Test for drug release for ER and delayed-release articles:

Based on drug dissolution from dosage unit against

elapse time.
Determines dissolution characteristics of modified-
release products.
Demonstrated by either of the 2 methods:

Weight variation

Content uniformity
Critical to development of oral extended-release
products.

Assessing IVICRs is important throughout:
A. product development
B. clinical evaluation
C. submission of an application for FDA approval for
marketing
D. Post approval for any proposed formulation or
manufacturing changes.
Published by FDA in 1997

Provides guidance to sponsors of NDAs for extended-
release oral products.


Developing IVIVC
and evaluating its
predictability
Using an IVIVC to
establish
dissolution
specifications
Applying an IVIVC as a
surrogate for in vivo
bioequivalence during
approval/post approval
for certain formulation or
manufacturing changes.
Level A

Predictive mathematical model for the relationship between
the entire in vitro in vivo dissolution and release time
course and the entire in vivo response time course

Example: time course of plasma drug concentration of
amount of drug absorbed
Predictive mathematical model of the relationship between
summary parameters that characterize the in vitro and in
vivo time courses.

Example: models that relate the mean in vitro dissolution
time to the mean in in vivo dissolution time.
Mean in in vitro dissolution time to the mean residence
time in vivo, or the vitro dissolution rate constant.
Predictive mathematical model between the amount
dissolved in vitro at a particular time and a summary
parameter that characterizes the in vivo time course.
Develop formulations with different release rates or a
single release rate if dissolution is independent of
condition

Obtain in vitro dissolution profiles and in vivo plasma
concentration profiles for these formulations

Estimate the in vivo absorption or dissolution time course
for each formulation and subject using appropriate
mathematical approaches.
In determining in vitro dissolution,
USP dissolution apparatus, type I (basket)
Type II (paddle)
are preferred.

Preferred medium for dissolution is aqueous medium with
pH not exceeding 6.8. If poorly soluble, surfactant may
be added.

Dissolution profiles of at least 12 individual dosage units
from each lot should be determined.

In in vivo studies, human subjects should be in the fasted
state. Accepted data sets have been shown to be
generated with use of 6-36 human subjects.

Crossover studies are preferred, but parallel
studies/cross-study analysis may be acceptable using
common reference treatment product.



Must be specific to the monograph article

Example:
Aspirin delayed-release tablets must state that the tablets
are enteric coated.

Theophylline extended-release capsules must indicate
whether drug dosing is every 12 or 24 hours and state
with which in vivo drug release test the product complies.
Patients should be advised of:
Dose

Dosing frequency

Not to use interchangeably with immediate-release forms
of same drug.

Modified release tablets and capsules should not be
crushed or chewed.

Patients fed by parenteral nutrition may through
nasogastric tube may receive modified-release
medication.

Patients and caregivers should be advised that nonerodible
plastic matrix shells and osmotic tablets:

Remain intact throughout gastrointestinal transit

Empty shells/ghosts from osmotic tablets may be seen in
the stool.


Cervidil vaginal insert (Forest Pharmaceutical)
- rectangular polymeric pouch containing dinoprostone (
Prostaglandin E2) in a cross-linked polyethylene oxide or
urethane polymer releasing the drug at a predetermined
controlled release rate for induction of labor.

Crinone gel (Wyeth-Ayerst)
- contains micronized progesterone and the polymer
polycarbophil in an oil in water emulsion system
-assist in reproduction

Estradiol vaginal ring (Estring pharmacia and Upjohn)
- unique method of administering estradiol
- core of ring contains a reservoir of estradiol which
releases immediately and at a continuous rate of 75ug
per 24 hrs over 90 days
-treatment of urogenital symptoms associated with
postmenopausal atrophy of vagina, inserted into the
upper 1/3 of the vaginal vault and worn continuously

-inserted under the skin by special injectors or by surgical
incision termed implants
-Provides continuous long term through the slow release
medication
EXAMPLES:
Goserelin acetate (zoladex implant, zeneca)
Treatment of advanced prostatic cancer
Biodegradable product for subcutaneous injection with
continuous medication release over a 4-12 week period


Levonorgestrel (Norplant System)
-provides 5 year protection from pregnancy after
subcutaneous insertion


Extended rate of drug action following injection may be
achieved in a number of ways
- use of crystal/amorphous drug forms having prolonged
dissolution characteristics
* slowly dissolving chemical complexes of the drug entity:
solutions or suspensions of drug in slowly absorbed
carriers or vehicles
* increased particle size of drug in suspension
* injection of slowly eroding microspheres of the drug
* slow IV infusion using controlled drug infusion pumps
Problems associated with ophthalmic solutions

*rapid loss of administered drug

* extended products of therapy achieved by:

- formulations increase in contact time between the
medication and the corneal surface by use of agents that
increase viscosity of solutions by ophthalmic suspensions
where drug particles slowly dissolve by slowly dissipating
ophthalmic ointments


Pilocarpine HS Gel
Timoptic XF

Occusert system :
- Elliptical
- Flexible
- Drug containing core surrounded on each side by a layer
of hydrophobic ethylene or vinyl acetate through which
drug diffuses at a constant rate

Lacrisert
- Rod shaped
- Water soluble
- Soften and slowly dissolve
- Thickens precorneal tear film
- Prolonging the tear film breakup