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3153 psych > formulations (CNS) > Flashcards

formulations (CNS) Flashcards

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1
Q

diff types of parenteral inj

A
  • 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)
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2
Q

IT (spinal fluid)

A

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

  • NO need bypass BBB
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3
Q

CSF

A
  • 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
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4
Q

CSF viscosity, flow rate, pressure varies by

A
  • 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
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5
Q

barriers and disadv of IT

A
  • dilution/ distribution (minor, 150mL vol)
  • reticuloendothelial system
  • metabolic enzymes
  • invasive
  • need trained medical professional
  • STRICT sterility (direct to CNS)
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6
Q

ADV of all parenteral

A
  • 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
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7
Q

parenteral to brain access

A
  • 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
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8
Q

1) paracellular

A

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

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9
Q

2) transcellular

A
  • Active efflux transporters
    □ Remove drugs from organs –> lumen (blood)
  • carrier mediated transports (CMT)
  • receptor mediated transports (RMT)
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10
Q

active efflux transporters (OUT)

A

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

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11
Q

CMT (carrier)

A

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

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12
Q

RMT (receptor)

A

□ 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
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13
Q

ideal drug candidate for CNS drug delivery
lipinski

A
  • MW < 450Da (larger is cleared slower)
  • H bond donors ( <3)
  • H bond acceptor ( <7)
  • LogP (1-3) not too lipo
  • UNIONISED
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14
Q

other factors for CNS penetration

A
  • 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)
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15
Q

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

A

○ Solutions
* Drug molecules
* Proteins/ peptides

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

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16
Q

excipients

A

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

17
Q

buffer

A

sodium acetate, citrate, phosphates (mixed), lactate

18
Q

preservatives

A

benzyl alcohol
chlorbutanol
methylparaben
propylparaben
phenol
thiomersal

19
Q

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

A

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

20
Q

solvent

A

ethanol
glycerin/ glycerol
glycine
PEG
propylene glycol

21
Q

surfactant

A

polysorbate 20 & 80

22
Q

parenteral packaging and storage

A
  • 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
23
Q

syringe (single-use & sterile)

components

A

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

24
Q

syringe needle

A
  • 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
25
Q

cetheters and reservoirs (implanted with surgery)

A

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

26
Q

haloperidol conc

A

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
27
Q

admin of haloperidol

A
  • 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
28
Q

API of haloperidol formulation

A

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
29
Q

haloperidol composition

A
  • Sesame oil (lipo solvent for lipo drug)
    ○ Forms depot that slowly breakdown haloperidol decanoate –> haloperidol
  • Benzyl alcohol (preservative)

No pH (lipo), osmolality (small vol)

30
Q

PK/PD of haloperidol

A
  • Sustained release from depot
    ○ SS plasma lvls reached within 2-4mnths
  • T1/2: 3 wks
  • M: liver
  • Plasma protein binding: 88-92%
31
Q

baclofen/ lioresal

A
  • 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
32
Q

baclofen API

A
  • 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

33
Q

baclofen IT

A

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

34
Q

baclofen composition

A
  • 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

35
Q

baclofen PK/PD

A
  • 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)
36
Q

ziconotide/ prialt MOA

A

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)

37
Q

ziconotide API

A
  • 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

38
Q

zicotonide composition

A
  • 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
39
Q

PK/PD of zicotonide

A
  • 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

3153 psych (11 decks)

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