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Pharmaceutical formulation and quality assurance > Macromolecules > Flashcards

Macromolecules Flashcards

1
Q

what are macromolecules

A

They are large molecules. This include proteins, lipid, nucleic acids and carbohydrates

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2
Q

uses of macromolecules

A

Replacement therapy
Supplement therapy
Therapeutic antibodies
Site specific carriers- recognise delivery site

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3
Q

Examples of peptide and protein macromolecules

A 
Colony stimulating factors
Interferons and interleukins
Enzymes
Hormones
Recombinant protein vaccines
Growth factor: tissue/bone growth and neurotropic factors
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3
Q

Examples of peptide and protein macromolecules

A 
Colony stimulating factors
Interferons and interleukins
Enzymes
Hormones
Recombinant protein vaccines
Growth factor: tissue/bone growth and neurotropic factors
Monoclonal antibodies
Recombinant soluble receptors
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4
Q

What are the barriers to manufacturing and delivery peptides and proteins

A
  1. In vitro stability barrier
  2. Metabolic barriers
  3. Absorption barriers
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5
Q

What are the 3 categories of in vitro stability barriers?

A

Instability due to reactive side chains
Degradation caused by environmental` factors
Manufacturing process

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6
Q

List some reactive side chains/reactions that alter side chains

A 
Transpeptidation
Deamination
Side-chain hydrolysis
Proteolysis
Disulfide exchange
b-elimination
Oxidation
Racemization
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7
Q

Environmental factors that cause degradation

A

Temp: increase flexibility of molecules so more collisions therefore more aggregation
pH: neutralizes charge
Ionic strength
Pressure
Detergents: can lead to aggregation if wrong amount is used.

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8
Q

What are the manufacturing process that determine in vitro stability

A
  1. Determine degradation routes
  2. Choose adequate additives
  3. Test stability of the solution
  4. (development of a solid formulation)
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9
Q

What 2 methods are used when developing solid formulations

A
  1. Lyophilization/freeze drying

2. Spray dry

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10
Q

How does freeze drying/lyophilization work?

A

sublimination of water (water form solid stage into vapour)

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11
Q

How does spray drying work

A

It is the atomization of a solution into hot air to dry it.

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12
Q

Benefits of freeze drying

A

Allows for the desorption of bound water so little water remains in the powder.

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13
Q

Problems with freeze drying

A

Irreversible aggregation can occur

denaturing

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14
Q

What are the solutions to the problem faced in freeze drying?

A

Add cryoprotectant and other additives

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15
Q

List some cryoprotectants

A

Sugars: sucrose, mannitol, sorbitol
Polymers: Dextrant, PVC, and PEG
others: Bovine serum albumin/BSA and AA

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16
Q

When would spray drying be used instead of freeze drying?

A

When making nasal and pulmonary formulations

17
Q

What are the metabolic barriers of macromolecules?

A

Enzyme degradation.
- site of enzyme degradation include:
= GI lumen: Pancreatic enzymes against larger peptides
= Brush boarders: Protease cleave oligopeptides (small bioactive peptides)
= Intracellular degradation:(lysosomes occurs in other intracellular organelles )

18
Q

What are the absorption barriers?

A

Too Large: cannot bass tight junction

Too hydrophilic: cannot pass through hydrophobic cell membrane

19
Q

What are the 4 types of transport that occurs and what are problems with them in relation to macromolecules?

A

Paracellular: Size
Passive: Size and hydrophilicity
Active transport: size
Endocytosis: enzymatic degradation in lysosomes

20
Q

What characteristics do absorption enhancers need to have?

A

Be pharmacologically inactive
Be specific in its action
Carry the intact drug to the site of absorption- not affect integrity
Prolong its residence time at the absorbing surface- prolong contact
Reversible increase the permeability of the mucosal epithelium
Do not damage the epithelium

21
Q

What are the 5 classes of absorption enhancers?

