Objectives

• Go over the practice exam
• Revise key concepts and topics
• Discuss common exam pitfalls and strategies

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Question 1 - Fentanyl

• opiate analgesic
• patient: haemodialysis
• Rx: transdermal patch, resp. inhalation also available

Q1 (a) Differences in absorption / effect on PK?

• thickness of the biological membrane
• thickness important because it governs drug absorption speed, thus C_max and T_max of the drug

Q1 (b) Which route more toxic?

• Much greater with respiratory
• Rapid rate of diffusion, higher peak concentration, so more likely

Q1 (c) 8 hour ambo

• pre-ambo: respiratory to give rapid analgesia
• during: transdermal for sustained effect (controlled release), steady plasma conc. level

Q1 (d) Why not both? Porque no los dos?

• Rapid absorption with resp. inhalation may further increase plasma concentration of fentanyl obtained from the transdermal patch
• Combination very likely to reach toxic conc.

Question 2 - Factors reducing oral absorption of insulin

1. Hydrophilic, hard to traverse lipid bilayer
2. CHONKY, so passive diffusion via parcellular transport not possible
3. Degradation in the GI tract by proteolytic enzymes
4. Subcut. inj. into adipose tissue -> diffusion from the depot into the bloodstream
5. No degradation at adipose tissue since pH = 7.4 and no proteolytic enzymes

Question 3 - Rectal vs Pulmonary

• Both rectal and pulmonary routes bypass first-pass metabolism
• Pulmonary is more suitable for rapid effect due to monolayer cell penetration + larger surface area
• Rectal also fast, but:
  • Base needs to melt,
  • Drug needs to diffuse out of the base to the rectal mucosa

Question 4 (A) Calcs

Information we have:

• Current dose : every 6 hr ().
• Oral Bio.
• Available strengths: ,

Q4 (A) Solve for clearance (), IV

Required Oral dose

Because , we can assume as dosing interval.

Suppose :

Administer 15 mg every 8 hours.

• Why didn't you use ? I did, but there was a discrepancy between CL calculated from and vs. back-calculated CL from the steady-state data - so I kept the one from the steady-state data.

Q4 (B) Nasal and dizzyness

• Nasal delivery yields rapid absorption and onset of action: likely cause of dizziness, due to high C_max
• Unlikely to occur with oral delivery
• But it takes much longer for the drug to be absorbed
• If the drug has a first-pass effect, buth bioav. will much lower.

Q5 (a) Ibuprofen in hot car

• Ibuprofen sublimes when heated
• Keeping it in the car will reduce the amount of drug available for absorption, thus sub-therapeutic
• Advise to buy fresh pack
• Store below 25'C
• or buy paracetamol, aspirin, diclofenac etc.

Q5 (b) Modified release for gastro-irritating drug

• MR can be used to slow down/delay drug availability to tissues (GI tract)
• This reduces the risk of irritation by having the drug be released in the duodenum and so on
• How? enteric coating, delayed release, etc.

Q6 Sandostatin has microparticles to delivery octereotide.

(a) Importance of PLGA for microparticles?

• PLGA are biodegradable polymer that can last for months
• Degradation byproducts (lactic/glycolic acids) are also naturally occurring and non-toxic
• These two things are compelling from regulatory perspective, over other polymers

Q6 Liposomes for Amphotericin B

(b) Describe Amphotericin B and the liposome

• Amphotericin B is a BS antifungal, used in hospital settings (i.e. IV)
• Target delivery at macrophages to reach spores
• Drug itself is nephrotoxic, due to renal clearance
• The drug is very hydrophobic, so we need to encapsulate in liposomes to improve solubility and bioavailability
• Ambisome is the version of Amph B. in liposome bilayer: better PK, reduced renal clearance, higher C_max

Q7 - Tragacanth and Na+ EDTA

• Tragacanth is a suspending agent: increases viscosity of the Aq. base.

• Viscosity is good because it reduces the rate of sedimentation of the particles improving stability and uniformity of the suspension.

• Vulnerable to traces of heavy metals, which can cause flocculation and sedimentation of the particles.

• EDTA is a chelating agent that can bind with the heavy metals, preventing them from interacting with the tragacanth and causing flocculation.

Q8 - Iso-osmotic vs isotonic

• Iso-osmotic: MEASURE OF TOTAL PARTICLE CONC. Same total osmolality as a reference solution (e.g., blood plasma)

• Isotonic: PHYSIOLOGICAL EFFECT ON CELL VOL. Does not cause net movement of water across a semipermeable membrane

• IO IT when it contains penetrating solutes that can cross cell membranes, such as urea or ethanol.

Q8 Examples

1. Urea solutions - solution IO to plasma but it crosses cell membraces via UTA transporters - causes osmotic swelling, which makes it hypotonic.
2. Ethylene glycol - Can also be IO to plasma but it penetrates cell membraces hypotonic and not IT.

