Modified-release products

There are two specific guidelines on prolonged-release oral dosage forms (3AQ10a, adopted November 1992) and on modified-release products—oral dosage forms and transdermal dosage forms (CPMP/QWP/604/96, adopted July 1999). The advice in the two documents differs in a number of ways. 

The purpose of this section of an application is to establish that the proposed manufacturing process is suitable and that it will yield consistently product of the desired quality. The concept is closely related to GMP and the detail of conventional manufacturing process validation may not be required. However, data will normally be required for nonstandard manufacturing processes (particularly nonstandard sterilization processes) and for those aspects of manufacture that are critical in terms of product quality, e.g., in the manufacture of modified-release products the quality, safety, or efficacy of which will be affected by the method of manufacture. 

Committee for Proprietary Medicinal Products (CPMP). Note For Guidance on Quality of Modified Release Products A. Oral Dosage Forms and B. Transdermal Dosage Forms Section I (Quality), July 1999. 

That said, the task should not be overcomplicated, and many good instances exist to illustrate successful conclusions to such efforts. For example, the data shown in Table 12 illustrate the scaling-up of the Wurster process in which an aqueous latex coating has been applied to drug-loaded pellets in order to prepare a modified-release product. It is appropriate to point out that since the 32" Wurster essentially comprises three 18" Wurster units, the airflow used in the former represents approximately a threefold increase over that of the latter, with the result that the spray rate is scaled... 

Visual inspection of a plot of response versus concentration will show a straight line. The correlation coefficient (r), residual sum of squares, and v-intercept should be reported. In the case of the dissolution profile for a modified release product, 20% of the stated range will need to be prepared. For example, a range of 0 to 110% of release will be required for a profile of 20 to 90% release. 

ORAL MODIFIED-RELEASE PRODUCT DESIGNS FOR WATER-INSOLUBLE DRUGS MODELS, THEORIES,... 

H. H. Blume, B. S. Schug, H. Potthast, Influence of food on the bioavailability of controlled/modified release products, Food-Drug Interactions (J. Kuhlmann, T. R. Weihrauch, eds.), W. Zuckschwerdt Verlag, Miinchen, Germany, 1995, pp. 25-33. 

Complex dosage forms, such as modified-release products, transder-mal patches, metered-dose inhalers... 

Modified-Release Products. Modified-release products include delayed-release products and extended (controlled)-release 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. 

Data from subjects who experience emesis during the course of a BE study for immediate-release products should be deleted from statistical analysis if vomiting occurs at or before two times median Tmax. In the case of modified-release products, the data from subjects who experience emesis any time during the labeled dosing interval should be deleted. 

EU CPMP (1999) Note for Guidance on Modified Reiease Orai and Transdermaf Dosage Forms Section II (Pharmacokinetic and Clinical Evaluation) July 1999 EU CPMP (2001) Note for Guidance on the Investigation of Bioavailability and Bioequivalence. July 2001 EU CPMP (2003) Points to Consider on the Clinical Requirements of Modified Release Products Submitted as a Line Extension of an Existing Marketing Authorization December 2003... 

One of the special situations for drug delivery is the assessment of the pharmacokinetic (PK) properties of a modified release formulation. Modified release products always gain importance if the PK/PD profile of a drug is not close to optimal for its target indication, mostly because the (short) PK or efficacy half-life does not match the intended dosing frequency. 

Details on the design, objectives and interpretation of bioavailability studies on modified release products can be found in the literature. 

The design of an exploratory bioavailability study on modified release drug products is presented below. For the design of the study information from a recent BA study with other modified release products, from a site-of-absorption study and from a modeling simulation experiment was used. 

Anonymous (1999, July), Note for guidance on quality of modified release products. Oral dosage forms and transdermal dosage forms, section 1 (quality), The European Agency for the Evaluation of Medicinal Products Human Medicines Evaluation (EMEA), London. 

Intravenous administration, or the use of enteric-coated formulations or modified-release products all appear to reduce the risk both of bleeding and more particularly of erosions/ulceration. However, because of the indirect effect noted above, such formulations do not eliminate the risk, although they may reduce the incidence of... 

Experimentally, potassium chloride is frequently used as a model drug in the development of new solid-dosage forms, particularly for sustained-release or modified-release products. 

A dissolution test procedure identified in the pharmacopoeia, generally a one time point dissolution test for immediate-release products and a three or more time points dissolution test for modified release products. multisource pharmaceutical products... 

Modified-release products include extended-release products and delayed-release products. Extended-release products are variously known as controlled-release, prolonged-release and sustained-release products. 

The comparator product in this study should be a pharmaceutically equivalent modified-release product. The pharmacokinetic bioequivalence criteria for modified-release products are basically the same as for conventional-release dosage forms. 

Level C correlation This correlation describes a relationship between the amount of drug dissolved (e.g., percent dissolved in one hour) at one time point and one pharmacokinetic parameter [e.g., either area under the curve (AUC) or Cmaxl-Level C correlation is considered the lowest correlation level as it does not reflect the complete shape of the plasma concentration time curve. Similarly, a multiple Level C correlation relates one or more pharmacokinetic parameters to the percent drug dissolved at several time points of the dissolution profile and thus may be more useful. Levels B and C correlations can be useful in early formulation development, including the selection of the appropriate excipients, optimization of manufacturing processes, for quality control purposes, and characterization of the release patterns of newly formulated immediate-release and modified-release products relative to the reference. 

The importance and need to study these factors increases if the substance has problematic absorption properties, or if the aim is to develop an advanced formulation, such as a modified release product, or if a dosage form affects the biopharmaceutical properties in any other way. 

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