JP2010202577A - Medicine for iontophoresis, and device for iontophoresis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new medicine for iontophoresis excellent in skin permeability and a device for the iontophoresis equipped with the medicine. <P>SOLUTION: This medicine for the iontophoresis is provided by consisting of a first compound having an anionic part and a cationic part and a second compound having an anionic part or cationic part, wherein, at least one of the first compound and second compound has medicinal activity, and contains an ionic complex having an anionic or cationic property as a whole as an active ingredient; and the device 1 for the iontophoresis is equipped with a first sheet 11 and second sheet 12 for holding the medicine, wherein, at least one of them holds the medicine, and also equipped with a first electrode 13 and second electrode 14 for impressing an electric voltage to the medicine in these sheets. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a drug for iontophoresis excellent in skin permeability, and a device for iontophoresis provided with the drug.

Iontophoresis is a technique for promoting penetration of an ionic drug into the skin by applying a voltage when the ionic drug is absorbed through the skin. The anionic drug penetrates into the skin from the cathode (cathode), the cationic drug penetrates from the anode (anode), and ions having the same polarity as the permeated ionic drug are extracted from the skin (see Non-Patent Document 1). ).
Since iontophoresis promotes the penetration of ionic drugs into the skin, it is suitable for the application of various cosmetics and various pharmaceuticals that can be administered into the body by transdermal absorption (see Patent Document 1).

Japanese Patent No. 3469973

S. K. Gupta et al. , J .; Pharm. ScI. , 87.976 (1998)

However, only a limited number of ionic drugs applicable to iontophoresis have been reported so far.
This invention is made | formed in view of the said situation, and makes it a subject to provide the device for iontophoresis provided with the novel chemical | medical agent for iontophoresis excellent in skin permeability, and this chemical | medical agent.

To solve the above problem,
The present invention comprises a first compound having an anion portion and a cation portion and a second compound having an anion portion or a cation portion, and at least one of the first compound and the second compound has a drug activity. And an iontophoretic agent characterized by containing an ionic complex that is anionic or cationic as a whole as an active ingredient.
In the iontophoretic agent of the present invention, the anion part of the first compound and / or the second compound is composed of a carboxylic acid group, a phosphoric acid group, a polyphosphoric acid group, a sulfuric acid group, a nitric acid group, and a carbonic acid group. It is preferable that it is an anionic group produced by dissociating one kind of acidic group selected from the group.
In the iontophoresis agent of the present invention, the cation moiety of the first compound and / or the second compound is an ammonium group, a sulfonium group, a phosphonium group, and one or more hydrogen atoms thereof are alkyl groups. It is preferably a kind of cationic group selected from the group consisting of substituted groups.
In the iontophoretic agent of the present invention, it is preferable that the first compound is represented by the following general formula (I) and the second compound is represented by the following general formula (II).

[Wherein, X ¹ is a group having an anionic group in which a hydrogen ion is removed from a group selected from the group consisting of a carboxylic acid group, a phosphoric acid group, a polyphosphoric acid group, a sulfuric acid group, a nitric acid group and a carbonic acid group. X ² is a group having a kind of cationic group selected from the group consisting of an ammonium group, a sulfonium group and a phosphonium group, and a group in which one or more hydrogen atoms thereof are substituted with an alkyl group; m is an integer of 0 to 4; R ¹ is an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an alkenyloxy group, an aryloxy group, a hydroxyl group or a halogen atom, and when m is 2 to 4 a plurality of R ¹ may be the same or different from each other. ]

[Wherein X ³ is a group having an anionic group obtained by removing a hydrogen ion from a group selected from the group consisting of a carboxylic acid group, a phosphoric acid group, a polyphosphoric acid group, a sulfuric acid group, a nitric acid group and a carbonic acid group. Or a group having one kind of cationic group selected from the group consisting of an ammonium group, a sulfonium group, a phosphonium group, and a group in which one or more of these hydrogen atoms are substituted with an alkyl group; R ² is an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an alkenyloxy group, an aryloxy group, a hydroxyl group, or a halogen atom, and when n is 2 to 5, a plurality of R ² May be the same or different from each other. ]
In the iontophoresis agent of the present invention, the ionic complex is preferably a 1: 1 (molecular number ratio) complex of the first compound and the second compound.

The present invention also includes an iontophoresis device comprising: a drug holding unit that holds the iontophoretic drug of the present invention; and an electrode that applies a voltage to the iontophoretic drug in the drug holding unit. A forensic device is provided.
In the iontophoresis device of the present invention, the drug holding part and the electrode are preferably in a sheet form.

  According to the present invention, it is possible to provide a novel drug for iontophoresis excellent in skin permeability and a device for iontophoresis provided with the drug, and an excellent medicinal effect can be obtained by promoting the skin permeability of the drug. It is done.

It is a schematic block diagram which illustrates the device of this invention. It is a schematic block diagram which shows the other example of the device of this invention. It is a schematic block diagram which illustrates the test apparatus for confirming the skin permeability | transmittance of an ionic complex. It is a graph which shows the result of the skin permeation experiment in Example 1, (a) shows the cumulative transmission amount of TXA, (b) shows the cumulative transmission amount of 4MS, respectively.

