CNS DRUG FORMULATIONS Flashcards
requirements to cross the BBB
lipid-soluble
MW <400 Da
why can/t dopamine pass the BBB
hydrophilic
too polar
low lipid solubility
why can the dopamine precursor levodopa pass the BBB but not dopamine
levodopa is hydrophobic but can cross the BBB by carrier-mediated transport
how do anti-epileptics cross the BBB
diffusion
dosing for AEDs
long enough half-life to allow once daily dosing (except sodium valproate, carbamazepine and gabapentin)
advantages of conventional tablets
- accurate dosing of the drug
- convenient to handle
- easy to take
- controlled release of the drug
disadvantages of conventional tablets
- poor bioavailability of some drugs
- local irritants effects
- harm caused to the GI mucosa
enteric coats for GR tablets
polyvinyl acetate phthalate
diethyl phthalate
gastro-resistant tablet design properties
- barrier coating to control the site of the release of the drug
- designed to resist the low pH of gastric fluids (1.5-4) but to dissolve when the tablet reaches the higher pH of the duodenum (from 5)
- should be swallowed whole
advantages of gastro-resistant tablets
- delay the release of the drug until it reaches the small intestine
- protect the drugs that would be degraded by gastric fluid
- protect the stomach against drugs that can produce nausea or mucosal irritation
orodispersible tablet properties
- disintegration of the tablet in the mouth within one min in the presence of saliva
- can be dispersed in a liquid
advantages of orodispersible tablets
- no difficulty swallowing
- more accurate dosage of drug to young children
- fast effect
example of gastro resistant tablets
sodium valproate (epilim)
examples of orodispersible tablets
co-beneldopa (PD)
lamotrigine (epilepsy)
chewable tablet properties
- tablets mechanically disintegrated in mouth
- drug dissolved in the stomach or intestine
- no need of a disintegrant (composition)
- need of flavouring: use of sorbitol and mannitol as fillers
advantages of chewable tablets
- quick and complete disintegration of the tablet
- rapid drug effect
- easy administration
examples of chewable tablets
carbamazepine (tegretol chewtabs)
phenytoin (epilepsy)
matrix system types in modified-release tablets
erosion-controlled matrix systems
diffusion-controlled matrix systems
diffusion-and-erosion controlled matrix systems
erosion-controlled matrix systems
- the rate of drug release is controlled by the erosion of a matrix in which the drug is dispersed
- eroding matrix: lipids, waxes, polymers (hydroxyethylcellulose)
example of erosion-controlled matrix system MR tablets
carbidopa + levodopa (sinemet)
diffusion-controlled matrix system
- drug dispersed as solid particles within a porous matrix formed of a water-soluble polymer (polyvinyl chloride)
- dissolution of drug particles located close to the surface
- diffusion of the drug through pores
example of diffusion-controlled matrix system MR tablets
ropinirole (ReQuip XL)
three-layered tablet
- a central, active-containing, slow-release layer
- 2 placebo outer layers acting as barrier layers
diffusion and erosion-controlled matrix systems
- penetration of GI fluids in the matrix
- dissolution of the drug, diffusion
- erosion: separation of the matrix surface from the core > release of the drug
examples of diffusion and erosion-controlled matrix systems MR tablets
pramipexole ER
sodium valproate (epilim chrono)
extended release tablets
- tri-layer capsule-shaped rigid tablet
- use of the osmotic release oral system (OROS) technology
osmosis
spontaneous flow of solvent through a selectively permeable membrane from a compartment with a low solute concentration to a compartment with a high solute concentration
disadvantages of modified-release capsules
- no opening of the capsules
- not suitable for patients with swallowing difficulties
- unsuitable for administration via enteral feeding tubes
advantages of granules
- ensures more even plasma concentration throughout the day
- easy to swallow
disadvantages of granules
- must not be administered with hot meals or drinks (damage to the ethyl cellulose shell granule coat)
- should not be crushed or chewed
when is an oromucosal solution the most suitable
- prefilled oral syringe containing midazolam solution, pH 2.9 to 3.7
- treatment of prolonged acute convulsive seizures in infants, toddlers, children and adolescents (3 months to <18)
- slow insertion of the solution into the space between the gum and cheek
- fast absorption of the drug in the circulation
transdermal administration CNS drug requirements
- have a low molecular weight (<500Da)
- have an aqueous solubility higher than 1mg/ml to be removed by the blood supply
- be moderately lipophilic (log P between 1 and 5)
- be effective at low dose
- have a low melting point
what do transdermal drugs need a low melting point
MP <250 degrees
the lower the melting point of the drug, the higher its solubility in the stratum corneum lipids
matrix-type transdermal patch (Neupro for PD)
ex. rotigotine (Neupro)
- application of the patch once a day at the same time
- patch remains on the skin for 24 hours
- it will be replaced by a new one at a different site
advantages of matrix-type transdermal patch (Neupro for PD)
- slow release and long lasting > indicated for the treatment of the signs and symptoms of early stage PD as monotherapy
- avoidance of hepatic first pass metabolism
- can be removed quickly and easily in case of adverse reactions
- application to various body parts
disadvantages of all matrix-type transdermal patches
- no exposure to external heat source: risk of increasing the rate and extent of drug absorption: overdose
- no exposure to water (adherence)
- the backing layer of Neupro contains aluminium > removal of the patch if the pt undergoes MRI or cardio version to avoid skin burns
