Lecture 5: Formulation and delivery of CNS treatments: neurodevelopmental & neurological disorders Flashcards
What are the requirements for a drug to cross the BBB?
- The drug has to be lipid soluble
- Molecular weight <400 Da
Does dopamine cross the BBB? Why?
No because dopamine is hydrophillic and 153g/ mol
What is a psychiatric disorder?
Disorders of the mind
Disorders of mood, thought, behaviour and perception
Primary “functional” in origin
Drugs commonly used
Psychological treatment may be suitable
Ex: anxiety, depression, schizophrenia
What is a neurological disorder?
“disorders of the brain”
Disorders of movements, intellect and sensation
Primary “organic” in origin
Drug therapy usually essential
Surgery sometimes effective
Ex: Parkinson’s disease, epilepsy, brain tumour, migraine
What is the pathophysiology of parkinsons disease?
Lack of dopaminergic signalling between Substantia Nigra and Striatum/Caudate
Does L dopa cross the BBB?
Yes, 197 g/mol, hydrophilic too, but can cross the BBB by carrier-mediated transport
(Large neutral amino acid transporter)
What is the problem with drugs used to treat parkisnons? How is it treated?
Levodopa and dopamine are metabolized and removed. To prevent this, co administer an enzyme inhibitor
How does the severity of parkinsosn relate to drug administration?
Early - oral
Late stage - transdermal/ SC administration, nasogastric tube
Increase of dyskinesia affects swallowing so ‘nil by mouth’ in late stage.
How do most anti epileptic drugs cross the BBB?
By diffusion
State the class of epilepsy, first line treatment and transport mechinism
- Generalised seizures - sodium valproate - Diffusion and carrier-mediated transport (monocarboxylate transporter)
- Focal seizure - lamotrigine - Carrier-mediated transport (organic cation transporter 1 OCT1)
- Absence seizures - ethosuximide - diffusion
- Status epilipticus - lorazepam - diffsion
What is the objective of treatment for epilepsy?
To prevent the occurrence of seizures by maintaining an effective dose of 1 or more AED
What are the advantages and disadvantages of tablets?
Advantages:
- Accurate dosing of the drug
- Convenient to handle
- Easy to take
- Controlled release of the drug
Disadvantages:
- Poor bioavailability of some drugs
- Local irritants effects
- Harm caused to the GI mucosa
What are gastroresistant tablets? Advanatges?
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 enters the higher pH of the duodenum (from 5)
Enteric coat: Polyvinyl acetate phthalate,
diethyl phthalate
Given twice daily
Should be swallowed whole (not crushed or chewed)
Advantages:
- Delay the release of the drug until it reaches the small intestine
- Protect the drugs that would be degraded by the gastric fluid
- Protect the stomach against drugs that can produce nausea or mucosal irritation if released at this site
Eg sodium valproate (Epilim® ) (epilepsy)
What are orodispersible tablets and what are the advnatages? Give an example
- Disintegration of the tablet in the mouth within one min in the presence of saliva
- Can be dispersed in a liquid before the drug is administered to the patient
Advantages:
- No difficulty for swallowing (early stage of PD)
- More accurate dosage of drugs to young children
- Fast effect
Ex: co-beneldopa (PD), lamotrigine (epilepsy)
What are chewable tablets and what are the advnatages? Give an example
Tablets mechanically disintegrated in the mouth. Drug is dissolved in the stomach or intestine. Use of sorbitol and mannitol as fillers
Advantages:
- Quick and complete disintigration of the tablet so rapid drug effect
- Easy administration
- No need for a diintegrant
Eg carbamazepine (Tegretol Chewtabs ®)(epilepsy), phenytoin (epilepsy)
What are the different types of modified release tablets and what are they?
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). Eg. carbidopa+levodopa (Sinemet ®) (PD)
Diffusion controlled matrix systems:
Drug dispersed as solid particles within a porous matrix formed of a water-insoluble polymer (polyvinyl chloride). Dissolution of drug particles located close to the surface. Diffusion of the drug through pores
Ex: ropinirole (ReQuip XL ®)(PD) It is a three layered tablet. Has 2 placebo outer layers acting as barrier layers and a central active containing slow release layer. Advantage is Prevention of in vitro burst effect, in vivo dose dumping. Disadvantage: Sophisticated trilayer tablet compression machine needed. More labour-intensive process
Diffusion- and erosion- controlled matrix systems:
Penetration of GI fluids in the matrix so dissolution of the drug and diffusion. Erosion - separation of the matrix surface from the core so release of the drug. Eg. pramipexole ER (Mirapexin ®, PD), sodium valproate (Epilim Chrono ®, Epival CR ®) (epilepsy)
What are extended release tablets? Give examples
Trilayer capsule shaped rigid tablet. Use of the osmotic release oral system technology. Eg carbamazapine (Tegretol XR ®) (epilepsy)
Drug overcoat: Dissolution of the drug overcoat so immediate release of 22% of the dose within 1 hour
1 hour later:
- Permeation of water through the membrane into the tablet core
- Expansion of the osmotically active polymer excipients in the push compartment, acting as an osmotic pump
- Regular release of the drug through the orifice
-Regular delivery of the drug for the rest of the morning
In the afternoon:
- The push mechanism continues to expand
- Increase of the drug release rate from the system with time, due to the drug concentration gradient incorporated into the two drug layers of the tablet
Advantages:
- Efficacy for 12h
- No impact of food intake
- Overcoming of the difficulties of multiple daily dosing
What is a modified release capsule? Give an example. What are the advantages and disadvantages?
