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BY
PRIYANKA ODELA (M pharm 1st yr)
Department of pharmaceutics
   Principle
   Definition
   Introduction
   Biological fate of liposomes
   Advantages and limitations
   Advancements in liposomes
   Stealth liposomes
   Pegylation
   Composition of liposomes
   Mechanism of liposome formation
   Classification of liposomes
   Methods of preparation
   Locus of drugs in liposomes
   Characterisation of liposomes
   Modes of liposome/cell interaction
   Stability of liposomes
   Storage of liposomes
   Pharmacokinetics of liposomes
   Uses of liposomes
   Therapeutic applications
   List of marketed products            1
   Conclusion
Targeted Drug Delivery System( liposomes )
must supply drug directly (selectively) to the
site(s) of action in a manner that provides
maximum therapeutic activity through kinetics.
 It prevents degradation or inactivation during
transmit to the target sites and protects the
body from adverse reaction because of
inappropriate disposition.



                                              2
The name liposome is derived from two Greek
words: 'Lipos' meaning fat and 'Soma' meaning
body.
 liposome's are concentric bilayered vesicles in
which an aqueous volume is entirely enclosed
by a membranous lipid bilayer mainly
composed of phospholipids.




                                                   3
Liposome was found by Alec Bangham of
Babraham Institute in Cambridge, England in
1965
 In 1990, drugs with liposome and Amphotericin
B were approved by Ireland.
In 1995 U.S.F.D.A approved liposor doxorubicin .
 Liposome is a lipid vesicle suspending in the
aqueous phase with a diameter around
0.0025~3.5um. The membrane of liposome is
made of phospholipids, which have phosphoric
acid sides to form the liposome bilayers .
                                               4
Liposomes in                                   Macrophages engulf
                        Taken by RES            liposomes(endocytosis)
   blood stream




                        Membrane of phago
                       lysosyme also contains
                         protonpumps which
Release of the drug      decrease pH of the       Phagosome+lysosome
    into cytosol        phagolysosyme n the         =phagolysosyme
                      enzymes phospholipases
                       destruct the liposomal
                             membrane



                                                                         5
6
Biocompatible, completely biodegradable, non-
toxic, flexible, nonimmunogenic .
Provides selective passive targetting to tumours.
 Liposomes supply both a lipophilic environment and
aqueous in one system. Can protect encapsulated drug.
Increased efficacy and therapeutic index
 Reduce exposure of sensitive tissues to toxic drugs.
 Alter the pharmacokinetic and pharmacodynamic
property of drugs (reduced elimination, increased
circulation life time ).
Flexibility to couple with site-specific ligands to achieve
active targeting ( Anticancer and Antimicrobial drugs).
Liposomes can encapsulate both micro and
macromolecules such as haemoglobin , erythropoeitin
, interferon g etc .
 Can be formulated into multiple dosage forms.
                                                         7
Production cost is high
 Leakage and fusion of encapsulated drug /
molecules.
 Sometimes phospholipid undergoes oxidation
and hydrolysis like reaction
Short half-life
 Low solubility
Fast elimination from the blood and localisation
in reticuloendothelial system primarily kupffer
cells of liver.
                                               8
Ethosomes : efficient at delivering to the
skin.composed of soya phosphotidylcholine + 30%
ethanol.
 Immunoliposomes : modified with antibodies.
Niosomes : SUV’s made from nonionic surfactants.
Proliposomes : dry, free flowing particles that
immediately form a liposomal dispersion on contact
with water.
 Stealth liposomes : coating of liposomes with
PEG(hydrophilic polymer) to improve Stability &
lengthens their half life in circulation.PEG coating
inhibits recognition by RES system.
                                                       9
hydrophilic




Coating liposomes with PEG reduces the rate of uptake by
macrophages(stealth effect) and leads to prolonged presence of
liposomes in the circulation and consequently provides ample
time for these liposomes to escape from the circulation through
leaky endothelium.
Liposomes can be composed of naturally derived phospholipids
with mixed lipid chains coated or stabilised by polymers of PEG.
Ex:doxorubicin loaded liposome in market as DOXIL or
CAELYX,treatment of solid tumours.
                                                             10
NATURAL POLYMERS:
-polyhydroxyethyl l-asparagines coated
-PEG coated
-H-PG-PEG coated
-dope coated
  Biocompatible synthetic polymers:
-polyvinyl pyrolidone
-polyaniline
-polyacrylamide
-poly (2- methyl 2- oxazoline)
                                         11
Process of construction of stealth liposomes
with PEG studding the outside membrane is
called as pegylation.

Increase in mole% of PEG on surface of
liposomes by 4 to 10% signifantly increased
circulation time invivo from 200-1000 minutes.
                                               12
Conventional   Long circulating




   Immuno
                  Cationic



                                  24
General representation of phospholipid




                                         13
The most common natural phospholipid is the
  phosphatidylcholine (PC ).
Naturally occurring phospholipids used in
  liposomes are:
   Phosphatidylcholine
   Phosphatidylethanolamine
  Phosphatidylserine
Synthetic phospholipids used in the liposomes
  are:
   Dioleoyl phosphatidylcholine
  Disteroyl phosphatidylcholine
  Dioleoyl phosphatidylethanolamine
  Distearoyl phosphatidylethanolamine         14
Phosphatidylcholine is an amphipathic
  molecule in which exists
  – a hydrophilic polar head group, phosphocholine .
  – a glycerol bridge
  – a pair of hydrophobic acyl hydrocarbon chains

