Delivery of nitrates Flashcards
what is systemic drug delivery
still largely tend to fill all of the body with drug even though only a specific region needs to be treated
- assume if drug is present in plasma, then also at site of action
what is absolute bioavailability
the amount of drug that can be absorbed into the bloodstream that is available to have an effect
what is the IV bioavailability
always 100%
how can bioavailability be measured
area under curve on a plasma conc time graph is an indication of bioavailability
what is the one compartment open model for the GIT
- drug in formulation
- drug in gastrointestinal fluid
- drug in body compartment (input)
- drug eliminated (output)
what are the assumptions of the open model for the GIT
- Once released from the formulation and absorbed, drug is distributed instantly throughout body
- changes in drug in plasma directly affects change in drug at the site of action
- drug input and output is described by first order kinetics
what is the rate of drug input
- rate of drug input is proportional to the concentration
rate of drug input (at time t)= -KaC
- C= Conc of drug available for absorption
- t= time
- Ka= apparent absorption rate constant in time^-1
what is the rate of drug elimination
rate of drug elimination (at time t) = -KeCt
- Ct= conc of drug in body compartment at time t
- Ke= apparent elimination rate constant
what is the biological/elimination half life of a drug in the body
t1/2= 0.693/Ke
- the time required for the body to eliminate 50% of the drug it contains
- inversely related to elimination rate
- first order elimination
what are multiple dosing regimes
when a drug is given repeatedly
- only a few drugs are given as one dose only, typically several doses given in a treatment
- the dose size, frequency and regularity can significantly affect therapy
describe the effect of multiple dosing on plasma concentration
steady state:
- attained after approximately four half times
- time to reach steady state depends on t1/2 and is independent of the dose size and dosing interval
what is the average steady state concentration of drug in the plasma
C^ss~Ave= FDt1/2 x 1.44/ TV~d
- F= fraction absorbed (bioavailability)
- D= dose
- t1/2= biological half life
- T= fixed time (dosing) interval
- Vd= volume of distribution
what is the volume of distribution
relates to the amount of drug in the body to the concentration of drug that is measured
describe the effect of changing dose size at constant dosing intervals
- the larger the administered drug dose, the higher the maximum, minimum and average plasma concentrations of the drug are achieved at steady state
- larger fluctuations in drug plasma concentrations
- can be dangerous for drugs with narrow therapeutic window
describe the effect of changing dosing intervals at constant dose size
- the dose of the administered drug is kept constant but dosing interval is varied
- if the dosing interval is shorter than the t1/2 of the drug, higher steady state plasma concentration is obtained
- of dosing interval is longer than the t1/2 of the drug, lower steady state plasma concentration obtained
- fluctuations between minimum and maximum drug concentrations stay the same
how is the loading dose calculated
4 variables used to calculate
Loading dose= C~pV~d/FS
- Cp= desired peak concentration of drug
- Vd= volume of distribution of drug in body
- F= bioavailability
- S= fraction of drug salt from which drug is active drug
define dose dumping
drug is released straight into the body- conventional tablets and capsules
what are modified release tablets
drug release is modified- usually extended
what are delayed release tablets
drug release is delayed d
what are prolonged/extended release tablets
allows extended therapeutic blood levels of the drug
what is zero order (controlled) release
drug is released at constant rate, independent of remaining drug within the formulation
what is variable release tablets
release is timed to optimise therapy
what is a bioresponsive release
drug is released in response to an external stimuli
why are modified/prologed released systems used
- improve patient compliance
- improve control of maintenance of therapeutic plasma levels of drug, leading to:
- improved therapy chronic conditions
- improved night time therapy
- reduce side effects
- reduced amount of drug administered - reduction in localised side effects
