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Pharmacy Year 3 > Biologics and Insulin > Flashcards

Biologics and Insulin Flashcards

1
Q

Why are biologics considered to be versatile?

A

They can replace disease tissue as well as modifying disease tissue

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2
Q

Why biologics over small molecules in terms of binding?

A

Therapeutic protein are more specific compared to small molecules which can bind at other sites and cause toxicity

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3
Q

Do biologics require frequent or less frequent dosing?

A

Less frequent - they have longer circulation times compared to small molecule drugs

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4
Q

How are immunogenic effects of biologics addressed?

A

Humanisation

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5
Q

How is biologic bioequivalence risk managed?

A

Supportive data for structural and functional characterisation

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6
Q

What is biologic bioequivalence not the same as?

A

Having 2 small drug formulations that become bioavailable at the same rate and extent after administration at the same dose

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7
Q

In terms of hydrophobicity, when are most globular proteins stable?

A

When the loops with the hydrophobic side chains are buried in the interior of the protein. Unfolding leads to aggregation and colloidal instability

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8
Q

Are proteins stable at their isoelectric point?

A

Many are, but they still aggregate

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9
Q

Describe the process of protein aggregation

A

Hydrophobic side chains are predominately internal

Side chains become exposed, and in aq environment, bond with those on other molecules

Unfolding protein molecules aggregate

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10
Q

What are the potential causes of chemical degradation of exposed susceptible side chains?

A

Oxidation
Deamidation
Hydrolysis

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11
Q

What are the factors inducing conformation change/instability?

A 
Extremes of pH
Shear Forces
Air/water interfaces 
Adsorption to solid surfaces
Freezing, drying and re-hydration
Elevated temperatures and pressures
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12
Q

How do amino acids stabilise biologic formulations?

A

Preferential hydration, preferential exclusion
Decrease protein-protein interaction
Increase solubility and reduce viscosity

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13
Q

How do polymers stabilise biologic formulations?

A

Competitive adsorption
Steric exclusion
Preferential exclusion, preferential hydration

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14
Q

How do polyols stabilise biologic formulations?

A

Preferential exclusion

Accumulation in hydrophobic regions

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15
Q

How do salts stabilise biologic formulations?

A

Preferential binding and interaction with protein bound water

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16
Q

How do surfactants stabilise biologic formulations?

A

Competitive adsorption at interfaces
Reduce denaturation at air/water interfaces
Interfere with ice/water interface on freezing

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17
Q

How does acylation with a fatty acid stabilise proteins?

A

Increasing binding affinity to serum albumin, resulting in longer acting insulin, glucagon and interferon

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18
Q

How does PEGylation stabilise stabilise proteins?

A

Reduces plasma clearance rate - so less frequent administration.
But some proteins can become less active when PEGylated

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19
Q

What is the purpose of surface engineering?

A

To remove sites on protein surface that are likely to cause aggregation

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20
Q

What effect do mutations have on proteins?

A

They alter surface structure and polarity

21
Q

How do denaturants work?

A

They interact with the polypeptide backbone of the protein.

Higher interaction when unfolded, there is a positive concentration difference between local and bulk domain

22
Q

How do protectants work?

A

They form an osmolyte strong interaction with water.
Lower interaction and higher exclusion when unfolded, there is a negative concentration difference between the local and bulk domain

23
Q

Define exclusion

A

The thermodynamic mechanism to explain stabilisation by excipients

24
Q

What is the degree of preferential exclusion and increase in chemical potential proportional to?

A

It is directly proportional to the protein molecule surface area exposed to solvent

25
Q

How does the process of exclusion work?

A

Minimises the thermodynamically unfavourable effect of preferential exclusion by favouring the state with the smallest surface area

26
Q

In terms of chemical potential, what happens to unfolded/denatured proteins?

A

There is an increase in chemical potential in those with a greater surface area

27
Q

Do unfolded proteins have low energy?

A

No
They have high energy, they have the potential to go back to their native stative or aggregate. Excipients used can play a role in whether they aggregate or not.

28
Q

What happens to biologic at low temperatures?

A

Low temperatures extend shelf life, cold denaturation is usually reversible, as temperature drops, solent properties change.

29
Q

What happens when biologics are frozen?

A

They are more stable due to the lower temperature
But repeated thawing and freezing causes aggregation by pH and concentration changes, and provision of nucleation points for aggregation on ice-water interfaces

30
Q

What kind of substances are used for cyroprotection?

A

Sugars, polyhydric alcohols, oligosaccharides, amino acids

31
Q

What is the process of cyroprotection?

A

Works by preferential exclusion, lowering cold denaturation temperature and stabilising osmotic stresses, whereas surfactants interfere with ice/water

32
Q

How should frozen vials be treated when thawing?

A

They should be gently mixed to avoid mis-dosing

33
Q

Why should frozen vials be gently mixed?

A

Concentration gradients are formed during freezing and remain if thawed without mixing

34
Q

What is the main advantage of freeze drying?

A

Formulations have greater long term stability that protein solutions

35
Q

What is the disadvantage of freeze drying?

A

Proteins go through reversible conformational changes during transition into the lyophilised state that exposes buried regions and makes them prone to aggregation - this can happen in reconstitution

Reactions and denauturation can continue when lyophilised.

36
Q

How can denaturation be avoided in lyophilised formulations?

A

Put them in a fridge to reduce denaturation rates

Make them sealed to avoid water vapour absorption

37
Q

Describe recombinant human insulin

A
  • Monomer
  • Exists naturally in a hexameric structure
  • Hexamer has globular protein structure
  • 2 axial Zn ions coordinated by 6 histidine side chains
38
Q

How is fast acting prandial insulin engineered?

A

Mutation of one or more amino acids in protein sequence to disrupt assembly through:

  • Conversion to dimeric and monomeric
  • Diffuses faster and improves transport
39
Q

What is the benefit of fast acting prandial insulin engineering?

A

Makes the insulin faster acting on sub-cut administration, there is rapid absorption at mucosal barriers and a rapid response from infusion pumps

40
Q

What is early basal intermediate insulin formulated with?

A

Protamine - to create suspensions forming crystals, when speed of dissociation and absorption varies in the same patient

41
Q

What does the long acting insulin glargine need?

A

Dissolution of isoelectric precipitates formed after injection which causes variability

42
Q

Describe long acting insulin detemir

A

Less variable, comes from fatty acid modification
Reversible stabilisation avoids precipitation and dissolution
Binds to albumin, when absorption rate is only slightly affected by blood levels, it circulates for longer

43
Q

How are mAbs produced?

A

Select B cell clones to form a mAb
Fuse with myeloma cell to form a hybridoma
Optimise hybridoma growth and mAb

44
Q

What is the disadvantage of mouse antibodies?

A

They cause immunogenic reactions, they are cleared rapidly and lack human Fc effector functions.

45
Q

What is a chimeric mAb?

A

It has a mouse variable gene

46
Q

What is a humanised mAb?

A

Has mouse antigen binding loops (CDRs)

47
Q

How are fully human antibodies produced?

A

Through mice

  • 4 mouse IgG gene is replaced with human transcends in transgenic mouse
  • Mouse is immunised to raise immune response
  • B cells are selected, a hybridoma is produced and bioreactor cell culture produces human antibodies
48
Q

What happens after antibodies are administered?

A

They distribute mainly within the central compartment, penetration inside cells is limited by high molecular weight and hydrophilicity

49
Q

What is the primary route of degradation and elimination?

A

Primary routes are by renal clearance and proteolytic catabolism after receptor mediated endocytosis in the cells or reticule endothelial system (RES)

Pharmacy Year 3 (11 decks)

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