Temperature Control System for a Diffusion Cell, Diffusion Cell, Diffusion Cell System, and Method for Controlling the Temperature in a Diffusion Cell

Abstract

A temperature control system for a diffusion cell. The temperature control system includes a cell head and a temperature control device connected to the cell head. Moreover, a diffusion cell having such a temperature control system. Furthermore a diffusion cell system having such a temperature control system or such a diffusion cell. Finally, a method for controlling the temperature of a cell head of a diffusion cell, including introducing the temperature control fluid into the cell head.

Claims

1. A temperature control system for a preferably vertical and static diffusion cell, comprising a cell head, in particular a donor chamber, and a temperature control device connected, particular fixed, to the cell head.

2. The temperature control system according to claim 1, wherein the temperature control device is integrally connected to the cell head.

3. The temperature control system according to claim 1, wherein the temperature control device comprises a preferably fluid heat exchanger.

4. The temperature control system according to claim 1, wherein the cell head substantially has a hollow cylindrical shape.

5. The temperature control system according to claim 1, wherein the cell head comprises: an inlet for supplying, preferably into the interior of the cell head, a temperature control fluid, in particular a temperature control liquid, and in particular an outlet for discharging the temperature control fluid, preferably from the interior of the cell head.

6. The temperature control system according to claim 5, wherein the inlet and the outlet are substantially arranged opposite and/or vertically offset from one another.

7. The temperature control system according to claim 1, wherein the temperature control fluid comprises water, preferably mixed with alcohol, in particular with ethylene glycol.

8. The temperature control system according to claim 1, wherein the temperature control device comprises a thermal radiator, in particular an IR radiator.

9. The temperature control system according to claim 1, comprising a temperature controller and/or a thermometer.

10. The temperature control system according to claim 1, wherein the cell head comprises metal, in particular brass and/or aluminum and/or steel and/or copper.

11. A diffusion cell, preferably 10 ml or 24 ml or 115 ml diffusion cell, comprising a temperature control system according to claim 1, an acceptor chamber connected to the temperature control system, and a membrane, preferably comprising skin, arranged between the temperature control system and the acceptor chamber.

12. The diffusion cell according to claim 11, wherein the cell head and the acceptor chamber are separated from each other in a fluid-tight manner, preferably by means of at least one seal and/or a retaining clip, via the membrane, and preferably in the connection area of the cell head and the acceptor chamber towards the environment.

13. A diffusion cell system, comprising at least one temperature control system according to claim 1; and a fluid provision device; wherein the fluid provision device is connected to the at least one temperature control system in a fluid-carrying manner, in particular via a hose connection.

14. A method for controlling the temperature of a cell head of a diffusion cell, in particular a dermal dosage form and/or a membrane in a diffusion cell, comprising the following steps: introducing a temperature control fluid, preferably a temperature control liquid, into the cell head of the diffusion cell, preferably into the interior of the cell head, and preferably omitting the temperature control fluid on the cell head, in particular from the interior of the cell head.

15. The method according to claim 14, wherein the method is carried out by means of: a temperature control system comprising a cell head, in particular a donor chamber, and a temperature device connected, in particular fixed, to the cell head.

16. A diffusion cell system, comprising a diffusion cell according to claim 11; and a fluid provision device; wherein the fluid provision device is connected to the at least one temperature control system in a fluid-carrying manner, in particular via a hose connection.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In the drawings:

[0032] FIG. 1 is a schematic sectional view of an embodiment of a diffusion cell according to prior art,

[0033] FIG. 2 is a perspective view of an embodiment of a diffusion cell according to prior art,

[0034] FIGS. 3 to 5 are schematic sectional views of several embodiments of a temperature control system according to the invention,

[0035] FIG. 6 is a perspective view of an embodiment of a diffusion cell according to the invention with a further embodiment of a temperature control system according to the invention,

[0036] FIG. 7 is a schematic view of an embodiment of a diffusion cell system according to the invention, and

[0037] FIGS. 8 and 9 are illustrations von comparative results of experimental tests of temperature control systems according to the invention with prior art.

