Insulin formulation and delivery Flashcards
- What are biomacromolecules/biologics
Biomacromolecules used as drugs – rather than small molecules
- What are the differences between small molecule and therapeutic proteins
Small molecule:
Molecule weight - <500g/M
Chemical nature – carbon chain – organic
Complexity – low homogenous
Delivery – site of action
Therapeutic protein
Molecule weight - >100g/M
Chemical nature – hydrophilic polypeptide – organic
Complexity – high single protein moderate heterogeneity
Delivery – site of action
- What are examples of small molecules and biologicals
Small molecule – aspirin
- Biologicals – monoclonal antibody and flu vaccine
- What are the 4 categories of biologicals And examples (?)
- Gene therapy – nucleic acid ( Gendicine )
- Protein and peptides – polypeptide (Insulin, Growth hormone, Clotting/blood factors)
- Monoclonal antibodies – polypeptide (Herceptin (Trastuzumab), MabThera (Rituximab), Remicade (Infliximab))
- Vaccine – mixture of lipids, polypeptides, nucleic acids ( Influenza vaccine, BCG tuberculosis vaccine, Hepatitis B vaccine)
- What are the challenges for all biologicals
- 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 is the complexity of biologics often higher than typical small molecule drugs
- Molecular complexity
- Functional complexity
- Complex composition
- More to go wrong- more expensive to manufacture
- Why are biologics typically so unstable?
- Instability of biomacromolecules inherent due to biological origin
- Conditions must be compatible with biological molecules
- BUT this means they are good food for microbes – or at least in a good environment
- Also, many reactions of biological molecules are thermodynamically favourable in these conditions
- Finally, almost all Biologics contain proteins- and proteins are relatively unstable
- What is more unstable
- Protein
- What is the mechanism of protein instability?
1) Proteins have three-four 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
- What is the importance of protein structure
- Denatured proteins – won’t work, often irreversible
- Delivery of biologics – availability often limited by large molecular size
how does it access
Permeability through epithelia
- Access to tissues from blood vessels
- Cell membranes *although drug target usually noy within cells
- What are the common problems of delivery of biologics
- Common problem- oral delivery unsuitable
- Different route for each class/example
- Route typically used is dictated by the characteristics of each class
- How is biomacromolecules delivered usually?
- In common
- Biomacromolecules won’t pass through epithelia or membranes
- Digested by gastric and intestinal components
- Oral biomacromolecules = food!
- Typically can’t use oral delivery => “PARENTERAL”
- What are the formulation and delivery areas of protein/insulin?
Formulation and delivery areas:
- Protein sequence (& source)
- Physical state of protein (phase, crystallinity)
- Subcutaneous delivery devices
- Alternative routes of administration
- What are the 2 main classes of therapeutic proteins
a. Proteins and peptides - Closest replacement of endogenous proteins
b. Monoclonal antibodies - Ability to bind any antigen target Range of effects- blocking, binding, activating, killing
- Production of pharmaceutical protein – methods
Production of pharmaceutical proteins
1: Biotechnology
* Protein examples: insulin, erythropoietin, monoclonal antibodies, cytokines and interferons
* Produced in microbial or animal cell cultures and isolated via chromatographic and filtration steps
2: Isolate from blood (or animal tissue)
* Protein examples: albumin and blood clotting factors
* Protein isolation focused on reduction of viral contamination
- What are the problems of biotechnology and isolating from blood to produce protein?
Bio tech
Problems:
Produce in microbes: non-mammalian protein
Produce in animal cells: high cost
Isolate
Problems:
Purify from animals- non-human sequence
Purify from humans- viral infection, BSE prion infection
- Why is insulin The most intensely researched therapeutic macromolecule
Large number of diabetics – market pull
Long term (lifetime) treatment – ease to use
Precise, continuous delivery needed – dose control
Dire consequence of failure to deliver- vital therapy
- What are the different insulin options?
Rapid-acting
- Short-acting
- Intermediate-acting
- Long-acting
- What is used in type 1 diabetes to treat it?
Type 1, insulin-dependent, autoimmune, child onset diabetes
- Precise, continuous delivery needed: replacing pancreatic glycaemic control
- What is used in type 2 diabetes to treat it?
- Type 2, “adult onset” noninsulin-dependent diabetes
- Supplementary extra insulin provided to prevent harm from high blood glucose
- What are the different types of insulin?
