMACY

THE UNIVERSITY OF LAHORE

 Liposomes
Introduction:

• Discovered by Alec Bangham of Babraham Institute in Cambridge, England

in 1965.
• In 1990, drugs with liposome containing Amphotericin B were approved by
Ireland.
• In 1995 America F.D.A approved Liposor doxorubicin.
• “Liposomes are microscopic spherical vesicles that are formed when
phospholipids are hydrated or exposed to an aqueous environment.”
• Microscopic vesicles composed of bilayer of phospholipids or any similar
amphipathic (molecule containing both polar (water-soluble) and non polar
(not water-soluble) portions in its structure) lipids.
• Encapsulate and deliver both hydrophilic and lipophilic substances.
 Characteristics of Liposomes

• Lipid bilayer nature (amphiphilic also called

amphipathic nature): polar head covalently attached
to one or two hydrophobic hydrocarbon tails.
• When these lipids exposed to an aqueous
environment, interactions between themselves
(hydrophilic interactions between polar head groups
and vander-waals interactions between hydrocarbon
chains and hydrogen bonding with water molecules)
lead to formation of closed bilayer.
 Size:
• Smallest vesicle liposome visible under light microscope, with diameter of
1µm or greater.
• Liposomes carry drugs in 1 or 3 potential compartments;
• Water soluble agents in central aqueous core.
• Lipid soluble agents in membrane.
• Peptide and small proteins at lipid aqueous interface.
 Classification:

• Lamella: A Lamella is a flat plate like structure that

appears during the formation of liposomes. The
Phospholipid bilayer first exists as a lamella before
getting converted into spheres.
• Based on number of lamellas there are two types:
• 1. Unilamellar Vesicles
• 2. Multilamellar Vesicles
 Based on size

• MLVs (multilamellar vesicles) 0.05-0.25µm

• LUVs (unilamellar vesicles) 100-1000nm.
• Medium 40-80 nm.
• SUVs (small unilamellar vesicles) 20-40nm.
• MVs (multi vesicular system) >1000nm.
 Based on method of preparation
• REV- single vesicle made by Reverse phase
evaporation method.
• SPLV-Sonicated plurilamellar vesicles.
• FATMLV-Frozen and Thawed MLVs
• VET-vesicle prepared by extrusion technique.
• DRV-dehydration-rehydration vesicles also called
dried reconstituted vesicles
 Loading of Drug in Liposomes

• Two methods are followed:

• Passive loading
• Remote loading

• Passive loading
It involves the loading of entrapped agents before or
during manufacture procedure.
• Remote loading
Certain types of compounds with ionisable groups, and
those which display both lipid and water solubility, can be
introduced into the liposomes after the formation of intact
vesicles.
 Interaction of Liposomes with cell:
• In vitro and in vivo studies of the interactions with cells
have shown that the predominant interaction of liposomes
with cells is either:
• Simple adsorption
• Subsequent endocytosis.
• Fusion with cell membrane is much more rare.
• Exchange of bilayer constituents such as lipids,
cholesterol and membrane bound molecules with
component of cell membrane
 Passive Loading Techniques:
• Mechanical dispersion Methods of Passive Loading:
• Thin Film Hydration Using Hand Shaking (MLVs) and Non-
Hand Shaking Methods(LUVs):
This method was first described in detail by Bangham
for the preparation of MLVs. In the procedure; the
phospholipids are dissolved in an organic solvent
(usually a chloroform/methanol mixture) and
deposited from the solvents as a thin film on the wall
of a round bottom flask by use of rotary evaporation
under reduced pressure. MLVs form spontaneously
when an excess volume of aqueous buffer containing
the drug is added to the dried lipid film. The
mechanical energy required for the swelling and
dispersion of lipid film is imparted by manual agitation
(hand shaking) or by exposing film to a stream of
water-saturated nitrogen for 15mins followed by
swelling of lipid in aqueous media without hand
shaking(non-shaken vesicles).
• It is interesting to note that as compare to hand shaking
method (that produces MLVs) the vesicles produced by
non-shaken method are LUVs .Drug containing
liposomes can be separated from non sequestered drug by
centrifugation of the liposomes or by gel filtration. The
time allowed for hydration of the dried film and
conditions of agitation are critical in determining the
amount of the aqueous buffer (or drug solution) that will
be entrapped within the internal compartments of the
MLVs. For instance, it is reported that more of the
aqueous phase can be sequestered when the lipid is
hydrated for 20 hours with gentle shaking, compared with
a hydration period of two hours, with vigorous shaking of
the flask, even though size distribution of the MLVs was
unaffected. This means that slow hydration is associated
with greater entrapment of aqueous volume.
 Pro-Liposomes:

• In order to increase the surface area of dried lipid film

and to facilitate instantaneous hydration, the lipid
film is dried over a finely divided particulate support,
such as powdered NaCl, or sorbitol or other
polysaccharides. These dried lipid coated particulates
are called Pro-liposomes. Pro liposomes form
dispersions of MLVs on adding water into them
where support is rapidly dissolved and lipid film
hydrates to form MLVs.
 Mechanical Treatment of formed
MLVs:
• Multi lamellar vesicles formed on hydration of dried
lipid film could further engineered or modified for their
size and other characteristics. A large number of
methods are devised to reduce size range and to convert
liposomes of the large size range into small
homogenous vesicles. These include techniques such as
micro-emulsification, extrusion, ultrasonication and use
of French pressure cell. A second set of methods that
are used to increase the entrapment volume of hydrated
lipids and/or to reduce the lamellarity of the vesicles
formed, these include Freeze-drying, freeze thawing or
induction vesiculation by ions or pH change.
 b) Sonication Method:
• At high energy level, the average size of the vesicles is further reduced. This
was first achieved by exposure of MLVs to ultrasonic irradiations. This
method is used in the preparation of SUVs and it involves the subsequent
sonication of MLVs prepared by the mechanical dispersion of lipid film
either with a bath type or a probe type sonicator under an inert atmosphere,
usually nitrogen or argon. The principle of sonication involves the use of
pulsed, high frequency sound waves (sonic energy) to agitate a suspension of
the MLVs. Such disruption of the MLVs produces SUVs with diameter in the
range of 15–50nm. The purpose of sonication, therefore, is to produce a
homogenous dispersion of small vesicles with a potential for greater tissue
penetration. The commonly used sonicators are of the bath and probe tip
type. A probe tip sonicator delivers high sonic energy to the lipid suspension
but has the disadvantage of overheating the lipid suspension to cause
degradation. The probe tip also tends to release titanium particles into lipid
suspension, which must be removed by centrifugation.
• For this reason, bath sonications are the more
widely used. By this technique, a test tube
containing the suspension is placed in the bath
sonicator and sonicating for 5–10 minutes above
the transitional temperature of the lipid (i.e., the
temperature at which the lipid melts).
Comparatively, sonication with a probe results in
faster breakdown of the MLVs to smaller structures
than can be achieved by a bath sonication. The
reduction in size of the liposomes, however, also
decreases the amount of interior aqueous space,
thereby limiting the amount of water-soluble drugs
that can be entrapped.
• However, degradation of lipids, metal particle shedding from
the probe tip (titanium particles) and generation of aerosols
from solutions containing radioactive traces, carcinogenic
chemicals or infectious agents that have been added to the
preparation by probe technique could cause serious
biohazards, which are less frequently encountered with bath
sonication. Bath sonication is a closed system allowing for
temperature control to minimize thermo degradation of the
lipid and entrapped substance. The position of the tube and
water level in the bath is also regulated for maximum
efficiency. The major drawbacks in the preparation of
liposomes by sonication include oxidation of unsaturated
bonds in the fatty acid chains of phospholipids and
hydrolysis of phospholipids to free fatty acids. Another
drawback is the denaturation or inactivation of some thermo
labile substances (e.g., DNA, certain proteins, etc) to be
entrapped.
 C) French Pressure Cell Liposomes:

• The ultrasonic radiations not only degrade the lipids but

also macromolecules and other sensitive compounds,
which are to be, entrapped in liposomes e.g. drugs. One
of the first and still very useful methods developed is
extrusion of pre formed large liposomes in a French
press under very high pressure.
• This technique yields rather uni- or oligo- lamellar
liposomes of intermediate size (30-80nm in diameter
depending on the applied pressure). These liposomes
are more stable as compared to sonicated liposomes.
 D) Micro Emulsification Liposomes (MEL):
• Micro fluidizer is used to prepare small MLVs from concentrated lipid
dispersion. Microfludizer pumps the fluid at very high pressure (10,000psi,
600-700bars) through a 5um orifice. Then it is forced along defined micro
channels, which direct two streams of fluid to colloid together at right
angles at a very high velocity, thereby affecting an efficient transfer of
energy. The lipids can be introduced into the fluidizer, either as a dispersion
of large MLVs, or as slurry of unhydrated lipid in an organic medium. The
fluid collected can be recycled through the pump and interaction chamber
until vesicles of the spherical dimension are obtained.
• After a single pass, the size of vesicles is reduced to a size 0.1 to 0.2 µm in
diameter. In addition to the high rate of production, this method has the
advantage of being able to process samples with a very high proportion of
lipids (20% or more by weight). This process is efficient for encapsulation
of water soluble materials. Percentage capture values up to 70% have been
reported.
 e) Vesicles prepared by Extrusion Technique
(VETs):
• This is another method for converting MLV to SUV suspensions. By this
method, suspensions of MLVs (prepared by the mechanical dispersion
method) are repeatedly passed through filters polycarbonate membranes
with very small pore diameter (0.8–1.0µm) under reduced pressure
(<100psi).
• By choosing filters with appropriate pore sizes, liposomes of desirable
diameters can be produced. The mechanism of action of this method
appears to be much like peeling an onion. As the MLVs are forced through
the small pores, successive layers are peeled off until only one remains.
Besides reducing the liposome size, the extrusion method produces
liposomes of homogeneous size distribution. A variety of different lipids
can be used to form stable liposomes by this method. Extrusion at low
pressures <1Mpa is possible when lipid concentration is low, but the most
commonly used pressures are about 5Mpa. The method is amenable to
small scale production only. In order to overcome this problem, Schneider
and co-workers designed and tested a new continuous extrusion apparatus,
which operates at high pressures of up to 10.5Mpa with the advantage of a
high output. (1 Psi = 0.00689475729 Megapascals Mpa)
 f ) Dried Reconstituted Vesicles: (DRVs)
• This method starts with freeze drying of a dispersion of empty SUVs and
then rehydrating it with the aqueous fluid containing the material to be
entrapped. This leads to a dispersion of solid lipids in finely subdivided
form. However the step of freeze drying is used to freeze and lyophilize a
preformed SUVs dispersion rather than to dry the lipids from an organic
solution (as in the case of other methods). This leads to an organized
membrane structure as compared to random matrix structure which on
addition of water (one tenth of volume of original SUVs) can rehydrate,
fuse and reseal to form vesicles with high capture efficiency. The water
soluble materials to be entrapped are added to the dispersion of empty
SUVs and they are dried together, so the material for inclusion is present in
the dried precursor lipid before the final step of addition of aqueous
medium.
• Liposomes obtained by this method are usually uni- or oligo- lamellar of
the order of the 0.1 µm or less in diameter.
 g) Freeze Thaw Sonication (FTS) Method:
• FTS method is the extension of classical DRV method. The
method is based on freezing of unilamellar (mainly SUVs)
dispersion and then thawing by standing at room temperature
for 15min (cf. DRV method where the freeze-dried lipids are
rehydrated with aqueous buffer) and finally subjecting to a
brief sonication cycle. Thus the process ruptures and re-fuses
SUVs during which the solute equilibrates between inside and
outside, and the liposomes themselves fuse and increase
markedly in size. Similar to DRV, the starting preparation of
empty liposomes is made by sonication and after thawing; the
liposomes are subjected to brief sonication again. The second
sonication considerably reduces the permeability of the
liposome membrane, perhaps by accelerating the rate at which
packing defects are eliminated.
 Other Methods:

• pH Induced Vesiculation
• Calcium Induced fusion
• Cochleate Method
• 2- Solvent Dispersion Methods of Passive
Loading:
• In solvent dispersion method, lipids are first
dissolved in an organic solution, which is then
brought into contact with an aqueous phase
containing materials to be entrapped within the
liposomes. The lipids align themselves at the
interface of organic and aqueous phase forming
monolayer of phospholipids, which forms the
half of the bilayer of the liposomes.
a) Ethanol Injection Method

• This method has been reported as one o the

alternatives for the preparation of SUVs without
sonication. An ethanol solution of lipids is injected
rapidly through a fine needle into an excess of saline or
other aqueous medium. The rate of the injection is
usually sufficient to achieve complete mixing, so that
the ethanol is diluted almost instantaneously in water,
and Phospholipid molecules are dispersed evenly
throughout the medium. This procedure yields a high
proportion of SUVs (~25nm), although lipid aggregates
and larger vesicles may form if the mixing is not
thorough enough. This method is extremely simple and
has low risk of degradation of sensitive lipids.
 b)Ether Injection Method:

• Ether injection method is similar to the ethanol

injection method however it contrasts markedly
with ethanol injection in many respects. It
involves injecting the immiscible organic solution
very slowly into an aqueous phase through a
narrow needle at the temperature of vaporizing
the organic solvent. This method may also treat
sensitive lipids very gently. It has little risk of
causing oxidative degradation provided ether is
free from per oxides. Its drawback is long time
taken to produce batch of liposomes and a careful
control needed for introduction of lipid solution.
 c) Rapid Solvent Exchange Vesicles
(RSEVs):
• This method has been a recent addition to the field of methodology of
liposome preparation. In this method principally, the lipid mixture is
quickly transferred between an essentially pure solvent environment and a
pure aqueous environment. This method is specifically designed to form
compositionally homogenous dispersion by sudden precipitation of a lipid
mixture in an aqueous buffer. Phospholipid/ cholesterol dispersion turns to
be free of artificial crystals when prepared by rapid solvent exchange
method.
• The method involves passing the organic solution of the lipids through the
orifice of blue-tipped syringe (injection needle) under the vacuum into a
tube containing aqueous buffer. The tube is mounted on the vortexer. Bulk
solvent vaporizes and is removed within seconds before coming in contact
with aqueous environment, while the lipid mixture rapidly precipitates in
aqueous buffer. Since the method is specifically designed for the fast and
efficient removal of organic solvent, it doesn’t require a highly volatile
solvent. RES liposomes require not more than a minute for preparation and
manifest high entrapment volumes with a high fraction of external surface
area.
•
 d) Reverse Phase Evaporation Technique:
• It consists of a rapid injection of aqueous solution of the drug
into an organic solvent, which contains the lipid dissolved with
simultaneous bath sonication of the mixture leading to the
formation of water droplets in the organic solvent (i.e., a
“water-in-oil” emulsion).
• The resulting emulsion is dried down to a semi solid gel
in a rotary evaporator. The next step is to subject the gel
to vigorous mechanical agitation to induce a phase
reversal from water-in-oil to oil-in-water dispersion
(i.e., an aqueous suspension of the vesicles).
• During the agitation, some of the water droplets
collapse to form the external phase while the remaining
portion forms the entrapped aqueous volume. Large
unilamellar vesicles (diameter 0.1–1µm) are formed in
the process. This method has been used to encapsulate
both small and macromolecules such as RNA and
various enzymes without loss of activity. The expected
limitation of this method is the exposure of the material
to be encapsulated to organic solvents and mechanical
agitation, which can lead to the denaturation of some
proteins or breakage of DNA strands.
 • Storage of Liposomes

• Liposome dispersions are potentially prone to

hydrolytic degradation and leakage. Hence, it is
desirable to freeze-dry the suspension to a powder
and store in this dried form. The powder can be
reconstituted to an aqueous suspension
immediately before use. By doing so, SUVs may
be converted to MLVs dispersion upon
rehydration. Addition of a carbohydrate (trehalose)
during freeze-drying prevents fusion and leakage
of the vesicles
 Pharmacokinetic considerations
• Most small molecular chemotherapeutic agents have a large
volume of distribution on intravenous (IV) administration of
liposomes. The result of this wide distribution is often a narrow
therapeutic index due to a high level of toxicity on healthy
tissues. Through encapsulation of drugs in liposomes, the
volume of distribution is significantly reduced and the
concentration of drug at the desired site of action increased. For
instance, liposomal drug delivery led to an increase in the
amount of drug that can be effectively delivered to tumour sites
in anticancer therapy. Liposomes are predominantly removed
from circulation by phagocyte cells of the reticuloendothelial
system (RES), thus accumulating to a large extent in organs
like liver and spleen. This bio distribution pattern can be used
for passive targeting of diagnostics to these organs. The RES
should, therefore be saturated with empty vesicles when other
sites are the drug targets. Information on bio distribution is,
therefore, important for drug targeting by liposomes.
• Liposomes given intravenously usually interact with at least two
distinct groups of plasma proteins. These are the plasma high density
lipoproteins and the so-called opsonins, which bind to the surface of
vesicles and mediate their endocytosis by thermonuclear phagocyte
system (macrophages).The rate of liposome clearance from blood
circulation will, therefore, depend on the ability of opsonins to bind to
the liposome surface. The rate can be manipulated through appropriate
selection of liposome characteristics. For instance, “fluid” vesicles are
removed more rapidly from blood circulation than “rigid” ones.
Clearance from the blood stream is also influenced by vesicle size and
surface charges. The longest half-life is obtained when liposomes are
relatively small (diameter <0.05µm) and carry no net surface charge.
The pharmacokinetic behavior of liposomes depends on the route of
injection such as intraperitoneal, subcutaneous or intramuscular route.
Lasic and Papahadjopoulos have shown that coating the liposome
surface with polyethyleneglycol and other hydrophobic part of
phospholipids substantially prolongs the half-life of liposomes in the
blood.
 Stability of liposomes

• Liposomes degrade rapidly as their shelf life is very small.

