ic13 pharm tech (parenteral)

Question 1

what are the different parenteral deliveries (specify the angle)

Answer 1

intramuscular (into the muscle) 90deg
subcutaneous (into the subcutaneous layer) 45deg
intravenous (into the vein) 25deg
intradermal (into the skin aka epidermis) 10-15deg
intrathecal (into the spinal fluid) 5-10deg

Question 2

which parenteral route has access to the brain and how does it have access to the brain

Answer 2

intrathecal

drug delivery into the cerebrospinal fluid flows directly to the brain

Question 3

how might a drug be administered via the intrathecal route

Answer 3

ommaya reservoir (soft plastic dome shaped device that is placed under the scalp)

lower back

Question 4

what are the physicochemical properties of the CSF (composition, pH, volume, viscosity, flow rate, pressure, circulation, flow motion for various type of molecules)

Answer 4

CSF is a clear solution
99% water, 1% proteins, ions, NT and glucose
pH 7.3
volume 150mL at any given time (total 430-530mL produced per day)
variable viscosity, flow rate and pressure
ebb and flow circulation (direction promoted by source (through conc gradient) and cilia)
large and charged molecules are cleared more slowly than small lipophilic molecules which are cleared more rapidly within the space

Question 5

what are the target layers and main composition at the different sites of injection

Answer 5

intramuscular: muscle; muscle, blood vessels

subcutaneous: subcutaneous tissue; fat, collagen, blood vessels

intravenous: dermis; blood vessels

intradermal: epidermis; epithelial cells

intrathecal: spinal canal; csf

Question 6

compare the barriers and disadvantages between nonIT and IT administration (BBB, dilution/ distribution, reticuloendothelial system, metabolic enzymes, invasiveness, medical professional, sterility)

Answer 6

BBB: [nonIT] BBB is a barrier [IT] BBB is not a barrier

dilution/ distribution: [nonIT] potentially major bc prob distribute to all parts of the body before reaching brain [IT] minor bc directly into csf so can delivery directly into the brain

reticuloendothelial system (part of immune system): is a barrier to nonIT and IT

metabolic enzymes: is a barrier to both nonIT and IT

invasiveness: both nonIT and IT require administration through a needle

medical professional: both req trained skills to administer correctly

sterility: both nonIT and IT have strict req regarding sterility

Question 7

what are the advantages of parenteral delivery

Answer 7

1. bypasses hepatic first pass metabolism
2. can control dosage (through conc and vol administered): relatively low conc (and thus low toxicity)
3. direct access to brain if IT route
4. sustained release if use IM depots or IT reservoir
5. ideal for non compliant, unconscious or dysphagic pts

Question 8

outline the path of the drug that is administered parenterally (non IT route) to access the brain

Answer 8

drug solution will flow through the circulatory system and access the brain via the systemic circulation

unless there is active targeting, drug will distribute everywhere (circulates to various organs like lungs, gut, liver, kidney, all the way back to the heart) and to reach the brain will have to bypass BBB (a very tight junc) but while circulating drug will be exposed to other biological components like the reticuloendothelial system which may cause a decr in drug conc

Question 9

what are the physicochemical properties of the BBB (proportion of molecules that can pass through, types of protein present and transport systems)

Answer 9

BBB is a very tight junction that blocks uptake of 98% of small molecule drug candidates

drugs might still pass through via paracellular or transcellular transport

drugs can also pass through via carrier mediated transporters (CMT) or receptor mediated transporters (RMT)
[CMT] CMT eg, GLUT1, LAT1, MCT1, OCTN2; drug molecule has a chemical structure that allows the formation of complex with the carriers thus allowing the complex to shuttle across and ejected into epithelial cells, subsequently interact with corresponding carriers on opposite side of the epithelial cell to be ejected into brain interstitial fluid
[RMT] drug molecule has a chemical structure that facilitates binding to the receptor on the epithelial cells which subsequently triggers a cascade of events and allowing transcytosis to occur and drug reaches the brain interstitial fluid

drugs are subjected to active efflux transporters like P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi-drug resistance protein (MRP) which remove drugs from the organ (brain) back into the lumen (blood)

Question 10

what is the idea drug candidate for parenteral delivery (non IT) (lipinski vs CNS modified)

Answer 10

LIPINSKI:
[MW] <500Da
[H bond donor] 5 or less
[H bond acceptor] 10 or less
[LogP] <5.0
[ionisation] unionised

