HK1110027A - Iontophoretic device and method for administering immune response-enhancing agents and compositions - Google Patents

Description

Iontophoresis device and method for administering immune response enhancers and compositions

Reference to related applications

According to 35 u.s.c. § 119(e), the present application claims benefit of united states provisional patent application No. 60/627,952 filed 11, 16, 2004 and united states provisional patent application No. 11/129,321, filed 5, 16, 2005, which was converted from united states official patent application No. 11/129,321 (courier EV718205539US), the entire contents of both provisional applications being incorporated herein by reference.

Background

Technical Field

The present disclosure relates generally to methods and devices for administering immune response enhancers or compositions. The present disclosure more particularly relates to methods of administering adjuvants and adjuvant-containing compositions, and iontophoresis devices suitable for administering these agents and compositions.

Description of the Related Art

Current methods for delivering compositions that enhance or stimulate an immune response, such as immunity against infectious diseases, typically require penetration of the skin or mucosa, such as by use of a needle. These methods are performed under sterile conditions and require specially trained personnel. These conditions and workers are not always readily available. In addition, repeated use of needles in non-sterile conditions can lead to the spread of disease. In addition, due to pain and the risk of infection, many individuals are reluctant to comply with treatment protocols, particularly when repeated administration is required for treatment or prophylaxis. Furthermore, when administering a drug to an infant or a small animal having a thin skin, a particularly skilled worker is required. Thus, there is a need to preferentially develop a needle-free method of administration of immune response enhancers or stimulators or compositions.

Us patent No. 6,797,276 describes a system for passive transdermal immunization in which antigen delivery is targeted to Langerhans islets cells (Langerhans isletcell) located on the outermost layer of the skin. U.S. patent No.5,910,306 describes the use of a formulation comprising an antigen and liposomes for skin, while U.S. patent No.5,980,898 describes a patch containing an antigen, an adjuvant, and a dressing for passive transdermal immunization. The entire contents of each of these patents are incorporated herein by reference.

A well-known method of administration for solving various problems associated with injection is iontophoresis (also known as "iontophoresis", or "iontophoresis"). Iontophoresis is a method of transdermal delivery of a drug or active agent (usually ionic or polar) across the skin or mucosa into the body by application of an electromotive force sufficient to transport or carry the drug or active agent into or across the skin or mucosa. In this delivery method, for example, a positively charged drug may be driven into or through the skin by the force applied by the anode, or a negatively charged drug may be driven into or through the skin by the force applied by the cathode. In addition to the migration of charged molecules in response to repulsive forces during iontophoresis, charged or uncharged drugs or active agents can be carried into or through the skin by electroosmotic solvent flow.

Studies using iontophoresis to deliver drugs or active agents across the skin or mucosa have generally described the delivery of small ionic or polar drugs or active agents. Examples of such drugs or active agents that may be delivered using iontophoresis include anesthetics such as procaine hydrochloride and lidocaine; gastrointestinal disease agents such as carnitine hydrochloride; skeletal muscle relaxants such as vancronium bromide; antibiotics such as tetracycline formulation, kanamycin formulation, and gentamicin formulation; vitamins such as B-2, B-12, C, E and folic acid; adrenocortical hormones such as hydrocortisone, dexamethasone, and prednisolone water-soluble formulations; antibiotics such as water-soluble preparations of penicillin and chloramphenicol.

Iontophoresis is not generally used for the delivery of larger drugs or active agents or those agents that are non-ionic and have limited solubility in aqueous media. For example, immune response enhancing adjuvants with poor water solubility and molecular weights above 1000, such as lipid a and lipid a analogs, have not been investigated as iontophoretic transdermal delivery subjects.

The methods described herein are intended to address some of the above problems by using an iontophoresis device that includes a plurality of ion exchange membranes. Different types of devices for administering drugs by iontophoresis are known.

An explanation and an example of an iontophoresis device having an ion exchange membrane are as follows.

JP03-504343a discloses an iontophoresis electrode comprising (i) an electrode portion, (ii) a penetrable container containing an ionic drug or an ionizable drug, and (iii) an ion-exchange membrane outside the container (on the side contacting the skin), and which is selected to be the same ion as the charged ion of the ionic drug. For example, ion exchange membranes limit the migration of ionic species such as sodium and chloride from the skin to the drug-containing electrode assembly.

US4722726B discloses an electrode comprising (i) an upper chamber (upper chamber) filled with a buffer and (ii) a lower chamber (lower chamber) filled with an anionic drug, separated from the upper chamber by an ion exchange membrane, with the aim of mitigating side effects due to hydrolysis of water.

JP03-94771A discloses an iontophoresis electrode comprising (i) a moisture storage member surrounded by an elastic support member, in which an electrode plate is disposed, (ii) an ion-exchange membrane disposed in front of (on the skin side of) the moisture storage member, and (iii) a drug layer (ionic drug layer) disposed in front of (on the skin side of) the ion-exchange membrane. The drug is spray dried or adhered or adsorbed onto the skin contacting surface of the ion exchange membrane.

Adjuvants are typically agents used to enhance the effectiveness of, for example, pharmacological compounds. In particular, an adjuvant is administered with a vaccine or antigen to enhance the immune response to the vaccine or antigen. Adjuvants are effective when delivered to the epidermis in which langerhans cells are present. Thus, adjuvants such as lipid a or lipid a analogs are typically administered by injection into the epidermis.

Lipid a is the active center of Lipopolysaccharide (LPS) obtained from gram-negative bacteria. Lipid A has interferon-inducing and TNF-inducing effects. In addition, lipid a has an immunostimulating effect, such as macrophage activating effect, β cell rejuvenating (juvenizing) effect, and cellular immunostimulating effect. The use of lipid a as an adjuvant for administration with different vaccines is currently under investigation. Some lipid a derivatives eliminate toxic or harmful effects while maintaining or enhancing the immunostimulatory effect of lipid a described above. These lipid a derivatives have a disaccharide structure (4-O-amino-2-deoxy- β -D-glucopyranosyl-amino-2-deoxy-D-glucopyranose) composed of two D-glucosamine molecules linked by β 1-6 bonds as the basic skeleton. Many compounds, including Monophosphoryl Lipid a, 3-O-deacylated-Monophosphoryl Lipid a, 4-phosphoaminoalkyl glucosaminide (AGP), and the like (hereinafter, referred to as "Lipid a analogs" in the present specification) have been synthesized as derivatives of Lipid a (see David et al, "Lipid a analogs as Adjuvant and immune activator", 2002, Trendin Microbiology, vol.10, No.10, page S32; Baker et al, "activation of presenting T Cell Activity non-toxic Monophosphoryl Lipid a" (disabling inhibition of T Cell Activity by non-toxic Monophosphoryl Lipid a), Interaction and Immunity, 1998, vol.56, No.5, page1076, and US 4912094B).

Iontophoresis devices, including those disclosed in JP03-504343A, US4722726B and JP03-94771A, appear to be unsuccessful in administering sufficient amounts of lipid a or lipid a analogs into the epidermis to produce immunologically significant immune response enhancing effects.

