Controlled release

Question 1

What are the challenges with the oral route of delivery?

Answer 1

• Patients with swallowing difficulties
• Masking the unpleasant taste of drugs
• low bioavailability of oral route of ‘problematic drug’

Question 2

What factors affect the rate of gastric emptying of tablets from the duodenum?

Answer 2

• Posture
• Volume of fluid taken
• Calorific value of food taken before or with the dose

Question 3

What is the difference between the principles of controlled and uncontrolled release ?

Answer 3

• Uncontrolled release- there is no formulation constraint on the release of the drug from the delivery system e.g. conventional tablets or capsules
• controlled release- There is a formulation constraint on the release of the drug from the delivery system. e.g. constant-release tablets or capsules or target-release tablets or capsules (such as enteric coated)

Question 4

What is Cmax?

Answer 4

The maximum concentration of drug in the blood (peak)

Question 5

What is Tmax?

Answer 5

The time after dosing at which Cmax is reached

Question 6

What is T1/2?

Answer 6

Time for the drug concentration to reduce by 50%

Question 7

What is AUC?

Answer 7

Area under the curve- amount of drug revived by the patient- exposure

Question 8

Compare the efficacy of a drug with a short half-life with a controlled release formulation:

Answer 8

Drug with a short half-life:
Duration of action is very short
AUC is low
Multiple doses per day are needed
uneven blood levels- uneven therapeutic response

‘constant-release formulation’:
reduce number of doses per day
improved patient compliance
more consistent blood level of drug
improve therapeutic effectiveness

Question 9

Which factors may determine the need for oral controlled release delivery?

Answer 9

Biological factors:
Pharmacokinetics following oral dosing- the activity of drugs in the body e.g. absorption, distribution, excretion
site of action- may want the drug to reach a certain point in the body
Toxicity at specific GI sites

Physiochemical factors:
Acid lability- how easily the drug is destroyed in an acidic environment

Therapeutic factors:|
Timing

Question 10

How do monolith devises of delivery work?

Answer 10

• The classic form of oral controlled release- is when there is a block of material through which a drug is dispersed and released slowly
• Commonly use HPMC ( hydroxypropyl methyl cellulose) as the material as is cheap, safe and easily compressed into tablets. on contact with water, the material will swell to form a viscous gel- the drug will dissolve out of the swollen matrix

Question 11

Give an example of a drug that uses a monolith system

Answer 11

• Geomatrix technology e.g. used in alfuzosin for treating BPH
• The drug swells in the stomach to increase gastro-residence time to 6 hours, 30% release of drug
• 40% of drug is then released in the small intestine for 6 hours
• then last 30% of drug is released in the colon where it resides for around 8 hours

The drug has different barrier layers to control surface area diffusion of the drug from the core

Question 12

What are the drug release kinetics of a monolith system?

Answer 12

• Has zero order kinetics (linear graph through origin)
• Simple- only diffusion controlled release as drug just diffuses out of the gel down a concentration gradient
  Described with Fick’s law:
  J= -D(dc/dx)
  J= flux rate across a surface unit of area
  dc/dx= conc gradient
  D= diffusion coefficient

is a square root relationship between release and time

Question 13

How do membrane limited systems of controlled release work?

Answer 13

• Instead of a matrix through which the drug must diffuse like in the monolith systems, the drug is housed I a reservoir and release is limited by a rate-limiting membrane.
• These systems don’t swell or erode
• The drug is immobile until water penetrates the membrane and forms a channel through which the drug can diffuse out
• commonly used polymers include ethyl cellulose and acrylic copolymers e.g. eudragits- these tend to be very water insoluble and ph sensitive

Question 14

What is an example of a membrane limited system?

Answer 14

• SODAS technology- spheroidal oral drug absorption system
  Involves a multi particulate drug delivery system- has layers including release control polymer, protective caring, core granules of crystals and then a drug layer in the centre

Question 15

How do osmosis controlled symptoms (osmotic pumps) work?