A 
Surfactants
AA Derivative
Ca2+ chelators
Fatty acids
polymers
22
Q

Types of surfactants and name some examples

A

Non-ionic (polysorbate 80) can be packed densely
Cationic
Anionic (SDS, sodium dodecyl sulfate): work better than non-ionic depending on MW

23
Q

Mechanism of actions of surfactants

A

shortening of microvilli of the cells
actin disbandment
structural separation of the tight junctions
damage to the apical cell membrane by detergent-like action, the monomeric form adsorbs and penetrates the plasma membrane leading to removal of membrane constituents

24
Q

What is the proposed mechanism of AA derivatives

A

condensation with the macromolecular drug and facilitation of its absorption into the lymphatic system
the condensation complex might reduce the hydrophilicity of the drug

25
Q

MOA of Ca2+ chelators

A
  • disruption of actin filaments, contraction of the junction-associated microfilament cytoskeleton
  • disruption of adherens junctions
  • diminished cell adhesion
  • activation of protein kinases
  • chelation of serosal Ca2+
26
Q

How do fatty acids aid with the absorption of macromolecules?

A

They can interact with the cell membrane.

C10-C12 is the ideal length.

27
Q

Why are polymers mostly used?

A
  • Safe: not absorbed therefore no systemic side effects
  • Mucoadhesion: prolong contact time between drug and site of absorption
  • Protection from enzymatic degradation: steric hindrance
  • Physically entrap the drug
28
Q

What is Chitosan and what properties does it have ?

A

It is a polysaccharide obtained from crabs and shrimps as chitin

  • Biocompatible
  • Slowly biodegradable
  • Semi-Natural polymer
  • Only protonated chitosan are effective : this means they are pH dependent
29
Q

What is poly acrylic acid and what propertied do they have?

A

A synthetic polymer
Mucoadhesive
Enzyme inhibitor: chelation of Ca2+ and Zn2+ ions that are cofactors needed for the proteolytic activity of the enzymes
Absorption enhancer: facilitates the paracellular transport of macromolecules

30
Q

How does polyacrylic acid and chitosan work

A

They both work in the paracellular route.

31
Q

Where can tight junction be found in the body

A

Epithelial lining of digestive system, ducts, cavities of glands, liver, pancreas capillary, walls urinary bladder , BBB, nasal mucosa

32
Q

What is the function of the tight junction?

A

1; prevent passage of molecules and ions through the space between cells, providing control over what substances are allowed through.
2: block the movement of integral membrane proteins between the surfaces of the cell maintaining their specific function: e.g., receptor-mediated endocytosis at the apical surface and exocytosis at the basolateral surface.

33
Q

What is the definition of a mucoadhesive

A
  • A molecule that sticks to mucosa (not mucus).

- Bio-adhesives are synthetic or biological and can stick to a biological structure or tissue

34
Q

What is mucous made up of

A

95% water
0.5-5% glycoproteins
1% minerals, salts and lipids
0.5-1% free proteins

35
Q

What is the function of mucus?

A

protect, lubricate and have site function: the stomach as mucus to protect it from the acid

36
Q

Why are mucoadhesive used

A

They increase the time that the drugs in contact with the absorbing mucosa and increase the chance of absorption.

37
Q

What is the mechanism of mucoadhesion

A
  1. wetting and swelling, the polymer comes into contact with the biological tissue 🡪 hydrophilicity
  2. interpenetration and entanglement of polymer chains and mucin macromolecules 🡪high molecular weight and chain flexibility
  3. formation of strong bonding between the entangled chains 🡪numerous hydrogen bond forming groups
38
Q

How do mucoadhesive promote oral drug bioavailability

A
  1. localising the drug in a specific site
  2. promoting intimate contact between drug and absorbing mucosa
  3. prolonging the residence time in the GIT
  4. protecting the drug from dilution and possible degradation
39
Q

What are the factors that affect mucoadhesion

A

Molecular weight- strength increases above 100,000. range form 200,000-1,000,000
Flexibility- for entanglement. More flexible = better efficacy
Hydration: required for mucoadhesive polymer to expand and create a macromolecular mesh
Cross-link density: increased density of cross linking means a reduced absorption of water into polymer network and so decreases rate of interruption between polymer and mucin
Charge
Concentration

Pharmaceutical formulation and quality assurance (14 decks)

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