The following documents, which are of relevance to the present disclosure, are hereby incorporated by reference: david et al, "Lipid a antigens as Adjuvant and immunoactive" (Lipid a analogs as adjuvants and immunoactive agents), 2002, Trend in Microbiology, vol.10, No.10, page S32; baker et al, "activation of Suppressing T Cell activity by intracellular Monophosphoryl Lipid A" (Inactivation of T Cell activity by non-toxic Monophosphoryl Lipid A), Interaction and Immunity, 1998, Vol.56, No.5, page 1076; US 4912094B; JP 03-504343A; US 4722726B; JP 03-94771; JP 04-297277A; JP 2000-229128A; JP 2000-229129A; JP 2000-237326A; JP 2000-237327A; JP 2000-237328A; JP 2000-237329A; JP 2000-288097A; JP 2000-288098A; JP 2004-188188A; and WO 03/037425.

In addition to lipid a and lipid a analogs, the use and study of many other adjuvants to enhance immune responses to different immunostimulants has been described or is being studied. These adjuvants include saponins such as QS-21 or derivatives thereof, CpG, imiquimod, Rasimmod, dSLIM, and agonists of toll-like receptors such as TLR-2, TLR-4, TLR-5, TLR-7, and TLR-9. These adjuvants can enhance the immune response to a variety of vaccines, antigens and allergens.

Because of the various problems described above with existing methods of administering agents or drugs that stimulate or enhance an immune response, there is a need in the art for improved devices and methods for effective, safe, painless transdermal administration of such agents or drugs.

Brief description of the invention

An iontophoresis device for administering an immune response-enhancing agent or a composition thereof, the iontophoresis device comprising: an active electrode assembly having a drug solution storage portion containing an immune response enhancer or a combination thereof, and a non-active electrode assembly.

In certain embodiments of the iontophoresis device, the immune response enhancer is an adjuvant. In certain embodiments, the adjuvant may be lipid a or an analog of lipid a. In certain such embodiments, the analog of lipid A may be selected from monophosphoryl lipid A (MPL), 3-O-deacylated monophosphoryl lipid A, or 4-phosphoaminoalkyl glucosaminide. In certain other embodiments, the adjuvant may be an agonist of a toll-like receptor. In certain such embodiments, the toll-like receptor may be selected from TLR-2, TLR-4, TLR-5, TLR-7 or TLR-9. In other embodiments, the adjuvant is a saponin or a derivative thereof. In certain such embodiments, the saponin or derivative thereof is QS-21. In other embodiments, the adjuvant is selected from CpG, imiquimod, ranisimmod or dsim.

In certain embodiments, the drug solution storage portion of the iontophoresis device further contains a vaccine or antigen. In certain embodiments, the vaccine or antigen comprises at least one antigen selected from the group consisting of: viral antigens, bacterial antigens (including bacterial endonucleases), protozoal antigens or parasitic antigens. In certain such embodiments, the parasite antigen is selected from a leishmania antigen or a malaria antigen. In certain other embodiments, the vaccine or antigen comprises at least one antigen selected from the group consisting of: various hepatitis antigens (including hepatitis a, hepatitis b or hepatitis c), hepatitis b surface antigen (HbsAg), mutants of hepatitis b surface antigen, and influenza antigens. In other embodiments, the vaccine or antigen comprises at least one antigen selected from the group consisting of: a Bordetella pertussis (pertussis) antigen, a corynebacterium diphtheriae (diphtheria) antigen, a clostridium tetani (tetanus) antigen, an influenza b virus antigen, or a poliovirus antigen. In other embodiments, the vaccine or antigen comprises a mixture of antigens selected from the group consisting of: a mixture of DTP (diphtheria, tetanus, pertussis) and HbsAg (hepatitis b surface antigen); a mixture of Hib (haemophilus influenzae type b) and HbsAg; a mixture of DTP, HbsAg and Hib; or a mixture of IPV (inactivated polio vaccine), DTP, HbsAg and Hib.

In certain embodiments, the drug solution storage portion of the iontophoresis device further contains a cancer antigen. In certain such embodiments, the cancer antigen is selected from a melanoma antigen, a basal cell carcinoma antigen, a breast cancer antigen, a prostate cancer antigen, a lung cancer antigen, or an ovarian cancer antigen.

In certain embodiments, the drug solution storage portion of the iontophoresis device contains an allergen. In certain such embodiments, the allergen is selected from the group consisting of insect venom, plant pollen, dust mites, animal dander, ragweed, or endotoxins.

An iontophoresis device for administering an immune response-enhancing agent or composition thereof, comprising: an active electrode assembly having a drug solution storage portion containing an immune response enhancer or a combination thereof, and a non-active electrode assembly; wherein the active electrode assembly further comprises: a first electrode means operable to provide a potential of a first polarity; a drug solution storage portion disposed on a front surface of the electrode part; and a first ion exchange membrane disposed on a front surface of the drug solution storage portion; and wherein the inactive-electrode assembly includes: a second electrode member operable to provide a second polarity potential; and a first electrolyte solution storage portion disposed on a front surface of the second electrode part.

In certain embodiments of the iontophoresis device, the active electrode assembly of the device further includes: a second electrolyte solution storage portion disposed on a front surface of the first electrode part; and a second ion exchange membrane interposed between the second electrolyte solution storage portion and the drug solution storage portion. In certain other embodiments, the inactive electrode assembly of the device further comprises: a third ion exchange membrane disposed on a front surface of the first electrolyte solution storage portion. In certain other embodiments, the inactive-electrode assembly further includes: a fourth ion exchange membrane disposed on a front surface of the first electrolyte solution storage portion; and a third electrolyte solution storage portion interposed between the fourth ion exchange membrane and the third ion exchange membrane. In certain other embodiments, the first polarity is a negative polarity; the second polarity is a positive polarity; the first ion exchange membrane and the fourth ion exchange membrane are anion exchange membranes; the second ion exchange membrane and the third ion exchange membrane are cation exchange membranes; and the immune response enhancer is lipid a or a lipid a analog. In other embodiments, the lipid a analog is selected from the group consisting of monophosphoryl lipid a (mpl), 3-O-deacylated monophosphoryl lipid a, and 4-phosphoaminoalkyl glucosaminide.

A method of administering an immune response-enhancing agent or composition thereof using an iontophoresis device, the device comprising: an active electrode assembly having a drug solution storage portion, and a non-active electrode assembly; the drug solution storage portion comprises an immune response enhancer or a combination thereof; the method comprises the following steps: electrically coupling the active electrode assembly and the inactive electrode assembly with electrodes of a power source; and applying a voltage or current to the active electrode assembly and the inactive electrode assembly; wherein the active electrode assembly and the inactive electrode assembly are brought into contact with the skin of the mammal.

In certain embodiments of the method of administering an immune response-enhancing agent or composition thereof using an iontophoresis device, the immune response-enhancing agent is an adjuvant. In certain embodiments of the method, the adjuvant may be lipid a or an analog of lipid a. In certain such embodiments of the method, the analog of lipid A may be selected from the group consisting of monophosphoryl lipid A (MPL), 3-O-deacylated monophosphoryl lipid A, or 4-phosphoaminoalkyl glucosamine. In certain other embodiments of the method, the adjuvant may be an agonist of a toll-like receptor. In certain such embodiments of the methods, the toll-like receptor may be selected from TLR-2, TLR-4, TLR-5, TLR-7 or TLR-9. In other embodiments of the method, the adjuvant is a saponin or a derivative thereof. In certain such embodiments of the methods, the saponin or derivative thereof is QS-21. In other embodiments of the method, the adjuvant is selected from CpG, imiquimod, ranisimmod or dsim.

