WO1996011034A2

WO1996011034A2 - Method of administrating water soluble steroids with iontophoresis

Info

Publication number: WO1996011034A2
Application number: PCT/JP1995/001652
Authority: WO
Inventors: Kenji Mori; Takahiro Hirata; Kazuya Katagai
Original assignee: Hisamitsu Pharmaceutical Co., Inc.
Priority date: 1994-10-07
Filing date: 1995-08-21
Publication date: 1996-04-18
Also published as: AU3231395A; JP3119488B2

Description

Description Method for administering iontophoresis of water-soluble steroids

The present invention relates to a method for administering iontophoresis of a water-soluble steroid. More specifically, a water-soluble steroid exhibiting excellent pharmacological effects in the treatment of rheumatoid arthritis, osteoarthritis, and the like can be obtained by using a pulse depolarized iontophoresis power supply and a conductor having a non-polarizable electrode and a non-polarizable electrode. The present invention relates to a method for administering iontophoresis of a water-soluble steroid, which is transdermally administered to a site of trouble such as a joint using a lead. Background art

Conventionally, the absorption of a drug from the skin of a living body is more effective than oral administration, which is known as a general drug administration method, in that it maintains the blood concentration, reduces the side effects of the drug on the gastrointestinal tract, and further administers the drug. It is known to have a number of advantages such as simplicity. However, due to the low permeability of the skin of the living body, there are only a limited number of drugs capable of delivering an effective dose sufficient for a therapeutic effect in the living body. However, as research on percutaneous absorption preparations has progressed, preparations using chemical absorption enhancement methods have been put on the market.On the other hand, physical absorption enhancement methods using phonophoresis and iontophoresis have been developed. Percutaneous absorption of the drug is expected. Above all, iontophoresis is an administration method in which an ionized drug is absorbed from the skin by an electric current, and the above-mentioned advantages can be expected. USP No. 4 is an alternative to painful injections at the time of administration. No. 2,087,878, USP. No. 4,141,359, and USP. No. 3,991,755. However, these are all DC-type current-carrying methods, so safety and practicability such as electrical stimulation of the skin at the time of administration (when power is applied) and charging (or polarization potential) of the skin occur. Problem of lack of Had. Pulse-type iontophoresis devices have also been developed in addition to the DC-type iontophoresis devices described above. However, similar to the DC-type devices, electrical stimulus to skin frost and the like poses a problem. I have.

By the way, water-soluble steroids having bioactivity are used as injections in various administration routes. This water-soluble steroid is obtained by esterifying fat-soluble steroids such as dexamethasone, betamethasone, and prednisolone with phosphoric acid or acetic acid to improve water solubility. In Japan, this water-soluble steroid is administered intra-articularly in the treatment of rheumatoid arthritis and osteoarthritis. However, when administering this water-soluble steroid intra-articularly, it is necessary to perform surface anesthesia such as lidocaine, etc. It may cause infectious disease, and is not a simple, safe and highly pharmaceutical useful and administration method.

Thus, James M. Glass et al., International Journal of Dermatology 19, 1990, pp. 519-525 (Int. J. Dermat 01. 1 9. (1 990) 51 9-525) also reported that TJ Pete 1 enz, et al., Published the Journal of Controls, Volume 20, Volume 19, (1992), pp. 55-66. (Journal of Controlled Release 20. (1992) 55-66), transdermal administration of dexamethasone sodium phosphate, a kind of water-soluble steroid, using direct current iontophoresis. Has been announced.

On the other hand, Japanese Patent Publication No. 2-45461 discloses a device for pulse depolarization type iontophoresis with little electrical stimulation to the skin. Using this technology, transdermal absorption of water-soluble steroids is performed. There has been no study on administration, and no disclosure or suggestion that a non-polarizable electrode such as silver / silver chloride is particularly effective for the electrode layer. However, these conventional configurations have the following problems. That is,

a, When DC-type iontophoresis was applied to the administration of a water-soluble steroid, when the applied current was increased to about 1 mAZcm ² or more, electrical stimulation occurred. For this reason, Terenz et al. Co-administered a local anesthetic, lidofin, to reduce this electrical stimulation and pain. However, since lidocaine was co-administered at each administration, it was not practically a simple and safe administration method. A patent publication published in the past suggests that dexamethasone sodium phosphate may be administered transdermally by iontophoresis. Similar to the above, electrical stimuli and electrification of the skin may be caused when power is applied, resulting in lack of safety. In addition, due to the aforementioned electrification of the skin, rheumatoid arthritis Pharmaceutical components could not be delivered sufficiently to the synovium, which is the site of inflammation such as osteoarthritis, and deep joints, such as the joint capsule consisting of the synovium and fibrous membrane, and were not effective for drug treatment.

b.Water-soluble steroids are administered intra-articularly as injections for the treatment of rheumatoid arthritis, osteoarthritis, etc. Must be administered at an interval, and a hospital visit is required. Therefore, it is not always a simple and highly useful administration method for seeking a therapeutic effect.

