DEVICE FOR ENHANCED DELIVERY OF BIOLOGICALLY ACTIVE SUBSTANCES AND COMPOUNDS IN AN ORGANISM

• US 20020123678A1
• Filed: 05/20/1998
• Published: 09/05/2002
• Est. Priority Date: 11/21/1995
• Status: Active Grant

• Current Assignee: Intrabrain International N.V.
• Original Assignee: Intrabrain International N.V.
• Inventors: LERNER, LEONID, LERNER, EDUARD N.
• Granted Patent: US 6,678,553 B2
• Time in Patent Office: Days
• US Class Current: 600/378
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61M 2210/0618 Nose
• CPC Class Codes: A61M 37/00 Other apparatus for introducing media into the body for reproduction or fertilisation A61B17/425; apparatus for iontophoresis or cataphoresis A61N1/30; Percutany, i.e. introducing medicines into the body by diffusion through the skin salt baths A61H33/04
• CPC Class Codes: A61N 1/0432 Anode and cathode
• CPC Class Codes: A61N 1/303 Constructional details electrodes for external use A61N1/0428
• CPC Class Codes: A61N 1/306 Arrangements where at least part of the apparatus is introduced into the body

Abstract

A device to enhance the delivery of a drug or other substance of interest into a selected organ or tissue, comprising special electrodes, one of the electrodes carrying a container with the selected drug or other substance of interest, said electrodes being capable of being positioned at preselected locations of said organ or tissue, wherein the electrodes are all connected with a selected energy source which generates and maintains an energy field before and during the enhanced delivery of said substance, under the influence of which delivery is accomplished in a direction from the active to the passive electrode and into said organ or tissue. The energy source may be selected from suitable sources providing an electric field, a magnetic field, ultrasonic waves, high energy waves like laser beams, or a combination thereof. Further a method for the enhanced delivery of said drug or other substance of interest to an internal organ or target tissue of an organism, for example the brain, bypassing the blood-brain barrier, is disclosed.

Claims

1. A device to enhance the delivery of a drug or other substance or compound of interest into a selected target organ or tissue of an organism, comprising a special apparatus, special electrodes, one of the special electrodes carrying a special container with the selected drug or other substance or compound of interest, said electrodes being capable of being positioned at preselected locations of said organ or tissue, wherein the electrodes are all connected with a selected energy source which generates and maintains an energy field before and during the enhanced delivery of said substance or compound, under the influence of which delivery is accomplished in a direction from the active to the passive electrode and into said organ or tissue.

2. A device according to the claim 1, wherein said device comprises an energy source which is provided with means for internal electrical circuiting the supply of energy in rest position of the device, which will automatically activate the electrodes in the delivery position upon connection to said organism.

3. A device according to claim 1 or 2, wherein said active electrode is provided with means for carrying said drug or other biologically active substance or compound.

4. A device according to one or more of the claims 1 to 3, wherein said active and/or said passive electrode are split into two or more parts.

5. A device according to the claims 1 or 2, wherein said energy source is selected from the group comprising sources providing an electric field, a magnetic field, ultrasonic waves, high energy waves like laser beams, or a combination thereof.

6. A device according to the claims 1 or 2, wherein said energy source is a source of thermal energy or a combination of such a source with another source of energy.

7. A device according to claim 4, wherein said energy source providing an electric field is adapted to provide a current of up to 25 mA, preferably up to 10 mA.

8. An assembly comprising a device as defined in one or more of the claims 1 to 7, wherein the active electrode is provided with at least one drug, or other biologically active substance or compound of interest.

9. An electrode to be used in a device according to claim 1, comprising an electric conductive base member which can be connected to said selected energy source, wherein the top area of said base member is capable of supporting the drug or other biologically active substance or compound, and all but the top area of said base member is coated with an insulating material.

10. An electrode according to claim 9, wherein said electrode is provided with a container for the drug or other biologically active substance or compound to be delivered into a targer organ or tissue, having a closable connection with the top area of the electrode.

11. An electrode according to the claims 9 or 10, wherein said base member has a substantial frusto-conical hollow or other form.

