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
How does water act as an anti-solvent?
Water from skin mixes with vehicle, increasing permeation of the molecule
What are eutectic systems?
Two components mixed in a specific ratio inhibiting crystalline process of each other
Combined melting point less than that of individual components
May contain penetration enhancer
What is hydration of the stratum corneum?
Safest and best modification
Expansion causes large cavities, allowing drug to pass through
Done using oil in water emulsions, moisturiser, patches
How do liposome/lipid particles alter the stratum corneum?
Alters properties of lipid layers
Deformable liposomes can alter their shape, enabling them to fit through small channels
What are ethosomes and niosomes?
Ethosomes fluidise the lipids
Niosomes are made of non ionic surfactants
What are solid lipid nanoparticles?
Carriers enhancing skin delivery of drugs
How do keratin and lipid fluidises work?
Form a homogenous mix with lipids, altering solubility properties
Extracts lipids to form pores or in high concentrations they pool to create permeable pores
Why do penetration enhancers cause skin irritation?
Pores in skin allow microbes to enter, causing irritation
What is the purpose of dispersing a solvent through the skin?
Match the solubility parameters of the skin to that of the drug
What is iontophoresis?
Low voltage current is used to drive the drug into the skin
Electroosmotic flow of water can help to move drug
Rate is current dependent
What is electroporation?
Short, high-voltage pulses temporarily disrupt lipid layers
Voltage restricted to stratum corneum by closely spaced microelectrodes
What is phonophoresis?
Ultrasound is used to make small lipophilic structures more permeable
Oscillating pressure causes cavitation
Can also use pulsed lasers
What are the local benefits of pulmonary administration?
Rapid action Avoids 1st pass Lower dosage - less ADRs Accurate dose adjustment (ideal PRN medicine) Small volumes Tamperproof container Drug protected from air and moisture
What are the systemic benefits of pulmonary administration?
Avoids variable pharmacokinetics
Can be used to treat acute or breakthrough pain
Avoids chemical/physical interactions
Can be used if formulation degraded in GIT
Briefly describe the physiology of the nasal cavity
Intake of warm, moist air
Cilia filter out particles >15mcm
Coughs/sneezes remove larger particles
Epiglottis protects airways from particles
What is the blow reflex reaction?
Isolates nasal cavity from rest of airway
What affects deposition of dry powder particles?
Diameter, density, shape, charge, chemical characteristics
What affects deposition of aerosol particles?
Velocity, propellant type, particle size, size distribution
What respiratory tract features affect deposition of particles?
Structure, geometry, breathing pattern, disease
How are particle size, density and deposition linked?
Minimum particle size for deposition decrease as density increases
What are the three methods of deposition?
Impaction
Sedimentation
Diffusion
How does particle size affect the type of deposition?
<0.5mcm more likely to be by diffusion
As size increases more likely to be impaction of sedimentation
Larger particles less likely to reach lower RT
What is inertial impaction?
Increased momentum prevents movement of particles with airflow, deposits when RT branches
What is gravitational sedimentation?
Low air velocity causes particles to deposit under gravity (e.g. when holding breath)
How do electrostatic interactions affect inhaled molecules?
Charge on particle induces charge on wall of RT, causes acceleration of particle
What is the ideal size range for aerosol particles and why?
2-8 micrometres for effective deposition
What are the different types of inhalation devices?
Sprays Pressurised MDIs Super-fine Particle Inhalers Nebulisers Dry Powder Inhalers (powder fluidises with inhalation)
How do bidirectional flow nasal sprays work?
Utilise blow reflex action
Air blown out through one nostril enters through the other, ensuring penetration of the nasal mucosa
Lung deposition prevented by closure of the soft palette
What is the benefit of electronic atomisers in nasal sprays?
Particle size and direction of flow controlled, penetration can also be controlled
How do MDIs work?
Fast moving solution or suspension taken in with slow, deep inhalation
Valve can be manual or breath actuated
Which excipients can be used in pulmonary formulations?
Cosolvents Surfactants Lubricant for valve Flavourings Anti-oxidants Moisture absorbers Preservatives
Why are super-fine particle inhalers used?
