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PH4701- clinical pharmaceutics > Lec 11- Liposomes (Part 1) > Flashcards

Lec 11- Liposomes (Part 1) Flashcards

1
Q

So what are liposomes

A
  • Spherical bilayer constructs built from phospholipids
  • Resembles lipid bilayer of mammalian membranes
  • Hid drugs in the sphere
    • Drugs will not act on the body apart from when released in the active site
    • Body is unable to degrade drug= increase F/stability
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2
Q

Lipid- a classification system

NOT a question in the exam

A
  • Non-polar lipids
    • Insoluble in water
    • Monolayers at the water-air interface
    • Aliphatic and aromatic carbohydrates, paraffin
  • Polar lipids
    • Surface active
      • Class I: Insoluble in water, do not swell in water e.g. triglycerides
      • Class II: Insoluble in water, swell in water
      • Class III: Some solubility, form micelles- ionic and non-ionic surfactants
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3
Q

Types of delivery systems

A
  • Class I: emulsions and solid lipid nanoparticles
  • Class II: Bilayer vesicles
  • Class III: micelles
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4
Q

Lipid molecular characteristics dictate construct

A
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5
Q

The shape of the lipid may be expressed as its critical packing parameter (p) which can be defined as

A
  • v= molecular volumes of the hydrophobic part of the polar lipid
  • ao= surface area per molecule at the hydrocarbon-water interface
  • Ic= length of the hydrocarbon region
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6
Q

Combinations of lipids can create a wide range of structures

A
  • For cancer, we want to use SUV <100nm hide from the body
  • Niosomes= non-ionic surfactant
  • Virosomes- Attenuated virus combined in a liposome
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7
Q

Commonly employed lipids in liposomes

A
  • Phosphatidylcholine is a commonly used component in liposomes however a range of other lipids are also used
  • The lipid head-group dictates the surface charge of the liposomes
  • The lipid acyl tail influences the melting point of the lipid bilayer and its permeability and therefore influences drug release rates from liposomes
  • The presence of cholesterol within the bilayers can reduce their permeability and drug leakage
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8
Q

Phospholipids- headgroup

A
  • The headgroup determines the charge
  • At neutral pH phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are uncharged (zwitterionic)
  • Phosphatidylglycerol (PG) and phosphatidylserine (PS) have 1 net-negative charge per molecule
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9
Q

Which of the following could you make liposomes from

A
  • Sodium dodecyl sulphate
  • Cetyl trimethylammonium
  • Phosphatidylcholine- Only one that makes liposomes
  • Dioleoyl phosphatidylethanolamine- the size of head group= micelles
  • if the molecule has two chains, it forms a liposome
  • If it has one, it will form a micelle
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10
Q

Bilayer properties- alkyl chain

A
  • Transition temperature- where the vesicle membrane forms a gel-like structure, more likely to give up the drug
  • We can apply heat to the skin- increase drug release in that area
    *
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11
Q

Phospholipids- tailgroup

A
  • Longer carbon chain= increase instability
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12
Q

Classification

A
  • There are various ways to classify liposomes including classification based on their composition and in vivo application e.g.
    • Stealth liposomes which have a polyethyleneglycol (PEG) coat
      • PEG hides liposome from MPS
    • Immunoliposomes which have an antibody targeting moiety
    • Cationic liposomes prepared using positively charged lipids
  • However, the most widely accepted is to classify liposomes into 3 main types, based on their size and number of bilayers
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13
Q

Types of liposomes

A
  • Modification of surface properties
  • Modification of size
    • Multilamellar vesicle (MLV)
    • Large unilamellar vesicles (LUV)
    • Small unilamellar vesicles (SUV)
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14
Q

Types of liposome

MLV vs SUV vs LUV

A
  • Can’t put much drug into SUV
  • LUV will be thrown out by MPS or Kidneys
    *
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15
Q

Liposomes

A
  • Characteristics offered by liposomes
    • Can entrap both water-soluble and poorly soluble drugs
    • Can protect drugs from degradation in vivo
    • Have been shown to be non-toxic
    • The structure can be easily manipulated and tailored
    • Can target and deliver drugs to required site of action
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16
Q