DESCRIPTION OF THE INVENTION

[0038] In the Figures, similar or identical components or elements are identified by the same reference numerals or variations thereof (e.g. 10, 10a and 10b). In particular in the interest of improved clarity, preferably elements already identified are not provided with reference numerals in all Figures.

[0039] FIGS. 1 and 2 were already explained above.

[0040] FIG. 3 is a sectional view of a temperature control system 10 according to the invention.

[0041] The temperature control system 10 shown is preferably a temperature control system for a vertical and/or static diffusion cell, for example for a FRANZ diffusion cell. In particular, the temperature control system 10 may be combined with an acceptor chamber 14 according to FIG. 1 or FIG. 2, and/or a retaining clip 22 according to FIG. 1 or FIG. 2, to form a diffusion cell. The temperature control system of FIG. 3 is substantially based on the corresponding embodiment shown of FIG. 1, however, the features according to the invention described below have been implemented.

[0042] The temperature control system of FIG. 3 comprises a cell head 12 which is formed here as a donor chamber. The cell head 12 substantially has the form of a hollow cylinder 18, wherein hollow cylinder 18 has, in the manner shown, a cylindrical shape in the upper area with a circular base area and a constant diameter. Moving downward, the diameter of hollow cylinder 18 increases and terminates with a flange device 15 for connection to a membrane 16 and/or an acceptor chamber 14 (see e.g. FIG. 1). In the upper area, cell head 12 has an access opening 20.

[0043] It is illustrated that cell head 12 of temperature control system 10 is connected to a membrane 16 on which, within the donor chamber, a dental dosage form in the form of a TTS 32 is arranged.

[0044] According to the invention, cell head 12 is connected to a temperature control device 13, wherein an integral connection is shown. The temperature control device 13 comprises a fluid inlet 40 and a fluid outlet 42. The fluid inlet 40 is designed as a hole 41 and fluid outlet as a hole 43 in hollow cylinder 18 of cell head 12. Inlet 40 and outlet 42 are shown opposite each other and arranged at the same vertical height. However, it is also possible for inlet 40 and outlet 42 to have a different arrangement, for example, instead of being arranged 180 C. opposite each other, they may only have a 90 C. arrangement, etc. Alternatively or additionally, a height offset between inlet and outlet 42 is also possible. Here, a height offset means in particular that an inlet 40 and an outlet 42 are arranged in different, preferably parallel, particularly preferably truly parallel, cross-sectional planes of hollow cylinder 18. On the other hand, it is also possible to design the inlet and the outlet as a single opening.

[0045] A temperature control fluid 36 can be introduced into the donor chamber through inlet 40, wherein temperature control fluid 36 can be discharged from the donor chamber through outlet 42 (see, e.g. FIG. 7). Preferably, temperature control fluid 36 is introduced into the interior of the donor chamber through inlet 40 so that, in particular, there is direct contact between temperature control fluid 16 and membrane 16 and/or the dental dosage form. It is preferred that temperature control fluid 36 is discharged through outlet 42 from the interior of the donor chamber. Preferably, the temperature control fluid is a temperature control liquid, in particular a liquid comprising water. The liquid preferably has a temperature, in particular a constant temperature, for temperature control for the donor chamber, particularly preferably a temperature control of membrane 16 and/or the dermal dosage form 32 is effected thereby. It is preferred that the temperature control fluid has a temperature of 37 C. to 51 C., in particular of 37 C. to 42 C. In FIG. 3, inlet 40 and outlet 42 are designed as simple holes 41, 43. However, other embodiments are also possible. For example, it is possible that inlet 40 and/or outlet 42 comprises a connection device, in particular for coupling connection with a (not shown) supply device, in particular a line, preferably a hose.