CNS MODIFIED:
[MW] <450Da
[H bond donor] <3
[H bond acceptor] <7
[LogP] 1-3
[ionisation] unionised

Question 11

how to interpret LogP

Answer 11

LogP = 0 means the drug partitions equally between the aq and lipid phase

LogP >0 means the drug partitions more into the lipid phase (aka higher conc in lipid phase aka lipophilic)

Question 12

should you use LogP for a drug that is ionisable (if not use what)

Answer 12

use LogD (the partition in qn for the ionisable compound is now a func of the pH which is not the same across all pH vs non ionisable compound’s LogP =LogD for all pH)

Question 13

what are the types of delivery systems that are used for parenteral delivery

Answer 13

1. solutions
   i) drug molecules
   ii) proteins/ peptides
2. suspensions
   i) nano/microemulsions
   ii) nanoparticles
   iii) liposomes and other lipid based self-assembled structures

Question 14

what are some products currently in the market for IT, IM and IV drug delivery

Answer 14

IT: baclofen, ziconotide, morphine

IM: haloperidol, morphine

IV: morphine

Question 15

what are the common excipients used for solutions for injections

Answer 15

1. diluent
2. buffer salts
3. tonicity adjusters
4. preservatives (minimal for IT)
5. stabilisers/ co-solvents

Question 16

why are preservatives likely kept to a minimum for IT especially

Answer 16

bc it would be an additional excipient that might complicate things bc IT is especially direct access to the brain and do not want anything that would inflamm the brain or if the raw ingredient introduces pathogens

Question 17

what are the pH, tonicity and particle size considerations for parenteral formulations

Answer 17

pH: ideally 7.4 (can range from 3-11 for IM; can range from 3-6 for SQ) but formulation stability prioritised

tonicity: 280-290mOsm/L for large volume parenterals, hypertonic solutions preferred over hypotonic (tonicity can be incr w tonicity adjusters)

particle size: no visible particles (more for IV than IM and SQ)

Question 18

why is tonicity only more of a consideration for large volume parenterals compared to small volume and why is hypertonic preferred over hypotonic if formulation cannot be isotonic

Answer 18

small volume will be quickly diluted vs large volume will replace a significant volume of blood

thus need ensure formulation is isotonic ideally but if not hypertonic > hypotonic bc hypertonic creates shrivelled cells which is reversible bc can just flow to a diff part of the body that is less hypertonic then reabsorb water again vs if hypotonic, will cause water to flow into cells which causes cells to burst which is irreversible

Question 19

list examples of buffers

Answer 19

sodium acetate, citrate and phosphates, lactate

Question 20

list examples of preservatives

Answer 20

benzyl alcohol, chlorbutanol, methylparaben, propylparaben, phenol, thiomersal

Question 21

list examples of tonicity adjusting agents

Answer 21

mannitol, sodium chloride, glycerin, glycine

Question 22

list examples of solvents

Answer 22

ethanol, glycerin, glycine, PEG, propylene glycol

Question 23

list examples of surfactants

Answer 23

polysorbate 20 and 80

Question 24

what are the kinds of packaging and storage used for parenteral formulations and what is the requirement for these packagings

Answer 24

1. glass ampoules (scored for breakage)
2. glass vials with rubber stopper
3. pre-filled syringe

packaging used must be able to withstand sterilisation processes (incl high temp req for sterilisation)

Question 25

what kind of formulation are glass vials with rubber stoppers typically used for as packaging

Answer 25

for powders that req reconstitution, sterile water can be included with the product

Question 26

what are the parts of a syringe (and its properties)

Answer 26

needle, barrel, plunger

needle: breaches the skin and has various gauges for different purposes

barrel: graduated for measurement and can be lubricated

plunger: administration of drug solution, lubricated with silicone

syringes are usually single use and sterile

Question 27

what kind of device might be used for IT delivery, how is it administered (func of various part of this device) and what are the considerations regarding such devices (what are its advantages and concerns)

Answer 27

catheters and reservoirs (surgically implanted)

for infusion, reservoir for refilling and catheter to deliver and pump to automate dosing

made of biocompatible materials like titanium to ensure wont react badly with pt at site of where the device is implanted into

advantage is that it is convenient, do not keep having to administer via IT needles, just have to refill reservoir

concern is that it can be dangerous if malfunction that result in high doses being administered to pt