Answer 15

Use of osmotic pressure to pump out a drug at a constant rate from the delivery system.
- Contains a water-soluble core with the drug inside and a water insoluble semi-permeable membrane coating
- Once in the presence of water, the core will solubilise , the water then permeates into the inner core and the drug and excipients will ungergo dissolution/suspension. the osmotic pressure will rise, and the drug is expelled

Question 16

What are the advantages and disadvantages of osmotic pumps?

Answer 16

+ Many drugs are compatible
+ coating technology is cheap and widely used
+ can use zero order release
- size of the hole is important and precision drilling is expensive
- integrity and consistency of coasting is essential and could lead to dose dumping or ineffective release

Question 17

Give an example of an osmotic pump

Answer 17

The OROS technology

Question 18

How do multiple-particulate systems work as controlled release systems?

Answer 18

• Consists of more than one discrete unit typically loaded into capsule shells
  + less likely to lead to dose dumping
  + Possibly reduce gastric irritation
  + can manipulate release mechanism by mixing units with different film thicknesses
• High cost
• Technical issues with coating and capsule filling

Question 19

Give an example of a multi-particulate system

Answer 19

e.g. Micropump technology- provided delayed and extended release of small drugs with a narrow window if absorption in the small intestine

Question 20

Why are gastro-retentive dosage forms desirable?

Answer 20

• Great interest in forms which are retained within the stomach for prolonged periods
• useful for drugs with a narrow intestine window in the intestine
• Good where local action is required e.g. peptic ulcer treatment or oesophagus reflux
• sustained release of drugs that are absorbed rapidly from the GI tract

Question 21

What are the formulation options available for gastroretentive dosage forms?

Answer 21

• Floating systems- make dosage less dense than the gastric fluids so the dose floats. e.g. Gaviscon used to treat oesphageal reflux
• Bioadhesive systems- composed of materials that adhere to biological membranes (e.g. alginates, cellulose derivatives) to form a protective layer on the internal epithelial surfaces of the GI tract
• Swelling systems- the drug expands to a size larger than the pylorus (the opening of the stomach into the duodenum)

Question 22

What is the colon also known as?

Answer 22

The large intestine

Question 23

What are the rationale for targeted controlled delivery to the colon?

Answer 23

• Treatments of local diseases that target the colon e.g. Crohn’s and inflammatory bowel diseases
• chronopharmacology- dosing at specific times of the day e.g. in asthma and arthritis the conditions are worse in the morning- can dose at night and will have effect in colon by morning

Question 24

Discuss rectal delivery as a formulation approach for colonic delivery?

Answer 24

• Insertion of enemas directly into the rectum- spread doses to the more distal areas of the colon
• Little of the drug will reach the proximal colon so is not suitable for diseases in this area
• There is cultural bias among rectal delivery in many countries/cultures

Question 25

Discuss pH controlled systems as a formulation approach for colonic delivery?

Answer 25

• Application of an enteric coating to the capsule/tablet e.g. Eudragit ( methacrylic acid and methylmethacrylate copolymers)
  These materials are insoluble in the acidic conditions of the stomach but will dissolve in areas of higher pH e.g. terminal ileum and colon

Question 26

Discuss timed-release systems as a formulation approach for colonic delivery?

Answer 26

• The average mouth-colon transmit time is used to develop timed controlled release systems
• e.g. the Pulsincap- has an insoluble capsule containing the drug and is sealed with a hydrogel plug. Once in the body, the hydrogel plug slowly hydrates and swells- will become too big and therefore be expelled from the capsule body. This exposes the drug for dissolution.
• e.g. the Egalet- 2-component system: The matrix containing the drug is surrounded by an impermeable, non-eroding shell made from Polylactic acid (PLA). The ends of the matrix is exposed at each end of the shell- a small surface area to slowly be exposed to the GI tract for slo- drug release rate

Question 27

In which two ways can we monitor what the dosage form is doing once inside the body?

Answer 27

• Measure blood levels as a function of time
• Use imaging to see dosage form inside the body e.g. gamma scintigraphy- patient is given radio labelled orange juice. The location of this radiojlabel can be monitored using a gamma camera