drug delivery to lungs Flashcards
limitations of current drug inhalation
- 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 - most drugs are rapidly absorbed from lungs
-high dosing frequency needed, systemic side effects, low efficacy in lungs
name two approaches to improve performance of delivery systems
-design of high tech inhalers
-design of particles with improved flow properties
list some requirements of inhalers
-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
name 2 types of particle engineering that improve flow properties of particles
spray drying and large porous particles
how does spray drying work
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
advantages and disadvantages of spray drying
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)
what does the addition of stabilisers do during spray drying
forms extra hydrogen bonds to prevent an air interphase forming
describe the large porous particles and how it gives a sustained release
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)
how are particles in conventional inhalers micro ionised and describe the particles produced
milling, irregular shapes w planar surfaces, no control on particle characteristics, peptides/proteins denatured by heat produced (why milling is bad)
strategies to increase drug retention in lungs
-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
problems with using liposomes for increasing drug retention in lungs
unstable, difficult to dry, needs nebulisers
problems with using liposome trapping for increasing drug retention in lungs
toxicity issues, accumulation of lipophilic basic drugs in lysosomes
why are polymeric microspheres not good for increasing drug retention in lungs
accumulation of polymers, long term toxicity
advantages and disadvantages of using nanoparticles for pulmonary delivery and strategies to fix it
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
what are trojan particles
large hollow microparticles with walls made of nanoparticles held together with lactose and surfactants
safety concerns of using nanoparticles for pulmonary delivery
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
describe alveolar as a target site
-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
why deliver to lungs
-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
name a describe 3 conventional inhalers and advantages/disadvantages of each
conventional inhalers:
- 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 - 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 - 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
