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Pharmaceutical formulation and quality assurance > Advanced drug monitoring: Drug targeting > Flashcards

Advanced drug monitoring: Drug targeting Flashcards

1
Q

What is meant by passive targeting

A

All strategies that employ the natural body response to the administration of a foreign molecule

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2
Q

What ways can passive targeting be optimised

A

-Adjusting the particle size
-Opination of the foreign molecule
> Phagocytosis transports it to the liver in macrophages
>used to target the liver
-MPS (mononuclear phagocytosis system)and RES(reticuloedothelial system) for particle between 0.4-2 micrometers

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3
Q

What are the MPS and RES targeting used to treat

A

Macrophage associated microbial diseases

Deficiencies of lysosomal enzymes

Immunopotentiation of vaccines

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4
Q

How can opsonisation be avoided to stop the RES and MPS, and promote the EPR

A

-Coat the particles in hydrophilic polymers that absorb water.
>Polyethylene glycol

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5
Q

Characteristics/ benefits of the EPR(enhanced permeability and retention) strategy.

A
  • does not reach the liver
  • Prolonged circulation time
  • can move to damaged tissue
  • Passive targeting to tumour of inflammed tissue by enhanced permeability
  • Accumulates in damaged tissue due to poor lymphatic drainage therefore has enhanced retention
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6
Q

How does the EPR strategy work

A

Leaky blood vessels in the tumour tissue or inflamed tissue allows big polymeric molecules to exit from the blood stream and accumulate at the site of the tumour

The particle doesn’t drain out due to in effective lymphatic systems.

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7
Q

What is active targeting

A

a method that delivers a certain amount of a therapeutic or diagnostic agent or both of them to a targeted diseased area within the special organ in the body

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8
Q

What are the 3 different types of active targeting systems

A

Drug

Homing device

Carrier

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9
Q

What are the homing devices available in active targeting system

A

Antibodies

Aptamers

Carbohydrates

Other molecules

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10
Q

What are the carriers available in active targeting system

A

Polymer conjugates

Micelles

Nano/micro particles

Lipid carriers

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11
Q

What are the advantages and disadvantages of the antibody homing device

A

Advantages:
>High degree of specificity

Disadvantages
>Complex and large molecules
>Expensive 
> immunogenic 
>scarce tumour penetration
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12
Q

What are the advantages and disadvantages of the oligonucleotides/Aptamer homing device

A 
Advantages: 
>Small sizes
>low immunogenicity 
>Good cell penetration
>Ease of production

Disadvantages
>Rapid blood clearance

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13
Q

What are the advantages and disadvantages of carbohydrates as homing device

A

Advantages
>Small molecules
>Cheap

Disadvantages
>Low specificity
>Low binding affinity so high density of surface modification

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14
Q

What are the advantages and disadvantages of other small molecule as homing device

A

Eg: folic Acids

Recognised by folate receptor overexpressed on certain tumour cell surfaces

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15
Q

What are the components/structure/moieties of a polymer conjugate carrier?

A

Molecular weight: must ensure access to target tissue

Target moiety (homing device) can be pendant or included in the backbone

Spacer between the drug and polymer can avoid shielding the active site an facilitate/control release
>eg degrade under specific conditions

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16
Q

What is the function of moieties on polymer conjugated

A

Increase absorption of the drug

  • Control the release
  • Provide protection from premature inactivation of the drug
  • Improve solubility profile of both the drug and the carrier
  • Targeting the system to its site of action
17
Q

List the advantages and disadvantages of polymer conjugates

A

Advantages:
>great ability to extravasate
>ease of attaching homing devices

Disadvantages
>limited drug loading capacity
>drug covalently bond can mask active site
>carrier can only partially protect the drug

18
Q

List some exaples of a polymer conjugate drugs

A

Doxorubicin and Poly(N-(2-hydroxypropyl)methacrylamide)

> reduced systemic toxicity
selective retention in tumour cells (EPR)- due to hydrophilicity
drug release by overexpressed thiol-dependent (cysteine) proteases in lysosomes

Neocarzinostatin (a peptide) that works by complexing a cromophore in it’s core

> polymer attached to 2 AA (position 1 and 20 of the peptide chain)
EPR effect used to avoid phagocytosis
Reduced the kidney clearance and reduced side effects