In certain embodiments of the method of administering an immune response-enhancing agent or composition thereof using an iontophoresis device, the drug solution storage portion of the device further contains a vaccine or antigen. In certain embodiments of the method, the vaccine or antigen comprises at least one antigen selected from the group consisting of: viral antigens, bacterial antigens (including bacterial endotoxins), protozoal antigens, or parasitic antigens. In certain such embodiments of the methods, the parasite antigen is selected from a leishmania antigen or a malaria antigen. In certain other embodiments of the method, the vaccine or antigen comprises at least one antigen selected from the group consisting of: hepatitis antigens (including hepatitis a, hepatitis b or hepatitis c), hepatitis b surface antigen (HbsAg), mutants of hepatitis b surface antigen, and influenza antigens. In other embodiments of the method, the vaccine or antigen comprises at least one antigen selected from the group consisting of: a Bordetella pertussis (pertussis) antigen, a Corynebacterium diphtheriae (diphtheria) antigen, a Bacillus tetanus (tetanus) antigen, an influenza B virus antigen, or a poliovirus antigen. In other embodiments, the vaccine or antigen comprises a mixture of antigens selected from the group consisting of: a mixture of DTP (diphtheria, tetanus, pertussis) and HbsAg (hepatitis b surface antigen); a mixture of Hib (haemophilus influenzae type b) and HbsAg; a mixture of DTP, HbsAg and Hib; or a mixture of IPV (inactivated polio vaccine), DTP, HbsAg and Hib.

In certain embodiments of the method of administering an immune response-enhancing agent or composition thereof using an iontophoresis device, the drug solution storage portion of the device further comprises a cancer antigen. In certain such embodiments of the method, the cancer antigen is selected from the group consisting of a melanoma antigen, a basal cell carcinoma antigen, a breast cancer antigen, a prostate cancer antigen, a lung cancer antigen, and an ovarian cancer antigen.

In certain embodiments of the method of administering an immune response-enhancing agent or composition thereof using an iontophoresis device, the drug solution storage portion of the device comprises an allergen. In certain such embodiments, the allergen is selected from the group consisting of insect venom, plant pollen, dust mites, animal dander, ragweed, or endotoxins.

A method of administering an immune response-enhancing agent or composition thereof using an iontophoresis device, the device comprising: an active electrode assembly having a drug solution storage portion, and a non-active electrode assembly; the drug solution storage portion comprises an immune response enhancer or a combination thereof; wherein the active electrode assembly further comprises: a first electrode part operable to provide a first polarity potential, a drug solution storage portion disposed on a front surface of the electrode part, and a first ion exchange membrane disposed on a front surface of the drug solution storage portion; and wherein the inactive-electrode assembly includes: a second electrode part operable to provide a second polarity potential, and a first electrolyte solution storage portion disposed on a front surface of the second electrode part; the method comprises the following steps: electrically coupling the active electrode assembly and the inactive electrode assembly with electrodes of a power source and applying a voltage or current to the active electrode assembly and the inactive electrode assembly, wherein the active electrode assembly and the inactive electrode assembly are in contact with skin of a mammal.

In certain embodiments of the method of administering an immune response-enhancing agent or composition thereof using an iontophoresis device, the active electrode assembly of the device further comprises: a second electrolyte solution storage portion disposed on a front surface of the first electrode part, and a second ion exchange membrane interposed between the second electrolyte solution storage portion and the drug solution storage portion. In certain other embodiments of the method, the inactive electrode assembly of the device further comprises: a third ion exchange membrane disposed on a front surface of the first electrolyte solution storage portion. In certain other embodiments of the method, the inactive-electrode assembly further comprises: a fourth ion exchange membrane disposed on a front surface of the first electrolyte solution storage portion, and a third electrolyte solution storage portion interposed between the fourth ion exchange membrane and the third ion exchange membrane. In certain other embodiments of the method, the first polarity of the device is negative, the second polarity of the device is positive, the first and fourth ion exchange membranes of the device are anion exchange membranes, the second and third ion exchange membranes are cation exchange membranes, and the immune response enhancer is lipid a or a lipid a analog. In other embodiments of the method, the lipid A analog is selected from the group consisting of monophosphoryl lipid A (MPL), 3-O-deacylated monophosphoryl lipid A, and 4-phosphoaminoalkyl glucosaminide.

In various embodiments, iontophoresis devices and methods are provided for administering any of a variety of adjuvants, including lipid a and lipid a analogs, to a mammal in a manner that is effective, safe, and painless to produce an immune response enhancing effect or an immune response stimulating effect.

In certain other embodiments, iontophoresis devices and methods are provided that are capable of administering an adjuvant, such as lipid a or a lipid a analog, to a living organism in the following manner: under the current application conditions that do not cause damage, pain and irritation to the skin of a living organism beyond the permissible limit range, a sufficient immune response-enhancing effect or immune response-stimulating effect can be produced, or in a manner that can produce an immune response-enhancing effect or immune response-stimulating effect that is equivalent to or greater than the effect of intradermal injection.

In certain other embodiments, iontophoresis devices and methods are provided that are capable of administering lipid a or lipid a analogs to a living organism in the following manner: capable of producing a sufficient immune response-enhancing effect or immune response-stimulating effect within a period of administration that is acceptable as a time of administration of the drug or agent, or in a manner capable of producing an immune response-enhancing effect or immune response-stimulating effect equivalent to or greater than the effect of intradermal injection.

Brief description of the drawings

In the drawings:

fig. 1 is a schematic view showing the configuration of an iontophoresis device according to an embodiment of the present invention.

Fig. 2 is a schematic view showing the construction of an iontophoresis device according to another embodiment of the present invention.

Fig. 3 is a schematic view showing the construction of an iontophoresis device according to still another embodiment of the present invention.

Fig. 4 is a schematic diagram of the configuration of an iontophoresis device used in an MPL administration experiment.

FIGS. 5(1) and 5(2) are graphs showing IgG1 and IgG2 antibody titers at day 43.

Detailed description of the invention

In the following description, certain specific details are set forth in order to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures associated with controllers, including but not limited to voltage and/or current regulators, have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

Unless the context requires otherwise, in the description and the claims, the term "comprise" and its variants such as "comprises" and "comprising" are to be interpreted in an open, inclusive sense, i.e. as "including but not limited to".

Reference in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, characteristic, or aspect of the method associated with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the unique features, structures, characteristics, or aspects of the methods may be combined in any suitable manner in one or more embodiments.

As used herein and in the claims, an "active electrode assembly" is an electrode assembly that stores a drug or active agent. The "inactive electrode assembly" is an electrode assembly that functions as a counter electrode of the active electrode assembly.

The term "membrane" as used herein and in the claims refers to a permeable or impermeable layer, barrier or material. Unless otherwise indicated, the films may take the form of a solid, liquid or gel, or may not have a different lattice or cross-linked structure. "anion exchange membrane" refers to a membrane having functional groups that enable it to bind and release negatively charged ions. The anion exchange membrane in the iontophoresis device allows only anions to pass through and substantially blocks cations from passing through. "cation exchange membrane" refers to a membrane having functional groups that enable it to bind and release positively charged ions. The cation exchange membrane in the iontophoresis device allows only cations to pass through and substantially blocks anions from passing through.

The term "skin" as used herein and in the claims refers to a body surface or biological interface, including mucous membranes, where delivery of drugs or active agents can be effected by iontophoresis.

The term "drug" or "active agent" as used herein and in the claims refers to an agent, substance or compound that elicits some type of action or biological response when delivered to a mammal, including a human. The "drug" or "active agent" may be an immunological agent, adjuvant, immune response enhancer, vaccine, antigen, drug, hormone, protein, peptide, or nucleic acid such as DNA. Many bioactive agents have functional groups that can be converted to charged ions or can dissociate into charged electrons and counter ions in aqueous media at a suitable pH. Other drugs or active agents may be polarized or polarizable, i.e., exhibit polarity at one part relative to another part of the molecule.

