Lecture 7: oral drug delivery II Flashcards
What are the two main classes of mechanism of drug absorption?
transcellular (across cells)
paracellular (between cells)
What does transcellular absorption encompass?
passive diffusion
active transport
facilitated diffusion
endocytosis
What is passive diffusion
simple diffusion
- concentration gradient = driving force
- no energy comsumption
What is active transport?
a form of carrier mediated diffusion where
- energy is required as the driving force
- can occur from low concentration to high concentration
- peptide, nucleotide, sugar, bile acid, amino acid, organic ion, vitamin transporters
- abundant in SI. each carrier system is concentrated in a specific segment of the SI
- many peptide drugs e.g. penicillins, cephalosporins, ACE inhibitors or amino acid like drugs use this
- can become saturated
- may have competition for same transport system by similar substances
What is facilitated transport?
a form of carrier mediate transport
- requires concentration gradient as driving force
- faster rate
- can be saturated and subject to inhibition
- minor route for drug absorption
what is endocytosis?
primary mechanism to absorb macromolecules
- used by fat soluble vitamins like A, D, E, K
- used for vaccine absorption (polio)
What are the different types of endocytosis?
receptor mediated
non-receptor mediated
what are examples of non receptor mediated endocytosis?
pinocytosis, adsorptive endocytosis, phagocytosis
What is paracellular drug absorption?
usually via aqueous pores between cells
- SI is relatively leaky
- importance of paracellular drug absorption decreases down the GIT
- used by ions, sugars, amino acids, peptides at concentrations above the capacity of their carriers
- also the route for small hydrophilic and charged drugs
Why is efflux of drugs from the intestine significant?
This is where proteins expel specific drugs back into the GIT
-p-glycoprotein
significant as it reduces absorption, however some drugs are targeted to these efflux pumps
What are the main factors influencing oral bioavailability?
physichochemical factors
biopharmaceutics classification scheme
dosage form factors
patient factors
What are the physicochemical factors which affect oral bioavailability?
1) dissolution and solubility
2) drug absorption factors
What affects dissolution and solubility?
governed by the Noyes Whitney equation (rate = DA(Cs-C)h
- physiological factors
- drug/formulation factors
- factors affecting concentration of drug in solution in GIT
- poorly soluble drugs
What are examples of physiological factors?
- presence of food
- surfactant levels in gastric juice and bile salts
- agitation
- concentration of drug in GI fluids
What are examples of drug/formulation factors?
- surface are and particle size
- solubility in pH in the diffusion layer
- pKa
- salt form
- crystal form (polymorphism, amorphous, solvates)
What are examples of factors affecting concentration of drug in solution in GIT?
- complexation (e.g. streptomycin binds to mucin to reduce bioavailability)
- micellar solubilisation
- adsorption (e.g. charcoal reduces rate and extent of absorption)
- chemical stability
What are the drug absorption factors?
drug dissociation
lipid solubility
molecular size and hydrogen bonding
what is the relevance of the pH partition hypothesis?
relates to drug dissociation and lipid solubility
What is the pH partition hypothesis?
- the gut epithelial = lipid barrier for drugs which are absorbed by passive diffusion
- only lipid soluble drugs pass through the barrier
- most drugs are weak electrolytes so only their unionised form will pass through
- the extent of ionisation of the drug depends on the pka of the drug and the pH of the environment
henderson hasselbach equation
pH = pKa + log (A-/HA)
WHat are the limitations of the pH partition hypothesis?
The extent of the unionised form is not the only factor determining rate and extent of absorption
- weak acids still quite well absorbed from SI due to large surface area
- some ionised drugs are readily absorbed
- does not take into account of effect of mucosal unstirred layer
- movement of water in and out of GIT also affects the rate of passage
What is lipid solubility?
- measured by partition coefficient
- drugs with higher lipid solubility exhibit greater affinity for GI membrane and are better absorbed but if logP>3, it makes them more susceptible to metabolism and biliary secretion.
- within a homologous serious drug absorption generally increases with lipophilicity
What is the significance of molecular size and hydrogen bonding?
- MW needs to be ideally <500Da for transcellular passive diffusion but larger examples exist also
- too many H bonds is detrimental for absorption as the larger number of H bonds , the poorer the absorption.