what are the factors in controlling drug release
usually require a rapid release priming (loading) dose and extended release component, to achieve rapid and then prolonged drug delivery
what are the mechanisms of controlling the rate of drug release from a formulation
- diffusion controlled
- dissolution controlled
- osmosis controlled
- mechanical controlled
- bioresponsive controlled
- 2 designs: matrix and barrier coating
describe the typical constituents of a modified release oral dosage form matrix tablet
- active drug
- release controlling agent
- release rate modifying agent
- aid to drug solubility
- lubricant/glidant
- coating
- can also have matrix pellets or granules
describe the components of a barrier/membrane controlled system in barrier coating design
- single unit systems
- coating- film coat
- polymer
- plasticiser
- other additives (colour, release modifiers) - core- usually a compressed tablet containing
- active drug
- filler
- lubricant/glidant - can also have pellets or granules with barrier coatings
how can diffusion be controlled in the rate of drug release from a formulation
- barrier coatings
- multiple unit system
- plastic matrices
- transdermal patch
what does a multiple unit system consist of
- core:
- spheroid pellets containing drug
- diluent
- binder - film coating (as for single unit dosage form)
- hard gelatine capsule
- loading dose in coat, or incorporated separately as uncoated particles
what are the constituents of a plastic matrix
- insoluble polymer- eg. polyethylene
- formulation additives- lubricant, fillers, aid to solubility
- coating
- can be made by compressing plastic particles with drug particles in a tablet machine, then coating
- eg. Gradumet
what is the gradumet system
M~t= Kt^0.5
- Mt= drug release at time t
- K= constant
what does a transdermal patch consist of
- backing layer- polyester film
- a drug reservoir alcohol USP gelled with hydroxyethyl cellulose or silicone oil
- an ethylene vinyl acetate copolymer membrane containing silicone adhesive
- protective liner covering the adhesive layer before application to skin
how can dissolution be controlled in rate of drug release from a formulation
- simplest (eg testosterone implants)- pellets/tablets/particles of sparingly soluble drug
- hydrophobic systems
- release by erosion/dissolution of fat to expose the drug
- multiple release products
- ion exchange resins
what does a dissolution controlled hydrophobic system contain
- drug
- sparingly soluble waxes (solid at body temperature)
- release modifiers
- aids to solubility
- lubricant/glidants
- binding agents
- coating
- manufacture- typically granulation and compression
what does multiple release products contain
- loading dose in uncoated granules
2. contains same waxes as matrices, but sprayed onto granules as a coating
what do ion exchange resins contain
- dissociation of drug resin complex
- formulation:
- resins (amberlite, dowex)
- obtained as spheres, loaded with drug
- diffusion alors helps regulate release
what is a suscard buccal/Buccastem
- release by hydration, gelation, dissolution of polymer then drug dissolution and diffusion
- controls dissolution and distribution in rate of drug release
what are the components of a hydrophilic matrix system
- active drug
- gelling agent/hydrophilic colloid
- aid to solubility
- binder/compression aid
- lubricant/glidant
- film coating
eg. suscard buccal
what is a continuous system
eg. Phyllocontin
1. controls dissolution and diffusion in rate of drug release
2. drug granulated with hydroxyalkyl cellulose, mixed with melted higher aliphatic alcohol (wax), granulated and compressed into tablets
3. on exposure to gastrointestinal fluid, wax erodes, cellulose swells and gels, drug release controlled by rate of wax erosion and diffusion through gel
how is osmosis controlled in rate of drug release
- principle
2. constituents osmotic pump
what does a constituent osmotic pump consist of
- core:
- active drug
- osmotically active agent
- filler
- lubricant/glidant
- aid to solubility
- viscosity modifier - coat
- polymer (with semi permeable membrane properties)
- plasticiser
- other (colour etc) - can get very close to zero order drug release from this formulation
describe the reasons for use of buccal/sublingual route
- local- treatment conditions of the oral cavity
- systemic- avoid first pass effects, veins don’t drain to the liver via the hepatic portal system