The headings provided herein are for convenience only and do not interpret the scope or meaning of the described embodiments.

Fig. 1 to 3 are schematic cross-sectional views each showing the basic structure of an iontophoresis device.

The device includes, as major constituent elements (components), an active electrode assembly 1 and an inactive electrode assembly 2 electrically coupled to a power source 3 operable to provide one or more drugs or active agents contained in the active electrode assembly 1 to a site 4 of the skin (or mucosa).

In the embodiment shown in fig. 1, the active electrode assembly 1 includes an electrode part 11 operable to supply a first polarity potential, a drug solution storage portion 14 disposed on a front surface of the electrode part 11, and an ion exchange membrane 15 disposed on a front surface of the drug solution storage portion 14. The inactive-electrode assembly 2 includes an electrode part 21 operable to provide a second polarity potential and an electrolyte solution storage part 22 disposed on a front surface of the electrode part 21.

In one embodiment of the device shown in fig. 1, electrode element 11 of active electrode assembly 1 is electrically coupled to the negative electrode of power source 3, electrode element 21 of active electrode assembly 2 is electrically coupled to the positive electrode of power source 3, and the ion-exchange membrane.

In each of the embodiments shown in fig. 2 and 3, the active electrode assembly 1 includes an electrode part 11 operable to supply a first polarity potential, an electrolyte solution storage portion 12 disposed on a front surface of the electrode part 11, an ion exchange membrane 13 disposed on a front surface of the electrolyte solution storage portion 12, a drug solution storage portion 14 disposed on a front surface of the ion exchange membrane 13, and an ion exchange membrane 15 disposed on a front surface of the drug solution storage portion 14.

In the embodiment shown in fig. 2, the inactive-electrode assembly 2 includes an electrode part 21 operable to provide a second polarity potential, an electrolyte solution storage portion disposed on a front surface of the electrode part 21, and an ion-exchange membrane 23 disposed on a front surface of the electrolyte solution storage portion 22.

In the embodiment shown in fig. 3, the inactive-electrode assembly 2 includes an electrode part 21 operable to provide a second polarity potential, an electrolyte solution storage part 22 disposed on a front surface of the electrode part 21, an ion-exchange membrane 23 disposed on a front surface of the electrolyte solution storage part 22, an electrolyte solution storage part 24 disposed on a front surface of the ion-exchange membrane 23, and an ion-exchange membrane 25 disposed on a front surface of the electrolyte solution storage part 24.

In certain embodiments, the working or active electrode component 11 and the non-working or counter electrode component 21 may preferably be electrochemically inert electrodes made of carbon, platinum, or the like. These carbon electrodes are particularly preferred, which may advantageously ensure that metal ions are not eluted and do not migrate into the living organism.

However, an electrochemically active electrode may also be employed, for example a silver/silver chloride coupled electrode comprising a working or active electrode part 11 made of silver chloride and a non-working or counter electrode part 21 made of silver.

For example, assume that a silver/silver chloride coupled electrode is used. On the non-working or counter electrode, silver electrode and chloride ion (Cl)^-) Through the reaction: ag⁺Cl^-→AgCl+e^-Readily reacted to form AgCl, insoluble in water, which in the case of the device delivering lipid a or an analogue thereof, is the anode (positive electrode). On the working or active electrode, chloride ions (Cl) are generated^-) The reaction eluted from the silver chloride electrode, in which case the working or active electrode is the cathode (negative electrode). Thus, the electrolytic reaction of water is avoided, and therefore, the presence of H on the anode (positive electrode) can be avoided⁺Acidification by ions and presence of OH on the cathode (negative electrode)^-Ion induced basification.

In contrast, in the active electrode assembly 1 and the inactive electrode assembly 2 in the iontophoresis device shown in fig. 2 and 3, by the action of the anion-exchange membrane and/or the cation-exchange membrane, the presence of OH due to the presence of OH can be avoided^-The ion alkalinizes the electrolyte solution storage part 12, and due to the presence of H⁺The ions acidify the electrolyte solution storage portion 22. Thus, the ions shown in FIGS. 1-3In an iontophoresis device, particularly the iontophoresis device shown in fig. 2 and 3, a carbon electrode, which is inexpensive and does not take into account elution of metal ions, may be advantageously used instead of an active electrode such as a silver/silver chloride coupled electrode.

The electrolyte solution storage portions 12, 22 and 24 in the iontophoresis device store electrolytes to ensure conductivity. Typical examples of electrolytes that can be used include phosphate buffered saline and physiological saline.

In order to effectively prevent gas generation and pH change caused by electrolysis of water, the electrolyte solution storage portions 12 and 22 may contain compounds that are more easily oxidized or reduced than the electrolysis reaction of water (oxidation on the positive electrode and reduction on the negative electrode). From the viewpoint of biocompatibility with living organisms and economy (inexpensive and readily available), it is preferable to use, for example, inorganic compounds such as ferrous sulfate and ferric sulfate, pharmaceutical agents such as ascorbic acid (vitamin C) and sodium ascorbate, acidic compounds such as lactic acid present on the skin surface, organic acids such as oxalic acid, malic acid, succinic acid and fumaric acid and/or salts thereof. These compounds may be used alone or in combination.

That is, in the electrolyte solution storage portions 12 and 22, an electrochemical reaction occurs to decompose the electrolyte or to decompose the ionic drug. Therefore, bubbles may be generated in the electrolyte solution storage parts 12 and 22 to avoid the electrode materials 11 and 21 from contacting the electrolyte. For example, hydrogen gas may be generated at the negative electrode. Chlorine gas and oxygen gas may be generated at the positive electrode. In this case, the resistance increases due to the presence of the bubble, and even when the voltage is further increased, the current does not flow. This can be a very serious problem from the standpoint of the practical utility of the iontophoresis device.

These causes of instability can be eliminated by adding the above-mentioned compound, for example, by using a 1: 1 mixed aqueous solution of 1 mole of (M) lactic acid and 1 mole of (M) sodium fumarate.

In order to prevent the composition change of the electrolyte solution storage portion 12 and the drug solution storage portion 14, which is caused by the mixing of the electrolyte solution storage portion 12 and the drug solution storage portion 14 (an aqueous solution containing, for example, lipid a or a lipid a analog), the electrolyte solution storage portion 12 may contain the same material as in the drug solution storage portion 14 (for example, an aqueous solution of lipid a or a lipid a analog).

As for the case of the electrolyte solution storage portion 24, the compositions of the electrolyte solution storage portions 22 and 24 may be similar or identical to prevent the composition of the electrolyte solution storage portion 24 from being changed due to mixing with the medium in the electrolyte solution storage portion 22.

The electrolyte solution storage portions 12, 22 and 24 may contain the above-described electrolyte in a liquid state. However, it is also possible to impregnate a water-absorbent film made of a polymeric material with the above-mentioned electrolyte to increase its operability. The film used herein may be the same as the film that can be used for the drug solution storage portion 14, and details about the film will be described later when the drug solution storage portion is described.

