Pharmaceutics Flashcards
Weak acids have a poor dissolution rate in acidic conditions. How can the dissolution rate be increased?
By increasing the pH of the diffusion layer by forming the alkaline salt of the weak acidic drug
By adding Na+/K+ salts as they dissolve more rapidly than weak acids, regardless of pH of medium
Which is the most common route of permeation for drugs?
Transcellularly as most drugs are lipophilic
Hydrophilic drugs permeate paracellularly through water channels
Is logP dependent on pH or independent of pH?
Independent
What does a logP of 1 indicate?
More soluble in organic phase
What does logP of -1 indicate?
More soluble in aqueous phase
Is logD pH dependent or independent?
Dependent
logP = logD at any pH for unionsed drugs. True or false?
True
How do amino acids stabilise proteins?
By preferential interaction or exclusion
They prevent protein-protein interactions as they bind to the unfolding protein instead
They increase the solubility and reduce viscosity therefore reducing aggregation
How do polymers stabilise proteins?
Cause competitive binding as they adsorb to surfaces instead of the proteins so there is less chance of unfolding and aggregation
How does the acylation of a protein increase its stability?
By adding a fatty acid, it increases its affinity to albumin, resulting in longer acting insulin etc.
Why are monomeric and dimeric forms of insulin better for diabetes treatment that hexameric?
Because they diffuse faster and hence improve transport due to being smaller
they are faster acting on SC administration, are absorbed faster at epithelial barriers and have faster response from infusion pumps
Why are short and rapid acting insulins less variable than other types?
Because of prandial administration, shorter duration of action with reduced extended insulin causing hypos
What factors in NPH insulin cause variability?
Formulated with protamine to create suspensions forming crystals. This means speed of dissociation and so absorption varies
Out of detemir and glargine, which is subject to more variability and why?
Glargine because isoelectric precipitates formed after injection require dissociation. This means greater care is needed with administration i.e. same time, same site, same needle technique.
Detemir is formulated with a fatty acid which stabilises the hexamer meaning slower dissociation and longer-acting. Fatty acid also allows binding to albumin, prolonging circulation levels
How are monoclonal antibodies produced?
Antigens stimulate an immune response, including B cell cloning and hence Ab production
Select the B cell clones that produce the desired Ab.
Fuse B cells with myeloma cells so they become hybridomas
Use robotics to optimise hybridoma growth and hence mAb production
How are fully human recombinant antibodies produced?
4 mouse IgG gene loci coding for 4 protein subunits on the antibody are replaced by human transgenes
the mouse is immunised to raise immune response
B cells selected, hybridomas produced, grown in bioreactor cell to produce human antibodies
After administration of mAbs, where do they distribute to?
Extracellular fluid as they have difficulty penetrating cells due to their large MW and hydrophilicity
What are the primary routes of elimination of mAbs?
Renal clearance and proteolytic catabolism following receptor-mediated endocytosis in the cells of the reticulo-endothelial system
Which receptor is responsible for antibody recycling?
FcRn (Brambell receptor)
Where is the FcRn receptor primarily expressed?
Vascular endothelial cells or RES
Lower levels found on monocyte cell surfaces and dendritic cells
What happens to FcRn receptor at high levels of IgG?
Becomes saturated so IgG starts to degrade i.e. high concentrations of IgG/antibody dose lead to lower half-life
What is the typical half-life of human IgG?
14-21 days
What are the 2 types of ADA?
Binding ADA which cause PK modifications and neutralising ADA which cause PD modifications
Name some ADA risk factors
Product related - homology to endogenous proteins, non-glycosylation
Underlying disease - chronic inflammation
Other meds - immunomodulators
Genetics - HLA
Dosage - higher freq dosing -> ADA formation
What limits the rate of absorption of a drug?
Dissolution - i.e. how quickly a drug is absorbed is dependent on how quickly it is dissolved
How does activity differ between the stomach and SI?
Contents of stomach static until gastric emptying however contents of SI are very active in both fed and fasted states.
How does rate of blood flow in the stomach and SI vary?
Food increase gastric secretions which leads to increased blood flow around stomach
Blood flow in intestines is always fast
Drugs that belong to which BCS classes are eligible for biowaiver?
Class 1
Class 2 - if WA demonstrates high solubility at pH 6.8
Class 3 - if rapidly dissolving
Not Class 4
In BCS, what is meant by highly soluble and highly permeable?