So it is very difficult to stabilize the liposomes.
• Types of De-stabilities:
• Physical de stability
• Chemical de stability
• Physical De-Stability:
• Leakage of drug contents
• Fusion of individual vesicles
• Aggregation of individual vesicles
• Chemical De-Stability:
• Oxidation
• Hydrolysis
• How to avoid Physical destability:-
• To prevent drug leakage, annealing is done.
• After preparation of liposomes, they are kept at a temperature below
the phase transition temperature of that liposome.
• Small vesicles fuse to form larger vesicles and make product unstable,
so to avoid this situation negative charge induction is done.
• To prevent aggregation, they may be converted to freeze dried form.
• Phase Transition:
• Temperature at which one phase is transformed to the other.
• Immediately after the formation, they are un-mature, if we keep at a
temp below the transition temperature, then phase transition is less
and they will become mature and drug leakage is prevented.
• How to avoid chemical destability:-
• Use freshly prepared solvents and phospholipids.
• Avoid procedures in which liposomes are exposed to high
temperature. i.e for removal of organic solvent from the medium. e.g
 Characterization of Liposomes
01) Size and size distributions:-
• To determine the Amount of the entrapped drug.
I. Microscopic Techniques
It include the followings:-
a) SEM ( Scanning electron microscopy)
b) Simple microscope
2. Laser diffraction method
3. Gel permeation chromatography
02) Morphology:-
• To determine the overall shape of the liposome.
• It can be detected by Electron microscope.
03) Lamellarity:-
• To determine the average no of bilayers present in the
liposomes.
a) Detected by NMR spectroscopy technique.
b) Or by Freeze Fractured Electron Microscopy.
04) Charge Determination:
• To determine the presence of charge and type of charge.
• Determination occurs by following methods.
a) Zeta Analyzer
b) Electrophoresis
05) Entrapment Efficiency:
• It determines that how much drug is entrapped inside vesicles.
a) Protamine Aggregation method
b) Minicolumn Centrifugation
• Remove the drug from each individual liposome by different
methods.
06) Entrapment Volume:
• It determines that how much volume of solvent is entrapped
inside individual liposome.
a) Determine the amount of solvent and then from it solute
quantity is measured.
b) Can also be determined by NMR spectroscopy analysis.
07) Phase Behaviour:
• Each phospholipid molecule have phase transition
temperature. At this temperature one form is converted into
another.
• Different temperatures are applied to liposomes to check the
temperature at which one phase changes into another. e.g
Gel ( Organized state) to fluid ( unorganized liquid form).
• It is determined by:
a) DSC ( Differential Scanning calorimetry )
b) Freeze fracture microscopic technique.
• Drug release:
• To determine that how much drug is released from
liposomes and at what rate it is released.
• Diffusion Cell
• Modified methods ( e.g Dialysis)
• Liposomal preparation is entrapped in a dialysis
tube or bags.
• Tubes are placed in solvent by 02 methods:
• Attached to paddle of dissolution apparatus.
• Or placed in solvent in apparatus.
• And through this drug release is determined.
 Biomedical Applications
• Both hydrophilic and hydrophobic drugs can be
encapsulated in liposomes. Liposomes are also
relatively non-toxic and biodegradable. They therefore
have a wide range of biomedical applications.

• 1-Protection against enzymatic degradation of drugs

• Liposomes are used to protect the entrapped drug
against enzymatic degradation whilst in circulation. The
basis is that the lipids used in their formulation are not
susceptible to enzymatic degradation; the entrapped
drug is thus protected while the lipid vesicles are in
circulation in the extracellular fluid.
• Upon penetration into the cell, the entrapped drug
is released either by diffusion through the
microsphere shell, dissolution of the shell or
degradation of the shell by lysosomal enzymes.
Thus, β-lactamase sensitive antibiotics, e.g., the
penicillins and cephalosporins have been
encapsulated due to this reason to protect against
the β- lactamase enzyme. Liposomes also offer
protection for its encapsulated drugs in the
environment of the gastrointestinal tract47 and
facilitate the gastrointestinal transport of a variety
of compounds.
• Liposomes are therefore candidates to be explored
for oral delivery of insulin and proteins for use as
vaccines, which are otherwise orally degradable.
Liposomes offer a number of advantages as
carriers of vaccine agents40 in that they are
biodegradable and non-toxic. Drugs encapsulated
in liposomes can elicit both humoral immunity
when given orally and cell-mediated immunity.
Liposomes are now being employed as oral
vaccines in numerous immunization procedures.
Twenty five years after the discovery of the
immunological adjuvant properties of liposomes,
they are now considered the major candidate as the
base for oral vaccine against hepatitis A, which is
being licensed for use in humans.
 2-Drug targeting
• The need for “drug targeting” arises from a problem situation
whereby a drug administered (iv for example) enters the blood
stream and is distributed to varying extents throughout the
body when the actual desire is to deliver or direct the drug
selectively to its site of action. This site could be an organ
structure, a cell subset, or even an intracellular region. In such
a case pumping the drug throughout the whole body is not
only wasteful but, more fundamentally, it is also likely to lead
to undesirable side effects. On the other hand, restricting the
distribution of the drug to the specific target site should allow
for an increase in efficacy at low dose with attendant decrease
in toxicity. Hence, the benefits of drug targeting include
reduced drug waste, and it is possible to deliver a drug to a
tissue or cell region not normally accessible to the free or
untargeted drug.
• The approach for drug targeting via liposomes involves the use of ligands
(e.g., antibodies, sugar residues, apoproteins or hormones), which are
tagged on the lipidvesicles. The ligand recognizes specific receptor sites
and, thus, causes the lipidvesicles to concentrate at such target sites. By this
approach the otherwise preferential distribution of liposomes into the
reticuloendeothelial system RES (liver, spleen and bone marrow) is averted
or minimized. The preferential distribution of liposomes into the RES can
be modified by the incorporation in the liposome membrane of protein or
carbohydrates possessing specific affinity toward a target tissue or organ. A
ligand selection is based on its recognition by, and specificity for, the target
site. In cancer treatment, for example, one of the approaches is to target the
drug to tumor cells via receptor specific ligands, which may be specific
antibodies for antigens produced by the tumor cells. The first step,
therefore, is to determine the antigens that are produced by the tumor cells.
Also, molecules bearing oligosaccharide chains have been used as ligands
for direction, and specific attachment, to ganglion sites in cells.
 3-Topical drug delivery

• The application of liposomes on the skin surface has been proven to

be effective in drug
• Delivery to the skin. Liposomes increase the permeability of skin for
various entrapped drugs and at the same time diminish the side
effect of these drugs because lower doses are now required.
Liposomes have also found an important application in cosmetics
for skin care preparations. In this regard, the liposomes are applied
to the skin in the form of solution or in hydrogels. Hydrophilic
polymers are suitable thickening agents for the gels. However, the
liposomes may in certain instances be trapped in the polymeric
network of the hydrogels and, hence, impair bioavailability into the
skin. Nevertheless, Gabrijelcic found enhanced transport of
liposome-entrapped substances into the skin from hydrogels
prepared from xanthan gum. The enhanced drug transport into the
skin is attributed to the lipid nature of the vesicles, which serve as
carriers for the drug
 4-Treatment of human immunodeficiency virus (HIV)
infections

• Several antiretroviral nucleotide analogues have been

developed for the treatment of patients suffering from the
acquired immunodeficiency syndromes (AIDS). These
include antisense oligonucleotide, which is a new antiviral
agent that has shown potential therapeutic application
against HIV-1. These antiviral agents are able to combat
replication of the HIV by inhibiting reverse transcriptase
and, thereby, viral DNA synthesis. However, these agents
display a dose-related toxicity. The effective dose can be
reduced by encapsulation of such drugs in liposomes, thus
reducing the incidence of toxicity. The greater efficacy of
the liposomal formulation relates to the preferential uptake
of the liposomes into the virus compared with the host
tissue.
 5-Enhanced antimicrobial efficacy/ safety

• Antimicrobial agents have been encapsulated in

liposomes for two reasons. First, they protect the
entrapped drug against enzymatic degradation. For
instance, the penicillins and cephalosporins are
sensitive to the degradative action of β-lactamase,
which is produced by certain microorganisms.
Secondly, the lipid nature of the vesicles promotes
enhanced cellular uptake of the antibiotics into the
microorganisms, thus reducing the effective dose
and the incidence of toxicity as exemplified by the
liposomal formulation of Amphotericin-B
 Constraints in Commercialization of Liposomal
Preparation
• Two major constraints are identifiable. First, the
lipids needed for their preparation are very scarce,
should be of high purity and, hence, expensive.
Secondly, liposomal preparations are inherently
unstable and require special storage conditions
(below 00C) even when the products are freeze-
dried. As a result of this stability problem the
dosage forms are limited to injection (freeze-
dried) powders for reconstitution immediately
before use. As a result of these constraints only a
few products (e.g., liposomal amphotericin B)
have actually been commercialized in spite of the
large volume of research on liposomes.
 Advantages of Liposomes over Conventional Dosage
Forms:

• (i) Improved solubility of lipophilic and amphiphilic drugs.

