Solid Oral MR Dosage Forms - Membrane-controlled, Osmotic, Gastro-retentive, & Repeat Action Systems

Membrane-controlled system

drug-rich core is surrounded by a polymer film or membrane

Membrane-controlled system on exposure to GI fluids

• water diffuses into system

• drug dissolves within the core

• dissolved drug then diffuses out

Factors controlling release of membrane-controlled systems

• membrane thickness

• membrane porosity

• drug solubility in GI fluids

Osmotic (OROS) system

• tablet core contains drug plus osmotic agents and excipients

• core is coated with semipermeable membrane that allows water in but not solutes

• small orifice is drilled or formed in coating

Osmotic system upon entering GI tract

• water diffuses through semipermeable membrane into the core

• core excipients and drug dissolve or form suspension

• osmotic pressure builds inside, pushing drug out through orifice

Factors controlling release of osmotic systems

• water permeability of the membrane

• thickness of membrane

• osmogen concentration in the core

• viscosity of internal drugs solution/suspension

• size & integrity of orifice

Biopharmaceutical considerations of osmotic systems

• require adequate GI fluid to build osmotic pressure

• must remain in absorptive region (stomach & small intestine) for designed duration

What will happen if a 12-hour osmotic system has a shorter transit?

not all drug will be released or absorbed

What are the differences between osmotic & membrane-controlled systems?

• only one diffusion process is required for osmotic system: “water in”

• components of osmotic membrane are biologically inert and are eliminated in feces as an insoluble shell

Gastro-retentive system

prolongs residence time of a dosage form in the stomach to:

• enhance local treatment

• maximize absorption of drugs with narrow absorption window

• avoid exposure to the colon for drugs degraded there

difficult to achieve

Strategies for gastro-retentive system

1. mucoadhesive system

2. floating systems

3. size-increasing systems

Mucoadhesive system

dosage form adheres to gastric mucosa via mucoadhesive polymers; mucus turnover is rapid, strong gastric motility in humans often prevents long-term adhesion

Floating systems

dosage form floats on stomach contents, staying above pylorus with use of gas-generating agents or low-density lipids; requires adequate gastric contents, limited clinical proof for drug delivery

Size-increasing systems

tablet expands after ingestion to a size too large to pass through pylorus using swellable polymers; must be dosed in fed state

Repeat action tablets

deliver two separate doses in a single dosage form

• 1st dose: released immediately

• 2nd dose: later as a second dose or extended-release manner

What separates the inner core and outer coating of repeat action tablets?

slowly permeable/barrier coating; GI fluids gradually penetrate barrier to trigger second dose

Can all drugs be formulated in extended-release dosage forms? Why/why not?

no, designing an ER product requires considering both drug characteristics and therapeutic indication; drugs must be able to be:

• released at a controlled rate

• dissolved in GI fluids

• retained long enough in GI tract

• absorbed consistently

Class I drug candidacy for ER dosage forms

generally ideal, especially if they rely on passive diffusion

Class II drug candidacy for ER dosage forms

drugs dissolve slowly, sometimes showing inherent “sustained release” behavior

Class III drug candidacy for ER dosage form

absorption is already the slow step, making an ER system useless and may reduce total exposure

Class IV drug candidacy for ER dosage forms

most challenging to formulate as modified-release products; suffer from both poor dissolution and poor absorption

Ideal t½ for ER design

• moderately short ~4-6 hours

• very long may already produce “pseudo-sustained” profiles

• very short may require very large dose to maintain therapeutic levels

Ideal therapeutic index for ER dosage forms

• drugs the possess wide therapeutic indices

• narrow therapeutic indices:

  • limited in precise control over release rate

  • risk of dose dumping

  • patient misuse can result in toxic drug level

Dose dumping

the unintended, rapid release of a large amount of drug from a modified-release dosage form

Dose dumping cause

• failure or damage of release-controlling coating/membrane

• chewing, crushing, or splitting modified release tablets/capsules, or taking with alcohol

Consequences of dose dumping

sudden increase in plasma drug concentration leading to acute toxicity or sever adverse effects