Small airways disease (diseases that cause narrowing of the airways)
Prevents deposition in upper airways
How do super fine particle inhalers work?
Mixture of ultra- and extra-fine particles more likely to be deposited by diffusion
Less exhaled or swallowed so required smaller dose required
Smaller particles at lower velocities
When are nebulisers used?
Severe conditions where traditional inhalers can’t be used
How do nebulisers work?
Compressed air forced through Venturi orifice, negative pressure sucks liquid up from capillary, liquid fragments into particles >40mcm, large molecules removed by impact deposition at a bend
Liquid on top of piezoelectric crystal, alternating voltage cause crystal to vibrate, agitation forms conical fountain above liquid, disperses to form aerosol. Larger molecules removed by impact deposition
What is the purpose of fine mesh in nebulisers?
Backwards and forwards movement, back picks up drug and forward propels it
What are the benefits and limitations of nebulisers?
Large dose can be given
Inefficient
How are dry powder inhalers activated?
Quick, powerful, deep breath
How do active DPIs work?
Standardise sheer and turbulence for controlled release in narrow therapeutic windows
What is the ideal particle size for DPIs?
1-5 micrometres
What is the advantage of powders over aerosols?
Shape of particle can be modified
What proportion of the new drug market is biologics?
~35%
What are the benefits of biologics productions?
Inclusion of large molecules in pharmaceuticals More parenteral RoAs developed Versatility Specificity reduces toxicity Can replace diseased tissue
What are biosimilars?
Biologics produced as generic medicines once they come off patent
Process varies to get same end product
What is biologic bioequivalence?
Demonstrates a same level of risk at same dose rather than same bioavailability
Why is animal data not as accurate for biologics?
Human proteins are not as effective in animals
What causes aggregation of a protein?
Unfolding into a higher energy state, may go back to native state or aggregate with other unfolded molecules
Charges at isoelectric point may cause aggregation
pH changes with COOH/NHS groups may cause unfolding and therefore aggregation
What physical factor could cause unfolding of a protein? How is this avoided?
Adsorption to physical surfaces may alter the structure of the protein
Consider materials used (e.g. packing) in relation to molecule structure
What are the particulate matter limits for light obscuration of large volumes?
25 particles/ml of >10mcm OR 3 particles/ml of >25mcm
What are the particulate matter limits for light obscuration of small volumes?
6000 particles/container of >10mcm OR 600 particles/container of >25mcm
What are the particulate matter limits for microscope examination of large volumes?
12 particles/ml of >10mcm OR 2 particles/ml of >25mcm
What are the particulate matter limits for microscope examination of small volumes?
3000 particles/container of >10mcm OR 300 particles/container of >25mcm
What part of a protein is susceptible to chemical degradation?
Side chains
What factors cause conformational changes in proteins?
pH extremes Shear forces Air/water interfaces Adsorption to surfaces Freezing, drying, rehydrating Elevated temperatures and pressures
How do amino acids stabilise proteins?
Decrease interaction between separate molecules
Increase solubility
Reduce viscosity
Preferential hydration and exclusion
How do polymers stabilise proteins?
Competitive adsorption
Steric exclusion
Preferential hydration and exclusion
How do polyols stabilise proteins?
Preferential exclusion
Accumulation in hydrophobic regions
How do salts stabilise proteins?
Preferential binding
Interact with protein-bound water
How do surfactants stabilise proteins?
Competitive adsorption at interface
Reduce denaturation at air/water interface
Interfere with ice/water interface at freezing
How do antioxidants stabilise proteins?
Oxidised in place of protein
What modifications stabilise proteins and how?
Acylation (F. Acids) - Inc. binding affinity to serum albumin
PEGylation - Slower plasma clearance (prevents immune recognition and renders less active)
Surface engineering - Remove sites causing aggregation (alter gene sequence)
What is preferential interaction?
Denaturants interact with polypeptide backbone, strength of interaction increases with unfolding
What is preferential exclusion?
Protectants do not interact with protein
Force protein back to native state when unfolding
Interact with water in environment instead
How does sucrose act as a preferential excluder?
Surrounds the protein and draws water away from it, causing it to shrink (fold)
How do low temperatures and freezing affect protein structures?