Examples include Porphyrins, Amphotericin B, Minoxidil, some
peptides, and anthracyclines, respectively; furthermore, in some
cases hydrophilic drugs, such as anticancer agent Doxorubicin or
Acyclovir can be encapsulateded in the liposome interior at
concentrations several fold above their aqueous solubility. This is
possible due to precipitation of the drug or gel formation inside the
liposome with appropriate substances encapsulated.
• (ii) Passive targeting to the cells of the immune system, especially
cells of the mononuclear phagocytic system (in older literature
reticuloendothelial system).Examples are antimonials, Amphotericin
B, porphyrins and also vaccines, immunomodulators or
immunosupressors;
• (iii) Sustained release system of systemically or locally administered
liposomes. Examples are doxorubicin, cytosine arabinose,
cortisones, biological proteins or peptides such as vasopressin.
• (iv) Site-avoidance mechanism: liposomes do not
dispose in certain organs, such as heart, kidneys, brain,
and nervous system and this reduces cardio-, nephro-
,and neuro-toxicity. Typical examples are reduced
nephrotoxicity of Amphotericin-B, and reduced
cardiotoxicity of Doxorubicin liposomes.
• (v) Site specific targeting: in certain cases liposomes
with surface attached ligands can bind to target cells
(‘key and lock’ mechanism), or can be delivered into the
target tissue by local anatomical conditions such as leaky
and badly formed blood vessels, their basal lamina, and
capillaries. Examples include anticancer, anti infection
and anti inflammatory drugs;
• (vi) Improved transfer of hydrophilic, charged molecules
such as chelators, antibiotics, plasmids, and genes into
cells
 Role of PEG and Stealth Liposomes:

• Further advances in liposome research have been able to allow

liposomes to avoid detection by the body's immune system,
specifically, the cells of reticuloendothelial system (RES). These
liposomes are known as "stealth liposomes", and are constructed with
PEG (Polyethylene Glycol) studding the outside of the membrane.
The PEG coating, which is inert in the body, allows for longer
circulatory life for the drug delivery mechanism. However, research
currently seeks to investigate at what amount of PEG coating the PEG
actually hinders binding of the liposome to the delivery site. In
addition to a PEG coating, most stealth liposomes also have some sort
of biological species attached as a ligand to the liposome in order to
enable binding via a specific expression on the targeted drug delivery
site.
• These targeting ligands could be monoclonal
antibodies (making an immunoliposome),
vitamins, or specific antigens. Targeted
liposomes can target nearly any cell type in the
body and deliver drugs that would naturally be
systemically delivered. Naturally toxic drugs
can be much less toxic if delivered only to
diseased tissues. Polymersomes,
morphologically related to liposomes, can also
be used this way.
REFERENCES:

• Lasic, D.D., 1992, Liposomes, Am. Sci. 80, 20–31

• Lasic, D.D., 1988, The mechanism of liposome formation. A review,

Biochem. J. 256, 1–11.

• Bangham, A.D. and R.W. Horne, 1964, Negative staining of

phospholipids and their structured modofication by surface active
agents as observed in the electron microscope, J. Mol. Biol. 8,660–
668.
•
• Fielding MR. Liposomal drug delivery: advantages and limitations
from a clinical pharmacokinetics and therapeutic perpective.Clin
Pharmacokinet 1991; 21:155–164.
• Akbarieh M, Besner JG, Galal A and Tawashi R. Liposomal delivery system
for the targeting and controlled release of praziquantel. Drug Dev Ind
Pharm 1992; 18: 303–317.
•
• Lidgate DM, Felgner PL, Fleitman JS, Whatley J and Fu RC. Invitro and
invivo studies evaluating a liposome system for drug solubilisation.
Pharm Res 1988; 5: 759–764.
•
• Weiner N, Martin F and Riox M. Liposomes as drug delivery system. Drug
Dev Ind Pharm 1989; 15(10): 1523–1554.
•
• Frezard F. Liposomes: from biophysics to the design of peptide vaccines.
Braz J Biol Res 1999; 32(2): 181–189.
•
• Perez-Solar R. Liposomes as carriers of antitumor agents: toward a clinical
reality. Cancer Treat Rev 1989; 16: 67–82.
•
• Harrington KJ, Konstantinos N and Richard GV. Liposomal targeted
cytotoxic drugs for the treatment of cancer. J Pharm Pharmacol 2002; 54:
1573–1600.
• Leyland-Jones B. Targeted drug delivery. Semin Oncol 1993; 20: 12–17.
•
• Storm G and Crommelin DJA. Liposomes: quo vadis. Pharm Sci Tech Today 1998;
1:19–31.
•
• Gregoriadis G. Overview of liposomes. J Antimicrob Chemother 1991; 28(supp.
B):39–48.
•
• Xian-rong Q, Yoshie M and Tsuneji N. Effect of soybean-derived sterols on the in
vitro© CMS UNIBEN JMBR 2005; 4(1): 9-21
•
• Rogers JA and Aderson KE. The potential of liposomes in oral drug delivery. Crit Rev
Ther Drug Carrier System 1998; 13(5): 421–480.
•
• Senior J and Gregoriadis G. Stability of small unilamellar liposomes in serum and
clearance from the circulation: the effect of the phospholipid and cholesterol com-
ponents. Life Sci 1982; 30: 2123–2136.
• Goldbach P, Herve B, Pascal W and Andre S.Sterile filtration of liposomes: retention
of encapsulated carboxyfluorescein. Int J Pharm 1995; 117: 225–230.
•
• Yoshihara E and Nakae T. Cytolytic activity of liposomes containing
stearylamine. Biochim Biophys Acta 1986; 854: 530–546.
•
• Fendler JH. Optimising drug entrapment in liposomes: chemical
and biophysical consideration in liposomes in biological systems.
In: G Gregoriadis and AC Allison (Eds.). New York: John Wiley and
Sons Ltd, 1980; 87–100.
•
• Saetern AM, Flaten GE and Brandl MA. A method to determine
the incorporation capacityof camptothecin in liposomes. AASP
Pharm Sci Tech 2004; 5(3): article 40.
•
• Frezard F, Santaella C, Montisci MJ, Vierling P and Riess JG.
Florinated phospholipidbase liposomes: H+/Na+ permeability,
active doxorubicin encapsulation and stability in human serum.
Biochim Biophys Acta 1994;1194: 61–68.
 Niosomes
History:
❖ At present no available drug delivery system achieves the site specific delivery with
controlled release kinetics of drug in predictable manner. The concept of targeted
drug delivery is designed for attempting to concentrate the drug in the tissues of
interest while reducing the relative concentration of the medication in the remaining
tissues. In addition, loss of drug does not happen due to localization of drug, leading
to get maximum efficacy of the medication.
❖ Niosomes were first reported in the seventies as a feature of the cosmetic industry.
Later it was stated that niosomes are the non-ionic surfactant vesicles and like
liposomes are bilayered structures, which can entrap both hydrophilic and lipophilic
drugs either in an aqueous layer or in vesicular membrane, made up of lipids,
osmotically active, relatively stable, biocompatible, and non-immunogenic and
suitable delivery system for both hydrophilic and lipophilic drugs.
❖ It was also explained that the non – ionic surfactants are preferred because the
irritation power of surfactants decreases in the following
order:Cationic > anionic > amphoteric > non-ionic.
❖ Paul Ehrlich, in 1909, initiated the era of development for targeted delivery when
he proposed a drug delivery mechanism that would target directly to diseased cell.
Since then, number of carriers was utilized to carry drug at the target organ/tissue,
which include immunoglobulin, serum proteins, synthetic polymers, liposome,
microspheres, erythrocytes, niosomes etc. Among different carriers liposome and
niosomes are well drug delivery systems. Niosomes are one of the best among
these carriers.

Drug targeting can be defined as the ability to direct a therapeutic agent

specifically to desired site of action with little or no interaction with non-
target tissue.
Introduction:
Niosomes are a novel drug delivery system, in which the medication is encapsulated in a vesicle.
They are structurally similar to liposomes in having a bilayer, however, the materials used to
prepare niosomes make them more stable and thus niosomes offer many more advantages over
liposomes. Niosomes are promising vehicle for drug delivery and being non-ionic; it is less toxic
and improves the therapeutic index of drug by restricting its action to target cells. Niosomes have
recently been shown to greatly increase transdermal drug delivery and also can be used in targeted
drug delivery.
Definition: Niosomes are Concentric bilayer vesicles made up of non ionic surfactants
obtained by the hydration of synthetic surfactants, with or without incorporation of
cholesterol or other lipids.
Structure of Niosomes:
Niosomes are microscopic lamellar structures, which are formed on the admixture of
non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with
subsequent hydration in aqueous media.

