9. Dosage Form Design for Cardiovascular Drugs Flashcards
What is controlled drug delivery?
Delivery of a drug at a rate and/or location, indicated by the needs of the body or disease state over a specified period of time
Temporal delivery - control over rate of drug release (delayed or constant)
Spatial delivery - control over location of drug release (localised delivery, targeting systems)
Combination of above also seen
Controlled release types (3)
- Matrix systems
- Membrane controlled systems - reservoir systems
- Osmotic pump systems
Matrix systems
Drug dispersed in polymer matrix (hydrophilic/lipophilic) & release is controlled by diffusion
Hydrophilic colloid matrices:
- Eroding systems - drug becomes available as matrix dissolves
- Rate of drug release controlled by dissolution of matrix
- Tablet can be cut in half, but cannot crush or chew
- E.g. Bulk-eroding, surface eroding
Lipid or insoluble polymer matrix:
- Non-eroding systems - drug becomes available as solvent enters matrix * dissolves drug
- Rate of drug release controlled by fluid penetration
Membrane controlled systems
- Type of reservoir system in which drug is contained within a reservoir
- Rate controlling step is the diffusion of drug through a membrane
- Dose dumping (rapid release) is a potential issue which must be considered
Tablet drug core surrounded with a polymeric membrane that is permeable to both drug & water
- Diffusion controlled release
- Zero order, independent of concentration
Osmotic pump systems
- Drug included in water soluble core
- Core coated in semi-permeable membrane to allow passage of water
- If water is present in the surrounding environment it will enter core & result in an increase in hydrostatic pressure
- This will force drug out of a hole drilled in the coating
- Outer core is lipophilic & non-biodegradable so will pass out of GIT
Nitrates
Glycerl trinitrate (GTN)
- AKA nitroglycerin
- Explosive (when pure)
- Low oral bioavailability & unpredictable
Isosorbide mononitrate:
- Good oral bioavailability
Nitrate tolerance
Nitrate free period ~8-12 hours / 24 hours
Mechanism for tolerance is unclear but may be:
- Increase in reactive oxygen species
- Increase in plasma volume
- Decrease in biotransformation of nitrates to NO
- Decreased responsiveness to NO
- Neurohormonal activation
- Cross tolerance between nitrates occur
- Issue in prophylaxis & treatment of acute attacks
- Tolerance is lost within 24 hours of discontinued therapy
Nitrolingual pump spray (GTN)
- Delivers 0.4 mg GTN per spray
- Rapidly absorbed from mouth mucosa,
- tmax = 4 min
- Plasma t1/2 = 2.5-4.5 min
- Shelf life = 3 years
- Check bottom of bottle for EXP
Lycinate Sublingual Tablets (GTN)
- Sublingual delivery
- Delivers 0.6 mg GTN
- Tmax = 4.9 min
- Shelf life of 8 weeks from opening
- 1 bottle = 100 tablets
Nitroderm TTS transdermal patch (GTN)
- Nitroglycerin release at 20-25 mcg/cm2/h
- TTS 5 & TTS 10 - numbers denote the amount of active (mg) released over 24 hours
- Apply patch during day & remove at night to account for nitrate free period
- Plasma levels plateau after 2 hours
- Plasma levels proportional to area available for drug release to skin
- Do NOT cut patch in half
Ismo 20 Immediate Release Tablets
- Delivers 20 mg isosorbide mononitrate
- Bioavailability ~100%
- Onset of action 20 min
- Tmax = 1 hour
- T1/2 = 5 hours
- Usual dose 20 mg bd/tds
- Governed by dissolution (rate limiting step)
Duride Modified Release Tablets
- Delivers 60 mg isosorbide mononitrate
- Modified release achieved though non-erodible matrix
- Bioavailability = 90%
- tmax = 4 hours
- t1/2 = 5 hours
- Taking duride at 24 hour intervals helps to keep them working properly
Digoxin
- Narrow therapeutic index 1-2 µg/mL
- Dose requires individual tailoring depending on age, lean body weight & renal function
- Bioavailability 63% tablet, 75% paediatric elixir (alcoholic preparation)
- Food slows rate but not total amount of digoxin absorbed
- Extensively tissue bound
- Terminal t1/2 = 30-40 h (extended with renal function)
- Loading dose required to achieve digitalisation
- Maintenance dose based on elimination rates (renal)
- Toxicity: Nausea, vomiting, loss of appetite, confusion, blurred vision
- Blood levels for digoxin should be taken > 6 hours after last dose
Amiodarone oral tablets
- Class III antiarrhythmic drug
- Oral bioavailability 22-86% incompletely & erratically absorbed with extensive intrasubject variation
- t1/2 = ~25 days (14-110 days)
- Due to unpredictability aim to use the lowest effective concentrations
- Extensively distributed into tissues, including adipose tissue
- Loading 200 mg TDS for 1 week, followed by 200 mg BD for 1 week
- Maintenance 200 mg (or less) OD
Amiodarone IV injection
- 150 mg amiodarone HCl in 3 mL ampoules
- 5 mg/kg IV infusion over 20 min – 2 hour
- Administered in 250 mL 5% glucose
- Incompatible with saline!
- Do not mix amiodarone with any other preparations
- Amiodarone may reduce drop size
- Amiodarone will absorb into PVD infusion bags & administration sets
- Thought to be due to plasticisers
- Prepare infusion immediately prior to use & use glass or rigid PVC bottles
- Amiodarone containing solutions may cause the plasticiser DEHP to leach out of plastics
- Use non-DEHP containing equipment