   Molecules of PC are not soluble in water.
   In aq media they align themselves in planar bilayer
   sheets inorder to minimize the Unfavorable action b/w
   the bulk aq phase & long hydrocarbon fatty chain.
    PC molecules contrast with other amphipathic
   molecules such as detergents, In that they form
-Bilayer sheets
- not micellar structures
                                                           15
Cholesterol: Stabilizes the Membrane
 Steroid lipid
 Interdigitates between phospholipids

   i.e. below Tc , it makes membrane less ordered & above
  Tc more ordered.
   Being an amphipathic molecule, cholesterol inserts into
  the membrane with its hydroxyl group of cholesterol
  oriented towards the aqueous surface and aliphatic
  chain aligned parallel to the acyl chains in the center of
  the bilayer

Role of cholesterol in bilayer formation: Restricts the
  transformations of trans to gauche Conformations.
  Incorporated into phospholipid membrane upto 1:1 or
  2:1 of cholesterol to PC.

                                                          16
TYPES



STRUCTURAL                 COMPOSITION
              METHOD OF
                               AND
PARAMETERS   PREPARATION
                            APPLICATION


                                      18
Based on structural
                               parameters



                                                                 MVV-Multi
MLV-Multilamellar   OLV-Oligolamellar        UV-Unilamellar
                                                                  vesicular
vesicles(>0.5um)    vesicles(0.1-1um)           vesicles
                                                               vesicles(>1um)




   MUV-Medium            SUV-Small
                                                LUV-Large        GUV-Gaint
    unilamellar         unilamellar
                                               unilamellar       unilamellar
     vesicles           vesicles(20-
                                            vesicles(>100nm)   vesicles(>1um)
                          100nm)
                                                                            19
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 convered into spheres.




                                                         20
21
22
23
25
17
26
PHYSICAL DISPERSION OR MECHANICAL
DISPERSION METHOD:
There are four basic methods of physical
dispersion :

1)Hand shaken method.
2)Non shaking method.
3)Pro – liposomes .
4) Freeze drying .

                                           27
28
29
The procedure differs from hand shaken method in
that it uses a stream of nitrogen to provide agitation
rather than the rotationary movements.
Here the lipid film is exposed to water - saturated
nitrogen(15 – 20min).
After Hydration, lipid is swelled by addition of bulk
fluid. 10-20ml of 0.2M sucrose in distilled
water(degassed) is introduced.
The flask is flushed with nitrogen, sealed and allowed
to stand for 2 hrs at 37 degrees celsius . After
swelling, the vesicles are harvested by swirling the
contents of the flask gently, to yield a
milky‐suspension        Centrifugation

                               LUV                       30
To increase the surface area of dried lipid film &
to facilitate instantaneous hydration.

          Dried over   Finely divided particulate
 LIPID                  support like powdered       PROLIPOSOMES
                       NaCl/sorbitol/polysacchari
                                   des




  PROLIPOSOMES                    WATER             Dispersion of MLV’s




                                                                  31
Another method of dispersing the lipid in a
finely divided form, prior to addition of aq.
Medium is to freeze dry the lipid dissolved in a
suitable organic solvent.
 Tertiary butanol us considered to be the most
ideal solvent.
After obtaining the dry lipid which is a
expanded foam like structure, water or saline
can be added with rapid mixing above the
phase tranisition temperature to give MLVs.

                                                   32
1) Micro Emulsification liposomes (MEL)
2)Sonicated unilamellar vesicles (SUVs)
3) French Pressure Cell Liposomes .
4) Membrane extrusion Liposomes
5)Dried reconstituted vesicles(DRVs)
6)Freeze thaw sonification (FTS)
7)pH induced vesiculation
8) Calcium Induced fusion
                                          33
34
35
36
37
38
The transient change in pH brings about an
increase in surface charge of the lipid bilayer
which induces spontaneous vesiculation .
COCHLEATE METHOD :

                                                               LUV’s
                                                  Removal of
                                                  calcium by
                                Cylindrical       EDTA
                                rolls(cochleate
                                cylinders)
                  Addition of
                  Ca++ ions


   SUV made
   from
   phosphatidyl                                                        39
   choline
• In this method lipids are first dissolved in an organic
  solution, which is then brought into contact with the aqueous
  phase containing materials to be entrapped within the
  liposome.

• At the interface between the organic and aqueous media ,the
  phospholipids align themselves into a monolayer which form
  the basis for half of the bilayer of the liposome.




                                                                  40
41
Generally the liposome is made up in 2 steps:
     1 st the inner leaflet of the bilayer .
     Then the outer half.
                                              Aq medium contng
                                             matrl to be entrapped

     Methods to prepare the droplets:
     1)Double emulsion vesicles              Add to immiscible org
                                                  sol of lipid
     2) Reverse phase evaporation vesicles
     3)Sonication methods
                                             Mechanical agitation



42                                            Microscopic water
                                                  droplets
In this method, the outer portion of liposome
membrane is created at a second Interface b/w
two phases by emulsification of an organic soln
in water.


   w/o      Excess aq    w/o/w     Removal of   Unilamellar
 emulsion   medium      emulsion     solvent     vesicles




                                                              43
44
The phospholipids are brought into contact with aq phase via the
   detergent,which associate with phospholipid molecules.The
   structures formed as a result of this association are MICELLES.
    Below CMC,detergent molecules exist in free soln.
   As the concentration is increased,micelles are formed.

