APPARATUS FOR DOSAGING AN ACTIVE INGREDIENT AND FOR INVESTIGATING THE DOSAGE

Abstract: The invention relates to a device based on iontophoresis and intended for transdermal dosing of an active agent, the device comprising: a pair of electrodes (11, 12) and a direct-current source in connection with the electrodes (11 and 12), two chambers (13, 14) insulated from each other, the first chamber (13) containing the active agent, and each chamber having a porous membrane (15, 16) on the side facing the skin of an individual. It is characteristic of the device that the first chamber (13) is divided into two sections (13a, 13b) in such a manner that the first section (13a) is in connection with an electrode (11) and the second section (13b) is in connection with the membrane (15) coming into contact with an individual's skin, there being between the sections (13a and 13b) a membrane (18) selectively permeable either to cations or to anions, and that the first section (13a) contains an electrolyte and the second section (13b) contains an ionic active agent, bound to an ion exchanger therein. The invention also relates to a device for the study of transdermal release of a substance to be dosed.

Description: APPARATUS FOR DOSAGING AN ACTIVE INGREDIENT AND FOR INVESTIGATING THE DOSAGE The invention relates to a device based on iontophoresis and intended for transder- mal dosing of an active agent. The invention also relates to an iontophoretic device intended for the study of the dosing, i.e. release, of an active agent. Transdermal dosing of drugs is an established administering method for many drugs. The long-term, even and controlled concentration of a drug in the body, provided by the transdermal administering method, is commonly considered an advan- tage of the method. By this administering method, the side effects of a drug can be reduced and a smaller amount of a drug can be used. Also, the metabolism caused by the liver and the intestinal wall is avoided when drugs are administered trans- dermally. Controlled drug release is of crucial importance in devices of this type. Release sys- tems based on ion exchange have been presented for ionic drugs. US patent 4,692,462 describes a transdermal release device wherein the drug carrier is an ion- exchange resin which, saturated with a drug and together with a salt required for the release, is mixed with a gel-form matrix. International publication WO 97/27844 describes a transdermal drug-dosing system which is based on an ion-exchange car- rier and in which the ion-exchange groups are grafted to a textile fiber. Transdermal dosing involves the problem of poor permeation of drugs through the skin, in particular with an increasing molecular size of the drug. One method for solving this problem is to promote the transport of the drug through the skin by means of electric current. This is iontophoresis, which has the crucial advantage that the permeation of the drug through the skin is determined primarily by the electric current and the physicochemical parameters of the drug. Devices based on iontophoresis and transdermal dosing of drugs are described in the literature. A summary of the device options and the drugs suitable for this administering method are presented in, for example, the following articles: Journal of Con- trolled Release Vol. 7, 1988, pp. 1-24; Drug Design and Delivery Vol. 4, 1989, pp. 1-12; and Journal of Pharmaceutical Sciences Vol. 78, 1989, No. 5, pp. 376-383. International patent application publication WO 97/47353 describes a transdermal preparation wherein the release of an ionic drug bound to an ion exchanger is promoted by means of electric current. However, owing to the large number of parameters, accomplishing a precise and at all times controllable permeation or flow, of a drug is not simple. It is an object of the present invention to provide a device based on iontophoresis and ion exchange for improving the precision and controllability of the dosing of an ionic drug. It is another object of the present invention to provide a device based on iontophoresis and ion exchange for the study of the dosing of drugs. The object is to provide a study device which simulates transdermal in vivo dosing, and by means of which it is possible to investigate the permeation parameters suited for each given drug and thereby to tailor drug-specifically optimal dosing devices. The characteristics of the invention are given in the independent claims. The invention is described below with reference to the accompanying drawings, wherein Figure 1 depicts a transdermal dosing device according to the invention, Figure 2 depicts a device according to the invention, intended for the study of the release of an active agent, Figure 3 depicts, as a function of time, the drug amount delivered by a device according to the invention, and Figure 4 depicts, as a function of