WO2003101607A1

WO2003101607A1 - Two-channel flow measuring cell

Info

Publication number: WO2003101607A1
Application number: PCT/EP2003/005392
Authority: WO
Inventors: Stephan Zinzen; Herbert Rupprecht
Original assignee: Grünenthal GmbH
Priority date: 2002-05-31
Filing date: 2003-05-23
Publication date: 2003-12-11
Also published as: DE10224518A1; AU2003232816A1

Abstract

The invention relates to a two-channel flow measuring cell that comprises two outer elements with respective liquid inlets and liquid outlets, a center element and a fixing device for a film-type, therapeutical system by which a chamber within the two-channel flow measuring cell can be divided up into two liquid-side compartments for the purpose of measurement. The invention further relates to a device for measuring the amounts of active substance released by a film-type, therapeutical system to two measuring liquids and to a method for measuring said amounts of active substance.

Description

TWO CHANNEL FLOW CELL

The invention relates to a two-channel flow measuring cell with a means for clamping a film-shaped, therapeutic system and with inlets and outlets for a measuring liquid. Furthermore, the invention relates to a device for measuring the amounts of active substance released by a film-like therapeutic system into two liquid streams and a method for measuring the release of an active substance from a film-like, therapeutic system.

When administering medicinal products to humans or animals, it is crucial how much and in what period of time the active ingredients are absorbed by the body. This bioavailability of the active ingredient must be ensured in a variety of therapeutic procedures. The availability is particularly dependent both on the place and the time in which the active substance is absorbed by the body and on the concentration of the active substance.

For the optimal application of a number of active ingredients, film-shaped therapeutic systems with a release that is controlled over a longer period of time have been developed, which release the active ingredient evenly, in defined amounts and over a defined period of time when attached to the mucous membrane. Bypassing the gastrointestinal tract, the active ingredients enter the body directly through the mucous membrane.

For unidirectional release of an active ingredient, multilayer films have also been developed, the side of which facing away from the mucous membrane has a barrier layer for the active ingredient. The measurement of such a unidirectional drug release in vivo is difficult. For this reason, one is interested in determining the drug release in vitro.

A flow measuring cell is available for this purpose, as it is on the market as a resorption model from Sartorius-Membranefilter GmbH under the trade name SM 16750. However, this device is used to measure the transfer of active substance from a first flowing liquid through a lipoid barrier into a second flowing liquid. In addition, the flow conditions over the Cross-section of the chamber and the capacity of the chamber for films of different thicknesses limited.

It was therefore an object of the present invention to solve the problems arising from the prior art and to provide a flow measurement line which is simple to manufacture or convert and, moreover, has the same flow conditions over the surface of the film-shaped, therapeutic system to ensure the respective measuring liquid.

The object is achieved by the two-channel flow measuring cell according to the invention with the features of claim 1. Preferred embodiments of the invention can be found in the dependent claims.

According to the invention, a two-channel flow measuring cell has been created which is easy to manufacture and can easily be used to measure the release of any thick film-shaped therapeutic systems. It allows an exact determination of the active ingredient release from a therapeutic system of measuring liquids and provides measurement results that allow an evaluation of in-vivo conditions.

Due to the construction of the two-channel flow measuring cell according to the invention, flow conditions of the measuring liquid are preferably achieved in the measurements within the chamber, which allow a particularly uniform and symmetrical flow around the respective surface of the therapeutic system. In particular, areas with still measuring liquid are avoided in a particularly preferred manner by a symmetrical construction of the two-channel flow measuring cell and by the derivation of the measuring liquids in the vicinity of the central axis of the chamber divided into two compartments by the therapeutic system to be measured. This further optimizes the agreement of the measured values achieved with the aid of the device according to the invention with in vivo releases of the active substance.

The invention and its preferred embodiments are explained in more detail below with reference to three figures. However, the figures only show examples Representations of devices according to the invention and in no way limit the inventive concept.

FIG. 1 shows a side view of a two-channel flow measuring cell according to the invention, cut along the plane of symmetry,

FIG. 2 shows a plan view of the lower outer part of the two-channel flow measuring cell without an upper outer part,

Figure 3 shows a schematic arrangement of the invention

Device for detecting the amounts of active substance released by a therapeutic system.