<Iontophoresis drug>
The iontophoresis drug of the present invention (hereinafter abbreviated as drug) comprises a first compound having an anion part and a cation part, and a second compound having an anion part or a cation part, At least one of the compound and the second compound has a drug activity, and contains an ionic complex that is anionic or cationic as a whole as an active ingredient.
The ionic complex is formed by binding the first compound and the second compound by an ionic bond, and further having an anion part or a cation part not involved in the ionic bond, The whole molecule is anionic or cationic. Thus, by making it an ionic complex, since lipophilicity increases rather than the case of the 1st compound or the 2nd compound alone, the skin permeability by iontophoresis improves.

(First compound)
The first compound has an anion portion and a cation portion in one molecule.
The anion portion and the cation portion are preferably present stably at pH 3.5 to 8, and more preferably stably present at pH 4.5 to 7. By setting it as such a range, the safety | security with respect to the biological body of an ionic complex improves further. In addition, the first compound exists stably as an amphoteric compound having both a cation part and an anion part, and can form an ionic complex more stably with the second compound described later, Penetration into the water becomes even easier. When the pH is too low, the first compound tends to show only cationic properties, and when the pH is too high, it tends to show only anionic properties.

Examples of the anion moiety include an anionic group and an anionic bond. An anionic bond refers to a bond having an anion in the main chain or side chain.
The anion moiety is not particularly limited as long as it satisfies such a condition, but a preferable example is an anionic group generated by dissociation of an acidic group. Preferred examples of the acidic group include a carboxylic acid group (—C (═O) —OH), a phosphoric acid group (—O—P (═O) (OH) ₂ ), and a polyphosphoric acid group ((—O—P). (= O) (OH)) _k- OH, k is an integer of 2 or more), sulfate group (-O-S (= O) _2- OH), nitrate group (-O-N (-O) ^- -OH) and a carbonate group (-O-C (= O) -OH) can be exemplified.

Examples of the cation moiety include a cationic group and a cationic bond. The cationic bond refers to a bond having a cation in the main chain or the side chain.
The cation portion is such not condition particularly as long as it satisfies the limitation, as preferred, an ammonium group ^(-N _{+ H} 3), sulfonium group ^(-S + _{H 2)} and phosphonium groups (-P ⁺ H ₃ ) can be exemplified. Further, a group in which one or more hydrogen atoms of these groups are substituted with a substituent can be exemplified as a preferable example.

The substituent is preferably an alkyl group, an alkenyl group or a hydroxyl group, more preferably an alkyl group or a hydroxyl group, and particularly preferably an alkyl group.
The alkyl group as the substituent may be linear, branched or cyclic. In the case of a linear or branched chain, the number of carbon atoms is preferably 1 to 15, more preferably 1 to 10, and particularly preferably 1 to 5. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, sec- Examples include a pentyl group, a tert-pentyl group, and an n-hexyl group. When it is cyclic, it may be monocyclic or polycyclic, and preferably has 3 to 12 carbon atoms.
Examples of the alkenyl group as the substituent include those in which a single bond (C—C) between at least one carbon atom of the alkyl group is a double bond (C═C).
The number of the substituents is not particularly limited, and may be one or plural, and all hydrogen atoms may be substituted with the substituents. When the number of the substituents is plural, these substituents may all be the same, a part of them may be different, or all may be different. When some or all are different, the combination of these substituents can be arbitrarily selected according to the purpose.

  Although the number of the anion part and cation part in a 1st compound is not specifically limited, It is preferable that the number of an anion part and a cation part is the same number.

  The first compound may or may not have a drug activity for a living body. However, in the case where the second compound described later has no drug activity, the first compound has drug activity. As what has a chemical | medical activity, if the said conditions are satisfy | filled, arbitrary things can be used, What can be used as active ingredients, such as a pharmaceutical, cosmetics, or a quasi-drug, can be illustrated.

  Specific examples of preferable drugs include penicillins such as amoxicillin and ampicillin; carbapenems such as imipenem; cephams such as cefaclor, cefothiam and ceftazidime; tetracyclines such as minocycline; and pyridone carboxyl such as pazufloxacin mesylate; Acids; antiviral agents such as acyclovir, valacyclovir, zanamivir; levodopas; L-carbocysteine; fudstein; ozagrel; vincristine; melphalan; 4-aminobenzoic acid; What became a part can be illustrated. However, it is not limited to these. Here, “a part of the structure of the compound becomes an anion part and a cation part” means that part of the structure in the compound (for example, a functional group or a bond) has a cation or an anion by pH adjustment. Refers to becoming. The same applies to the following.

  For cosmetics and quasi-drugs, for example, a component having a skin whitening effect is particularly suitable, and particularly preferred is a part of a structure such as 4- (aminoethyl) -cyclohexanecarboxylic acid (tranexamic acid). Can be an anion portion and a cation portion.

  Moreover, the amphoteric compound represented with the following general formula (I) can also be illustrated as a preferable 1st compound.

