This document discusses various colloidal drug delivery systems including liposomes, niosomes, solid lipid nanoparticles, polymeric nanoparticles, and carbon nanotubes. It provides details on the composition, advantages, methods of preparation, and drug incorporation for each system. The key points are that nanocarriers can improve drug solubility and stability, target drug delivery, and reduce toxicity. The document outlines various fabrication techniques for each nanocarrier type such as homogenization, solvent evaporation, and polymerization.

1. COLLOIDAL
DRUG
DELIVERY
SYSTEM
Submitted by :- Pratik Kharat
PE/2019/313

2. INTRODUCTION
Delivering the drug specifically to its target site
at the right period of time to have a controlled release and achieve the
maximum therapeutic effect remains the main reason in the designing and
development of novel drug delivery systems. The concept of drug
targeting is all about to minimize the risk-to-benefit ratio in targeting.
Nanocarriers, in their various forms, have the possibility of providing
endless opportunities in the area of drug delivery and therefore are
increasingly being investigated to show their potential.
Nanotechnology, as defined by the National Nanotechnology Initiative
(NNI), is the study and use of structures roughly in the size range of 1
to 100 nm. The overall goal of nanotechnology is the same as that of
medicine: to diagnose as accurately and early as possible and to treat as
effectively as possible without any side effects. As nanocarriers have
higher surface area this shows improved pharmacokinetics and bio
distribution of therapeutic agents and this minimizes the toxicity by their
preferential accumulation at the target site. They improve the solubility of
hydrophobic compounds and make them effective for parenteral
administration. They also increase the stability of a variety of therapeutic
agents, like peptides, oligonucleotides, and many more. They can be used
to deliver the drug to the central nervous system owing to their smaller
size and higher barrier permeability. Use of biodegradable materials
minimizes the possibilities of hypersensitivity reactions and affords good
tissue compatibility . A nanocarrier should be capable of providing

3. extended blood circulation, delivering the active moiety at the targeted
site and bypassing the endosome-lysosome processing.
 LIPOSOMES & NIOSOMES
Liposome are simple microscopic, concentric
bilayered vesicles in which an aqueous volume is entirely enclosed by a
membranous lipid bilayer mainly composed of natural or synthetic
phospholipids. The liposome was discovered in 1960's by Bangham and
coworker. The main structural components of liposome are phospholipids
and cholesterol.
There are various type of liposome based pn the preparation this includes
following:

4. A. Conventional liposome
B. PEGylated liposome
C. Theranostic liposome
D. Ligand targeted liposome
Classification of liposome :

5. Acceptance of liposome into cell :

6.  METHOD OF PREPARATION
Physical dispersion method :-
1. Hand shaking MLVs
2. Non shaking LUVs
3. Feeze drying
4. Pro-liposome
To reduce liposome size
1. Micro emulsification
2. Membrane extrusion
3. Ultrasonication
4. French pressure cell
To increase liposome size
1. Dried reconstituted vesicle
2. Freeze thawing
3. Induction of vesiculation by pH change
Solvent dispersion method
1. Ethanol injection method
2. Ether injection method
3. Water organic phase :

7. a. Double emulsion method
b. Reverse phase evaporation
c. Stable plurilamellar vesicle
Hand shaken MLV's
Lipid + Solvents (Chloroform:Methanol) in 250ml RBF
Evaporate for 15 min above phase transition temperature (flush with
nitrogen)
Till residues dry
Add 5ml buffer containing material to be entrapped
Rotate flask at room temp, at 60 RPM for 30 min until lipid removes
from wall of RBF

8. Milky white dispersion (stand for 2 hr to get MLV’s)
Non Shaking vesicle
Lipid + Solvent
Evaporate at room temperature by flow of nitrogen for drying
Add water saturated nitrogen until opacity disappears
Add bulk fluid (drug) & 10-20 ml 0.2M sucrose solution to swell
(Flush again with nitrogen)
Stand for 2 hrs at 370C, do not disturb for 2 hrs
(swirl to yeild milky dispersion)
Centrifuge at 12000 rpm for 10min at room temp
(MLV on surface is removed)