At three stage model of interaction for detergents with lipid bilayers :
   At low concn,detergent equilibrates b/w vesicular lipid and water
   phase.
    After reaching CMC, membrane tends to be unstable & transforms
   into micelles
    At stage three, all lipid exists in mixed micelle form.

 In all the methods,the basic feature is to remove the detergent from
  preformed Mixed vesicles contng phopholipid,whereupon
  unilamellar vesicles form spontaneously.
Methods to remove detergents :
 Dialysis
 Column chromatography
 Use of bio-beads
                                                                      45
The lipid bilayer membrane is impermeable to
  ions & hydrophilic molecules.
  But, Permeation of hydrophobic molecules can be
  controlled by concentration gradients.

   Some weak acids or bases can be transported due
   to various transmembrane gradients
-Electrical gradients.
-Ionic(pH) gradients.
-Chemical potential gradients.

 Weak amphipathic bases accumulate in aq phase
  of lipid vesicles in response to difference in pH
  b/w Inside & outside of liposomes .               46
Liposomes with low internal
                                      pH
Solute bearing no charge at
neutral pH




                                                     Neutral solute passes easily
                                                     through bilayer membrane by
                                                     diffusion




                              Charge aquired by solute
                              inside liposomes makes                                47
                              them unable to exit
pH gradient is created by preparing liposomes with low internal
pH.



            Addtn of base to extraliposomal medium.



        [Basic compds ( lipophilic (non ionic) at high pH &
                  hydrophilic(ionic) at low pH)]



  Lipophilic (UNPROTONATED) drug diffuse through the bilayer .




 At low pH side, the molecules are predominantly protonated .

                                                                  48
The following have beem successfully
 encapsulated:
Weak bases such as
 Doxorubicin
 Adriamycin
 Vincristine
 Short modified peptides and insulin


                                        49
HYDROPHILIC (DOXORUBICIN)
Low entrapment
Leakage
Hydrolytic degradation
 LIPOPHILIC (CYCLOSPORINE)
 High entrapment
 Low leakage
 Chemical stability
 AMPIPHILIC (VINBLASTIN)
 High entrapment
 Rapid leakage
  BIPHASIC INSOLUBLE
  (ALLOPURINOL, 6-
  MERCAPTOPURINE)
  Poor loading and entrapment




                             50
CHARACTERISATION OF LIPOSOMES

CHARACTERISATION PARAMETERS                   ANALYTICAL METHOD/INSTRUMENT

1. Vesicle shape and surface morphology       Transmission electron microscopy,
                                              Freeze-fracture electron microscopy
2. Mean vesicle size and size distribution     Photon correlation spectroscopy, laser
(submicron and micron range)                  light scattering, gel permeation and gel
                                              exclusion
3. Surface charge                             Free-flow electrophoresis
4. Electrical surface potential and surface   Zetapotential measurements
pH
5. Lamellarity                                Small angle X-ray scattering, 31 P-NMR,
                                              Freeze-fracture electron microscopy
6. Phase behavior                             Freeze-fracture electron microscopy,
                                              Differential scanning calorimetery
7. Percent of free drug/ percent capture      Minicolumn centrifugation, ion-exchange
                                              chromatography, radiolabelling
8. Drug release                               Diffusion cell/ dialysis
                                                                                         51
CHARACTERISATION PARAMETERS     ANALYTICAL METHOD/INSTRUMENT


1. Phospholipid concentration   Barlett assay, stewart assay, HPLC

2. Cholesterol concentration    Cholesterol oxidase assay and HPLC

3. Phopholipid peroxidation     UV absorbance

4. Phospholipid hydrolysis      Cholesterol auto-oxidation. HPLC and TLC

5. Osmolarity                   Osmometer




                                                                     52
CHARACTERISATION PARAMETER   ANALYTICAL METHOD/INSTRUMENT

1. Sterility                 Aerobic or anaerobic cultures

2. Pyrogenicity              Limulus Amebocyte Lysate (LAL) test

3. Animal toxicity           Monitoring survival rates, histology and
                             pathology




                                                                        53
Adsorption   Endocytosis




Fusion       Lipid transfer




                              54
 Stability invitro .
  Lipid oxidation
  Lipid peroxidation
 Lipid hydrolysis
  Long term & accelerated stability

 Stability invivo
Stability after systemic administration.
Stability after oral administration.
                                           55
STORAGE CONDITIONS
  Liposomes are packed in 1-2 ml sterile vials and stored
  at 4 C and room temperature.
  The samples stored at 4 C exhibited activity in
  transfection showed no aggregation or precipitation.
  The samples stored at RT still showed some transfection
  activity.

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.
                                                              56
Stability of liposomes mainly depend on
structure of lipids and its amount.
Examples:
1)DOXIL: stable for more than 18 months in
liquid state without lyophilisation due to
pegylated nature.
2)AMBISOME: liposomal preparation of
Amphotericine available as lyophilised
cake.After reconstitution not stable for more
than a day.