time, the drug amount delivered by a device according to the invention, for two electrolyte concentrations prevailing in the ion- exchange space. Figure 1 depicts a device according to the invention, based on iontophoresis and intended for transdermal dosing of an active agent. The device comprises a pair of electrodes 1 1 , 12 and a direct-current source (not shown in the figure) in connection with the electrodes, as well as two chambers 13 and 14, which are insulated from each other by an insulator 17, which in this option also serves as the supporting structure of the chambers. Each chamber has a porous membrane 15 respectively 16 on the side facing the skin of an individual. The first chamber 13 is divided into two sections 13a and 13b in such a manner that the first section 13a is in connection with the electrode 1 1 and the second section 13b is in connection with the membrane 15 coming into contact with the skin 20 of an individual. Between the sections 13a and 13b there is a membrane 18 which is selectively permeable to ions (either cations or anions). The first section 13a contains an electrolyte and the second section 13b contains an ionic active aεent bound to an ion exchanger therein. The negatively or positively charged ion-exchange groups may be attached to an ion-exchange resin or some other matrix. Preferably they are grafted to a fiber. If the drug to be dosed is cationic, negatively charged ion-exchange groups, i.e. a cation exchanger, is used. The membrane 18 which separates the sections 13a and 13b of the chamber 13 from each other is, depending on whether the drug to be dosed is cationic or anionic, a membrane selectively permeable either to cations or to anions. Even though the membranes 15 and 16 coming against the patient's skin 20 may be ordinary porous membranes, it is, however, preferable that, depending on whether the drug to be dosed is cationic or anionic, both are membranes selectively perme- able either to cations or to anions. The electrolyte in the first section 13a of the chamber 13 may be in solution form. Alternatively, the electrolyte may be in dry form, in which case the electrolyte can be activated by means of an activator (such as water) added into the section 13a. There may also be a separate electrolyte storage arranged in connection with the section 13a. The operation of the device can be described according to the following example, which relates to the dosing of a cationic drug: Electrode 1 1 is an anode and 12 a cathode. The electrodes are, for example, Ag, respectively AgCl. In the chamber 13 section 13a, which contains an electrolyte, e.g. NaCl, there is caused by an electrode reaction a selective transport of the cation through the cation-selective membrane 18 to section 13b, in which the cationic drug is bound to an ion exchanger. Section 13b also contains an electrolyte (NaCl). Section 13a of the chamber must contain a sufficiently large amount of salt in order to provide a sufficient cation flow, and in some cases a sufficient electrode reaction, for a sufficiently long time. The required amount of electrolyte can be calculated on the basis of Faraday's law. When the anode is silver and the electrolyte is NaCl, silver chloride is formed through the electrode reaction. In this case the electrode reaction is Ag(s) + Cl-(I) -> AgCl(s) + e If it is desired to use some other electrode material, for example, one which generates gases, the anion in the anode space, i.e. in chamber section 13a, must be changed (to prevent the formation of chlorine) and the electrode must be made porous. That anode surface which is oriented towards outside air should preferably be covered with a hydrophobic. microporous membrane to let out the gases formed. If the electrode material used is, for example, platinum or graphite, the electrode reaction may be, for example, 2H 2 0 - O2 + 4H+ + 4e In this case, buffering of the anode space must be attended to, since in many cases, depending on the electrode material, the reaction produces protons. When the cation (in this example case Na+) is transported, in the manner determined by the electric current, to chamber section 13b, i.e. the ion-exchange space, quantitatively almost the same number of cations is transported from this space through the porous membrane 15 which is selectively permeable to cations, and thereafter through the skin 20. If the membrane 15 is a merely microporous membrane and not a cation-selective membrane, a portion of the cation flow is lost for the benefit of anions. Thus, if there is used a merely microporous membrane, the salt concentration in the ion-exchange space (section 13b) tends to rise considerably more than when a cation-selective membrane is used. As a consequence of the in- creasing salt concentration in the ion-exchange section, the drug flow through the skin may weaken somewhat. The change can be