other types of delivery- peptides/proteins Flashcards
what is the problem with delivering protein
large hydrophilic molecules, extravascular access is hard, poor stability, hard to absorb, complex pharmacological action
size and shape of macromolecules and proteins
macromolecules have limited size, molecular weight and size relationship depends on shape, proteins usually globular and tightly packed
the amount of macromolecules reaching tissues are affected by
rate of elimination by kidneys and metabolism
how are macromolecules eliminated
kidney filtration
small proteins are eliminated from kidney by glomerular filtration, larger molecules are not
how are small proteins eliminated from the kidney
glomerular filtration
what are macromolecules
molecule containing lots of atoms eg. protein
why are proteins needed as drugs/medicine
to meet unmet conditions idk
properties of protein and peptide drugs
large hydrophilic molecule (0.5-100kDa), not well transported across biological membrane, <2% bioavailability, instabilities
describe the physical instability of protein/peptide drugs
proteins can easily lose their 3d structure (secondary, tertiary, quaternary denaturation)
what causes physical instability of protein/peptide drugs
hydrophobic conditions, surfactants, pH, solvent, temperature, dehydration, lyophilisation
results of physical instability in protein/peptide drugs
adsorption- at interfaces
aggregation/precipitation- denatured unfolded proteins interact
main processes of chemical instability in protein/peptide drugs
deamidation- asparagine and glutamine residues hydrolysed to form a carboxylic acid
oxidation- methionine, cysteine, oxygen in air, oxygen radical, catalysed by transition metal, peroxide formation
photo-oxidation
comment on the biological stability of protein/peptide drugs
hydrolysed into amino acids and small peptides by GI tract, very few are stable to biodegradation
gastric acid causes denaturation
small intestine
colon- less digestive enzymes, substantial microbial enzymes
roles of additives in preformulation of protein/peptide drugs
salts- decrease denaturation by binding to protein
polyalcohol- stabilise by selective solvation
surfactants- prevent adsorption of proteins at surfaces and aggregation
chemical modifications of proteins
synthetic polymers or lipids covalently bound to proteins
primary sequence alterations of proteins
specific amino acid can be changed, improves physical and chemical stability
why chemically modify proteins
control pharmacokinetics and pharmacodynamics through the formulation
describe the routes of administration of protein/peptide drugs
parenteral- only practical method for most, intravenous/subcutaneous/intramuscular
non parenteral- highly desirable, oral is best, low absorption
advantages and disadvantages of parenteral delivery in protein/peptide drugs
advantages- controlled drug release, improves therapeutic index, protects from unwanted drug disposition, extravascular access
disadvantages- particulate system but particles cant cross vascular endothelium, soluble carrier systems have transport/stability problems
types of implantables
polymer gel matrix, polymer fibre system, osmotic mini pump, tablet type implants, automatic feedback system
how do implantables work
delivered through intramuscular or subcutaneous route
chronobiological effects of protein/peptide drugs
zero order controlled released may not be optimal, pulsatile or complex delivery kinetics is beneficial sometimes, optimal pattern for delivery unknown, non zero order delivery difficult to produce
oral delivery of proteins
avoids acidic pH and proteolysis
problems with using protein/peptide drugs
physiological barriers and stability is big issue
what is topical delivery
delivery of drugs on surface of skin, local action, skin diseases
what is transdermal delivery
delivery of drugs across/through skin, maximises systemic absorption, drug target in body
describe skin structure and function
subcutaneous tissue- adipose tissue, fat insulates and prevents mechanical shock, rich blood supply, nerves
dermis- collagen/elastin in mucopolysaccharide gel, nerve endings, sweat and sebaceous glands, low drug conc drugs due to rich blood supply, conc gradient drives drug penetration, drug taken away quickly, lots of water, high aqueous environment
epidermis- keratinocytes differentiates to form corneocytes, Langerhans cells, melanocytes
what do melanocytes do
produce melanin
different routes drugs get transported into skin
intracellular route- stratum corneum
intercellular route- main route
shunt route- minor route
drug properties that affect permeation
drug conc in vehicle
partition coefficient- must be soluble in both oil and water to pass through layers
lipophilic drugs more likely to pass through than hydrophilic- if too lipophilic slow permeation
molecular weight- small penetrate faster
drug structure- hydrogen bonding to skin constituents, pKa causes drug to diffuse into unionised form, unionised is better
ideal drug properties for a transdermal drug
Log P between 1-4
max molecular weight <500 (low dose is ok)
daily dose 10-20mg, flux 1mg/cm^2 per day, patch size 20cm^2
unionised at pH of skin
why is it better for transdermal drugs to be unionised at pH of skin
ionised/charged+ more polar so the intercellular route is less of an option
adhesive patches for transdermal delivery
designed for constant controlled release over an extended period of time, avoids first pass metabolism, liner adhesive and backing layer, low delivery efficiency
biological factors of transdermal delivery
specify where to apply patch, skin age affects permeability, skin conditions (injury, solvents, disease, hydration), site of application (variation of stratum corneum thickness), skin metabolism, penetration enhancers
common targets of topical delivery
surface microorganisms, nail, hair, stratum corneum, viable epidermis and dermis
functions of a good topical formulation
cleansing, lubricant, emollient action
formulations of topical delivery
complex multicomponent base needed- aqueous bas, thickening/emulsifying agents
vehicle cosolvents enhance permeability and partition into skin
buffer/antioxidant/preservatives
formulation designs of topical delivery
thin film, open to atmosphere changes in use, short acting, variable delivery rate, low delivery efficiency
factors that affect topical delivery
application of film, diffusion of drug through vehicle, partitioning of drug from vehicle into skin, partitioning of drug from stratum corneum into viable epidermis, diffusion of drug across skin membrane
what is the main barrier of permeation of drugs on skin
stratum corneum
use of topical delivery
skin disease
use of transdermal delivery
systemic delivery
formulation types of transdermal/topical
transdermal patches, creams, ointments, gels
what does gingival mean
on gums
what does sublingual mean
under tongue
what does buccal mean
mucosa of mouth, often inside cheek or behind lips
issues with buccal and sublingual
wet layer with mucin on surface. structure of mucosa shows epithelial tissue like skin, some keratinised epithelium but thickness and keratinisation varies
common targets of buccal and sublingual conditions
mouth ulcers, sore throat, gum disease, breath freshening, infections, dry mouth, angina, analgesia
benefits of buccal and sublingual delivery
easy/convenient to administer, easy removal if theres side effects, direct route to systemic circulation avoids first pass metabolism in liver and enzymatic degradation in GI tract, fast action
how is drug absorbed by in buccal and sublingual delivery
passive diffusion
relative permeability for buccal and sublingual delivery
sublingual>buccal>external skin
sublingual mucosa structure
thin membrane, large veins, rapid absorption and good bioavailability
what type of drugs has the best absorption and bioavailability and why
lipid soluble drugs with small dose, avoids large 1st pass effect, better predictability of dose
formulation designs of buccal and sublingual delivery
palatable- taste masking, flavouring for patient compliance
buccal dose form- formulated to stick ot mucosa otherwise it might be swallowed, viscous polymer, bioadhesive polymer, design to erode slowly
sublingual tablet- designed to dissolve rapidly for fast and rapid absorption/effect
types of buccal and sublingual delivery designs
lozenges- sugar/sorbitol glass/compressed tablets, suck to release active agent (like strepsils)
gels-polymers
mouthwash- solution/suspension to rise in mouth
polymer patches- adhesive hydrogel disc