The two-channel flow measuring cell 1 according to the invention essentially consists of two preferably identical outer parts 2, 4 and a middle part 3, the height of which can be varied in each case with the thickness of the film-shaped, therapeutic system 12 clamped in the chamber 10 for measurement. With the middle part 3, the height of the compartments 11, 13 formed by the film-shaped, therapeutic system 12 is also set during the measurement. In any case, the measurement is attempted to reduce the size of the chamber 10 to a minimum in order to ensure flow conditions that do not allow dormant measuring liquid layers on the film-shaped, therapeutic system 12. The middle part 3 is particularly preferably adapted to the thickness of the film-like therapeutic system 12 such that the measurement can always be carried out with a constant height of the compartments 11, 13.

To clamp a film-shaped therapeutic system 12 to be measured, the flow measuring line 1 according to the invention in a preferred embodiment of the invention has two adjacent O-rings 17, 18, which in the case of assembly in a particularly preferred embodiment of the invention also the lateral boundary walls of the chamber 10 represent. As a result, an easily convertible device is created in a particularly simple manner, which on the one hand has sufficient tightness and on the other hand an optimal adaptation to the thickness of the therapeutic film-shaped to be measured Systems 12 guaranteed. Even when converting, according to this preferred embodiment of the invention, the same outer parts 2, 4 can be used on a regular basis; the conversion is carried out only by exchanging and using different middle parts 3.

In a preferred embodiment of the invention, the film-shaped therapeutic system 12 to be measured is clamped in the two-channel flow measuring cell 1 in such a way that the supply channels 8, 33 each open into a channel 14 surrounding the flow breakers 21. In this way, a uniform flushing of the respective surface of the film-shaped therapeutic system 12 is achieved in a particularly simple manner without mixing the measuring liquids 23, 24.

The measuring liquids 23, 24 are preferably suitable for allowing comparisons with processes in the human or animal body. It is therefore particularly preferred to use measuring liquids which have the properties of the mucous membrane or saliva which are relevant for the absorption of the active substance.

In a preferred embodiment of the invention, the fluid-tight connection between the outer parts 2, 4 and the middle part 3 for forming a chamber 10 is made via the means 17, 18 for reversibly clamping the film-shaped therapeutic system 12. This means 17, 18 can be in a particularly preferred one Design consist of two identical, superimposed O-rings.

In a preferred embodiment of the invention, the chamber is sealed with respect to a heating or cooling liquid surrounding the measuring cell via an at least partially form-fitting connection of the contact surfaces of parts 2, 3, 4 to one another. In addition, in a particularly preferred embodiment of the invention, 3 grooves 19, 20 can be provided in the middle part for receiving a further seal, in particular an O-ring. In a very preferred embodiment of the invention, the sealing of the chamber and of the entire two-channel flow measuring cell 1 is supported by a locking means, for example a screw 6 that braces the two outer parts 2, 4 together. In a particularly advantageous manner, a device is created, the tightness of which is ensured in every position of the two-channel flow cell 1, for example also in the case of vertical storage.

This liquid-tight connection of the parts 2, 3, 4 ensures that the measuring liquids 23, 24 do not escape. However, it is also ensured that no liquids get into the flow cell 1 from the outside. This opens up the possibility of letting the entire two-channel flow measuring cell 1 into a water bath 29 in order to set the required test temperatures in a particularly simple manner. This is particularly necessary in experiments that are intended to simulate in vivo processes, because the diffusion-controlled release of active substances from film-like, therapeutic systems can be temperature-dependent. Measurement results directly comparable to the processes in the human or animal body can thus only be achieved if the flow cell 1 is continuously set to the appropriate body temperature during the experiment.

The outer parts 2, 4 are structurally identical in a preferred embodiment of the invention. In particular, this simplifies the manufacturing process and the assembly of the two-channel flow measuring cell 1. In addition, an identical construction of the outer parts 2, 4 also ensures that the compartments 11, 13 are identical, as a result of which identical test conditions can be established in a particularly simple manner on both surfaces of the film-shaped, therapeutic system 12.

