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LIPOSOMES
Liposomes
   Definition:
   Liposomes are simple microscopic
    vesicles in which an aqueous volume
    is entirely enclosed by a membrane
    composed of lipid molecule.
   Structurally, liposomes are concentric
    bilayered vesicles in which an
    aqueous volume is entirely enclosed
    by a membranous lipid bilayers
    mainly composed of natural or
    synthetic phospholipids.

                                             2
Advantages
   Provide selective passive targeting to tumour tissues
    (liposomal doxorubicin).
   Increased efficacy and therapeutic index.
   Increased stability via encapsulation.
   Reduction in toxicity of the encapsulated agent.
   Improved pharmacokinetic effects (reduced
    elimination, increased circulation life times).
   Flexibility to couple with site-specific ligand to
    achieve active targeting.
                                                            3
STRUCTURE AND COMPOSITION OF LIPOSOMES
 There are number of components of
  liposomes however phospholipids and
  cholesterol being main components.
 Phospholipids are the major structural
  components of biological membranes,
  where two types of phospholipids exist –
  phosphodiglycerides and sphingolipids,
  together with their corresponding
  hydrolysis products.
 The most common phospholipid is
  phosphatidylcholine (PC) molecule.
                                             4
   Commonly used synthetic Phospholipids:
   DOPC = Dioleoyl Phosphatidylcholine
   DOPE = Dioleoyl phosphatidylethanolamine
   DSPC = Distearoyl phosphatidylcholine
   DSPE = Distearoyl phosphatidylethanolamine
   DLPC = Dilauryl phosphatidylcholine
   DMPC = Dimyristoyl phosphatidylcholine
   DLPE = Dilauryl phosphatidylethanolamine



                                                 5
   Cholesterols:
 Incorporation of sterols in liposome
  bilayer can bring about major changes in
  the preparation of these membranes.
 Cholesterol does not by itself form
  bilayer structure, but can be incorporated
  into phospholipid membranes in very
  high concentration unto 1:1 or even 2:1
  molar ratios of PC.
 Cholesterol incorporation increases the
  separation between the cholin head
  groups and eliminates the normal
  electrostatic and hydrogen-bonding
  interactions.                                6
Classification Based on structural parameters

TYPE          SPECIFICATIONS
MLV           Multilamellar large vesicles- >0.5 μm
OLV           Oligolamellar vesicles- 0.1-1 μm
UV            Unilamellar vesicles (all in size)
SUV           Small unilamellar vesicles-20-100nm
MUV           Medium sized unilamellar vesicles
LUV           Large unilamellar vesicles->100nm
GUV           Giant unilamellar vesicles->1 μm
MV            Multivesicular vesicles->1 μm
                                                      7
Classification Based on the method of liposome
                    preparation

TYPE             SPECIFICATIONS
REV              Single or oligolamellar vesicles made by
                 reverse-phase evaporation method
MLV-REV          Multilamellar vesicles made by reverse-
                 phase evaporation method
SPLV             Stable plurilamellar vesicles

FATMLV           Frozen and thawed MLV

VET              Vesicles prepared by extrusion technique

DRV              Dehydration-rehydration method
                                                            8
Chemical Characterization

Characterization parameters     Analytical methods
Phospholipid concentration      Lipid phosphorous content using
                                Barlett assay,HPLC
Cholesterol concentration       Cholesterol oxidase assay and
                                HPLC
Drug concentration              Appropriate method given in
                                monograph
Phospholipid peroxidation       UV absorbance,
                                TBA,indometric and GLC
Phospholipid hydrolysis         HPLC and TLC
Cholesterol auto-oxidation      HPLC and TLC
Anti-oxidant degradation        HPLC and TLC
pH                              pH meter
                                                                9
osmolarity                      Osmometer
Physical Characterization
Characterization parameters     Analytical methods
Vesicle shape    and    surface Transmission electron
morphology                      microscopy, freeze-fracture
                                electron microscopy.
Surface charge                  Free-flow electrophoresis.