12. An electrode according to one or more of the claims 9 to 11, wherein at least one through-opening is present in the area coated with the insulating material in said base member.

13. Use of a drug or other biologically active substance or compound of interest for the manufacture of an iontophoretic assembly comprising of an electrode as defined in one or more of the claims 9 to 11, and said compound, wherein said compound is for delivery directly or by carrier and is selected from the group of drugs and other substances or compounds of interest, that can be selected from the following listed, and that are given as examples and without limitation:

amino acids, anabolics, analgesics and antagonists, anesthetics, anthelmintics, anti-adrenergic agents, anti-asthmatics, anti-atherosclerotics, antibacterials, anticholesterolics, anti-coagulants, antidepressants, antidotes, anti-emetics, anti-epileptic drugs, ant-fibrinolytics, anti-inflammatory agents, antihypertensives, antimetabolites, antimigraine agents, antimycotics, antinauseants, antineoplastics, anti-obesity agents, anti-Parkinson agents, antiprotozoals, antipsychotics, antirheumatics, antiseptics, antivertigo agents, antivirals, appetite stimulants, bacterial vaccines, bioflavonoids, calcium channel blockers, capillary stabilizing agents, coagulants, corticosteroids, detoxifying agents for cytostatic treatment, diagnostic agents (like contrast media and radioisotopes), drugs for treatment of chronic alcoholism, electrolytes, enzymes, enzyme inhibitors, ferments, ferment inhibitors, gangliosides and ganglioside derivatives, hemostatics, hormones, hormone antagonists, hypnotics, immunomodulators, immunostimulants, immunosuppressants, minerals, muscle relaxants, neuromodulators, neurotransmitters and nootropics, osmotic diuretics, parasympatholytics, para-sympathomimetics, peptides, proteins, psychostimulants, respiratory stimulants, sedatives, serumlipidreducing agents, smooth muscle relaxants, sympatholytics, sympathomimetics, vasodilators, vasoprotectives, vectors for gentherapy, viral vaccines, viruses, vitamins, and every kind of neurotropic drugs and other substances.

15. Use according to claim 14, wherein said electrode is an electrode as defined in one or more of the claims 9 to 12.

17. An enhanced delivery according to claim 15, wherein said carrying location is spaced apart from the target organ or tissue by a membrane having a low electric resistance.

18. An enhanced delivery according to claims 15 or 16, wherein said drug or other substance or compound of interest is delivered transnasally into the central nervous system from the nasal cavity bypassing the blood brain barrier, by using a current intensity of up to 10 mA or more, between an active electrode introduced internally into at least one nostril, and a passive electrode fixed on the head.

19. An enhancement according to claims 15 or 16, wherein the delivery of said drug or other substance or compound of interest is enhanced transnasally to the central nervous system by using an active electrode fixed externally on the nose of the organism, a passive electrode fixed on the head, while the active compound is applied intranasally after the generation of the energy field.

26. An enhanced delivery to claim 16, wherein the active electrode being provided with the drug or other substance or compound of interest is placed in the sublingual space, and the passive electrode is fixed submandibulary or in another place, to deliver said drug or other substance or compound of interest intravenously.

27. An enhanced delivery according to claim 16, wherein the active electrode being provided with the drug or other substance or compound of interest is placed in the rectum or vagina, and the passive electrode is fixed externally on the spine or another place on the skin of the organism to deliver said drug or other substance or compound of interest intravenously.

28. An enhanced delivery according to claim 16, wherein said active electrode being provided with the drug or other substance or compound of interest is introduced into a vein or artery, and brought directly to the pathological point, for instance a thrombus, and the passive electrode is fixed on the projection on the skin of the pathological organ or tissue to which said drug or other substance or compound of interest is delivered.

29. An enhanced delivery according to claim 16, wherein said active electrode being provided with the drug or other substance or compound of interest is introduced into the stomach or bladder or intraperitoneally or into another cavity or tissue, and the passive electrode is fixed externally on the skin of the organism to enhance the delivery of said compound into the tumour or lesion.