In a particularly advantageous embodiment of the invention, the outer parts 2, 4 have essentially the shape of disks and the chamber 10 has a circular shape.

The inlets 8, 33 are preferably located on the same side of the outer parts 2, 4. For this purpose, the outer parts 2, 4 have recesses 9 in a preferred embodiment of the invention. In a further preferred embodiment of the invention, the inlets 8, 33 each lead into channels 14. This supports in a particularly simple and effective manner a uniform distribution of the measuring liquids 23, 24 in each case over the entire film surface. The measuring liquids 23, 24 flow from the compartments 11, 13 to the measuring device 32 via the drains 15, 34, which are preferably located on the same side of the outer parts 2, 4. Analogously to the inlets 8, 33, the outer parts 2, 4 in a preferred embodiment of the invention also recesses 16. In a particularly preferred embodiment of the invention, the chamber-side openings of the drains 15, 34 lie in the vicinity of the central axis of the compartments 11, 13. This advantageously ensures that the measuring liquids 23, 24 smoothly flow past each surface of the film-shaped, therapeutic system 12 guaranteed with simple constructive means.

In a preferred embodiment of the invention, flow breakers 21 are provided on the side surfaces 36, 37, which ensure a steady flow on each surface of the film-shaped, therapeutic system 12 without the formation of areas with little or no liquid movement. In a particularly preferred embodiment, the flow breakers 21 are evenly distributed over the side surfaces 36, 37. In an extremely preferred embodiment of the invention, the flow breakers 21 consist of pyramid shapes arranged side by side and one behind the other, the tips of which are as close as possible to the film-shaped, therapeutic system 12 during the measurement. The pyramids are separated from one another by a grid of longitudinal and transverse notches that are perpendicular to one another. Thus, flow breakers 21 that are particularly easy to manufacture have been created, which also ensure a uniform distribution of the measuring liquids 23, 24 over the compartments 11, 13 and at the same time prevent areas with still liquid layers, in particular in the direct vicinity of the film-shaped therapeutic system 12.

The middle part 3 serves on the one hand as a spacer between the outer parts 2, 4. The height of the middle part 3 also determines the height of the chamber 10. In a preferred embodiment of the invention, the means 17, 18 for clamping the arranged to be measured film-shaped, therapeutic system 12. In this way, the film-shaped therapeutic system 12 can be adjusted in a particularly simple manner by means 17, 18, preferably by two O-rings arranged one above the other. In addition, the film-shaped, therapeutic system 12 is secured in this preferred manner against slipping out of the clamping position.

In a further preferred embodiment of the invention, the central part 3 has contact surfaces with the outer parts 2, 4, which allow the assembled parts to be positively locked. In a particularly advantageous embodiment of the invention, a circumferential groove 19, 20 is made in each of the contact surfaces for receiving a further seal, preferably an O-ring. As a result, the liquid-sealing connection of the parts 2, 3, 4 is efficiently supported with particularly simple means.

In the case of outer parts 2, 4 in the form of disks and a round chamber 10, a particularly advantageous embodiment of the invention is when the middle part 3 consists of a ring, the outer dimension of which corresponds to that of the outer parts. A compact two-channel flow measuring cell 1 is thus obtained in a particularly simple manner, the individual parts 2, 3, 4 of which are also particularly easy to manufacture. In a particularly preferred embodiment of the invention, the two-channel flow measuring cell 1 according to the invention can therefore be converted to different thickness film-shaped therapeutic systems 12 simply by replacing a first middle part 3 by another middle part 3 with the same outside and inside diameters, but different heights, whereby In a very preferred embodiment of the invention, the height of the compartments 11, 13 remains the same regardless of the film thickness of the therapeutic system 12.

In a preferred embodiment of the invention, the outer parts 2, 4 and the middle part 3 consist of the same material. This can be, for example, a metal, as well as plastic or glass. In a particularly preferred embodiment of the invention, however, the individual parts 2, 3, 4 consist of an inert material which has no or only negligibly small interactions with the measuring liquids 23, 24 or the active substances released. In addition, a particularly advantageous embodiment of the invention provides that the two-channel flow measuring cell 1 is made of a particularly smooth material, as a result of which buildup is avoided during the measurement and, moreover, cleaning is made significantly easier. In an extremely advantageous embodiment of the According to the invention, the various parts 2, 3, 4 of the two-channel flow measuring cell 1 therefore consist of Teflon or a material coated with Teflon.