Q9 - Ostwald ripening

• thermodynamic phenomenon where smaller drug particles dissolve and redeposit onto larger particles from high solub. that results in crystal growth
• AIAO avoid mixed-phase system where {un}dissolved drug particles co-exist. Control through:
• Elimination of solubility gradients - drug is only in one phase state so there's no conc difference
• Thermo equilibrium - chemical potential is equal across the system, so no net movement of drug particles preventing the ripening

Q10 - Role of excipients for emulsions and creams

1. Ionic surfactants

• STAB: electrostatic repulsion between droplets prevents coalescence, surface films with high activity, reduced interfacial tension
• DESTAB: pH senstiive and ionic strength - prone to flocculation. Incompatible with opposite charge surfactants, leading to precipitation or breakdown of the emulsion.

Q10 - Cont'd

2. Non-ionic surfactants

• STAB: lack of charge promotes compatibility, steric stabilisation prevents droplet coalescence, less sensitive to pH and electrolytes
• DESTAB: Temp-sensitive (cloud point phenomenon), leading to phase inversion. Lower surface activity cf. ionic so less efficient emulsification.

Q10 - Cont'd

3. Viscosity-increasing agents

• STAB: Reduce droplet mobility through restricted Brownian motion, network structures that physically entrap that dispersed phase, thus preventing coalescence
• DESTAB: Traps air during manufacture, could create foam instability and might interfere with emulsifier distribution leading to bad interfacial coverage.

Q10 - Cont'd

4. Hydrophilic solvents (ethanol)

• STAB: improves lipophilic emulsifier solubilisation, modify surfactant H-L balance, thus improving emulsification
• DESTAB: reduced interfacial tension coalescence, altered emulsifier partitioning between phases, and causes composition changes that can lead to phase separation.

Q10 - Cont'd

5. Salts and electrolytes

• STAB: Enhances non-ionic surfactant performance thru salting-out effects and might improve continuous phase viscosity, droplet mobility
• DESTAB: Compress electrical double layers, droplet electrostatic repulsion, could cause surfactant precipitation at high ionic strength

Q10 - Cont'd

6. Buffers

• STAB: pH control maintains emulsifier performance and consistent ionisation state of pH-sensitive surfactants
• DESTAB: add to ionic strength leading to electrostatic destabilisation, some buffers can also interact with emulsifiers causing surface activity

Q11 (a) Oral mucosal delivery advantages

• Avoidance of first-pass metabolism (PK advantage)
• Rapid onset of action (clinical benefit)
• Non-invasive (patient compliance)
• Easy removal if needed (safety)
• Not exposed to GI fluids (drug stability/protection)

Q11 (b) Acidic/basic ionisation on permeability/absorption

• Unionised molecules are lipophilic and can partition through lipid cell membranes
• Ionised species are hydrophilic and poorly permeable.
• Acidic drugs (e.g., salicylic acid) become unionised below their pKa in low pH environments, favouring absorption from acidic sites like the stomach.
• Basic drugs (e.g., diltiazem) become unionised above their pKa in higher pH environments, showing better permeability in less acidic regions

Q11 (c) Factors affecting percutaneous absorption

• Drug lipophilicity (log P) and molecular weight
• Drug concentration
• Stratum corneum thickness (or other site)
• Skin hydration
• Temperature

Q12 Antibody-based therapeutic considerations

A. Stability issues

• Degradation of amino acid sequenceCorrectly identify one of Asp, Asn, Glu, or Gln as susceptible to hydrolysis
• Adjacent amino acid can also increase hydrolysis
• Cystine susceptible to oxidation/reduction
• Denaturing of secondary structure and conformational change
• Caused by exposure to heat and freeze thaw cycles
• Aggregation - formation of dimers/oligomers leading to immunogenicity
• Adsorption to container surfaces causing loss of activity

Q12 Cont'd

B. Addressing stability

• Refrigeration
• Freeze-drying (lyophilisation)
• Sequence optimisation
• Appropriate excipients (trehalose, sucrose) for stabilisation
• Control pH and ionic strength to retain conformational stability

Q12 Cont'd

C. Delivery

• Oral: not suitable due to degradation in the GI tract
• IV: effective but needs to be done often due to clearance issues lower patient compliance
• Nasal/pulm.: Ab too big to cross membranes
• Subcut.: preferred, good bioavail.
• IM: absorption slower but depot effect possible for sustained release

Q13 Batch Form

A. What record?

• Prescription and batch records extemp compounded product

Q13 Batch Form Contd'

B. Expiry date without info?

Q13 Batch Form Contd'

C. GMP Chapters

Any of these:

• There is a quality assurance documentation
• Premises are appropriate and clean
• You have the right equipment and that it is clean
• The right excipients and active have been received
• Manufacture: follow the manufacturing process if available
• Visually Control that the product appropriateness
• Appropriate packaging and labelling

Good luck and see you next semester!

Gentle reminder...

Recognising Education Excellence

• It is a way to recognise my teaching
• It is a way to support my career
• Takes two minutes
• [email protected]