Delivery of Biologics Flashcards
What drives the transfer of small molecules?
Concentration gradient between the two sides of a cell
-f.e. from muscle cell to the blood vessel and vice versa
Why do large Biologicals not pass the membrane by passive diffusion or channel transfer?
-because their log P/D is too low
-glycosylated proteins are polar and have high water solubility and low lipophilicity
-large size is a barrier channel transfer
Why do Biologicals have a low log P/D (low lipophilicity) even though they have hydrophobic regions?
Because their hydrophobic regions are hidden in the core of the protein
How do molecules (proteins) <20 kD enter the venous circulation?
Squeeze through gaps in the endothelium
-f.e. vascular absorption of Insulin (MW, ~ 6 kD)
How do molecules (proteins) bigger than 20 kD enter the venous circulation?
they enter the lymphatic circulation
from the interstitial fluid into the lymphatic system -> into the vein
-f.e. Monoclonal Antibodies
Where do drugs enter the lymphatic capillaries?
Through cleft (gaps) between lymphatic endothelial cells (they open when the amount of fluid outside is high)
Once the drug enters the lymphatic capillary, where does it go?
Lymph nodes
-from there to systemic circulation and the targeted tissue
How fast is the lymphatic transport compared to the direct vascular route?
The lymphatic route is slowly absorbed (takes hours)and it is slower than the direct vascular route
What is a factor that determines how much a drug is absorbed by the lymphatic pathway?
-Molecular weight
-the bigger the molecule, the more it gets absorbed by the lymphatic pathway
What is the advantage of giving a drug by IV and what causes that?
Disadvantage?
-Quick onset
-drug enters the systemic circulation fast because there is no barrier
-Disadvantage: Elimination is faster than SC or IM administration -> lower AUC
What causes a prolonged half-life for a drug
-SC or IM-administered drugs
-> It takes more time for the drug to cross the endothelial barrier causing a larger AUC
-> if Elimination and metabolism are saturated the drug will have a longer Half-life
Why may Biological drugs have lower Bioavailability when given by SC or IM?
Because of degradation by Tissue peptidases
-f.e. in diabetic patients taking Insulin for a period of time by SC, the tissue will build up peptidases that can destroy some of the Insulin
Which structural modification increases the duration of action of a drug?
PEGylation
-f.e. Urokinase linked to PEG chains
Why do PEGylatd drugs have a longer half-life?
-more stable
-more soluble (PEG has polar groups - more interaction with H2O; it will AGGREGATE less likely)
-less readily metabolized (peptidases cant bind as well)
-PEGylation reduces immune recognition
Why are PEGylated proteins metabolized slowlier?
Because PEGs prevent digesting enzymes from binding to PEGylated proteins
Why is oral administration considered NOT the best route for Biological (protein) drugs?
Because of the proteolytic enzymes in the stomach, digesting the protein drug
Why are some Biologics given orally, despite having a low Bioavailability? Give an example.
-for vaccines, a small dose is enough for the GALT (Peyer’s patch, M cells) to create a long-term immune response
-f.e. Polio vaccine is given to neonates
-Semaglutide:
Sodium N Caprylate changes the pH in the stomach so that Pepsin doesn’t digest Semaglutide + it increases absorption of Semaglutide
What is an example of a pulmonary Biologic, and what is its difficulty?
-AFREZZA (Insulin) is given by Inhaler with a quick onset, able to match the quick Insulin response of healthy people after having a meal
-the problem is that only 10-15% of the Insulin reaches systemic absorption -> loss of drug when inhaling due to the small particle size
Advantages of Intranasal Drug Delivery
-Examples: Naloxone, Insulin, Glucagon, Calcitonin
-Glycocholate (Bile salt) acting as a Permeability enhancer
-used for drug delivery to the brain (f.e. brain tumor)
-quick delivery into systemic circulation due to the great number of blood vessels in the Cribriform plate (nose)
What is the role of Glycocholate in Intranasal drugs?
Permeability enhancer
Example of a locally acting Biological
-anti-VEGF antibodies blocking VEGF
-VEGF stimulates blood vessel formation (angiogenesis)
-increased blood vessels cause increased blood flow and increased pressure in the retina -> macular degeneration
Example of a locally acting Biological (Inhalational)
-Dornase alfa (Pulmozyme) is a DNAase administered through inhalation to break up DNA in the mucus of cystic fibrosis patients
How does Fatty acid Conjugation prolong Insulin’s time of action
-conjugated fatty acid: Myristic acid has a high affinity to Albumin
-Myristic acid conjugated to Insulin will link Insulin to Albumin and thereby prolong its duration of action
