Routes of Administration Flashcards
What is dissolution?
Disintegration of the dosage form making it soluble so it can be absorbed
What causes poor absorption?
Precipitation as drug moves through GIT
Diffusion layer around drug
How does absorption by diffusion work?
Drug saturates diffusion layer and moves into bulk fluid, particles in diffusion layer are then replaced due to concentration gradient
Particles constantly moved away from site by blood flow - sink conditions
What is the significance of different pH diffusion layers?
Overprediction of ionisation and dissolution for WAs and WBs
How do salts improve dissolution of WAs in the stomach?
Low solubility in diffusion layer in stomach
Alkaline salt increases diffusion layer pH, making the drug more soluble in the diffusion layer
Salt increases speed of dissolution
What are the three methods of permeation?
Paracellular - Small, hydrophilic drugs pass through water channels between cells
Transcellular - Lipophilic compounds partition into and through lipid bilayer
Membrane transporters can transport some molecules into cells across the membrane
Why is logD preferred to logP?
LogP does not consider pH
pH has an effect on ionisation, and therefore solubility and absorption
What is the equation for logD?
WB: logP - log(1+10^(pKa-pH))
WA: logP - log (1+10^(pH-pKa))
What is the pKa of a molecule?
The pH at which the molecule is 50% ionised
What are the limitations of logD?
Ionised drug may also be absorbed
pH at membrane surface may be different
Ionisation and absorption may be altered by secretions
Disruption to the lipid membrane
What affects the rate of carrier-mediated transport?
Concentration - saturation of carriers limits rate
Affinity of molecule to carrier
Define the absorption rate of carrier-mediated transport
VmaxC/(Km+C)
Where Vmax is the max. rate of transport, C is the concentration of free drug and Km is the affinity constant
Describe the ionisation, solubility and absorption of WB drugs through the GIT
Protonated in stomach increasing solubility but decreasing permeability
Permeability increases in the intestine but unionisation may decrease solubility
How are the issues surrounding absorption of WB drugs managed?
Increase transit time by taking with food, more time to solubilise and then absorbed once gets to intestine
Food also stimulates stomach secretions, increasing blood flow and rate of absorption (sink conditions)
Describe the ionisation, solubility and absorption of WA drugs through the GIT
Unionised in stomach, poorly soluble
Ionised in intestine but less permeable due to charge
Ionisation equilibrium replaces unionised drug as it is moved across the intestinal membrane - eventually all drug moves across
How can toxic effects be reduced for soluble, lipophilic drugs?
Take with food so peak concentration is delayed
What are the general pKa values for acidic and basic drugs?
VWA: >8 WA: 2.5-7.5 SA: <2 VWB: <7 WB: 7-10 SB: >11
Which types of drugs are unionised through the majority of pH values?
Very weak acids and bases
Which types of drugs are ionised at the majority of pH values?
Strong acids and bases
What are the BCS classifications for drugs?
Class 1: Highly soluble and permeable
Class 2: Poorly soluble but highly permeable
Class 3: Highly soluble but poorly permeable
Class 4: Poorly soluble and permeable
What is a biowaiver and which drugs are eligible for one?
Bioavailability testing doesn’t have to be done in vivo, can be done through dissolution testing
Class 1
Class 2 WAs which are highly soluble at pH6.8
Class 3 if very fast dissolution rate
When is a drug considered highly soluble?
Largest dose is soluble over a large pH range in a volume less than 250ml
When is a drug considered highly permeable?
> 90% of the drug is absorbed
What are the lower thresholds for solubility?
<0.1mg or 10mg /ml
What are the issues with a poorly soluble drug?
Decreased bioavailability Increased variability with food Issues in diseased state Incomplete drug release from formulation Interpatient variability Limited delivery technologies More dissolution testing required Dissolution not correlated to in vivo absorption Can halt development of new compounds
What factors affect dissolution and absorption?
Wettability Particle size Solid dispersions Polymorphs pH solubility Prodrug solubility Complexation Adsorbents Viscosity enhancing agents Degradation Diluents Surfactants
How do cyclodextrins improve solubility?
Cylindrical cage formed around poorly soluble drug, presenting hydrophilic group to outside and increasing solubility
Either formulated as a solution or as solid
What are amorphous solid dispersions and how are they made?
Drug formulated with polymers
Hot melt extrusions - Add API to softened polymer and mix whilst flowing through extruder. Polymeric glass strands formed by rapidly cooling, mill pellets into powder
How does PEG improve solubility?
How are they formulated?
Co solvent in liquid formulations
Dispersion-enhancing/wetting agent in solid formulations
Works with surfactants
Solvent evaporation or freeze drying
How does gelatin improve solubility?
