Title of Invention

"A METHOD FOR THE DETERMINATION OF DOSE-LEVEL"

Abstract

The invention relates to a method for the determination of dose-level characteristics, such as physicochemical properties, functionality and/or quality, of a multiple unit system comprising a plurality of individual subunits (12). A number of said subunits (12) are individually analysed for obtaining precise characteristics for each individually analysed subunit (12). Said dose-level characteristics of the multiple unit system are determined based the thus-obtained precise characteristics for each individually analysed subunit (12). The invention also relates to an industrial process in which this method is used, and to the use of the claimed method in a process for designing a multiple unit system formulation product.

Full Text

The present invention relates to a method for the determination of dose-level. The present invention broadly relates to the field of so called multiple unit systems, especially but not exclusively pharmaceutical formulations designed as multiple unit dosage forms. More specifically, the invention relates to a method for determining characteristics on dose-level of multiple unit systems, such as dose-level properties relating to the release rate or release profile of one or more active substances. Other aspects of the invention relates to an industrial process for the manufacture of multiple unit system formulations, including such a method, and to the use of the method in a process for designing a multiple unit system formulation product. The present invention is especially useful in connection with in vitro dissolution tests on drug products where the therapeutic performance of drugs is highly dependent on the drug dissolution properties. Therefore, the technical background of the invention and objects and embodiments thereof, will be described with reference to such dissolution tests. However, the invention may also be applicable in connection with tests on other industrial products than pharmaceutical drugs, such as food industry products. The invention may also be implemented by the use of non-destructive tests. BACKGROUND Pharmaceutical formulations can be designed as Multiple Unit Systems, an example of which is the so called MUPS (Multiple Unit Pellet Systems), where a dose is administrated for example as a tablet (tableted dosage form) or as a capsule (capsulated dosage form), each dose comprising a plurality of individual pellets or granules, referred to as subunits in the following. Each subunit carries one or more active drug or substance. A typical number of subunits in one dose form is 50, 100, 1000 or more. Prior art discloses many different types of units intended for MUPS, such as for instance those described in US 5 085 968. Usually, this type of formulation is preferred for controlled or sustained release formulations as well as for enteric coated formulations. The dose of the active substance may be administrated in the form of a tablet or a capsule or a like which disintegrates to make available a multitude of coated subunits, which release the active substance during the dissolution. Other prior-art MUPS are disclosed in US 4 957 745, US 4 927 640, US 4 994 260, and US 5 085 868. Today, the common test procedure for determining the content, the functionality and/or the quality, etc. of MUPS is to analyse the formulation on a dose-level, i.e. to perform the analysis on a whole tablet or capsule. In conventional methods for determining the dose-level release profile the dosage form is placed in a test solution (in vitro testing) under controlled conditions, whereupon the test solution containing the dissolved active substance is analysed, typically by determining a release profile by the use of an optical absorption measurement. However, MUPS are characterised in that the dose is the summation of the individual subunits and, therefore, by such prior-art test methods for analysing properties on dose-level of MUPS one only obtains a measurement of the cumulative release property of the entire subunit population. Variations in structure and release property between the individual subunits are not detectable, such as variations in film thickness, film defects, uneven subunit surfaces, deviations from spherical form of some subunits, etc. As a result, with presently available MUPS test methods it is not possible to identify the exact causes leading to unintended or intended variations on dose-level, such as variations in the release profile. Thus, even if it is possible to identify an "error" in the test results obtained by the conventional dose-level test methods, these methods will limit the possibilities to measure the product quality in terms of process parameters, i.e. the possibility to achieve detailed information is limited. Dissolution testing provides essential information for the development of formulations, but the above limitations of the conventional test methods creates undesired limitations for obtaining a desired release profile. Especially, these limitations make it difficult to obtain a sufficiently exact and responsible release profile. Many mathematical models have been suggested in the literature for the description of release profiles. These models suffer from the drawback that it is difficult to correlate the obtained data, completely or partly, with a model when the result can be due to unknown sample variations. SUMMARY OF THE INVENTION The present invention is based on the insight that the functionality and quality of an entire does or a MUPS dosage is directly correlated to the functionality and quality of the individual subunits forming said dose. One example thereof is film-coated pellets where the individual pellets are designed to deliver the active drug(s) at a specified and controlled rate. Another example of such functionality of a pellet film is to protect the pellets from deterioration during the administration (enteric coating). The present invention is also based on the insight that further information is required in order to make it possible to optimize process parameters in the manufacturing of products having a multiple unit systems design. In one aspect of the invention, there is provided a method for the determination of dose-level characteristics of a multiple unit system comprising a plurality of individual subunits, wherein