Kinetics Lecture 10-18 Part 18

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modified-release dosage form is:

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a dosage form having the time course and/or location of the drug release chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms

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conventional dosage forms:

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fast release of the drug at the site of administration

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various types of modified- release products:

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mainly oral, but also transdermal, intramuscular, subcutaneous

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(modified- released products)

extended-release dosage form:

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- the release starts immediately, but is slow
- results in at least two-fold reduction in the dosing frequency

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(modified- released products)

delayed-release dosage form:

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- releases a discrete portion of the dose at a later time, although one portion can be released immediately

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(modified- released products)

targeted-release dosage form:

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- releases drug at or near the intended physiologic site of action

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(extended- released dosage forms)

prolonged-release dosage form

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- releases the drug slowly
- provides a drug continuous supply over an extended period
- oral dosing + all other categories

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(extended- released dosage forms)

sustained- release dosage form

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- delivers an initial (loading) dose immediately

- the loading dose is followed by a slow and constant release

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(delayed-release dosage forms)

enteric-coated tablet

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- the enteric coating is stable in stomach
- it will dissolve in the higher pH of small intestine
- used for drugs irritating stomach and to increase stability of hydrolyzing drugs

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(delayed-release dosage forms)

repeat-release tablet

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- the first dose is released immediately
- the second dose is released later
- saves one administration

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(targeted-release dosage form)

first-order targeting

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drug is delivered to the capillary bed of the site of action

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(targeted-release dosage form)

second-order targeting

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drug is delivered to the surroundings of a special cell type (eg tumor cells)

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(targeted-release dosage form)

third-order targeting

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drug is delivered to intracellular space of the target cells

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pharmacokinetics of modified release products: drug release

release of the drug can be:

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instantaneous (delayed-release)

zero-order process (extended release products, mostly non-oral)

approximately first order process- oral extended-release products

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If the release is not immediate, one more compartment is added to the compartment model:

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dosage-form compartment

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pharmacokinetics of extended-release products I

designed for :

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zero- order release (ideal case)

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for oral products, zero-order kinetics frequently not achieved in vivo due to irregularities in:

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- the stomach (food, change of pH; absorption; agitation

- small intestine (transit time too short: 4-6 hrs

- large intestine (bacteria, lack of water)

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pharmacokinetics of extended- release products II

fast absorption eliminates what compartment?

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dosing compartment

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pharmacokinetics of extended- release products II

fast plasma/tissue equilibriation eliminates what compartment (s)?

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tissue compartment and deep tissue compartment

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Used compartment models

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see pg 2 slide 5

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pharmacokinetics of extended- release products II

for fast absorption and fast plasma/tissue distribution, both two-compartment models will be used in:

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a similar way as previously for slow absorption

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pharmacokinetics of extended- release products II

the rate constant of absorption will be substituted by:

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the rate constant of drug release

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pharmacokinetics of extended- release products II

there are separate descriptions for the zero-order release and the first-order release

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true

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zero-order drug release: time of drug release

drug release proceeds at a constant rate until :

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the amount of the drug in the dosage form is depleted

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zero-order drug release: time of drug release

effective dose is:

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Deff= Fr * D (1)
the drug amount available for release

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zero-order drug release: time of drug release

what is Kro?

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the rate at which the effective dose is released

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zero-order drug release: time of drug release

the time of release is (equation)?

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Fr * D (2)
tr= ---------------
Kro * Vd

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zero-order drug release: time course of plasma concentration

there are 2 phases:

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release phase

elimination phase

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zero-order drug release: time course of plasma concentration

release phase:

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cp --> increasing

cp(t)= Kro/ke * (1-e^-ke*t)

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zero-order drug release: time course of plasma concentration

the elimination phase:
t=tr

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cp --> decreasing

cp(t)= cp(tr) * e^-ke*t

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zero-order drug release: time course of plasma concentration

the elimination phase:
starts at time of administration:

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cp--> decreasing

cp(t)= cp(tr) * e^-ke * (t-tr)

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zero-order release: plasma concentration- time profile II

the rate at which the (ss) is achieved depends on the :

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elimination rate constant, ke

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zero-order release: plasma concentration- time profile II

the duration (length) of the plateau level depends on:

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the dose, D

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zero-order release: plasma concentration- time profile II

during the plateau level, in plasma- rate of release =

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rate of elimination

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at the plateau level, the two rates are equal

equation:

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Kro= ke * cp(ss)

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first order drug release: models and descriptions:

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kr
dosage form compartment ----> central compartment---->
ke

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first-order drug release: time course of the plasma concentration

fast absorption and fast plasma/tissue equilibrium is assumed

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true

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what is peak time?

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the time when the maximum plasma concentration is achieved