The present invention solves the above-mentioned conventional problems, and provides a water-soluble physiologically active steroid that is transdermally administered with high absorbability without electrical stimulus to the skin during administration. The present invention provides a method for administering iontophoresis of a water-soluble steroid having excellent safety and pharmacological effects, which is highly safe and has pharmacological effects. The purpose is to: Disclosure of the invention In order to achieve this object, a method for iontophoresis administration of a water-soluble steroid according to the present invention has the following configuration. That is,

A method for administering iontophoresis of a water-soluble steroid according to claim 1, comprising: an iontophoresis power supply device; and a method for administering iontophoresis of a water-soluble steroid using an inductor and an inductor. A pulse depolarization type iontophoresis power supply device is used as the iontophoresis power supply device, and a non-polarizing electrode is used for the electrode layers of the inductor and the inductor. I have.

The method for administering iontophoresis of a water-soluble steroid according to claim 2 is the method according to claim 1, wherein the pulse depolarization type iontophoresis power supply is configured to supply a current between the inductor and the non-inductor. A power supply for supplying the Z voltage, a pulse oscillator for pulse-modulating the current Z voltage from the power supply, and a switch for depolarizing the polarization potential between the conductor and the unrelated conductor when the pulse voltage from the pulse oscillator is stopped. It has a configuration with and.

The method for administering iontophoresis of a water-soluble steroid according to claim 3 is the method according to claim 1, wherein the non-polarizable electrode is made of silver, silver chloride, or the like. It has a configuration.

The method for administering iontophoresis of a water-soluble steroid according to claim 4 is the method according to any one of claims 1 to 3, wherein the inductor is a non-polarizable electrode and a drug storage layer. And a configuration in which an ion-exchange membrane is provided between them.

5. The method for administering iontophoresis of a water-soluble steroid according to claim 5, wherein the water-soluble steroid is dexamethasone sodium phosphate, dexamethasone acetate, It has a composition consisting of dexamethasone metasulfobenzoate sodium, hydrocortisone sodium succinate, sodium hydrocortisone phosphate, predniblone sodium succinate, mesonadium sodium phosphate and the like, or a mixture thereof.

Here, the pulse depolarization type iontophoresis power supply includes A power supply unit that supplies a current z voltage between the electrode layers of the indifferent inductor, a pulse oscillator that pulse-modulates the current Z voltage output from the power supply unit, and a pulse voltage output from the pulse oscillator that is related to the rest of the pulse voltage And a switch portion for depolarizing the polarization potential between the element and the unrelated element are preferably used.

The pause of the pulse voltage output from the pulse oscillator refers to the period excluding the pulse width in the pulse interval (or pulse period).

A pulse depolarization type iontophoresis power supply is formed by integrating a conductor and a conductor, or separating a conductor and a conductor to separate the conductor and the conductor. The child may be connected by a connection cord or the like.

Current value of the pulse depolarized type iontophoresis power supply, usually, 0. 0 0 1 ~1 O mA / cm 2, is preferably 0. 0 l~lm AZcm ^2, the output currents and skin Although it depends on the contact area with the conductor and the non-conductor, it is approximately 0.5 to 18 V, preferably 3 to 9 V. Therefore, if necessary, a plurality of light-weight batteries, which will be described later, as a power supply unit may be provided or stacked, or a combination of chipped amplification elements may be used. Further, if necessary, a constant current element, a light emitting element for indicating conduction, or the like may be added.

The pulse depolarization type iontophoresis power supply is used when the condition of the living body changes according to the dose of the water-soluble steroid or when the dose of the water-soluble steroid needs to be controlled according to the condition of the living body. Alternatively, a feed knock mechanism for automatically controlling the output current while monitoring the state of the living body may be provided.

The power supply unit may be separated from the iontophoresis device and connected with a connection cord or the like, or may be integrated with the device.

In particular, when the pulse depolarization type iontophoresis power supply is used in combination with the inductor and the non-inductor, the manganese dry battery, the alkaline dry battery, the lithium battery, the tunicad battery, and the silver oxide are used as the power supply unit. Batteries, mercury batteries, air batteries, alkaline manganese batteries, plastic batteries, etc. A rechargeable battery, a sheet battery, or the like is preferably used.

The pulse oscillator performs pulse modulation of the current and voltage from the power supply unit. The pulse generator may appropriately use a pulse voltage, such as a periodic pulse or an aperiodic pulse, depending on the dose of the water-soluble steroid, the state of the living body, and the like.

Further, the pulse oscillator may be provided with an output limiting circuit for limiting a large peak current flowing through the human body when the pulse voltage rises and falls.

The switch removes the polarization potential (or polarization voltage) accumulated between the conductor and the non-conductor in the pause of the pulse voltage, that is, the skin or the like of the living body. For this purpose, a transistor switch such as an FET switch is preferably used as the switch unit.

