ABSTRACT
JEROME PHILIP SKELLY / Center for D r u g s and Biologies, Food and Drug Adminis t rat ion, Rockville, Maryland
WILLIAM H. BARR / Medical College of Virginia, Richmond, Virginia
I . In t roduct ion 294
I I . Terminology 294
III . Rationale for Controlled Release Dosage Forms 296
IV. Potential Pharmacodynamic Problems with
Continuous Release Produc t s 298
V. Ideal Input Function 299
VI. Potential Bioavailability Problems of Oral Controlled Release Products 304 A. Gastrointest inal Trans i t Times and Regional
Absorpt ion 304 B . Decreased Systemic Availability due to
Incomplete Absorption 304 C. Decreased Bioavailability due to Increased
Firs t Pass Metabolism 305 D. Dose Dumping 305 E. Effect of Food 306 F . Effect of Diurnal Variation 306 G. Increased Variability 307
VII. Dissolution Rate--Assessment 309
VIII . Biopharmaceutic Considerations in the Regulatory Assessment of Controlled Release Produc t s 321
A. Demonstration of Safety and Efficacy of Controlled Release Drugs 322
B . Submitted Data 323 C. Recommended Reference S tanda rd for
Comparative Studies 324 D . Demonstration of a Produc t ' s Controlled
Release Nature 325 E. Considerat ion for Specialized Controlled
Release Drug Delivery Systems 328
References 332
I . INTRODUCTION
A discussion of regula tory assessment is usually limited to p rov id ing an explanation of the governing regu la t ions , how they should be implemented and the t y p e of s tud ies that should be conducted in o r d e r to provide t he r equ i r ed da ta . The area of controlled release d r u g del ivery is evolving so rapidly that it is necessa ry to go beyond defini t ions, regulat ions and data r equ i remen t s . Accordingly, it is our intent ion to also d iscuss the rationale and pharmacokinetic basis of controlled release labeling claims, types of problems that can be anticipated with controlled release d r u g p r o d u c t s , and type of s tudies necessa ry to es tabl ish labeling claims and rule out problems. In addi t ion, the complex relat ionship of in vitro dissolution ra te da ta to in vivo blood level da ta for controlled release p roduc t s will be explored and compared to the simpler relat ionships found with conventional release dosage forms.
