STRUCTURE OF ELECTRODE FOR LONTOFORESIS USED PAPA ADMINISTER MEDICINAL CLOSED IN NANOPARTICLES AND DEVICE OF LONTOFORESIS THAT MAKES USE OF THE SAMEBACKGROUND OF THE INVENTIONFIELD OF THE INVENTION The present invention relates generally to the field of iontophoresis and in particular to an iontophoresis electrode assembly for delivering a medicament enclosed in an ionic nanoparticle to a subject, and with an iontophoresis device using the assembly of electrode.
BACKGROUND OF THE ART Iontophoresis refers to a method of delivering an ionic medication placed on the surface of the biological contact surface such as the skin or mucosa of a subject and within the body of the subject by the use of sufficient electromotive force. to boost the ionic medication. See JP 63-35266 A for an example of iontophoresis. The positively charged ions can be driven (transported) to the biological contact surface on the anode side (positive electrode) ofan iontophoresis device, for example, negatively charged ions can be driven into the biological contact surface on the cathode side (negative electrode). Various iontophoresis devices have been proposed as described in the above (see, for example, JP 63-35266 A, JP 04-297277 A, JP 2000-229128 A, JP 2000-229129 A, JP 2000-237327 A , JP 2000-237328 A, WO 03/037425 Al, JP 2004-518707 A, JP 2004-231575 A and JP 2003-501379 A). However, it can be difficult to apply iontophoresis for the delivery of a drug which does not dissociate into ions, which is insoluble in water or which is liposoluble or which has a high molecular weight. Therefore, the number of potential drugs susceptible to be supplied by conventional iontophoresis is limited. In addition, it has been desired to provide a medicament that is provided by iontophoresis with a functionality to be delivered in specific areas in a subject. Consequently, it is a major problem to allow the application by iontophoresis of a drug which does not dissociate into ions or which is insoluble or sparingly soluble in water. It is also a problem to provide a drug with the functionality in the drug supply.
BRIEF DESCRIPTION OF THE INVENTION The present invention has been completed based on the problems of the prior art. Accordingly, an object of the present invention is to provide an electrode assembly for iontophoresis and an iontophoresis device that utilizes same which makes it possible to administer by iontophoresis a drug that does not dissociate into ions or that is insoluble or sparingly soluble in water and which makes it possible to provide the drug, including an ionic medicine with the functionality in the drug supply. To solve the aforementioned problems, the electrode assembly for iontophoresis of the present invention comprises a medicament enclosed in an ionic nanoparticle. In a preferred aspect, the electrode assembly of the present invention comprises at least one electrode coupled to an electrical power source device having the same polarity as the ionic nanoparticle in the electrode assembly, a reservoir of impregnated electrolyte solution With the electrolyte solution, the electrolyte solution tank is placed adjacent to the electrode, a ion exchange membrane selective for the ions with a polarity opposite to that of the ionic nanoparticle, the ion exchange membrane isplaced adjacent to the electrolyte solution reservoir, a reservoir of drug solution impregnated with the ionic nanoparticle, the medicament solution reservoir is placed adjacent to the ion exchange membrane and an ion-selective ion exchange membrane with the same polarity as that of the ionic nanoparticle, the ion exchange membrane is placed adjacent to the drug solution reservoir. In a preferred aspect, the electrode assembly of the present invention is one in which the drug solution reservoir includes pores capable of retaining and allowing the ionic nanoparticle to pass through. In a preferred aspect, the electrode assembly of the present invention is one in which the ion exchange membrane which is selectively permeable to ions having the same polarity as those of the ionic nanoparticle includes pores capable of passing the nanoparticle ionic and ion exchange membrane which is selectively permeable to ions having a polarity opposite to that of ionic nanoparticles does not include pores capable of passing through the ionic nanoparticle. In a preferred aspect, the electrode assembly of the present invention is one in which the ionic nanoparticle is a cationic nanoparticle.