The guide wire includes a drug storage layer to which a water-soluble steroid is adhered, dispersed, or impregnated, an electrode layer electrically connected to a non-guide wire on the opposite side via skin or the like, A backing layer for supporting the electrode layer; and the non-inductive element includes a conductive layer, an electrode layer electrically connected to the counter electrode-side inductor, and a conductive layer or an electrode layer. And a support layer for supporting.

The size of the backing layer and the like and the area of the drug storage layer and the like are determined so that an effective blood concentration set in advance when applied to a patient can be obtained for an effective time. As the backing layer and the support layer, a material that is impermeable to at least a water-soluble steroid is used. This is to prevent leakage of the water-soluble steroid ゃ additives and the like. Examples of the material include a woven fabric, a nonwoven fabric, a paper, a synthetic paper, or a composite thereof formed of a polymer film or sheet, or a film or fiber made of a natural fiber or a float, a synthetic resin, or a composite thereof. Laminated synthetic resin films are used. Specific examples include polyethylene, polypropylene, polyethylene terephthalate, polyvinyl chloride, polyvinylidene chloride, plasticized vinyl acetate copolymer, plasticized vinyl acetate-vinyl chloride copolymer, and polyamide. Films or sheets made of synthetic resin such as cellulose, cellophane, cellulose acetate, ethyl cellulose and the like are used alone or in a multilayer structure. Further, as these synthetic resin films / sheets, it is possible to use a laminate of aluminum foil, aluminum vapor deposition or ceramic coating, or a laminate of these materials. The backing layer and the support layer may form a depression for holding the preparation if necessary. The backing layer—the shape of the support layer and the shape of the depression are not particularly limited, but are generally preferably formed in a circular, elliptical, or substantially rectangular shape.

As the electrode layer, a non-polarizable material such as silver / silver chloride is preferable. An electrode protective layer made of a conductive material may be partially or entirely laminated between the electrode layer and the drug storage layer in order to prevent the influence of the water-soluble steroid depending on the type of the electrode layer. . The durability of the electrode layer can be improved.

The electrode layers are preferably laminated so as not to come into direct contact with each other. This is because electrical stimulation can be further reduced.

The formation of the electrode layer on the backing layer or the support layer may be performed by mixing the material with a printing ink for electric wiring or the like, coating and drying the material, or spreading and fixing the material, or depositing the material. A known method such as a method of forming the electrode layer by photoetching is used.

As the ion exchange membrane, a cation exchange membrane is used when the drug ion is an anion, and an anion exchange membrane is used when the drug ion is a cation. Preferred ion-exchange membranes include Neocebu-Yu CMS (manufactured by Tokuyama Soda Co., Ltd.) for the cation-exchange membrane, and Neosep-Yu ACM (Made by Tokuyama Soda Co., Ltd.) for the anion-exchange membrane.

By using the ion exchange membrane, it is possible to prevent the permeation of the ion from the electrode material released from the electrode layer at the time of energization, and to remarkably improve the percutaneous absorption of the water-soluble steroid.

The conductive layer is made of natural wood such as karaya gum, tragacanth gum, and xanthan gum. Fatty polysaccharides or polyvinyl alcohol and its partial genated products, polyvinyl formal, polyvinyl methyl ether and its copolymers, polyvinyl resins such as polyvinyl pyridine, polyvinyl methacrylate, polyacrylic acid and its sodium salt, polyacrylamide and its parts Various hydrophilic or natural resins, such as hydrolysates, partially saponified polyacrylates, and acrylic resins such as poly (acrylic acid-acrylamide), can be prepared by adding water, ethyl alcohol, ethylene diol, Flexible plasticized with polyhydric alcohols such as glycerin or a mixture thereof and used as a flexible film or sheet gel having self-retaining property and skin adhesiveness o

The conductive layer is in the form of a flexible film or sheet and can adhere to the skin, so it has low skin contact resistance and is effective not only for percutaneous penetration of water-soluble steroids, but also for adhesive tapes and other materials. It also has an advantage in use that it can be adhered and supported without the need for a means for bonding the skin. In particular, when a natural resin polysaccharide such as calayagum is used as the base material of the conductive layer, pH buffering property or skin protection property due to its natural polymer acid structure, remarkably high water retention, moderate skin adhesion, etc. Thus, more suitable suitability for skin is obtained. Also, a required amount (usually about 1 to 15%) of an electrolyte such as sodium chloride, sodium carbonate, or potassium citrate may be added to impart sufficient conductivity. In addition, the composition of these conductive layers is mainly determined by electrochemical considerations such as the type and required dosage of the water-soluble steroid used, the application time of application, the output of the battery used, and the skin contact area. The ion mobility or conductivity is appropriately determined so as to be a required value.