Low temps - Extend shelf life of products, may cause reversible denaturation. Alter solvent properties and interactions
Freezing - pH/conc. changes from constant freezing and thawing can cause aggregation, may aggregate at ice/water interface
What molecules can be used for cryoprotection?
Sugar, polyhydric alcohols, oligosaccharides, amino acid
How to cryoprotectors work?
Preferential exclusion
Denaturation temperature is lowered and osmotic stresses are stabilised
Surfactants prevent interactions at interface
Describe the freezing process
Ice nuclei formed, pull water in to create pure ice
Molecules concentrate unfrozen region causing a freezing point depression (temp has to be further lowered too freeze)
Concentrated matrix
What is the difference between slow cooling and rapid cooling?
Slow cooling produces bigger crystals than rapid cooling
Why should medicinal products be mixed when thawing?
Concentration gradient formed from freezing may be maintained
What is lyophilisation?
Freeze-drying
What are the benefits of freeze-drying?
Greater long-term stability than solutions
Reversible conformational states
What are the limitations of freeze drying?
Aggregation may occur when reconstituted
Products still have to be sealed due to hygroscopicity
Products still have to be refrigerated to prevent denaturation
How is water removed during freeze drying?
Sublimination
Describe the structure of insulin
6 insulin monomers aggregated
Aggregation creates secondary and tertiary structure
Zn ions connected to histidine side chains of polypeptides
Alteration of structure and formulation can alter duration of action
How are fast-acting insulins made?
Alter amino acid sequence to disrupt assembly, remains as monomer/dimer to allow easier passage through membrane
How are intermediate/long acting insulins made?
Protamine (cationic peptide) causes protein aggregation, converting fast-acting to intermediate acting insulin
Normal insulin has an isoelectric point of pH 5-6, arginine groups shift isoelectric point to pH7, in solution at pH 4 so when administered at pH 7.4 insulin precipitates. Exopeptidases remove arginine groups, slowly breaking down aggregate for use (Insulin glargine)
Modification of lysine fatty acid side chain forms more stable hexameter and increases albumin binding. Recirculation due to recycling receptors (insulin detemir)
What is one disadvantage of the insulin detemir modification?
Modification of fatty acid side chain reduces insulin activity so a larger dose is needed
Why do shorter-acting insulins have less variability?
Administered prandially
Shorter duration of action
Reduced risk of hypo
Why is there variability in intermediate acting insulins?
Crystals are formed, dissociation and absorption varies even in same patient
What factor reduces variability in long-acting insulins?
Complete solubility
Why is detemir even less variable than glargine?
Dissolution/precipitation issues avoided when bound to albumin
Absorption only minority affected by rate of blood flow
What is the limitation due to the variability of biphasic insulin?
Can only be used if patient has very predictable lifestyle
How are monoclonal antibodies produced?
B-cells extracted after injecting mouse with antigen
B-cells fused with myeloma cells (due to poor growth), hybridoma formed
Grown in bioreactor, produces protein
Robot used to optimise process
What are the issues surrounding use of mouse antibodies?
Immunogenic reaction and rapid clearance
Lack of Fc effector regions result in shorter circulation time and reduced immune interaction
Can cause anaphylactic shock
How have mouse antibodies been humanised?
Genes coding for 4 areas of antibody have been replaced with human genes in mouse cells
Describe the absorption and distribution of mAbs
Absorbed and distributed in extracellular fluid, only taken up by transporters/endocytosis
Describe the degradation and elimination of mAbs
Renally cleared
Proteolytic catabolism by receptor-mediated endocytosis in cells of reticulo-endothelial system
Half life 14-21 days
High peak conc. so trough level has to measured before next dose
How are mAbs recirculated?
Fc region binds to Brambell receptor on vascular-/reticulo-endothelial cells
If bound, taken up and excytosed
pH 6 allows binding
What happens when there are high concentrations of mAbs?
Receptor is saturated so mAb broken down in lysosome
What are anti drug antibodies?
Attack and eliminate therapeutic antibodies
Give one use of antibody fragments
Fragments of variable region are used in imaging, no interaction with immune system due to no Fc region
Give one purpose of engineering Fc regions on antibodies
Maintain immune/circulatory interaction