In another preferred aspect, the electrode assembly of the present invention is one in which the ionic nanoparticle is an anionic nanoparticle. In a preferred aspect, the electrode assembly of the present invention is one in which the medicament enclosed in the ionic nanoparticle is selected from cancer therapeutic agents, nucleic acids such as genes and peptides. In a preferred aspect, the iontophoresis device of the present invention comprises a power source device, a medicament delivery means comprising two or more electrode assemblies, at least one of the electrode assemblies comprising a medicament enclosed in an ionic nanoparticle and a current control means for controlling the current flow to each of the electrode assemblies, the current flows from the current control means and causes the electrode assembly to release the ionic nanoparticle so that is administered transdermally to a subject. In a preferred aspect of the present invention, the iontophoresis device is one in which the medicament delivery means is integrally configured. In accordance with the present invention, the electrode assembly comprises a medicament enclosed in aionic nanoparticle and therefore it becomes possible to administer by iontophoresis a drug that does not dissociate into ions or that is insoluble or sparingly soluble in water and provide the drug with functionality in the delivery of the drug.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a frame format of an electrode assembly for iontophoresis. Figure 2 shows a frame format of an iontophoresis device that includes an electrode assembly for iontophoresis.
DETAILED DESCRIPTION OF THE INVENTION As mentioned in the foregoing, the electrode assembly for iontophoresis of the present invention comprises a medicament enclosed in an ionic nanoparticle. As used herein, the term "nanoparticle" refers to a hollow particle having a diameter of 4 nm to 400 nm and capable of enclosing a substance therein. Ionic nanoparticles have functional groups positively or negatively charged on a surface film thereof. This charged natureallows ionic nanoparticles to be administered via iontophoresis. For example, a cationic nanoparticle may have a functional group such as -NH3 +. The functional group can reinforce an interaction with a negatively charged biological cell. By way of comparison, an anionic nanoparticle can have a functional group such as a carboxyl group so that interactions with negatively charged biological cells can be suppressed. Non-limiting examples of materials that can be used to form ionic nanoparticles include PLGA (polylactic acid-glycolic acid) and PLA (polylactic acid). The use of such material may delay the release of a drug as the molecular weight of the ionic nanoparticle becomes larger. In addition, the period of time during which a drug is effective may be prolonged due to sustained release properties found when such materials are used. This can help reduce any load placed on a subject. In addition, the ionic nanoparticles can be coated with lecithin, for example. Coated ionic nanoparticles can accumulate on a portion of the biological contact surface that is inflamed or similar, thereby enabling targeted delivery. In addition, said ionic nanoparticles can besusceptible to deformation, similar to erythrocytes by energization and therefore ionic nanoparticles are allowed to pass through and be absorbed by an ion exchange membrane or the biological contact surface. Ionic nanoparticles that enclose a drug in them can be shaped by using any of a variety of methods, some of which are indicated in the following. The following method can be used when a water-soluble drug is to be enclosed in the ionic nanoparticles. The drug can be dissolved in acetone along with PLGA (or PLA) and zinc acetate can be added to the solution. The resultant can then be added dropwise to water and lecithin can be added later and in this way nanospheres are formed. Below is a specific example. It can dissolve 1 mg of triptorelin in 100 μ? of an aqueous solution (pH 7, W1). The solution can then be emulsified with an organic solvent (ethyl acetate, dichloromethane) in which PLGA has been dissolved and the resulting can be exposed to ultrasonic irradiation. Then 2 ml of an aqueous solution containing 1% PVA (W2) can be added to the resultant and the whole can be exposed to ultrasonic radiation to prepare aemulsion W1 / 0 / W2. The emulsion can then be diluted with 15 ml of a 0.3% aqueous PVA solution and the organic solvent is evaporated under reduced pressure. The resulting nanoparticles can be separated by ultracentrifugation (13,000 x g, 30 minutes). The resulting supernatant can be separated and washed with purified water. The fine particles prepared by using PLGA50 / 50 having a large number of free carboxyl groups, each with a negative charge. Furthermore, when fine