formulations (CNS) Flashcards
diff types of parenteral inj
- IV (into vein, 25*) blood vessels
- SC (into sc layer, 45*) fat, collagen, blood vessels
- IM (into muscles 90*) muscle, blood vessels
- Intradermal (into epidermis 10-15*) epithelial
- intrathecal (spinal canal 5-15*) CSF
- Epidural (into epidural space. Still need diffuse through epithelial layer)
IT (spinal fluid)
○ Drugs administered into a (Ommaya) reservoir / lower back
○ Drug delivered directly into cerebrospinal fluid, flows directly to brain
- NO need bypass BBB
CSF
- clear solution. 99% water.
- 1% protein, ions, neurotransmitters, glucose
- pH ~ 7.3
- Vol 150mL
* 430 - 530 mL produced per day (replaced every 5hrs) - Viscosity, flow rate, pressure varies
CSF viscosity, flow rate, pressure varies by
- Depends on time of day, amt of body fluids etc)
- Ebb and flow “circulation”
- Back and forth. But overall flow = forward
* Movement promoted by: Cilia & Conc gradient
barriers and disadv of IT
- dilution/ distribution (minor, 150mL vol)
- reticuloendothelial system
- metabolic enzymes
- invasive
- need trained medical professional
- STRICT sterility (direct to CNS)
ADV of all parenteral
- bypass hepatic first pass metabolism
- control dosage (lower conc, less toxicity)
- direct access to brain (IT)
- SR (IM depots, IT reservoirs)
- non-compliant/ unconscious/ dysphagic pts
parenteral to brain access
- Drug sol flows through circ system
○ Reticuloendothelial system (RES): phagocytes, lymphocytes
○ Distributed everywhere, not targeted (unless there is active targeting) - Drugs must bypass BBB to access brain
○ Blocks 98% of small molecules (drug candidate)
1) Paracellular transport (tight junctions)
2) transcellular transport
1) paracellular
○ Paracellular transport (tight junctions)
○ tight junctions (epithelium of cerebral vasculature)
2) transcellular
- Active efflux transporters
□ Remove drugs from organs –> lumen (blood) - carrier mediated transports (CMT)
- receptor mediated transports (RMT)
active efflux transporters (OUT)
□ P-glycoprotein (P-gp)
□ breast cancer resistance protein (BCRP)
□ multi-drug resistance protein (MRP)
CMT (carrier)
Solute carrier complexes: transports natural solutes in body. Same carrier on other end of epithelial cells to cross to brain interstitial fluid
□ LAT1: natural aa
□ GLUT-1: glucose
□ MCT1: mono-carboxylates (lactate, ketones)
□ OCTN2: organic cations
RMT (receptor)
□ Solute has specific functional grps
- Solute binds to IR (insulin receptor)/ TfR (transferrin receptor)
a) Should design drug that targets carriers found more specifically in the brain - Triggers cascade
- Transcytosis to internalise solute into vesicle
- Vesicle fused on apical side and is released into brain interstitial fluid
ideal drug candidate for CNS drug delivery
lipinski
- MW < 450Da (larger is cleared slower)
- H bond donors ( <3)
- H bond acceptor ( <7)
- LogP (1-3) not too lipo
- UNIONISED
other factors for CNS penetration
- pH ideal 7.4 (but wide range, promote stability of formulation)
* IM: 3-11
* SC: 3-6 - tonicity (hypertonic > hypo)
* 280-290 mOsm/L for large vol (replaces more body fluid)
* hypertonic (water leave cells, but can be adj later), but hypotonic (BURST) - particle size
* no visble particle (block syringe/ capillaries)
delivery systems for parenterals
is in lq state (can be freeze-dried solid –> reconstituted)
○ Solutions
* Drug molecules
* Proteins/ peptides
○ Suspensions
* Nano/microemulsions (oil, lq phases + emulsifier)
* Liposomes/ other lipid-based self assembled structures
* Nanoparticles
excipients
○ Diluent (water)
○ Buffer salts (maintain pH, unionised)
○ Tonicity adjusters
○ Preservatives (minimal in IT – cause inflamm in brain)
○ Stabilisers/ co-solvents
buffer
sodium acetate, citrate, phosphates (mixed), lactate
preservatives
benzyl alcohol
chlorbutanol
methylparaben
propylparaben
phenol
thiomersal
tonicity adj adjust (280-290 mOsm/L) for large vol
mannitol — also cryoprotectant (lipophilise)
NaCl
glycerine/ glycerol
glycine
solvent
ethanol
glycerin/ glycerol
glycine
PEG
propylene glycol
surfactant
