Dr. Mohammad Javed Ansari, PhD. Contact info: [email protected]
COLLEGE OF PHARMACY
PHARMACEUTICS II
(PHT 312)
OBJECTIVES OF THE LECTURE
• At the end of this lecture, you will be aware of:
• What are liposomes?
• What are liposomes structure, Classification,
Preparation, Application advantages &
disadvantages?
• What are Nanoparticles?
• What are different types of Nanoparticles?
• How to preparation nanoparticles?
• What are Application advantages & disadvantages
of Nanoparticles?
• What are some marketed colloidal formulations?
What are Liposomes? • Derived from two Greek words: 'LIPO' meaning FAT and
'Soma' meaning BODY.
• Lipsomes are FAT BODIES / vesicular structures
consisting of hydrated bilalyers of phospholipids.
• Liposomes were discovered accidently by British
haematologist Dr. Alec D Bangham in 1961, at the
Babraham Institute, in Cambridge.
• They were testing the institute's new electron microscope
by adding negative stain to DRY PHOSPHOLIPIDS,
observing CELL MEMBRANE LIKE STRUCTURE.
• Note: Phospholipids are a special group of lipids
containing phosphate which is hydrophilic or polar (able
to be mixed in water).
What are Liposomes?
• When phospholipids are immersed in water they arrange
themselves so that their hydrophilic regions point toward
the water and their hydrophobic regions point away from
the water and stick together in bilayer form.
What are Liposomes? • PHOSPHOLIPID BILAYERS are the core structure of
liposome and cell membrane formations.
`
Liposome
Cell Membrane
Hydrophilic heads
Lipophilic tails
Aq. cavity
TYPES OF LIPOSOMES Liposomes are classified based on their structure as:
Vesicle Types Abbr Diameter Size
Number of lipid bilayers
Small unilamellar vesicles
SUV Diameter of 20-100nm.
One lipid bilayer
Large unilamellar vesicles
LUV Diameter of 100nm.
One lipid bilayer
Oligolamellar vesicles
OLV Diameter of 0.1-1m.
Approximately five lipid bilayers
Multilamellar vesicles
MLV Diameter of 0.5m.
Five to twenty lipid bilayers
Multivesicular vesicles
MVV Diameter of 1m.
Multi-compartmental
structure
Conventional Long circulating
Immuno Cationic
1) Multi-lamelar vesicles(MLV): (a) Liquid hydration method:
• In this method a solution of lipid is taken and it is
evaporated which leaves a film in the vessel on complete
evaporation of the solvent .
• The film is hydrated and subjected to centrifugal force
which produce liposomes
This method is not so advantageous as it involves very
low loading of drug.
The drug content can be increased by the use of
immiscible solvent (petroleum ether or diethyl ether) to it.
(b) Solvent spherule method:
• This method produces liposomes of uniform size
distribution. It is achieved by the use of lipid dissolved
hydrophobic solvent dispersed in the aqueous solvent.
2) Small unilaminar vesicle:
(a) sonication method:
• Multi lamelar liposomes (MLV) are subjected to
sonication by bath type sonicator or probe type
sonicator.
o But the major drawback is that as we have selected
the MLV which posses very small internal volume
with in SMV so formed will also be having a small
internal diameter.
(b) French pressure cell method:
• MLV are allowed to pass through a small orifice at a
pressure of 20000 psi and a temperature of 400C.
there is a reduction in the outer layers during the
passage and would result in SULV.
·
3) Large unilaminar vesicles:
• It has a very high encapsulation efficiency.
(i) Solvent injection method:
(a) Ether infusion method: a lipid solution is prepared in
diethyl ether or ethanol/ ether and injected into the aqueous
solution of material to be incorporated under reduced
pressure at a temperature of 55 to 60oC.
(b) ethanol injection method: the ehanolic solution of lipid was
injected rapidly into excess of buffer solution. But so formed
liposomes will have a a wide range of heterogeneity of 30-110
nm.
(c) Detergent removal method: detergents are prepared at
their critical micelle concentration to solubilize the lipids.
Once the lipids are solubilized the detergent is evaporated by
dialysis or by gel chromatography or other methods.
Applications of liposomes
• Liposomes as drug delivery carrier
Liposomes can be loaded by pharmaceutical or other
ingredients by two principal ways:
1. Lipophilic substances can be associated with liposomal
membrane,
2. hydrophilic substances can be dissolved in the inner liquid
core of liposomes.