observed and, when necessary, be corrected by adjusting the electric current (the power of the direct-current source is preferably controllable). The ions transported from the device through the skin 20 into the body are Na + and the drug cation is L + . If the membrane 15 used is a merely microporous membrane, some Cl " ions are also transported from the body through the skin. The quantity of L + and Na + ions transported into the body depends on the salt concentration in the ion-exchange space (section 13b), on the distribution constant between the drug and the salt, typical of the ion exchanger, and on the electric mobilities of the salt cation and the drug cation. This arrangement en- ables the drug to be dosed precisely, since the flow of drug cations through the skin can be determined by control of the electric current. It is suitable to use in the cathode chamber 14, for example, a NaCl solution. The cathode 12 can be an AgCl electrode or a gas-generating electrode in the same manner as in the anode space. In this case it is also necessary to attend to buffering, since the electrode reaction in most cases develops hydroxyl ions. If it is desired to dose an anionic drug, the electrodes are exchanged so that 1 1 is the cathode and 12 is the anode. Membrane 18 must be a membrane selectively permeable to anions. Membranes 15 and 16 must also be membranes selectively perme- able to anions, unless they are merely microporous membranes. The ion exchanger in the space 13b must be an anion exchanger. Figure 2 shows a device according to the invention, suitable for the study of drug release. The device is structurally the same as the dosing device of Figure 1, except that the skin 20 of an individual has been replaced with human or animal skin or a synthetic membrane, and that the chamber 14 serves as a sample-taking container. The container 14 contains a salt solution, for example, a physiologic salt solution or a suitable NaCl solution. By means of this device it is, for example, possible to determine the distribution constant prevailing in the ion-exchange space between the drug cations (respectively anions) and the electrolyte cations (respectively anions) and to determine the ratio of the electric mobilities of the said ions at different salt concentrations for different types of ion exchangers. By means of the device it is thus possible to determine suitable permeation parameters for each given drug and thereby to tailor drug-specifically optimal dosing devices. The invention is described in greater detail with the help of the following examples. EXAMPLE 1 By means of a device according to Figure 2, the transport of metoprolol from the ion-exchange space 13b to the cathode chamber 14 was tested. Metoprolol, which is a cationic drug, was bound to ion exchanger S-102 (Smoptech), which is a weak fi- ber-form cation exchanger, which consists of polyethylene fibers grafted with acrylic acid groups. The ion exchanger space 13b contained 0.15 M NaCl. The anode space 13a contained 0.5 M NaCl and the cathode chamber 14 contained 30 ml of 0.15 M NaCl. The membrane 15 was a porous membrane in which the pore diameter was 5 μm. The membrane was cation-selective (PVDF-PAA (4 %)). The cation-exchange membrane 18 was Nafion, in Na + form. The electric current I was 3.171 rriA (= 0.45 mA/cm^). The quantity of metoprolol accumulated in the chamber 14 was measured as a function of time. Results (Test 1): time/min amount/mg error/±mg n/μmol 60 0.054 0.002 0.202 120 0.393 0.017 1.472 190 1.476 0.060 5.528 240 2.251 0.090 8.431 300 3.152 0.122 1 1.805 370 4.222 0.156 15.813 420 4.846 0.184 18.150 480 5.562 0.213 20.831 1440 17.956 0.514 67.251 The cumulated metoprolol amount m as a function of time t is presented in Figure 3; m is the amount of the substance. The correlation of the straight line is 0.9994. The flow, which is constant and is obtained from the angular coefficient 0.013 mg/min of the line, is 0.098 mg/cm 2 h. EXAMPLE 2 The test was carried out as in Example 1 , except that the electrolyte concentration in the ion-exchanger space 13b was 0.015 M NaCl and in the anode space 13a 0.15 M NaCl. Results (Test 2): time/min amount/mg error/±mg n/μmol 60 0.604 0.016 2.263 122 2.378 0.061 8.905 180 3.848 0.098 14.412 240 5.127 0.130 19.201 310 6.552 0.166 24.538 366 7.564 0.191 28.331 420 8.361 0.21 1 31.314 480 8.915 0.224 33.388 Figure 4 shows as a function of time the cumulative metoprolol amounts accumulated in the cathode chamber 14 in both of the tests 1 and 2. It is seen that a decrease in the electrolyte concentration in the ion-exchange space increases the drug ion flow. The above embodiments of the invention are only examples of the implementation of the idea according to the invention. For a person skilled in the art it is clear that the various embodiments of the invention may vary within the claims presented below.

