Embedding drug in Slowly Eroding or Hydrophilic Matrix System

The drug substance is combined and made into granules with an excipient material that slowly erodes in body fluids, progressively releasing the drug for absorption. Hydrophilic cellulose polymers
- commonly used as excipient base in tablet matrix systems - Hydroxypropyl methylcellulose (HPMC)

Embedding Drug in Inert Plastic Matrix

The drug is granulated with an inert plastic material such as polyethylene, polyvinyl acetate, or polymethacrylate, and the granulation is compressed into tablets.

Complex Formation
Form complexes that may be soluble in body fluids, depending on the pH of the environment. The slow dissolution rate provides extended release of the drug.
Salts of Tannic acid, Tannates, provide this quality in a variety of products.

Ion Exchange Resins

The release of the drug depends on the pH and electrolyte concentration in the gastrointestinal tract. Release is greater in the acidity of the stomach than in the less acidic environment of the small intestine.

Osmotic Pump
The system is composed of a core tablet surrounded by a semipermeable coating having a 0.4mm diameter hole produced by laser beam.
The core tablet has 2 layers, one containing the drug and the other containing a polymeric osmotic agent. The system is designed such that only a few drops of water are drawn into the tablet every hour.

Repeat Action Tablets

Prepared so that an initial dose of drug is released immediately and a second dose follows later. In general, the drug from the inner core is exposed to body fluids and released 4 to 6 hours after administration.

Delayed Release Oral Dosage Forms

Release of a drug that may be intentionally delayed until it reaches the intestines for several reasons.

Properties of Enteric Coated Tablets

pH dependent
Breaks down in the less acidic environment of the intestine.

Time dependent
Enzyme dependent

Erodes by moisture over time during gastrointestinal transit.

USP REQUIREMENTS AND FDA GUIDANCE FOR MODIFIEDRELEASE DOSAGE FORMS

Drug Release
Test for drug release for ER and delayed-release articles: dissolution form the dosage unit against elapsed time

Example
Aspirin Extended-Release tablet

Uniformity of Dosage Units

Uniformity of dosage units may be demonstrated by either of two methods:

weight variations or content uniformity

In Vitro-In vivo Correlations

Critical to the development of oral extended-release products
Important throughout product development ,clinical evaluation submission of an application for FDA approval for marketing, & during post approval for any proposed formulation or manufacturing changes it provides guidance to sponsors of new drug applications and abbreviated new drug applications and abbreviated new drug applications for extended release of oral products

IVIVC provides methods of:

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

3 Categories of IVIVCs include in the document

Level A
the relationship between the entire in vitro dissolution and release time course and the entire in vivo response time course Example: the time course of plasma drug concentration or

Level B
predictive mathematical model of the relationship between summary parameters that characterize in vitro and in vivo time courses Example: models that relate the mean in vivo dissolution time to the mean in vitro dissolution time

Level C
a predictive mathematical model of the relationship between the amount dissolved in vitro at a particular time and a summary parameter that characterizes the time in vivo time course or area under the curve the level of IVIVCs may be useful in the early stages of formulation development when pilot formulations are being selected

MOST COMMON PROCESS FOR DEVELOPING IVIVC MODEL (LEVEL A)

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

CRITERIA IN DEVELOPMENT APPLICABLE TO THE DEVELOPMENT OF IVIVCS ARE THE FOLLOWING:

in determining in vitro dissolution, USP dissolution apparatus; type I (basket) or type II (paddle) is preferred, although type III (reciprocating cylinder) or type IV (flow-through cell) may be applicable in some substances
aqueous medium with a pH not exceeding 6.8 is preferred as the medium for dissolution studies. For poorly soluble drugs, a surfactant may be added

CRITERIA IN DEVELOPMENT APPLICABLE TO THE DEVELOPMENT OF IVIVCS ARE THE FOLLOWING:

The dissolution profiles of at least 12 individual dosage units from each lot should be determined for vivo studies, human subjects are used in the fasted state unless the drug is not well tolerated, in which case the studies may be conducted in the fed state. Acceptable data sets have been shown to be generated with use of 6 to 36 human subjects

CRITERIA IN DEVELOPMENT APPLICABLE TO THE DEVELOPMENT OF IVIVCS ARE THE FOLLOWING:

Crossover studies are preferred, but parallel studies or cross-study analysis may be acceptable using a common reference treatment product, such as an intravenous solution, an aqueous oral solution, or an immediate-release product

LABELING
They must be specific for the monograph article
Aspirin delayed-release tablets must state that the tablets are enteric coated Capsules must indicate whether the product is intended for dosage every 12 to 24 hours and state which in vitro drug release test the product complies

CLINICAL CONSIDERATIONS IN THE USE OF ORAL MODIFIED-RELEASE DOSAGE FORMS

Not to be used interchangeably or concomitantly with immediate-release forms of the same drug patients using a modified release product should not be changed into immediate release without consideration to the blood concentration

patients should not be changed to another extended-release product unless there is assurance of equivalent bioavailability
Different product can result in a marketed shift in the patients drug blood level because of differences in drug release characteristics

Modified release tablets and capsules should not be crushed or chewed Patients if fed through the nasogastric tube may receive modified- release medications

Non-erodible plastic matrix shells and osmotic tablets remain intact throughout gastrointestinal transit and the empty shells or ghosts from osmotic tablets may be seen in the stool