Extended-release drug products

Modified Release Dosage Forms Dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form. Modified release solid oral dosage forms include both delayed and extended release drug products. 

Typically, coatings (e.g., enteric coatings) are intended to delay the release of medication until the dosage form has passed through the acidic medium of the stomach. In vivo tests for delayed-release drug products are similar to those for extended-release drug products. In vitro dissolution tests for these products should document that they are stable under acidic conditions and that they release the drug only in a neutral medium (e.g., pH 6.8). 

This guidance recommends that the following BA studies be conducted for an extended-release drug product submitted as an NDA ... 

BE studies are recommended when substantial changes in the components or composition and/or method of manufacture for an extended-release drug product occur between the to-be-marketed NDA dosage form and the clinical trial material. 

Mauger DT, Chinchilli VM. In vitro-in vivo relationships for oral extended-release drug products. J Biopharm Statist 1997 7(4) 565-578. 

Modified Release In this type of release dosage forms include both delayed and extended - release drug products. Delayed release is defined as the release of a drug at a time other than immediately following administration, while extended release products are formulated to make the drug available over an extended period after administration [114]. 

These dosage forms include tablets, capsules, solutions, suspensions, conventional/immediate release, and modified (extended, delayed) release drug products. 

An NDA can be submitted for a previously unapproved new molecular entity, or for a new salt, new ester, prodrug, or other noncovalent derivative of a previously approved new molecular entity, formulated as a modihed-release drug product. The first modified-release drug product for a previously approved immediate-release drug product should be submitted as an NDA. Subsequent modified-release products that are pharmaceutically equivalent and bioequivalent to the listed drug product should be submitted as ANDAs. BA requirements for the NDA of an extended-release product are listed in 320.25(f). The purpose of an in vivo BA study for which a controlled-release claim is made is to determine if all of the following conditions are met. 

The study described here has a very complex design for its exploratory approach. It combines four different extended release formulations, each tested under fasting and non-fasting conditions, and compares the results to the immediate release drug product as the reference formulation. The bilayer tablets combines an immediate release component and an extended release component in one vehicle. In this project a close cooperation between the galenics department and the clinical pharmacokinetic function was mandatory. The in vitro/in vivo correlation was done by means of the deconvolution which is an appropriate surrogate to describe the in vivo dissolution. 

For Suspension, Extended Release A product, usually a solid, intended for suspension prior to administration once the suspension is administered, the drug will be released at a constant rate over a specified period. 

The jejunal perfusion approach generates data, which may be used to predict absorption/bioavailability and to establish in viva-in vitro correlation even for extended-release (ER) products. If a drug is transported mainly by passive diffusion and has a jejunal eff higher than that for metoprolol (1.5 x 10 4 cm/s = high-permeability compound), it can be expected to be completely absorbed throughout the small and large intestines [5, 51]. 

Traditionally, the ideal extended-release product has been conceived as providing essentially stable blood levels over the whole dosing frequency interval. Thus, unlike the saw-edge blood concentration time profile of a non-controlled-release product that may show rather wild fluctuations between sub- and su-pratherapeutic blood levels, the ideal extended-release product avoids both nontherapeutic blood levels and those likely to have an increased frequency of dose-related side effects. However, in recent years con-trolled-release products that deliberately exploit a pulsatile drug release time profile have also attracted attention. 

Over the years, dissolution testing has expanded beyond ordinary tablets and capsules—first to extended-release and delayed-release (enteric-coated) articles, then to transder-mals, multivitamin and minerals products, and to Class Monographs for non-prescription drug combinations. (Note at the time, sustained-release products were being tested, unofficially, in the NF Rotating Bottle apparatus). 

This equipment has one calibrator tablet a single tablet product, chlorpheniramine extended-release tablets (drug-release calibrator, single unit). It has been found that this equipment is not particularly sensitive to vibration and has reliable and consistent operation (17). 

Additional criteria for waiver of evidence of in vivo BA/BE are given in 21 CFR 320.22 (d)(3). For certain solid oral dosage forms (other than a delayed or extended-release dosage forms), a waiver for the submission of in vivo evidence of BA/BE is possible if the drug product has been shown to meet the requirements of an in vitro dissolution test, which in turn has been shown to correlate with in vivo data. A biowaiver may also be addressed to a reformulated solid oral dosage form identical to another drug product except for color, flavor, or preservatives for which the same manufacturer has obtained approval, if BA data are available for the approved... 

For an extended-release dosage form, at least three test time points are chosen to characterize the in vitro drug-release profile for the routine batch-to-batch quality control for approved products. Additional sampling times may be required for formulation development studies, biopharmaceutical evaluations, and drug approval purposes. An early time... 

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