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Fall 2 > Insulin formulation and delivery > Flashcards

Insulin formulation and delivery Flashcards

1
Q

What are Biomacromolecules/Biologicals used as?

A

Used as drugs instead of small molecules

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2
Q

What is the molecular weight of therapeutic protein in comparison to a small molecule ?

A

Therapeutic protein: >1000g/M

Small Molecule: <500g/M

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3
Q

What is the chemical nature of therapeutic protein in comparison to a small molecule ?

A

Therapeutic protein: Hydrophillic polypeptide

Small Molecule: Carbon chain

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4
Q

What is the complexity of therapeutic protein in comparison to a small molecule ?

A

Therapeutic protein:High, Single protein, Moderate heterogeneity

Small Molecule: Low homogeneous

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5
Q

What is the delivery of therapeutic protein in comparison to a small molecule ?

A

Therapeutic protein: Site of action

Small Molecule: Site of action

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6
Q

State the 4 categories of Biologicals and include an example

A
  1. Gene therapy (Nucleic acids) e.g. Gendicine
  2. Proteins & Peptides
    (Polypeptides) e.g. Insulin, Growth hormone
  3. Monoclonal antibodies (Polypeptides) e.g. Herceptin, Remicade (Infliximab), MabThera (Rituximab)
  4. Vaccines (mix of lipids, polypeptides & nucleic acids) e.g. Influenza vaccine, BCG, Hep B vaccine
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7
Q

What are the challenges for biomacromolecules?

A

Complexity of biologics higher than typical drugs

Instability of biomacromolecules inherent due to biological origin

Availability often limited by large molecular size

Immunogenicity immune response to drug (hypersensitivity) can lead to loss of efficacy and more serious adverse effects

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8
Q

Why are Biologics typically so unstable?

A
  1. Conditions must be compatible with biological molecules

2. almost all Biologics contain proteins- and proteins are relatively unstable

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9
Q

List 3 mechanisms of protein instability?

A
  1. Proteins have 3-4 layers of vital structure
  2. Basic polypeptide chain is susceptible to a range of degrading reactions with water and oxygen
  3. Many changes are irreversible
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10
Q

What is a common problem of the delivery of biologics and why?

A

Oral delivery unsuitable

Availability often limited by large molecular size:

  1. permeability through epithelia
  2. access to tissues from blood vessels
  3. cell membranes
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11
Q

which delivery route is best for biomacromolecules? Why?

A

PARENTERAL

because orally… they wont pass through epithelia or membranes
Digested by gastric and intestinal components

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12
Q

What are the areas of formulation and delivery in particular Insulin?

A
  • Protein sequence (& source)
  • Physical state of protein (phase, crystallinity)
  • Subcutaneous delivery devices
  • Alternative routes of administration
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13
Q

What two ways can proteins be manufactured?

A
  1. Biotechnology

2. Isolate from blood/animal tissue

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14
Q

What sort of proteins are produced from biotechnology? and How?

A

Protein examples: insulin, erythropoietin, monoclonal antibodies, cytokines and interferons
Produced in microbial or animal cell cultures and isolated via chromatographic and filtration steps

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15
Q

What sort of proteins are produced from isolation from blood? and How?

A

Protein examples: albumin and blood clotting factors

Protein isolation focused on reduction of viral contamination

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16
Q

What are some problems with biotechnology process?

A

Problems:
Produce in microbes: non-mammalian protein
Produce in animal cells: high cost

17
Q

What are some problems with isolation from blood process?

A

Problems:
Purify from animals- non-human sequence
Purify from humans- viral infection, BSE prion infection

18
Q

What are the different insulin options?

A

Rapid-acting
Short-acting
Intermediate-acting
Long-acting

19
Q

Name the different types of insulin? (2)

A
  1. Purified animal insulin

2. Recombinant human insulin

20
Q

Give some examples of Rapid acting insulins?

A 
Insulin lispro (Humalog®), 
insulin aspart (NovoRapid®), 
insulin glulysine (Apidra®)
21
Q

How long does it take for rapid acting insulin to work and how long does it last?

A

Onset of action of 15 minutes; Duration of 2-5 hours

22
Q

How does Insulin aspart modification work?

A

Insulin aspart – position B28 proline replaced with negatively charged aspartic acid = faster dissociation of hexamer

23
Q

Give some examples of Long acting insulins?

A 
Insulin glargine (Lantus®) 
Insulin detemir (Levemir®)
Insulin degludec (Tresiba®)
24
Q

How does Insulin glargine modification work?

A

Asparginine residue substituted with glargine at position 21 of A chain = stabilise hexamer interactions
Add 2 arginine residues on C-terminus of B chain = less soluble at pH of subcutaneous tissue

25
Q

How long does it take to reach steady state when using a long acting insulin?

A

Taken once daily to maintain level of insulin. Steady state = 2-4 days

26
Q

What can be changed in insulin which allows us to change kinetics of insulin to release/ solubility & availability?

A

Modification of aggregation, quaternary structure and crystallinity

27
Q

When insulin is injected subcutaneously, what is formed?

A

A depot

28
Q

Insulin can have different quaternary structures.

What form is 6-mer and the single molecule of insulin?

A

6mer = “Stored form” - slower release after injection

Single molecule = Active form - released faster

29
Q

What are the three insulin regimes? and describe each

A

One, two or three insulin injections per day of a short-acting or rapid-acting insulin analogue with an intermediate-acting insulin

Multiple daily injections. A short-acting or rapid-acting insulin analogue is injected before meals, together with one or more separate daily injections of an intermediate-acting insulin or a long-acting insulin.

Continuous sub-cutaneous insulin infusion. A programmable pump delivers a regular or continuous amount of insulin (usually short-acting or rapid-acting insulin analogue) via a SC needle or cannula.

30
Q

Why is cold chain storage needed for insulin?

A

Protein solutions not stable at elevated temperatures

31
Q

What future delivery methods of insulin are there?

A
  1. needle free injection
  2. inhaled
  3. transdermal
  4. oral
32
Q

What is an ad and disad of needle free injectors?

A

Advantages: no more needles, many happy users

Disadvantages: supply, complex to use, bruising

33
Q

What challenges are there with Transdermal insulin?

A
  1. Low bioavailability through skin: hydrophilic, high molecular weight
  2. precise dosing with cream impossible
  3. cost
  4. reliability
  5. Reactivity/Dermatitis

Fall 2 (33 decks)

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