The material for forming the drug storage layer is a polymer film or sheet to which water-soluble steroids can be attached, dispersed or impregnated.L is made of natural fibers, felts, synthetic resin films and fibers, etc. The formed woven or nonwoven fabric is used. As these materials, widely known water-soluble polymer materials, hydrophilic synthetic polymer materials, hydrophobic polymer materials, natural materials, and composites thereof are used. Films made of synthetic resins such as polyethylene, polypropylene, polyethylene terephthalate, polyvinyl chloride, polyvinylidene chloride, plasticized vinyl acetate copolymer, plasticized vinyl acetate-vinyl chloride copolymer, polyamide, cellophane, cellulose acetate, and ethyl cellulose.ゃ A sheet or an ion exchange resin membrane or the like is used alone or in a multilayer structure. In addition, cotton, hemp, silk, rayon, polyvinyl alcohol, gelatin, agar, starch, xanthan gum, gum arabic, tragacanth gum, karaya gum, echo gum, oral cast bean gum, sodium alginate, pectin, methyl cellulose, ethyl cellulose, propyl Cellulose, ethyl methylcellulose, hydroxyethylcellulose, hydroxycellulose, carboxymethylcellulose, cellulose acetate phthalate, polymethylvinylether, polyvinylpyrrolidone, carboxyvinyl polymer, casein, albumin, chitin, chitosan, sodium polyacrylate and The crosslinked product and, if necessary, a conventionally known plasticizer may be used by mixing a softener.

In the drug storage layer, paper materials such as water-absorbing paper, cloth materials such as gauze, fiber materials such as absorbent cotton, synthetic resin continuous foam such as sponge, water-absorbing resin or porous material, etc. It is also possible to enclose the member.

Examples of the water-soluble steroids include dexamethasone sodium phosphate, dexamethasone acetate, dexamethasone sodium metasulfobenzoate, hydrocortisone sodium succinate, sodium hydrocortisone phosphate, sodium blednibron succinate, and sodium metazone sodium phosphate. It can be used but is not limited to these.

As the shape of the iontophoresis device containing the water-soluble steroid, a reservoir type, a matrix type, or the like can be used.

When using an unstable water-soluble steroid in an aqueous solution, apply only the water-soluble steroid to the preparation in a dry state in advance, and add the aqueous solution immediately before use, or add a water-soluble steroid to the drug storage layer. Water-soluble steroid and water in a dry state without mixing steroid The solution may be stored separately in separate containers, etc., and the water-soluble steroid and dried solution may be mixed immediately before use, and the dissolved water-soluble steroid solution may be added to the drug storage layer. For this purpose, an aqueous solution storage layer for storing an aqueous solution may be provided adjacent to a backing layer or a support layer, an electrode layer, a drug storage layer, or a conductive layer of a reservoir-type preparation or a matrix-type preparation. Examples of the aqueous solution storage layer include paper materials such as water-absorbing paper, cloth materials such as gauze, fiber materials such as a degreased surface, synthetic resin continuous foam such as sponge, water-absorbing resin or

And a water-absorbing member for impregnating a chemical such as a porous material, a nonwoven fabric, and the like.

The amount of water-soluble steroids contained or deposited in the drug reservoir is determined so that when applied to a patient, a preset, effective blood concentration is obtained for an effective time.o

If necessary, it is also possible to add an electrolyte such as sodium chloride, sodium carbonate, potassium citrate or the like in order to impart sufficient conductivity.

In addition to water-soluble steroids, additives include solvents such as water and ethanol as required, emulsifiers such as phosphazidonic acid derivatives, lecithin, cephaline, and polyalkylene glycol, methyl laurate, methyl carboxylate, aison, and oleic acid. , Pyrothiodecane 1 — Clotamiton, an absorption enhancer such as menthol, limonene, and heart oil

, Ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, dimethylperylamide, isosorbitol, olive oil, castor oil, squalene , Lanolin and other solubilizers or solubilizers, as well as thickeners such as cellulose acetate, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and stearyl alcohol, glycerin monooleic acid, glycerin mono. Irritation reducing agents such as laurate, sorbitan monolaurate, karaya gum, tragacanth gum, polyvinyl alcohol and That portion Gen product, dextran, albumin, polyamino acids, poly Binirupirori pyrrolidone, It is also possible to add hydrophilic and water-absorbing polymers such as poly (meth) acrylate, polyacrylic acid and its sodium salt, polyacrylamide and its partial hydrolyzate, and plasticizers such as glycerin.

These additives are determined for each type of water-soluble steroid to the extent that the type and concentration appear to be optimal, as long as they are therapeutically beneficial and pharmacologically acceptable.

The drug storage layer or the conductive layer may have an adhesive layer on its surface. As the adhesive layer, a pressure-sensitive adhesive or a gel adhesive is suitably used. The pressure-sensitive adhesive or gel adhesive can hold a device for iontophoresis or a conductor or an inducible conductor on the patient's skin, and is not limited as long as it is perceptually acceptable. For example, acrylic adhesives such as poly (2-ethylhexyl acrylate), methacrylic adhesives such as polybutyl methacrylate, and silicone adhesives such as polydimethyl siloxane. , Polyisoprene rubber, polybutylene rubber, polybutadiene rubber, rubber-based adhesives such as natural rubber, polyvinyl alcohol, gelatin, polyvinylpyrrolidone, carboxyvinyl polymer, sodium polyacrylate, and cross-linked products thereof And sodium alginate and its crosslinked products, cellulose derivatives and the like.