In the device according to the invention, shown by way of example in FIG. 3, for measuring the amounts of active substance delivered by a film-like, therapeutic system 12 to two circulating liquids 23, 24, the active substance concentrations are measured in a device 32 provided for this purpose outside the two-channel flow cell 1. This device 32 can all known analytical measuring methods for determining the amount or concentration of active substance in liquids such as use the UV method or the HPLC method. In a particularly preferred embodiment of the invention, the HPLC method is used. As a result, the measured value can be recorded in a particularly simple manner and with high accuracy.

After passing through the measuring device 32, the liquids 23, 24 are fed back into the two-channel flow cell 1 either directly or via a storage container 25, 26. During the entire measurement, the entire device or only a few parts of the device can be heated or cooled to a certain temperature. In a preferred embodiment of the device according to the invention, only the storage containers 25, 26 and the two-channel flow cell 1 are brought to the predetermined temperature. In a particularly preferred embodiment of the invention, this is done by placing the measuring cell 1 and the storage containers 25, 26 in a temperature-controlled water bath 29. This ensures a sufficient temperature control of the liquids 23, 24 in a particularly simple and effective manner.

The method according to the invention for measuring the preferably unidirectional release of an active substance from a film-like, therapeutic system 12 by means of the device according to the invention described above provides for the film-like, therapeutic system 12 to be clamped in with the aid of means 17, 18 and the device according to the invention being assembled. The Measuring liquids 23, 24 flow through the compartments 11, 13, each surface of the film-shaped therapeutic system 12 being rinsed. The various measuring liquid slides 23, 24 flow separately from one another to the measuring device 32, in which the concentration of the active substance in the liquids 23, 24 is determined. This measurement can take place both continuously and discontinuously. Finally, the measuring liquids 23, 24 are returned to the two-channel flow measuring cell 1 for measurement and come back into contact with the therapeutic system 12 there. The cumulative absorption of active substances by the measuring liquids 23, 24 can thus be measured in a particularly simple manner over time.

However, the process steps mentioned are not to be understood as a final list of the steps to be carried out when carrying out the process according to the invention. Likewise, every technically meaningful sequence of the method steps is encompassed by the inventive concept.

FIG. 1 shows a section through a two-channel flow measuring cell 1 according to the invention during the measurement with an upper outer part 2, a middle part 3 and a lower outer part 4. The two-channel flow measuring cell 1 is mounted on a table 5 and also has a screw 6 which braces the individual parts 2, 4 with one another via a pressure plate 7. The parts of the two-channel flow measuring cell 1 form a chamber 10, which is separated during the measurement into a first compartment 11 and a second compartment 13, which is separated in a liquid-tight manner by the clamped film-shaped, therapeutic system 12. The upper outer part 2 has an inlet 8 with a recess 9 for the feed line (not shown) for a first measuring liquid. The inlet 8 opens into a first channel 14 enclosing the first compartment 11. The outlet 15 also has a recess 16 for an outlet line (not shown). The opening of the drain 15 lies in the vicinity of the central axis (not shown) of the two-channel flow measuring cell 1. The lower outer part 4 is of identical construction. The film-shaped therapeutic system 12 is clamped for measurement between two O-rings 17, 18 lying one above the other and connected to the middle part 3 and the outer parts 2, 4. Further O-ring seals are located in the grooves 19, 20, which in the respective contact surfaces of the Middle part 3 are molded with the outer parts 2, 4. In addition, pyramidal flow breakers 21 are formed on the side surfaces 36, 37 of the outer parts 2, 4 forming the walls of the compartments 11, 13.

FIG. 2 shows a top view of the lower outer part 4 of the two-channel flow cell 1. This lower outer part 4 rests on a table 5 and has, within the channel 14, a grid 22 made of notches arranged perpendicular to one another, which delimit the individual pyramids of the flow breakers 21.