19
Q

Design considerations for carriers

A
  • Size
    • <10nm cleared by kidney
    • <100nm increase circulation time and reduce elimination form live
    • > 400nm taken to the liver
  • Shape:
    • spherical shapes travel in the centre of vessels and reduced interaction with endothelial
    • irregular particle tend to avoid elimination but the studies are few
  • surface properties
    • Hydrophobicity
    • Zeta-potential
20
Q

Types of particulate carriers

A
  • Micelles
  • Nano/micro-particles
  • Lipidic particles
21
Q

What are the advantages and disadvantage of particulate carriers

A

Advantages

  • high drug loading capacity
  • drug can be physically entrapped
  • the system can confer protection to the drug

Disadvantages

  • inability to cross the endothelial barrier
  • subject to phagocytosis
22
Q

What are the 2 types of micelles carriers available and it uses

A

The Di-block: Hydrophilic and hydrophobic

The tri block Hydrophilic and hydrophobic and hydrophilic /benefits
(Join in a chain)

Used to load hydrophobic drugs

Diameter of 20-40 nm to expolit EPR effect

  • high loading dose
  • LMW to favor glomerular eliminate
23
Q

Which system so micelle carriers used

A

-EPR

24
Q

Examples of micelle carrier medications

A
  • doxorubicin
  • Koniakon mixed-micelles: phytomenadione, prophylaxis and treatment of vitamin K deficiency bleeding (VKDB) in neonates and infants.
25
Q

What are the different subclasses of polymer nanoparticulate

A
  • Biodegradable polymers:
  • Synthetic: PLGA/PLA/PCL
  • Natural: Chitosan, alginate, other polysaccharides
26
Q

what is the selection criteria for the polymeric nanoparticles

A

compatibility, functionalisation needed

27
Q

What are the different types of nanoparticle medications available

A
  • Plain nanoparticle
  • Stealth
  • Charge
  • Targeting
  • Stimuli
28
Q

Properties of plain nanoparticulate

A

High aggregation
Low loading concentration
easily opsonised
Rapid clearance

29
Q

Properties of stealth nanoparticulate

A

Steric stability
High drug protection
Slow opsonisation
biocompatibility

30
Q

Properties of Charge nanoparticulate

A

High cellular uptake
high toxicity
Low specificity

31
Q

Properties of Targeting nanoparticulate

A

High cellular uptake

High specificity

32
Q

Properties of stimuli-responsiveness nanoparticulate

A

High selectivity

33
Q

Example of protein nanoparticle

A
  • Albumin
    • Transports hydrophobic molecules and interacts with vitamin and hormone
    • Reversible non-covalent bond
    • Helps endothelial transcytosis- allows accumulation into tumours
33
Q

Types lipidic particle

A
  • conventional-phagocytosis
  • Stealth- EPR
  • Targeted: specific
  • Cationic
34
Q

What advantage do liposomes have over micelles

A

They can have hydrophilic drugs in their core and and hydrophobic drugs in their bilayers.

35
Q

Exmple of liposome formulation

A

Ambisome: contains the drug Amphotericin B (antifungal)
-formed by phospholipids and cholesterol
-rapid uptake by MPS to the spleen and liver
》Abelcet: ribbon like particle (DMPC and DMPG)
》Amphotec: disk like (cholesteyl sulfate)
》Ambisome: Unilaminar (HSPC, DSPG,cholesterol)

Doxurubicin (caelyx): stealth liposomes which are not immunogenic
-EPR effect

36
Q

Advantages of lipidic particle carrier

A

tissue targeting

reduced side effects

improved drug stability and solubility

possible intracellular drug delivery by addition of a ligand recognised by receptors on the cell membrane

37
Q

Considerations that go into making a drug carrier:

A
  • Purity of the carrier material: important to guarantee quality of the product
  • Reproducibility: full physicochemical characterisation has to be carried out during the fist stages of development, later it will be included in the approval application documents
  • Safety (i.e. immunological responses)
  • Scaling-up possibility
  • Shelf life
38
Q

What are the general pharmaceutical considerations for development of a drug carries

A
  • Purity of carries is guaranteed
  • reproducibility
  • Safety
  • Scalling up probability
  • shelf life

Pharmaceutical formulation and quality assurance (14 decks)

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