long acting injectables

Question 1

what are clinical needs for long acting injectables

Answer 1

-maintenance of therapeutic concentrations over an extended period of time
-reduce number of injections, improves patient comfort/decreases healthcare professional time needed

Question 2

name 3 injection sites

Answer 2

intravenous, intramuscular, subcutaneous routes

Question 3

describe the 3 injection sites and how each can achieve long duration action

Answer 3

intravenous= drug directly delivered to systemic circulation, long duration of action achieved with particles that slowly release drug

intramuscular= high vascularisation means rapid absorption, absorption depends on blood flow and muscle fat content, long duration can but drug PK profile hard to control

subcutaneous= drug injected to loose connective tissue, lower vascularisation than muscular tissue, drug slowly absorbed into blood or lymphatic capillaries, long duration of action more easily achieved with range of formulations

Question 4

strategies to get long duration of action

Answer 4

peptides/proteins- design of analogues/molecular engineering

formulation approaches- conventional formulations (oils, suspensions, emulsions), solid implants, in situ forming implants/depot formulations, liposomes, microspheres, nanoparticles

Question 5

what are solid implants

Answer 5

a device inserted into tissue via surgical procedure or injection using a trocar

Question 6

requirements of solid implants

Answer 6

-can be matric/membrane/osmotic systems
-delivers drug up to 1 year
-drug must be potent and stable at body temp
-no resorbable, must be removable or biodegradable
-can be removed if side effects appear

Question 7

what are biodegradable implants based on and what is required

Answer 7

based on polymers that break down slowly
must contain chemical groups that hydrolyse, must be water insoluble, degradation products must be water soluble and non toxic

Question 8

what are in situ forming implants or depot formulations

Answer 8

fluid formulation that forms a solid or semi solid depot in situ

-injected with standard syringe

Question 9

principles of depot formulations

Answer 9

-drug formulated as liquid with polymer and a solvent
-polymer solidifies in physiological conditions to form a viscous gel

Question 10

name the 3 mechanisms of depot formulations

Answer 10

precipitation, crosslinking, solidification

Question 11

describe the mechanisms of depot formulations

Answer 11

precipitation= water insoluble polymers formulated in a non aqueous solvent, polyelectrolytes unionised at neutral pH, non neutral formulations cause irritation during injections

crosslinking= polyelectrolytes cross linked by multivalent salts, covalent cross linking by addition of cross linker, photo responsive polymers crosslinked by uv light in presence of photo initiators

solidifying= injected as melt and solidifies at body temp, limited range of acceptable temperatures, thermoplastic pastes

Question 12

what causes irritation during depot formulation injection

Answer 12

non neutral formulations, cross linkers, photo initiators, non aqueous solvents

Question 13

what are thermoplastic pastes

Answer 13

low MW polymers with low melting points

Question 14

what are photo responsive polymers crosslinked by

Answer 14

UV light in presence of photo initiators

Question 15

limitations of depot formulations

Answer 15

-cant be removed after injection
-high burst release
-poor control of shape and size of implant
-toxicity of formulation
-incompatibility between formulation components
-sustained release in limited period (like a month)

Question 16

what is PLGA

Answer 16

poly lactic acid co glycolic acid
-addition of glycolic acid monomer to PL to produce a co polymer. faster degradation due to absence of methyl group, variable GA content to tailor degradation to clinical needs

Question 17

why does PLGA have faster degradation

Answer 17

absence of methyl group

Question 18

what is autocatalysis effect

Answer 18

hydrolysis of copolymer decreases at local pH, faster degradation

Question 19

factors that affect PLGA degradation rate

Answer 19

-MW of polymer chains
-crystallinity of polymer
-size/shape of matrix
-pH
-drug type and load
-presence or absence of enzymes

Question 20

describe the drug release of PLGA

Answer 20

1. initial drug release by diffusion, burst effect
2. slow release by diffusion and bulk erosion of polymer matrix
3. fast release after complete hydrolysis of polymer chains

Question 21

issues caused by implants/foreign body response to implants

Answer 21

insertion of implant causes injury to tissue, inflammation, healing occurs but disturbed by implant

Question 22

describe host response to long acting injectables

Answer 22

-serum protein adsorb at surface of particulates in blood
-recognition by phagocytes
-reduced circulation time

Question 23

stages of foreign body response

Answer 23

1. response of opsonin on implant surface
2. attraction of neutrophils then macrophages
3. frustrated phagocytosis, fusion of macrophages to form multinucleate FBGCs, release of degradation mediators, chronic inflammation, promotion of fibrogenesis of fibroblasts

Question 24

how can implant failure be reduced

Answer 24

anti inflammatory drugs, increasing hydrophilicity and smoothness of surface

Question 25

candidate drugs for long acting injections

Answer 25

pain killers, contraceptives, anti cancer drugs, antipsychotics, vaccines, drugs with poor oral bioavailability, peptides/proteins