[Wherein, X ¹ is a group having an anionic group in which a hydrogen ion is removed from a group selected from the group consisting of a carboxylic acid group, a phosphoric acid group, a polyphosphoric acid group, a sulfuric acid group, a nitric acid group and a carbonic acid group. X ² is a group having a kind of cationic group selected from the group consisting of an ammonium group, a sulfonium group and a phosphonium group, and a group in which one or more hydrogen atoms thereof are substituted with an alkyl group; m is an integer of 0 to 4; R ¹ is an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an alkenyloxy group, an aryloxy group, a hydroxyl group or a halogen atom, when m is 2 to 4 a plurality of R ¹ may be the same or different from each other. ]

In the formula, X ¹ is a group having an anionic group in which a hydrogen ion is removed from a group selected from the group consisting of a carboxylic acid group, a phosphoric acid group, a polyphosphoric acid group, a sulfuric acid group, a nitric acid group and a carbonic acid group ( Hereinafter, it is abbreviated as an anionic group-containing group). The number of hydrogen ions removed by the anionic group is not particularly limited, and a plurality of phosphoric acid groups, polyphosphoric acid groups, and the like may be used.
Examples of the anionic group-containing group include those composed only of the anionic group and monovalent groups in which the anionic group is bonded to a divalent group.

  Preferred examples of the divalent group include a group in which one hydrogen atom is removed from a group selected from the group consisting of an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an alkenyloxy group, and an aryloxy group; Examples include carbonyl group (—C (═O) —); amide bond (—NH—C (═O) —); ester bond (—C (═O) —O—) and the like.

Examples of the alkyl group and alkenyl group excluding a hydrogen atom include the same alkyl groups and alkenyl groups as substituents in the cation moiety.
Examples of the aryl group excluding a hydrogen atom include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
Examples of the alkoxy group excluding a hydrogen atom include a monovalent group in which the alkyl group is bonded to an oxygen atom.
Examples of the alkenyloxy group excluding a hydrogen atom include a monovalent group in which the alkenyl group is bonded to an oxygen atom.
Examples of the aryloxy group excluding a hydrogen atom include a monovalent group in which the aryl group is bonded to an oxygen atom.
In these groups, the position of the hydrogen atom to be removed is not particularly limited.

In the divalent group, one or more carbon atoms may be substituted with a hetero atom such as an oxygen atom, a nitrogen atom, or a sulfur atom, and the substitution position at this time is not particularly limited.
In the divalent group, one or more hydrogen atoms may be substituted with a substituent, and examples of the substituent include halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. it can.

  Furthermore, a divalent group formed by bonding a plurality of the divalent groups can be exemplified as a preferable example. The combination of divalent groups to be bonded can be arbitrarily selected according to the purpose.

In the formula, X ² represents an ammonium group, a sulfonium group, a phosphonium group, and a group having a kind of cationic group selected from the group consisting of a group in which one or more hydrogen atoms thereof are substituted with an alkyl group (hereinafter, Abbreviated as a cationic group-containing group).
Examples of the cationic group-containing group include those composed only of the cationic group, and monovalent groups in which the cationic group is bonded to a divalent group. And as a bivalent group, the thing similar to the bivalent group in the said anionic group containing group can be illustrated.

Examples of the alkyl group for substituting a hydrogen atom in X ² include the same alkyl groups as substituents in the cation moiety.

In the formula, R ¹ represents an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an alkenyloxy group, an aryloxy group, a hydroxyl group or a halogen atom.
Here, the alkyl group, alkenyl group, aryl group, alkoxy group, alkenyloxy group, and aryloxy group are the same as those excluding the hydrogen atom in the divalent group of the anionic group-containing group.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In formula, m is an integer of 0-4.
when m is 2 to 4, a plurality of R ¹ may be the same or different from each other.
When m is 1 to 4, the bonding position of R ¹ is not particularly limited.

Particularly preferable examples of the amphoteric compound represented by the general formula (I) include a carboxylic acid group (carboxyl group) of 4- (aminoethyl) -cyclohexanecarboxylic acid (tranexamic acid) dissociated and an anion (—C ( ═O) —O ⁻ ) and the amino group is an ammonium group.

  A 1st compound may be used individually by 1 type, and may use 2 or more types together. When two or more kinds are used in combination, the combination and ratio may be appropriately selected according to the purpose.

(Second compound)
The second compound has an anion part or a cation part.
The anion part or cation part in the second compound is preferably one that stably forms ionic bonds at pH 3.5 to 8 with the cation part or anion part of the first compound, and pH 4.5 to 7 Those that stably form ionic bonds are more preferred.
For that purpose, the anion part or cation part in the second compound is also preferably present stably at pH 3.5 to 8, more preferably present stably at pH 4.5 to 7. The second compound tends to lose anionicity or cationicity when the pH is too high or too low.

  The anion part and cation part in the second compound are the same as the anion part and cation part in the first compound.

  The number of anion parts and cation parts in the second compound is not particularly limited, but the second compound preferably has only an anion part or only a cation part. When both an anion part and a cation part are included, it is necessary that at least these numbers are not the same. By doing in this way, the 2nd compound becomes anionic or cationic as the whole molecule | numerator, and formation of an ionic complex is attained.

  The second compound may or may not have a drug activity with respect to the living body. However, when the first compound has no drug activity, the second compound has drug activity. As what has a chemical | medical activity, if the said conditions are satisfy | filled, arbitrary things can be used, What can be used as active ingredients, such as a pharmaceutical, cosmetics, or a quasi-drug, can be illustrated.