30. The container holding the drug or other substance or compound of interest to be connected to the active electrode according to claim 14, can be made of any suitable material or combination of materials, that fulfills relevant criteria with respect to compatibility with the drug or other substance or compound of interest and with the biological environment, but also with respect to ease of manufacturing, sterilizability, re-usability, low environmental impact, flexibility, connectibility, durability and disposability.

31. The drug container or reservoir to be connected to the active electrode according to claim 14, should be constructed of any material in such way that it is adapted to absorb and hold a sufficient quantity of liquid in order to permit transport of drug through its wall by means of iontophoresis.

32. Optionally, the drug container or reservoir to be connected to the active electrode according to claim 14, should hold a self-sealing membrane or valve that allows the in-situ refilling with drug solution, without the necessity of removal and re-insertion of the present device.

33. The drug container or reservoir to be connected to the active electrode according to claim 14, could consist for example of sponges, gauzes or pads consisting of cotton or other absorbent fabric, either or natural or synthetic origin, may be used. More preferably, containers or reservoirs are composed, at least in part, of one or more hydrophylic polymers.

34. The drug container or reservoir to be connected to the active electrode according to claim 14, may consist of a multilayered solid polymer matrices, composed, at least in part, of hydrophylic polymer. Insoluble hydrophylic polymer matrices are preferred over soluble hydrophylic polymers since the probability of delivering insoluble polymer by iontophoresis is very low.

35. The drug container or reservoir to be connected to the active electrode according to claim 14, may consist of a matrix that can be cross-linked with the drug components in place such as a silastic matrix, or the polymers can be prefabricated and sorbed with the components from solutions, for example with sponges or pads made of cellulose or woven fibre. The container may also consist of a gel matrix structure, or be of a classical reservoir type holding a liquid. The polymers can be either of linear or cross-linked type. Examples of suitable hydrophylic polymers include polyethylene glycols, polyacrylates, polyoxyethylene alkylethers, polyvidone, poloxamers, polyethylene oxides, polyvinyl alcohols, polyacrylamide, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose, co-polyesters, cyclodextrins, crospovidone, crosslinked dextrans, crosscarmellose sodium, natural gums, and starch, and mixtures thereof.

36. The drug container or reservoir to be connected to the active electrode according to claim 14, may consist optionally of a matrix containing also a hydrophobic polymer, to improve structural integrity. Preferably the hydrophobic polymer is heat fusible in order to enhance the lamination of container layers. Examples of suitable hydrophobic polymers include but are not limited to polyethylene, polypropylene, ethylene-vinylacetate copolymers, polyvinylacetate, polyisobutylenes, polyamides, polyurethanes, polyvinylchloride, and acrylic or methacrylic resins.

37. The drug container or reservoir to be connected to the active electrode according to claim 14, may be a polymeric matrix structure formed by mixing the selected drug, solvent, electrolyte, or other component(s) with an inert polymer by means of melt blending, solvent casting, compression or extrusion.

38. The drug container or reservoir to be connected to the active electrode according to claim 14, may have such a form as to enable its combination and attachment or coupling with the active electrode. The form, size and shape of the active electrode and its drug container are determined by the physiological environment related to its application and introduction into the body, for instance in the nostril, in the blood vessels, in the stomach, in the rectum, and in the vagina.

39. The drug container or reservoir to be connected to the active electrode according to claim 14, may have a connection of permanent or semi-permanent type, or of cartridge type for easy exchange of containers. Use of suitable adhesives for permanent connection of container and active electrode is foreseen, while physical locking and connecting means like slide lock, luer-lock, screw lock are more suitable for semi-permanent connections to enable exchange or cartridge type containers.

40. The drug or other biologically active substance or compound of interest according to claim 13, intended for enhanced delivery by means of an iontophoretic assembly comprising of an electrode as defined in one or more of the claims 9 to 11 and contained in a container or reservoir as defined in the claims 28 to 35, should be in part ionized, which can be brought about by dissolution in a medium or solvent that is able to conduct electric current and posesses an electric dipole, preferably a polar solvent having a high dielectric constant, allowing the separation of oppositely charged ions. Examples of some useful polar solvents include but are not limited to Water, Glycerin, Ethylene glycol, Methyl alcohol, Ethyl alcohol, n-propyl alcohol, and mixtures thereof. The degree of dissolution and subsequent ionization can be improved and regulated by means of the addition of suitable electrolytes forming buffer systems in the selected polar solvent or mixtures thereof.

