Device for enhanced delivery of biologically active substances and compounds in an organism

• US 6,678,553 B2
• Filed: 05/20/1998
• Issued: 01/13/2004
• Est. Priority Date: 11/21/1995
• Status: Expired due to Fees

• Current Assignee: Intrabrain International N.V.
• Original Assignee: Intrabrain International N.V.
• Inventors: Lerner, Leonid, Lerner, Eduard N.
• Primary Examiner(s): Mendez, Manuel
• Assistant Examiner(s): MAYNARD, JENNIFER J
• Application Number:
  US09/077,123
• Publication Number:
  US 20020123678A1
• Time in Patent Office: 2,064 Days
• Field of Search: 604/20-22, 604/504, 604/514, 604/70, 604/19, 604/48, 604/500, 604/501, 604/290, 604/294, 604/93.01, 600/372, 600/380, 600/382, 600/383, 600/554, 600/378, 607/1, 607/2, 607/3, 607/35, 607/45, 607/96, 607/98, 607/99, 607/100, 607/101, 607/104, 607/105, 607/108, 607/109, 607/113, 607/115, 607/120, 607/135
• US Class Current: 604/20
• 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 and methods are described for a non-invasive transnasal and transocular drug delivery to the central nervous system using iontophoresis technology. By delivered through the olfactory nerve and the optical nerve, a biologically active substance of interest can be enhanced to be delivered into the CNS and CSF and bypassing the blood-brain barrier. Such drug delivery system can also be enhanced by using phonophoresis and other enhancement techniques.

Claims

1. An apparatus to enhance delivery of at least one delivery substance into the central nervous system of a mammal, utilizing the olfactory pathway(s) as a direct delivery route for the substance from an exogeneous source via the mammal'"'"'s olfactory area to a target site of the mammal'"'"'s central nervous system, bypassing the mammal'"'"'s blood brain barrier comprising:

a tube-shaped or frusto-conical shaped first electrode sized to be located in the olfactory area of the mammal wherein the distal tip or top area of the tube-shaped or frusto-conical shaped first electrode carries a biological substance in a container, said first electrode being an active electrode constructed and arranged, shaped and sized to be non-invasively positioned in the olfactory area of the mammal at least as far as the superior nasal turbinate and having at least one perforation therein;

second electrode being a passive electrode and being constructed and arranged to be positioned on or in proximity to the head of a mammal in one or more locations, but non-invasively of the mammal, and said first and second electrodes constructed and arranged for cooperation with an energy source to establish a radiant energy gradient across at least a portion of the mammal'"'"'s central nervous system; and

an energy source for providing a potential gradient between said first and second electrodes so that iontophoretic delivery of the delivery substance is accomplished in a direction from said active electrode directly into one or more target sites of a mammal'"'"'s central nervous system via the olfactory pathway(s) essentially bypassing the vascular system of the mammal wherein the energy source comprises an internal electrical circuit to hold a supply of energy in a rest position, prior to delivery of said at least one delivery substance, and, when said first and second electrodes are positioned in a delivery position, said internal electrical circuit activates said electrodes upon application of said electrodes to said mammal.

2. The apparatus according to claim 1 wherein the energy source comprises an electric current source with means for circuiting a supply of energy through the mammal between the electrode in a delivery position connection to said mammal and producing a current of up to 10 mA.

3. The apparatus according to either claim 1 or 2, wherein said energy source is constructed and arranged to provide a type of energy selected from the group consisting of thermal energy, an electric field, a magnetic field, high energy waves or ultrasonic waves and combinations thereof.

4. The apparatus according to claim 1 wherein said first electrode including said container holding a formulation suitable for iontophoretic delivery of the substance of interest and said first electrode together with said container is shaped to be insertable in an upper part of a nasal cavity of the mammal and constructed and arranged to make contact with nasal mucosa in an olfactory area of a mammal in order to enhance delivery of the substance of interest via said olfactory area directly into the mammal'"'"'s nervous system, thereby essentially bypassing the mammal'"'"'s vascular system.

