Device for ionophoresis comprising at least a membrane electrode assembly, for the transcutaneous administration of active principles to a subject

• US 6,064,908 A
• Filed: 07/08/1999
• Issued: 05/16/2000
• Est. Priority Date: 11/07/1996
• Status: Expired due to Term

• Current Assignee: Sanofi
• Original Assignee: Elf Aquitaine (Cook Composites and Polymers), Sanofi
• Inventors: Muller, Daniel, Barbier, Alain, Perie, Frederic
• Primary Examiner(s): Coggins, Wynn Wood
• Assistant Examiner(s): MENDEZ, MANUEL A
• Application Number:
  US09/284,971
• Time in Patent Office: 313 Days
• Field of Search: 604/20, 604/501, 604/890.1, 604/19, 604/21, 607/149, 607/152, 607/153, 607/115, 424/449, 435/173.4, 435/173.5
• US Class Current: 604/20
• CPC Class Codes: A61N 1/30 Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis

Abstract

The device for ionophoresis combines a donor electrode assembly, a counter electrode assembly and a generator of electricity. The donor assembly comprises a primary reservoir element containing the active principle and a secondary reservoir element containing a neutral electrolyte, these reservoir elements being separated by a semipermeable membrane in polymer material in contact with each of them, and an electrode in contact with the secondary reservoir element. The polymer material of the membrane consists at least in polyethyerblocamide with an Mn between 10000 and 300000 and containing by weight, 35% to 90% of polyamide sequences. The invention is applicable to the transcutaneous administration of active principles to a subject with improved efficiency.

Claims

1. Iontophoresis device, for transcutaneous administration of an active principle to a subject, comprising (a) a first electrode assembly, called the donor electrode assembly, consisting of a first electrode called the active electrode, a primary reservoir element designed to contain a primary electrolyte medium containing the active principle in an at least partially ionized form or in a neutral form in order to ensure, when it is placed in contact with an area of the subject'"'"'s skin, ionically conducting continuity between the said first electrode and the said area, and a membrane made of polymer material in contact, via one face, with the first electrode and, via another face, with the primary reservoir element, the said membrane being selectively permeable to ions and molecules of sizes smaller than a chosen threshold, (b) a second electrode assembly consisting either (i) of a second electrode, called the back electrode, or preferably (ii) of a second electrode of this type in contact with a reservoir element, called the back electrode, designed to contain at least one electrolyte medium and to ensure, when it is placed in contact with a portion of the subject'"'"'s skin, ionically conducting continuity between the second electrode and the said portion and (c) an electric signal generator which can be connected to each of the said first and second electrodes in such a way that the first electrode has the same polarity as the ions of the active principle or a positive polarity if the said active principle is neutral and that the second electrode has a polarity opposite to that of the first electrode, wherein in the said device the polymer material constituting the selectively permeable membrane consists of at least one polyether block amide formed by identical or different units corresponding to the formula ##STR6## in which A is a polyamide sequence derived, by losing its COOH groups, from a dicarboxylic polyamide having a COOH group at each of the ends of its chain, and B is a polyoxyalkylene sequence derived, by losing two hydroxyl groups, from a polyoxyalkylene glycol whose chain is formed by oxyalkylene units having 2 to 4 carbon atoms and has an OH group at each of its ends, the said polyether block amide having a number-average molecular mass of between 10,000 and 300,000 and containing a proportion by weight of polyamide sequences A of between 35% and 90%.

2. Device according to claim 1, wherein the polyether block amide of which the membrane is formed has a number-average molecular mass of between 10,000 and 200,000.

3. Device according to claim 1 wherein the polyether block amide of which the membrane is formed has a proportion by weight of polyamide sequences A of between 45% and 85%.

4. Device according to one of claim 3, wherein the dicarboxylic polyamide from which the polyamide sequence A derives is obtained by polycondensation, in the presence of a dicarboxylic acid having 4 to 20 carbon atoms in its molecule, of one or more monomers selected from he group formed by lactams and amino acids having 4 to 6 carbon atoms in their molecules and the combinations of one or more diamines having 4 to 16 carbon atoms in their molecules with one or more dicarboxylic acids having 4 to 18.