Drug loading and release

Three categories of drug types may be differentiated in terms of their incorporation and retention in liposomes

A
  1. Hydrophilic drugs (log P <1.7): these are retained well in the aqueous core of liposomes
  2. Lipophilic drugs (Log P >5): These are easily incorporated and retained within the liposome bilayer
  3. Intermediate drugs (Log P 1.7-5): these partition between the bilayer and aqueous phase which can result in rapid loss from the liposome
17
Q

Liposomes as medicines

A
  • Currently a range of drugs formulated in liposome products on the market
  • The majority used in chemotherapy due to their passive targeting
  • However, their biphasic nature makes them effective targeting systems for low solubility drugs
18
Q

Liposome-based products

A
  • Depocyt (Cytarabine) - these are multivesicle liposomes composed of DOPC, cholesterol, triolein and DPPG
    • The vesicles are in size range 3-30 microns (TARGET MPS organs)
  • AmBisome (Amphotericin B)- these vesicles are <100nm in size and composed of soy phosphatidylcholine, cholesterol, diasteroyl
19
Q

Depocyte offers sustained release

A
  • An injectable, sustained-release formulation
  • Gradually releases cytarabine into the cerebral spinal fluid (CSF) and extends the dosing interval to once every two weeks
    • Standard intrathecal chemotherapy dosing of 2 times per week
  • MLV multiple layers degrade one after another to give controlled release of cytarabine (cytarabine concentrations split between the layers)
20
Q

Improving solubility

A
  • Modify molecule
    • Salts, pro-drugs, co-solvents
  • Physical modification
    • Crystal engineering, amorphous systems, particle size (reduction)
  • Drug delivery systems
    • Inclusion complexes, Emulsions, Lipid-based systems
21
Q

Case studies: Lipid formulations of amphotericin B

A
  • Amphotericin B used is comprised of associated adverse side effects
  • Lipid formulations of the drug offer a better therapeutic index and there are three commercially available lipid formulations of amphotericin B in clinical use
22
Q

Ambisome: passive targeting

A
  • Amphotericin B is incorporated within the liposomal bilayers
  • Formulations: 50mg Amphotericin B; 213mg SoyPC; 52mg ChE; 84mg DSPG; 0.64mg a-tocopherol
23
Q

AmBisome

A
  • This is a small unilamellar liposome formulation with a well defined size range of ~80nm
  • Due to it’s aqueous core this can be described as the only true liposome formulation of the three products
  • It is composed to hydrogenated soy PC, ChE, disteroylphosphatidylglycerol and amphotericin B in 2:1:0.8:0.4 molar ratio
  • It also contains a-tocopherol as an anti-oxidant
  • The drug is intercalated within the liposomal membrane
24
Q

Ambisome: passive targeting

Leishmaniasis

A
  • The parasitic disease spread by the bite of infected sandflies
  • The most common forms are cutaneous, causing skin sores, and visceral, affecting the spleen, liver and bone marrow
  • Advantages of liposomal delivery: Enhanced circulation and targeting of the drug, therefore reduced toxicity profile
25
Q

Passive targeting of liposomes to the MPS

A
  • Liposomes, due to their particulate nature are taken up by the MPS
  • This allows passive targeting of sites including liver, spleen, bone marrow
26
Q

Abelect

A
  • This formulation is composed of Am B, dimyristoyl phosphatidylcholine, and mimyristoyl phosphatidylglycerol in a 1:1 drug to lipid molar ratio, it forms ribbon-like complexes which due to their structure are difficult to size however have been reported to be around 1.6 to 11um in diameter, with 90% of the particles being smaller than 6um
27
Q

Amphotec

A
  • This formulation consists of AmB in a complex with cholesteryl sulfate at a 1:1 molar ratio to form stable colloidal disc-like structures with diameters of 100-140nm in size
28
Q

How would you design a liposome with long circulation and good drug retention

A
  1. Use a high melting point lipid e.g. DSPC- higher transition temperature
  2. Include ChE
  3. Make it an SUV (<100nm)
  4. PEG coating- Avoid opsonisation

PH4701- clinical pharmaceutics (20 decks)

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