  Preferred examples of the second compound include compounds represented by the following general formula (II).

Wherein, X ³ is a carboxylic acid group, a phosphoric acid group, polyphosphoric acid, a group having a sulfuric acid group, anionic group hydrogen ions from one group selected from the group consisting of nitric acid group, and a carbonate group has been removed Or a group having one kind of cationic group selected from the group consisting of an ammonium group, a sulfonium group, a phosphonium group, and a group in which one or more of these hydrogen atoms are substituted with an alkyl group; R ² is an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an alkenyloxy group, an aryloxy group, a hydroxyl group, or a halogen atom, and when n is 2 to 5, a plurality of R ² May be the same or different from each other. ]

In the formula, X ³ is the same as the anionic group-containing group or the cationic group-containing group in the first compound, and is the same as X ¹ or X ² .

In the formula, R ² is an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an alkenyloxy group, an aryloxy group, a hydroxyl group or a halogen atom, and is the same as R ¹ in the first compound.

In formula, n is an integer of 0-5.
When n is 2 to 5, a plurality of R ² may be the same or different from each other.
When n is 1 to 5, the bonding position of R ² is not particularly limited.

Particularly preferable compounds represented by the general formula (II) are those having an anion moiety, and the carboxylic acid group (carboxyl group) of 4-methoxysalicylic acid is dissociated to form an anion (—C (═O ) -O ^- that became) can be exemplified.

  A 2nd compound may be used individually by 1 type, and may use 2 or more types together. When two or more kinds are used in combination, the combination and ratio may be appropriately selected according to the purpose.

(Ionic complex)
The ionic complex is formed by an ionic bond between the anion part of the first compound and the cation part of the second compound, or by an ionic bond between the cation part of the first compound and the anion part of the second compound. Is done.
In the ionic complex, the first compound forming the ionic complex has an anion portion or a cation portion that is not involved in the ionic bond (hereinafter abbreviated as an unbound anion portion and an unbound cation portion, respectively). By remaining, it is not electrically neutral as a whole, but becomes anionic or cationic, and penetration into the skin becomes possible by applying a voltage. And by making it an ionic complex in this way, the lipophilicity is increased, for example, the number of carbons is higher than in the case of the first compound or the second compound alone, so that the skin permeability by iontophoresis is improved. To do.

  As described above, for the ionic complex, the combination of the first compound and the second compound is selected so that the unbound anion portion or unbound cation portion remains in the first compound. In the first compound, it is preferable to leave only one of the unbound anion portion and the unbound cation portion. If both the unbound anion portion and the unbound cation portion remain in the ionic complex, the penetration promoting effect into the skin may be reduced due to the interaction between the ionic complexes. Therefore, the larger the difference in the number of unbound anion parts and unbound cation parts in one molecule of the ionic complex, the better.

  For example, in order to leave the anion part in the first compound so as not to participate in the ionic bond, the second compound having an anion part equal to or more than the number of cation parts in the first compound is used. It is preferable. And in order to leave the cation part in a 1st compound so that it may not participate in an ionic bond, the 2nd compound which has the cation part more than the number of the anine part in a 1st compound is used. It is preferable.

  The number of anion portions or cation portions remaining in the ionic complex is not particularly limited, and may be appropriately adjusted according to the purpose.

  In general, an ionic complex having a larger number of carbon atoms is preferable in terms of higher lipophilicity, but if the molecular size is too large, the effect of promoting penetration into the skin is reduced. From such a viewpoint, the molecular weight of the ionic complex is preferably 1000 or less.

  The ratio of the number of molecules of the first compound and the second compound constituting the ionic complex may be appropriately adjusted according to the number of anion parts and cation parts in these compounds. For example, when using a first compound having one anion portion and one cation portion and a second compound having one anion portion or one cation portion, the ratio of the number of these molecules is 1: 1. Preferably there is.

  As the ionic complex, a complex of the first compound represented by the general formula (I) and the second compound represented by the general formula (II) is preferable. More preferred are composites with a ratio of 1: 1.

In the ionic complex, at least one of the first compound and the second compound may have a drug activity, but both may have a drug activity. For example, as the first compound and the second compound, those having the same kind of drug activity can be used together to obtain a greater effect in one iontophoresis, and those having different kinds of drug activity can be used in combination. Different effects can be obtained at the same time. For example, as the first compound, the carboxylic acid group (carboxyl group) of 4- (aminoethyl) -cyclohexanecarboxylic acid is dissociated to become an anion (—C (═O) —O ⁻ ), and the amino group is ammonium. As the second compound, a compound obtained by dissociating the carboxylic acid group (carboxyl group) of 4-methoxysalicylic acid into an anion (—C (═O) —O ⁻ ) was used. In these cases, although these compounds have different mechanisms of action, they all have a whitening effect, and as a result, a greater whitening effect can be expected.