Suitable cation exchange membranes may include NEOSEPTAs (CM-1, CM-2, CMX, CMs, CMB, CLE04-2, etc.) manufactured by Tokuyama co. Suitable anion exchange membranes may include NEOSEPTAs (AM-1, AM-3, AMX, AHA, ACH, ACS, ALE04-2, AIP-21, etc.) manufactured by Tokuyama Co. Among them, in some applications, a cation exchange membrane including a porous membrane in which an ion exchange resin having a cation exchange function is filled in a part or all of the cavities may be preferable, or an anion exchange membrane including a porous membrane in which an ion exchange resin having an anion exchange function is filled in a part or all of the cavities may be preferable.

The above ion exchange resin may be a fluorine-based resin including a perfluorocarbon skeleton having ion exchange groups, and a hydrocarbon-based resin including a non-fluorinated resin as a skeleton. From the viewpoint of convenience of the production process, hydrocarbon-based ion exchange resins may be preferred. The filling rate of the ion exchange resin depends on the porosity of the porous membrane, and is usually 5 to 95% by mass, or 10 to 90% by mass, or 20 to 60% by mass.

The ion exchange group in the above ion exchange resin is not particularly limited as long as it is a functional group capable of generating a group having a negative or positive charge in an aqueous solution. Specific examples of functional groups that can be used as such ion exchange groups include cation exchange groups such as sulfonic acid groups, carboxylic acid groups, and phosphonic acid groups. These acid groups may be free acids or present in the form of salts. Counter cations (counter cations) of the salts of the acids include alkali metal ions such as sodium ions and potassium ions and ammonium ions. Among these cation exchange groups, in general, a sulfonic acid group, which is a strong acid group, may be particularly preferred. The anion exchange groups include, for example, primary amine groups, secondary amine groups, tertiary amine groups, quaternary ammonium groups, pyridyl groups, imidazole groups, pyridine transport salt groups (quaternary pyridinium groups), and imidazolium salt groups (quaternary imidazolium groups). Counter anions (counter anions) of these anion exchange groups include halides such as chloride, hydroxyl ions, and the like. Among these anion exchange groups, quaternary ammonium groups and pyridinium salt groups, which are strong base groups, may generally be preferred.

The above porous film is not particularly limited, and any porous film may be used as long as it is a film or sheet having many pores communicating both sides thereof. In order to satisfy both high strength and elasticity, a porous film made of a thermoplastic resin is preferable.

Examples of the thermoplastic resin constituting the porous film include, but are not limited to: polyolefin resins such as homopolymers or copolymers of α -olefins such as ethylene, propylene, 1-butene, 1-pentene, 1-hexene, 3-methyl-1-butene, 4-methyl-1-pentene and 5-methyl-1-heptene; vinyl chloride resins such as polyvinyl chloride, vinyl chloride-vinyl acetate copolymers, vinyl chloride-1, 1-dichloroethylene copolymers and vinyl chloride-olefin copolymers; fluorine resins such as polytetrafluoroethylene, polychlorotrifluoroethylene, poly-1, 1-difluoroethylene, tetrafluoroethylene-hexafluoropropylene copolymers, tetrafluoroethylene-perfluoroalkyl vinyl ether copolymers and tetrafluoroethylene-ethylene copolymers; polyamide resins such as nylon 6 and nylon 66; and those made of polyamide resins. Since the polyolefin resin is excellent in mechanical strength, elasticity, chemical stability and chemical resistance and has good compatibility with the ion exchange resin, the polyolefin resin may be preferable. As the polyolefin resin, polyethylene and polypropylene may be particularly preferable, and polyethylene may be most preferable, depending on the specific application.

The physical properties of the above porous film made of the thermoplastic resin are not particularly limited. However, pores having an average pore size of preferably 0.005 μm to 5.0 μm, or more preferably 0.01 μm to 2.0 μm, or most preferably 0.02 μm to 0.2 μm may be preferable because an ion exchange membrane which is thin and has excellent strength and low resistance can be easily obtained. The above-mentioned average pore size as used herein means the average flow pore size as measured by the bubble pressure method according to JIS-K3832-1990. The porosity of the porous membrane may be preferably 20 to 95%, and more preferably 30 to 90%, and most preferably 30 to 60%, depending on the application. In order to obtain an ion exchange membrane having a thickness as described below, the thickness of the porous membrane may preferably be 5 μm to 140 μm, and more preferably 10 μm to 120 μm, and most preferably 15 μm to 55 μm, depending on the specific application. Typically, the anion exchange membrane and the cation exchange membrane comprising the porous membrane have the same thickness as the porous membrane, or are up to about 20 μm thicker than the thickness of the porous membrane.

The drug solution storage portion 14 in the iontophoresis device of the present invention stores an aqueous solution containing at least one lipid a or lipid a analog (as an example of any one of a plurality of adjuvants). Because lipid a or lipid a analog dissociates into negatively charged ions when dissolved in water, the resulting aqueous solution contains the negatively charged ions of the lipid a or lipid a analog.

The drug solution storage portion 14 may be designed to store an aqueous solution of lipid a or a lipid a analog in a liquid state. When this aqueous solution of lipid a or lipid a analog is impregnated into and held by the following water-absorbing film, the handleability and other characteristics of the drug solution storage portion 14 can be improved.

Examples of materials that can be used as the above water-absorbent film include hydrogel forms of acrylic resins (acrylic hydrogel films), gel films based on block polyurethane, and ion-conductive porous sheets for forming gel-like solid electrolytes. When the membrane is impregnated with the above aqueous solution and impregnated at an impregnation rate of 30% to 40%, a high transport number (high drug delivery) can be obtained, for example 70% to 80%.

The impregnation rate as used herein is% by weight and is defined as 100 × (W-D)/D (%), wherein D represents a dry weight and W represents a weight after impregnation. The rate of impregnation must be measured immediately after impregnation with the aqueous solution to exclude the effect over time.

The transport number as used herein is the ratio of the current due to migration of the drug ions (ions of lipid a or lipid a analog) to the total current flowing through the electrolyte solution. The transport number is measured by placing the membrane impregnated with the ionic drug between ion exchange membranes 13 and 15, then assembling the other component parts, and measuring the transport number in such a way as to minimize the change over time.

The above acrylic hydrogel films (available, for example, from Sun Contact Lens co., ltd.) are gels having a three-dimensional network (cross-linked structure). Such a gel may be used as a polymer adsorbent having ion conductivity, wherein an aqueous electrolyte solution is added to the gel as a dispersant. The relationship between the impregnation rate and the transport number of the acrylic hydrogel film can be adjusted according to the size of the three-dimensional network and the kind and ratio of monomers constituting the resin. The above acrylic hydrogel film having an impregnation rate of 30% to 40% and a carrying number of 70% to 80% can be prepared from 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate (monomer ratio: (98-99.5): (0.5-2)). It has been confirmed that the above impregnation rate and the transport number are almost the same in the ordinary thickness range of 0.1 to 1 mm.

Gel films based on segmented polyurethane have polyethylene glycol (PEG) segments and polypropylene glycol (PPG) segments. The physical properties of the block polyurethane-based gel film can be adjusted by varying the ratio of the monomers and diisocyanate constituting the block polyurethane-based gel film. The block polyurethane-based gel film has a three-dimensional structure crosslinked by urethane bonds. Therefore, in the same manner as the above-described acrylic hydrogel film, the impregnation rate, the transfer number and the adhesive force can be easily adjusted by controlling the size of the three-dimensional network and the kind and ratio of monomers constituting the resin. In the block polyurethane-based gel film (porous gel film) in which water is used as a dispersant and an electrolyte (for example, an alkali metal salt), oxygen in ether bond of polyether constituting the segment and the alkali metal salt form a complex. When electricity is applied to the complex, the ions of the metal salt migrate to the oxygen at the next empty ether linkage to create electrical conductivity. The block polyurethane based gel film contains a PEG-PPG-PEG copolymer that makes up the segment. The PEG-PPG-PEG copolymer is approved for use as a cosmetic material. This indicates that the block polyurethane-based gel film does not cause irritation to the skin and is highly safe.