Structurally, niosomes are similar to liposome, in that they are also made up of a bilayer.
However, the bilayer in the case of niosomes is made up of non-ionic surface active
agents rather than phospholipids as seen in the case of liposome. Most surface active
agents when immersed in water yield micellar structures; however some surfactants can
yield bilayer vesicles which are niosomes. Niosomes may be unilamellar or multilamellar
depending on the method used to prepare them.
The niosomes are made of a surfactant bilayer with its hydrophilic ends exposed on the
outside and inside of the vesicle, while the hydrophobic chains face each other within the
bilayer. Hence, the vesicle holds hydrophilic drugs within the space enclosed in the
vesicle, while hydrophobic drugs are embedded within the bilayer itself. The figure below
will give a better idea of what a niosomes looks like and where the drug is located within
the vesicle.
A typical niosomes vesicle would consist of a vesicle forming amphiphilic
i.e. a non-ionic surfactant such as Span-60, which is usually stabilized by
the addition of cholesterol and a small amount of anionic surfactant such
as di acetyl phosphate, which also helps in stabilizing the vesicle.

Size: The niosomes are very small, and microscopic in size. Their size lies in the nanometric scale. Based on
the vesicle size, niosomes can be divided into three groups.

• Small unilamellar vesicles (SUV, size=0.025-0.05 μm)

• Multilamellar vesicles (MLV, size=>0.05 μm)
• Large unilamellar vesicles (LUV, size=>0.10 μm)
Methods of preparation:
Niosomes are prepared by different methods based on the sizes of the vesicles and their distribution, number of
double layers, entrapment efficiency of the aqueous phase and permeability of vesicle membrane. Hand shaking
method forms vesicles with greater diameter (0.35-13 nm) compared to the ether injection method (50-1,000
nm). Small-sized niosomes can be produced by Reverse Phase Evaporation (REV) method. Micro fluidization
method gives greater uniformity and small-sized vesicles.

•Preparation of small unilamellar vesicles

•Sonication
•Micro fluidization
•Preparation of multilamellar vesicles
•Hand shaking method (Thin film hydration technique)
•Trans-membrane pH gradient (inside acidic) drug uptake process (Remote Loading)

•Preparation of large unilamellar vesicles

•Reverse phase evaporation technique (REV)
•Ether injection method
•Miscellaneous
•Multiple membrane extrusion method
•The “Bubble” Method
•Formation of niosomes from pro-niosomes
•Niosomes preparation using polyoxyethylene alkyl ether
Niosomes preparation using Micelle

Method of preparation Drug incorporated

• Sodium Stibogluconate
Ether Injection
• Doxorubicin

• Methotrexate
Hand Shaking
• Doxorubicin

• 8-arginine
Sonication
• Vasopressin
Comparison of Niosome v/s Liposome:
Niosomes are different from liposomes and are now widely studied as an alternative to liposomes in that they offer certain advantages over
liposomes.

Niosomes Liposomes

Similarities

• As with liposomes, the properties of the niosomes depend both- on the composition of the bilayer, and the method of
production used.

• Niosomes can also be used for targeted drug delivery, similar to liposomes.

• Niosomes also increase the bioavailability of the drug and reduce the clearance like liposomes.

• Niosomes behave in-vivo like liposomes, prolonging the circulation of entrapped drug and altering its organ distribution
and metabolic stability

Dissimilarities

Niosomes are made of uncharged single-chain surfactant Liposomes which are made from neutral or charged double
molecules and cholesterol. chained phospholipids.

They are osmotically active and stable.

Their ingredients like phospholipids are chemically unstable
because of their predisposition to oxidative degradation.

Handling and storage of surfactants do not require any special

conditions They require special storage and handling and purity of natural
phospholipids is variable.

They are cheap. They are expensive.

1) Preparation of small unilamellar vesicles (SUVs):

1)Sonication:

A typical method of production of the vesicles is by sonication of solution. In this method drug

solution in buffer is added to the surfactant/cholesterol mixture in a 10-ml glass vial. The mixture is probe
sonicated at 60°C for 3 minutes using a sonicator with a titanium probe to yield niosomes. The vesicles
formed are small and uniform in size.

2)Microfluidization:

Micro fluidization is a recent technique used to prepare unilamellar vesicles of defined size distribution. This
method is based on submerged jet principle in which two fluidized streams interact at ultra-high velocities,
in precisely defined micro channels within the interaction chamber. Here, a common gateway is arranged
such that the energy supplied to the system remains within the area of niosomes formation. The result is a
greater uniformity, smaller size and better reproducibility.
2;Preparation of multilamellar vesicles (MLVs):

Hand shaking method (Thin film hydration technique)

In the hand shaking method, surfactant and cholesterol are dissolved in a volatile organic solvent
such as diethyl ether, chloroform or methanol in a rotary evaporator. The organic solvent is
removed at room temperature (20°-250C) using rotary evaporator leaving a thin layer of solid
mixture deposited on the wall of the flask. The dried surfactant film can be rehydrated with
aqueous phase at 0-60°C with gentle agitation. This process forms typical multilamellar niosomes.
The multilamellar vesicles thus formed can further be processed to yield unilamellar niosomes or
smaller niosomes using sonication, micro fluidization or membrane extrusion techniques.

Trans-membrane pH gradient (inside acidic) drug uptake process (remote Loading)

Surfactant and cholesterol are dissolved in chloroform. The solvent is then evaporated under
reduced pressure to obtain a thin film on the wall of the round-bottom flask. The film is hydrated
with 300 mM citric acid (pH 4.0) by vortex mixing. The multilamellar vesicles formed are then
frozen and thawed three times and later sonicated. To this niosomal suspension, aqueous solution
containing 10 mg/ml of drug is added and vortexed. The pH of the sample is then raised to 7.0-7.2
with 01M disodium phosphate. This mixture is later heated at 60°C for 10 minutes to produce the
desired multilamellar vesicles.
 3 Preparation of large unilamellar vesicles (LUVs):

1) Reverse phase evaporation technique (REV) :

In this method, cholesterol and surfactant (1:1) are dissolved in a mixture of ether and chloroform.
An aqueous phase containing drug is added to this and the resulting two phases are sonicated at 4-
5°C. The clear gel formed is further sonicated after the addition of a small amount of phosphate
buffered saline (PBS). The organic phase is removed at 40°C under low pressure. The resulting
viscous niosome suspension is diluted with phosphate-buffered saline and heated in a water bath at
60°C for 10 min to yield niosomes.

2)Ether injection method:

Ether injection method is essentially based on slow injection of niosomal ingredients in ether
through a 14-gauge needle at the rate of approximately 0.25 ml/min into a pre-heated aqueous
phase maintained at 60°C. The probable reason behind the formation of larger unilamellar vesicles
is that the slow vaporization of solvent. The disadvantage of this method is that a small amount of
ether is frequently present in the vesicles suspension and is difficult to remove.
 4 ;Miscellaneous:

1)Multiple membrane extrusion method:

A mixture of surfactant, cholesterol, and di acetyl phosphate in chloroform is made into

thin film by evaporation. The film is hydrated with aqueous drug solution and the resultant
suspension extruded through polycarbonate membranes, which are placed in a series for
up to eight passages. This is a good method for controlling niosome size.
2) The “Bubble” Method:
It is a technique which has only recently been developed for the one step preparation of
liposomes and niosomes without the use of organic solvents. The bubbling unit consists of
round-bottomed flask with three necks positioned in water bath to control the
temperature
Water-cooled reflux and thermometer is positioned in the first and second neck and
nitrogen supply through the third neck. Cholesterol and surfactant are dispersed together
in this buffer (pH 7.4) at 70°C, the dispersion mixed for 15 seconds with high shear
homogenizer and immediately afterwards “bubbled” at 70°C using nitrogen gas that
results in the formation of niosomes.
3) Formation of niosomes from pro-niosomes:
To create pro-niosomes, a water soluble carrier such as sorbitol is first coated
with the surfactant. The coating is done by preparing a solution of the
surfactant with cholesterol in a volatile organic solvent, which is sprayed onto
the powder of sorbitol kept in a rotary evaporator. The evaporation of the
organic solvent yields a thin coat on the sorbitol particles. The resulting coating
is a dry formulation in which a water soluble particle is coated with a thin film
of dry surfactant. This preparation is termed Pro-niosomes.
The niosomes can be prepared from the pro niosomes by adding the aqueous
phase with the drug to the pro niosomes with brief agitation at a temperature
greater than the mean transition phase temperature of the surfactant.
4) Niosomes preparation using polyoxyethylene alkyl ether:
• Size and number of bilayer of vesicles consisting of polyoxyethylene alkyl ether and
cholesterol can be changed using an alternative method.
• Temperature rise above 60°C transforms small unilamellar vesicles to large
multilamellar vesicles (>1 μm)
• While vigorous shaking at room temperature shows the opposite effect, i.e.,
transformation of multilamellar vesicles into unilamellar ones.