- rapid onset of action (sublingual)
- controlled drug release possible (buccal)
- avoid acid/digestive enzymes in lower GIT
Describe the structure of oral cavity
- beginning of alimentary tract
2. bound by cheeks, lips, hard palate sublingual mucosa
describe the functions of the oral cavity
- process food
- mastication
- lubrication
- digestion
- sampling and evaluation foodstuffs (taste)
what is teeth enamel made from
hydroxyapatite
what does the oral mucosa consist of
- squamous stratified epithelia
- keratinised- gingiva (gums), hard palate (areas abrasion)
- non keratinised- buccal mucosa, sublingual mucosa
- specialised mucosa- upper tongue
what is the role of saliva
lubrication, digestion, remineralisation of teeth, antimicrobial effects
describe the flow rates of saliva
- background- mainly mucous secretions, circa 0.5ml min-1- varies with time of day (greatest afternoon, least at night)
- stimulated- mainly serous secretions, up to circa 7ml min-1
what is the salivary pellicle
a salivary coating of all internal surfaces of the oral cavity, protective or lubricating
describe the microbiology of the oral cavity
bacteria: including Streptococcus, enterococcus, staphylococcus
- also some fungi, viruses, mycoplasmas and protazoa
what is dental plaque
- teeth- a hard, non shedding surface for microbial colonisation
- microorganisms exist in a biofilm, a complex matrix composed of microbial extracellular products and salivary compounds
- multiple habitats are associated with the tooth surface, each supporting different populations of oral bacteria
describe the absorption across the oral mucosa
- not designed for absorption
- small surface area for absorption
- best absorption in thinnest areas (sublingual), worst through keratinised epithelia (gingiva)
- so variable but generally low permeability
- smaller, stable, potent, lipophilic molecules absorbed best
- therapeutic proteins poorly absorbed
describe the route for drug permeability through the oral mucosa
- mucosal barrier formidable
- major barrier is stratified epithelia
- possible routes: transcellular, paracellular
what are the main problems of drug delivery via the oral cavity
- patient acceptability- taste, mouthfeel, odour
- ease of absorption- normally only small amounts of drug absorbed from mouth, needs to have correct properties
- retention- duration of application (mouthwashes less than a minute) and salivary washout
- distribution within oral cavity and salivary route- drugs follow saliva when released, pool in lower part oral cavity and swallowed, not distributed throughout cavity
what are formulations and mechanisms of drug release relevant to nitrate drug delivery
- aerosol sprays
- orally disintegrating/orodispersible tablets
- sublingual tablets
- bioadhesive tablets
- injection
- transdermal patches
what aerosol sprays could be used in nitrate drug delivery
eg. nitrolingual, core nitro spray
- delivers unit dose of GTN under the tongue for rapid absorption
what orodispersable tablets could be used in nitrate drug delivery
- lightly compressed, porous tablets
- rapidly disintegrate, normally to allow drug to be swallowed, by those with difficulty
- similar to tablets but with less binder and a very effective disintegrant
- eg. calpol fast melts, nurofen meltlets, zydis ODT
what sublingual tablets could be used in nitrate drug delivery
- drug to be mainly absorbed in the sublingual region, under tongue
- eg. glyceryl trinitate tablets
what bioadhesive tablets could be used in nitrate drug delivery
- adhere to the oral mucosa, usually the upper buccal pouch and deliver drugs slowly either systemically into the mucosa or into the oral cavity
- no need for disintegrant since want to achieve slow release
- eg. suscard buccal, GTN
- small compressed tablets with flat face for adhesion, contains a bioadhesive polymer that adheres on moistening
what injections could be used in nitrate drug delivery
- glyceryl trinitate for injection contains 1-5mg/mL of glyceryl trinitate, absolute ethanol and propylene glycol in water for injections
- must be diluted and often given in infusion
- glycerol trinitate is compatable with following infusion solutions: 0.9% NaCl solution, 5% dextrose/glucose
what transdermal patches could be used in nitrate drug delivery
- 5-10mg in a patch, slowly released over day
2. patch applied during the day and removed at night
