Parenteral (IC13) Flashcards
(44 cards)
Parenteral delivery - types of injection
Intramuscular - 90dc, into muscle
Subcutaneous - 45dc, into sc layer
Intravenous - 25dc, into vein (dermis)
Intradermal - 10-15dc, into skin (epidermis) - more often for testing allergies, diagnostic tests; not really for drug delivery
Intrathecal - 5-15dc, into spinal canal (CSF, directly into brain)
Intrathecal injections
- How is it administered?
- Via scalp, into ommaya reservoir (implant)
- Via lower back, into cerebrospinal fluid
Epidural VS intrathecal
- Epidural: into epidural space, need to diffuse across epithelial layer into CSF
- Intrathecal: directly into CSF
Describe the cerebrospinal fluid
- Composition
- Volume
- Produced by choroid plexus
- Clear solution: 99% water, 1% protein, ions, neurotransmitters, and glucose
- 150ml volume (450-530ml produced per day, replaced every 5h)
- Variable viscosity, flow rate, and pressure
- Ebb and flow circulation, direction promoted by source (conc. gradient) and cilia
What are the barriers/disadvantages of non-intrathecal parenteral delivery to the brain?
- Need to bypass BBB
- More potential to distribute to other areas in the body via blood circulation
- Encounters the reticuloendothelial system
- Encounters metabolic enzymes
- Invasive route
- Require medical professional
- Strict sterility
What are the barriers/disadvantages of intrathecal parenteral delivery to the brain?
- Less potential to distribute to other areas in the body as more able to distribute directly to the brain via the CSF
- Encounters the reticuloendothelial system
- Encounters metabolic enzymes
- Invasive route
- Require medical professional
- Strict sterility
What are the advantages of parenteral delivery to the brain?
- Bypass hepatic first pass metabolism
- Can control dosage (relatively low drug conc., and low toxicity)
- Direct access to the brain for intrathecal route, reduce systemic side effects
- Sustained release for IM depots, intrathecal reservoirs
- Ideal for non-compliant, unconscious, or dysphagic patients
Blood to brain barriers:
- Drug solution flows through circulatory system, what barriers?
- Reticuloendothelial system - include liver, spleen, lung etc.
- Phagocytic system involve immune cells such as macrophages that may digest/phagocytosize the drug molecules
- Drug distribution
- Unless there is active targeting, drug will distribute to other areas of the body including other organs
Blood to brain barriers:
- Blood brain barrier (BBB)
Explain the transport across epithelial cells
Blocks uptake of 98% of small molecule drug candidates
Paracellular (tight junctions) and transcellular transport from blood through epithelial cells, into brain interstitial fluid
Blood to brain barriers:
- Blood brain barrier (BBB)
Explain the action of active efflux transporters
- Remove drugs from brain into the blood
- P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi-drug resistance proteins (MRP)
Blood to brain barriers:
- Blood brain barrier (BBB)
Explain the action of transporters that facilitate entry into the brain
Carrier-mediated transporters (CMT)
- e.g., transport amino acids (LAT1), glucose (GLUT1)
Receptor-mediated transporters (RMT)
- involves transcytosis of receptor + drug ligand in a vesicle, vesicle fuse with membrane on the other side, exocytosis of drug into brain interstitial fluid
Ideal drug candidate for parenteral (non-intrathecal, need to pass BBB):
modified lipinski’s rule of 5
Molecular weight: <450 Da (instead of <500Da)
Hydrogen bond donors: <3 (instead of =<5)
Hydrogen bond acceptors: <7 (instead of =<10)
LogP: 1-3 (instead of <5)
Ionisation state: Unionized
Does intrathecal formulation need to fulfill lipinski’s rule?
No, intrathecal delivery can accomodate large molecules
Formulations for parenteral delivery can include:
Solutions
- drug molecules
- proteins/peptides
Suspensions
- nano/microemulsions
- liposomes and other lipid-based self-assembled structures
- nanoparticles
Common excipients of solutions for injection
- Diluent
- Buffer salts
- Tonicity adjusters
- Preservatives (minimal for intrathecal)
- Stabilizers/co-solvents
Considerations for parenteral delivery
- pH
Ideally 7.4, but a wide range is tolerated
Intramuscular: 3-11
Subcutaneous: 3-6
Formulation stability is prioritized over ideal pH
Considerations for parenteral delivery
- Tonicity
Ideally isotonic with blood (blood tonicity: 290 mOsm/L)
280-290 mOsm/L for large-volume parenteral
Tonicity can be increased with tonicity adjusters
Hypertonic solutions are preferred over hypotonic solutions
- hypertonic: water leaves blood cell, into drug solution
- hypotonic: water leaves drug solution and enters blood cell, causing them to burst/lyse
Considerations for parenteral delivery
- Particle size
No visible particles (more applicable for IV, than SC or IM)
Considerations for parenteral delivery
- Volume
Volume not an issue, as infusion pumps can be used to administer large volumes overtime
[Excipients of solutions for injection]
- Buffer
- Sodium acetate, citrate, phosphates, lactates
- L-methionine
[Excipients of solutions for injection]
- Preservative (non-intrathecal formulation)
- Benzyl alcohol
- Chlorbutanol
- Methylparaben
- Propylparaben
- Phenol
- Thiomersal
[Excipients of solutions for injection]
- Tonicity adjusting agent
- Mannitol (also a cryoprotectant for lyophilized formulations to protect it during sublimation process)
- Sodium chloride
- Potassium chloride (IC8)
- Glycerine/Glycerol
- Glycine
[Excipients of solutions for injection]
- Solvent
- Ethanol
- Glycerine/Glycerol
- Glycine
- PEG
- Propylene glycol
[Excipients of solutions for injection]
- Surfactant
- Polysorbate 20 & 80
(From IC8)
- Glyceryl dioleate/monoleate
- Lecithin