Lamellarity                     Small angle X-ray scattering,
                                freeze-fracture      electron
                                microscopy, 31P-NMR.
Phase behavior                  Freeze-fracture         electron
                                microscopy,          differential
                                scanning calorimetry
Percent capture/percent of free Minicolumn centrifugation, gel
drug                            exclusion,        ion-exchange
                                                             10
                                chromatography, radiolabelling
Biological Characterization

Characterization         Analytical methods
parameters
sterility                Aerobic    or   anaerobic
                         cultures


pyrogenicity             Limulus        amebocyte
                         lysate (LAL) test


Animal toxicity          Monitoring       survival
                         rates,  histology    and
                         pathology


                                                     11
TECHNIQUES OF LIPOSOMES PREPARATION
(A) physical dispersion
    a) Hand-shaken multilamellar vesicles (MLVs)
    b) Non-shaking vesicles
    c) Pro-liposomes
    d) Freeze drying
(B) Processing of lipids hydrated by physical means
    a) Micro emulsification liposomes (MEL)
    b) Sonicated unilamellar vesicles (SUVs)
    c) French pressure cell liposomes
    d) Membrane extrusion liposomes
    e) Dried-reconstituted vesicles (DRVs)
    f) Freeze thaw sonication (FTS)
    g) pH induced vesiculation
    h) Calcium induced fusion
                                                      12
(C ) Solvent dispersion methods
     Ethanol Injection
     Ether injection
     Water in organic phase
     Reverse phase evaporation vesicles
     Stable plurilamellar vesicles (SPVs)
     Double emulsion vesicles
(D) DETERGENT SOLUBILIZATION




                                            13
All the methods of preparing liposomes involve three or four basic
stages:
        •Drying down lipids from organic solvent,
        •Dispersion of lipids in aqueous media,
        •Purification of resultant liposomes, and
        •Analysis of final product.




                                                                     14
Physical dispersion:
There are four basic method of physical dispersion. I.e. hand shaking,
non-shaking, freeze dry and proliposomes.

   Hand-shaken multilamellar vesicles (MLVs) :




                                                                   15
Sonicated Unilamellar Vesicles (SUVs) :




                                          16
French pressure cell liposomes   :

                 Type of liposomes : ULV or OLV
                 Pressure :20000 or 40000
                 Sample volume : maximum 40ml
                                     Minimum 4ml
                 Out flow : 0.5-1 ml / min.




                                              17
Membrane extrusion liposomes :


                Type of liposomes : MLV or
                                     LUV
                Pressure : 100 psi
                Type membranes : Tortuous path,
                Nucleation track (polycarbonate )




                                             18
   Solvent dispersion methods:
   In this methods, lipids are first dissolved in an organic
    solution, which is then brought into contact with the aqueous
    phase containing material to be entrapped within the
    liposomes.
   Methods employing solvent dispersion fall into one of three
    categories.
      The organic solvent is miscible with the aqueous phase.

      The organic solvent is miscible with the aqueous phase, the

        latter being in a large excess.
      Organic solvent is in large excess, and is again immiscible




                                                                 19
Ether injection &ethanol injection




                                     20
   DETERGENT SOLUBILIZATION :
   In this method, the phospholipids are brought into intimate contact
    with the aqueous phase via the intermediary of detergents, which
    associate with phospholipid molecules and serve to screen the
    hydrophobic portions of the molecule from water.
   The structures formed as a result of this association are known as
    micelles, and can be composed of several hundred component
    molecules.
   Their shape and size depends on chemical nature of the detergent,
    the concentration and other lipids involved.
   As a general rule, membrane-solubilizing detergents have a higher
    affinity for phospholipid membranes than for the pure detergent
    micelles.



                                                                     21
ACTIVE LOADING TECHNIQUE




                           22
   Active loading method have following advantages
    over passive encapsulation techniques:

       A high encapsulating efficiency and capacity.
       A reduced leakage of the encapsulated compounds.
       “Bed side” loading of drug thus limiting loss of retention of
        drug by diffusion or chemical degradation during storage.
       Flexibility for the use of constitutive lipids, as drug is
        loaded after the formation of carrier units.
       Avoidance of biological compound during preparation
        steps in the dispersion thus reducing safety hazards.
       The transmembrane pH gradient can be developed using
        various method depending upon the nature of the drug be
        encapsulated.
       For amphipathic weak bases by active loading procedures
        such as using a proton gradient or an ammonium sulphate
        gradient or calcium acetate gradient.
                                                                   23
    STABILITY OF LIPOSOMES

    The stability studies could be broadly covered under
     two main sections.
1.   The stability in vitro, which covers the stability
     aspects prior to the administration of the formulation
     and with regard to the stability of the constitutive
     lipids.
2.   The stability in vivo, which covers the stability
     aspects once the formulation, is administered via
     various routes to the biological fluids. These include
     stability aspects in blood (serum) if administered by
     systemic route or in gastrointestinal tract, if
     administered by oral or preoral routes.