                                                57
Pharmacokinetics of liposomes mainly deals with time
course of absorption, distribution and degradation of
liposomal carriers invivo.
Pharmacokinetic information can be used to interpret
the differences in pharmacological effect of the
liposome entrapped drug and free drug and
subsequently can be exploited for dose regimen.
Liposomes can alter both tissue distribution and rate of
clearance of the drug as they are affected by
pharmacokinetic parameters of the carrier.
Bioavailabilty in case of liposomal carriers can be
defined as the amount of free drug that is able to
escape the carriers and thus available for redistribution
to neighbouring tissue.                                 58
 Protection of drug from metabolism and
  inactivation in plasma.
 Reduced volume of distribution and hence
  decrease in non specific localisation.
 Higher therapeutic index.
 Decrease in amount and type of non specific
  toxicity.
 Increase in concentration of drug at target site.


                                                      59
 As drug delivery carriers.
 Enzyme replacement therapy.
 Chelation therapy for treatment of heavy metal
  poisoning.
 Liposomes in antiviral/anti microbial therapy.
 In multi drug resistance.
 In tumour therapy.
 In gene delivery.
 In immunology.
 In cosmetology
                                               60
THERAPEUTIC APPLICATIONS OF LIPOSOMES
DRUG             ROUTE OF                      APPLICATION                        TARGETED DISEASES
                 ADMINISTRATION
Amphotericin B   Oral delivery                 Ergosterol membrane                Mycotic infection
Insulin          Oral,ocular,pulmonary         Decrease glucose level             Diabetic mellitus
                 And transdermal
Ketoprofen       Ocular delivary               Cyclooxygenase enzyme inhibitor    Pain muscle condition

Pentoxyfyllin    Pulmonary delivery            phosphodiesterase                  Asthama
Tobramycin       Pulmonary delivery            Protein synthesis inhibitor        Pseudomonas
                                                                                  infection,aeroginosa
Salbutamol       Pulmonary delivery            ß2-adrenoceptor antagonist         Asthama
Cytarabin        Pulmonary delivery            DNA-polymerase inhibition          Acute leukameias

Benzocaine       Transdermal                   Inhibition of nerve impulse from   Ulcer on mucous surface
                                               sensory nerves                     with pain

Ketaconazole     Transdermal                   Inhibit ergosterol membrane        Candida albicans

Levanogesterol   Transdermal                   Rhamnose receptor                  skin disorder
hydroxyzine      Transdermal                   H1-receptor antagonist             Urtecaria,allergic skin
                                                                                  disease
Ibuprofen        Oral delivery                 Chaemoceptor,free ending           Rheumatoid arthritis

triamcilonone    Ocular delivery,Transdermal   Inhibition of prostaglandin        Anti-inflammatory

                                                                                                            61
NAME                     TRADE NAME     COMPANY            INDICATION
Liposomal                Abelcet        Enzon              Fungal infections
amphotericin B
Liposomal                Ambisome       Gilead Sciences    Fungal and protozoal infections
amphotericin B
Liposomal cytarabine     Depocyt        Pacira (formerly   Malignant lymphomatous meningitis
                                        SkyePharma)
Liposomal                DaunoXome      Gilead Sciences    HIV-related Kaposi’s sarcoma
daunorubicin
Liposomal doxorubicin    Myocet         Zeneus             Combination therapy with cyclophosphamide
                                                           in metastatic breast cancer
Liposomal IRIV vaccine   Epaxal         Berna Biotech      Hepatitis A

Liposomal IRIV vaccine   Inflexal V     Berna Biotech      Influenza

Liposomal morphine       DepoDur        SkyePharma, Endo   Postsurgical analgesia
Liposomal verteporfin    Visudyne       QLT, Novartis      Age-related macular degeneration, pathologic
                                                           myopia, ocular
                                                           histoplasmosis
Liposome-PEG             Doxil/Caelyx   Ortho Biotech,     HIV-related Kaposi’s sarcoma, metastatic
doxorubicin                             Schering-Plough    breast cancer, metastatic
                                                           ovarian cancer
Micellular estradiol     Estrasorb      Novavax            Menopausal therapy
                                                                                                      62
MARKETED           DRUG USED                  TARGET DISEASE          COMPANY
PRODUCT
Doxil              Doxorubicin                Kaposis sarcoma         SEQUUS,USA

Amphotec           Amphotericin B             Fungal infections       SEQUUS,USA
                                              leishmaniasis

Fungizone          Amphotericin B             Fungal infections       Bristol squibb
                                              Leishmaniasis           netherland

Ventus             Prostaglandin –E1          Systemic inflammatory   The liposome
                                              disease                 company USA

Topex Br           Terbutaline sulphate       asthma                  Ozone ,USA
Depocyt            cytarabine                 Cancer therapy          Skye pharm,USA


Novasome           Small pox vaccine          Small pox               Novavax,USA

Avian retrovirus   Killed avian retro virus   Chicken pox             Vineland lab,USA
vaccine

Vincasome          vincristine                Solid tumours           Nextar, USA

                                                                                         63
Several methods of preparing liposomes were
identified, which could influence the particle
structure, degree of drug entrapment and leakage of the
liposomes.
 It was also identified that there are improved pharmacokinetic
properties with liposomal drugs compared to the free drugs.
 Furthermore, liposomes are tools for drug targeting in certain
biomedical situations (e.g., cancer) and for reducing the
incidence of dose related drug toxicity.
 Instability of the preparations is a problem, which is yet to
be overcome before full commercialisation of the process
can be realised.