particles and cetylbutylammonium bromide (C ) are prepared and mixed and stirred overnight, CTAB adsorbs onto the surface of each particle so that the charge of each fine particle becomes positive. The following method (method of solvent diffusion) can be used when a liposoluble medicine is to be enclosed in the ionic nanoparticles. PLGA (or PLA) can be dissolved in acetone together with the medicine. The acetone solution can be added dropwise to an aqueous solution including polyvinyl alcohol, Pluronic F68 or Tween 20 while stirring. In this way a fine particle emulsion is obtained. The emulsion can be separated by using centrifugation and the resulting supernatant can be separated and washed with waterpurified. Alternatively, the following method can also be adopted (a method of solvent evaporation). PLGA (or PLA) can be dissolved in 1 ml of dichloromethane together with the medicine. An aqueous solution of added egg yolk lecithin and the dichloromethane solution can be mixed and stirred and the resultant exposed to ultrasonic irradiation. The resultant is then stirred at room temperature for 2 hours. The resulting fine particles can then be separated by the use of ultracentrifugation. The resulting supernatant can be separated and washed with purified water. Examples of drugs that can be included in the ionic nanoparticles include those listed below. In the examples narrowly defined ionic drugs, i.e., drugs which by themselves can be dissociated into ions, can be directly administered to form an electrode assembly comprising the same without being enclosed in ionic nanoparticles. Examples of medicaments include various therapeutic agents against cancer, therapeutic genes and peptides. Such drugs can be directed to specific sites of a subject when they are enclosed in an ionic nanoparticle and can be delivered byiontophoresis Medications may also incorporate sustained release properties. In addition, the drug can be administered by the use of iontophoresis even if the drug itself does not actually dissociate easily into ions and even if the drug is substantially insoluble in water. When applied to a drug that has a large molecular weight, a valence greater than that of the original ionic charge can be provided for the entire drug, for example, by adjusting the number of functional groups in the nanoparticles and thus increasing mobility and facilitate increased transport. Examples of cationic drugs that can be enclosed in ionic nanoparticles include: local anesthetics (such as procaine hydrochloride and lidocaine hydrochloride); therapeutic substances for gastrointestinal diseases (such as carnitine chloride); skeletal muscle relaxants (such as vancuronium bromide) and antibiotics (such as tetracycline-based preparations, kanamycin-based preparations and gentamicin-based preparations.) Examples of anionic drugs that can be enclosed in ionic nanoparticles include: vitamins (such as riboflavin phosphate, acidnicotinic acid, ascorbic acid and folic acid); hormones of the adrenal cortex (such as water-soluble hydrocortisone-based preparations and water-soluble preparations based on dexamethasone and prednisolone such as prednisolone sodium phosphate and dexamethasone sodium phosphate); and antibacterial agents (such as quinolone-based preparations). Examples of vaccines that can be enclosed in ionic nanoparticles include the BCG vaccine, hepatitis A vaccine, melanoma vaccine, measles vaccine, polio vaccine, and influenza vaccine. Examples of adjuvants that can be enclosed in ionic nanoparticles include MPL (monophosphoryl lipid)A), DMPC (dimyristoylphosphatidylcholine), QS-21, DDA (dimethyl dioctadecyl ammonium chloride) and RC-529. In addition, combinations of a vaccine and an adjuvant can also be included such as a combination of a positively ionized vaccine and RC-529; a combination of a negatively ionized vaccine and DDA; a combination of a BCG and MPL vaccine; a combination of hepatitis A vaccine and DMPC; and a combination of a melanoma vaccine and QS-21. Other drug combinations can also be used such as: a combination of a hypotensive drug and a hypotensive diuretic agent, for examplelisinopril and hydrochlorothiazide, methyldopa and hydrochlorothiazide, clonidine hydrochloride and chlorthalidone and benazepril hydrochloride and hydrochlorothiazide; a combination containing an antidiabetic agent such as insulin and metformin hydrochloride; and other combinations such as ozagrel hydrochloride and sodium ozagrel, and codeine hydrochloride and promethazine hydrochloride. Various types of ionic drugs (ionic nanoparticles and narrowly defined ionic drugs) may be used in combination in combination depending