lecture 7 Flashcards
stages in drug development
research + discovery to launching them on the market
what must drug formulations be optimised for
optimised for their intended use
when are drug formulation studies help
from preclinical to the launch of the drug
they just continue and continue
what must be known about the drug before preclinical studies
its intended use
different routes of drug administration
oral
nasal
injection / intravenous
whats different about different routes of administration
they have different formulations
what is the F in bioavailaility controlled by
- rate + extent of release of drug from dosage form 9aka the amount that is acc released)
- absorption from solution state
- biotransformations during absorption
what does the shape of plasma concentration profiles depend on
the relative rates of absorption and elimination
what does a plasma conc profile vary between
vary between different forms of drug administration.
aka intravenous would have a higher + earlier peak as it is absorbed with 100% bioavailability - fast absorption
describe an oral dose peak on a plasma conc profile
smaller peak + later on due to slower absorption
different administration routes but the same active principle haveth same
rate of elimination
this depends on the active principle!!
their absorption will vary,, but elimination will be the same
disposition
distribution
metabolism
excretion
plasma conc axis
conc up and down
time left and right
single dose plasma conc description
single peak
- absorbance phase (increasing conc)
- elimination phase (decreasing conc over time)
Cmax and Tmax : time and conc was the highest here
multiple repeated dose plasma conc profile
furry graph of absorbance and elimination
Css = steady state average when abs = elim // input = output.
what happens to a drug whn it is given in multiple doses:
conc accumulates in the body until plateu is reached
too high drug conc when given in multiple doses
excessive diverse effects are observes
in multiple dose plasma conc profiles,, where is the plasma conc preferred
in the therapeutic window
affects are seen buyt there are no adverse ones
when are adverse effects seen on a plasma conc profile for multiple doses
when the plasma concentration increases too fast and too high
areas of preformulation research
- physiochemical properties
bulk characterisation
solubility analysis
stability analysis
preformulation research: physiochemical properties
purity
surface area
particle size
particle shape
preformulation research: bulk characteristics
powder flow properties
bulk density
preformulation research: solubility analysis
pka
dissolution
ph solubility profile
preformulation research: stability analysis
solution
solid state
bulk
compatibility stability
apart from the active principle,, what must also be studies
excipients
what solubility must be studied
solubility of both active principle and excipients in an aqueous media
what can be used in solubility tests in an aqueous media
37*
aqueous buffer to allow equilibrium
solubility: meaning of max saturation // solubility
max amount of drug / excipient that can be dissolved in a fixed volume
what changes in ionisable groups
their solubility changes between their neutral state and ionised state
solubility of groups like NH2 and COOH must be tested when neutral + ionised as their solubility changes
ionic compounds must have their solubility tested using what
using different ph environments as there are many different areas of ph in the body
allows us to gain insight of their state in different ph environments
what can solubility profiles be used for
knowing which solvent to use in formulations for injections, nasal drops etc
when does pka = ph
when 50% of the drug is ionised
ionic drugs have diff what in diff whattt
diff solubilities in diff environments
COOH solubility: most common form in stomach,, ph1
mostly COOH
COOH solubility: most common form in plasma,, ph7
mostly COO-
whats a positive consequence of ionisable groups having diff solubilities in diff conditions
prevents the group from returning back to environments with different phs.
aka when COOH is ionised into COO- when it enters the plasma, it can no longer return back to the stomach as they have diff phs
compounds with ionisable groups first have their solubility measured when they are
not ionised
intrinsic solubility
solubility profiles at different phs can also help us do what
find solvents to use for formulation
name diff solid dosage forms
- chewable tablet
- sugar coated tablet
- film coated tablet
- buccal tablet
what is the meaning of dosage form
the way the drug is delivered to the site of action in the body
what determines if a drug reaches the site of action
physical state
chemical composition
what gives a drug its suitable consistency
the vehicle aka the excipients
what are the positives of solid oral dosage forms
accurate
good shelf life
can self administer it
easy to store and distribute
negatives of solid oral dosage forms
hard to administer t unconscious ppl
takes long for it to be absorbed
for a drug to be successful,, what two things must be compatible
the active principle
the excipient
both physically and chemically compatible
diff types of solid dosage forms
tablets
capsules
granules
powders
describe solid dosage form: capsule
- hard/soft gelatin shell
- colourants
describe solid dosage form: tablets
- compressed + molded tablets
- various excipients: anticaking//bulking agents, flavoures, colourants
when can sugar coated tablets be used
to mask flavour
- water soluble sugar shell on outside
when does polymorphism occur
when a chemical compound crystallises with a different internal structures
diff types of polymorphism
crystalline
polycrystalline
amorphous
polymorphism structures: which is more soluble
amorphous
polycrystalline
crystalline
difference between diff polymorphism structures
diff polymorphic form = diff physiochemical characteristics (solubility, melting point, bioavailability, stability)
what is solubility rate // dissolution
the rate at which a drug or excipient dissolves in any particular medium
what does solubility rate depend on
particle size
particle size distribution
particle porosity // surface area
wettability of surface (to initiate dissolution)
nature of dissolution fluid
what changes as dissolution occurs
the particle porosity // surface area
what size particle is wanted
small,, increases the dissolution // solubility rate
why is moisture uptake // sorption measured
to find ideal conditions of storage and packaging
what are excipients
inactive substances that serve as vehicles//mediums for drugs
should be inert
normally no therapeutic effect
examples of excipients
binders - keep the tablet together
colouring agents - helps the tablet look nice
what must be done to excipients
they must be tested alongside the drug to make sure they are physically and chemically compatible + dont react under any diff environments.