FIG. 3 shows a schematic arrangement of a device according to the invention for measuring the amounts of active substance released from a film-shaped, therapeutic system (not shown) on two circulating measuring liquid streams 23, 24. The measuring liquids 23, 24 are located in pistons 25, 26 which are in a water bath 29 heated by the heating plates 27, 28. The temperature of the water bath 29 is regulated by a thermostat 35. Both measuring liquids 23, 24, which are identical at the start of the measurement, are each conveyed by a pump 30, 31 to a measuring device 32, such as, for example, a UV photometer 32 in which the active substance concentrations in the measuring liquids 23, 24 are measured , The measuring liquids 23, 24 are then led through the inlets 8, 33 into the various compartments (not shown) of the two-channel flow measuring cell 1 which are separated by the film-shaped therapeutic system (not shown). After flowing through the processes 15, 34, the measuring liquids 23, 24 are returned to the pistons 25, 26 and finally returned to the circuit. The measurement is carried out until there is no increase in the active substance concentrations in the measuring liquids 23, 24. Reference numerals:

1 flow meter

2 upper outer part

3 middle section

4 lower outer part

5 table

6 screw

7 pressure plate

8 inlet

9 recess

10 chamber

11 first compartment

12 therapeutic system

13 second compartment

14 channel

15 process

16 recess

17 O-ring

18 O-ring

19 groove

20 groove

21 flow breakers

22 grids

23 first measuring liquid

24 second measuring liquid

25 pistons

26 pistons

27 heating plate

28 heating plate

29 water bath

30 pump

31 pump

32 measuring device

33 inflow

34 process

35 thermostat

36 side surface

37 side surface

Claims

claims:

1. Two-channel flow cell (1) with two external parts (15, 34) arranged in the region of the central axis of the respective compartment (11, 13) and each with an external part (15, 34) arranged in the area of the central axis of the respective compartment (11, 13) (2, 4) and a central part (3) with which the outer parts (2, 4) are each connected so as to be liquid-tight that a chamber (10) forms and with a means (17, 18) for reversibly clamping a separating membrane ( 12), with which the chamber (10) can be divided into two compartments (11, 13) which are separate on the liquid side and can be flowed through.

2. Two-channel flow cell (1) according to claim 1, characterized in that the separating membrane (12) between two between the outer parts (2, 4) attached and the lateral boundary of the chamber (10) forming seals (17, 18) is clamped ,

3. Two-channel flow cell (1) according to one of the preceding claims, characterized in that in the contact surfaces between the central part (3) and the outer parts (2, 4) each have a circumferential groove (19, 20) for receiving a seal, preferably an O-ring.

4. Two-channel flow cell (1) according to one of the preceding claims, characterized in that the outer parts (2, 4) have essentially the shape of round disks and the central part (3) has essentially the shape of a ring.

5. Two-channel flow cell (1) according to one of the preceding claims, characterized in that flow breakers (21) are arranged in the compartments (11, 13).

6. Two-channel flow cell (1) according to claim 6, characterized in that the flow breakers (21) have a pyramidal shape.

7. Two-channel flow cell (1) according to one of the preceding claims, characterized in that the outer parts (2, 4) are essentially identical.

8. Two-channel flow cell (1) according to one of the preceding claims, characterized in that the outer parts (2, 4) and the central part (3) consist of an inert material, preferably Teflon.

9. Device for detecting the amounts of active substance delivered by a therapeutic system (12) in the form of a film to two separately circulating liquid streams (23, 24) with a two-channel flow cell (1) according to one of the preceding claims, with a conveying means assigned to each liquid stream (30, 31), each have a means (32) for measuring the amounts of active substance in the liquids, if appropriate a respective liquid buffer and optionally a means (27, 28, 29, 35) for heating the liquids (23, 24).

10. A method for measuring the amounts of active substance delivered by a therapeutic system (12) in the form of a film to two circulating liquid streams (23, 24) using a device according to claim 10, comprising the following steps:

- clamping the film (12),

- joining the middle part (3) with the outer parts (2, 4),

Connecting the liquid drains (15, 34) with the means for measuring (32) the active substance concentrations and the conveying means (30, 31),

- flow through the two-channel flow cell (1),

- measuring the amounts of active substance in the outflowing liquids (23, 24),

- Returning the liquids (23, 24) to the liquid inlets (8, 33).