5. Device according to claim 4, wherein the dicarboxylic polyamide from which the polyamide sequence A derives is obtained from one or more monomers chosen from caprolactam, cenantholactam, dodecalactam, undecanolactam, decanolactam, 11-amino undecanoic acid and 12-amino dodecanoic acid.

6. Device according to claim 4, wherein the dicarboxylic polyamide from which the polyamide sequence A derives is produced by polycondensation of hexamethylene diamine with adipic acid, azelaic acid, sebacic acid or 1,12-dodecanedioic acid or by polycondensation of nonamethylene diamine with adipic acid.

7. Device according to claim 1, wherein the number-average molecular masses of the sequences A derived from the dicarboxylic polyamides lie between 300 and 15,000.

8. Device according to claim 1, wherein the polyoxyalkylene glycols from which the sequence B of the units constituting the polyether block amide derives are polymers consisting of one or more of the repeat units ##STR7## selected from the group consisting of polyoxyethylene glycols, polyoxypropylene glycols, polyoxytetramethylene glycols, copoly(oxyethylene/oxypropylene)glycols, copoly(oxyethylene/-oxytetramethylene)glycols, copoly(oxyethylene/-oxypropylene/oxytetramethylene) glycols and mixtures of such polyoxyalkylene glycols and/or their copolymers.

9. Device according to claim 1, wherein the number-average molecular masses of the sequences B are between 100 and 6000.

10. Device according to claim 1, wherein the polyether block amide membrane has a thickness of between 10 μ

m and 200 μ

m.

11. Device according to claim 1, wherein the primary reservoir element of the first electrode assembly has a thickness of between 50 μ

m and 1000 μ

m.

12. Device according to claim 1, wherein the first electrode assembly is also provided with a secondary reservoir element containing an arbitrary electrolyte, the said secondary reservoir element being arranged between the electrode of the said assembly and the polyether block amide membrane so as to be in contact with each of them.

13. Device according to claim 12, wherein the volume of the secondary reservoir element is greater than or equal to the volume of the primary reservoir element.

14. Device according to claim 1, wherein at least the electrode of the first electrode assembly is an electrode which can be consumed electrochemically when the current flows during operation of the ionophoresis device, the consumable electrode being a reversible electrode.

15. Device according to claim 14, for administering a given total quantity of the active principle to the subject, wherein one or other of the electrodes is designed to form an electrode, called the limiting electrode, formed by a limited quantity of an electrochemically consumable material combined either with an electronically conducting support or an insulating support, the said electrochemically consumable material being either an electrochemically reducible metal compound when the limiting electrode is a cathode or a metal consumable by electrochemical oxidation when the limiting electrode is an anode, and the said electronically conducting support being made of a material which resists corrosion by the electrolyte associated with the limiting electrode in the absence of current and which has, when the limiting electrode is a cathode, a hydrogen overpotential in the presence of the said electrolyte at least equal to that of aluminium or which is not consumable by electrochemical oxidation when the limiting electrode is an anode, while the said limited quantity of electrochemically consumable material is chosen so that the quantity of electricity needed to consume it electrochemically corresponds to the quantity of electricity needed to administer the given total quantity of active principle to the subject so that the flow of current between the electrodes is substantially interrupted when the consumable material of the limiting electrode has been consumed, and the active principle is initially present in the primary reservoir element in a quantity greater than the given total quantity to be administered to the subject.

16. Device according to claim 1, wherein the electrical generator applies between the electrodes of the said device an intensiometric electric signal or a potentiometric signal or both types of signals, the said electric signal being continuous or pulsed and permanent or intermittent, with or without temporary polarity inversion, and having a frequency ranging from 0 to 500 kHz.

17. Device according to claim 16, wherein the electric signal is a pulsed signal having a duty cycle ranging from 0.05 to 0.95.

18. Device according to claim 16, wherein the electric signal applied between the electrodes has an average voltage chosen between 0.1 and 50 volts so that the density of the average current generated between the said electrodes has a value less than 0.50 mA/cm².

19. Device according to claim 1, wherein the primary electrolyte medium present in the primary reservoir element of the first electrode assembly consists of an aqueous solution or of an adhesive or nonadhesive hydrogel containing the active principle to be administered in an at least partially ionized form or in a neutral form, or is in the form of a hydratable solid consisting of a selfadhesive or non-self-adhesive matrix made of a hydrophobic material in which one or more water-soluble or hydrophilic polymers and the active principle to be administered are dispersed.