The ionic complex can be formed by mixing the first compound and the second compound. At this time, it is preferable to mix the first compound and the second compound under conditions of pH at which they can each exist stably. In addition, a precursor that becomes the first compound at a predetermined pH (hereinafter abbreviated as first precursor) and a precursor that becomes the second compound (hereinafter abbreviated as second precursor) are mixed in advance. In addition, the mixture may be placed under pH conditions where the first compound and the second compound can exist stably. Here, the “first precursor” means, for example, a state in which, in the first compound, the anion portion and / or the cation portion lose their properties under the influence of pH and are electrically neutral. Refers to things. If it is an anion part, for example, it means that the pH is in an acidic range and is not dissociated (such as a carboxylic acid group), and if it is a cation part, for example, the pH is in an alkaline range, The hydrogen ion is in a removed state (amino group (—NH ₂ ) or the like). The same applies to the “second precursor”.
The first compound and the second compound are preferably mixed in an aqueous solution state.

The presence of the ionic complex can be confirmed by analysis means such as electrical conductivity measurement, high performance liquid chromatography (HPLC), and oil / water partition rate measurement.
When measuring electrical conductivity, for example, an electrode cell is immersed in an aqueous solution as a specimen, and a constant AC voltage is applied between the electrode plates. What is necessary is just to confirm that conductivity (conductivity) is a value (value peculiar to an ionic complex) which does not correspond to any of a 1st compound and a 2nd compound.
In the case of HPLC, an aqueous solution as a sample is introduced into a column, and the elution time of the main detection substance is a value that does not correspond to either the first compound or the second compound (elution time peculiar to an ionic complex). ).
In the case of measuring the oil / water distribution ratio, for example, the oil / water distribution ratio obtained from the concentration distribution of n-octanol and water transferred to the two layers does not correspond to either the first compound or the second compound. What is necessary is just to confirm that it is (a value peculiar to an ionic complex).

The drug of the present invention may contain other components in addition to the ionic complex as long as the effects of the present invention are not hindered.
The other components may or may not have drug activity. When it has a drug activity, it may be skin-permeable or skin-impermeable and may be used in combination. Specifically, the component which improves the skin state of the site | part to which iontophoresis is applied can be illustrated separately from the said ionic complex.
Examples of other components that do not have drug activity include components that stabilize the drug of the present invention, moisturizers, preservatives, fragrances, dyes, and various solvents. Examples of the component that stabilizes the drug include a pH adjuster, and examples of the solvent include various organic solvents such as water and alcohols.

  One of these other components may be used alone, or two or more thereof may be used in combination. When two or more kinds are used in combination, the combination and ratio may be appropriately selected according to the purpose.

<Devices for iontophoresis>
The iontophoresis device of the present invention (hereinafter abbreviated as “device”) includes a drug holding unit that holds the iontophoretic drug of the present invention, and a voltage applied to the iontophoretic drug in the drug holding unit. FIG. 1 is a schematic configuration diagram illustrating a device of the present invention.

The device 1 shown here includes a first sheet 11, a second sheet 12, a first electrode 13, a second electrode 14, a power supply 15 and a frame 16. These are all sheet-like, but are not limited to this in the present invention. However, a thin configuration is preferable in terms of improving the handleability of the device.
In the device 1, the power source 15 is laminated on a part of the frame 16, and the first electrode 13 and the second electrode 14 are partly laminated on the power source 15 and the other parts are laminated on the frame 16. ing. Further, the first sheet 11 is laminated on the first electrode 13, and the second sheet 12 is laminated on the second electrode 14. However, the 1st electrode 13 and the 2nd electrode 14, and the 1st sheet | seat 11 and the 2nd sheet | seat 12 are spaced apart so that it may not contact mutually. These may be arranged in contact with each other via an insulating material.
The power supply 15, the first electrode 13, the first sheet 11, the second electrode 14, and the second sheet 12 are electrically connected. The power source 15 may be laminated on the entire surface of the frame 16, but even if it is partially laminated as shown here, there is no problem in voltage application, the device can be simplified, and the cost can be reduced. Suitable for manufacturing.

  The 1st sheet | seat 11 and the 2nd sheet | seat 12 are the chemical | medical agent holding parts which hold | maintain a chemical | medical agent, At least one of these hold | maintains the chemical | medical agent of this invention. One of the first electrode 13 and the second electrode 14 is a cathode, and the other is an anode, and a voltage is applied to the drug in the first sheet 11 and the second sheet 12. That is, the 1st sheet | seat 11 and the 2nd sheet | seat 12 hold | maintain the chemical | medical agent which applies a voltage on the 1st electrode 13 and the 2nd electrode 14. FIG. The sheet on the cathode contains a drug containing an anionic ionic complex, and the sheet on the anode contains a drug containing a cationic ionic complex. The drug may be held on both the sheet on the cathode and the sheet on the anode, but may be held on only one of them.

  The first sheet 11 and the second sheet 12 are parts that are brought into contact with the skin, and are preferably arranged so as not to have a step difference in order to facilitate the mounting of the device 1. For example, the thickness of each of the first sheet 11, the second sheet 12, the first electrode 13, the second electrode 14, and the power supply 15 is not particularly limited. It is preferable that the total thickness of the electrodes 13 and the total thickness of the second sheet 12 and the second electrode 14 are substantially equal.