on the diseases or conditions in a subject. These various ionic drugs can exist separately in different electrode assemblies or can be combined together in an electrode assembly. The amount of each ionic drug present can be set so that a desired blood concentration occurs when applied to a subject for a certain period of time. The amount can be set by a person skilled in the art according, for example, to the size or thickness of the drug solution reservoir, the size of a drug release surface area, the size of an applied electric potential, the time of administration or similar. Preferably an inactive electrode made from a conductive material such ascarbon or platinum as the electrode of the electrode assembly. The electrolyte solution reservoir can be constituted of a thin film which can be impregnated with an electrolyte solution. The thin film can be made from the same material as that used for a tank of drug solution described below, which is impregnated with an ionic medicine. One desired can be used appropriately as the electrolyte solution depending on conditions such as the medicament to be applied; however, solutions that damage the skin of a subject due to the reaction of the electrode should be avoided. An organic acid or a salt thereof present in a metabolic cycle of the subject is preferable for the electrolyte solution in the present invention in terms of safety. Typical examples include lactic acid and fumaric acid. Specifically, an aqueous solution of 1M lactic acid and 1M sodium fumarate (1: 1) can be used. Said electrolyte solution is preferably because it has a high solubility with respect to water, the current passes well and allows small changes in the pH at constant current. The medication solution reservoir may comprise a thin film which may be impregnatedwith an ionic medication or similar. It is important that the film has sufficient capacity to be impregnated with an ionic drug and have sufficient capacity (ion transfer capacity, ionic conductivity) to move the ionic drug to the skin side under predetermined electric field conditions). Examples of a material having both satisfactory impregnation characteristics and satisfactory ion conductivity include hydrogel forms of acrylic resins (acrylic-hydrogel film), segmented polyurethane-based gel matrix films and porous ion conducting sheets to form a solid electrolyte similar to gel matrix (see a porous polymer described in Japanese patent publication open to the public 273452/1936 A using, as a base, an acrylonitrile copolymer containing 50 mole percent or more, preferably 70 to 98 mole% or more of acrylonitrile and having a porosity of 20 to 80%). In the case where the drug solution tank is impregnated with the solution, the impregnation rate thereof (defined as (-D) / D, where D indicates the dry weight and W indicates the weight after impregnation ) is preferably 30 to 40%. In addition, the drug solution reservoir may have pores capable of retaining ionic nanoparticlesand allow the ionic nanoparticles to pass through it. The drug solution reservoir having said porous structure can easily retain ionic nanoparticles by being submersible in a liquid containing the ionic nanoparticles or by aspirating a liquid containing the ionic nanoparticles therethrough. The cation exchange membrane and the anion exchange membrane are preferably used in combination for the electrode assembly. Examples of cation exchange membrane include NEOSEPTAs (CM-1, CM-2, CMX, CMS, CMB and CLE04-2) manufactured by Tokuyama Co., Ltd. Examples of anion exchange membrane include NEOSEPTAs (AM-1, AM-3, AMX, AHA, ACH, ACS, ALE04-2 and AIP-21) manufactured by Tokuyama CO., Ltd. Cation exchange membranes may comprise a porous film having cavities, a portion of the entirety of which It is filled with a cation exchange resin. The anion exchange membranes may comprise a porous film having cavities, a portion of which is filled with an anion exchange resin. The ion exchange membranes may have pores through which. the ionic nanoparticles can pass. In particular, an ion exchange membrane having the same polarity as that ofthe ionic nanoparticles used can have pores through which the ionic nanoparticles can pass, while an ion exchange membrane having a polarity opposite to the ionic nanoparticles can comprise a non-porous membrane that allows the ionic nanoparticles to be efficiently delivered towards the biological contact surface. The ion exchange resins can be fluorinated and include a perfluorocarbon backbone having an ion exchange group or can be based on hydrocarbons and include a non-fluorinated resin as a backbone. The hydrocarbon-based ion exchange resins are