                                                            64
 Target and Controlled Drug delivery – Novel Carrier Systems by
  S.P. Vyas and R.K. Khar
 Controlled and Novel Drug Delivery Systems by Sanjay K. Jain
  and N.K.Jain .
 www.pharmaxchange.info
 http://www.pharmainfo.net/reviews/liposome-versatile-
  platform-targeted-delivery-drugs
 “Liposomes preparation methods” a review by Mohammad riaz
  in Pakistan journal of pharmaceutical sciences
 “A review on liposomes” by venkateshwarlu in Research
  Journal of Pharmaceutical, Biological and Chemical Sciences
 “Stealth liposomes” a review by Kataria Sahil in IJRAP
PRESENTED BY
PRIYANKA ODELA
Department of pharmaceutics
M –PHARM 1st yr
Roll.no.5
GPRCP.

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Liposomes

  • 1. BY PRIYANKA ODELA (M pharm 1st yr) Department of pharmaceutics
  • 2. Principle  Definition  Introduction  Biological fate of liposomes  Advantages and limitations  Advancements in liposomes  Stealth liposomes  Pegylation  Composition of liposomes  Mechanism of liposome formation  Classification of liposomes  Methods of preparation  Locus of drugs in liposomes  Characterisation of liposomes  Modes of liposome/cell interaction  Stability of liposomes  Storage of liposomes  Pharmacokinetics of liposomes  Uses of liposomes  Therapeutic applications  List of marketed products 1  Conclusion
  • 3. Targeted Drug Delivery System( liposomes ) must supply drug directly (selectively) to the site(s) of action in a manner that provides maximum therapeutic activity through kinetics. It prevents degradation or inactivation during transmit to the target sites and protects the body from adverse reaction because of inappropriate disposition. 2
  • 4. The name liposome is derived from two Greek words: 'Lipos' meaning fat and 'Soma' meaning body. liposome's are concentric bilayered vesicles in which an aqueous volume is entirely enclosed by a membranous lipid bilayer mainly composed of phospholipids. 3
  • 5. Liposome was found by Alec Bangham of Babraham Institute in Cambridge, England in 1965 In 1990, drugs with liposome and Amphotericin B were approved by Ireland. In 1995 U.S.F.D.A approved liposor doxorubicin . Liposome is a lipid vesicle suspending in the aqueous phase with a diameter around 0.0025~3.5um. The membrane of liposome is made of phospholipids, which have phosphoric acid sides to form the liposome bilayers . 4
  • 6. Liposomes in Macrophages engulf Taken by RES liposomes(endocytosis) blood stream Membrane of phago lysosyme also contains protonpumps which Release of the drug decrease pH of the Phagosome+lysosome into cytosol phagolysosyme n the =phagolysosyme enzymes phospholipases destruct the liposomal membrane 5
  • 7. 6
  • 8. Biocompatible, completely biodegradable, non- toxic, flexible, nonimmunogenic . Provides selective passive targetting to tumours. Liposomes supply both a lipophilic environment and aqueous in one system. Can protect encapsulated drug. Increased efficacy and therapeutic index Reduce exposure of sensitive tissues to toxic drugs. Alter the pharmacokinetic and pharmacodynamic property of drugs (reduced elimination, increased circulation life time ). Flexibility to couple with site-specific ligands to achieve active targeting ( Anticancer and Antimicrobial drugs). Liposomes can encapsulate both micro and macromolecules such as haemoglobin , erythropoeitin , interferon g etc . Can be formulated into multiple dosage forms. 7
  • 9. Production cost is high Leakage and fusion of encapsulated drug / molecules. Sometimes phospholipid undergoes oxidation and hydrolysis like reaction Short half-life Low solubility Fast elimination from the blood and localisation in reticuloendothelial system primarily kupffer cells of liver. 8
  • 10. Ethosomes : efficient at delivering to the skin.composed of soya phosphotidylcholine + 30% ethanol. Immunoliposomes : modified with antibodies. Niosomes : SUV’s made from nonionic surfactants. Proliposomes : dry, free flowing particles that immediately form a liposomal dispersion on contact with water. Stealth liposomes : coating of liposomes with PEG(hydrophilic polymer) to improve Stability & lengthens their half life in circulation.PEG coating inhibits recognition by RES system. 9
  • 11. hydrophilic Coating liposomes with PEG reduces the rate of uptake by macrophages(stealth effect) and leads to prolonged presence of liposomes in the circulation and consequently provides ample time for these liposomes to escape from the circulation through leaky endothelium. Liposomes can be composed of naturally derived phospholipids with mixed lipid chains coated or stabilised by polymers of PEG. Ex:doxorubicin loaded liposome in market as DOXIL or CAELYX,treatment of solid tumours. 10
  • 12. NATURAL POLYMERS: -polyhydroxyethyl l-asparagines coated -PEG coated -H-PG-PEG coated -dope coated Biocompatible synthetic polymers: -polyvinyl pyrolidone -polyaniline -polyacrylamide -poly (2- methyl 2- oxazoline) 11
  • 13. Process of construction of stealth liposomes with PEG studding the outside membrane is called as pegylation. Increase in mole% of PEG on surface of liposomes by 4 to 10% signifantly increased circulation time invivo from 200-1000 minutes. 12