Granulating aid, increases wettability through polar interactions
What is particle engineering?
What processes?
Decrease particle size
Increase particle surface area
Decrease diffusion thickness
Increase saturation solubility
Recrystallisation, milling, micro-milling
What are the in vivo benefits of particle engineering?
Increase bioavailability, less food effect, dose proportionality
How are particles engineered when milling/grinding don’t produce small enough sizes?
Supercritical fluids - gas (e.g. CO2) at temperature/pressure where both liquid and gaseous properties are adopted
Pressure and temperature manipulated to control solubility
Temperature/pressure changes alter density, mass transport and solvating power
What are self-emulsifying systems?
Generally gelatine capsules with liquid inside
Non ionic surfactants used to increase drug solubilisation
What is the purpose of drying suspensions?
Increase shelf life
How do self-emulsifying systems increase bioavailability?
Drug dissolved in lipid
Lipid presence in duodenum stimulates secretion of biliary lipids, forms micelles
Absorbed through lymphatic system, prevents 1st pass metabolism
Why are parenteral routes used?
Avoid GI issues
Delivery is device controlled
Nanomedicines, biologics, large molecules can be administered
What are the benefits of parenteral routes?
Better control of peak concentration Biologic effect may not work orally Can be used if patient cannot take orally Rapid action Can be used for local effect
What is referred to as percutaneous administration?
Intramuscular, intravenous, subcutaneous, intradermal (dermis layer)
Where are the common IV injection sites?
Veins in arms, feet, hands, legs
Describe the characteristics of IV injections
Solution, suspension, emulsion or reconstituted solid
Aq. buffer at neutral pH
Solubilised
No particles
Isotonic injection or hypertonic infusion
Describe the characteristics of IM injections
Less rapid than IV but more rapid than SC
Prolonged release, solubility depends on fluid composition in area
Higher absorption in more vascularised muscles
Degradation may occur at site of injection
Dose proportionate to size of muscle
Describe the characteristics of SC injections
Solutions or suspensions
Rapid and predictable profile
Can be used for self medication due to low infection risk
Generally used for poorly absorbed, fragile drugs
Where are the common SC injection sites?
Abdomen, upper back, arm, hips
What is intraperitoneal administration and what are the benefits and limitations?
Injected into a cavity or organ
Benefits: Smaller, lipid soluble drugs are absorbed faster
Limitations: Goes into portal circulation (1st pass), have to be careful to avoid bowel puncture
Give 3 uses for intraperitoneal administration
Chemotherapy, dialysis, diagnostics
When would intraspinal administration be used?
Ineffective movement from bloodstream to CNS/through BBB
What is intraventricular administration?
Administered into lateral ventricles of the brain
What are the other routes of injection?
Intra-articular (joints)
Intra-cardiac
Intra-synovial (joint fluids)
Intra-arterial
How does pain and needle free injection work?
What is the benefit?
Spring-powered/high pressure gas forces drug powder through skin
Drug penetrates to SC, ID or IM level
Less pain and damage than using a needle
How do microneedle patches work?
Very short, fine needles pierce stratum corneum, drug is driven into the skin during needle insertion
Needles may also pierce epidermis/superficial dermis
What are the unconventional microneedle patches?
Drug coated needles
Drug encapsulating needles (needle dissolves)
What are the limitations of creams, gels and patches?
Difficulty passing stratum corneum
Only potent drugs can be used due to small formulation
How is penetration of topical administrations improved?
Improve drug delivery vehicle
Modify the stratum corneum
Powered penetration devices
What are the three routes of transdermal administration?
Through the sweat ducts
Through the hair follicles
Through the stratum corneum (main)
How do iontophoric drug delivery systems penetrate and why?
Through shunts (hair follicle, sweat ducts)
Less electronically resistance
Describe the structure of the stratum corneum
Lipid matrix produced by keratinocytes surrounds corneocytes (dead cells)
Intercellular lipid lamellae
Expands when hydrated from 10-15mcm to 40mcm
How is the stratum corneum kept supple?
Water is used to produce natural moisturising factor, prevents cracking
What is the main issue for drugs when crossing the stratum corneum?
Number of partitions through lipid lamellae and aq. regions between
Describe transcellular penetration of the stratum corneum
Passes through aq. region inside cells (contains keratin filaments)
Has to pass through lipid intercellular region
What properties are ideal for drugs administered through the transdermal route?
LogP 1-3 - balance of hydrophilic and lipophilic properties MW ~500 Da MP <200°C Few polar centres Short half life, <6-8hrs Max. SA 50cm2 5-20mg max dosage