9. To remaining fluid add iso-osmolar glucose solution
(Centrifuge at 12000rpm)
LUV is formed
Freeze Drying
Lipid + Solvent (Tertiary butanol)
Freeze drying
Add aqueous phase / Saline containing drug
Rapid mixing above phase transition temp
MLV’s formed
Ethanol injection method
Lipid + ethanol solution in the syringe

10. Inject rapidly
In the aqueous phase
Small unilamellar vesicle
Ether injection method
Lipid + ether solution in the syringe
Inject slowly
In the aqueous phase ( On heated water bath 600C)
Large unilamellar vesicles
Water organic phase: double emulsion
Oraganic sokution + Lipid + Aqueous Phase
Emulsion (W/O)
Hot aqueous solution of buffer

11. Multi compartment vesicle W/O/W (double emulsion)
LUV’s
Niosomes are the hydrated vesicular systems containing
nonionic surfactants along with cholesterol or other lipids delivering drug
to targeted site which are non toxic in nature, requiring less production
cost, stable over a longer period of time in different conditions, so
overcomes drawbacks of liposome carrier system.
Use of cholesterol and its impact :
Cholesterol influences the physical properties and structure of niosomes it
is due to its interaction with the nonionic surfactants present in the
niosome. The interaction is of biological interest, cholesterol is always
present in biological membranes here it influences membrane properties
such as aggregation, ion permeability, elasticity, enzymatic activity, size
and shape. The effect of cholesterol in lipid bilayers is mostly to modulate
their cohesion and mechanical strength and their permeability to water.

12. Niosome structure
 METHOD OF PREPARATION
a. Ether injection
b. Trans membrane pH gradient method
c. Reversed phase evaporation
d. The single pass technique
e. Micro fluidization
f. Lipid layer hydration
g. The Handjani–Vila method
h. Bubbling of nitrogen
a. Ether injection method:
Lipid & drug + ether solution in the syringe
Inject slowly
In the aqueous phase (On heated water bath 600C)
Unilamellar vesicles
b. Reversed phase evaporation:
Surfactants are dissolved in a mixture of ether and
chloroform in which an aqueous phase containing the drug is added. The
resulting two-phase system is then homogenized and the organic phase
evaporated under reduced pressure to form niosomes which are dispersed
in the aqueous phase.

13. SOLID LIPID NANOPARTICLE AND NANOSTRUCTRED
LIPID CARRIERS
Solid lipid nanoparticle is the new generation of
colloidal drug carrier delivery system for targeted therapeutic effect. This
consist of lipids which are stabilized by surfactant i.e. surfactant –
stabilized lipids that are solid in nature both at room and body
temperature. They combine the advantages of polymeric nanoparticles,
emulsion, liposome, and various carrier systems while minimizing some
of their individual disadvantages. Solid lipid nanoparticle typically
contain a hydrophobic solid matrix core with a phospholipid coating. The
hydrophobic tail regions of the phospholipid are embedded into the core
matrix and that is why the core possesses a hydrophobic nature.
Due to this hydrophobic nature of the solid lipid
nanoparticle it is expected that they have higher entrapment efficiency for
hydrophobic drug in the core as compared with conventional liposome.
They are suitable for intravenous adm. and can be successfully dispersed
in aqueous and aqueous-surfactant solution. Several other advantages of
solid lipid nanoparticle involves easy scale-up, low cost of production,
nontoxic nature, biodegradable composition, stability.
Fig. Schematic representation of the structures of liposome and solid
lipid nanoparticle