1: Purified animal insulin
Oldest form of insulin
Still available: porcine (pig) and bovine (cow; rare use
2: Technological breakthrough for recombinant DNA technology:
- “Recombinant” human insulin
- Variants of human insulin have now been genetically engineered (altered amino acid sequence) with changes to speed of onset and duration of activity
- Give examples of rapid- acting insulins and means ?
- Onset of action of 15 minutes; Duration of 2-5 hours
- Insulin lispro (Humalog®),
- insulin aspart (NovoRapid®),
- insulin glulysine (Apidra®)
- how does insulin aspart modification work?
- Insulin aspart – position B28 proline replaced with negatively charged aspartic acid = faster dissociation of hexamer
- What is long acring insulins and what are examples of them?
- Longer effect than intermediate-acting insulins; Normally used once daily to maintain a constant level of insulin (steady state achieved after 2-4 days). Examples:
- 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
what allows tuning of kinetics of insulin release? ( diff physical forms of insulin)
Modification of aggregation, quaternary structure and crystallinity alters solubility and availability: allows tuning of kinetics of insulin release
Changes in rapidity of onset and duration
when insulin is injected subcutaneously what is formed?
depot
Lowest molecular weight monomeric insulin is most rapidly released
Dissociation of aggregates/crystals/complexed insulin results in slow release of active therapeutic
different forms of insulin - physical form:
Insulin protein can have different quaternary structures
i.e. 6 single insulin protein molecules forms complex with zinc
6-mer is ‘stored form’ – also has slower release after injection
Single molecule is ‘active form’ – but is released faster
what does 6-mer mean
6-mer is ‘stored form’ – also has slower release after injection
what is single molecule mean
Single molecule is ‘active form’ – but is released faster
what are the Three basic regimes for T1D
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.
Insulin regimes are individualised for each patient
true or false
true
delivery of insulin ( availability)
Availability of protein drugs limited by large molecular size
Common problem- oral delivery unsuitable
Different route for each class/example
Route typically used is dictated by the characteristics of each class, and clinical need
INSULIN:
can be infused intravenous (i.v.) – not practical for everyday use
can be subcutaneous (s.c.)
Depends on clinical need- i.v. infusion in hospital only, for acute treatment. In community, routine treatment, s.c. injection
what devices are used for insulin administration?
Pre-filled injectors or
Solution for injection plus
- syringe and needle
- Injectors, autoinjectors
- Needle-free injectors
- Pumps
Needle disposal needed
how should insulins be stored?
For almost all insulins:
(including pre-filled injectors,
solution for injection)
Protein solutions not stable at elevated temperatures
what are the potential future for insulin?
1- Needle-free injectors
2- Inhaled
development
3- Transdermal
4- Oral
what are the advantages and disadvantages of needle free inhectors
Advantages: no more needles, many happy users
Disadvantages: supply, complex to use, bruising
what is pulmonary delivery of insulin?
Joint development between Aventis and Pfizer, Exubera was an inhaled short-acting insulin preparation indicated for the treatment of type 1 and type 2 diabetes.
The approval of the world’s first inhaled insulin marked an important advance in the treatment of diabetes.
Product failed to gain acceptance from both patients and clinicians.
what are the challenges with transdermal insulin delivery
Cream:
Challenge:
Low bioavailability through skin
-high molecular weight
-hydrophilic
Assuming permeability barrier overcome, precise dosing impossible with cream.
Watches :
Holy grail: real-time transdermal glucose monitoring and insulin dosing
Delivery challenge x2:
glucose measured from blood/ insulin delivery into blood
Further challenges:
-reactivity/dermatitis
-cost
-reliability
-complex user requirements
oral insulin
protein = food
Market pull drives experimental attempts:
e.g. microencapsulation to protect from gastric/intestinal degradation
Further challenges:
?mechanism of absorption of microencapsulated protein?
artifical pancreas
All the technology is available to replace the pancreas
Blood glucose monitors
Mini-pumps with cannula delivery
Computation and wearable electronics
Summary
Drug Class: Proteins and peptides
General challenges for formulation and delivery of proteins.
Protein sequence, physical form, both used to control PK
Insulin formulation and delivery:
Many routes explored, some achieved, but subcutaneous injection remains dominant.
Different physical and protein sequence forms of insulin have differing pharmacokinetic properties.
Examples of possible routes explored for insulin include injection, needle-free injection, inhaled, transdermal and oral