polysorbate 20 & 80
parenteral packaging and storage
- Glass ampoules
○ Scored for breakage (risk injury) - Glass vials with rubber stoppers
○ For powders that require reconstitution (separate containment of sterile water) - Pre-filled syringes
○ Measured out amt - Must be able to withstand the sterilisation process (temp)
- Amber coloured if light sensitive
syringe (single-use & sterile)
components
needle
barrel - graduated for measurement, can be lubricated
plunger - lubricated w/ silicone (flow smoothly)
syringe needle
- Breeches the skin
- Gauge (thick, sturdy 14 —– thin, filmsy 27)
* Depends on:
□ Thickness of site of inj (buttock vs arm)
□ How much formulation to deliver
□ Particle size
cetheters and reservoirs (implanted with surgery)
○ For infusions
- Reservoir for refilling
- Catheter to deliver
- Pump to automate dosing
○ Biocompatible materials
- Titanium (not degrade, react with tissue implanted in)
haloperidol conc
FGA, dopamine receptor agonist
- Haldol 50mg/mL
- Haloperidol decanoate 70.52mg = 50mg/mL haloperidol base
- Haldol conc 100mg/ml
- Haloperidol decanoate 141.04mg = 100mg/mL haloperidol base
admin of haloperidol
- Deep IM inj into gluteal region
- 2inch long, 21G needle
- Max vol per inj site =/<3mL
○ Forms depot: slow release of drug over time
○ LAI (improve adherence) - Interval b. doses: 4wks
API of haloperidol formulation
slow break down of ester linkage haloperidol decanoate —> haloperidol
* MW: 530.1g/mol –> 375.9 g/mol
* logP: 7.22~7.9 –> 4.3
* Hydrogen bond donor (0 –> 1)
* Hydrogen bond acceptor (5 –> 4)
* Non Ionisable –> ionisable
- fulfils lipinski, slight too lipophilic (logP1-3), but since released in muscle its ok
haloperidol composition
- Sesame oil (lipo solvent for lipo drug)
○ Forms depot that slowly breakdown haloperidol decanoate –> haloperidol - Benzyl alcohol (preservative)
No pH (lipo), osmolality (small vol)
PK/PD of haloperidol
- Sustained release from depot
○ SS plasma lvls reached within 2-4mnths - T1/2: 3 wks
- M: liver
- Plasma protein binding: 88-92%
baclofen/ lioresal
- baclofen: skeletal muscle relaxant
* severe spasticity due to spinal cord injury/ multiple sclerosis - GABA receptor agonist, induce inhibitory action in CNS
- 0.05mg/mL ampoule
- 2mg/mL ampoule
- 0.5mg/mL (20mL) (infusion)
- PO but undesired SE
baclofen API
- MW: 213.67 g/mol
- LogP: 1.3
- H bond donor: 3
- H bond acceptor: 4
- fulfils lipinski
Ionisable:
* COO-: 3.87 (ionised first, stronger acid than CA of amine)
* NH3+: 9.62
baclofen IT
IT: bypass absorption, bind to receptor sites in dorsal horn of spinal cord
baclofen composition
- Water (solvent, diluent)
- NaCl (tonicity adjuster)
pH: 5-7 (no buffering agents, is natural pH of API)
Osmolality: 270-300 mOsm/kg (0.05 mg/mL, within range
baclofen PK/PD
- Conc in CSF is 100x > after PO absorption
○ dont need bypass hepatic + BBB - Infusion:
○ Antispastic action: 6-8hr after admin
○ Max effect: 24-48hr - Bolus:
○ Onset: 0.5-1hr after admin
○ Antispastic effect: 4hr after dose (lasts 4-8hr)
ziconotide/ prialt MOA
ω-conotoxin class of neurotoxic peptides
inhibits N-type voltage gated Ca channel blocker
* severe chronic pain in pt, intolerant/ refractory to other tx (systemic analgesics, adjunct therapies, morphine)
PRIALT: ONE VIAL PER CARTON
* 25ug/mL in glass vial (20mL)
* 100ug/mL in glass vial (1 or 5mL)
Requires infusion system or infusion pump (specific)
ziconotide API
- MW: 2639.2 g/mol
○ Very large size so need IT (amide bonds, peptide molecules) - Log P: -2 or -23 (very hydrophilic)
- H bond donor: 42
- H bond acceptor: 46
Ionisable, too large, v hydrophilic compensate by IT
zicotonide composition
- Water (solvent)
- NaCl (tonicity adjuster)
- L-methionine (pH adjuster/ buffer agent)
○ Also has antioxidant, flavouring effect but not here - pH: 4-5 (protein needs specific pH, DENATURE)
- Osmolality: Isotonic
PK/PD of zicotonide
- T1/2: 4.6 +/- 1.8hrs
- M: peptidases/ proteases
- Vd: 140mL (vol of CSF)
○ 50% bound to human plasma proteins
Worst if given IV (fast CL: 270ml/min, t1/2: 1.3hr)
CSF minimal proteolytic / hydrolytic degradation of ziconotide