  Especially, when handleability etc. are considered, it is preferable that the thickness of the 1st sheet | seat 11 and the 2nd sheet | seat 12 is 0.1-10 mm, and it is more preferable that it is 0.1-5 mm. The thicknesses of the first electrode 13 and the second electrode 14 are preferably 0.1 to 5 mm, and more preferably 0.1 to 3 mm. And it is preferable that it is 0.1-5 mm, and, as for the thickness of the power supply 15, it is more preferable that it is 0.1-3 mm. The thickness of the frame 16 can be arbitrarily selected in consideration of these thicknesses and the strength of the device 1.

The first sheet 11 and the first electrode 13 have substantially the same shape, and the same applies to the second sheet 12 and the second electrode 14. However, the present invention is not limited to this, and these sheets and electrodes may have different shapes.
Here, the first sheet 11, the second sheet 12, the first electrode 13, and the second electrode 14 are all substantially semicircular, but the present invention is not limited to this. The shape can be set to an arbitrary shape in consideration of the mounting position of the device.
The shape of the frame 16 is substantially elliptical and has a surface area equal to or greater than the combined shape of the first electrode 13 and the second electrode 14, but the first electrode 13 and the second electrode What is necessary is just to select suitably according to the shape of 14 and if it is a shape which can maintain the structure of the device 1 stably, it will not specifically limit. However, it is preferable that the first electrode 13, the second electrode 14, and the power source 15 are not exposed.

  The material of the first electrode 13 and the second electrode 14 is not particularly limited as long as it can be used as a cathode or an anode. For example, in the case of a cathode, a preferable example is silver chloride (AgCl). If it is an anode, as a preferable thing, silver (Ag) and carbon (C) can be illustrated.

The base material excluding the drug of the first sheet 11 and the second sheet 12 is not particularly limited as long as it can hold the drug and does not hinder the movement of the ionic complex, but preferably has conductivity. Those having adhesiveness to the skin are preferred. Specifically, a conductive gel is preferable, and a gel obtained by mixing an aqueous solution containing a conductor and a thickener is more preferable. By doing in this way, the shape as a sheet | seat can be maintained stably, the skin permeability of an ionic complex further improves, and the adhesiveness to the skin of a sheet | seat also becomes favorable. Examples of the conductor include inorganic salts such as potassium chloride and sodium chloride.
Moreover, as an electroconductive base material, carbon fiber can be illustrated as a preferable thing other than electroconductive gel.
Furthermore, since the electrical conductivity can be maintained even in an aqueous solution containing a drug, a woven fabric, a non-working fabric or the like can be used as a base material.
Furthermore, you may use what laminated | stacked the several base material.

When water is contained in the first sheet 11 and the second sheet 12, it is preferable to further contain a humectant such as glycerin.
The first sheet 11 and the second sheet 12 are parts to be brought into contact with the skin. For example, when the substrate is not a gel, at least a part of the exposed surface, preferably the peripheral part is coated with an adhesive. For example, it is preferable to have skin adhesiveness.

  The 1st sheet | seat 11 and the 2nd sheet | seat 12 are producible by making the said base material hold | maintain the chemical | medical agent of this invention. For example, a liquid containing a drug may be applied to the base material, the base material may be immersed in a liquid containing the drug, or the liquid containing the drug may be solidified. The liquid is preferably an aqueous solution. Moreover, the application method is not particularly limited, and any method can be applied. Examples thereof include application by spraying, application by a push nozzle, application by an applicator such as a brush.

  The material of the frame 16 is not particularly limited as long as the structure of the device 1 can be stably maintained, but a material having higher insulation is preferable. Specific examples include resins such as polyester and polyethylene; woven fabrics; unemployed fabrics, and a laminate of a plurality of these materials may be used.

The power source 15 is not particularly limited as long as it has a performance capable of generating a current density of about 0.1 to 1 mA / cm ² , for example. Among them, a print battery can be exemplified as a preferable one.
In addition, here, the power source is shown to be integrated and integrated in the device. However, the power source is not limited to this. For example, the power source may be connected to the electrode through an electric wire and separately provided outside the device.

  The first sheet 11, the second sheet 12, the first electrode 13, the second electrode 14, the power supply 15, and the frame 16 are fixed using an adhesive or a jig at the time of lamination. Is preferred.

  Here, as the device, the electrode and the medicine holding part are in the form of a sheet, but the present invention is not limited to this. For example, it is also possible to use a configuration in which the electrode and the drug holding part are not in a sheet form, but a non-sheet electrode is connected to a cell filled with a liquid drug.

FIG. 2 is a schematic configuration diagram showing another example of the device of the present invention. The device 2 shown here is different from the device 1 in the arrangement of the power source and the electrodes.
The device 2 includes a first sheet 21, a second sheet 22, a first electrode 23, a second electrode 24, a power supply 25 and a frame 26. Moreover, the power supply 25 and the 1st electrode 23, and the conductor sheets 27 and 27 which electrically connect the power supply 25 and the 2nd electrode 24, respectively are provided. These are all sheet-like. One of the first electrode 23 and the second electrode 24 is a cathode, and the other is an anode.
In the device 2, an integrated power source 25, a first electrode 23, a second electrode 24, and a conductor sheet 27 are laminated on a frame 26. Then, the first sheet 21 is laminated on the frame 26 so as to cover the entire exposed surface of the first electrode 23, and the second sheet 22 is covered so as to cover the entire exposed surface of the second electrode 24. Are stacked on the frame 26. The conductor sheet 27 is entirely covered by the first sheet 21 or the second sheet 22. And the 1st sheet | seat 21 and the 2nd sheet | seat 22 are arrange | positioned mutually spaced apart.
The power supply 25, the first electrode 23, the first sheet 21, the second electrode 24, and the second sheet 22 are electrically connected.