The adhesive layer may be added with a required amount (usually about 15%) of an electrolyte such as sodium chloride, sodium carbonate, potassium citrate or the like in order to impart sufficient conductivity thereto. The adhesive layer may be provided with a hole for allowing the passage of ionized water-soluble steroids from the drug storage layer, if necessary. The shape of the pressure-sensitive adhesive layer and the holes formed in the pressure-sensitive adhesive layer is not particularly limited, but is generally formed in a circular shape, an elliptical shape, a substantially rectangular shape, or the like. desirable.

With this configuration, the pulsed depolarization type iontophoresis power supply and the inductor or non-inductor having a non-polarizing electrode are used for the method of administering the water-soluble steroid, so that the water-soluble steroid can be removed from the skin. Into the body, especially rheumatoid arthritis and osteoarthritis It is possible to highly absorb a therapeutically effective amount of a drug sufficient for a therapeutic effect up to the deep part of the joint where an inflammation site such as a symptom or a joint capsule is present. In addition, it can suppress electrical stimulation and electrification on the skin during administration. In addition, when an ion exchange membrane is provided, the adverse effect of ions of the electrode material can be prevented, and the transport number of the water-soluble steroid can be significantly increased. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a block circuit diagram showing a device for pulse depolarization type iontophoresis used in a method for administering iontophoresis of a water-soluble steroid in a first embodiment of the present invention.

FIG. 2 (a) is a perspective view showing the guide element.

FIG. 2 (b) is a perspective view showing an unrelated inductor.

FIG. 3 is an exploded perspective view showing a conductor for an electrical stimulation test.

FIG. 4 is an exploded perspective view showing an unrelated inductor for an electrical stimulation test.

FIG. 5 is a schematic view showing a mounted state of a conductor and an open conductor for an electrical stimulation test.

FIG. 6 is a characteristic diagram showing a current value at which an electric stimulus is sensed.

FIG. 7 (a) is an exploded perspective view showing a 2-chamber-diffusion cell for a permeation experiment.

FIG. 7 (b) is a sectional view showing a 2-chamber-diffusion cell for a permeation experiment. FIG. 8 is a characteristic diagram showing the accumulated permeation amount of the steroid after 6 hours. Fig. 9 is a characteristic diagram showing the concentration of dexamethasone sodium phosphate in the joint capsule. Fig. 10 is a characteristic diagram showing the increase and decrease of the joint circumference based on the joint circumference on the 11th day. FIG. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, an embodiment of the present invention will be described with reference to the drawings.

(Example 1)

FIG. 1 is a block diagram showing a block diagram of a device for pulse depolarization iontophoresis used in a method for administering iontophoresis of a water-soluble steroid according to a first embodiment of the present invention.

1 is a device for pulse depolarization type iontophoresis, 2 is a conductor containing water-soluble steroid, 3 is a non-inductor, 4 is a power supply unit 5, a pulse oscillator 6, and a switch unit 7 described later. Pulse depolarization type iontophoresis power supply, 5 is a power supply such as a dry battery for applying a current Z voltage between each electrode layer of the inductor 2 and the non-inductor 3, and 6 is supplied from the power supply 5 A pulse oscillator that modulates the current / voltage to a DC pulse voltage of about 100 kHz to 100 kHz, 7 is a pulse oscillator that is output from the pulse oscillator 6, and at the same time the pulse voltage is paused. 2, a switch part for depolarizing the polarization potential of the unrelated inductor 3, 8 is an administration site such as a joint, and 9 and 10 are connection terminals such as jacks. Next, the conductor and the non-conductor will be described with reference to the drawings.

FIG. 2 (a) is a perspective view showing the inductor, and FIG. 2 (b) is a perspective view showing the non-inductor.

In FIG. 2 (a), 2a is a lead wire connected to an electrode layer 2c to be described later, 2b is a backing layer made of a polyolefin film such as polyester or polyethylene, and 2c is a backing layer 2b. An electrode layer formed of silver chloride or the like on one side of the electrode, 2 d is laminated on the electrode layer 2 c and has a slightly larger diameter than the electrode layer 2 c and contains sodium alginate or polyvinyl alcohol containing a water-soluble steroid as a drug. A drug storage layer composed of chitin and the like.

In FIG. 2 (b), 3a is a lead wire connected to an electrode layer 3c described later, 3b is a support layer made of a film / sheet of a polyolefin such as polyester or polyethylene, and 3c is a support layer. 3b is an electrode layer formed by evaporating silver etc. on one surface, 3d is a conductive layer formed on the electrode layer 3c and having a diameter slightly larger than the electrode layer 3c Layer.