                                                          24
Stability in vitro


          Lipid oxidation an peroxidation
          Lipid hydrolysis

          Long term and accelerated stability

    Stability after systemic administration
    Stability in vivo after oral administration




                                                   25
   APPLICATION OF LIPOSOMES

   Liposomes as drug/protein delivery vehicles
      Controlled and sustained drug release in situ.

      Enhanced drug solubilization

      Altered pharmacokinetics and biodistribution

      Enzyme replacement therapy and lysosomal storage
       disorders

   Liposomes in antimicrobial, antifungal and antiviral therapy
      Liposomal drugs

      Liposomal biological response modifiers



   Liposomes in tumour therapy
      Carrier of small cytotoxic molecules

      Vehicle for macomolecules as cytokines o genes


                                                                   26
   Liposomes in gene delivery
      Gene and antisense therapy

      Genetic vaccination



   Liposomes in immunology
      Immonoadjuvant

      Immunomodulator

      Immunodiagnosis



   Liposomes as artificial blood surrogates

   Liposomes as radiophamaceutical and radiodiagnostic cariers

   Liposomes in cosmetics an dermatology

   Liposomes in enzyme immobilization and bioreactor
    technology                                                    27
Some liposomal formulation of Amphotericin B

System      Target disease    Brand name Product

Liposomes   Systemic fungal   AmBisome   NeXstar, USA
  (i.v)       infection,
              Visceral
              leishmaniasis
Liposomes   Systemic fungal   Amphocil   SEQUUS, USA
  (i.v)       infection

Liposomes   Systemic fungal   ABELECT    The Liposome
  (i.v)       infection                    company,
                                           USA
                                                    28
Liposomes in gene therapy:
Type of Advantages                          Disadvantages
  vector
  Viral   • Relative high transfection      • Immunogenicity, presence of
   vector   efficiency                        contaminants and safety
                                            • Vector restricted size limitation
                                              for recombinant gene
                                            • Unfavourable p’ceutical issue-
                                              large scale production, GMP,
                                              stability and cost

Non-viral • Favourable p’ceutical issue-    • Relative low transfection
            large scale production, GMP,      efficiency
            stability and cost
          • Plasmid independent structure
          • Low immunogenicity
          • Opportunity for
            chemical/physical
            manipulation
                                                                          29
Various liposomal product in dermatology and cosmetics
                 (launched or investigated)

  Vesicular       Marketed by          Liposomes and
    system                                ingredients
  CaptureTM      Christian Dior     Liposomes in gel with
                                          ingredients
 PlentitudeTM       L’Oreal           Tanning agent in
                                          liposomes
DermosomeTM       Microfluidics       Skin care, loaded
                                           liposomes
   PentaTM        Pentapharm      Humectant pentavitin R in
                                         liposomes
Coatsome NCTM Nichiya liposomes Liposomes with humectant
                       Co                             30
Imaging modality and required concentration of diagnostic
                         moieties:

Imaging modality     Diagnostic moiety             Concentrat
                                                     ion
γ-scintigraphy       Diagnostic      radio-nucleus 10-10M
                       such as 111In, 99mTc, 67Ga

Magnetic             Po-magnetic ions such as 10-4M
  resonance(MR)        Gd, Mn and iron oxide

Computed             Iodine, Bromine an Barium     10-2M
  tomography(CT)
Ultrasound imaging   Gas (Air,      Argon    and
  or                   Nitrogen)
  Ultrasonography(
  US)                                                         31
COMMERCIAL MANUFACTUING OF LIPSOMAL DRUG

NO    Problems            Remedies

1     Poor quality of the High quality products with improved
      raw       material purification protocol and validated
      mainly          the analytical techniques are available
      phospholipids.
2     Pay load is too Use either lipophilic drug/lipophilic
        low           prodrug of hydrophilic drug or using
                      active techniques.
3     Poor                Quality control assay can be performed
      characterization of using sophisticated instruments and batch
      the                 to batch variability can be checked.
      physicochemical
      properties of the
      liposomes
                                                                32
NO   Problems            Remedies

4    Shelf life is too Improved by appropriate cryoprotectant
     short             and lyoprotectant and product can be
                       successfully freeze dried.

