Lecture 5 - formulation of CNS treatments

Question 1

describe the difference between psychiatric disorders and neurological disorders.

Answer 1

neurological disorders are disorders of the Brian. disorders of movements, intellect, and sensation whereas psychiatric disorders are disorders of the mind. disorders of mood, thought, behaviour and perception.

neurological disorders are primary organic in the brain whereas psychiatric disorders are primarily fictional in origin

in neurological disorders drug therapy is usually essential whereas in physiatrics drugs are commonly used.

in neurological surgery sometimes effective whereas psychological treatment may be useful

examples of neurological disorders are Parkinson disease, epilepsy, brain tumour, migraine whereas psychiatric disorders are anxiety, depression, schizophrenia

Question 2

Describe Parkinsons disease and its treatment drug

Answer 2

In Parkinson’s disease there is a lack of dopaminergic signalling between substantial nigra and striatum.
Dopamine is hydrophilic and too large to cross the BBB, so treatment is with the dopamine precursor, Levodopa.
Levodopa is also hydrophilic, but can cross the BBB by carrier mediated transport.

Question 3

what problem is associated with the drug treatment of Parkinson disease?

Answer 3

levodopa and dopamine are metabolised and removed. t prevent this there is co-administration of enzyme inhibitors.

Question 4

describe gastro resistant tablets and their advantages

Answer 4

designed to resist the low pH of gastric fluids (1.5-4) but to dissolve when the tablets enters the higher pH of the duodenum (from 5). the enteric coat is polyvinyl acetate phthalate, diethyl pthalate.

Advantages are
* delays 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

example: sodium valopoate or epilim for epilepsy

Question 5

what are orodispersibel tablets and their advantages?

Answer 5

disintegration of the tablet in the mouth within one minute in the presence of saliva. can be dispersed in a liquid before the drug is administered to the patent.

advantages are no diffusely for swelling esp early stages of PD , more accurate dosage of drugs to young children and fast effect. examples are co-beneldopa (PD) and lamotrigine (epilepsy)

Question 6

what are chewable tablets ad their examples?

Answer 6

chewable tablets are mechanically disintegrated in the mouth. the drug is dissolved in the stomach or intestine.

advantages are quick and complete disintegration of the tablet –> there is rapid drug effect, easy administration (difficulty to swallow). there is no need of a disintegrate, need of flavouring: use o sorbitol and mannitol as fillers.

examples are carbamazepine (Tegretol Chewtabs ®)(epilepsy), phenytoin (epilepsy)

Question 7

what are modified release tabelst with an erosion controlled matrix system?

Answer 7

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)

Ex: carbidopa+levodopa (Sinemet ®) (PD)

Question 8

explain the modified release tablets with diffusion controlled matrix systems

Answer 8

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)
  Three-layered tablet:

Advantage:
* Prevention of in vitro burst effect, in vivo dose dumping

Disadvantages:
* Sophisticated trilayer tablet compression machine needed
* More labour-intensive process

• Ex: ropinirole (ReQuip XL ®) - parkinsons disease

Question 9

explain diffusion and erosion controlled modified release tablets

Answer 9

• Penetration of GI fluids in the matrix leading to dissolution of the drug by diffusion
• Erosion : separation of the matrix surface from the core leading to release of the drug
• Ex: pramipexole ER (Mirapexin ®, PD), sodium valproate (Epilim Chrono ®, Epival CR ®) (epilepsy)

Question 10

explain extended release tablets

Answer 10

• Ex: carbamazepine (Tegretol XR ®) (epilepsy)
• Trilayer capsule-shaped rigid tablet
• Use of the Osmotic release oral system (OROS) technology

In the morning:
Dissolution of the drug overcoat
Immediate release of 22 % of the dose within 1h

1 h 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 11

explain co-beneldopa modified release capsules

Answer 11

• Ex: Prolonged-release co-beneldopa capsules (Madopar® CR capsules, PD): the gelatine capsule contains a matrix (hydrophilic polymers)
• Erosion of the matrix Release of the drug by diffusion

Advantage:
- 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

Disadvantage:
- No opening of the capsules
- Not suitable for patients with swallowing difficulties
- Unsuitable for administration via enteral feeding tubes

Question 12

explain sodium valproate episenta modified release capsules

Answer 12

capsule contains prolonged release granules coated with indigestible ethyl cellulose shell. the shells may be visible as what residue in the stools.

advantage are
* slow release of the drug: particularly useful in the management of epileptic patients with the fluctuations related to drug plasma cocentraiosn or timing of doses
* can be opened prior to administration

disadvantages
* the granules must be swallowed without chewing
* unsuitable for administration via babies bottles

Question 13

modified release granules

Answer 13

advanatges
* ensures more even palsma cocnetrations throughout the day
* more easier to swallow

disadvantages
* must not be adminsistreed with hot drinks or foods - damagae to the ethyl cellulose granule coat
* should not be crushed or chewed

example: sodium valporate episenta

Question 14

liquid formualtions

Answer 14

• 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

• Ex: midazolam (Buccolam ®, epilepsy)

Question 15

what are the conditions To be suitable for transdermal drug delivery, the CNS drugs should

Answer 15

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 16

describe patches

Answer 16

• Matrix-type transdermal patch
  Ex: Rotigotine (Neupro ®) (PD) :
• 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)

Question 17

what are advantages of patches?

Answer 17

ADVANATGES
Slow release and long-lasting effect
Indicated for the treatment of the signs and symptoms of early-stage Parkinson’s disease as monotherapy (i.e. Restless Legs Syndrome)

• Avoidance of 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

Question 18

what are disadvantages of patches and examples

Answer 18

Limitations:
- No exposure to external heat sources: risk of increasing the rate and extent of drug absorption
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

Ex: Rotigotine (Neupro ®) (PD)

Question 19

what are examples of rectal administration medication

Answer 19

• Ex: co-beneldopa (Duodopa ®, PD): gel that is pumped
  continuously through a tube inserted into the intestine (jejunum)
• Absorption of the drug by the blood

Question 20

what are advantages of intestinal gel

Answer 20

• 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
• Ex: co-beneldopa (Duodopa ®, PD)

Question 21

what are advantages and disadvantages of roslutiosn for injection/ infusion?

Answer 21

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 22

when is IV and IM used?

Answer 22

IV: Urgent treatment if seizures lasting longer than 5 min
IV injection of lorazepam
(repeated once after 10 min if seizures fail to respond)

• IM: procyclidine hydrochloride: IM injection for the treatment of acute dystonia (PD)
• Ex: 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 23

what are subcutaneous injection/ infusion

Answer 23

• SC: Apomorphine hydrochloride: treatment of disabling motor fluctuations (“on-off” phenomena) in PD which persist 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)