oral modified release drug delivery systems

define the limits of therapeutic range

above the minimum effective concentration

below the minimum toxic concentration

what happens if the drug concentration exceeds minimum toxic concentration

side effects will be experienced

what is the main function of the intestine

to extract nutrients and absorb them

what is the difference between immediate release (IR) or modified release (MR)

• IR is when the drug is released faster so quicker onset

• MR is when the drug is released slower and delayed so drug is released further down GIT

official definition of modified release systems

where formulations are prepared using substances or procedures (which separately or together) are designed to control the rate or place at which active ingredients are released in GI tract

name the 2 types of oral modified release systems

• delayed release DR

• extended release ER

true or false: delated release systems are also known as gastro-resistant or enteric systems

true

how do delayed release systems work

• thin coating is applied to tablet/capsule/pellet surface

• coating delays the release of drug to small or large intestine

what factor determines when the drug is released from tablet

pH of the delayed release coatings

at what pH would the drug be if target is:

• small intestine

• stomach

• large intestine

• small intestine = pH > 5-6

• stomach = pH 1.5

• large intestine = pH > 7

• if you want to deliver drug to [first/end] part of small intestine, then use coating which dissolves at pH 5.6-6

• if you want to deliver drug to [first/end] part of small intestine, then use coating which dissolves at pH 7.4

• if you want to deliver drug to [first/end] part of small intestine, then use coating which dissolves at pH 5.6-6

• if you want to deliver drug to [first/end] part of small intestine, then use coating which dissolves at pH 7.4

what functional group do all pH sensitive polymers have

carboxylic acid

what happens to the carboxylic acid group of polymers at:

• low pH in the stomach

• higher pH in the intestine

• low pH in the stomach - COOH remains unionised so does not dissolve

• higher pH in the intestine - ionises and becomes COO- so dissolves

examples of pH sensitive polymers

• polyvinyl derivatives

• polymethacrylates

how do enteric coated systems for delayed release targetting the colon work

the drug and tablet remain intact until the start of the large intestine where enteric coating dissolves and drug enters and is carried throughout large intestine

what is Phloral colonic coating

dual trigger coating system designed to deliver drugs to colon specifically by combining pH sensitive release (responds to intestinal pH) and microbiota triggered release (responds to colonic bacteria)

what are the 2 components that make up the Phloral outer coating

• pH-sensitive polymer (e.g. Eudragit)

  • insoluble in stomach and small intestine

  • dissolves at pH < 7

  • acts as the first trigger

• polysaccharide (e.g. resistant starch)

  • not digested in upper GI tract

  • specifically broken down by colonic bacteria

  • acts as second trigger

true or false: the 2 polymers in Phloral outing coating are mixed together into a single coating layer

true - not 2 separate coats

advantages of Phloral outer coating vs normal coating

• two independent triggers so more reliable targetting

• reduces premature drug release due to variable gut pH

• ideal for GI disorders lower in GIT e.g. ulcerative colitis, Crohn’s colitis

what is the purpose of extended release systems

to reduce frequency of dosing

advantages of extended release systems

• maintenance of therapeutic plasma levels

• improved patient compliance

• economics

what are some synonymous names of extended release

• controlled release

• sustained release

• prolonged release

• slow release

what does the conc-time graph for extended release drug systems look like

define half life

• rate of elimination of drug from the body

• how quickly drug is metabolised by liver

what is the ideal half life range for drug

4-6hrs

why is it difficult to formulate drugs into MR system if drugs have half life < 2hrs

because large doses would be necessary

why does a half life of 8hrs mean its unnecessary to modify drug into MR system

because it already naturally takes a long time to be metabolised

what are the disadvantages of extended release systems

• drugs with absorption windows

• drugs with short half lives

• variable conditions/transit time through GIT

• size of formulation

• dose-dumping

• expensive

what is an absorption window

some drugs are only absorbed efficiently in specific region of GIT like stomach or duodenum - this region is called absorption window

why are absorption windows a limitation for ER systems

• ER systems are designed to release drug slowly along whole GIT

• once drug moves past absorption window, any drug later is poorly/not absorbed

• reduces bioavailability and increases variability between patients

why are short half life drugs a limitation for ER systems

because ER releases drug slowly so the drugs with short half lives are eliminated faster than released and plasma levels may not reach therapeutic levels

how can transit time affect drug release

• rapid transit

• slow transit

• pH variation

• Rapid transit → incomplete drug release

• Slow transit → risk of over-release

• pH variation → coating dissolves too early or too late

why are ER tablets/capsules larger in size

because ER systems require:

• large amounts of polymer

• multi layers

this means difficulty swallowing and not suitable for elderly or paediatric patients

what is dose dumping

unintended rapid release of entire drug dose form ER system

why does dose-dumping occur

due to:

• coating failure

• alcohol interaction

• mechanical damage (chewing or crushing)

• manufacturing defects

why is dose-dumping dangerous

increased risk of:

• toxicity

• side effects

• overdose

why are ER systems more expensive

• Specialized polymers

• Complex manufacturing

• More stringent quality control

• Stability testing requirements

difference between single unit and multi-unit systems

• single unit - tablets and capsules

  • dose of drug within single unit

• multi-unit - pellets, mini-tablets and granules

  • dose of drug distributed among several units

advantages of multi-unit systems

• drug is distributed along various units smaller in size

• spread easily throughout GIT

• more expensive to make than single unit

what are the 3 main mechanisms of extending drug release

• dissolution controlled release

• diffusion controlled release

• osmosis

describe the dissolution controlled release mechanism

• polymeric coating takes time to dissolve

• this means drug also takes time to come out

describe diffusion controlled mechanism

• coating does not dissolve

• GI fluid goes into system

• drug is dissolved

• drug moves out of system and is released

examples of coatings or reservoirs

difference between dissolution and diffusion systems

• Dissolution systems = coatings will dissolve

  • dissolution system takes a long time to dissolve so takes a while for drug to come out

Vs

• Diffusion systems = coating does not dissolve

  • Diffusion system remains intact but it’s a physical barrier through which the drug has to diffuse which takes a long time

how does the osmotic system release drug

• semi permeable polymer coating

  • fluid can enter

  • drug cannot leave

• GI fluid enters system through semi permeable coating

• fluid dissolves drug and osmotic agent

• KCl builds up osmotic pressure

• to reduce pressure, drug is released out of tablet over long time through the osmotic delivery orifice (hole in coating)

summary of osmotic system