• The transformation from unilamellar to multilamellar vesicles at higher temperature

might be the characteristic for polyoxyethylene alkyl ether (ester) surfactant, since it is
known that polyethylene glycol (PEG) and water remix at higher temperature due to
breakdown of hydrogen bonds between water and PEG moieties. Generally, free drug
is removed from the encapsulated drug by gel permeation chromatography dialysis
method or centrifugation method. Often, density differences between niosomes and
the external phase are smaller than that of liposomes, which make separation by
centrifugation very difficult. Addition of protamine to the vesicle suspension facilitates
separation during centrifugation.
Materials used in Niosomes:

a) Surfactants:

Surfactants are usually organic compounds that are amphiphilic meaning they contain both hudrophobic groups (their tails) and hydrophilic groups (their
heads). Therefore, a surfactant molecule contains both a water insoluble (and oil soluble component) and a water soluble component.

b) Cholesterol:

Steroids are important components of cell membranes and their presence in membranes
brings about significant changes with regard to bilayer stability, fluidity and permeability.
Cholesterol, a natural steroid, is the most commonly used membrane additive and can be
incorporated to bilayer at high molar ratios. Cholesterol by itself, however, does not form
bilayer vesicles. It is usually included in a 1:1 molar ratio in most formulations to prevent
vesicle aggregation by the inclusion of molecules that stabilize the system against the
formation of aggregates by repulsive steric or electrostatic effects. It leads to the transition
from the gel state to liquid phase in niosome systems. As a result, niosomes become less
leaky.
c) Drug:
Entrapment of drug in niosomes increases vesicle size, probably by
interaction of solute with surfactant head groups, increasing the charge
and mutual repulsion of the surfactant bilayer, thereby increasing vesicle
size. In polyoxyethylene glycol (PEG) coated vesicles; some drug is
entrapped in the long PEG chains, thus reducing the tendency to increase
the size. The hydrophilic lipophilic balance of the drug affects degree of
entrapment.

d) Other Additives:
As is the case with liposomes, charged phospholipids such as
dicethylphosphate (DCP) and stearyl amine (SA) have been used to
produce charge in niosome formulations, The former molecule provides
negative charge to vesicles whereas the later one is used in the
preparation of positively charged (cationic) niosomes
Evaluation Parameters:
1) Separation of Unentrapped Drug:
The removal of unentrapped solute from the vesicles can be
accomplished by various techniques, which include;
Dialysis:
The aqueous niosomal dispersion is dialyzed in dialysis tubing against
phosphate buffer or normal saline or glucose solution.
Gel Filtration:
The unentrapped drug is removed by gel filtration of niosomal
dispersion through a Sephadex-G-50 column and elution with
phosphate buffered saline or normal saline.
Centrifugation:
The niosomal suspension is centrifuged and the supernatant is
separated. The pellet is washed and then resuspended to obtain a
niosomal suspension free from unentrapped drug.
2) Characterizations of niosomes:
Size:
Shape of niosomal vesicles is assumed to be spherical, and their mean diameter can be
determined by using:
Laser light scattering method,
Electron microscopy,
Molecular sieve chromatography,
Ultracentrifugation,
Photon correlation microscopy,
Optical microscopy.
Bilayer formation:
Assembly of non-ionic surfactants to form a bilayer vesicle is characterized by an X-cross
formation under light polarization microscopy.
Number of lamellae:
This is determined by using:
Nuclear magnetic resonance (NMR) spectroscopy,
Small angle X-ray scattering,
Electron microscopy.
 Membrane rigidity:

Membrane rigidity can be measured by means of mobility of fluorescence probe as a function of temperature.

Entrapment efficiency:

After preparing niosomal dispersion, unentrapped drug is separated and the drug remained entrapped in niosomes is
determined by complete vesicle disruption using 50% n-propanol or 0.1% Triton X-100 and analyzing the resultant solution
by appropriate assay method for the drug.

It can be represented as:

Percent % Entrapment Efficiency = (Amount entrapped / total amount) Χ 100

In vitro Release Study:

A method of in vitro release rate study was reported with the help of dialysis tubing. A dialysis sac was washed and soaked
in distilled water. The vesicle suspension was pipetted into a bag made up of the tubing and sealed. The bag containing the
vesicles was then placed in 200 ml buffer solution in a 250 ml beaker with constant shaking at 25°C or 37°C.

In vivo Release Study:

Albino rats were used for this study. These rats were subdivided with groups. Niosomal suspension used for in vivo study
was injected intravenously (through tail vein) using appropriate disposal syringe.
Advantages of Niosomes:
• Use of niosomes in cosmetics was first done by L’Oreal as they offered the following advantages:
• The vesicle suspension being water based offers greater patient compliance over oil based
systems
• Since the structure of the niosome offers place to accommodate hydrophilic, lipophilic as well as
amphiphilic drug moieties, they can be used for a variety of drugs.
• The characteristics such as size, lamellarity etc. of the vesicle can be varied depending on the
requirement.
• The vesicles can act as a depot to release the drug slowly and offer a controlled release.
• Other advantages of niosomes are:
• They are osmotically active and stable.
• They increase the stability of the entrapped drug
• Handling and storage of surfactants do not require any special conditions
• Can increase the oral bioavailability of drugs
• Can enhance the skin penetration of drugs
• They can be used for oral, parenteral as well topical use
• The surfactants are biodegradable, biocompatible, and non-immunogenic
• Improve the therapeutic performance of the drug by protecting it from the biological
environment and restricting effects to target cells, thereby reducing the clearance of the drug.
• The niosomal dispersions in an aqueous phase can be emulsified in a non-aqueous phase to
control the release rate of the drug and administer normal vesicles in external non-aqueous
phase.
 Applications of Niosomes:
The application of niosomal technology is widely varied and can be used to treat a number of diseases. The following are a few
uses of niosomes which are either proven or under research.

• Drug Targeting:

One of the most useful aspects of niosomes is their ability to target drugs. Niosomes can be used to target drugs to the reticulo-
endothelial system. The reticulo-endothelial system (RES) preferentially takes up niosome vesicles. The uptake of niosomes is
controlled by circulating serum factors called opsonins. These opsonins mark the niosome for clearance. Such localization of drugs
is utilized to treat tumors in animals known to metastasize to the liver and spleen. This localization of drugs can also be used for
treating parasitic infections of the liver.
Niosomes can also be utilized for targeting drugs to organs other than the RES. A carrier system

(such as antibodies) can be attached to niosomes (as immunoglobulin bind readily to the lipid surface of the niosome) to target
them to specific organs. Many cells also possess the intrinsic ability recognize and bind specific carbohydrate determinants, and
this can be exploited by niosomes to direct carrier system to particular cells.

• Anti-neoplastic Treatment:

Most antineoplastic drugs cause severe side effects. Niosomes can alter the metabolism; prolong circulation and half-life of the
drug, thus decreasing the side effects of the drugs. Niosomal entrapment of Doxorubicin and Methotrexate (in two separate
studies) showed beneficial effects over the unentrapped drugs, such as decreased rate of proliferation of the tumor and higher
plasma levels accompanied by slower elimination.
Leishmaniasis:
Leishmaniasis is a disease in which a parasite of the genus Leishmania invades the cells of
the liver and spleen. Commonly prescribed drugs for the treatment are derivatives of
antimony (antimonials), which in higher concentrations can cause cardiac, liver and kidney
damage. Use of niosomes in tests conducted showed that it was possible to administer
higher levels of the drug without the triggering of the side effects, and thus allowed
greater efficacy in treatment.
Delivery of Peptide Drugs:
Oral peptide drug delivery has long been faced with a challenge of bypassing the enzymes
which would breakdown the peptide. Use of niosomes to successfully protect the peptides
from gastrointestinal peptide breakdown is being investigated. In an in-vitro study
conducted by Yoshida et al, oral delivery of a vasopressin derivative entrapped in
niosomes showed that entrapment of the drug significantly increased the stability of the
peptide.
Use in Studying Immune Response:
Due to their immunological selectivity, low toxicity and greater stability; niosomes are
being used to study the nature of the immune response provoked by antigens
• Niosomes as Carriers for Hemoglobin:

Niosomes can be used as carriers for hemoglobin within the blood. The niosomal vesicle is permeable to
oxygen and hence can act as a carrier for hemoglobin in anemic patients.

• Transdermal Drug Delivery Systems Utilizing Niosomes:

One of the most useful aspects of niosomes is that they greatly enhance the uptake of drugs through the
skin. Transdermal drug delivery utilizing niosomal technology is widely used in cosmetics; in fact, it was
one of the first uses of the niosomes. Topical use of niosome entrapped antibiotics to treat acne is done.
The penetration of the drugs through the skin is greatly increased as compared to un-entrapped drug.
Recently, transdermal vaccines utilizing niosomal technology is also being researched. A study conducted
by P. N. Gupta et al has shown that niosomes (along with liposomes and transfersomes) can be utilized
for topical immunization using tetanus toxoid. However, the current technology in niosomes allows only
a weak immune response, and thus more research needs to be done in this field.