20. Device according to claim 12, wherein the arbitrary electrolyte contained in the secondary reservoir element of the first electrode assembly consists of an aqueous solution or a hydrogel containing one or more pharmaceutically acceptable salts which can be ionized in the aqueous phase, or is in the form of a hydratable solid formed by a hydrophobic polymer matrix in which one or more hydrophilic polymers and the ionizable salt or salts are dispersed, or consists of a hydrophilic absorbent matrix containing the ionizable salt or salts in the dispersed state.

21. Device according to claim 19, wherein the primary reservoir element and the secondary reservoir element are in the form of hydratable solids, and in that the said primary and secondary reservoir elements are assembled dry with the membrane and the associated electrode to form a first electrode assembly in the nonhydrated state.

22. Device according to claim 1, wherein the selectively permeable membrane prevents the migration of ions and molecules having molecular masses higher than 100 daltons.

23. Device according to claim 1, wherein the second electrode assembly has a structure similar to that of the first electrode assembly, and in that the electrode of each of the said assemblies is a reversible consumable electrode based on the Ag/AgCl pair.

24. Device according to claim 19, wherein the concentration of active principle in the aqueous phase of the primary electrolyte medium of the primary reservoir element is between 0.2% by weight of the aqueous phase and the saturation concentration of the said aqueous phase.

25. Donor electrode assembly, in particular for an iontophoresis device, comprising an active electrode, a primary reservoir element, designed, on the one hand, to contain a primary electrolyte medium containing an active principle in an at least partially ionized form or in a neutral form and, on the other hand, in order to ensure, when it is placed in contact with an area of the subject'"'"'s skin, ionically conducting continuity between the said electrode and the said area, and a membrane made of polymer material in contact, via one face, with the electrode and, via another face, with the primary reservoir element, the said membrane being selectively permeable to ions and molecules of sizes smaller than a chosen threshold, the said donor assembly being wherein the polymer material constituting the selectively permeable membrane consists of at least one polyether block amide formed by identical or different units corresponding to the formula ##STR8## in which A is a polyamide sequence derived, by losing its COOH groups, from a dicarboxylic polyamide having a COOH group at each of the ends of its chain, and B is a polyoxyalkylene sequence derived, by losing two hydroxyl groups, from a polyoxyalkylene glycol whose chain is formed by oxyalkylene units having 2 to 4 carbon atoms and has an OH group at each of its ends, the said polyether block amide having a number-average molecular mass of between 10,000 and 300,000 and containing a proportion by weight of polyamide sequences A of between 35% and 90%.

26. Assembly according to claim 25, wherein the polyether block amide of which the membrane is formed has a number-average molecular mass of between 10,000 and 200,000.

27. Assembly according to claim 25 wherein the polyether block amide of which the membrane is formed has a proportion by weight of polyamide sequences A of between 45% and 85%.

28. Assembly according to claim 25, wherein the dicarboxylic polyamide from which the polyamide sequence A derives is obtained by polycondensation, in the presence of a dicarboxylic acid having 4 to 20 carbon atoms in its molecule, of one or more monomers selected from the group formed by lactams and amino acids having 4 to 16 carbon atoms in their molecules and the combinations of one or more diamines having 4 to 16 carbon atoms in their molecules with one or more dicarboxylic acids having 4 to 18 carbon atoms in their molecules.

29. Assembly according to claim 28, in that the dicarboxylic polyamide from which the polyamide sequence A derives is obtained from one or more monomers chosen from caprolactam, oenantholactam, dodecalactam, undecanolactam, decanolactam, 11-amino undecanoic acid and 12-amino dodecanoic acid, the said polyamide being, in particular, like polyamide-6, polyamide-11, polyamide-12, copolyamide-6/11 or copolyamide-6/12.

30. Assembly according to claim 28, wherein the dicarboxylic polyamide from which the polyamide sequence A derives is produced by polycondensation of hexamethylene diamine with adipic acid, azelaic acid, sebacic acid or 1,12-dodecanedioic acid or by polycondensation of nonamethylene diamine with adipic acid.

