Insulin formulation and delivery Flashcards
What are Biomacromolecules/Biologicals used as?
Used as drugs instead of small molecules
What is the molecular weight of therapeutic protein in comparison to a small molecule ?
Therapeutic protein: >1000g/M
Small Molecule: <500g/M
What is the chemical nature of therapeutic protein in comparison to a small molecule ?
Therapeutic protein: Hydrophillic polypeptide
Small Molecule: Carbon chain
What is the complexity of therapeutic protein in comparison to a small molecule ?
Therapeutic protein:High, Single protein, Moderate heterogeneity
Small Molecule: Low homogeneous
What is the delivery of therapeutic protein in comparison to a small molecule ?
Therapeutic protein: Site of action
Small Molecule: Site of action
State the 4 categories of Biologicals and include an example
- Gene therapy (Nucleic acids) e.g. Gendicine
- Proteins & Peptides
(Polypeptides) e.g. Insulin, Growth hormone - Monoclonal antibodies (Polypeptides) e.g. Herceptin, Remicade (Infliximab), MabThera (Rituximab)
- Vaccines (mix of lipids, polypeptides & nucleic acids) e.g. Influenza vaccine, BCG, Hep B vaccine
What are the challenges for biomacromolecules?
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
Why are Biologics typically so unstable?
- Conditions must be compatible with biological molecules
2. almost all Biologics contain proteins- and proteins are relatively unstable
List 3 mechanisms of protein instability?
- Proteins have 3-4 layers of vital structure
- Basic polypeptide chain is susceptible to a range of degrading reactions with water and oxygen
- Many changes are irreversible
What is a common problem of the delivery of biologics and why?
Oral delivery unsuitable
Availability often limited by large molecular size:
- permeability through epithelia
- access to tissues from blood vessels
- cell membranes
which delivery route is best for biomacromolecules? Why?
PARENTERAL
because orally… they wont pass through epithelia or membranes
Digested by gastric and intestinal components
What are the areas of formulation and delivery in particular Insulin?
- Protein sequence (& source)
- Physical state of protein (phase, crystallinity)
- Subcutaneous delivery devices
- Alternative routes of administration
What two ways can proteins be manufactured?
- Biotechnology
2. Isolate from blood/animal tissue
What sort of proteins are produced from biotechnology? and How?
Protein examples: insulin, erythropoietin, monoclonal antibodies, cytokines and interferons
Produced in microbial or animal cell cultures and isolated via chromatographic and filtration steps
What sort of proteins are produced from isolation from blood? and How?
Protein examples: albumin and blood clotting factors
Protein isolation focused on reduction of viral contamination
What are some problems with biotechnology process?
Problems:
Produce in microbes: non-mammalian protein
Produce in animal cells: high cost
What are some problems with isolation from blood process?
Problems:
Purify from animals- non-human sequence
Purify from humans- viral infection, BSE prion infection
What are the different insulin options?
Rapid-acting
Short-acting
Intermediate-acting
Long-acting
Name the different types of insulin? (2)
- Purified animal insulin
2. Recombinant human insulin
Give some examples of Rapid acting insulins?
Insulin lispro (Humalog®), insulin aspart (NovoRapid®), insulin glulysine (Apidra®)
How long does it take for rapid acting insulin to work and how long does it last?
Onset of action of 15 minutes; Duration of 2-5 hours
How does Insulin aspart modification work?
Insulin aspart – position B28 proline replaced with negatively charged aspartic acid = faster dissociation of hexamer
Give some examples of Long acting insulins?
Insulin glargine (Lantus®) Insulin detemir (Levemir®) Insulin degludec (Tresiba®)
How does Insulin glargine modification work?
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