The device for pulse depolarization iontophoresis configured as described above, that is, a pulse depolarization type iontophoresis power supply, and a conductor and a non-conductor associated with a non-polarizable electrode The method of iontophoresis administration of the water-soluble steroid used will be described based on an example applied to a human joint.

First, the inductor 2 and the non-inductor 3 are attached to the administration site 8. Since the drug storage layer 2 d and the conductive layer 3 d are made of a flexible material, the administration site 8 can be brought into close contact with a relatively uneven portion such as a joint without falling. Next, the main power supply of the pulse depolarization type iontophoresis power supply 1 is turned on. Next, the frequency of the pulse oscillator 6 and the output time of the pulse voltage are adjusted, and the designed dose is administered. Next, the administration is terminated after a lapse of a predetermined administration time or the like. After the administration is completed, the switch of the pulse depolarization type iontophoresis power supply 1 is turned off, and the treatment is completed by separating the guide 2 and the guide 3 from the administration site. During administration, the switch section 7 is automatically turned on and off upon detecting the falling Z rise of the pulse voltage output from the pulse generator 6, and is not related to the inductor 2 when the switch section 7 is turned on. As described above, according to the present embodiment, the designed amount of the water-soluble steroid was produced without electrical stimulation or electrification at the administration site during the administration period. It can be administered smoothly to the body, for example, to the deep joints where the synovium and the joint capsule composed of the synovium and the fibrous membrane are present. Performance comparison tests were performed on the pulse depolarization type iontophoresis device and the conventional iontophoresis device configured as described above. Hereinafter, the results will be described.

(Example 2) Electrical irritation comparative test

FIG. 3 is an exploded perspective view showing a conductor for an electrical stimulus test, FIG. 4 is an exploded perspective view showing an unrelated conductor for an electrical stimulus test, and FIG. 5 is an electrical stimulus. FIG. 3 is a schematic view showing a state where a test inductor and an unrelated inductor are attached. First, as shown in FIG. 3, a polyethylene terephthalate (PET) film 2b 'was prepared as a backing layer. Next, silver chloride was applied to one surface of the backing layer (or PET film) 2b 'to form an electrode layer 2c'. Next, a nonwoven fabric 2d 'was laminated as a drug storage layer on the upper surface of the electrode layer (or silver chloride) 2c'. Next, an acryl-based adhesive 2e 'is attached as an adhesive layer on the upper surface of the drug storage layer (or non-woven fabric) 2d' as an adhesive layer, and the backing layer 2b ', the electrode layer 2c', and the drug The storage layer 2d 'and the adhesive layer 2e' were fixed. Next, the drug storage layer 2 d ′ was impregnated with the aqueous solution lml through the pores of the adhesive layer 2 e ′, to prepare a guide 2 ′. Next, as shown in FIG. 4, a PET film 3b ′ was prepared as a support layer. Next, silver was applied to one surface of the support layer (or PET film) 3b 'to form an electrode layer 3c'. Next, an acrylic pressure-sensitive adhesive 3e 'is adhered in a 0-ring shape as a binding layer on the upper surface of the electrode layer (or silver) 3c', and is adhered to the support layer 3b 'and the electrode layer 3c'. Layer 3e 'was fixed. Next, an aqueous solution of polyvinyl alcohol (PVA) containing 0.9% of sodium chloride was stored in the pores of the adhesive layer 3e ', and these were frozen at 130 ° C to gel the PVA. , Insulator 3 'was created. The lead wires 2a 'and 3a' were connected to the respective electrode layers 2c 'and 3c' of the prepared inductor 2 'and non-inductor 3', respectively. Next, as shown in FIG. 5, a guide 2 ′ was attached inside the knee joint 13 of the subject, and a guide 3 ′ was attached outside the knee joint 13 of the subject. Next, using the pulsed depolarization type iontophoresis power supply 4 as the cathode on the side of the inductor 2 'and the anode on the side of the inductor 3', the current was gradually increased, The current value at which an electric stimulus was felt was examined. The results are shown in FIG. FIG. 6 is a characteristic diagram showing a current value at which an electric stimulus is sensed.

(Comparative Example 1)

The current value at which an electric stimulus was sensed was examined in the same manner as in Example 2 except that a direct current iontophoresis power supply (manufactured by Motion Control; trade name: Holeser) was used instead of the pulse depolarization type iontophoresis power supply. . This result Figure 6 shows.

(Comparative Example 2)

The current value at which electric stimulation was felt was examined in the same manner as in Example 2 except that a non-depolarizing pulse iontophoresis power supply was used instead of the pulse depolarization iontophoresis power supply. The results are shown in FIG.

As is clear from FIG. 6, when the electric current was supplied using the pulse depolarization type iontophoresis power supply, most subjects did not feel electrical stimulation below Sm AZcm ² . And power, and, when energized with DC type iontophoresis power supply as in Comparative Example 1, all subjects feel electrical stimulation I mAZcni ^2. Similarly, in the case where power is supplied by using a non-depolarizing pulse iontophoresis power supply as in Comparative Example 2, almost all subjects feel electrical stimulation at lmA / cm ² . Therefore, it was proved that the iontophoresis administration method of the water-soluble steroid using the pulse depolarization type iontophoresis power supply was an energization method with little electrical stimulation.