  • 14. Conventional Long circulating Immuno Cationic 24
  • 15. General representation of phospholipid 13
  • 16. The most common natural phospholipid is the phosphatidylcholine (PC ). Naturally occurring phospholipids used in liposomes are: Phosphatidylcholine Phosphatidylethanolamine Phosphatidylserine Synthetic phospholipids used in the liposomes are: Dioleoyl phosphatidylcholine Disteroyl phosphatidylcholine Dioleoyl phosphatidylethanolamine Distearoyl phosphatidylethanolamine 14
  • 17. Phosphatidylcholine is an amphipathic molecule in which exists – a hydrophilic polar head group, phosphocholine . – a glycerol bridge – a pair of hydrophobic acyl hydrocarbon chains Molecules of PC are not soluble in water. In aq media they align themselves in planar bilayer sheets inorder to minimize the Unfavorable action b/w the bulk aq phase & long hydrocarbon fatty chain. PC molecules contrast with other amphipathic molecules such as detergents, In that they form -Bilayer sheets - not micellar structures 15
  • 18. Cholesterol: Stabilizes the Membrane  Steroid lipid  Interdigitates between phospholipids i.e. below Tc , it makes membrane less ordered & above Tc more ordered. Being an amphipathic molecule, cholesterol inserts into the membrane with its hydroxyl group of cholesterol oriented towards the aqueous surface and aliphatic chain aligned parallel to the acyl chains in the center of the bilayer Role of cholesterol in bilayer formation: Restricts the transformations of trans to gauche Conformations. Incorporated into phospholipid membrane upto 1:1 or 2:1 of cholesterol to PC. 16
  • 19. TYPES STRUCTURAL COMPOSITION METHOD OF AND PARAMETERS PREPARATION APPLICATION 18
  • 20. Based on structural parameters MVV-Multi MLV-Multilamellar OLV-Oligolamellar UV-Unilamellar vesicular vesicles(>0.5um) vesicles(0.1-1um) vesicles vesicles(>1um) MUV-Medium SUV-Small LUV-Large GUV-Gaint unilamellar unilamellar unilamellar unilamellar vesicles vesicles(20- vesicles(>100nm) vesicles(>1um) 100nm) 19
  • 21. 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 convered into spheres. 20
  • 22. 21
  • 23. 22
  • 24. 23
  • 25. 25
  • 26. 17
  • 27. 26
  • 28. PHYSICAL DISPERSION OR MECHANICAL DISPERSION METHOD: There are four basic methods of physical dispersion : 1)Hand shaken method. 2)Non shaking method. 3)Pro – liposomes . 4) Freeze drying . 27
  • 29. 28
  • 30. 29
  • 31. The procedure differs from hand shaken method in that it uses a stream of nitrogen to provide agitation rather than the rotationary movements. Here the lipid film is exposed to water - saturated nitrogen(15 – 20min). After Hydration, lipid is swelled by addition of bulk fluid. 10-20ml of 0.2M sucrose in distilled water(degassed) is introduced. The flask is flushed with nitrogen, sealed and allowed to stand for 2 hrs at 37 degrees celsius . After swelling, the vesicles are harvested by swirling the contents of the flask gently, to yield a milky‐suspension Centrifugation LUV 30
  • 32. To increase the surface area of dried lipid film & to facilitate instantaneous hydration. Dried over Finely divided particulate LIPID support like powdered PROLIPOSOMES NaCl/sorbitol/polysacchari des PROLIPOSOMES WATER Dispersion of MLV’s 31
  • 33. Another method of dispersing the lipid in a finely divided form, prior to addition of aq. Medium is to freeze dry the lipid dissolved in a suitable organic solvent. Tertiary butanol us considered to be the most ideal solvent. After obtaining the dry lipid which is a expanded foam like structure, water or saline can be added with rapid mixing above the phase tranisition temperature to give MLVs. 32
  • 34. 1) Micro Emulsification liposomes (MEL) 2)Sonicated unilamellar vesicles (SUVs) 3) French Pressure Cell Liposomes . 4) Membrane extrusion Liposomes 5)Dried reconstituted vesicles(DRVs) 6)Freeze thaw sonification (FTS) 7)pH induced vesiculation 8) Calcium Induced fusion 33
  • 35. 34
  • 36. 35
  • 37. 36
  • 38. 37
  • 39. 38
  • 40. The transient change in pH brings about an increase in surface charge of the lipid bilayer which induces spontaneous vesiculation . COCHLEATE METHOD : LUV’s Removal of calcium by Cylindrical EDTA rolls(cochleate cylinders) Addition of Ca++ ions SUV made from phosphatidyl 39 choline
  • 41. • In this method lipids are first dissolved in an organic solution, which is then brought into contact with the aqueous phase containing materials to be entrapped within the liposome. • At the interface between the organic and aqueous media ,the phospholipids align themselves into a monolayer which form the basis for half of the bilayer of the liposome. 40
  • 42. 41
  • 43. Generally the liposome is made up in 2 steps: 1 st the inner leaflet of the bilayer . Then the outer half. Aq medium contng matrl to be entrapped Methods to prepare the droplets: 1)Double emulsion vesicles Add to immiscible org sol of lipid 2) Reverse phase evaporation vesicles 3)Sonication methods Mechanical agitation 42 Microscopic water droplets
  • 44. In this method, the outer portion of liposome membrane is created at a second Interface b/w two phases by emulsification of an organic soln in water. w/o Excess aq w/o/w Removal of Unilamellar emulsion medium emulsion solvent vesicles 43