• Other Applications:

Niosomes can also be utilized for sustained drug release and localized drug action to greatly increase the
safety and efficacy of many drugs. Toxic drugs which need higher doses can possibly be delivered safely
using niosomal encapsulation
Toxicity of niosomes:
• Unfortunately, there is not enough research conducted to investigate toxicity of
niosomes.
• Researchers measured proliferation of keratinocytes in one of the topical niosome
formulations.
• The effect of surfactant type on toxicity was investigated. It was determined that
the ester type surfactants are less toxic than ether type surfactants. This may be due
to enzymatic degradation of ester bounds.
• In general, the physical form of niosomes did not influence their toxicity as
evident in a study comparing the formulations prepared in the form of liquid
crystals and gels. However, nasal applications of these formulations caused
toxicity in the case of liquid crystal type niosomes.
• In some instances, encapsulation of the drug by niosomes reduces the toxicity as
demonstrated in the study on preparation of niosomes containing vincristine. It
decreased the neurological toxicity, diarrhea and alopecia following the
intravenous administration of vincristine and increased vincristine anti-tumor
activity
 Marketed Products:
Drug Purpose

• Doxorubicin Anti-cancer affectivity.

• Methotrexate

• Sodium Stibogluconate Effective against parasites in the liver, spleen and bone
marrow.

• Ciprofloxacin Chemotherapeutic antibiotic

• Norfloxacin

• Indomethacin Non-steroidal anti-inflammatory

• Vincristine sulfate Used in cancer chemotherapy

• Diclofenac sodium Anti-inflammatory activity

• Lancôme Anti-ageing cosmetic products.

• L’Oreal
 NIOSOMES
A Novel Drug Delivery System
 Polymers
 Polymers are the large compounds or molecules made up of basic
unit structure called monomer, which is joined covalently or by strong
bonding.
 Polymer contains more than 1 functional group or binding site.
 If monomer with one binding site is present then it cannot be
produced. e.g. Carboxylic group is in polyesters, polyamides,
polycarbonate.
 Classification
➢ On basis of monomer units
❖ Homo-polymer
 In this type only one type of polymers are present.
 E.g. A-A-A-A, B-B-B-B
❖ Copolymer
 2 type of monomer units are present
 Copolymers are further divided into 4 types.
▪ Random copolymer: it have non specific pattern of bonding. E.g. A-
A-B-A-B-B-A-B
▪ Alternating: in this type of copolymer monomers are repeatedly
alternative. e.g. A-B-A-B-A-B
▪ Blocks: in this type of copolymer monomer form one block and other
form second block. E.g. A-A-A-B-B-B-A-A-A (tri-block).
▪ Graft polymer: in this main chain of one type of monomer and
branched chain of different monomers are joined to form a polymer.
E.g. A-A-A-B-B
| | | |
A-B-B-A
❖ Ter-polymer
 it contains 3 type of monomer units.
❖ Tetra-polymer
 It contains 4 type of monomer units.
❖ Penta-polymer
 It contains 5 monomer units.

➢ On basis of arrangement
❖ Linear polymer
 Straight chain, no branches.
❖ Branched polymer
 Arranged in such a way that there are several branches
❖ Cross linked
 Various straight chain polymers are connected by cross linkers to
form network like structure.
➢ On basis of origin
❖ Natural
 Plants and animal sources like proteins, polysaccharides, gums
resins.
❖ Synthetic polymer
 Synthesized in lab.
 These are further divided into fibers that is subdivided into following:
▪ Thermoplastic: that flow upon force application and come original
position on removal of external force.
▪ Thermoset: upon force no movement or flow occurs, these are brittle
and break on stress.
 Elastomers.
 Polymerization and Types
 Process in which monomers are converted into polymers.
 Following are the types of polymerization.

➢ Step growth polymerization

 Monomers → Dimers/Trimers/Tetramer → Oligomer → Polymers
 It is also called condensation polymerization because when two or
more monomers react with each other then a low molecule weight
product may eliminate like water but sometimes may not remove.
➢ Additional polymerization
 Monomers added to growing polymer chain one at a time.
 New monomers are added to already growing chain and chain
continues to grow so also called chain growth polymerization.
 Mostly used technique in Pharma industry.
❖ Steps of additional polymerization
 Initiation
▪ To initiate polymerization some initiators are added which can be free
radical, anionic initiators and cationic initiators. Low molecular weight
alkenes, benzyl peroxide are used.
 Propagation
▪ These free radicals are combined and growth is continues to
increase.
 Termination
▪ Reaction retarders are added to stop the reaction or when all
monomers are utilized.
➢ Insertion polymerization
 In this technique there is insertion of monomers at the end of growing
chain and process is mediated by catalyst.
 Catalyst must be present at the end of the growing chain to ensure
the proper reaction. Also called “ Ziegler nata polymerization”.
 Polymers on basis of Degradation
 Polymers are the backbone of conventional and novel dosage form
and delivery systems.
 It is included in excipients.
 Initially research was carried out on Non-bio-degradable polymers
but after ingestion these are not degraded and excrete slowly from
body after long time residence in the body that causes complications.
 So this brings focus on bio-degradable polymers that are degraded
and converted into monomers and excrete out.
 Bio-degradable polymers are less toxic.
 Types of polymers
➢ Biodegradable polymers
 “Biodegradable polymers are the polymers that are degradable in
vivo, either enzymaticaly or non-enzymaticaly to produce
biocompatible or non-toxic by-products.”
 Physical properties that contribute to the rate of polymer degradation
are as follow:
▪ Water permeability and water solubility: a reflection of the free
volume of the polymer and its hydrophilicity, will determine the rate of
hydrolysis and whether bulk or surface hydrolytic degradation
occurs. Autocatalysis is possible if acidic or basic groups are
produced by the polymer breakdown, as in case of polyesters and
other esters.
▪ Crystillinity of the polymer: only the amorphous phase of the
polymer is accessible to permeates and to enzymatic attacks.
▪ Glass-transition temperature: the glassy or rubbery nature of the
polymer will be reflected In its permeability and molecular chain
mobility. The chain mobility appears to be an important factor in
determining the susceptibility to enzymatic attack. In addition, the
inability of cleaved fragments to defuse out of a glassy polymer will
magnify an autocatalytic hydrolytic process.
▪ Physical dimensions; these appear to become significant in the
advanced stages of biodegradation, when phagocytosis may come
into play.
 These polymers are degraded in biological system like gelatin, starch
and PEG.
 From these polymers drug release with specific mechanism like drug
is release from HPMC by swelling of HPMC or drug release from
ethyl cellulose by erosion.
 Natural biodegradable polymer are degraded by enzymatic action
while synthetic biodegradable polymer degraded by hydrolysis which
breaks linkages b/w amides and esters. E.g. polylactide degrade into
lactic acid and polyglycoside degrade into glycolic acid.
 Biodegradable polymers are of two types:
▪ pH responsive ( release at particular target e.g. colon targeting at
specific pH)
▪ Bio responsive (release drug at organ from where enzymes are
present which degrade the polymer and cause release of drug. It
does not produce side effect and especial used in chemotherapy)
 Need for Biodegradable polymers
 It was recognized that the surgical removal of a drug depleted
delivery system was difficult yet leaving non-biodegradable foreign
materials in the body for an indefinite period of time caused toxicity
problem.
 Diffusion controlled release is an excellent means of achieving
controlled drug delivery.
 Permeability and the characteristic of a drug increases, its diffusion
coefficient decreases.
 There is no need for a second surgery for removal of polymer.
 Avoid stress shielding.
 Offer tremendous potential as the basis for controlled drug delivery.
 Advantages
 provides a drug at a constant controlled rate owes a prescribed
period of time.
 The polymer carrier would degrade into nontoxic, absorbable
subunits which would be subsequently metabolized.
 The system would be biocompatible would not exhibit dose dumping
at any time and polymer would retain its characteristics until after
depletion of the drug.
 Degradable system eliminates the necessity for surgical removal of
implanted device following depletion of a drug.
 They are broken into biologically acceptable molecules that are
metabolized and removed from the body via normal metabolic
pathways.
 Disadvantages
 Sometimes the degradable polymers exhibit substantial dose
dumping at some point following implantations.
 A “burst effect” or high initial drug release soon after administration is
typical of most system.
 Degradable systems which are administered by injection of a
particulate form are non re-treiveable.
➢ Basis of location of degradation
 Homogenous erosion: cleavage of dosage from throughout the
delivery system is uniform and independent of surface area.
 Hetero erosion: it occurs at the surface of DDS. Limited to surface
area and ratio of drug release can affect by geometry of device.
➢ Selection of polymer
 It is based on:
▪ What release rate required?
▪ What are preferred for drug?
▪ E.g. CMC 40% decrease release rate, PVP increase release rate,
PVP+CMC moderates the release rate.
 Factors affecting degradation of
polymers
 Chemical structure: strong bonding → less degradation rate
 Distribution of Monomer units: linear polymer → Less
degradation rate.
 Molecular weight: high molecular weight → less degradation rate.
 Polydispersity: different chains presence makes different
degradation rates. E.g. PVP k30 → stable, PVPK40 → more stable
 Low molecular weight compounds presence: PVP + water +
impurities → increase degradation rate.
 Ionic groups: charge on polymer increases its degradation rate.
 Hydrophilic backbone: e.g. cellulose derivatives contain OH-
group on end. –OH group increase the hydrophilicity hence
increase rate of degradation.
 Crystallinity: crystal polymers are stable.
 Porousity: increase the degradation rate due to presence of water
that enters the polymer. E.g. HPMC high porousity and Ethyl
cellulose has less degradation due to less porousity.
 Device size: short size increases rate of degradation. More size
less degradation. E.g. intra-uterine device implants for treatment of
hormonal disturbances. Like LEVOGESTROL different dose make
different effect, it can be contraceptive and can increase fertility
also so used with care with help of polymers.
 Determination of polymer
degradation
 Morphologic changes
1. Swelling
2. Deformation
3. Disappearance
 Weight loss
 Thermal behaviours
▪ Sharp peaks of melting point confirms degradation.
▪ Degradation patters of polymer are determined by different models
that are:
1. Higuchi
2. Hixon crowell
3. Pappas
 Properties of biodegradable
polymers
 Should not evoke sustained inflammatory response upon
implantation in body.
 Does not require surgical procedure for removal.
 Excrete out from body after specific period of time.
➢ Why we use biodegradable polymers
 Surgical removal of drug delivery system is difficult.
 Diffusion controlled drug delivery system are excellent means of
achieving pre dominant rates of drug delivery.
 Acceptable shelf life.
 Should have appropriate mechanical properties for the indicated
applications and any variation in mechanical properties with the
degradation should be compatible with healing or regeneration
process.
 Degradation products should be nontoxic and able to get
metabolized and cleaned from body.
 Material should have appropriate permeability and processibility for
intended purpose.
 Some inherit properties of polymeric biomaterial that can effect on
their biocompatibility include:
I. Material chemistry
II. Molecular weight
III. Solubility
IV. Shape
V. Shape and structure of implant
VI. Hydrophilic/hydrophobic
VII. Lubricity
VIII. Surface energy
IX. Water absorption
X. Degradation and erosion of mechanism.
 Biomedical application
 Large implants e.g. bone screws, bone plates and contraceptives
reservoirs.
 Small implants, sutures, nano or micro-sized drug delivery system.
 Plain membrane for guided tissue generation.
❖ Approaches which governs the design of drug delivery system
containing biodegradable polymer
 Erosion of polymer surface with concomitted release of physically
entrapped drug.
 Cleavage of covalent bond b/w polymer bulk or at the surface
followed by diffusional drug loss.
 Diffusion control release of physically entrapped drug with bio-
absorption of polymer delayed until after drug depletion.
 Classification of Hydrolytically
degradable polymers
❖ Polyesters
a) Polyglycolides
b) Polylactides
c) Polylactide co glycolide
d) Polyxanone
e) Polytrimethylene carbonate
f) Bacterial polyesters
g) Polycaprolactone
❖ Polyurithanes
❖ Polyesteamide
❖ Polypropylene fumarate
❖ Poly alkyl cyanocylate
❖ Poly phosphoesters
❖ Poly ortho esters
❖ Poly ahydrides
❖ Pseudo polyamino acids
❖ Polyphosphosphaxene
❖ Crossed linked polyanhydride
 Polyester
➢ Polyglycolide / Polylactide
 1st biodegradable synthetic polymer investigated for biomedical
applications.
 Highly crystalline polymer (45-55%) so exhibit high tensile modulus
with very low solubility in organic solvents.
 Tg → 35-40 C (it must be below body temperature i.e. 37 C)
 Melting point → 200 C
 Fabricated into a no. of dosage forms in spite it has low solubility as
there was no other option that time
 DEXON ( 1st biodegradable synthetic structure)
 Excellent mechanical properties due to its Crystillinity
 Polyglycolides are stiffer than any other biodegradable polymer or
polymeric system used clinically due to its good initial mechanical
properties.
 It is bulk degradation polymer that degrades by non-specific scission
of ester backbone, then losses its strength into 1-2 months and when
hydrolyzed it loses its mass within 6-12 months.
 Polyglycolides are converted into glycine which is excreted or may
further converted into carbon dioxide or water by krebs cycle and
excreted out.
 Its low solubility and high degradation rate limits is biomedical
applications.
 For this several co-polymers are added that developed to overcome
the inherit disadvantages.