(Example 3) Cumulative permeation amount comparison test

FIG. 7 (a) is an exploded perspective view showing a 2-chamber-diffusion cell for a permeation experiment, and FIG. 7 (b) is a cross-sectional view showing a 2-chamber-diffusion cell for a permeation experiment.

First, as shown in 7 (a) Fig effective area 2. 5 cm ² of permeation experiments for 2 Chiya members each cell diffusion cell 1 4 1 4 a, 1 4 b at one end to Kutsugae設the Inductor 2 and Inducer 3 were installed in each. Next, as shown in FIG. 7 (b), the extracted human skin 15 was set in a 2-chamber-diffusion cell for permeation experiments. In addition, it was set so that the stratum corneum of the human extirpated skin 15 was opposed to the side of the guide 2. Next, the cell 14a on the side of the inductor 2 is filled with dexamethasone sodium phosphate at 1 Omg Zm1, and the cell 14b on the side of the inductor 3 is filled with saline. did. Next, connect the pulse depolarization type iontophoresis power supply with the inductor and the non-inductor so that the inductor 2 is the cathode and the non-inductor 3 is the anode. Powered on. In addition, during energization, unrelated inductor 3 The physiological saline in the cell 14 b on the side was stirred with a stirrer 16. Next, 6 hours after the start of energization, the solution on the 3rd side of the unrelated inductor was collected, and the concentration of dexamethasone sodium phosphate in the collected solution was measured by high performance liquid chromatography. Was determined. The results are shown in FIG. FIG. 8 is a characteristic diagram showing the accumulated permeation amount of stelloid after 6 hours.

(Comparative Example 3)

The accumulated permeation amount of dexamethasone after 6 hours was examined in the same manner as in Example 3 except that dexamethasone phosphate was used instead of dexamethasone sodium phosphate. Figure 8 shows the results.

(Comparative Example 4)

The accumulated permeation amount of dexamethasone sodium phosphate after a lapse of 6 hours was examined in the same manner as in Example 3 except that a platinum electrode was used for each of the inductor 2 and the inductor 3. Figure 8 shows the results.

(Comparative Example 5)

The accumulated permeation amount of dexamethasone sodium phosphate after 6 hours was examined in the same manner as in Example 3 except that the pulse depolarization type iontophoresis power supply was not used. The results are shown in FIG.

As is evident from Fig. 8, a pulsed depolarizing iontophoresis power supply and a lead / insensitive lead having a nonpolarizable electrode layer of silver / silver chloride were used on the isolated skin of the human. When mA was supplied and 1 O mg Zm 1 of dexamethasone sodium phosphate was permeated, about 40 μg Zcm ² of dexamethasone sodium phosphate was transmitted by 6 hours. On the other hand, as shown in Comparative Example 3, a pulsed depolarized iontophoresis power supply and a conductor having a nonpolarizable electrode layer of silver Z silver chloride and a non-polarized electrode layer were used for 3 m on the human skin. When A was supplied and 1 O mg / m 1 of dexamethasone was permeated, only about 2 wg Zcm ^{2 of} dexamethasone was permeated by 6 hours. Also, when a polarizable platinum electrode was used for the electrode layer as in Comparative Example 4, Without using the pulse depolarized iontophoresis power supply as in Example 5, dexamethasone sodium phosphate was hardly permeated. Therefore, by administering a water-soluble steroid using a pulse depolarization type iontophoresis power supply device and a conductor and a non-receptor having a non-polarizing electrode layer of silver-silver chloride, more water-soluble steroids can be obtained. It has been found that steroids can be delivered from the skin.

(Example 4) Dexamethasone sodium phosphate concentration comparison test

ゥ Egret (Japanese white rabbit) was anesthetized with pentobarbital. Next, a cylindrical cell having a diameter of 1 cm and fitted with a guide having a silver chloride electrode layer as shown in Fig. 7 (a) was set outside the right rear knee of the egret. Next, a conductive layer of PVA gel containing 0.9% of sodium chloride and a silver electrode layer as shown in Fig. 2 (b) were superimposed on the inside of the right knee of the rear of the egret. The lead was set. Here, the inductor side was used as the anode, and the non-inductor side was used as the cathode. The cylindrical cell is filled with radiolabeled dexamethasone sodium phosphate (3 O mg / m 1, 33 33 / C i / m 1) and linked to a pulse depolarization type iontophoresis power supply. After connecting the probe and the unrelated probe, 3 mA was supplied. Two hours later, the egret was exsanguinated and killed. The joint capsule was taken out from the joint of the hind right foot knee, weighed, burned with an oxidizer, and the radioactivity was measured. The results are shown in FIG. FIG. 9 is a characteristic diagram showing the concentration of dexamethasone sodium phosphate in the joint capsule.