5. The apparatus according to claim 4 wherein said active electrode means comprises an electroconductive base member and all but a top area of said base member is coated with an insulating material having at least one opening, and further being provided with an electroconductive material in said container supported by said top area of said base member, holding a formulation that is constructed and arranged for iontophoretic delivery of the substance of interest;

said container having a form as to enable its attachment and coupling with said active electrode,

the form, size and a shape of said active electrode means and its container being determined by a structure of a nasal cavity and related to its application and introduction into a nasal cavity.

6. The apparatus according to claim 5 wherein

said active electrode comprises an electroconductive part having electroconductive material selected from the group consisting of stainless steel, gold, silver, titanium, copper, zinc, graphic and metal salts.

7. The apparatus according to claim 5 wherein said active electrode is formed of a polymer matrix containing an electroconductive filler material selected from the group consisting of a metal powder, powdered graphite and carbon fibers.

8. The apparatus according to any one of the claims 5-7, wherein said active electrode is provided with the container for the substance of interest, said container having a closable connection means with said top area of said active electrode.

9. The apparatus according to claim 8 wherein said container holds a self-sealing membrane that allows an in-situ refilling with a formulation containing the substance of interest, without a necessity of removal from and re-insertion into a nasal cavity.

10. The apparatus according to claim 8 wherein said container is constructed of material that is adapted to absorb, hold and release the active substance.

11. The apparatus according to claim 8 wherein said container is made of materials compatible with the formulation and with a biological environment.

12. The apparatus according to claim 8 wherein said container comprises a polymeric material consisting of hydrophilic and hydrophobic matrix structure, formed by mixing of the active substance with an inert biocompatible polymer by means of a method selected from the group consisting of melt blending, solvent coating, compression and extrusion.

13. The apparatus according to claim 12 wherein said polymeric material consisting of hydrophilic and hydrophobic matrix is cross-linked with formulation components and held in a silastic matrix.

14. The apparatus according to claim 12 wherein said inert biocompatible polymer is prefabricated and sorbed with components from a formulation containing at least one substance of interest.

15. The apparatus according to claim 1 wherein said container is made of a hydrogel that holds the delivery substance and has the structural strength to be placed in an upper part of a nasal cavity and in contact with the nasal mucosa of an olfactory area.

16. The apparatus for enhanced delivery according to claim 1, wherein said first electrode is split into two parts, one part being constructed and arranged to be fixed externally to a nose and the other part with the active substance, being constructed and arranged to be introduced into the olfactory area.

17. The apparatus according to claim 1

wherein said active electrode and passive electrode, container and an electric current source are formed as an iontophoretic assembly and the delivery substance is selected from the group consisting of amino acids, anabolics, analgesics, anesthetics, anti-adrenergic agents, antiasthmatics, anti-atherosclerotics, antibacterials, anticholesterolics, anti-coagulants, antidepressants, antidotes, anti-emetics, anti-epileptic drugs, anti-fibrinolytics, antiinflammatory agents, antihypertensives, antimetabolites, antimigraine agents, antimycotics, antinauseants, antineoplastics, anti-obesity agents, anti-Parkinson agents, antipsychotics, antirheumatics, antiseptics, antivertigo agents, antivirals, appetite stimulants, bioflavonoids, calcium channel blockers, capillary stabilizing agents, coagulants, corticosterioids, detoxifying agents for cytostatic treatment, diagnostic agents, 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, neurotropics, oligonucleotides and derivatives, osmotic diuretics, parasympatholytics, sympathomimetics, vasodilators, vasoprotectives, vectors for gene therapy, viruses, vitamins and any therapeutic agent capable of affecting a nervous system.

18. The apparatus for enhanced delivery according to any one of claim 1 or 2 wherein said apparatus is adapted to deliver at least one substance of interest from an eyelid by a transocular pathway via an optic nerve region directly into a nervous system by applying an electric field between said first electrode carried by said eyelid and a second electrode constructed and arranged for being fixed on the back of a mammal'"'"'s head.

19. The apparatus according to claim 2 or 1, wherein the energy source provides an electrical current up to 10 mA.

20. The apparatus according to claim 2 or 1, wherein the energy source provides an electrical current up to 10 mA.