14.  METHOD OF PREPARATION
a. Hot Homogenization
b. Cold Homogenization
c. Micro emulsification
d. Solvent Emulsification-Evaporation Method
e. Solvent Emulsification -Diffusion
a. Hot Homogenization :
Solid lipid are melted by heating 5-100C above
its melting temp. The drug is dissolved, dispersed or solubilized in hot
melted lipid, followed by the dispersion of the drug lipid melt into an
aqueous surfactant solution (heated to the same temperature) to form an
O/W preemulsion. It is then homogenized to get a nanoemulsion. This
nanoemulsion is cooled to room temperature to recrystallize the lipids and
to obtain solid lipid nanoparticle.
b. Cold Homogenization
Solid lipid are melted by heating 5-100C above its
melting temp. The drug is dissolved, dispersed or solubilized in hot
melted lipid,followed by cooling to room temp. The resultant substance is
ground to obtain microparticles (50-100µm). Then microparticles are
suspended in a cold aq. surfactant solution to obtain presuspenion. This
presuspension is homogenized below room temperature to obtain solid
lipid nanoparticle.
c. Microemulsification
Surfactants / co-surfactants such as lecithin, bile salts, or
butanol are dissolved in water to form an aqueous phase. This aqueous
phase is heated to the same temperature as that of molten lipids, following
which it is added to the molten lipids under stirring to obtain a
thermodynamically stable microemulsion. This mixture is transferred to a

15. cold aqueous medium (2-30C) under gentle stirring to obtain the solid
lipid nanoparticles.
d. Solvent evaporation – Evaporation method
This method is suitable for heat sensitive compounds.
Lipids are dissolved in an organic solvent that is immiscible in water such
as toluene or chloroform. Then the lipid solution is transferred to an
aqueous phase to form the primary emulsion followed by the evaporation
of organic solvent. After the evaporation, the lipids precipitates to form
solid lipid nanoparticles.
This are several methods which are used in the
preparation of solid lipid nanoparticle.
Drug Incorporation in Solid Lipid Nanoparticles
There are three major ways to incorporate drug into
solid lipid nanoparticle. It is based on the properties of the drug and
excipients and their interactions with each other. The three major ways
include the homogenous matrix model, the drug enriched shell model, and
the drug-enriched core model.
POLYMERIC NANOPARTICLES
Polymeric nanoparticles are solid colloidal particles
ranging in size from 10 to 1000 nm. In this the drug may be dissolved,

16. entrapped, encapsulated or attached to a nanoparticle matrix, as these
system have very high surface area, drug may also be adsorbed on their
surface. Polymer based nanoparticles effectively carry drugs, proteins and
DNA to target cells and organs. Their nanometer size promotes effective
permeation through cell membranes and stability in the blood stream.
Nanocapsules are the systems in which the drug is confined to a cavity
surrounded by a unique polymer membrane.
Nanospheres are the matrix systems in which the drug is physically
dispersed.

17.  METHODS OF PREPARATION
1. Amphiphilic macromolecule cross-linking
a) Heat Cross-linking
b) Chemical Cross-linking
2. Polymerization based methods
a) Polymerization of monomers
b) Dispersion polymerization
c) Interfacial condensation polymerization
d) Emulsion polymerization
e) Interfacial complexation
3. Polymer precipitation methods
a) Solvent extraction/ evaporation
b) Solvent displacement (nano precipitation)
c) Salting out

18. 1.Amphiphilic macromolecule cross-linking
Aqueous protein (BSA), Surfactant + Oil
High pressure
Homogenization
W/O emulsion
Add cross-linking agent
Dilution with preheated {Chemical cross linking}
Oil {Heat cross linking}
Centrifugation and isolation of nanoparticles
2. Polymerization based methods
Emulsion Polymerization
It may be conventional or reverse, depending upon nature of
continuous phase,
Conventional method= Aq phase in Continuous
Reverse method= Organic is continuous phase
Monomer is emulsified in non-solvent partially soluble phase
with stabilizer, leading to formation of monomer swollen
micelles
Polymerization takes place in presence of initiator
(chemical/physical), which provides energy to monomer, So that
in becomes free reactive radical