5    Scale up related Scaling up can be improved by
     problems         carefully    selecting      method     of
                      preparation, sterilization by autoclaving
                      or membrane filtration coupled with
                      aseptic processing and pyrogen removal
                      using properly validated LAL test
6    Absence of any      By choosing candidate potent drugs
     data on safety of   with narrow therapeutic window the
     these     carrier   drug elated safety problems can be
     systems        on   alleviated.
     chronic use.                                            33
34

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Liposomes

  • 2. Liposomes  Definition:  Liposomes are simple microscopic vesicles in which an aqueous volume is entirely enclosed by a membrane composed of lipid molecule.  Structurally, liposomes are concentric bilayered vesicles in which an aqueous volume is entirely enclosed by a membranous lipid bilayers mainly composed of natural or synthetic phospholipids. 2
  • 3. Advantages  Provide selective passive targeting to tumour tissues (liposomal doxorubicin).  Increased efficacy and therapeutic index.  Increased stability via encapsulation.  Reduction in toxicity of the encapsulated agent.  Improved pharmacokinetic effects (reduced elimination, increased circulation life times).  Flexibility to couple with site-specific ligand to achieve active targeting. 3
  • 4. STRUCTURE AND COMPOSITION OF LIPOSOMES  There are number of components of liposomes however phospholipids and cholesterol being main components.  Phospholipids are the major structural components of biological membranes, where two types of phospholipids exist – phosphodiglycerides and sphingolipids, together with their corresponding hydrolysis products.  The most common phospholipid is phosphatidylcholine (PC) molecule. 4
  • 5. Commonly used synthetic Phospholipids:  DOPC = Dioleoyl Phosphatidylcholine  DOPE = Dioleoyl phosphatidylethanolamine  DSPC = Distearoyl phosphatidylcholine  DSPE = Distearoyl phosphatidylethanolamine  DLPC = Dilauryl phosphatidylcholine  DMPC = Dimyristoyl phosphatidylcholine  DLPE = Dilauryl phosphatidylethanolamine 5
  • 6. Cholesterols:  Incorporation of sterols in liposome bilayer can bring about major changes in the preparation of these membranes.  Cholesterol does not by itself form bilayer structure, but can be incorporated into phospholipid membranes in very high concentration unto 1:1 or even 2:1 molar ratios of PC.  Cholesterol incorporation increases the separation between the cholin head groups and eliminates the normal electrostatic and hydrogen-bonding interactions. 6
  • 7. Classification Based on structural parameters TYPE SPECIFICATIONS MLV Multilamellar large vesicles- >0.5 μm OLV Oligolamellar vesicles- 0.1-1 μm UV Unilamellar vesicles (all in size) SUV Small unilamellar vesicles-20-100nm MUV Medium sized unilamellar vesicles LUV Large unilamellar vesicles->100nm GUV Giant unilamellar vesicles->1 μm MV Multivesicular vesicles->1 μm 7
  • 8. Classification Based on the method of liposome preparation TYPE SPECIFICATIONS REV Single or oligolamellar vesicles made by reverse-phase evaporation method MLV-REV Multilamellar vesicles made by reverse- phase evaporation method SPLV Stable plurilamellar vesicles FATMLV Frozen and thawed MLV VET Vesicles prepared by extrusion technique DRV Dehydration-rehydration method 8
  • 9. Chemical Characterization Characterization parameters Analytical methods Phospholipid concentration Lipid phosphorous content using Barlett assay,HPLC Cholesterol concentration Cholesterol oxidase assay and HPLC Drug concentration Appropriate method given in monograph Phospholipid peroxidation UV absorbance, TBA,indometric and GLC Phospholipid hydrolysis HPLC and TLC Cholesterol auto-oxidation HPLC and TLC Anti-oxidant degradation HPLC and TLC pH pH meter 9 osmolarity Osmometer
  • 10. Physical Characterization Characterization parameters Analytical methods Vesicle shape and surface Transmission electron morphology microscopy, freeze-fracture electron microscopy. Surface charge Free-flow electrophoresis. Lamellarity Small angle X-ray scattering, freeze-fracture electron microscopy, 31P-NMR. Phase behavior Freeze-fracture electron microscopy, differential scanning calorimetry Percent capture/percent of free Minicolumn centrifugation, gel drug exclusion, ion-exchange 10 chromatography, radiolabelling