preferably used because these resins are easier to manufacture. The rate of filling of the porous film by the ion exchange resins varies based on the porosity of the porous film and the speed can be from 5 to 95% by mass, preferably 10 to 90% by mass, more preferably by weight. to 60% by mass. The exchange groups in the ion exchange resins are not limited insofar as these functional groups have a negative or positive charge when they are in aqueous solution. The functional groups may also be present in the form of a free acid or a salt. The examples of cation exchange groupsinclude sulfonic groups, carboxylic acid groups and phosphonic acid groups. Examples of counter cations for the cation exchange group include: alkali cations such as sodium ions and potassium ions as well as ammonium ions. Examples of anion exchange groups include primary amino groups, secondary amino groups, tertiary amino groups, quaternary ammonium groups, pyridyl groups, imidazole groups, quaternary pridinium groups and imidazole and quaternary groups. Examples of counter cations for the anion exchange group include: halogen ions such as chlorine ions and hydroxy ions. In addition, any film or film which has pores passing through it can be used as the porous film, without specific limitations. However, to satisfy high strength and flexibility, it may be advantageous if the porous film is made of a thermoplastic resin. Examples of thermoplastic resins include: 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; resins based on vinyl chloride such as polyvinyl chloride, vinyl chloride-vinyl acetate copolymers, vinyl chloride-chloride copolymersvinylidene and vinyl chloride-olefin copolymers; fluorine-based resins such as polytetrafluoroethylene, polychlorotrifluoroethylene, polyvinylidene fluoride, tetrafluoroethylene-hexafluoropropylene copolymers, tetrafluoroethylene-perfluoroalkyl vinyl ether copolymers and tetrafluoroethylene-ethylene copolymers; polyamide resins such as nylon 66 and polyimide resins. Furthermore, in view of mechanical strength, flexibility, chemical stability and chemical resistance, the thermoplastic resins are preferably polyolefin resins, more preferably polyethylene or polypropylene and even more preferably polyethylene. In addition, the average pore size of the porous films may preferably be from 0.005 to 5.0 pm, more preferably from 0.01 to 2.0 pm, and even more preferably from 0.02 to 0.2 pm. The average pore size, as used herein, indicates the average pore size of the flow, measured according to the bubble tip method (JIS-K3832-1990). In addition, the porosity of the porous film can preferably be from 20 to 95%, more preferably from 30 to 90%, still more preferably from 30 to 70%. In consideration of the thickness of a ion exchange membrane finally formed, the thickness of the porous film can preferably be from 5 to 140 μm,more preferably from 10 to 130 pm, still more preferably from 15 to 55 μtt ?. An anion exchange membrane or a cation exchange membrane formed by the use of a porous film generally has the same thickness as that of the porous film but can also have a thickness of up to about 20 and more than that of the porous film. Figure 1 is a schematic view showing an electrode assembly 1 for iontophoresis placed on the skin 2. The electrode assembly 1 can be used as an active electrode assembly to tansmerically administer an ionic medicine. The electrode assembly 1 may comprise: an electrode 11 coupled via an electric cable 31 to an electrical power source device having the same polarity as that of the ionic medication, a reservoir 12 of electrolyte solution impregnated with an electrolyte solution, the electrolyte solution reservoir 12 is positioned adjacent the electrode 11. an ion exchange membrane 13 which is selectively permeable to ions with a polarity opposite to that of the ionic drug, the ion exchange membrane 13 is placed adjacent to the reservoir 12 of electrolyte solution, a reservoir 14 of drug solution impregnated with the ionic nanoparticles, the reservoir 14 of drug solution is placed adjacentto the ion exchange membrane 13 and an ion exchange membrane 15 which is selectively permeable to ions with the same polarity as that of the ionic drug, the ion exchange membrane 15 is placed adjacent to the drug solution reservoir 14. A cover or container 16 is used to house the electrode assembly 1. Figure 2 is a schematic view showing an iontophoresis device X placed on the skin 2. The iontophoresis device X comprises: the electrode assembly 1 (active electrode assembly) for iontophoresis; an electrical power source device 3 and an inactive electrode assembly 4 as an electrode assembly. The