• Flexible Liposomes dosage forms: Liposomes can be
formulated as a suspension, as an aerosol, or in a semisolid
form such as gel, cream and lotion, as a dry vesicular powder
(pro-liposome) for reconstitution.
• Flexible Liposomes route of administration: Liposomes can
be administered through most routes of administration
including ocular, pulmonary, nasal, oral, intramuscular,
subcutaneous, topical and intravenous.
Applications of liposomes
• Liposomal protection of sensitive drugs
Liposomes form a barrier around their contents, which is resistant to
enzymes in the mouth and stomach, alkaline solutions, digestive
juices, bile salts, and intestinal flora that are generated in the human
body, as well as free radicals
The contents of the liposomes are, therefore, protected from oxidation
and degradation.
Liposomal solubilisation of insoluble drugs
Improve solublization and bioavalability of hydrophobic drugs such as
Amphotericin, cyclosporin, minoxidil, paclitoxel etc.
• Liposomes as drug targeting carrier
Site specific delivery of anticancer drugs to tumor cells.
• Liposomes as macro/biomolucular delivery system
Macromolecules like superoxide dismutase, haemoglobin,
erythropoietin, interleukin-2 and interferon-g.
• Liposomes are biocompatible, completely biodegradable,
non-toxic, flexible and non-immunogenic for systemic and
non-systemic administrations.
• Improved solubility of insoluble /hydrophobic drugs.
• Improved Stability of drugs (Protects sensitive drug).
• Improved PK (Changes the absorbance and
biodistribution).
• Increased efficacy and therapeutic index.
• Reduced toxicity and side effects.
• Site specific delivery (Directly to site).
• Controlled drug release: Prolong time -increase duration of
action and decrease administration.
• Altered liposome surface with ligand (antibodies,
enzymes, protein A, sugars).
• The main disadvantage of the standard liposome
formulations:
• their rapid clearance from circulation due to uptake, by the
reticuloendothelial system(RES), primarily in the liver.
• Short half-life.
• Fewer stability
• Low solubility.
• Low encapsulation efficiency
• Leakage and fusion of encapsulated drug / molecules.
• Production cost is high.
• Nanoparticles (NP) are solid colloidal particles ranging in size
from 10 nm to 1000nm.
• NP consist of macromolecular materials in which the active
principle /drugs are dissolved, entrapped or encapsulated,
and/or to which the active principle is absorbed or attached.
• Based on the arrangement of drug and polymer matrix,
nanoparticles can be classified into two types: nanospheres
and nanocapsules.
• In nanospheres, drugs are either adsorbed or entrapped inside
the polymeric matrix. In nanocapsules, drugs are confined to
the inner liquid core while the external surface of nanoparticles
is covered by the polymeric membrane.
• PNP for drug delivery are generally made up of biocompatible
and biodegradable polymers obtained from either natural or
synthetic source.
• Natural polymers include chitosan, albumin, rosin, sodium
alginate and gelatin.
• Synthetic polymers include poly (lactic acid) PLA, poly (D,L-
glycolide), poly (lactide-co-glycolide), poly (caprolactones)
(PCL) and poly (cyanoacrylates).
• The kinetics of drug release from nanoparticles depends on the
strength of hydrophobic interactions between the polymer and
drug and polymer degradation rate.
• The uptake and distribution of nanoparticles depend on its size.
Nanoparticles of size ~10 nm are utilized for extended
circulation, while ~100 and ~200 nm particles are utilized for
passive targeting and intracellular drug delivery respectively.
• Natural or synthetic polymer
• Inexpensive
• Nontoxic
• Biodegradable
• Nonthrombogenic & Nonimmunogenic
• Particle diameter <100nm
• No platelet aggregation
• Noninflammatory
• Prolonged circulation time
• SLN have been developed as alternative delivery system
to conventional polymeric nanoparticles.
• SLN are composed of physiological lipid, dispersed in
water or in an aqueous surfactant solution.
• SLNs combine advantages of polymeric nanoparticles, fat
emulsions and liposomes, but avoid some of their
disadvantages.
• They are biodegradable, biocompatible and non-toxic.
• Advantages: Avoidance of coalescence leads to enhanced
physical stability.
• Reduced mobility of incorporated drug molecules leads to
reduction of drug leakage.