Highly soluble - largest dose soluble in <250ml of water in pH range 1-7.5
Highly permeable - >90% absorption of administered dose
Why is solubility a growing issue in drug development?
Because 40% of NCE are poorly soluble
More drugs made using tech such as throughput screening so aren’t as good in vivo
More reliance on formulation patents addressing solubility issues to extend product life
What are the in vivo consequences of low solubility?
Reduced bioavailability Increase chances of food effects Increased issues during disease states Increased interpatient variability More frequent incomplete release from dose form
What are the in vitro consequences of low solubility?
Limited choice of delivery tech e.g. MR
Poor correlation with in vivo absorption
Increased complexity of dissolution testing
How would you improve the solubility of a BCS class II drug to make it a class I drug?
Addition of surfactants, soluble salts, reduce the particle size, nanoparticles, cyclodextrins
How would you improve the permeability of a BCS class III drug to make it a class I drug?
Permeation enhancers, absorption enhancing excipients, efflux inhibitors, lipid-filled capsules
How would you improve both the solubility and permeability of a class IV drug to make it class I?
Prodrug, salt forms, co-solvents, lyophilisation, nanoparticles
What are the two ways particle size can be reduced in particle engineering?
Recrystallisation using liquid solvents and anti-solvents - this increases manufacturing complexity
Comminution and spray drying
- rely on mechanical stresses to disaggregate which could lead to drug degradation
What are the benefits of nano-particles?
Increased bioavailability
Reduced food variability i.e. fed:fasted smaller
Better dose proportionality i.e. dose proportional to AUC so plasma conc predictable
Name two drugs that nanoparticulation methods are used for
Ibuprofen and naproxen
What are the two methods of creating nanoparticles?
Comminution i.e. milling, piston gap method - both damaging to drug as physical stress
Supercritical fluids - control solubility using temp and pressure e.g. CO2
At what temp do supercritical fluids have properties of both liquids and gases?
Temperature above their thermodynamic critical points
What are the properties of SCFs at near-critical temperatures?
They are highly compressible allowing moderate changes in pressure and temperature to greatly alter their density, mass transport and solvating power
Manipulation of pressure of SCF allows favourable characteristics of gases to be imparted on liquids. What are these characteristics?
High diffusibility
Low surface tension
Low viscosity
How do SEDDS increase absorption and bioavailability of drugs?
Presence of lipids in duodenum leads to lipid secretions and formation of micelles
Triglycerides and surfactants react with walls of GIT to aid solubilisation and absorption of drug
Use of lipid based formulations leads to drug being absorbed into lymphatic system and into systemic circulation, avoid 1st pass metabolism
What is the most common route of permeation?
Transcellularly - lipophilic drugs
Hydrophilic drugs however permeate paracellularly
What is PEG used for and how does it influence particle size?
Incorporated as a co-solvent in liquid based formulations. It reduces particle size by preventing precipitation of poorly soluble particles
How is PEG used in solid dosage forms to reduce particle size?
Used as a wetting agent incorporated by solvent evaporation or freeze drying
Why is reducing particle size important in the solubilisation of poorly soluble drugs?
Because it increases SA, reduces the diffusion thickness and increases saturation solubility
What are the 5 ways in which particles can be deposited?
Inertial impaction Gravitational sedimentation Brownian diffusion Electrostatic interaction Interception
What is meant by inertial impaction?
Momentum leads to particle not being able to change direction with flow so hits side of airways
What is meant by gravitational sedimentation?
When air velocity is low e.g. when holding breath. Greater when long residence time in the region
Which particles are affected by Brownian diffusion?
Particles <0.1um in size
What is meant by electrostatic interaction?
Charged particle inflicts opposite charge on the wall and so accelerates particle to proximity
What is meant by interception?
When width of wall meets the diameter of the particle so particle is forced to deposit
Which regions does the upper respiratory tract entail?
Buccal, sublingual and nasal cavity
What is the difference in the solvents used in DPIs, pMDIs and nebulisers>
Non-polar solvent in pMDIs
Polar solvent in nebuliser
No solvent in DPIs
Why may ethanol be used in pMDIs>
It is used as a co-solvent to enhance the solubility of propellant
Why may oleic acid be used in pMDIs?
Oleic acid is a surfactant used to stabilise the suspension. It adsorbs to particles and acts as a steric barrier to agglomeration
Which exipient may be used for lubricative purposes in pMDIs?
Surfactants
Impaction and sedimentation and directly proportional to particle size. True or false?
True
Diffusion is inversely proportional to particle size. True or false?
