formulations (CNS)

Question 1

diff types of parenteral inj

Answer 1

• 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)

Question 2

IT (spinal fluid)

Answer 2

○ Drugs administered into a (Ommaya) reservoir / lower back
○ Drug delivered directly into cerebrospinal fluid, flows directly to brain

• NO need bypass BBB

Question 3

CSF

Answer 3

• 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

Question 4

CSF viscosity, flow rate, pressure varies by

Answer 4

• 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

Question 5

barriers and disadv of IT

Answer 5

• dilution/ distribution (minor, 150mL vol)
• reticuloendothelial system
• metabolic enzymes
• invasive
• need trained medical professional
• STRICT sterility (direct to CNS)

Question 6

ADV of all parenteral

Answer 6

• 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

Question 7

parenteral to brain access

Answer 7

• 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

Question 8

1) paracellular

Answer 8

○ Paracellular transport (tight junctions)
○ tight junctions (epithelium of cerebral vasculature)

Question 9

2) transcellular

Answer 9

• Active efflux transporters
  □ Remove drugs from organs –> lumen (blood)
• carrier mediated transports (CMT)
• receptor mediated transports (RMT)

Question 10

active efflux transporters (OUT)

Answer 10

□ P-glycoprotein (P-gp)
□ breast cancer resistance protein (BCRP)
□ multi-drug resistance protein (MRP)

Question 11

CMT (carrier)

Answer 11

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

Question 12

RMT (receptor)

Answer 12

□ Solute has specific functional grps

1. Solute binds to IR (insulin receptor)/ TfR (transferrin receptor)
   a) Should design drug that targets carriers found more specifically in the brain
2. Triggers cascade
3. Transcytosis to internalise solute into vesicle
4. Vesicle fused on apical side and is released into brain interstitial fluid

Question 13

ideal drug candidate for CNS drug delivery
lipinski

Answer 13

• MW < 450Da (larger is cleared slower)
• H bond donors ( <3)
• H bond acceptor ( <7)
• LogP (1-3) not too lipo
• UNIONISED

Question 14

other factors for CNS penetration

Answer 14

• 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)

Question 15

delivery systems for parenterals
is in lq state (can be freeze-dried solid –> reconstituted)

Answer 15

○ Solutions
* Drug molecules
* Proteins/ peptides

○ Suspensions
* Nano/microemulsions (oil, lq phases + emulsifier)
* Liposomes/ other lipid-based self assembled structures
* Nanoparticles

Question 16

excipients

Answer 16

○ Diluent (water)
○ Buffer salts (maintain pH, unionised)
○ Tonicity adjusters
○ Preservatives (minimal in IT – cause inflamm in brain)
○ Stabilisers/ co-solvents

Question 17

buffer

Answer 17

sodium acetate, citrate, phosphates (mixed), lactate

Question 18

preservatives

Answer 18

benzyl alcohol
chlorbutanol
methylparaben
propylparaben
phenol
thiomersal

Question 19

tonicity adj adjust (280-290 mOsm/L) for large vol

Answer 19

mannitol — also cryoprotectant (lipophilise)
NaCl
glycerine/ glycerol
glycine

Question 20

solvent

Answer 20

ethanol
glycerin/ glycerol
glycine
PEG
propylene glycol

Question 21

surfactant

Answer 21

polysorbate 20 & 80

Question 22

parenteral packaging and storage

Answer 22

• 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

Question 23

syringe (single-use & sterile)

components

Answer 23

needle
barrel - graduated for measurement, can be lubricated
plunger - lubricated w/ silicone (flow smoothly)

Question 24

syringe needle

Answer 24

• 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

Question 25

cetheters and reservoirs (implanted with surgery)

Answer 25

○ For infusions - Reservoir for refilling - Catheter to deliver - Pump to automate dosing ○ Biocompatible materials - Titanium (not degrade, react with tissue implanted in)

Question 26

haloperidol conc

Answer 26

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

Question 27

admin of haloperidol

Answer 27

* 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

Question 28

API of haloperidol formulation

Answer 28

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

Question 29

haloperidol composition

Answer 29

* Sesame oil (lipo solvent for lipo drug) ○ Forms depot that slowly breakdown haloperidol decanoate --> haloperidol * Benzyl alcohol (preservative) No pH (lipo), osmolality (small vol)

Question 30

PK/PD of haloperidol

Answer 30

* Sustained release from depot ○ SS plasma lvls reached within 2-4mnths * T1/2: 3 wks * M: liver * Plasma protein binding: 88-92%

Question 31

baclofen/ lioresal

Answer 31

* 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

Question 32

baclofen API

Answer 32

* 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

Question 33

baclofen IT

Answer 33

IT: bypass absorption, bind to receptor sites in dorsal horn of spinal cord

Question 34

baclofen composition

Answer 34

* 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

Question 35

baclofen PK/PD

Answer 35

* 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)

Question 36

ziconotide/ prialt MOA

Answer 36

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)

Question 37

ziconotide API

Answer 37

* 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

Question 38

zicotonide composition

Answer 38

* 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

Question 39

PK/PD of zicotonide

Answer 39

* 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