Lactide polylactide
 ❖ important factors which can be applicable for polymer to
formulate dosage form
 Co-monomer ratio
▪ directly affects the polymer.
▪ High molecular weight in polymer by co-polymer addition increase its
tensile property and hence ultimately increase mechanical
properties.
 Monomer stereochemistry
▪ Racemic poly-d,l lactide and dl,poly lactic acid are less crystalline
and low melting point then the stereo isomers of d-PLA and L-PLA.
 Molecular weight
 Chain linearity
▪ Increase chain linearity → increase degradation
o Co-polymer of lactide or glycolide are less crystalline then homo-
polymer of these compounds.
o Hydrophilicity increase with increase in glycolide ratio on copolymer.
But in organic solvent glycolide ratio does not affect its solubility.
o With introduction of lactic acid in co-polymer lipophilicity increases.
o Extent of block and random structure of co-polymer also effect
hydration and degradation.
o Lactide composition is responsible for interlocking segments in poly-
l-lactide.
o Crystalline phase and higher melting point improves mechanical
properties of polymer.
➢ Lactide/Glycolide based Drug Delivery System
 Ease of fabrication into various drug delivery systems ( Micro
particles, implants, fibers)
 Microparticles are prepared by following methods.
❑ Solvent Evaporation
 Particularly develop for biodegradable polymer
 Polymer + organic solvent → remove solvent to form discrete
monolithic devices.
❑ Phase seperation
 Suitable for entrapping water soluble agents in lactide/glycolide
excipients.
 This process involves conversion of polymer from an organic solvent
by addition of non solvent such as silicon oil.
❑ Fluidized bed coating
 Bioactive agent is dissolved in organic solvent along with polymer
solution is then processed in a water air suspension coater
apparatus to form microcapsules.
 Polycaprolactone
 It is semi-crystalline polyester
 Preparation

 Polymerization of caprolactone can be affected by four mechanisms

1. Anionic
2. Cationic
3. Radical
4. Co-ordinate formation
 Glass transition is -60 C.
 Soluble in chloroform, methylene chloride, carbon tetrachloride,
benzene, toluene, hexane.
 Insoluble in alcohol, petroleum and ethers.
 It degrades hydrolytically in two steps and degrade due to presence
of aliphatic ester linkage.
 Rate of degradation is slow (2-3 years) because of this it have
permeability to many drugs.
 Initially investigation as long term drug vaccine delivery.
 Two step degradation,1st is change scission and 2nd is erosion.
 Ideal candidate for release of drug by zero order.
 Its copolymer PCL + Decaprolactone can also degrade enzymatically
due to presence of decalactone which imparts non-Crystillinity.
 CAPRONORS → long term contraceptive device for zero order
release.
 Enzymatically Degradable
Polymers
➢ Collagen
 Component of skin
 Rod type polymer of 300nm long and molecular weight 300,000
 22 different types in body
 Type-I is single most abundant protein. Have polypeptide sub-units
each have 1050 amino acids (33% glycine, 25% proline,
25%hydroxyproline.)
 Degrade by metalloproteinase
 Soluble in acidic medium
 High cross linking power.
 Sources are bovine or porcine skin
 Disadvantage : can be immunogenic.
➢ Albumin
➢ Polysaccharides (hyaluronic acid)
 Hyaluronic acid isolated from vitreous of eye.
 Member of glycosaminoglycans family
 H.A is not covalently bounded to proteins
 Unique visco-elastic properties an forms viscous solutions
 Have extensive H-Bonding
 High concentration present in synovial fluid, vitreous of eye, articular
cartilage
 Provide mechanical support due to its visco-elastic property
❑ Synthetic biodegradable polymers
1. Aliphatic polyesters(PGA, PLA, PCL)
2. Polyanhydrides
3. Polyphosphazenes
4. Polyaminoacids
5. Polyorthoesters
❑ Natural biodegradable polymers
1. Albumin
2. Dextran
3. Gelatin
4. Pectin
5. Starch
❑ Natural water soluble polymers
1. Xanthane gum
2. Pectins
3. Chitosan
4. Dextran
5. Carrageenan
6. Guar gun
7. Cellulose esters (HPMC, HPC, HEC, Na-CMC)
8. Hyaluronic acid (HA)
9. Albumin
10. Starch, starch based derivatives
❑ Hydrophobic polymers
1. PPG
2. Polyvinylactate
3. Eudragit (eudragit R100,L100, RS100)
4. Polycarpolactone (PCL)
❑ Synthetic water soluble polymers
1. PEG
2. PVP
3. PVA(poly vinyl alcohol)
4. Polyacrylic acid
5. Polyacrylamide
6. Polyphosphates
7. Polyphasphazenes