(Comparative Example 6)

The dexamethasone phosphate concentration in the joint capsule was examined in the same manner as in Example 4 except that the pulse depolarization type iontophoresis power supply was not used. Figure 9 shows the results.

As is clear from Fig. 9, when dexamethasone sodium phosphate was administered using a pulse depolarization type iontophoresis power supply, the knee on the side to which dexamethasone sodium phosphate was administered had intra-articular (specifically, Dexamethasone sodium phosphate could be delivered at a high concentration. However, as in Comparative Example 6, The radioactivity of dexamethasone sodium phosphate was not detected when the pulse depolarized iontophoresis power supply was not used. Therefore, dexamethasone sodium phosphate could be delivered into the joint by administering dexamethasone sodium phosphate using a pulse depolarization iontophoresis power supply.

(Example 5) Comparative study of joint circumference in adjuvant arthritis model

(4) An adjuvant arthritis model was prepared using a heron, and inflammation was induced at the hindfoot joint. Next, a cylindrical cell with a diameter of 1 cm fitted with a conductor having an electrode layer of silver chloride as shown in Fig. 7 (a) was set outside the right knee of the posterior foot of the inflamed area. A non-inductive element in which a conductive layer of a PVA gel containing sodium chloride and a silver electrode layer were superimposed as shown in FIG. 2 (b) was set inside the knee of the rear right foot. Here, the side of the conductor was the anode, and the side of the non-conductor was the cathode. Next, the column-shaped cell was filled with dexamethasone sodium phosphate (30 mg gZm l), and a pulse depolarized iontophoresis power supply (frequency 40 kHz, duty ratio 30%) was used. A current of 3 mA was applied to the inductor and the unrelated inductor for 1 hour. The change around the joint over time was measured using the length around the joint before the induction of inflammation (-1 day) as a reference value. The results are shown in FIG. FIG. 10 is a characteristic diagram showing the increase and decrease of the joint circumference based on the joint circumference on the 11th day.

(Comparative Example 7)

ア Create an adjuvant arthritis model using a heron, induce inflammation in the hind foot joint area, and use the length around the joint before inflammation induction (day 1) as a reference value, and change over time around the joint. Was measured. The results are shown in FIG.

As is clear from FIG. 10, the group to which dexamethasone sodium phosphate was administered only once using the pulse depolarization type iontophoresis power supply had a larger joint joint than the untreated group as in Comparative Example 7. The inflammation healed and the periarticular length decreased. Therefore, the water-soluble steroid is associated with the pulse depolarization type iontophoresis power supply. It has been delivered to the depth of the node and has shown medicinal effects. These results show that the present invention is highly useful. Industrial applicability

Since the present invention is constituted as described above, a water-soluble steroid having bioactivity is efficiently used in a living body, particularly in a synovial membrane or a joint capsule comprising the synovial membrane and fibrous membrane. It can be absorbed in a large amount, and the electrical stimulation and electrification at the administration site such as the skin can be extremely low, and a clinically excellent method of administering iontophoresis of a water-soluble steroid can be realized. Things. The method for administering iontophoresis of a water-soluble steroid of the present invention having such excellent effects can be applied to a site of administration in a living body and applied with a voltage so that the desired excellent effects can be exhibited without any effect. Very useful in industry.

Claims

The scope of the claims

1. An iontophoresis power supply device and a method for administering iontophoresis of a water-soluble steroid using a conductor and an inductor, wherein the iontophoresis power supply device is a pulse depolarization type iontophoresis. A method for administering iontophoresis of a water-soluble steroid using a cis power supply device and a non-polarizable electrode for an electrode layer of the conductor and the non-conductor.

2. The pulse depolarization type iontophoresis power supply unit supplies a current Z voltage between the inductor and the uninductor, and pulse modulates the current Z voltage from the power source. The pulse generator according to claim 1, further comprising: a pulse oscillator; and a switch unit configured to depolarize a polarization potential between the inductor and the uninductor when the pulse voltage from the pulse oscillator is stopped. A method for administering iontophoresis of the water-soluble steroid according to the above.

3. The iontophoresis of a water-soluble steroid according to claim 1 or 2, wherein the non-polarizable electrode is made of silver, silver chloride, or the like. Administration method.

4. The ion guide according to any one of claims 1 to 3, wherein an ion exchange membrane is provided between the non-polarizable electrode and the drug storage layer. The method for administering iontophoresis of a water-soluble steroid described in the section.

5. The water-soluble steroids include dexamethasone sodium phosphate, dexamethasone sodium state, dexamethasone sodium metasulfobenzoate, hydrocortisone sodium succinate, sodium hydrocortisone phosphate, predniblon sodium succinate, betamethasone sodium phosphate, and the like. 5. The method for iontophoresis administration of a water-soluble steroid according to any one of claims 1 to 4, wherein the method comprises a mixture thereof.