The ion-conductive porous sheet for forming the gel-like solid electrolyte includes, for example, a porous sheet disclosed in JP 11-273452A. It comprises acrylonitrile copolymer as matrix and in particular porous polymers with a porosity of 20% to 80%. More specifically, the above matrix is an acrylonitrile copolymer containing 50 mol% or more (preferably 70 to 98 mol%) of acrylonitrile and having a porosity of 20 to 80%. The above-mentioned acrylonitrile-based gel-like solid electrolyte sheet (solid battery) is prepared by impregnating an acrylonitrile-based copolymer sheet soluble in a nonaqueous solvent containing an electrolyte and having a porosity of 20% to 80% with the nonaqueous solvent and gelling the resultant. The resulting gel forms range from gel-like to dura-like forms.

The acrylonitrile copolymer sheet soluble in a nonaqueous solvent may be composed of acrylonitrile/C1-C4 alkyl (meth) acrylate copolymer, acrylonitrile/vinyl acetate copolymer, acrylonitrile/styrene copolymer, acrylonitrile/1, 1-dichloroethylene copolymer, or the like, in terms of ion conductivity, biocompatibility, and the like. The copolymer sheet can be made porous by a usual method, for example, a wet (dry) papermaking method, a needle punching method which is one production method of a nonwoven fabric, a water jet method, a method of melt-extruding a sheet to be subjected to drawing and porosification (drawing porosification) or a method of solvent extraction porosification. In the ion-conductive porous sheet made of an acrylonitrile-based copolymer for the above-described solid battery, a gel form (gel-like form to hard film-like form) that retains the above-described aqueous solution within the three-dimensional network of the polymer chains is used as a thin film used in the drug solution storage portion 14 or the electrolyte solution storage portions 12, 22 and 24.

The conditions for impregnating the above-mentioned thin film (porous gel film) with an aqueous solution of lipid A or an aqueous solution of a lipid A analog or a conductive medium can be optimally determined depending on the impregnation amount, impregnation rate and the like. For example, the dipping conditions may be selected to be 30 minutes at 40 ℃.

The power supply 3 that can be used in the iontophoresis device includes, for example, a battery, a constant voltage device, a constant current device (galvanic device), and a constant voltage-constant current device. It may be preferable to use a constant current device whose current can be controlled in the range of 0.01mA to 1.0mA, although 0.01mA to 0.5mA is more preferable, and which operates under a safe voltage condition, specifically, at a voltage of 50V or less, although a voltage of 30V or less is more preferable.

Further, the power supply 3 may be a power supply capable of changing a current with time while applying the current.

Adjuvants are generally agents used to enhance the effectiveness of, for example, pharmaceutical compositions. In particular, an adjuvant is administered with a vaccine or antigen to enhance the immune response to the vaccine or antigen. In certain embodiments, any of a variety of adjuvants, exemplified herein as lipid a and lipid a analogs, can be used in the iontophoresis devices disclosed herein and methods of using the devices.

Lipid A is a glycolipid having the chemical structure shown in formula 1 and obtained from gram-negative bacteria, such as Escherichia coli. The lipid A analogue is a derivative of lipid A. The derivative has a disaccharide structure (4-O-2-amino-2-deoxy-beta-D-glucopyranosyl-amino-2-deoxy-D-glucopyranose) as a basic skeleton, which consists of two D-aminoglucose molecules linked by beta 1-6 bonds. Examples of lipid A analogs include monophosphoryl lipid A having the chemical structure shown in formula 2 (e.g., "MPL", manufactured by Corixa Corporation (Seattle, Wash., U.S.), 3-O-deacylated monophosphoryl lipid A disclosed in US4912094B, and 4-aminoalkylglucosaminide phosphate having the chemical structure shown in formula 3 (e.g., "RC-529", manufactured by Corixa Corporation supra). MPL may be isolated and prepared from natural sources or the synthetic formulation may be the resulting MPL.

[ formula 1]

[ formula 2]

[ formula 3]

The iontophoresis device and the method of administering lipid a or lipid a analog may be used and practiced, respectively, in conjunction with administering a vaccine and an allergen to a living organism by injection. For example, the iontophoresis device may be used to administer lipid a or a lipid a analog to a living organism simultaneously with or after a predetermined time after injection of a vaccine or allergen. This can increase the effect of the vaccine or allergen.

The lipid A or lipid A analogue loaded into the drug solution storage portion may be an agonist of a toll-like receptor (TLR), examples of which include TLR-2, TLR-4, TLR-5, TLR-7 and/or TLR-9.

The pharmaceutical solution storage portion may be designed to contain a vaccine or allergen in addition to lipid a or lipid a analogues. By this design, lipid a or lipid a analogue and the vaccine or allergen may be administered transdermally at the same time.

Examples of such vaccines that can be used include hepatitis antigens, hepatitis b surface antigen mutants, influenza antigens, leishmaniasis antigens and endotoxins. Alternatively, one or more substances obtained from non-hepatitis antigens and having a protective effect against one or more pathogenic microorganisms or viruses such as bordetella pertussis, corynebacterium diphtheriae, clostridium tetani, pertussis, influenza b virus, or poliovirus; a mixture of DTP (diphtheria, tetanus, pertussis) and HBsAg (hepatitis b surface antigen); a mixture of Hib (haemophilus influenzae type b) and HBsAg; a mixture of DTP, HBsAg and Hib; or a mixture of IPV (inactivated polio vaccine), DTP, HBsAg and Hib.

In other embodiments, the iontophoresis device and method of administering lipid a or lipid a analog may be designed to contain one or more adjuvants in addition to or in place of lipid a or lipid a analog, such as other agonists of toll-like receptors (e.g., TLR-2, TLR-4, TLR-5, TLR-7, and TLR-9), saponins or derivatives thereof such as QS-21, or CpG (disclosed in US5856462B, the contents of which are incorporated herein by reference).

In certain other embodiments, the iontophoresis device and method of administering lipid a or lipid a analogs can be designed to contain imiquimod, ranisimmod, or dsim in addition to or in place of lipid a or lipid a analogs.

The iontophoresis device and method of administering lipid a or lipid a analog can be designed to contain imiquimod or flagellin in addition to lipid a or lipid a analog.

The iontophoresis device and the method of administering lipid a or a lipid a analog may be designed such that the above-described drug solution storage portion contains, in addition to lipid a or a lipid a analog, one or more allergens such as pollen, mites constituting house dust, dander (minute fragments from feathers, skin, hair, etc. of animals), and ragweed (Ambrosia artemia var. elatior). With this design, the iontophoresis device and method of administering lipid a or lipid a analog can be used or practiced in the treatment of allergic diseases.

Examples

The following experiment was conducted to evaluate the enhancement of immune response obtained when the lipid a analog monophosphoryl lipid a (mpl) was administered using an iontophoresis device.

Vaccine

Tuberculosis vaccine (Mtb72F, available from Corixa Corporation, seattle, washington) was used.

Adjuvant

Clinical trial formulation MPL of monophosphoryl lipid a produced by Corixa was used as an adjuvant. As reference data, the hydrophilic preparation MPL-AF of monophosphoryl lipid A prepared by Corixa and the lipophilic preparation MPL-SE of monophosphoryl lipid A prepared by Corixa were injected intradermally and evaluated for their immunostimulatory effect.