What is the biopharmaceutics classification scheme?
- scientific framework for classifying ddrug substances based on aqueous solubility and intestinal permeability
- guide to determine whether in vitro-in vivo correlation can be expected (brand bs. generics)
- used as a practical starting point to consider issues related to absorption and suitable dissolution test conditions to use
What are the main factors considered in the biopharmaceutics classification scheme?
solubility
permeability
dissolution
What is the significance of solubility in the BCS?
a drug substance = highly soluble when the highest dose strength is soluble in 250mL or less of aqueous media at pH 1-7.5, 37 degrees C
relevant as aqueous solubility of <100ug/mL indicates drug is problematic in vivo
What is the significance of permeablity in the BCS?
This is based on fraction of dose absorbed.
a drug substance = highly permeable when the extent of human absorption is 90% or more of an administered dose.
What is the significance of dissolution in the BCS?
IR product considered rapidly dissolving when no less than 85% of labelled amount of drug dissolves within 30 minutes
What is class I of the BCS?
high solubility/high permeability
- ideal properties for absorption
- not usually a problem to demonstrate bioequivalence of generic drugs
- metoprolol, propranolol
What is class II of the BCS?
low solubility/high permeability
- common combination
- in vivo dissolution rate = rate limiting step for absorption
- demonstration of BE of diff. formulations or generics is important
- NSAIDs, CV drugs, antifungals, carbamazapine, naproxen etc.
What is class III of the BCS?
high solubility/low permeability
- permeability is rate limiting
- appropriate formulation is critical to maximise the time that high drug concentrations in contact with absorbing site
- acyclovir, neomycin, atenolol, ranitidine
What is class IV of the BCS?
low solubility/low permeability
- inherent limitations to efficacy by oral delivery
- furosemide
What is an example of a drug that isboderline BCS classifications?
-chlorothiazide is borderline class III and IV
-a 100mg dose gives 60% bioavailability, soluble in 250mL
a 500mg dose gives a bioavailability of 20-30%, soluble in 1250mL
What is the BCS definition of rapidly dissolving?
the drug must meet the criteria at these 3 pHs:
- 0.1N HCl or stimulated gastric fluid USP without enzymes
- pH 4.5 buffer
- pH 6.8 buffer or stimulated intestinal fluid USP
What is the BCS definition of permeation?
Where a drug demonstrates:
- absolute bioavailability in humans
- in vivo or in situ intestinal perfusion in animals
- in vitro permeation - human or animal tissues using a chamber
- in vitro permeation across a monolayer of cultured human cells (Caco-2 cells whih are adenocarcinoma colon cells)
can a generic drug have a different colour, order or inactive ingredient to a brand drug?
yes as long as it has the same dosage, safety, strength, route of administration, quality, performance and intended use.
Why is BE testing doing?
to relate a generic formulation to innovator formulation which is used to establish safety and efficacy
required for approval
What is a waiver of in vivo bioavailability and bioequivalency studies?
document specifying that a BE test is not required.
What drugs does the waiver apply to?
intermediate release solid oral dosage forms based on the BCS.
BCS class I BCS class II only in cases where in vitro in vivo relationships may be developed
What drugs does the waiver NOT apply to?
BCS III and IV
drugs with narrow therapeutic range
products to be absorbed in the oral cavity e.g. buccal, sublingual
what is dissolution rate a function of?
solubility, formulation
What is disintegration rate a function of?
formulation
what is solubilisation rate a function of?
solubility
what is permeability rate a function of?
molecular structure, salt form, excipients
What class of drug woud kd &kp = fast be?
class I. fast dissolution and permeablity rate
What class of drug would kd»kp be?
class III and IV permeation is the rate limiting step
what class of drug would kd«kp be?
class II where dissolution is the rate limiting step
What are the advantages of the oral route?
- patient acceptability and compliance
- large surface area (~200m^2)
- rich blood supply
- prolonged retention
- possibilities of controlled release
- low cost of therapy
What are the limitations of the oral route?
- variability
- adverse reactions
- adverse environmental effects
- high metabolic activity
- extremes of pH
- intestinal motility
- mucus barrier
- p glycoprotein efflux
- impermeable epithelium
