Macromolecules

Question 1

what are macromolecules

Answer 1

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

Question 2

uses of macromolecules

Answer 2

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

Question 3

Examples of peptide and protein macromolecules

Answer 3

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

Question 3

Examples of peptide and protein macromolecules

Answer 3

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

Question 4

What are the barriers to manufacturing and delivery peptides and proteins

Answer 4

1. In vitro stability barrier
2. Metabolic barriers
3. Absorption barriers

Question 5

What are the 3 categories of in vitro stability barriers?

Answer 5

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

Question 6

List some reactive side chains/reactions that alter side chains

Answer 6

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

Question 7

Environmental factors that cause degradation

Answer 7

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.

Question 8

What are the manufacturing process that determine in vitro stability

Answer 8

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

Question 9

What 2 methods are used when developing solid formulations

Answer 9

1. Lyophilization/freeze drying

2. Spray dry

Question 10

How does freeze drying/lyophilization work?

Answer 10

sublimination of water (water form solid stage into vapour)

Question 11

How does spray drying work

Answer 11

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

Question 12

Benefits of freeze drying

Answer 12

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

Question 13

Problems with freeze drying

Answer 13

Irreversible aggregation can occur

denaturing

Question 14

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

Answer 14

Add cryoprotectant and other additives

Question 15

List some cryoprotectants

Answer 15

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

Question 16

When would spray drying be used instead of freeze drying?

Answer 16

When making nasal and pulmonary formulations

Question 17

What are the metabolic barriers of macromolecules?

Answer 17

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 )

Question 18

What are the absorption barriers?

Answer 18

Too Large: cannot bass tight junction

Too hydrophilic: cannot pass through hydrophobic cell membrane

Question 19

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

Answer 19

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

Question 20

What characteristics do absorption enhancers need to have?

Answer 20

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

Question 21

What are the 5 classes of absorption enhancers?

Answer 21

Surfactants
AA Derivative
Ca2+ chelators
Fatty acids
polymers

Question 22

Types of surfactants and name some examples

Answer 22

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

Question 23

Mechanism of actions of surfactants

Answer 23

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

Question 24

What is the proposed mechanism of AA derivatives

Answer 24

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

Question 25

MOA of Ca2+ chelators

Answer 25

- 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+

Question 26

How do fatty acids aid with the absorption of macromolecules?

Answer 26

They can interact with the cell membrane. C10-C12 is the ideal length.

Question 27

Why are polymers mostly used?

Answer 27

- 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

Question 28

What is Chitosan and what properties does it have ?

Answer 28

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

Question 29

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

Answer 29

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

Question 30

How does polyacrylic acid and chitosan work

Answer 30

They both work in the paracellular route.

Question 31

Where can tight junction be found in the body

Answer 31

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

Question 32

What is the function of the tight junction?

Answer 32

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.

Question 33

What is the definition of a mucoadhesive

Answer 33

- A molecule that sticks to mucosa (not mucus). | - Bio-adhesives are synthetic or biological and can stick to a biological structure or tissue

Question 34

What is mucous made up of

Answer 34

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

Question 35

What is the function of mucus?

Answer 35

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

Question 36

Why are mucoadhesive used

Answer 36

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

Question 37

What is the mechanism of mucoadhesion

Answer 37

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

Question 38

How do mucoadhesive promote oral drug bioavailability

Answer 38

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

Question 39

What are the factors that affect mucoadhesion

Answer 39

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