Laboratory animal

57BL/6 mice (7-24 weeks old, female) were used.

Conditions of the experiment

The 57BL/6 mice were divided into 4 groups, each consisting of 2-5 mice. Animals in each group were given a vaccine (Mtb72F) and adjuvant (MPL, MPL-AF or MPL-SE).

The protocol for administering the vaccine and adjuvant to each group is described in the "experimental context" below.

Group 1: (examples)

(a) Mtb 72F: administration by intradermal injection

(b) MPL-AF: transdermal administration using a TCT instrument (the instrument is described in "instrument used";

group 2: comparative example 1

(a) Mtb 72F: administration by intradermal injection

(b) MPL-AF: administration by intradermal injection

Group 3: comparative example 2

(a) Mtb 72F: administration by intradermal injection

(b) MPL-SE: administration by intradermal injection

Group 4: (comparative example 3)

(a) Mtb 72F: administration by intradermal injection

(b) MPL-AF: is not administered

Used instrument

To administer MPL (example) to mice of group 1, an iontophoresis device shown in fig. 4 was used.

In fig. 4, the apparatus comprises an active electrode assembly 1, an inactive electrode assembly 2 and a constant current source 3.

The active electrode assembly 1 includes a cylindrical acrylic container 51 having a top wall 51a and a side wall 51b and having a lower end opened. In the container 51, a carbon electrode element 11 having a diameter of about 10mm and connected to the negative electrode of the constant current power supply 3, a cation exchange membrane 13(CLE04, manufactured by Tokuyama co., ltd., tokyo, japan), and an anion exchange membrane 15(AIP-21, manufactured by Tokuyama co., ltd.) were placed in the order shown in fig. 4.

The space between the carbon electrode 11 and the cation exchange membrane 13 constitutes an electrolyte solution storage portion 12 in which about 0.8ml of a liquid conductive medium is contained. The space between the cation exchange membrane 13 and the anion exchange membrane 15 constitutes a drug solution storage portion 14 containing about 1.2ml of the liquid drug.

In this example, an aqueous MPL solution having 300. mu.g of MPL dissolved in 15ml of sterile water was injected as a drug solution into the drug solution storage portion 14. An MPL aqueous solution having the same composition as the above-described drug solution is used as a conductive medium of the electrolyte solution storage portion 12.

The inactive electrode assembly 2 includes a cylindrical acrylic container 52 having a top wall 52a and a side wall 52b and having a lower end opened. In the container 52, a carbon electrode 22 having a diameter of about 20mm (Φ) and connected to the positive electrode of the constant current power supply 3, an anion exchange membrane 23(ALE04-2, manufactured by Tokuyama co., ltd.) and a cation exchange membrane 25(CLE04-2, manufactured by Tokuyama co., ltd.) were placed in the order shown in fig. 4.

The space between the carbon electrode 21 and the anion-exchange membrane 23 and the space between the cation-exchange membrane 23 and the anion-exchange membrane 25 constitute electrolyte solution storage portions 22 and 24, respectively, and the electrolyte solution storage portions 22 and 24 contain about 0.8ml and about 1.2ml of a liquid electroconductive medium, respectively.

In this embodiment, phosphate buffered saline is used as the conductive medium in the electrolyte solution storage portions 22 and 24.

Galvanostat (HA5010m, manufactured by Hokuto Denko co., ltd., tokyo, japan) was used as the constant current power supply 3.

Content of the experiment

Day 1

(A) The tail base of each mouse in groups 1 to 4 was injected with 10 μ g of vaccine (Mtb 72F).

(B) Subsequently, the following method was used to administer the adjuvant (MPL, MPL-AF or MPL-SE) to the mice in groups 1 to 4.

Group 1: transdermal administration of MPL was performed using the TCT instrument described above.

The target mouse was subjected to depilation treatment (shaving after application of depilatory cream) on the previous day, and the active electrode assembly 1 and inactive electrode assembly 2 of the iontophoresis device were attached to the abdomen of the mouse with an adhesive. The current was applied for 30 minutes under the following conditions.

0.02mA for 0 to 15 minutes

0.04mA for 15 to 27 minutes

0.15mA for 27 to 30 minutes

Group 2: MPL-AF (20. mu.g) was injected intradermally at a site 1 inch (2.54cm) from the base of the tail of the mouse.

Group 3: MPL-SE (20. mu.g) was injected intradermally at a site 1 inch (2.54cm) from the base of the tail of the mice.

Group 4: and (4) untreated.

Day 22: blood samples were taken from the mice and tested for antibody responses by conventional methods (IgG1 and IgG2 a).

Day 35: mice in groups 1 to 4 were boosted (additional immunizations) in the same manner as day 1.

Day 43: blood samples were taken from the mice and tested for antibody responses by conventional methods (IgG1 and IgG2 a). In addition, two mice were selected from each group, and the spleens were removed and treated with 10. mu.g/ml mtb72F, ConA (concanavalin A), PPD (tuberculin-purified protein) and solventIn vitro cultures were performed for stimulation tests. After 72 hours, supernatants were collected and evaluated for immunogen growth and cytokine (IFN-. gamma.) according to conventional methods.

Results

FIGS. 5(1) and 5(2) show the antibody titers of IgG1 and IgG2 at day 43. In fig. 5(1) and 5(2), the line segment on the histogram indicates the standard deviation.

Figures 5(1) and 5(2) clearly show that transdermal administration of MPL, either by iontophoresis or by intradermal injection, produced significantly higher antibody titers to IgG1 and IgG2 than did MPL not administered. The results obtained with iontophoretic delivery of MPL or with intradermal injection of MPL were nearly identical.

Taken together, it has been demonstrated that iontophoretic administration of MPL provides a significant immune response enhancement equivalent to that obtained by intradermal injection.

All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the application data sheet, are incorporated herein by reference, in their entirety.

It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not to be restricted except in light of the attached claims.

Claims (47)

1. An iontophoresis device for administering an immune response-enhancing agent or a composition thereof, the iontophoresis device comprising:

an active electrode assembly having a drug solution storage portion containing an immune response enhancer or a combination thereof;

an active electrode element operable to apply a potential of a first polarity to drive at least a portion of the immune response-enhancing agent or a combination thereof out of the iontophoresis device,

an inactive electrode assembly having an inactive electrode element operable to apply a second polarity potential.

2. The device of claim 1, wherein the immune response enhancer is an adjuvant.

3. The device of claim 2, wherein the adjuvant is lipid a or an analog of lipid a.

4. The device of claim 3, wherein the analog of lipid A is selected from monophosphoryl lipid A (MPL), 3-O-deacylated monophosphoryl lipid A, or 4-phosphoaminoalkyl glucosaminide.

5. The device of claim 2, wherein the adjuvant is an agonist of a toll-like receptor.

6. The device of claim 5, wherein the toll-like receptor is selected from TLR-2, TLR-4, TLR-5, TLR-7 or TLR-9.

7. The device of claim 2, wherein the adjuvant is a saponin or a derivative thereof.

8. The apparatus of claim 7, wherein the saponin is QS-21.

9. The device of claim 2, wherein the adjuvant is selected from CpG, imiquimod, ranisimmod or dsim.

10. The device of any one of claims 1-9, wherein the drug solution storage portion further contains a vaccine or antigen.

