MODIFIED RELEASE DOSAGE FORM

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MODIFIED RELEASE DOSAGE FORM

• by
• A. S. Adebayo, PhD

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Introduction

• Modified release dosage forms are drug delivery
  systems (DDS) which, by virtue of formulation and
  product design, provide drug release in a
  modified form distinct from that of the
  conventional dosage forms. Drug release can
  either be delayed or extended in nature.

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Delayed-release products

• Usually enteric coated tablets or capsules
  designed to pass through the stomach unaltered to
  release their medication within the intestinal
  tract.

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Extended-release products

• Designed to release their medication in
  controlled manner, at pre-determined rate,
  duration and location in the body to achieve and
  maintain optimum therapeutic blood levels of
  drug.

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Rationale for extended release pharmaceuticals

• Drugs that are not inherently long lasting
  require multiple daily dosing to achieve the
  desired therapeutic effects.
• Multiple daily dosing is often inconvenient and
  can result in missed doses, made-up doses and
  patient non-compliant with therapeutic regimen.
• Blood levels of drugs from conventional
  immediate-release dosage forms taken more than
  once daily following definite schedule usually
  demonstrate sequential peaks and troughs
  (valleys) associated with each dose.

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Rationale for extended release pharmaceuticals

• Extended release tablets or capsules are commonly
  taken only once or twice daily compared with the
  conventional dosing of 2 to 4 times daily
• Products are designed to provide an immediate
  release of drug which promptly produces the
  desired therapy, followed by gradual and
  continual release of additional amounts of drug
  to maintain this effect over a predetermined
  period of time.
• The need for night dosing of drugs may be
  eliminated

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Advantages of Extended-release Dosage Forms over
Conventional Forms

• Reduction in drug blood level fluctuations
• Reduction in frequency of dosing
• Enhanced patient compliance
• Reduction in incidence of adverse side effects
• Reduction in overall healthcare costs.

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Terminology

• The following terms have been applied to
  extended or sustained drug delivery systems
• Controlled-release
• Extended release (ER)
• Sustained-release (SR)
• Timed-release (TR)
• Long-acting (LA)
• Prolonged-action (PA), and
• Sustained-action (SA)

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Extended-release dosage forms

• The US FDA defines ER dosage form as
• one that allows a reduction in dosing frequency
  to that presented by a conventional dosage form
  such as a solution or an immediate release dosage
  forms.

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Delayed-release

• These are dosage forms designed to release the
  drug at a time other than promptly after
  administration.
• The delay may be time-based or based on the
  influence of environmental conditions such as
  g.i. pH, enzyme, pressure, etc

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Repeat action

• These are dosage forms usually containing 2
  single doses of medication, one for immediate and
  the second for delayed release e.g. bi-layered
  tablets.

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Targeted release

• Drug release that is directed towards isolating
  or concentrating a drug in a body region, tissue,
  or site for absorption or drug action

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Extended-release Oral Dosage Forms

• The general properties of drugs best suited for
  ER product design are
• They exhibit neither very slow nor very fast
  rates of absorption and excretion
• They are uniformly absorbed from the g.i.t.
• They are administered in relatively small doses.
• They possess a good margin of safety i.e.
  Therapeutic Index (TI)

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Technology of ER Dosage Forms

• ER Coated Beads, Granules or Microspheres
• Granules of drug may be coated with lipid
  materials such as beeswax, carnuba wax, glyceryl
  monostearate, cetyl alcohol, etc.
• Careful blending of coated and un-coated
  granules and with coatings of different
  thicknesses will provide drug release of desired
  characteristics.

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COMMERCIAL EXAMPLES

• Toprol-XL (metoprolol succinate) tabs. (Astra)
• Indocin SR (indomethacin capsules (Merck)
• Compazine (prochloperazine) Spansule Capsules
  (SmithKline Beecham)

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Technology of ER Dosage Forms - Multitablet
system
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Technology of ER Dosage Forms

• Embedding drug in slowly eroding or hydrophilic
  matrix system The design comprises of the drug
  substance plus excipient material that slowly
  erodes in body fluids thereby progressively
  releasing the drug for absorption
• E.g. Quinidex Quinine SO4 tablets (Robins)
  Oramorph SR Morphine SO4 tabs. Roxane

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Technology of ER Dosage Forms ER
Microencapsulated Drug

• Microencapsulation is a process by which solids,
  liquid and semi-solid substances may be
  encapsulated into microscopic size particles
  through the formation of thin coating of wall
  material around the substance.
• Different rate of drug release can be obtained by
  changing the core to wall ratio, the type of
  polymer coat and the method of microencapsulation.
  
• E.g. K-Dur Microburst Release System (KCl) tabs.
  (Key)

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Technology of ER Dosage Forms Osmotic pump
device

• This consists of a core tablet surrounded by a
  semi-permeable membrane coating with a 0.4 mm
  diameter hole produced by laser beam.
• The core tablet has 2 layers, one containing the
  drug (the active layer) and the other
  containing the polymeric osmotic agent (the
  push layer).
• E.g. Glucotrol XL (glipizide) tablets (Pfizer)
• Covera HS (verapamil HCl) tabs. (Searle)

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Other methods

• Embedding drug in an inert plastic matrix e.g.
  Desoxyn (methamphetamine HCl) tabs (Abbott)
  Procanbid (procainamide HCl tabs. (Parke-Davis)
• Complex formation
• Ion exchange resins

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Kinetics of Drug release

• Drug release from conventional dosage forms, like
  the other processes of ADME, are governed by the
  first-order kinetics model.
• In First-order model, drug release is dependent
  on the amount of drug available for release and
  therefore the rate of release declines
  exponentially with time.

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Kinetics of Drug release

• Extended release dosage forms are governed by
  zero-order kinetics in which the rate of release
  is independent of amount of drug remaining in the
  dosage form.
• Therefore a constant amount of drug will be
  released over time from extended release dosage
  forms

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Assignments (Due Feb. 4, 2010)

• Identify 3 controlled release formulation
  excipients, giving chemical and commercial names
• What is the kinetic mechanism of drug release
  followed by Osmotic controlled delivery devices?
• Using a suitable graph, illustrate the profile
  that would be observed in the following
  scenarios
• Burst release at peal plasma level
• Design failure leading to Dose dumping
• Design failure leading to drug being withheld

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MODIFIED RELEASE DOSAGE FORM
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