Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Chemical analysis
Reexamination Certificate
2001-11-05
2004-09-28
Hoff, Marc S. (Department: 2857)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Chemical analysis
C702S022000, C702S024000, C702S050000
Reexamination Certificate
active
06799123
ABSTRACT:
BACKGROUND
The rate at which pharmaceutically active compounds dissolve in gastrointestinal fluids is of crucial importance in the design and use of orally administered medications. The active compound must be dissolved before it can be absorbed by the body. The rate at which the active substance enters into solution is know in the art as the dissolution rate, and the determination of the dissolution rate in vitro is known as dissolution testing.
The concept of using in vitro data to predict or model in vivo behavior, referred to as in vitro—in vivo correlation, or IVIVC, is of great interest to the pharmaceutical arts. Test methods with good IVIVC are much more capable of detecting problems with existing formulations and in the development of new formulations. Systems which correlate closely with the dissolution and absorption data obtained in vivo can be used in developing dosage forms as well as in the production, scale-up, determination of lot-to-lot variability, testing of new dosage strengths, testing of minor formulation changes, testing after changes in the site of manufacture and for determining bio-equivalence.
Various methods and devices for dissolution measurement are well known and described in the art.
The US Food and Drug Administration (US FDA) has issued guidelines on the levels of correlation that are more or less desirable in in vitro testing (Guidance for Industry, Extended Release Oral Dosage Forms: Application of In vitro/In vivo Correlations, September 1997). A Level A correlation is one that predicts the entire in vivo time course from the in vitro data. A Level B correlation is one that uses statistical moment analysis. The mean dissolution time is compared either to the mean residence time or to the mean in vivo dissolution time. A Level C correlation establishes a single point relationship between a dissolution parameter and a pharmacokinetic parameter. Level B and Level C correlations do not reflect the complete shape of the plasma concentration-time curve. A Multiple Level C correlation relates in vitro data at several time points to several pharmacokinetic parameters. It is generally considered that if a multiple level C is possible, then Level A correlation should also be possible. Rank order correlations are those where only a qualitative relationship exists between in vitro and in vivo.
A Level A correlation is considered to be the most informative and is recommended by the USFDA wherever possible. Multiple Level C correlations can be as useful as Level A, but a Level A is preferred. Single point Level C correlations are considered useful only in the early stages of formulation development. Level B correlations are the least useful for regulatory purposes. Rank order correlations are not considered useful for regulatory purposes.
Having a high level of correlation, eg Level A, can reduce the amount of in vivo testing necessary for new formulations and can therefore be very valuable to pharmaceutical companies.
The US Pharmcopeia (USP24, pages 1941-1951) describes seven different sets of apparatus for performing dissolution testing. Apparatus 1 and 2 in section <711> (pages 1941-1942) are essentially containers with a suitable stirring device into which is placed a fixed volume of dissolution medium, and the formulation being tested. Samples of the medium are withdrawn at various times and analyzed for dissolved active substance to determine the rate of dissolution. Section <724> (pages 1944-1951) describes various apparatus designed to test dissolution of extended release, delayed release, and transdermal delivery systems. Apparatus 3 (extended release) uses a reciprocating cylinder, Apparatus 4 (extended release) uses a flow-through cell, Apparatus 5 (transdermal) utilizes a paddle over a disk, Apparatus 6 (transdermal) uses a cylinder design, and Apparatus 7 (transdermal) uses a reciprocating holder. Apparatus 1, 2, 3, 5, 6, and 7 use a fixed volume of the dissolution medium. Apparatus 4 uses a continuous flow of dissolution medium. In all cases the volume of dissolution medium used is sufficient to completely dissolve the test substance, frequently known as sink conditions.
For many active substances and dosage forms the principles behind the USP dissolution tests are limiting. These limitations are true for those active substances for which the rate of dissolution is dependent upon the amount of said active substances already dissolved in the release medium. These include, but are not limited to complexes between active substances and ion exchange resins, and poorly soluble active substances. Some combinations of ion exchange resin and active substances form an equilibrium state under fixed volume conditions such that some of the drug remains on the resin, even at infinite time and under sink conditions. This will give rise to incomplete dissolution when using test methods similar to those described in USP24. When an active substances has been dissolved in the gastrointestinal system it is absorbed by the body through the walls of the gastrointestinal system. This results in a decrease in the concentration of the active substance in solution. In the case where the active substance is in equilibrium with the polymeric complex, as described above, this decrease in concentration will displace the equilibrium such that more active substance will be released. As absorption by the body continues, the release of drug from the polymeric complex will be essentially complete. It is therefore clear that the in vitro test as described above, indicating incomplete release, is not predictive of the release in vivo. A similar deficiency will occur with poorly soluble materials when sink conditions do not occur in vivo. The concentration will reach saturation, and the dissolution rate will then depend on the rate of absorption of the active substance by the body. The fixed volume limitation does not apply to the flow-through equipment (Apparatus 4 as described in USP24). In this case the test material is constantly exposed to fresh dissolution medium, where the concentration of active substance is always zero. While this eliminates the equilibrium constraint, and therefore does permit the complete dissolution of such active substances, it still does not simulate the physiological condition where the concentration of active substance is zero only at the start. With formulations controlled by equilibrium or limited solubility it is clear to one skilled in the art that the USP methods cannot be expected to give good IVIVC without further mathematical manipulation of the data. In the current art, Level A IVIVC is obtained by the use of mathematical tools to convert the in vitro data into predicted plasma concentration curves, or similar pharmacokinetic data that reflect the entire time course of the drug in the body. While this is acceptable to the regulatory authorities it is not completely satisfactory because any mathematical model involves basic assumptions, and a major change in a formulation, for example release mechanism or change in solubility, may render those assumptions invalid, requiring the use of a different mathematical model. This limits the predictive power of the IVIVC.
The use of a mathematical model to transform the data is also not ideal because it is not immediately apparent from the raw data obtained in the dissolution test if a change has been significant. It is necessary to transform the data using the model before the effect of the change can be evaluated. The value of a mathematical model is frequently related to the number of independent variables used to adjust the model to fit the in vivo data. As a guideline the USFDA recommends no more than three independent variables.
The conditions that affect dissolution in the gastro-intestinal system are known to vary with position within the gastro-intestinal system. These variations can affect the rate of dissolution of active substances. There have been attempts to simulate these changes in in vitro testing. The main focus has been on the very large pH change between the sto
Hoff Marc S.
Suarez Felix
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