Lecture 5: Formulation and delivery of CNS treatments: neurodevelopmental & neurological disorders

Question 1

What are the requirements for a drug to cross the BBB?

Answer 1

• The drug has to be lipid soluble
• Molecular weight <400 Da

Question 2

Does dopamine cross the BBB? Why?

Answer 2

No because dopamine is hydrophillic and 153g/ mol

Question 3

What is a psychiatric disorder?

Answer 3

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

Question 4

What is a neurological disorder?

Answer 4

“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

Question 5

What is the pathophysiology of parkinsons disease?

Answer 5

Lack of dopaminergic signalling between Substantia Nigra and Striatum/Caudate

Question 6

Does L dopa cross the BBB?

Answer 6

Yes, 197 g/mol, hydrophilic too, but can cross the BBB by carrier-mediated transport
(Large neutral amino acid transporter)

Question 7

What is the problem with drugs used to treat parkisnons? How is it treated?

Answer 7

Levodopa and dopamine are metabolized and removed. To prevent this, co administer an enzyme inhibitor

Question 8

How does the severity of parkinsosn relate to drug administration?

Answer 8

Early - oral

Late stage - transdermal/ SC administration, nasogastric tube

Increase of dyskinesia affects swallowing so ‘nil by mouth’ in late stage.

Question 9

How do most anti epileptic drugs cross the BBB?

Answer 9

By diffusion

Question 10

State the class of epilepsy, first line treatment and transport mechinism

Answer 10

• 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

Question 11

What is the objective of treatment for epilepsy?

Answer 11

To prevent the occurrence of seizures by maintaining an effective dose of 1 or more AED

Question 12

What are the advantages and disadvantages of tablets?

Answer 12

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

Question 13

What are gastroresistant tablets? Advanatges?

Answer 13

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)

Question 14

What are orodispersible tablets and what are the advnatages? Give an example

Answer 14

• 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)

Question 15

What are chewable tablets and what are the advnatages? Give an example

Answer 15

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)

Question 16

What are the different types of modified release tablets and what are they?

Answer 16

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)

Question 17

What are extended release tablets? Give examples

Answer 17

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

Question 18

What is a modified release capsule? Give an example. What are the advantages and disadvantages?

Answer 18

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)

Question 19

How do modified release sodium valproate work?

Answer 19

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

Question 20

What are the advantages and disadvanatged of modified release granules?

Answer 20

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

Question 21

What is an oromucosal solution?

Answer 21

• 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)

Question 22

What are the requirements for a drug to be suitable for transdermal drug delivery?

Answer 22

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

Question 23

What is a matrix type transdermal patch. Give an example

Answer 23

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)

Question 24

What are the advantages and limitation of patches?

Answer 24

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

Question 25

Give an example of a intestinal gel? and Advantages

Answer 25

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

Question 26

What are the advantages and disadvantages of Solutions for injection/infusion?

Answer 26

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

Question 27

When is IV used? Give an example

Answer 27

Urgent treatment if seizures last longer than 5 mins

IV injection of lorazepam

Repeated once after 10 min if seizure fails to respond

Question 28

When is IM used? Give an example

Answer 28

IM injection for the treatment of acute dystonia - Parkinsons disease

Procyclinide hydrochloride is used

Question 29

Give examples of injections and their indications

Answer 29

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)

Question 30

When is SC injection used? Give an example

Answer 30

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