Erosion of the matrix so release of the drug by diffusion.
Eg. Prolonged-release co-beneldopa capsules (Madopar® CR capsules, PD): the gelatine capsule contains a matrix (hydrophilic polymers)
Advantages:
- Slow release of the drug: particularly useful for the treatment of Parkinson’s disease patients with fluctuations related to levodopa plasma concentrations or timing of dose
Disadvantages:
- No opening of the capsules
- Not suitable for patients with swallowing difficulties
- Unsuitable for administration via enteral feeding tubes
Eg; co-beneldopa (Madopar CR ®) (PD)
How do modified release sodium valproate work?
Prolonged-release sodium valproate capsules (Episenta®, epilepsy): the capsule contains prolonged-release granules coated with an indigestible ethyl cellulose shell. These shells may sometimes be visible as a white residue in the stools
What are the advantages and disadvanatged of modified release granules?
Advantages:
- Ensures more even plasma concentration throughout the day
- Easy to swallow
Disadvantages:
- Must not be administered with hot meals or drinks (damage to the ethyl cellulose shell granule coat)
- Should not be crushed or chewed
What is an oromucosal solution?
- Pre-filled oral syringe containing midazolam solution, pH 2.9 to 3.7
- Treatment of prolonged, acute, convulsive seizures in infants, toddlers, children and adolescents (from 3 months to < 18 years)
- Slow insertion of the solution into the space between the gum and the cheek
- Fast absorption of the drug in the circulation
Eg. midazolam (Buccolam ®, epilepsy)
What are the requirements for a drug to be suitable for transdermal drug delivery?
To be suitable for transdermal drug delivery, the CNS drugs should :
have a low molecular weight (less than 500 Da)
have an aqueous solubility higher than 1 mg/ml to be removed by the blood supply
be moderately lipophilic (logP between 1 and 5)
be effective at low dose (20 mg)
have a low melting point (MP < 250°C): the lower the melting point of the drug, the higher its solubility in the stratum corneum lipids
What is a matrix type transdermal patch. Give an example
Application of the patch once a day, at the same time every day. The patch remains on the skin for 24h. It will be replaced by a new one at a different site of application (abdomen, thigh, hip, flank, shoulder, or upper arm)
Eg. Rotigotine (Neupro ®) (PD)
What are the advantages and limitation of patches?
Advantages:
- Slow release and long lasting effect so Indicated for the treatment of the signs and symptoms of early-stage Parkinson’s disease as monotherapy (i.e. Restless Legs Syndrome)
- Avoids hepatic first pass metabolism
- Can be removed easily and quickly in case of adverse reactions
- Application to various body parts: limitation of the risks of contact sensitization (erythema, edema, vesicles)
High patient compliance:
- One application per day
- Regular drug release for 24 hours
Limitations:
- No exposure to external heat sources: risk of increasing the rate and extent of drug absorption - risk of overdose
- No exposure to water: can affect patch adherence
- The backing layer of Neupro® contains aluminium, Removal of the patch if the patient has to undergo magnetic resonance imaging (MRI) or cardioversion to avoid skin burns
Give an example of a intestinal gel? and Advantages
Co-beneldopa (Duodopa ®, PD): gel that is pumped
continuously through a tube inserted into the intestine (jejunum). Absorption of the drug by the blood
Advantages:
- Suitable for patients who have no control of Parkinson’s disease symptoms with traditional treatments
- Continuous release of co-beneldopa (100 ml cassette: 2000 mg drug) - Less likely involuntary movements, fewer ‘off’ periods, help to control PD’s symptoms at night
- Avoid problems of gastric emptying
What are the advantages and disadvantages of Solutions for injection/infusion?
Advantages:
- Dependable and reproducible effects
- Entire administered dose reaches the systemic circulation immediately
- Preferred route when rapid absorption is essential
Disadvantages:
- Pain at the injection site
- All parenteral products must be sterile
- IV injection of drugs may cause local reactions
When is IV used? Give an example
Urgent treatment if seizures last longer than 5 mins
IV injection of lorazepam
Repeated once after 10 min if seizure fails to respond
When is IM used? Give an example
IM injection for the treatment of acute dystonia - Parkinsons disease
Procyclinide hydrochloride is used
Give examples of injections and their indications
lorazepam (injection, epilepsy), lacosamide (infusion, epilepsy), phenytoin (injection, epilepsy), sodium valproate (injection, epilepsy), procyclidine hydrochloride (solution for IM/IV injection, acute dystonia, PD), apomorphine hydrochloride (Sc injection Apo-go ®, Apo-go-pen ®, PD), continuous Sc injection (Apo-go-PFS ®, PD)
When is SC injection used? Give an example
For the treatment of disabling motor flunctuations (on - off phenoma) in Parkinsomns disease which persists despite treatment with levodopa
Subcutaneous use by intermittent bolus injection
Continuous subcutaneous infusion by minipump and/or syringe driver
Mini-pump for patients who require many and frequent injections (more than 10 per day)
Eg. Apomorphine hydrochloride