  • 45. 44
  • 46. The phospholipids are brought into contact with aq phase via the detergent,which associate with phospholipid molecules.The structures formed as a result of this association are MICELLES. Below CMC,detergent molecules exist in free soln. As the concentration is increased,micelles are formed. At three stage model of interaction for detergents with lipid bilayers : At low concn,detergent equilibrates b/w vesicular lipid and water phase. After reaching CMC, membrane tends to be unstable & transforms into micelles At stage three, all lipid exists in mixed micelle form.  In all the methods,the basic feature is to remove the detergent from preformed Mixed vesicles contng phopholipid,whereupon unilamellar vesicles form spontaneously. Methods to remove detergents :  Dialysis  Column chromatography  Use of bio-beads 45
  • 47. The lipid bilayer membrane is impermeable to ions & hydrophilic molecules. But, Permeation of hydrophobic molecules can be controlled by concentration gradients. Some weak acids or bases can be transported due to various transmembrane gradients -Electrical gradients. -Ionic(pH) gradients. -Chemical potential gradients.  Weak amphipathic bases accumulate in aq phase of lipid vesicles in response to difference in pH b/w Inside & outside of liposomes . 46
  • 48. Liposomes with low internal pH Solute bearing no charge at neutral pH Neutral solute passes easily through bilayer membrane by diffusion Charge aquired by solute inside liposomes makes 47 them unable to exit
  • 49. pH gradient is created by preparing liposomes with low internal pH. Addtn of base to extraliposomal medium. [Basic compds ( lipophilic (non ionic) at high pH & hydrophilic(ionic) at low pH)] Lipophilic (UNPROTONATED) drug diffuse through the bilayer . At low pH side, the molecules are predominantly protonated . 48
  • 50. The following have beem successfully encapsulated: Weak bases such as  Doxorubicin  Adriamycin  Vincristine Short modified peptides and insulin 49
  • 51. HYDROPHILIC (DOXORUBICIN) Low entrapment Leakage Hydrolytic degradation LIPOPHILIC (CYCLOSPORINE) High entrapment Low leakage Chemical stability AMPIPHILIC (VINBLASTIN) High entrapment Rapid leakage BIPHASIC INSOLUBLE (ALLOPURINOL, 6- MERCAPTOPURINE) Poor loading and entrapment 50
  • 52. CHARACTERISATION OF LIPOSOMES CHARACTERISATION PARAMETERS ANALYTICAL METHOD/INSTRUMENT 1. Vesicle shape and surface morphology Transmission electron microscopy, Freeze-fracture electron microscopy 2. Mean vesicle size and size distribution Photon correlation spectroscopy, laser (submicron and micron range) light scattering, gel permeation and gel exclusion 3. Surface charge Free-flow electrophoresis 4. Electrical surface potential and surface Zetapotential measurements pH 5. Lamellarity Small angle X-ray scattering, 31 P-NMR, Freeze-fracture electron microscopy 6. Phase behavior Freeze-fracture electron microscopy, Differential scanning calorimetery 7. Percent of free drug/ percent capture Minicolumn centrifugation, ion-exchange chromatography, radiolabelling 8. Drug release Diffusion cell/ dialysis 51
  • 53. CHARACTERISATION PARAMETERS ANALYTICAL METHOD/INSTRUMENT 1. Phospholipid concentration Barlett assay, stewart assay, HPLC 2. Cholesterol concentration Cholesterol oxidase assay and HPLC 3. Phopholipid peroxidation UV absorbance 4. Phospholipid hydrolysis Cholesterol auto-oxidation. HPLC and TLC 5. Osmolarity Osmometer 52
  • 54. CHARACTERISATION PARAMETER ANALYTICAL METHOD/INSTRUMENT 1. Sterility Aerobic or anaerobic cultures 2. Pyrogenicity Limulus Amebocyte Lysate (LAL) test 3. Animal toxicity Monitoring survival rates, histology and pathology 53
  • 55. Adsorption Endocytosis Fusion Lipid transfer 54
  • 56.  Stability invitro . Lipid oxidation Lipid peroxidation Lipid hydrolysis Long term & accelerated stability  Stability invivo Stability after systemic administration. Stability after oral administration. 55
  • 57. STORAGE CONDITIONS Liposomes are packed in 1-2 ml sterile vials and stored at 4 C and room temperature. The samples stored at 4 C exhibited activity in transfection showed no aggregation or precipitation. The samples stored at RT still showed some transfection activity. 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. 56
  • 58. Stability of liposomes mainly depend on structure of lipids and its amount. Examples: 1)DOXIL: stable for more than 18 months in liquid state without lyophilisation due to pegylated nature. 2)AMBISOME: liposomal preparation of Amphotericine available as lyophilised cake.After reconstitution not stable for more than a day. 57
  • 59. Pharmacokinetics of liposomes mainly deals with time course of absorption, distribution and degradation of liposomal carriers invivo. Pharmacokinetic information can be used to interpret the differences in pharmacological effect of the liposome entrapped drug and free drug and subsequently can be exploited for dose regimen. Liposomes can alter both tissue distribution and rate of clearance of the drug as they are affected by pharmacokinetic parameters of the carrier. Bioavailabilty in case of liposomal carriers can be defined as the amount of free drug that is able to escape the carriers and thus available for redistribution to neighbouring tissue. 58