11. The device of claim 10, wherein the vaccine or antigen comprises at least one antigen selected from the group consisting of: viral antigens, bacterial antigens including bacterial endotoxins, protozoal antigens or parasitic antigens.

12. The device of claim 11, wherein the parasite antigen is selected from a leishmania antigen or a malaria antigen.

13. The device of claim 10, wherein the vaccine or antigen comprises at least one antigen selected from the group consisting of: a plurality of hepatitis antigens including hepatitis a, hepatitis b and hepatitis c; hepatitis b surface antigen (HBsAg); a hepatitis b surface antigen mutant or an influenza antigen.

14. The device of claim 10, wherein the vaccine or antigen comprises at least one antigen selected from the group consisting of: (ii) a bordetella pertussis (pertussis) antigen; corynebacterium diphtheriae (diphtheria) antigen; tetanus bacillus (tetanus) antigen; an influenza b virus antigen or a poliovirus antigen.

15. The device of claim 10, wherein the vaccine or antigen comprises a mixture of antigens selected from the group consisting of a mixture of DTP (diphtheria, tetanus, pertussis) and HBsAg (hepatitis b surface antigen); a mixture of Hib (haemophilus influenzae type b) and HBsAg; a mixture of DTP, HBsAg and Hib; or a mixture of IPV (inactivated polio vaccine), DTP, HBsAg and Hib.

16. The device of any one of claims 1-9, wherein the drug solution storage portion further contains a cancer antigen.

17. The device of claim 16, wherein the cancer antigen is selected from a melanoma antigen, a basal cell carcinoma antigen, a breast cancer antigen, a prostate cancer antigen, a lung cancer antigen, or an ovarian cancer antigen.

18. The device of any one of claims 1-9, wherein the pharmaceutical solution storage portion further comprises an allergen.

19. The device of claim 18, wherein the allergen is selected from the group consisting of insect venom, plant pollen, dust mites, animal dander, ragweed, or endotoxins.

20. The device of claim 1, wherein the active electrode assembly further comprises:

a first ion exchange membrane disposed on a front surface of the drug solution storage portion; and

wherein the inactive-electrode assembly further includes:

a first electrolyte solution storage portion disposed on a front surface of the inactive electrode element.

21. The device of claim 20, wherein the active electrode assembly further comprises:

a second electrolyte solution storage portion disposed on a front surface of the active electrode element; and

a second ion exchange membrane interposed between the second electrolyte solution storage portion and the drug solution storage portion.

22. The device of claim 21, wherein the inactive electrode assembly further comprises:

a third ion exchange membrane disposed on a front surface of the first electrolyte solution storage portion.

23. The device of claim 22, wherein the inactive electrode assembly further comprises:

a third electrolyte solution storage portion disposed on a front surface of the third ion exchange membrane; and

a fourth ion exchange membrane disposed on a front surface of the third electrolyte solution.

24. The device of claim 23, wherein the first polarity is a negative polarity; the second polarity is a positive polarity; the first ion exchange membrane and the fourth ion exchange membrane are anion exchange membranes; the second ion exchange membrane and the third ion exchange membrane are cation exchange membranes; and the immune response enhancer is lipid a or a lipid a analog.

25. The device of claim 24, wherein the lipid a analog is selected from monophosphoryl lipid a (mpl), 3-O-deacylated monophosphoryl lipid a, or 4-phosphoaminoalkyl glucosaminide.

26. A method of administering an immune response-enhancing agent or composition thereof using an iontophoresis device comprising an active electrode assembly having a drug solution storage portion containing the immune response-enhancing agent or composition thereof, and a non-active electrode assembly; the method comprises the following steps:

electrically coupling the active electrode assembly and the inactive electrode assembly with electrodes of a power source; and

applying a voltage or current to the active electrode assembly and the inactive electrode assembly for a period of time;

wherein the active electrode assembly and the inactive electrode assembly are brought into contact with the skin of the mammal.

27. The method of claim 26, wherein the immune response enhancer is an adjuvant.

28. The method of claim 27, wherein the adjuvant is lipid a or an analog of lipid a

29. The method of claim 28, wherein the analog of lipid a is selected from monophosphoryl lipid a (mpl), 3-O-deacylated monophosphoryl lipid a, or 4-phosphoaminoalkyl glucosaminide.

30. The method of claim 27, wherein the adjuvant is an agonist of a toll-like receptor.

31. The method of claim 30, wherein the toll-like receptor is selected from TLR-2, TLR-4, TLR-5, TLR-7 or TLR-9.

32. The method of claim 27, wherein the adjuvant is a saponin or a derivative thereof.

33. The method of claim 32, wherein the saponin is QS-21.

34. The method of claim 27, wherein the adjuvant is selected from CpG, imiquimod, ranisimmod or dsim.

35. The method of any one of claims 26-34, wherein the pharmaceutical solution storage portion further comprises a vaccine or antigen.

36. The method of claim 35, wherein the vaccine or antigen comprises at least one antigen selected from the group consisting of: viral antigens, bacterial antigens (including bacterial endotoxins), protozoal antigens, or parasitic antigens.

37. The method of claim 36, wherein the parasite antigen is selected from leishmania antigens or malaria antigens.

38. The method of claim 35, wherein the vaccine or antigen comprises at least one antigen selected from the group consisting of: a plurality of hepatitis antigens (including hepatitis a, hepatitis b and hepatitis c), hepatitis b surface antigens (HBsAg), hepatitis b surface antigen mutants or influenza antigens.

39. The method of claim 35, wherein the vaccine or antigen comprises at least one antigen selected from the group consisting of: a Bordetella pertussis (pertussis) antigen, a Corynebacterium diphtheriae (diphtheria) antigen, a Bacillus tetanus (tetanus) antigen, an influenza B virus antigen, or a poliovirus antigen.

40. The method of claim 35, wherein the vaccine or antigen comprises a mixture of antigens selected from the group consisting of a mixture of DTP (diphtheria, tetanus, pertussis) and HBsAg (hepatitis b surface antigen); a mixture of Hib (haemophilus influenzae type b) and HBsAg; a mixture of DTP, HBsAg and Hib; or a mixture of IPV (inactivated polio vaccine), DTP, HBsAg and Hib.

41. The method of any one of claims 26-34, wherein the pharmaceutical solution storage portion further comprises a cancer antigen.

42. The method of claim 41, wherein the cancer antigen is selected from a melanoma antigen, a basal cell carcinoma antigen, a breast cancer antigen, a prostate cancer antigen, a lung cancer antigen, or an ovarian cancer antigen.

43. The method of any one of claims 26-34, wherein the pharmaceutical solution storage portion further comprises an allergen.

44. The method of claim 43, wherein the allergen is selected from the group consisting of insect venom, plant pollen, dust mites, animal dander, ragweed, and endotoxins.

45. The method of claim 44, wherein the inactive electrode assembly further comprises:

a fourth ion exchange membrane disposed on a front surface of the first electrolyte solution storage portion; and

a third electrolyte solution storage portion interposed between the fourth ion exchange membrane and the third ion exchange membrane.

46. The method of claim 45, wherein the first polarity is a negative polarity; the second polarity is a positive polarity; the first ion exchange membrane and the fourth ion exchange membrane are anion exchange membranes; the second ion exchange membrane and the third ion exchange membrane are cation exchange membranes; and the immune response enhancer is lipid a or a lipid a analog.

47. The method of claim 49, wherein the lipid A analog is selected from monophosphoryl lipid A (MPL), 3-O-deacylated monophosphoryl lipid A, or 4-phosphoaminoalkyl glucosaminide.