the multiple unit system is a pharmaceutical multiple unit dosage formulation, characterized by the step of individually analysing a number of said subunits in the manner as herein described on the subunit level for obtaining precise characteristics for each individually analyzed subunit, and the step of determining said dose-level characteristics of the multiple unit system based on the thus-obtained precise characteristics for each individually analyzed subunit. The method according to the invention will increase the possibilities for obtaining essential information from which new pharmaceutical multiple unit system formulations can be developed or designed. Also, the invention will be useful in connection with determining characteristics of existing multiple unit system products, such as the homogeneity, the distribution profile of the film thickness, etc. Furthermore, the manufacture of multiple unit systems may be optimised in detail for obtaining higher product qualities, e.g. by the development of better theoretical models describing how the characteristics on subunit-level influence on the dose-level characteristics, e.g. how the properties of the individual subunits influence on a dose-level release profile. The multiple unit system may be a pharmaceutical multiple unit dosage formulation, such as a tablet or a capsule, and the subunits may comprise at least one active drug. Said subunits may comprise a protective film, such as a film giving a controlled release of an active drug, or an enteric coating polymer. The number of subunits which are individually analysed is preferably determined with respect to the number of subunits included in the multiple unit system, and an statistical accuracy to be obtained in the determination of said dose-level characteristics. Specifically, the number of subunits which are individually analysed may be equal to, or essentially equal to, the number of subunits included in the multiple unit system. In general, the number of subunits to be individually analysed will have to be so high that the features or characteristics of the entire dose can be predicted, evaluated or determined with an accuracy which is acceptable under the actual circumstances. The step of individually analysing the subunits may comprise the step of performing a destructive test on each analysed subunit, especially a dissolution test for individual monitoring the dissolution characteristics of film-coated subunits. The individual analysis on the subunits may be performed in parallel, e.g. by using a micro-titer equipment with a plate containing a plurality of wells, where one subunit is placed in each well. The release of the drug(s) in a liquid, such as a buffer system, can then be monitored by different techniques, such as absorption spectrometry (e.g. UV-VIS, NIR, IR), emission spectrometry (e.g. fluorescence), scattering spectrometry (e.g. Raman) and electrochemical techniques (e.g. amperometry, coulometry, conductometry). Alternative procedures can also be based on the use of techniques where a small portion of the dissolution media is frequently sampled from each respective well by using single- or multiple-capillary systems, whereafter the samples are subjected to e.g. flow-injection analysis or any separation technique (e.g. capillary electrophoresis, liquid chromatography). In accordance with the invention, the step of individually analysing the subunits may include not only destructive tests, such as a dissolution test, but also non-destructive tests, using e.g. NIR spectrometry or other detection techniques (e.g. Raman, fluorescence, X-ray). The information in a NIR spectrum is correlated to the release profile and can be determined within a very short time, such as 10 ms. One possible solution would be to focus the NIR beam down on the individual subunits by using fiber optics, a microscope or the equivalent. Subunits with damaged films or variations in film thickness can be identified in the NIR spectra obtained or by other techniques. In one aspect of the invention, there is also provided an industrial process for the manufacture of multiple unit system formulations, including a method according to the invention, wherein the obtained precise characteristics for each individually analysed subunit are continuously used in the process as feed-back control data in the process in order to maintain predetermined dose-level characteristics of the manufactured multiple unit system formulations. The invention also encompasses the use of the inventive method in a process for designing a multiple unit system formulation product. The above and other features of the invention are set out in the claims. DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic representation of a micro-titer tray and a sample of subunits, for performing a subunit dissolution test in accordance with an embodiment of the invention. Fig. 2 illustrates the use of the micro-titer tray in Fig. 1 Fig. 3 shows dissolution profiles from a plurality of subunits. Fig. 4 shows a mean dissolution profile from a plurality of subunits. Fig. 5 illustrates an implementation of the invention in an industrial process. DETAILED DESCRIPTION OF THE INVENTION The applicant has performed experiments according to the inventive method, using an analyse equipment having a large number of separate wells (96 or 384 well plates (ELISA)) for the dissolution, and a Spectra MAX spectrophotometer (wavelength 250nm - 750 nm) for performing an individually detection of dissolved substance in each well. Fig. 1 illustrates a sample 10 of subunits 12, and a sample tray 14 having a plurality of separate wells 16. As illustrated in Fig. 2, during the measurement each well 16 contains one subunit 12 and a predetermined volume of a test solution 18. The total dissolution volume 18 in each well 16 was 300µL. A multichannel detector 20 receives light or radiation 21 passing through each well 16. Alternative optical designs can be used, such as confocal coupling of light and detection. In order to avoid interference between the subunits 12 present in each well 16 and the optical path of the spectrophotometer, the microplate 14 may be tilted and/or shaken during the analysis. Such interference can also be avoided by stirring the contents of each well, e.g. by the use of a small glass bead in each one of the wells 16. The active substance