[0046] FIG. 4 shows a further embodiment of a temperature control system 10 according to the invention, the embodiment being based on that of FIG. 3. Instead of temperature control device 13 with inlet 40 and outlet 42 of FIG. 1, the embodiment of FIG. 4 comprises a temperature control device 13 with thermal radiator 38. The thermal radiator may be a heating, for example. It is preferred that thermal radiator 38 is an IR radiator that emits IR rays for temperature control of cell head 12, in particular membrane 16 and/or dermal dosage form 32.

[0047] Furthermore, temperature control system 10 of FIG. 4 comprises a thermometer 44. Thermometer 44 is particularly designed as an IR thermometer. It is preferred that thermometer 44 detects the temperature inside cell head 12. It is particularly preferred that thermometer 44 detects the temperature of the dermal dosage form and/or membrane 16. Temperature control device 13 and thermometer 44 are connected to a temperature controller 46 via a data-transmitting connection device 47. For example, the data transmission device 47 may be a wired and/or wireless connection. Preferably, temperature controller 46 is configured to control the temperature of the cell head. Here, it is particularly preferred that temperature controller 46 detects an actual temperature by means of a thermometer 44 and regulates this temperature to a set temperature, in particular a preset temperature, with the aid of temperature control device 13.

[0048] FIG. 5 shows a further embodiment of a temperature control system 10 according to the invention, wherein temperature control system 10 of FIG. 5 is substantially based on the embodiment of FIG. 3.

[0049] A seal 56 is provided to connect cell head 12 to an acceptor chamber 14 (not shown) and membrane 16 in order to form a diffusion cell 100 (not shown). It is illustrated that seal 56 comprises an O-ring 57a for connection between cell head 12 and membrane 16 as well as another O-ring 57b for connection of membrane 16 and acceptor chamber 14. On the other hand, it is possible to provide only one of the two O-rings 57a or 57b.

[0050] FIG. 6 shows an embodiment of a diffusion cell 100 according to the invention with a further embodiment of a temperature control system 10 according to the invention.

[0051] Temperature control system 10 of FIG. 1 comprises a cell head with an inlet 40 and an outlet 42 opposite each other, wherein these are arranged vertically offset from each other.

[0052] The remaining embodiment of diffusion cell 100 of FIG. 6 corresponds in particular substantially to the configuration of FIG. 2 (without cell head 12 illustrated there).

[0053] FIG. 7 shows an embodiment of a diffusion cell system 1000 according to the invention with two embodiments of temperature control systems 10a, 10b according to the invention. Here, the temperature control systems 10a, 10b are based in particular on the embodiment shown in FIG. 3.

[0054] The temperature control systems 10a, 10b are connected via the respective inlets 40b to fluid-carrying inlet lines 52a, 52b for fluid introduction, and via outlets 42a, 42b to outlet lines 54a, 54b for fluid discharge. The lines 52a, 52b, 54a, 54b are preferably hoses, so that together they form a hose connection 50. As an example, the flow of temperature control fluid 36 is shown with arrows. Temperature control fluid 36 is in particular a temperature control liquid, preferably comprising water.

[0055] In the illustrated form, temperature control fluid 36 is provided by a fluid provision device 60. It is preferred that fluid provision device 60 comprises a heat exchanger 48 and/or a temperature controller 46 for, in particular controlled, temperature control of the temperature control systems 10a, 10b.

[0056] It is particularly preferred that the embodiments of the temperature control system according to the invention, in particular those described above, are configured such that they can be integrated into standard FRANZ diffusion cells 100 (see e.g. FIGS. 1 and 2) in order to form the respective cell head 12 of diffusion cell 100, wherein the standard cell head 12 is replaced by temperature control system 10 according to the invention.

[0057] Experimental tests were performed to evaluate the invention and are described below.

[0058] 1. Preparation of Skin for In Vitro Permeation Studies

[0059] Human skin dermatomized to 500 m (example Na-diclofenac) as well as to 800 m (example nicotine), which was obtained as post-operative skin from a cosmetic surgery clinic, was used as the skin model for membrane 16. The skin was dermatomized or sectioned to the appropriate layer thicknesses using an electric battery dermatome Acculan 3TI (Aesculap AG, Tuttlingen, Germany). From this prepared donor skin (abdomen, female, age 50 years for Na-diclofenac as well as abdomen, female, age 60 years for nicotine), circular punched blanks with a diameter of 25 mm were punched out and stored sealed in PE bags at 20 C. (maximum storage time at these conditions up to 16 months) until further use.