electrode assembly 1 for iontophoresis is coupled via the electrical cable 31 to one side of the electrical power source device 3 having the same polarity as that of the medicament. The inactive electrode assembly 4 may comprise: an electrode 41 coupled via an electrical cable 32 to one side of the source 3 of electrical energy having a polarity opposite to that of the charge of an ionic medicine; a reservoir 42 of electrolyte solution impregnated with an electrolyte solution, the reservoir 42 of electrolyte solution is placed adjacent to the electrode 41; an ion exchange membrane 43which is selectively permeable to ions with the same polarity as that of the ionic drug, the ion exchange membrane 43 is placed adjacent to the electrolyte solution reservoir 42; a reservoir 44 of electrolyte solution impregnated with an electrolyte solution, the deposit 44 of electrolyte solution is placed adjacent to the ion exchange membrane 43; and an ion exchange membrane 45 which is selectively permeable to ions having a polarity opposite to that of the ionic drug, the ion exchange membrane 45 e. placed adjacent to reservoir 44 of electrolyte solution. The entire inactive electrode assembly 4 may be housed in a cover or container 46. The inactive electrode assembly 4 is one of a preferred embodiment, and may also acquire other configurations. For example, the electrolyte solution reservoir 42 and the ion exchange membrane 43 which is selectively permeable to the ions with the same polarity as those of the ionic drug may be omitted. When an electrode assembly that retains an ionic medication is energized by the electrical energy source device 3, the ionic medication can move to an opposite side of the electrode due to electrophoresis caused by an electric field and therefore can be administered transdermally to a subjectvia the ion exchange membrane 15. The ion exchange membrane 13 placed on the electrode side selectively passes ions having a polarity opposite to that of the ionic drug, and therefore substantially prevents movement of the ionic drug towards the electrode. By having the above configuration, the electrode assembly of the present invention allows to avoid damaging the skin by electrochemical reaction and therefore a safe administration of the ionic medicines is obtained. In addition, the following conditions are preferably adopted as operating conditions in an iontophoresis device. Constant current condition, specifically 0.1 to 0.5 mA / cm2, preferably 0.1 to 0.3 mA / cm2. A safe voltage condition that verifies the previous constant current, specifically 50 V or less, preferably 30 V or less. In addition, in the present invention, a configuration including a plurality of active (or inactive) electrode assemblies can also be used. In this way, a plurality of different types of ionic medicines can be maintained by the active electrode assemblies and the ionic drugs comprising at least one ionic nanoparticle which encloses a medicament. In addition, in case of administration of two or more ionic medicines which have different chargesbetween each other, the active electrode assemblies and the inactive electrode assemblies can be placed not only on the anode side but also on the cathode side of an iontophoresis device. In addition, a plurality of electrode mounts can be configured as medication delivery means and can be integrally assembled in a package for handling convenience, for example. No particular limitations are placed on the packaging materials in this case, with the proviso that the material and packaging does not substantially affect the administration of an ionic medication. An example of a material and packaging is polyolefin for a medical device. In addition, a current control means may be provided in order to deliver a predetermined amount of a medicament within a predetermined period of time. The medicament delivery means, the current control means and an electrical power source device can be integrally configured. For example, the size of the iontophoresis device can be reduced in case a button-type battery is used as the power source device and an IC chip is used as the current control means. In addition, the total number of electrode assembliesas well as the combination of active electrode assemblies and inactive electrode assemblies can be altered without losing the capacity requirements of the present invention. Those skilled in the art can distribute such configurations based on the specific example mentioned above. WO 03/037425 Al, the content of which is hereby incorporated by reference in its entirety, by the applicant of the present disclosure presents specific elements in greater detail.