Question 28

consider haloperidol (haldol), elaborate on its moa, product conc, storage and packaging, administration, properties of API (MW, LogP, Hbond donors and acceptors, ionisability), excipients, pH, osmolality, PK (duration to ss, half life, metabolism, protein binding)

Answer 28

moa: dopamine receptor antagonist

product conc: haldol 50mg/mL (70.52mg of haloperidol decanoate), haldol concentrate 100mg/mL (141.04mg of haloperidol decanoate)

storage and packaging: glass ampoule

administration: IM injection into gluteal area, 2inch 21G needle, q4w (forms depot thus helps with slow release of drug)

API MW: 375.9 for non ester (haloperidol), 530.1 for ester (haloperidol decanoate)

API LogP: 4.3 for non ester, 7.22-7.9 for ester (ester has an additional hydrophobic region)

API Hbond donor: 1 for non ester, 0 for ester

API Hbond acceptors: within limit

API ionisability: ester ionisable but weak acid thus unlikely to ionise at physiological pH

excipients: sesame oil (diluent/ solvent), benzyl alcohol (preservative)

pH: NA (bc need water to have pH, here all oil)

osmolality: NA (bc no tonicity agent and not much of an issue bc injecting into muscle)

duration to ss: 2-4m

half life: 3w (thus administering q4w allows drug serum level to reach low enough first)

metabolism: in liver

protein binding: 88-92%

Question 29

what is the mechanism of release for haloperidol decanoate

Answer 29

one part attributed to formation of depot due to drug’s lipophilicity vs rest of body is water

another part attributed to having to undergo enzymatic reaction to convert ester into haloperidol which is the form req for pharmacological activity

Question 30

consider baclofen (lioresal), elaborate on moa, product conc, administration, packaging, properties of API (MW, LogP, Hbond donors and acceptors, ionisability), excipients, pH, osmolality, PK (compare conc in CSF between IT and PO product, compare onset of action between given infusion and bolus)

Answer 30

moa: GABA receptor agonist; inhibitory action in CNS thus allowing to act as a muscle relaxant

product conc:
i) 0.05mg/mL (1mL)
ii) 2mg/mL (5mL)
iii) 0.5mg/mL (20mL)

administration: IT

packaging: glass ampoules

API MW: 213.67

API LogP: 1.3

API Hbond donors and acceptors: within limit

API ionisability: yes, ionisable (pKa of COOH 3.87; pKa of NH2 9.62)

excipients: water (diluent), sodium chloride (tonicity adjuster)

pH: 5-7

osmolality: 270-300 mOsm/kg for 0.05mg/mL

PK conc in CSF: 100x higher for IT compared to PO

onset for infusion: 6-8hr (likely lower dose than bolus and given over a longer period of time)

onset for bolus: 0.5-1hr

*note also avail in PO but alot of adverse effects

Question 31

why does baclofen have a lower LogP than haloperidol

Answer 31

baclofen has lesser bulky hydrocarbon chains which are hydrophobic in nature thus baclofen is more hydrophilic than haloperidol since it also has relatively more hydrophilic groups

Question 32

consider ziconotide (prialt), elaborate on moa, product conc, administration, packaging, properties of API (MW, LogP, Hbond donors and acceptors, ionisability), excipients, pH, osmolality, PK (half life, metabolism, Vd, plasma protein binding)

Answer 32

moa: N-type voltage gated Ca channel blocker; block propagation of pain signal in CNS thus for management of severe chronic pain

product conc: 25µg/mL (20mL) 100µg/mL (1 or 5mL)

administration: IT through infusion system or ambulatory infusion pump

packaging: glass vial

API MW: 2639.2

API LogP: -2 or -3 (basically hydrophilic)

API Hbond donors/ acceptors: alot

API ionisability: yes

*all do not fulfil ideal drug properties for any other administration routes to cross BBB thus must be given via IT

excipients: water (diluent), sodium chloride (tonicity adjuster), L-methionine (pH adjuster/ buffer)
*pH adjuster impt bc if not the protein denatures and cannot exert pharmacological action

pH: 4-5

osmolality: isotonic

half life: 5hr for IT (vs 1.3hr if given IV)

metabolism: metabolised by proteases or peptidases (bc ziconotide is a peptide molecule)

Vd: approx 140mL (aka vol of CSF meaning it highly concentrates in csf)

protein binding: 50%

Question 33

are proteases and peptidases found more in IT space or in systemic circulation (relate to administration route of ziconotide)

Answer 33

found more in systemic circulation than in IT space thus further highlighting why ziconotide is given as IT formulation