Exam 2 Flashcards
Suspensions
type of dispersed system containing finely divided solid particles in water
insoluble drug particles suspended in solvent
thermodynamically unstable
particle size greater than 500nm
Dispersed phase
internal phase of suspensions (particles)
Dispersion medium
external phase of the suspension (solvent)
Examples of pharmaceutical suspensions
orally-administered mixtures
externally applied lotions
injectable preparations
Why are suspensions useful?
Drugs with limited solubility in water (25-100 mg/mL)
taste-masking
improved chemical stability than solutions
longer-acting drugs; slower drug absorption from suspensions
Short (regular) insulin is a solution with a high efficacy after x hours?
2
Intermediate (NPH/long acting form) is a suspension with a high efficacy after x hours
4
Duration of NPR
less than 6 hours
Duration of NPH
up to 14 hours
Desirable characteristics of a suspension
adequate dispersion of particles in solvent
minimal aggregation/clumping of particles in suspension
prevent caking (formation of sedimentation that can’t be resuspended)
Formulation of a suspension has to be prepared such that it can be suspended upon?
moderate agitation/shaking
v= {d^2 x (pi-pe) x g} / 18n
stokes equation; relates sedimentation velocity to particle size and density, and solvent viscosity
As solvent viscosity increases, sedimentation velocity…
decreases
What are the 2 key approaches to improve suspension stability
use a viscosifier: MC/HPMC
use a flocculating agents: electrolytes such as aluminum chloride, polymers, surfactants
Flocs
loosely bound particle clusters
stabilized by weak H-H bonds and van der Waals forces
Flocculated suspensions structure and redispersion
structure: scaffold-like, weak bonds
redispersion: easy
Deflocculated suspensions structure and redispersion
structure: closely packed, cake
redispersion: difficult/impossible
Suspending agent
increases viscosity
wetting agent
disperse hydrophobic drug particles
decrease interfacial tension
Antioxidants
prevent oxidation
Buffers maintain
pH
Biologics
derived from biological organisms/biological material
have action specificity
require lower doses compared to traditional small molecule APIs
improved safety profile of protein drugs
How would you describe biologics approval over time?
steady rise
Major PO delivery factors of biologics
- high molecular mass means lower membrane permeability
- relative hydrophilicity/hydrophobicity balance
- ionic charge- function of proteins hydrophilicity and pH environment
5 challenges to delivery of polypeptide drugs
- lower permeability across biological membranes
- lower solubility of hydrophobic proteins
- smaller molecular mass/particle diameter means rapid kidney clearance
- immunogenicity of recombinant proteins
- susceptibility to proteolytic degradation
Advantages of Oral protein and peptide delivery systems
protect drug from enzymatic degradation and decrease systemic clearance
increased cargo solubility
controlled release and minimize undesirable side effects
improve biodistribution, decrease non specific uptake
low immunogenicity
3 characteristics of PEGylated proteins
- increase in size to reduce kidney filtration
- increase in solubility due to PEG hydrophilicity
- decreased accessibility for proteolytic enzymes and antibodies
Pegylated protein advantages
sustained absorption
increased half life
decreased systemic clearance
How does PEGylation affect dosing?
decreases dosing intervals
increases patient compliance
What are challenges for nucleic acid delivery?
hydrophilic molecules limit permeation into hydrophobic membrane
have a high molecular mass
Short interfering RNA (SiRNA)
interferes with the translation of mRNA into a protein
Vectors
carry nucleic acids to their sites of action
What are the extracellular steps in nucleic acid delivery?
circulation
accumulation
penetration
Intracellular steps in nucleic acid delivery
fusion
endocytosis
release
endo/lysome escape
nuclear localization
mRNA delivery
siRNA delivery
DNA delivery
What barriers can carriers overcome?
extracellular and intracellular barriers