  The 1st sheet | seat 21 and the 2nd sheet | seat 22 are the chemical | medical agent holding parts which hold | maintain a chemical | medical agent, What is necessary is just to make it hold | maintain the chemical | medical agent of this invention at least one of these.

The materials and thicknesses of the first sheet 21, the second sheet 22, the first electrode 23, the second electrode 24, the power source 25, and the frame 26 are the same as those in the device 1 shown in FIG. The power source 25 only needs to have the same performance as the power source 15 of the device 1.
The material of the conductor sheet 27 may be a known material, and the thickness can be arbitrarily adjusted. The thickness may be the same as that of the power source 25 or may be different.

The first sheet 21 and the second sheet 22 are both substantially semicircular, and the first electrode 23 and the second electrode 24 are both rectangular. However, the present invention is not limited to this and is different. The shape may be sufficient, and it is good also as a shape which changes with sheets or electrodes.
The shape of the frame 26 is substantially elliptical, and has a surface area that is equal to or greater than the combined shape of the first sheet 21 and the second sheet 22.

  Each element constituting the device 2 is preferably fixed using an adhesive or a jig at the time of lamination.

Hereinafter, the present invention will be described in more detail with reference to specific examples. However, the present invention is not limited to the following examples.
[Example 1]

Using the test apparatus shown in FIG. 3, the skin permeability of the ionic complex to the test piece was confirmed. Here, the test apparatus will be described.
(1) Test apparatus FIG. 3 is a schematic configuration diagram showing the test apparatus.
The test apparatus 3 shown here includes a power supply 31, an electric wire 32, a first cell 33, and a second cell 34. The first cell 33 and the second cell 34 are electrically connected to the power source 31 by electric wires 32, respectively.
A first filling portion 33a for filling a desired liquid sample is provided inside the first cell 33, and the first filling portion 33a is surrounded by a first circulation layer 33b for circulating water. It has become. The second cell 34 is provided with a second filling part 34a for filling a desired liquid sample, and the second filling part 34a is surrounded by a second circulating layer for circulating water. 34b. The first filling part 33a and the second filling part 34a are drug holding parts, and a liquid sample can be taken in and out through the first port 332 and the second port 342, respectively. And the 1st electrode 33c protrudes from the outer side of the 1st cell 33 to the inside of the 1st filling part 33a, and similarly, from the outside of the 2nd cell 34 to the inside of the 2nd filling part 34a, the 2nd Electrodes 34c are provided so as to be connected to the electric wires 32 on the outside of the cell. One of the first electrode 33c and the second electrode 34c is a cathode, and the other is an anode, and a voltage is applied to the drug in the liquid sample filled in the first filling part 33a and the second filling part 34a. It can be applied.
The end portion 331 where the first filling portion 33a of the first cell 33 is opened and the end portion 341 where the second filling portion 34a of the second cell 34 is opened are both portions that sandwich the test piece. .

In the test apparatus 3, when a voltage is applied, if the anionic ionic complex is contained in the liquid sample in the first filling portion 33 a, when the complex permeates the test piece, the second filling portion Move into 34a. If a cationic ionic complex is contained in the liquid sample in the second filling portion 34a, the complex moves into the first filling portion 33a when passing through the test piece.
Here, the first electrode 33c is a cathode made of silver chloride (AgCl), and the second electrode 34c is an anode made of silver (Ag). Moreover, although the material of the 1st cell 33 and the 2nd cell 34 has insulation, such as various resin and glass normally, it was set as glass here.

(2) Preparation of Ionic Complex Aqueous Solution First, an aqueous carbonate solution having a pH of 8.8 is prepared, and this is used to produce trans-4- (aminoethyl) -cyclohexanecarboxylic acid (tranexamic acid, having a concentration of 100 μmol / mL. Hereinafter, an aqueous solution (abbreviated as TXA) and an aqueous 4-methoxysalicylic acid (hereinafter abbreviated as 4MS) solution having a concentration of 50 μmol / mL were prepared. And the said aqueous solution was mixed so that the density | concentration of TXA might be set to 50 micromol / mL and the density | concentration of 4MS to 25 micromol / mL, and aqueous solution containing the ionic complex whose pH is about 7.4 was prepared. Here, the concentration of TXA is set to be twice the concentration of 4MS so that TXA having low solubility of 4MS and low signal intensity at the time of detection can be detected with high accuracy.

(3) Preparation of test piece Anesthetized with pentobarbital, the abdominal skin of the rat fixed on the back surface was removed, and the fat was peeled off. This was hydrated with a phosphate buffer solution of pH 7.4 for 30 minutes to obtain a test piece.

