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sr pm4b > Advanced Drug Delivery 2 - liposomes > Flashcards

Advanced Drug Delivery 2 - liposomes Flashcards

1
Q

What are liposomes and their size

A
  • Microparticulate or colloidal drug carriers
  • Vesicular structures composed of one or more lipid bilayers encapsulating a central aqueous core
  • The lipid molecules are normally phospholipids
  • Size: 0.05 – 5 µm
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2
Q

Chemical structure of phospholipids

A

Contains
- 2 hydrophobic tails of fatty acid
- 1 hydrophilic head of phosphate moiety joined together by an alcohol or glycerol molecule

  • This structural arrangement allows them to form lipid bilayers
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3
Q

Characteristics of fatty acids

A
  • fatty = lipophilic
  • acid = COOH carboxylic group
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4
Q

What charge is phosphate

A

Negative

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5
Q

Phosphatidylcholine (PC) derivatives

A
  • Phosphate group is -
  • PC is +
  • So overall neutral
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6
Q

Phosphatidylethanolamine (PE) derivatives

A
  • Phosphate group is -
  • PE is +
  • So overall neutral
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7
Q

Phosphatidylserine (PS) derivatives

A
  • Phosphate group is -
  • PS has one + and one -
  • So overall negative
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8
Q

Phosphatidylglycerol (PG) derivatives

A
  • Phosphate group is -
  • PG is -
  • So overall negative
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9
Q

Discuss cholesterol in the context of liposomes

A
  • Component that is normally added to liposomes
  • Cholesterol is largely hydrophobic
  • But presence of OH group confers some hydrophilicity = amphiphilic molecule
  • This allows cholesterol to insert itself in the bilayer with the hydrophilic part (OH group) close to polar head and hydrophobic part next to lipophilic chains
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10
Q

The presence of OH group and the properties of liposomes

A
  • The OH groups can form hydrogen bonds with other molecules in the liposome membrane which can increase its stability and rigidity.
  • Can impact the solubility and permeability of the liposome
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11
Q

What is the main transition temperature, TM

A

Phospholipid membranes have a parameter called TM

Below the TM:
- cholesterol has a fluidising, disorganising action
- phospholipids bilayer is less fluid, more gel like

Above TM:
- cholesterol has a condensing action
- a lot of energy in system
- bilayer very fluid

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12
Q

Conformation of a lisaphospholipid

A
  • e.g. detergents
  • Geometry: like a cone
  • Therefore most thermodynamically stable conformation is a micelle
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13
Q

Conformation of double chain phospholipids with LARGE head groups

A
  • e.g. PC
  • Large polar head and smaller tails that occupy smaller volume
  • Geometry: like truncated cone
  • Therefore, most thermodynamically stable conformation is bilayer vesicle
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14
Q

Conformation of double chain phospholipid with SMALL head groups

A
  • e.g. PE
  • Geometry: like a cyclinder
  • Therefore, most thermodynamically stable conformation is planar bilayer
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15
Q

Conformation of phospholipid with two chains and unsaturation

A
  • e.g. Phosphatidylethanol amine (unsaturated)
  • Double bonds = tails spreads wider
  • Geometry: Inverted truncated cone
  • Therefore, most thermodynamically stable conformation is inverted micelle
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16
Q

Classification of Liposomes

A
  • SUV - small unilamellar vesicles
  • LUV - large unilamellar vesicles
  • MLV - multilamellar vesicles
  • MVV - multi vesicular vesicles
17
Q

SUV

A

small unilamellar vesicle (SUV)

18
Q

LUV

A

large unilameller vesicles (LUV)

19
Q

MLV

A

multilamellar vesicles

20
Q

MVV

A

multi vesicular vesicles

21
Q
  • How can liposomes be used as drug carriers?
A
  • Can carry both hydrophobic and hydrophilic drugs
  • Encapsulate the drug within the liposome; which protects from degradation and improves solubility in water
  • Target specific cells/tissues; improves efficiency of drug and reduce SE
  • Liposomes can be designed to release the drug in a controlled manner
22
Q

Where hydrophobic and hydrophilic drugs inserts themselves in the liposomes

A
  • hydrophobic drugs = hydrophobic tails (middle of bilayer)
  • hydrophilic drugs = aqueous core
23
Q

4 Characteristics of liposomes

A
  1. Drug:lipid ratio
  2. Encapsulation efficiency
  3. Size
  4. Lamellarity
24
Q

Challenge of liposomes

A
  • Bilayers form spontaneously after addition of water to phospholipids.

The challenge is forming stable vesicles with the desired:

  • Size
  • Physio-chemical properties
  • A high drug encapsulation frequency
25
Q

What is high drug encapsulation efficiency

A
  • Measure of how efficiently the drug is incorporated into the liposome
  • Allowing for less liposomes to be administered (based on efficacy)
26
Q

Typical methodology of preparing liposomes

A
  1. Lipid hydration
  2. Selection of liposomes based on size
  3. Remove the non-encapsulated drug
27
Q

Thin layer evaporation method of preparing liposomes

A
  1. Mixture of phospholipids dissolved in organic solvent
  2. Solvent evaporation leads to phospholipid film in flask
  3. Add water-based buffer solution into phospholipid film for lipid hydration
  4. Stirring; temperature > transition temperature
  5. This causes film hydration under stirring
  6. Liposome will start forming
28
Q

Additional methods to form desired lysosome

A

e.g. Sonification and extrusion

29
Q

What is sonification

A
  1. Prepare a solution of PC in chloroform
  2. Place it in a round bottom flask and evaporate solvent
  3. Add an aqueous solution of the drug
  4. Put liposome mixture in an ultrasound bath to reduce particle size
30
Q

What is extrusion

A
  • Process carried out through polycarbonate filters
  • to control size under pressure by controlling size of pores in filter
31
Q

Administration routes of liposomes

A
  • Parenteral
  • Pulmonary
  • Oral
  • Topical
32
Q

Biodistribution of liposomes and PK of the API depend on

A
  • size of vesicles
  • composition of bilayer
  • fluidity of bilayer
33
Q

Stability of issues before administration and solution

A
  • Oxidation of lipophilic chains
  • Hydrolysis and formation of lysophospholipids
  • Tendency to form aggregates
  • Solution: freeze drying
34
Q

Stabilities issues of liposomes after administration and solution

A
  • Captured by macrophages
  • Solution: long circulating liposomes (LCL) aka sterically stabilised liposomes (stealth)
  • attach PEG chains, macrophages will not recognise them, allowing them to circulate for longer
35
Q

4 types of liposomes based on composition and application

A
  1. Conventional liposomes
  2. Sterically stabilised (stealth) liposomes
  3. Immunoliposomes (antibody targeted)
  4. Cationic liposomes (for gene delivery)
36
Q

Clinical applications of liposomes

A
  1. Abelcet
  2. AmBisome
  3. Doxil
37
Q

What is Abelcet

A
  • Contains amphotericin B, anti fungal with good activity BUT nephrotoxic
  • Liposomal formulation less toxic
  • Sodium chloride added for tonicity
38
Q

What is AmBisome

A
  • Amphotericin B encapsulated in liposomes
  • Conventional liposomes for parenteral use
  • SUV (small unilamellar vesicles) 50-100nm
  • Lower toxicity than normal amphotericin B
39
Q

What is Doxil

A
  • Liposomal encapsulated doxorubicin
  • Doxil is an anticancer agent that is very cardiotoxic
  • Liposomes reduce toxicity
  • Contain PEGlyated liposomes (long circulating liposomes)

sr pm4b (41 decks)

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