  • 11. Biological Characterization Characterization Analytical methods parameters sterility Aerobic or anaerobic cultures pyrogenicity Limulus amebocyte lysate (LAL) test Animal toxicity Monitoring survival rates, histology and pathology 11
  • 12. TECHNIQUES OF LIPOSOMES PREPARATION (A) physical dispersion a) Hand-shaken multilamellar vesicles (MLVs) b) Non-shaking vesicles c) Pro-liposomes d) Freeze drying (B) Processing of lipids hydrated by physical means a) Micro emulsification liposomes (MEL) b) Sonicated unilamellar vesicles (SUVs) c) French pressure cell liposomes d) Membrane extrusion liposomes e) Dried-reconstituted vesicles (DRVs) f) Freeze thaw sonication (FTS) g) pH induced vesiculation h) Calcium induced fusion 12
  • 13. (C ) Solvent dispersion methods Ethanol Injection Ether injection Water in organic phase Reverse phase evaporation vesicles Stable plurilamellar vesicles (SPVs) Double emulsion vesicles (D) DETERGENT SOLUBILIZATION 13
  • 14. All the methods of preparing liposomes involve three or four basic stages: •Drying down lipids from organic solvent, •Dispersion of lipids in aqueous media, •Purification of resultant liposomes, and •Analysis of final product. 14
  • 15. Physical dispersion: There are four basic method of physical dispersion. I.e. hand shaking, non-shaking, freeze dry and proliposomes. Hand-shaken multilamellar vesicles (MLVs) : 15
  • 17. French pressure cell liposomes : Type of liposomes : ULV or OLV Pressure :20000 or 40000 Sample volume : maximum 40ml Minimum 4ml Out flow : 0.5-1 ml / min. 17
  • 18. Membrane extrusion liposomes : Type of liposomes : MLV or LUV Pressure : 100 psi Type membranes : Tortuous path, Nucleation track (polycarbonate ) 18
  • 19. Solvent dispersion methods:  In this methods, lipids are first dissolved in an organic solution, which is then brought into contact with the aqueous phase containing material to be entrapped within the liposomes.  Methods employing solvent dispersion fall into one of three categories.  The organic solvent is miscible with the aqueous phase.  The organic solvent is miscible with the aqueous phase, the latter being in a large excess.  Organic solvent is in large excess, and is again immiscible 19
  • 20. Ether injection &ethanol injection 20
  • 21. DETERGENT SOLUBILIZATION :  In this method, the phospholipids are brought into intimate contact with the aqueous phase via the intermediary of detergents, which associate with phospholipid molecules and serve to screen the hydrophobic portions of the molecule from water.  The structures formed as a result of this association are known as micelles, and can be composed of several hundred component molecules.  Their shape and size depends on chemical nature of the detergent, the concentration and other lipids involved.  As a general rule, membrane-solubilizing detergents have a higher affinity for phospholipid membranes than for the pure detergent micelles. 21
  • 23. Active loading method have following advantages over passive encapsulation techniques:  A high encapsulating efficiency and capacity.  A reduced leakage of the encapsulated compounds.  “Bed side” loading of drug thus limiting loss of retention of drug by diffusion or chemical degradation during storage.  Flexibility for the use of constitutive lipids, as drug is loaded after the formation of carrier units.  Avoidance of biological compound during preparation steps in the dispersion thus reducing safety hazards.  The transmembrane pH gradient can be developed using various method depending upon the nature of the drug be encapsulated.  For amphipathic weak bases by active loading procedures such as using a proton gradient or an ammonium sulphate gradient or calcium acetate gradient. 23