(4) In vitro skin permeation experiment The prepared ionic complex aqueous solution is filled in the first filling portion 33a of the first cell, and the pH of the second filling portion 34a of the second cell 34 is set to 7 with a phosphate buffer. 4 was filled with the aqueous solution adjusted to 4. And the 1st cell 33 and the 2nd cell 34 are arrange | positioned so that the said edge part 331 and the said edge part 341 may oppose, a stratum corneum side is faced to the said edge part 331, and a test piece is said edge part 331. And 341, and fixed in that state. Next, a constant current is applied at a current density of 0.3 mA / cm ² , a voltage is applied, and sampling is performed from the second filling part 34a (the dermis side of the test piece) on the way to measure the concentrations of TXA and 4MS in the sample. The cumulative permeation amount for these test pieces was calculated. Concentration measurement was performed by HPLC under the following conditions. The measurement results are shown in FIG. 4A shows the cumulative transmission amount of TXA, and FIG. 4B shows the cumulative transmission amount of 4MS.

<HPLC conditions>
Column: CAPCELL PAK SCX UG80 (4.6 mm id x 250 mm)
Mobile phase: (0.1 mol / L KH ₂ PO ₄ ) / (H ₂ O / CH ₃ CN) = 80/20
Flow rate: 1.0 mL / min Detection wavelength: TXA-210 nm, 4MS-250 nm

[Comparative Example 1]
Except that no voltage was applied, the concentrations of TXA and 4MS in the sample were measured in the same manner as in Example 1. The measurement results are shown in FIG.

  As is clear from FIG. 4, in Example 1, the cumulative transmission amounts of TXA and 4MS increased with the passage of time. By applying a voltage, the anionic ionic complex in the first filling portion 33a is transferred from the stratum corneum side to the dermis side from the first cell 33 provided with the first electrode (cathode) 33c. In Example 1, the ionic complex was continuously and efficiently tested over time as it was transferred to the second cell 34 provided with the second electrode (anode) 34c. It shows that the piece has been transmitted. On the other hand, in Comparative Example 1, the cumulative permeation amount of the ionic complex did not increase so much. Thus, it was confirmed that Example 1 was clearly superior to Comparative Example 1 in skin permeability of the ionic complex.

  The present invention can be used in the medical field, the beauty field, and the like using pharmaceuticals, cosmetics, quasi drugs, and the like.

1, 2 ... Device for iontophoresis, 11, 21 ... First sheet, 12, 22 ... Second sheet, 13, 23 ... First electrode, 14, 24 ...・ Second electrode

Claims (7)

  It consists of a first compound having an anion part and a cation part and a second compound having an anion part or a cation part, and at least one of the first compound and the second compound has drug activity, and as a whole An agent for iontophoresis comprising an ionic complex that is anionic or cationic as an active ingredient.   The anion moiety of the first compound and / or the second compound is a kind of acidic group selected from the group consisting of a carboxylic acid group, a phosphoric acid group, a polyphosphoric acid group, a sulfuric acid group, a nitric acid group, and a carbonic acid group. The agent for iontophoresis according to claim 1, which is an anionic group generated by dissociation.   The cation moiety of the first compound and / or the second compound is selected from the group consisting of an ammonium group, a sulfonium group, a phosphonium group, and a group in which one or more hydrogen atoms thereof are substituted with an alkyl group. The iontophoretic agent according to claim 1, wherein the iontophoretic agent is a kind of cationic group. The first compound is represented by the following general formula (I), and the second compound is represented by the following general formula (II). Drug for iontophoresis.

[Wherein, X ¹ is a group having an anionic group in which a hydrogen ion is removed from a group selected from the group consisting of a carboxylic acid group, a phosphoric acid group, a polyphosphoric acid group, a sulfuric acid group, a nitric acid group and a carbonic acid group. X ² is a group having a kind of cationic group selected from the group consisting of an ammonium group, a sulfonium group and a phosphonium group, and a group in which one or more hydrogen atoms thereof are substituted with an alkyl group; m is an integer of 0 to 4; R ¹ is an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an alkenyloxy group, an aryloxy group, a hydroxyl group or a halogen atom, and when m is 2 to 4 a plurality of R ¹ may be the same or different from each other. ]

[Wherein X ³ is a group having an anionic group obtained by removing a hydrogen ion from a group selected from the group consisting of a carboxylic acid group, a phosphoric acid group, a polyphosphoric acid group, a sulfuric acid group, a nitric acid group and a carbonic acid group. Or a group having one kind of cationic group selected from the group consisting of an ammonium group, a sulfonium group, a phosphonium group, and a group in which one or more of these hydrogen atoms are substituted with an alkyl group; R ² is an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an alkenyloxy group, an aryloxy group, a hydroxyl group, or a halogen atom, and when n is 2 to 5, a plurality of R ² May be the same or different from each other. ]   The ionic complex is a complex of 1: 1 (molecular number ratio) between the first compound and the second compound, according to any one of claims 1 to 4. The agent for iontophoresis as described.   A drug holding unit that holds the iontophoretic drug according to claim 1, and an electrode that applies a voltage to the iontophoretic drug in the drug holding unit. Iontophoresis device.   The device for iontophoresis according to claim 6, wherein the drug holding part and the electrode are in a sheet form.

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