Claims: CLAIMS 1. A device based on iontophoresis and intended for transdermal dosing of an active agent, the device comprising a pair of electrodes (1 1 , 12) and a direct-current source in connection with the electrodes ( 1 1 and 12), - two chambers (13, 14) insulated from each other, the first chamber (13) containing the active agent, and each chamber having a porous membrane (15, 16) on the side facing an individual's skin, characterized in that the first chamber (13) is divided into two sections (13a, 13b) in such a manner that the first section (13a) is in connection with the electrode (1 1) and the second section (13b) is in connection with the membrane (15) coming into contact with an individual's skin, there being between the sections (13a and 13b) a membrane (18) selectively permeable either to cations or to anions, and that - the first section (13a) contains an electrolyte and the second section (13b) con- tains the ionic active agent, bound to an ion exchanger therein. 2. A device according to Claim 1 , characterized in that the electric current is controllable. 3. A device according to Claim 1 or 2, characterized in that the ion exchanger comprises ion-exchange groups bound to a textile fiber. 4. A device according to Claim 1, 2 or 3, characterized in that both of the membranes (15, 16) are membranes selectively permeable either to cations or to anions. 5. A device according to any of Claims 1 - 4, characterized in that the first section (13a) contains an electrolyte in solution form. 6. A device according to any of Claims 1 - 4, characterized in that the first sec- tion (13a) contains an electrolyte in dry form, in which case the electrolyte can be activated by means of an activator added into the section ( 13a). 7. A device according to any of the above claims, characterized in that the second section ( 13b) of the first chamber ( 13) contains an electrolyte solution. 8. A device according to any of the above claims, characterized in that the sec- ond chamber ( 14) contains an electrolyte solution. 9. A device according to any of Claims 1 -8, characterized in that the electrode (1 1) in connection with the first section (13a) of the first chamber (13) is an anode, the active agent is cationic, the ion exchanger is a cation exchanger, the membrane (18) between the sections (13a and 13b) is a membrane selectively permeable to cations. 10. A device according to Claim 9, characterized in that the membranes (15, 16) are membranes selectively permeable to cations. 1 1. A device according to any of Claims 1 - 8, characterized in that the electrode (1 1) in connection with the first section (13a) of the first chamber ( 13) is a cathode, the effective agent is anionic, the ion exchanger is an anion exchanger, the membrane (18) between the sections ( 13a and 13b) is a membrane selectively permeable to anions. 12. A device according to Claim 1 1 , characterized in that the membranes ( 15, 16) are membranes selectively permeable to anions. 13. A device intended for the study of transdermal dosing of an active agent, the device comprising - a pair of electrodes ( 1 1 , 12) and a direct-current source in connection with the electrodes (1 1 and 12), - two chambers (13, 14) insulated from each other, the first chamber (13) containing an active agent, and the first chamber (13) has a porous membrane (15) on the side facing a piece of skin (21) and the second chamber (14) contains a suitable so- lution, characterized in that - the first chamber (13) is divided into two sections (13a, 13b) in such a manner that the first section ( 13a) is in connection with the electrode ( 1 1) and the second section (13b) is in connection with the membrane (15) which comes into contact with the piece of skin (21 ), there being between the sections (13a and 13b) a mem- brane (18) selectively permeable either to cations or to anions, and that - the first section (13a) contains an electrolyte and the second section (13b) contains an ionic active agent, bound to an ion exchanger therein. 14. A device according to Claim 13, characterized in that the ion exchanger comprises ion-exchange groups bound to a textile fiber. 15. A device according to Claim 13 or 14, characterized in that the electric current is controllable. 16. A device according to Claim 13, 14 or 15, characterized in that the membrane (15) is a membrane selectively permeable either to cations or to anions. 17. A device according to any of Claims 13 - 16, characterized in that the electrode (1 1) in connection with the first section (13a) of the first chamber (13) is an anode, the active agent is cationic, the ion exchanger is a cation exchanger, the membrane ( 18) between the sections ( 13a and 13b) is a membrane selectively per- meable to cations. 18. A device according to Claim 17, characterized in that the membrane (15) is a membrane selectively permeable to cations. 19. A device according to any of Claims 13 - 16, characterized in that the electrode (1 1) in connection with the first section (13a) of the first chamber (13) is a cathode, the active agent is anionic, the ion exchanger is an anion exchanger, the membrane (18) between the sections (13a and 13b) is a membrane selectively permeable to anions. 20. A device according to Claim 19, characterized in that the membrane (15) is a membrane selectively permeable to anions.

Inventors: EKMAN KENNETH, HIRVONEN JOUNI, JASKARI TARJA, KONTTURI KYOESTI, PELTONEN ROBERT, SUNDELL MATS, VUORIO MARJA, EKMAN, KENNETH, HIRVONEN, JOUNI, JASKARI, TARJA, KONTTURI, KYOESTI, PELTONEN, ROBERT, SUNDELL, MATS, VUORIO, MARJA
Applicants: EKMAN KENNETH, HIRVONEN JOUNI, JASKARI TARJA, KONTTURI KYOESTI, NOVAGENT OY, PELTONEN ROBERT, SUNDELL MATS, VUORIO MARJA, EKMAN, KENNETH, HIRVONEN, JOUNI, JASKARI, TARJA, KONTTURI, KYOESTI, PELTONEN, ROBERT, SUNDELL, MATS, VUORIO, MARJA
Application year: 2000
Main classification: A61N1
IPC codes: A61N1