in the subunits 12 was remoxipride in the form of subunits (microcapsules). Remoxipride microcapsules for control release capsules (Ethanol based coating on microcapsules) are manufactured by coating remoxipride microcapsules in a fluidized bed. Uncoated microcapsules are charged and a polymer solution is sprayed onto the microcapsules. The microcapsules are then dried in the fluidized bed and emptied from the bed. The thus-prepared microcapsules are aerated to remove solvent residues. Finally, the microcapsules are passed through a screen to remove agglomerates and fines. The experiments illustrate that there is a large variation in the dissolution profiles of the individual subunits, see Fig. 3. With an analysis on the subunit-level, the release profile of each individual subunit or pellet pres- ents an initial lagtime-phase and a subsequent steady-state phase. Contrary to the essentially linear appearance of the release profile on subunit-level, a dissolution test on dose level (the entire dose) results in an essentially different release profile. Fig. 5 is a schematic diagram illustrating how the invention may be implemented in an industrial process for the manufacture of multiple unit system formulations. The subunit measurement may be performed on subunits in a completed batch, or on subunits in a continuous subunit flow. In either case, the obtained precise characteristics for each individually analysed subunit may be used as feed-back control data for the calculation of process parameters, in order to obtain predetermined dose-level characteristics of the manufactured multiple unit system formulations. Optionally, a process model can be used for receiving the control data in order to calculate the process parameters. WE CLAIM: 1. A method for the determination of dose-level characteristics of a multiple unit system comprising a plurality of individual subunits (12), wherein the multiple unit system is a pharmaceutical multiple unit dosage formulation, characterized by the step of individually analysing a number of said subunits (12) in the manner as herein described on the subunit level for obtaining precise characteristics for each individually analyzed subunit (12), and the step of determining said dose-level characteristics of the multiple unit system based on the thus-obtained precise characteristics for each individually analyzed subunit (12). 2. A method as claimed in claim 1, wherein said pharmaceutical multiple unit dosage formulation is in the form of a tablet or a capsule. 3. A method as claimed in claim 1, wherein the number of subunits (12) which are individually analyzed is determined with respect to the number of subunits (12) included in the multiple unit system, and a statistical accuracy in the determination of said dose-level characteristics. 4. A method as claimed in claim 3, wherein the number of subunits (12) which are individually analyzed is essentially equal to the number of subunits (12) included in a complete dose of the multiple unit system. 5. A method as claimed in any of the preceding claims, wherein said subunits (12) has at least one active drug. 6. A method as claimed in any of the preceding claims, wherein said subunits (12) has a protective film. 7. A method as claimed in claim 5 and 6, wherein the protective film is an film giving a controlled release of the active drug. 8. A method as claimed in claim 6, wherein the protective film is an enteric coating polymer. 9. A method as claimed in any of the preceding claims, wherein the step of individually analyzing said number of subunits (12) is performed by individually analyzing said subunits (12) in parallel. 10. A method as claimed in any of the preceding claims, wherein the step of individually analyzing the subunits (12) comprises the step of performing a destructive test on the subunits (12). 11. A method as claimed in claim 10, wherein said destructive test comprises a dissolution test, in which precise dissolution characteristics of each analyzed subunit (12) is individually monitored, and wherein dose level dissolution characteristics of the multiple unit system are determined on the basis of the obtained dissolution characteristics of each analyzed subunit (12). 12. A method as claimed in claim 11, wherein said dissolution test is monitored by a technique selected from the group of absorbtion spectrometry, emission spectrometry, scattering spectrometry and electrochemical techniques. 13. A method as claimed in claim 12, wherein said dissolution test is monitored by absorption spectrometry. 14. A method as claimed in any of claims 11-13, wherein said dissolution test is performed by the use of a microplate-type spectrophotometer, including a microplate (14) having a plurality of each subunit (12) to be individually analyzed is placed in a respective one of said wells (16). 15. A method as claimed in claim 14, wherein the microplate (14) is titled during the analysis in order to avoid interference from subunits (12). 16. A method as claimed in claim 14 or 15, wherein, in order to avoid interference from subunits (12), the microplate (14) is shaken during the analysis in such a way that the subunits (12) present in each well (16) do not interfere with the optical path of the spectrophotometer. 17. A method as claimed in any of claims 14-16, wherein, in order to avoid interference from subunits (12), the contents of each well is subjected to stirring. 18. A method as claimed in claim 17, wherein the stirring is achieved by a small glass bead in each one of the wells. 19. A method as claimed in any of claims 1-9, wherein the step of individually analyzing the subunits (12) comprises a non destructive test on each analyzed subunit (12). 20. A method for the determination of dose-level substantially as herein described with reference to the accompanying drawings.

Documents:

1608-del-1998-abstract.pdf

1608-del-1998-claims.pdf

1608-del-1998-correspondence-others.pdf

1608-del-1998-correspondence-po.pdf

1608-del-1998-description (complete).pdf

1608-del-1998-drawings.pdf

1608-del-1998-form-1.pdf

1608-del-1998-form-13.pdf

1608-del-1998-form-19.pdf

1608-del-1998-form-2.pdf

1608-del-1998-form-3.pdf

1608-del-1998-form-4.pdf

1608-del-1998-form-6.pdf

1608-del-1998-gpa.pdf

1608-del-1998-pct-210.pdf

1608-del-1998-pct-409.pdf

1608-del-1998-petition-137.pdf

1608-del-1998-petition-138.pdf