True
How can aerodynamic diameter be decreased?
Decreased particle size
decreased density
Increased shape factor - elongation
Why does hygroscopicity adversely affect lung deposition?
Because water attaches to particles in lungs because lung is humid and so leads to aggregation and an increase in particle size leading to an increase in aerodynamic diameter - but you want small diameter so particles deposit further down in lungs
What methods are used to create particles for DPI?
Spray drying, SCFs, solvents and anti-solvents
Excipients are not usually used in DPIs, but when they are used which excipients are used and why?
Lactose and lipids to avoid agglomeration
How do needle-free injections inject the drug into the skin?
Spring-power or high pressure gas
How can the penetration of a transdermal drug be enhanced?
Modifying the formulation by either modifying the drug/delivery vehicle or modifying the stratum corneum
Use of powered devices
Do lipophilic transdermal drugs pass intercellularly or transcellularly?
Intercellularly
Why is a logP between 1-3 preferred in transdermal drugs?
So drug can pass through both lipid and aqueous region as there is aqueous region between the lipids
What are the most ideal drug characteristics for a patch?
Melting point <200 degrees C Molecular weight <1000Da, preferably <500Da Daily dose 5-20mg LogP 1-3 Max patch size 50cm2 t1/2 6-8hrs
How is a supersaturated solution formed for transdermal patches and what is the benefit?
Skin permeation is enhanced by having supersaturated solution. Produced by evaporating solvent from warm skin surface or mixing co-solvents
What is the role of an anti-nucleating agent in transdermal patches?
Stabilises supersaturated solutions as they are unstable
What is meant by the enhancement ratio?
Penetration enhancer activity
ER = drug permeability after enhancement treatment divided by before enhancement treatment
How does hydration of the skin by modifying SC enhance drug permeability?
Hydration opens the SC structure allowing more penetration of drug
Occlusion via patches keeps water in skin
Oil-in-water emulsion donates water to skin
What are the 4 types of liposomes?
Deformable
Ethosomes
Niosomes
Solid lipid particles
What are the ways in which the stratum corneum can be modified to increase penetration of a drug?
Hydration Liposomes Bypass/remove lipid layers Powered electrical device Increase partitioning and solubility Penetration enhancers
How can the partitioning of and solubility of SC be modified?
Shift the solubility parameter of the skin to make it similar to that of the drug
Solubility parameter of the skin lipids is usually 10
When partitioning parameter of the drug is greater than skin - irritation occurs
How does keratin and lipid disruption in SC increase permeation?
Fluidising lipids with alcohol will enhance solubility
Extracting lipids to form aq channels so drug gets in easily
How do you modify the the drug/vehicle to enhance penetration through the skin?
Selection of a drug with suitable characteristics Use of a prodrug Ion complex Eutectic mixture Chemical potential
How does a eutectic mixture improve the penetration of a drug through the skin
The mixture of two solvents will reduce the melting point as when they are combined at the same ratio, they will inhibit the crystalline process of each other
How does altering the chemical potential of a drug enhance penetration through the skin?
Skin penetration is enhanced by supersaturated solution - achieved by evaporation of solvent from the skin.
Supersaturation makes system unstable so need to add anti-nucleating agent
What are the two types of microneedle patches?
Dissolving polymer
Drug coated spears
How do microneedle patches work?
They create micron size pathways in the skin to enhance permeability of skin
They drive drug into skin when patch placed
Target SC
Outline the protein aggregation process
Starts as a tertiary (native) structure which unfolds -> intermediate -> denatures to a primary aggregate -> releases energy to become more stable -> fibril which is insoluble
What factors induce protein instability
pH high temps and pressures adsorption onto solid surfaces freezing and thawing shear forces air/water interfaces
How can proteins be stabilised?
Amino acids Polymers Surfactants Anti-oxidants Salts Polyols
What are the 3 methods that can be used to stabilise proteins?
PEGylation
Acylation
Surface engineering
How can surface engineering stabilise a protein?
Removal of sites on the protein surface that are likely to cause aggregation
How does preferential exclusion increase protein stability?
Sucrose has no hydrophobic groups so doesn’t interact with the protein and is preferentially excluded. The protein unfolds and is forced back to refold by sucrose. The degree of exclusion is directly proportional to the protein SA exposed to the solvent. The system minimises the thermodynamically unfavourable effect of preferential exclusion by favouring state with lowest SA
Sucrose increases chemical potential for protein to degrade so protein remains in the favoured (native) state as a result