• Static interface solid/liquid facilitates surface modification
Nanoparticles can be produced by either
Dispersion-based processes (which involves breaking
larger micrometer-sized particles into nanoparticles) or
precipitation-based processes /condensation.
Dispersion-based processes
a) Wet milling : Wet milling is an attrition-based process in
which the drug is dispersed first in an aqueous-based
surfactant solution. The resulting suspension is subjected to
wet milling using a pearl mill in the presence of milling
media.
b) Probe sonication
High-pressure homogenization is based on the principle of
cavitation (i.e., the formation, growth, and implosive collapse
of vapor bubbles in a liquid.
c) High-pressure Homogenization
In this process, a drug presuspension is subjected to
homogenization at high pressure (50-100 Mpa).
PREPARATION OF NANOPARTICLES
Precipitation-based processes
a) Emulsification Technology
Drug solution in an organic solvent is dispersed in the
aqueous phase containing surfactant to prepare emulsion.
Evaporation of organic solvent under reduced pressure,
results in the precipitation of drug particles to form a
nanoparticle suspension which is stabilized by the added
surfactant.
b) Spray freezing into liquid (SFL):
Drug solution is atomized into a cryogenic liquid such as
liquid nitrogen to produce frozen nanoparticles which are
subsequently lyophilized to obtain free flowing powder.
c) Evaporative precipitation into aqueous solution (EPAS).
Drug solution in a low boiling organic solvent is heated under
pressure to a temperature above the solvent's normal boiling
point and then atomized into a heated aqueous solution
containing stabilizing surfactant.
PREPARATION OF NANOPARTICLES
• Increased active agent surface area results in a faster
dissolution of the active agent in an aqueous environment,
such as the human body.
• Faster dissolution generally equates with greater
bioavailability, smaller drug doses, less toxicity.
• Decreased toxicity.
• Longer shelf-stability
• High carrier capacity
• Ability to incorporate hydrophilic and hydrophobic drug
• Can be administered via different routes
• Longer clearance time
• Ability to sustain the release of drug
• Targeted delivery of drugs at cellular and nuclear level.
• Involves higher manufacturing costs which may in turn
lead to increase in the cost of formulation.
• Involves use of harsh toxic solvents in the preparation
process.
• May trigger immune response and allergic reactions.
• Extensive use of poly(vinyl alcohol) as stabilizer may have
toxicity issues
Doxil® Doxorubicin
hydrochloride encapsulated in Stealth
® liposomes (100
nm)
FDA 1995 AIDS-related KS, multiple myeloma, ovarian cancer
DaunoXome® Daunorubicin citrate
encapsulated in liposomes (45 nm)
FDA 1996 HIV-related KS
AmBisome® Amphotericin B
encapsulated in liposomes (60–70 nm)
FDA 1997 Systemic fungal infections
DepoCyt® Cytarabine encapsulated
in multivesicular liposomes
FDA 1999/2007 Lymphomatous malignant meningitis
Inflexal®
V Influenza virus antigens (hemagglutinin, neuraminidase) on surface of 150 nm Liposomes
Switzerland 1997 Influenza vaccine
Marqibo
®
Vincristine sulfate encapsulated in sphingomyelin/cholesterol (60/40, molar) 100 nm liposomes
FDA 2012 Acute lymphoid leukemia,
Abraxane
®
Nanoparticles (130 nm) formed by albumin with conjugated paclitaxel44,45
FDA 2005 Metastatic breast cancer, non-small-cell lung cancer (IV)
Opaxio® Paclitaxel covalently linked to solid
nanoparticles composed of polyglutamate
FDA 2012 Glioblastoma
Rapamune® Rapamycin (sirolimus) as
nanocrystals formulated in tablets FDA 2002 Immunosuppressant (oral)
Emend® Aprepitant as nanocrystal FDA 2003
Emesis, antiemetic (oral)
Tricor®
Triglide®
Fenofibrate as nanocrystals FDA 2004
Megace ES® Megestrol acetate as nanocrystal FDA 2005
Anorexia, cachexia
Opaxio® Paclitaxel covalently linked to solid
nanoparticles composed of polyglutamate
FDA 2012 Glioblastoma
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172146/table/t1-ijn-9-4357/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172146/ http://www.drug-dev.com/Main/Back-Issues/NANOTECHNOLOGY-MARKET-Nanotechnology-Markets-in-He-803.aspx http://jocpr.com/vol7-iss6-2015/JCPR-2015-7-6-257-264.pdf
GOOD LUCK ..
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