31. Assembly according to claim 25, wherein the number-average molecular masses of the sequences A derived from the dicarboxylic polyamides lie between 300 and 15,000.

32. Assembly according to claim 25, wherein the polyoxyalkylene glycols from which the sequence B of the units constituting the polyether block amide derives are polymers consisting of one or more of the repeat units ##STR9## selected from the group consisting of polyoxyethylene glycols, polyoxypropylene glycols, polyoxytetramethylene glycols, copoly(oxyethylene/oxypropylene) glycols, copoly(oxyethylene/oxytetramethylene) glycols, copoly(oxyethylene/oxypropylene/oxytetramethylene) glycols and mixtures of such polyoxyalkylene glycols and/or their copolymers.

33. Assembly according to claim 25, wherein the number-average molecular masses of the sequences B are between 100 and 6000.

34. Assembly according to claim 25, wherein the polyether block amide membrane has a thickness of between 10 μ

m and 200 μ

m.

35. Assembly according to claim 25, wherein the primary reservoir element has a thickness of between 50 μ

m and 1000 μ

m.

36. Assembly according to claim 25, wherein it is also provided with a secondary reservoir element containing an arbitrary electrolyte, the said secondary reservoir element being arranged between the electrode of the said assembly and the polyether block amide membrane so as to be in contact with each of them.

37. Assembly according to claim 36, wherein the volume of the secondary reservoir element is greater than or equal to the volume of the primary reservoir element.

38. Assembly according to claim 25, wherein its electrode is an electrochemically consumable electrode, the said electrode being a reversible electrode.

39. Assembly according to claim 38, wherein the said consumable electrode is designed to form an electrode, called the limiting electrode, formed by a limited quantity of an electrochemically consumable material combined either with an electronically conducting support or an insulating support, the said electrochemically consumable material being either an electrochemically reducible metal compound when the limiting electrode is a cathode or a metal consumable by electrochemical oxidation, in particular a metal such as Al, Mg, Zn or Ag, when the limiting electrode is an anode, and the said electronically conducting support being made of a material which resists corrosion by the electrolyte associated with the limiting electrode in the absence of current and which has, when the limiting electrode is a cathode, a hydrogen overpotential in the presence of the said electrolyte at least equal to that of aluminium or which is not consumable by electrochemical oxidation when the limiting electrode is an anode, while the said limited quantity of electrochemically consumable material is chosen so that the quantity of electricity needed to consume it electrochemically corresponds to the quantity of electricity needed to administer a given total quantity of an active principle to a subject, so that the flow of current between the electrode of the said assembly and a back electrode is substantially interrupted when the consumable material of the limiting electrode has been consumed, and the active principle is initially present in the primary reservoir element in a quantity greater than the given total quantity to be administered to the subject.

40. Assembly according to claim 25, wherein the primary electrolyte medium present in the primary reservoir element of the said assembly consists of an aqueous solution or of an adhesive or nonadhesive hydrogel containing the active principle to be administered in an at least partially ionized form or in a neutral form, or is in the form of a hydratable solid consisting of a self-adhesive or non-self-adhesive matrix made of a hydrophobic polymer material in which one or more water-soluble or hydrophilic polymers and the active principle to be administered are dispersed.

41. Assembly according to claim 36, wherein the arbitrary electrolyte contained in the secondary reservoir element of the said assembly consists of an aqueous solution or a hydrogel containing one or more pharmaceutically acceptable salts which can be ionized in the aqueous phase, or is in the form of a hydratable solid formed by a hydrophobic polymer matrix in which one or more hydrophilic polymers and the ionizable salt or salts are dispersed, or consists of a hydrophilic absorbent matrix containing the ionizable salt or salts in the dispersed state.

42. Assembly according to claim 40, wherein the primary reservoir element and the secondary reservoir element are in the form of hydratable solids, and in that the said primary and secondary reservoir elements are assembled dry with the membrane and the associated electrode to form the said assembly in the nonhydrated state.

43. Assembly according to claim 25, wherein the selectively permeable membrane prevents the migration of ions and molecules having molecular masses higher than 100 daltons.

44. Assembly according to claim 40, wherein the concentration of active principle in the aqueous phase of the primary electrolyte medium of the primary reservoir element is between 0.2% by weight of the aqueous phase and the saturation concentration of the said aqueous phase.