  • 60.  Protection of drug from metabolism and inactivation in plasma.  Reduced volume of distribution and hence decrease in non specific localisation.  Higher therapeutic index.  Decrease in amount and type of non specific toxicity.  Increase in concentration of drug at target site. 59
  • 61.  As drug delivery carriers.  Enzyme replacement therapy.  Chelation therapy for treatment of heavy metal poisoning.  Liposomes in antiviral/anti microbial therapy.  In multi drug resistance.  In tumour therapy.  In gene delivery.  In immunology.  In cosmetology 60
  • 62. THERAPEUTIC APPLICATIONS OF LIPOSOMES DRUG ROUTE OF APPLICATION TARGETED DISEASES ADMINISTRATION Amphotericin B Oral delivery Ergosterol membrane Mycotic infection Insulin Oral,ocular,pulmonary Decrease glucose level Diabetic mellitus And transdermal Ketoprofen Ocular delivary Cyclooxygenase enzyme inhibitor Pain muscle condition Pentoxyfyllin Pulmonary delivery phosphodiesterase Asthama Tobramycin Pulmonary delivery Protein synthesis inhibitor Pseudomonas infection,aeroginosa Salbutamol Pulmonary delivery ß2-adrenoceptor antagonist Asthama Cytarabin Pulmonary delivery DNA-polymerase inhibition Acute leukameias Benzocaine Transdermal Inhibition of nerve impulse from Ulcer on mucous surface sensory nerves with pain Ketaconazole Transdermal Inhibit ergosterol membrane Candida albicans Levanogesterol Transdermal Rhamnose receptor skin disorder hydroxyzine Transdermal H1-receptor antagonist Urtecaria,allergic skin disease Ibuprofen Oral delivery Chaemoceptor,free ending Rheumatoid arthritis triamcilonone Ocular delivery,Transdermal Inhibition of prostaglandin Anti-inflammatory 61
  • 63. NAME TRADE NAME COMPANY INDICATION Liposomal Abelcet Enzon Fungal infections amphotericin B Liposomal Ambisome Gilead Sciences Fungal and protozoal infections amphotericin B Liposomal cytarabine Depocyt Pacira (formerly Malignant lymphomatous meningitis SkyePharma) Liposomal DaunoXome Gilead Sciences HIV-related Kaposi’s sarcoma daunorubicin Liposomal doxorubicin Myocet Zeneus Combination therapy with cyclophosphamide in metastatic breast cancer Liposomal IRIV vaccine Epaxal Berna Biotech Hepatitis A Liposomal IRIV vaccine Inflexal V Berna Biotech Influenza Liposomal morphine DepoDur SkyePharma, Endo Postsurgical analgesia Liposomal verteporfin Visudyne QLT, Novartis Age-related macular degeneration, pathologic myopia, ocular histoplasmosis Liposome-PEG Doxil/Caelyx Ortho Biotech, HIV-related Kaposi’s sarcoma, metastatic doxorubicin Schering-Plough breast cancer, metastatic ovarian cancer Micellular estradiol Estrasorb Novavax Menopausal therapy 62
  • 64. MARKETED DRUG USED TARGET DISEASE COMPANY PRODUCT Doxil Doxorubicin Kaposis sarcoma SEQUUS,USA Amphotec Amphotericin B Fungal infections SEQUUS,USA leishmaniasis Fungizone Amphotericin B Fungal infections Bristol squibb Leishmaniasis netherland Ventus Prostaglandin –E1 Systemic inflammatory The liposome disease company USA Topex Br Terbutaline sulphate asthma Ozone ,USA Depocyt cytarabine Cancer therapy Skye pharm,USA Novasome Small pox vaccine Small pox Novavax,USA Avian retrovirus Killed avian retro virus Chicken pox Vineland lab,USA vaccine Vincasome vincristine Solid tumours Nextar, USA 63
  • 65. Several methods of preparing liposomes were identified, which could influence the particle structure, degree of drug entrapment and leakage of the liposomes. It was also identified that there are improved pharmacokinetic properties with liposomal drugs compared to the free drugs. Furthermore, liposomes are tools for drug targeting in certain biomedical situations (e.g., cancer) and for reducing the incidence of dose related drug toxicity. Instability of the preparations is a problem, which is yet to be overcome before full commercialisation of the process can be realised. 64
  • 66.  Target and Controlled Drug delivery – Novel Carrier Systems by S.P. Vyas and R.K. Khar  Controlled and Novel Drug Delivery Systems by Sanjay K. Jain and N.K.Jain .  www.pharmaxchange.info  http://www.pharmainfo.net/reviews/liposome-versatile- platform-targeted-delivery-drugs  “Liposomes preparation methods” a review by Mohammad riaz in Pakistan journal of pharmaceutical sciences  “A review on liposomes” by venkateshwarlu in Research Journal of Pharmaceutical, Biological and Chemical Sciences  “Stealth liposomes” a review by Kataria Sahil in IJRAP
  • 67. PRESENTED BY PRIYANKA ODELA Department of pharmaceutics M –PHARM 1st yr Roll.no.5 GPRCP.

Hinweis der Redaktion

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  3. Lamella: A Lamella is a flat plate like structure that appears during the formation of liposomes. The Phospholipidbilayer first exists as a lamella before getting convered into spheres.
  4. French pressure cell liposomes: Extrusion of preformed large liposomes in a french press under high pressure--- Uni or oligolammellarliposomes Advantages: More stable & less leakage of contents compared to sonicatedliposomes .
  5. BIPHASIC INSOLUBLE Poor loading and entrapment
  6. PRESENTED BY:PRIYANKA ODELADepartment of pharmaceuticsM –PHARM 1st yrRoll.no.5GPRCP.