[0060] 2. Conducting the In Vitro Permeation Studies

[0061] The permeation studies were performed exemplarily in a static and vertical diffusion cell 100 designed as a Franz cell (Glastechnik Grfenroda, Germany) with a diffusion area of 1.595 cm 2 and an acceptor volume of 10 ml. The diffusion cell 100 used according to the invention corresponds to that shown in FIG. 6, wherein a standard diffusion cell 100 according to FIG. 2 was used as a reference. Phosphate buffer with a pH value of 5.5 according to DAB 10 and with an addition of 0.1% sodium azide as a bactericidal preservative was used as acceptor medium 24, tempered at 32 C. throughout the entire permeation period and stirred continuously for uniform mixing of the permeated active ingredient. At the scheduled sampling times, the acceptor medium was completely replaced with a fresh one. After applying the TTS 32 to the epidermal side of the skin punched blanks 15, it was then placed on glass rim 102 of the cell base, acceptor chamber 14 and the Franz cells. The dermal side of the TTS points to the acceptor chamber. The temperature control system 10 (FIG. 6) and a standard cell head of a Franz cell (FIG. 2) used as a reference were placed on top of this. By means of a corresponding retaining clip 12, both cell chambers 12, 14 of both systems were sealed liquid-tight and finally each was filled with acceptor medium 34.

[0062] 3. Analytical Determination of Na-Diclofenac in the Acceptor Samples

[0063] The analytical determination was carried out by HPLC on a special acid- and base-deactivated Zorbax C8 separation column (1504.6 mm, 5 m particle size; VDS Optilab, Berlin) using UV detection at 225 nm and at 30 C. separation column temperature. A 50:50 (v %/v %) mixture consisting of acetonitrile and 0.025 m sodium dihydrogen phosphate solution adjusted to a pH value of 3.2 was used as an eluent. The flow rate was 1.5 ml/min and 50 l was injected. The quantitative evaluation was performed using an external reference standard.

[0064] 4. Analytical Determination of Nicotine in the Acceptor Samples

[0065] The analytical determination was carried out by HPLC on a special graphite separation column HyperCarb (1504.6 mm, 5 m particle size; Thermo Fischer, Berlin) using UV detection at 258 nm and at 40 C. separation column temperature. A mixture consisting of acetonitrile, HPLC water and triethylamine 20:80:0.1 (v %/v %/v %) was used as an eluent. The flow rate was 1.2 ml/min and 50 l was injected. The quantitative evaluation was performed using an external reference standard.

[0066] 5. Result

[0067] The comparative results of the experiments are shown in FIGS. 8 and 9.

[0068] Here, FIG. 8 shows a comparison of the permeation profile of the embodiment according to the invention with the permeation profile of a standard FRANZ diffusion cell as a reference using the example of an in vitro permeation with Na-diclofenac (Dojin TTS).

[0069] It can be determined that the release quantity or release rate of the embodiment according to the invention is statistically significantly larger by a factor of about 2 compared with the reference after 24 hours (corresponding approximately to the usual wearing time).

[0070] FIG. 9 shows a comparison of the permeation profile of the embodiment according to the invention with a standard FRANZ diffusion cell as a reference using the example of in vitro permeation with nicotine (Habitol TTS).

[0071] Here it results that the release quantity or release rate of the embodiment according to the invention is statistically significantly larger by a factor of about 1.2 compared to the reference after 24 hours. It can also be seen that due to the lower cell head temperature of 42 C. compared to the experiment in FIG. 8 with 51 C., there is a lower degree of increase in permeated quantity.

[0072] Thus, the experiments demonstrate the advantageous function of the present invention.