  • 24. STABILITY OF LIPOSOMES  The stability studies could be broadly covered under two main sections. 1. The stability in vitro, which covers the stability aspects prior to the administration of the formulation and with regard to the stability of the constitutive lipids. 2. The stability in vivo, which covers the stability aspects once the formulation, is administered via various routes to the biological fluids. These include stability aspects in blood (serum) if administered by systemic route or in gastrointestinal tract, if administered by oral or preoral routes. 24
  • 25. Stability in vitro   Lipid oxidation an peroxidation  Lipid hydrolysis  Long term and accelerated stability Stability after systemic administration Stability in vivo after oral administration 25
  • 26. APPLICATION OF LIPOSOMES  Liposomes as drug/protein delivery vehicles  Controlled and sustained drug release in situ.  Enhanced drug solubilization  Altered pharmacokinetics and biodistribution  Enzyme replacement therapy and lysosomal storage disorders  Liposomes in antimicrobial, antifungal and antiviral therapy  Liposomal drugs  Liposomal biological response modifiers  Liposomes in tumour therapy  Carrier of small cytotoxic molecules  Vehicle for macomolecules as cytokines o genes 26
  • 27. Liposomes in gene delivery  Gene and antisense therapy  Genetic vaccination  Liposomes in immunology  Immonoadjuvant  Immunomodulator  Immunodiagnosis  Liposomes as artificial blood surrogates  Liposomes as radiophamaceutical and radiodiagnostic cariers  Liposomes in cosmetics an dermatology  Liposomes in enzyme immobilization and bioreactor technology 27
  • 28. Some liposomal formulation of Amphotericin B System Target disease Brand name Product Liposomes Systemic fungal AmBisome NeXstar, USA (i.v) infection, Visceral leishmaniasis Liposomes Systemic fungal Amphocil SEQUUS, USA (i.v) infection Liposomes Systemic fungal ABELECT The Liposome (i.v) infection company, USA 28
  • 29. Liposomes in gene therapy: Type of Advantages Disadvantages vector Viral • Relative high transfection • Immunogenicity, presence of vector efficiency contaminants and safety • Vector restricted size limitation for recombinant gene • Unfavourable p’ceutical issue- large scale production, GMP, stability and cost Non-viral • Favourable p’ceutical issue- • Relative low transfection large scale production, GMP, efficiency stability and cost • Plasmid independent structure • Low immunogenicity • Opportunity for chemical/physical manipulation 29
  • 30. Various liposomal product in dermatology and cosmetics (launched or investigated) Vesicular Marketed by Liposomes and system ingredients CaptureTM Christian Dior Liposomes in gel with ingredients PlentitudeTM L’Oreal Tanning agent in liposomes DermosomeTM Microfluidics Skin care, loaded liposomes PentaTM Pentapharm Humectant pentavitin R in liposomes Coatsome NCTM Nichiya liposomes Liposomes with humectant Co 30
  • 31. Imaging modality and required concentration of diagnostic moieties: Imaging modality Diagnostic moiety Concentrat ion γ-scintigraphy Diagnostic radio-nucleus 10-10M such as 111In, 99mTc, 67Ga Magnetic Po-magnetic ions such as 10-4M resonance(MR) Gd, Mn and iron oxide Computed Iodine, Bromine an Barium 10-2M tomography(CT) Ultrasound imaging Gas (Air, Argon and or Nitrogen) Ultrasonography( US) 31
  • 32. COMMERCIAL MANUFACTUING OF LIPSOMAL DRUG NO Problems Remedies 1 Poor quality of the High quality products with improved raw material purification protocol and validated mainly the analytical techniques are available phospholipids. 2 Pay load is too Use either lipophilic drug/lipophilic low prodrug of hydrophilic drug or using active techniques. 3 Poor Quality control assay can be performed characterization of using sophisticated instruments and batch the to batch variability can be checked. physicochemical properties of the liposomes 32
  • 33. NO Problems Remedies 4 Shelf life is too Improved by appropriate cryoprotectant short and lyoprotectant and product can be successfully freeze dried. 5 Scale up related Scaling up can be improved by problems carefully selecting method of preparation, sterilization by autoclaving or membrane filtration coupled with aseptic processing and pyrogen removal using properly validated LAL test 6 Absence of any By choosing candidate potent drugs data on safety of with narrow therapeutic window the these carrier drug elated safety problems can be systems on alleviated. chronic use. 33
  • 34. 34