Lecture 7 - routes of administration and considerations in formulation design Flashcards
what must a drug do other than bind?
dissolve
survive a range of pHs 1.5 to 8.0
survive intestinal bacteria
cross membranes
survive liver metabolism
avoid active transport to bile
avoid excretion by kidneys
partition into target organs
avoid partition into undesired places eg brain, foetuses
what are some important drugs properties?
Potency
Selectivity
Solubility and dissolution rate
Absorption/Distribution
Metabolic stability, metabolite ID (active, reactive)
Route of elimination
Predictable PK, exposure, clearance, half-life
Safety
Minimal drug-drug interactions (inhibition, induction)
”Drugability” (Chemical stability, formulation, etc) (Chemical stability, formulation, etc)
IP (freedom to operate)
Low cost of goods
describe ionisation of a molecule
Ionisation refers to the process where a molecule either gains or loses a proton, resulting in a charged form of the molecule.
A significant proportion (about 85%) of drugs have functional groups that can be ionised within the range of physiological pH (1.5 to 8).
the acidity or basicity of a champion palsy a major ole in
Absorption and transport: The ionisation state influences a drug’s solubility, bioavailability, ability to penetrate cells, how it binds to proteins in the plasma, and its volume of distribution within the body.
Binding: Drugs may bind to their targets differently depending on their ionisation state. The un-ionised form usually engages in hydrogen bonding, while the ionised form may form salt bridges or stronger hydrogen bonds.
Elimination: The excretion of drugs through the bile or urine can be affected by ionisation, as can metabolism by cytochrome P450 enzymes in the liver.
how does pH vary in the body
So the same compound will be ionised to different extents in different parts of the body.
This means that, for example, basic compounds will not be so well absorbed in the stomach than acidic compounds since it is generally the unionised form of the drug which diffuses into the blood stream.
what is the ridicule for ionisation constants ?
The equilibrium between un-ionised and ionised forms is defined by the acidity constant Ka or pKa = -log10 Ka
when an acid or a base is 50% ionised, then pH = pKa
descried how lipophilcity of a drug affects ADME.
Lipophilicity (‘fat-liking’) is the most important physical property of a drug in relation to its absorption, distribution, potency, and elimination
Lipophilicity is often an important factor in all of the following, which include both biological and physicochemical properties:
solubility
absorption
plasma protein binding
metabolism clearance
volume fo distribution
enzyme/ receptor binding
biliary and renal clearance
CNS penetration
storage in tissues
bioavailability
toxicity
what are partition coefficients?
P is a measure of the relative affinity of a molecule for the lipid and aqueous phases in the absence of ionisation.
1-Octanol is the most frequently used lipid phase in pharmaceutical research because it has a polar and non polar region (like a membrane phospholipid)
Po/w is fairly easy to measure
Po/w often correlates well with many biological properties
It can be predicted fairly accurately using computational models
what can Log P also effect?
increases binding to the enzyme or receptor
decreases aqueous solubility
increases binding to P450 metabolising enzymes
increase absorption through membrane
increases binding to blood / tissue pretisn - less drug free to act
increases binding to hERG ion channel which has cardio toxicity risk
what is the distribution co-efficient?
distribution coefficient is the effective lipophilicity of a compound at a given pH and there is a function of both the lipophilicity pf the un-ionised compound and the degree of ionisation
what are bulk physical properties that are examined for clinical trials?
solubility including in humans intestinal fluid
hydrogoscopicity ie how readily a compound absorbs water from the atmosphere
crystalline forms - may have different properties
chemical stability
these can be altered by different counter ion or salt and different method of crystallisation
what is lipinskis rule of 5 ?
MW is less than 500 DA
LogP is less than 5
hydrogen bond donors is less than 5
hydrogen bond acceptors is less than 10
what are the routes of drug administration ?
buccal - through check
cutaneous - to the skin
enteral - into intestines
intravenous - veins
intraviteal - vitreous body of eye
parenteral - injection, infusion or implantation
rectal - rectum
respiratory or inhalation - inhaling orally or nasally for systemic effect
sublingual - bennata Tongue
topical - outer surface of body
transdermal - through dermal layer of skin to the systemic circulation by diffusion
what are considerations in the design of dosage forms ?
therapeutic aspects
nature of the clinical indication, local or systemic therapy, duration of action, emergency situations and age of patient
physicochemical properties of the drug
solubility, dissolution, particle size and surface area, partition coefficient and pKa, Crystal properties, stability and organoleptic
what are barriers to drug absorption?
epithelia are tissues composed of one or more layers of cells, these layers are supported by a basement membrane which lies on top of the supporting connective tissue. their function includes absorption, secretion and protection and is dependant in their location within the body
describe passive diffusion transcellular
passive diffusion in the transport through the cells without energy. rate is usually determined by the diffusion across the lipid bilayer of cell membrane from high to low concentration
Lipophilicity is important and an optimum log Pis usually observed
