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									               MODIFIED RELEASE
               DOSAGE FORM

                        A. S. Adebayo, PhD

Tuesday, May 29, 2012                        1

      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

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Rationale for extended release
     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
    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

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Advantages of Extended-release
Dosage Forms over Conventional

      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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   The following terms have been applied to
    “extended” or “sustained” drug delivery
         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
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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      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
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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    Toprol-XL® (metoprolol succinate) tabs.

    Indocin SR ® (indomethacin capsules

    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

      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
           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

      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.

      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

     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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