41. With respect to the electrodes which can be used in the present invention according to claims 1 to 4, and 8 to 15, they are comprised of electrically conductive material such as a metal like aluminum, stainless steel, gold, silver, titanium, and zinc. Examples of other suitable electrically conductive materials include carbon, graphite, and metal salts like silver chloride. Electrodes may be formed of metal foil, metal screen, metal deposited or painted on a suitable carrier backing by means of calendaring, film evaporation, or by mixing the electrically conductive material in a polymer binder matrix. Alternatively, electrodes may be formed of a polymer matrix containing a conductive filler such as a metal powder, powdered graphite, carbon fibers, or other known electrically conductive filler material.

14. Use of an electrode, provided with a drug or other substance or compound of interest, in the manufacture of an iontophoretic device, for the enhanced delivery of said substance or compound to a target organ or tissue of said organism without obtaining significant plasma levels of said drug, substance or compound by generating and maintaining an electric field over said target organ or tissue before and during the delivery of said drug or other substance or compound of interest.

16. An enhanced delivery of an effective amount of a drug or other biologically active substance or compound into an internal target organ or tissue of an organism, such as a mammal, particularly a human being, being in need of such a delivery with such a drug, or other substance or compound of interest, wherein said compound is enhanced as such to said organ or tissue from a carrying location in the body of said organism by means of energy-stimulated penetration generated and maintained by a field set between at least two electrodes being split or not, upon connection with a selected energy source, of which electrodes one electrode can function as an active electrode and one as passive electrode, of which at least one electrode is placed on the skin layer of said organism, and one electrode, having the opposite polarity, is placed near the place where said drug or other substance or compound of interest is to be delivered.

20. An enhanced delivery according to one or more of the claims 16 to 18, wherein the active electrode is split into two parts, one of which is fixed externally to the nose, and the other one, being provided with the said active compound is introduced into a nostril.

21. An enhanced delivery according to one or more of the claims 16 to 18, wherein the delivery of said drug or other substance or compound of interest is enhanced into some specific region of the brain by using an active electrode fixed intranasally or extranasally and a split passive electrode, whereof one part is fixed externally on the projection of said specific region on the head, while said compound has been applied into a nostril.

22. An enhanced delivery according to one or more of the claims 16 to 18, wherein the delivery of said drug or other substance or compound of interest is enhanced into some specific region of the brain, for example to a tumour, the direction of delivery of the active substance can be bended by means of another set of active and passive electrodes, connected to a different energy source.

The first pair of electrodes being positioned in the nasal cavity and on the back of the head, while the second pair of electrodes is positioned as follows:

the passive on the projection of the tumour on the outside of the skull and the active, this time wetted in water, on the opposite side of the head, relative to the last mentioned passive electrode.

23. An enhanced delivery according to any of the claims 16 and 17, wherein the passive electrode is split into two parts, of which one is connected with the back of the head, and the other part is connected with the forehead of said organism, while the active electrode carrying the drug or other substance or compound of interest is connected with the palate of the mouth of said organism.

24. An enhanced delivery according to any of the claims 16 and 17, wherein said drug or other substance or compound of interest is delivered transocular to the central nervous system from the eyelid by using a current intensity of up to 10 mA between an active electrode fixed over the drug or other substance or compound of interest carried by said eyelid, and a passive electrode fixed on the back of the head of the organism.

25. An enhanced delivery according to any of the claims 16 and 17, wherein said drug or other substance or compound of interest is delivered to the central nervous system by using an active electrode, brought into contact with said compound, and both being introduced into the lower part of the rectum of the organism, and a passive electrode, fixed on the spine or other place, by using a current intensity of up to 10 mA.