- contact sensitisation: erythema
rectal administration formulation and drug example
suppositories
intestinal gel
Ex: co-beneldopa (duodopa): gel that is pumped continuously through a tube inserted into the intestine (jejunum)
absorption of the drug in the blood
advantages of duodopa
- suitable for patients who have no control of PD symptoms with traditional treatments
- continuous release
- less likely involuntary movements, fewer ‘off’ periods, help to control PD symptoms at night
- avoid problems of gastric emptying
advantages of solutions for injections/infusions
- dependable and reproducible effects
- entire administered dose reaches the systemic circulation immediately
- preferred route when rapid absorption is essential
disadvantages of solutions for injections/infusions
- pain at the injection site
- all parenteral products must be sterile
- IV injection of drugs may cause local reactions
preferred formulations in neurosis
oral/transdermal
preferred formulations in psychosis
IV/IM
compliance with benzodiazepines
- dependence may occur after 4-6 weeks of treatment
- decrease dose by 1/8th every fortnight
- withdrawal can take months
compliance with antidepressants SSRIs
- use of full dose for 4-6 months after symptoms have subsided is essential to prevent relapse
- non-compliance is frequent when the patient’s mood has improved
- withdrawal over 2-4 weeks
schizophrenia - issues with compliance and formulations
paranoid delusional state > pt not swallowing tablets
concentrated oral liquid forms help because they cannot be hidden in the mouth rather than swallowing
syrup-base preparations can cause tooth decay and obesity in long term > oral dispersible forms are preferred
- minimum 5 year maintenance period recommended
- compliance discouraged with weight gain, precipitates diabetes
sublingual tablets
- drug release in the mouth followed by systemic uptake of the drug
- rapid systemic effect, without first pass liver metabolism
- placed under the tongue
Ex: buprenorphine (addiction)
extended release capsules containing 2 types of beads
beads without release control membrane (uncoated beads): 30% of dose rapidly released
beads with release control membrane (coated beads):
70% of dose continuously release
advantages of suspensions
- drug absorption faster than tablets or capsules
- convenient when the drug is not soluble in water and when non-aqueous solvent cannot be used
- the insoluble solids act as a reservoir and continuously release the drug > long-term efficacy
disadvantages of suspensions
- risk of sedimentation
- risk of inaccurate dosage (use of a spoon)
advantages of solutions/syrups
- drug already dissolved > absorption faster than solid dosage forms or suspensions
- masking the unpleasant taste of the drug
- easy to adjust the dose for a child’s weight
disadvantages of solutions/syrups
- risk of deterioration faster than solid dosage forms
- risks of inaccurate dosage (spoon)
matrix-type transdermal patch (methylphenidate and buprenorphine)
- application of the patch to the hip area 2 hours before an effect is needed
- removal of the patch 9 hours after application
- regular drug release for 9 hours
injections
sterile solutions, emulsions or suspensions, in water or non-aqueous liquid
depot therapy
- injection of a drug with a substance that slows the release and prolongs the action of the drug
- IM injection into skeletal muscle > slow release of the drug to the plasma
chemistry behind depot therapy
esterification of the drug, dispersion of the drug in an oily vehicle
de-esterification of the drug by hydrolysis to be active
duration of depot therapy
effective plasma therapeutic level reached within one week, maintained for 14 to 28 days > injection every 2 to 4 weeks
advantages of depot therapy
- lower dose compared to oral administration
- regular contact with patient by carers
- supervised administration
- no accumulation or abuse of unused tablets
- no issue of compliance
disadvantages of depot therapy
- pain at the injection site
- no rapid elimination from the body
- considerable patient resistance
BBB crossing - donepezil hydrochloride
carrier mediated transport (organic cation transporter such as choline transport system)
BBB crossing - rivastigmine
diffusion
BBB crossing - galantamine
choline and carnitine transport systems
BBB crossing - memantine
organic cation/carnitine transporter
formulation/compliance issues with elderly patients
- high numbers of drugs to take > risk of mistakes
- difficulties to remove meds from their blisters/containers
- may not remember to take their medication
- difficulties swallowing (dysphagia)
dose and side effects of conventional tablets of donepezil (Aricept)
- coated tablets to facilitate swallowing
- 5mg daily at bedtime
- increased to 10mg after 1 month if no s/e
side effects: diarrhoea, muscle cramps, fatigue, nausea, vomiting and insomnia
dose and side effects of conventional tablets of memantine (Ebixa)
- 5mg once daily
- increased weekly to max 20mg
side effects: dizziness, headache, constipation, somnolence and hypertension
dispersible tablets of donepezil hydrochloride
- taken at bedtime
- should be placed on the tongue, allowed to disperse and swallow
- disintegration of the tablet in the mouth within one minute in the presence of saliva
advantages of dispersible tablets
- suitable for patients who cannot swallow tablets or capsules
- fast release of the drug
3 layers in dispersible tablets
drug
fast dissolving granules
disintegration agent
process of disintegration of dispersible tablets
- contact with saliva
- swelling of the disintegration agent
- creation of channels for the saliva
- penetration of saliva
- dissolution of fast dissolving granules
- disintegration of the tablet
