drug delivery to lungs

Question 1

limitations of current drug inhalation

Answer 1

1. inhalers used in asthma/COPD are poorly efficient
   -low dose delivered to lungs, poor reproducibility of dose delivered, not suitable for expensive drugs/drugs with narrow therapeutic window
2. most drugs are rapidly absorbed from lungs
   -high dosing frequency needed, systemic side effects, low efficacy in lungs

Question 2

name two approaches to improve performance of delivery systems

Answer 2

-design of high tech inhalers
-design of particles with improved flow properties

Question 3

list some requirements of inhalers

Answer 3

-compact, portable, multi dose
-easy to use correctly
-lower mouth deposition, higher lung deposition
-emitted dose and dose delivered to lungs reproducible, independent of patients inhalation technique
-cost effective

Question 4

name 2 types of particle engineering that improve flow properties of particles

Answer 4

spray drying and large porous particles

Question 5

how does spray drying work

Answer 5

drug solution atomised by spinning disk or gas under pressure, solvent evaporated by heated gas in main chamber, dry particles collected by impaction on walls of a cyclone

Question 6

advantages and disadvantages of spray drying

Answer 6

advantages: one step process, scalable, particles in respirable size range, spherical and hollow particles, control on size/size distribution/density/morphology/moisture content and more, heat conditions favourable to proteins, amorphous particles increase protein stability

disadvantages: low recovery (bad if drug expensive due to waste), final moisture content can be high which increases cohesiveness, creation of an air interface during atomisation leading to protein denaturation and needs to incorporate stabilisers (sugars, amino acids(forms extra hydrogen bonds to prevent reaching interphase), phospholipids)

Question 7

what does the addition of stabilisers do during spray drying

Answer 7

forms extra hydrogen bonds to prevent an air interphase forming

Question 8

describe the large porous particles and how it gives a sustained release

Answer 8

particles <5um are cohesive

larger geometric size but decrease density= less cohesive and flow better so higher deposition in alveolar region (geometric diameter >5um with wrinkled surfaces to reduce cohesiveness)

larger so escapes phagocytosis by alveolar macrophages so sustained release (lasts longer)

Question 9

how are particles in conventional inhalers micro ionised and describe the particles produced

Answer 9

milling, irregular shapes w planar surfaces, no control on particle characteristics, peptides/proteins denatured by heat produced (why milling is bad)

Question 10

strategies to increase drug retention in lungs

Answer 10

-delivery poor soluble drug particles

-polymeric microspheres, accumulation of polymers, long term toxicity

-liposomes, safe, not stable, difficult to make dry, needs nebulisers which isnt good

-prodrugs

-nanoparticles

-liposomal trapping, accumulation of lipophilic basic drugs in lysosomes, toxicity issues

-targeting lung transporters

Question 11

problems with using liposomes for increasing drug retention in lungs

Answer 11

unstable, difficult to dry, needs nebulisers

Question 12

problems with using liposome trapping for increasing drug retention in lungs

Answer 12

toxicity issues, accumulation of lipophilic basic drugs in lysosomes

Question 13

why are polymeric microspheres not good for increasing drug retention in lungs

Answer 13

accumulation of polymers, long term toxicity

Question 14

advantages and disadvantages of using nanoparticles for pulmonary delivery and strategies to fix it

Answer 14

advantages- sustained release, retention in lungs, escapes clearance mechanism in lungs, slow release of encapsulated drug, avoids phagocytosis by alveolar macrophages and mucocilliary clearance if able to penetrate mucus, targets specific cells

disadvantages/delivery issues- nanoparticles too small to deposit in lungs and are exhaled

fix:
- administer as suspension using nebulisers but its inconvenient and forms aggregates
-administer as dry powder in micron range using carrier
-use of carrier, nanoparticles incorporated into porous lactose microparticles by spray drying, lactose dissolves in lung fluid to release the nanoparticles
-form trojan particles (large hollow microparticles with walls made of nanoparticles held together with lactose and surfactants), disassemble in lung fluid to release nanoparticles

Question 15

what are trojan particles

Answer 15

large hollow microparticles with walls made of nanoparticles held together with lactose and surfactants

Question 16

safety concerns of using nanoparticles for pulmonary delivery

Answer 16

large surface area=more reactive, can bypass clearance mechanisms in lungs, can accumulate in lung tissue, can be absorbed into systemic circulation if very small and then cause toxicity

Question 17

describe alveolar as a target site

Answer 17

-high surface area
-thin barrier to blood stream, short diffusion pathway
-high bloodflow, constant concentration gradient
-no mucus/mucocilliary clearance
-low enzymatic activity, neutral pH, avoidance of first pass hepatic metabolism

Question 18

why deliver to lungs

Answer 18

-achieves long duration of action
-delivery by inhalation to improve local therapies and delivery drugs to bloodstream by inhalation to overcome poor oral bioavailability for example

Question 19

name a describe 3 conventional inhalers and advantages/disadvantages of each

Answer 19

conventional inhalers:

1. nebulisers
   -aqueous drug solution aerolised into droplets, energy provided by compressed airadvantages- easy to use, aq environment means ok for peptides and proteins
   disadvantages- not portable, aq environment affects drug stability and pathogen formation
2. pMDI (pressurised metered dose inhaler
   -drug formulated in liquified gas under pressure, aerosol formed by gas evaporation at atmospheric pressureadvantages- portable, multidose, cheap
   disadvantages- not breath actuated, needs coordination of pressing and inhaling, propellants
3. DPI (dry powder inhaler)
   -drug and excipients in a dry powder state aerolised by patient’s inhalationadvantages- portable, multi dose, breath actuated, no coordination needed, dry state increases stability
   disadvantages- breath actuated so its patient dependent, affected by humidity