must be tested together in a range of different phs, environments etc etc
what is an extended release dosage form
drug is released over a long period of time.
normally for oral doses: tablets + capsules
what must be considered for extended release dosage forms
- rate of absorption
- rate of excretion
- solubility
- potency
- TI
- intended use
extended release dosage forms intended use
chronic conditions
not acute conditions
sterile formulations product examples
sterile fluids
medical devices
what is pharmacopoeia: certified analysis
- list of quantitative + qualitative medicine compositions
- tests that should be carried out on medicine + the raw materials used to produce medicine
what must be followed in order to have a drug approved by the fda
pharmacopoeia must have been followed
medicine quality control: medicines should have xxx quality standards
high quality standards
what is gqs
good quality standards
manufacturing industry is full of them
what 2 things play a crucial part in lab studies
the lab procedure
the people carrying out the labs // the ppl executing the labs
every step of drug synthesis is covered by what
GxP
what can x stand for in gxp
good laboratory practice
good manufacturing practice
what is covered by gxp
design + testing
manufacturing and distribution
of pharmaceutical products or medical devices
when and who first established glp
the fda
1970s
why were glps introduced
- assess nonclinical safety
- protect integrity of scientific data
- aid in product advancement - providing open ended research studies
- ## regulate non clinical lab studies for humans, animals, perfumes etc
when must glps be used // applied
when handling live animals + plants
what testing should be performed under glp
safety + efficacy testing
when is glp not needed
discovery
screening
basic research
in vitro studies
studies where safety assessment is not a concern
4 glp practices
- audit and introspection (internal + external performed by external regulatory bodies to check that procedures are being followed)
- standard operating procedures,, SOP
clearly written guidelines labs should follow + everyone should see - data recording
what u did, how it was done, when it was done, who did it : record data correctly + without error - staff
trained staff should perform tests + their qualifications should be kept
when do gmp practices apply
apply to every step of the drug manufacturing process
not just the testing
why did the fda adopt the term current gmp
to make sure manufacturers continuously re evaluate their manufacturing practice to stay up to date as tech changes in their industry.
when do gmp regulations apply
when products are being manufactured for consumers to use
u must batch test,, test ingredients from suppliers + any other tests during the manufacturing process.
what data is covered by glp
safety of the molecule + all necessary experiments
what data is covered by gmp
manufacturing + associated safety testing
what happens after preclinical research
federal law that a drug must be subject to approved marketing application before being transported to clinical trial centers around the world
what is EU - IMPO
european
investigational
medicinal
product
dossier
what is IND
investigational new drug
what is CTA
clinical trial authorisations
what does the clinical trial sponsor provide
a document that supports the investigational use of the medicinal product in clinical trials
what happens once the IND is submitted
u wait 30 days for the fda to approve it,, make sure all data is correct or else u just waste ur time.
u wait 30 days then u can start clinical trials
fda makes sure clinical trial subjects will not be subjected to unreasonable risks
what does a good GMP system ensure
ensures that products are consistently produced + controlled according to quality standards
why are gmps important
make sure high quality medicines are produced
describe poor quality medicines: if gmp was not a thing
- health hazard
- waste of money
- waste of time
- may have had toxic substances unintentionally added
- too small amount of active principle -> no therapeutic effect
- countries only allow the importation + sale of medicine that has been manufactured respecting gmp practices.
