Lecture 18 & 19: Insulin Formulations, SC injections, impermeable barriers Flashcards
1
Q
What are the different forms insulin can associate and dissociate into?
A
- Subunits: A and B
- Monomers
- Dimers
- Hexamers (6 insulin molecules, 3 dimers)
2
Q
What are some factors that affect insulin self-asociation and dissociation?
A
- Relative conc of each monomeric/multimeric form: increase conc = more hexamers
- Excipients
- Faster acting encourage dissociation and longer acting encourage association
3
Q
How are dimers stabilised?
A
- Hydrophobic interactions between GluB21 and GlyB23 of 1 monomer and ProB28 on another monomer
4
Q
How are hexamer formulations stabilised?
A
- By Zn2+ and phenol
5
Q
What are the rapid insulin analogues called?
A
- Lispro (Humalog)
- Aspart (Novolog)
- Glulisine (Aspidra)
6
Q
What are the less soluble, long acting insulin analogues called?
A
- Degludec (Tresiba)
- Detemir (Levemir)
- Glargine (Lantus)
7
Q
What are the 3 principles of insulin formulation?
A
- Insulin
- Excipients: formulate insulin as solution or suspension
- Device: Enhance insulin delivery across biological barriers
8
Q
What are the factors that affect insulin self-association or dissociation?
A
- Relative concentration of each monomeric/ multimeric form: conc increases and associates more
- Excipients
9
Q
How is recombinant human insulin formed?
A
- Structurally identical to endogenous human insulin but produced in bioreactor.
- Isolate insulin genes, grow, purify, place in cloning vector
10
Q
What is the formulation appearance for short, intermediate and long acting insulin?
A
- Short: neutral, clear, colourless solution
- Intermediate: Isophane, white suspension
- Long: Lente, protamine zinc, white suspension
11
Q
What are some excipients used in short acting insulin?
A
- Phenol
- m-cresol - both help stabilise and antimicrobial activity
- glycerol
- water
12
Q
What are some excipients used in intermediate and long acting insulins?
A
- Protamine sulfate, zinc chloride, methylparahydroxybenzoate
- Zinc and phenolic compounds promote self-association of insulin into hexamers
13
Q
How is intermediate release (NPH) insulin formed?
A
- Neutral Protamine Hagedorn
- Protamine complexes with insulin to form aggregates through ionic interactions: suspensions
14
Q
What is the onset, peak and duration of rapid acting insulins?
A
- Onset: 15-30mins
- Peak: 1-3hrs
- Duration: 4-6hrs
15
Q
What is the onset, peak and duration of short acting insulins (reg insulin)?
A
- Onset: 30-60mins
- Peak: 2-4hrs
- Duration: 5-8hrs
16
Q
What is the onset, peak and duration of intermediate acting insulins?
A
- Onset: 2-4hrs
- Peak: 8-12hrs
- Duration: 10-18hrs
17
Q
What is the onset, peak and duration of long acting insulins?
A
- Onset: 1-2hrs
- No peak
- Duration: 24hrs +
18
Q
What is the onset, peak and duration of ultra long acting insulins?
A
- Onset: 1 hr
- No peak
- Duration: 42hrs +
19
Q
What was the changed in Insulin Lispro (Humalog)?
A
- ProB28 and LysB29 are swapped
20
Q
What is the effect of changes in insulin lispro?
A
- Proab28 is responsible for stabilising the insulin diner
- Swap is enough to destabilise the diner and less likely bind to zinc
- More stable in monomer form and more soluble than native insulin
21
Q
A
22
Q
What was changes in Insulin Aspart?
A
- ProB28 switched with Asp
23
Q
What is the effect of the changes in Insulin Aspart?
A
Proab28 is responsible for stabilizing the insulin dimer. So the swap is enough to destabilase the dimer and less likely to bind to zinc.
Most stable in monomer form and more soluble than native insulin.
24
Q
What was changes in Insulin Glulisine?
A
- AsnB3 to Lys
- LysB29 to Glu
25
What is the effect of the changes in Insulin Glulisine?
- Decreased hexamer formation
- Monomer stabilization
- Enhance solubility.
26
What was the changes in Insulin Glargine?
- AsnA21 to Gly
- Add ArgB31 and 32
27
What is the effect of the changes in Insulin Glargine?
- Less soluble at physiological pH
- Forms a precipitate to stabilise hexamer
28
What was changes in Insulin Degludec?