19. It collides with the surrounding unreactive monomers, and
initiates the polymerization reaction.
It continues till concentration of monomer/intiator is consumed
Mechanism is micellar polymerization were Swollen monomer
micelles act as a site of nucleation & polymerization
As monomer is slightly soluble in surrounding phase, it diffuses
from monomer droplets and reach monomer micelles through
continuous phase.
Thus polymerization takes places in micelles.
Dispersion polymerization
Monomer is dissolved in the Aq medium, which act as a precipitant for
formed polymer. Nucleation is directly induced in Aq. Monomer solution.
So no stabilizer or surfactant is required
Initiation is achieved by irradiating solution with
high energy radiation (UV). Process goes as emulsion polymerization.
3. Polymer precipitation methods
Solvent extraction/ evaporation
Organic phase, Solvent, + Aq. phase, Distilled water,
Drug, Polymer Stabilizer

20. Sonication, homogenization
O/W emulsion
Solvent evaporation
Nano particles obtained
Salting out / Emulsion diffusion method
In this water-soluble polymers are dissolved in a
highly concentrated solution of electrolytes or nonelectrolytes to obtain a
viscous gel (aqueous phase). This aqueous gel is added to an organic
phase such as acetone to obtain an O/W emulsion under vigorous stirring.
The formation of nanoparticles is facilitated by adding an excess amount
of water, which diffuses the acetone out.
These are the several method discussed for preparation of polymeric
nanoparticles.
Various polymers are used in the preparation of polymeric
nanoparticle, these includes
Natural hydrophilic
Proteins eg. Gelatin, albumin, lectin, legumine
Polysaccharides eg. Alginate, Dextran, Chitosan,
Synthetic hydrophobic
Pre-polymerized eg. Poly E caprolactone, PLA, PLGA
Polymerized in process eg. Poly isobutyl cyano

21. Acrylates
Advantages of Polymeric nanoparticles
 Increases the stability of any volatile agents & can be easily and
cheaply fabricated in large quantities by a multiple methods.
 Has significant advantages over traditional oral and intravenous
methods of administration in terms of efficiency and effectiveness.
 Delivers a higher concentration of pharmaceutical agent.
 The choice of polymer and the ability to modify drug release from
polymeric nanoparticles have made them ideal candidates for
cancer therapy, delivery of vaccines, contraceptives and delivery
of targeted antibiotics.
Disadvantages of Polymeric nanoparticles
 Productivity is more difficult. As a industrial applications,
technology transfer to commercial production is very difficult.
 Reduced ability to adjust the dose
 Highly sophisticated technology
 Requires skills to manufacture.
 Stability of dosage form is big issue owing to its nano size
CARBON NANOTUBES

22. Carbon nanotubes are capable of delivering
peptides, vaccines, proteins, nucleic acids, and other therapeutic agents.
These are formed by natural folding behavior of graphene sheets.
There are two categories of carbon nanotubes.
It is depend on the number of graphene sheet layers involved, the first
type is the single-walled nanotube (SWNT diameter 1-2 nm and length 50
nm-1cm) and the second type is the multi walled nanotube (length 10-100
nm). Nanotubes possess a positive charge and hydrophobic nature that
make them unsuitable for most drug delivery applications. However,
functionalization or modification of these nanotubes makes them
dispersible in water and they can serve as potential carriers for a wide
variety of compounds. The functional groups on modified carbon
nanotubes are capable of forming conjugates with drug moieties that
would produce a pharmacological effect in the body.
Functional modification of carbon nanotube

23.  METHOD OF PREPARATION
Arc discharge evaporation method
Laser Ablation Method
Thermal Synthesis Process
Chemical vapor deposition (CVD)
Arc discharge evaporation method
Use of higher temperatures (above 700 ⁰C) for
CNT synthesis, which usually causes the growth of CNTs with fewer
structural defects in comparison with other techniques.
Electric arc created between two graphite
electrodes leads to an extremely high temperature which is
sufficient to sublimate carbon. Either MWCNTs or SWCNTs can he
formed when the carbon vapours cools and condenses.
Laser Ablation Method
This method uses a pulsed and continuous laser to
vaporize a graphite target in an oven, which is filled with helium or argon
gas to keep pressure. The laser ablation is similar to the arc discharge,
both taking advantage of the very high temperature generated, with the
similar optimum background gas and catalyst.
This is in general about Colloidal drug delivery system.
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