- Remove ThrB30 and attach a longer chain molecule (hecadecandioyl through glutamic acid spacer) at LysB29
29
What is the effect of the changes in Insulin deugledec?
- The long chain attachment helps to stabilize the insulin in hexametric structure. As phenol from the vehicle diffuses
- Once the zinc diffuses out, the hexamers disassemble releasing monomer
- Monomers diffuse into circulation from depot.
30
What was changes in Insulin detemir?
- ThrB30 removed
- Add myristic acid at LysB29.
- Binds albumin
31
What is the effect of the changes in Insulin detemir?
- Long hydrocarbon chain reduces solubility of the insulin analogue.
- But its main action is to help it bind to albumin in the blood.
32
In an inhaled insulin the excipients are: sodium citrate, sodium hydroxide, mannitol and glycine?
- Sodium citrate: buffering agent important for stability and absorption
- Sodium hydroxide: pH adjuster, raise ph for stability
- Mannitol: bulking agent. Adds vol to dry powder which helps with consistent aerolisation
- Glycine: stabiliser and bulking agent
33
What are the 2 main types of impermeable barriers in the body?
- Anatomical: lipid bilayers
- Physiological: mucus, enzymes and transporters
34
What are examples of impermeable barriers in the body?
- Skin
- Blood brain barrier: need transport mechanism (receptor)
- Intestinal mucosal barrier: mucus
35
What are the differences between paracellular and transcellular pathways?
- Paracellular: Movement between cells, through the tight junctions connecting them
- Transcellular: Movement through the cells.
36
Why are macromolecules hard to deliver through biological membranes?
- Due to size, polarity and presence of tight junctions and viscous membranes
37
What are the limitations of traditional needle-based injections?
- Painful
- Requires trained personnel
- Causes needle phobia and carries infection risk
38
What are the chemical approaches to enhancing drug delivery through barriers?
- Chemical penetration enhancers
- Prodrug: add functional group to side chain (changes lipophilicity)
- Carriers
39
How do chemical penetration enhancers work?
- They disrupt lipid bilayers or interact with proteins to increase permeability
40
What is a prodrug and name an example?
- An inactive molecule with temporary linkage that becomes active after cleavage in vivo
- Enalaprilat (ACE inhibitor), the prodrug is enalapril, it has 8 fold higher intestinal permeability than enaliprilat
41
What is a co-drug?
- A mutual prodrug that releases 2 active drugs without producing inactive by products
42
What are common types of drug carriers?
- Lipid vesicles
- Dendrimers
- Nanoparticles
- Drug-carrier conjugates
- Viral carriers
43
What are the advantages of drug carriers?
- Improve solubility
- Control release
- Enhance targeting
- Respond to stimuli
44
List physical device based strategies to overcome impermeable barriers?
- Iontophoresis
- Electroporation
- Ultrasound
- Jet injectors
- Laser-assisted strategies
- Microneedles
45
How does iontophoresis work?
- Uses electrical current for electro repulsion (ionic drug propelled across bnarrier) and electro osmosis (electrorepulsion creates solvent flow which carries dissolved neutral/polar molecules) to enhance drug penetration
46
What is electroporation?
- Application of short electrical pulses that create temporary pores in membrane for drug diffusion
- Causes destabilisation of lipid bilayer, drug diffuses through hydrophilic pores
47
How does ultrasound (sonopheresis & sonoporation) aid drug delivery?
- Creates vibrations and cavitation that disrupt membranes
- Shockwaves that disrupt barrier - Sonopheresis
- Sonoporation: drug delivery into cells across plasma membrane
48
What are jet injectors and how do they work?
- Needle-free devices that deliver drugs using high pressure liquid jet to breach barrier
- Types: spring loaded and pressurised gas
49
What does laser pre-treatment of skin achieve?
- Improves skin permeability
- Improve depth of drug penetration
- High energy beam, removes tissue
50
What are microneedles and what are the advantages?
- Tiny needles (hundred of um) used in patches or injectors
- Painless, self-administered, no cold chain needed, no sharps waste
51
What are the types of microneedles?
- Solid: pretreatment followed by topical application
- Coated: Drug coated onto microneedle surface
- Dissolving: Drug encapsulated within microneedle that dissolves in barrier
- Hydrogel- forming: Drug diffuses into barrier from reservoir as the needles swell in fluid
- Hollow: Drug injected from reservoir through orfice and absorb
